WO2012129792A1 - Pyrimidinone compounds, preparation methods, pharmaceutical compositions and uses thereof - Google Patents

Pyrimidinone compounds, preparation methods, pharmaceutical compositions and uses thereof Download PDF

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Publication number
WO2012129792A1
WO2012129792A1 PCT/CN2011/072302 CN2011072302W WO2012129792A1 WO 2012129792 A1 WO2012129792 A1 WO 2012129792A1 CN 2011072302 W CN2011072302 W CN 2011072302W WO 2012129792 A1 WO2012129792 A1 WO 2012129792A1
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Prior art keywords
reaction
compound
oxo
dihydro
cyclopenta
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PCT/CN2011/072302
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French (fr)
Chinese (zh)
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王凯
沈建华
王逸平
王文义
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中国科学院上海药物研究所
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Priority to PCT/CN2011/072302 priority Critical patent/WO2012129792A1/en
Publication of WO2012129792A1 publication Critical patent/WO2012129792A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a novel class of pyrimidinone compounds and a process for the preparation thereof, pharmaceutical compositions containing the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity Application in .
  • Atherosclerosis is the pathophysiological basis of cardiovascular and cerebrovascular diseases.
  • the formation of thrombus after rupture of atheromatous plaques leads to vascular occlusion, which is the main cause of cardiovascular events. Therefore, prevention and treatment of atherosclerosis is an important issue that needs to be solved urgently in the medical field.
  • the standard clinical drug regimen is: statins regulate blood lipids, antihypertensive drugs to control blood pressure, and take drugs that resist platelet aggregation.
  • Oxidized low-density lipoprotein (ox-LDL) is a risk factor present in plasma that promotes inflammation and causes atherosclerosis.
  • Zalewski A et al. (Arterioscler Thromb Vase Biol, 2005, 25(5): 923-931) pro-inflammatory effects of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) in ox-LDL and atherogenesis It plays an important role in mediating the above biological effects of ox-LDL.
  • Lp-PLA 2 is a member of the PLA 2 superfamily and belongs to VD type PLA 2 .
  • Lp-PLA 2 also known as plasma platelet-activating factor acetylhydrolase, contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to LDL, and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL), which means that it is easily transported to the site of damage caused by LDL into the vessel wall. .
  • Lp-PLA 2 can hydrolyze PAF, PAF-like phospholipids, and oxidatively modified phosphatidylcholines.
  • Lp-PLA 2 has strong specificity for the short strand residues of the phosphonium at the sn-2 position, and has the maximum hydrolytic activity when the sn-2 residue is an acetyl group, and the phospholipid of a long chain fatty acid at the sn-2 position.
  • the substrate has no enzymatic activity.
  • Site-directed mutagenesis Ser-273, Asp-296 and His-351 in Lp-PLA 2 have been identified to constitute the center of their enzyme activity.
  • Lp-PLA 2 maps atherosclerosis.
  • the long strand of the sn-2 position of the component lecithin of LDL is shortened by oxidative modification, and enters the arterial intima to become a substrate of Lp-PLA 2 .
  • Lp-PLA 2 hydrolyzes it to hydrolyze it, producing lysophosphatidylcholine (Lyso-PC) and oxidized free fatty acid (OX-NEFA), both of which have a strong pro-inflammatory effect.
  • cytokines such as Interferon expression, activation of leukocytes, induction of oxidative stress, induction of cell membrane permeability and apoptosis.
  • Lp-PLA 2 inhibitor may reduce the occurrence of the aforementioned inflammatory response, and is a new, non-lipid-lowering strategy for atherosclerosis.
  • Selective inhibitors of Lp-PLA 2 were observed in humans to significantly reduce ox-NEFA production and ox-LDL-induced apoptosis in macrophages (Rosenson RS, Vracar-Grabar M, Helenowski I. Cardiovasc Drugs Ther 2008 22:55-8).
  • Experiments performed on animal models also support the role of Lp-PLA 2 inhibitors, and Wilensky et al. (Wilensky RL, Shi Y, Mohler ER, et al.
  • Lp-PLA 2 is predictive of coronary heart disease events independent of traditional risk factors and C-reactive protein. For every one standard deviation of Lp-PLA 2 levels, the incidence of coronary heart disease events will increase by 22%. The risk of developing one-fifth of the highest Lp-PLA 2 levels is twice the lowest of the lowest level.
  • Lp-PLA 2 should be used as a diagnostic indicator to alert patients with low LDL levels but at high risk of coronary heart disease.
  • "Rotterdam study” (Oei HH, van der Meer IM, Hofman A, et al. Circulation 2005; 111 : 570-5) studies of 7,983 people with no history of coronary heart disease and older than 55 years of age indicate widespread Among the population, regardless of the level of cholesterol, Lp-PLA 2 is an early warning factor for coronary heart disease events and an early warning factor in ischemic cerebral palsy.
  • Lp-PLA 2 is also a risk factor for predicting the periodic occurrence of the disease.
  • One study pointed out (Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Eur Heart J 2005; 26: 137-144), elevated Lp-PLA 2 levels in patients undergoing coronary angiography With a standard deviation, the incidence of coronary heart disease events will increase by 30%. This effect of Lp-PLA 2 is independent of traditional risk factors.
  • Lp-PLA 2 inhibitors may improve this condition.
  • Lp-PLA 2 inhibitors may be used for treatment.
  • Lp-PLA 2 in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.)
  • Lp-PLA 2 inhibitors can therefore be used in the treatment of conditions associated with inflammatory cells, such as psoriasis.
  • Lp-PLA 2 inhibitors may be universally applicable to any process involving the hydrolysis of lipids into the two inflammatory traits with the participation of Lp-PLA 2 . This includes the aforementioned atherosclerosis, diabetes, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, reperfusion, acute and chronic inflammatory diseases.
  • Patent applications W096/13484, W096/19451, WO97/02242, W097/21765, W097/21766, WO97/41098 and WO97/41099 disclose a series of monocyclic beta lactam derivatives which are Lp- A non-reversible, acetylation inhibitor of PLA 2 (Tew et al, Biochemistry, 37, 10087, 1998).
  • SmithKline Beecham pic has developed a class of potent reversible inhibitors of Lp-PLA 2 (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08 /048867, etc., characterized by a pyrimidinone or pyridone group in the structure.
  • Lp-PLA 2 inhibitor Darapladib (SB480848) is in the phase III clinical stage.
  • An object of the present invention is to provide a pharmaceutically acceptable pyrimidinone compound represented by the formula (I), an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically thereof thereof Acceptable salt.
  • Another object of the present invention is to provide a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof Preparation.
  • a further object of the present invention is to provide a pyrimidinone compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof
  • a medicament for the preparation of an Lp-PLA 2 inhibitor thereby for use in the preparation of a medicament for preventing, treating or ameliorating a disease associated with Lp-PLA 2 enzyme activity, such as atherosclerosis, stroke , myocardial infarction, angina pectoris, myocardial ischemia, reperfusion injury and other coronary heart disease, diabetes, rheumatoid arthritis, acute and chronic inflammatory diseases.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising one or more effective therapeutic doses of a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer A body, a racemate and a mixture, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pyrimidinone compound provided by the present invention or a pharmaceutically acceptable salt thereof is represented by the formula (I):
  • (IA: IB: 1 and R 3 are each independently selected from the group consisting of: a straight or branched alkyl group of ⁇ , _ 1 () , a cycloalkyl group of C, a hydroxyl group, -NR 4 R 5 , , Or five to seven yuan aromatic or non-aromatic heterocyclic ring containing one to three nitrogen atoms, and not necessarily be d_ 3 alkyl substituents;
  • R 2 is an alkyl group of H or d 3 ;
  • R 1 —(CH 2 )m and R 2 together with the N to which they are bonded constitute a five- to seven-membered non-aromatic heterocyclic ring, and the non-aromatic heterocyclic ring is optionally substituted by an alkyl group of d_ 3 or —NR 4 R 5 , For example, but not limited to "4-dimethylaminopiperidinyl";
  • R 4 and R 5 are each independently selected from: an alkyl group of H or d 3 ;
  • R 6 may be in the para, para or meta position, selected from H, a halogen atom, d_ 4
  • R 7 is selected from H, a halogen atom, an alkyl group of d 2 or an alkyl group of d 2 substituted by three halogen atoms.
  • Substituted as used in the present invention means replaced by one or more groups. When a plurality of substituents are selected from the same series of candidate substituents, they may be the same or different.
  • the phrase "independently” as used in the present invention means that a plurality of defined groups can be selected from the same series of candidate groups, and they do not affect each other, that is, they may be the same or different.
  • the "effective therapeutic dose” as used in the present invention means that the disease, disorder, side effect, and the like of the subject receiving the dose are cured, improved, effectively prevented, or the incidence thereof is significantly lowered as compared with the subject not receiving the dose. In addition, it also includes an effective dose that enhances normal physiological function.
  • mercapto as used in the present invention includes all branched and straight chain isomers of a specific number of carbon atoms. Representative examples are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
  • cycloalkyl group represents a non-aromatic, saturated, cyclic aliphatic hydrocarbon group at a specific number of carbon atoms.
  • Representative examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • halogen as used in the present invention includes fluorine, chlorine, bromine and iodine unless specifically defined.
  • the pyrimidinone compound represented by the formula (I) may exist in the form of a pharmaceutically acceptable salt, which is a particularly important part within the scope of the present invention.
  • “Pharmaceutically acceptable salt” means that the compound of formula (I) retains the desired biological activity and has minimal toxic side effects.
  • the pharmaceutically acceptable salt can be obtained directly during the preparation and purification of the compound, or it can be obtained indirectly by reacting the free acid or free base of the compound with another suitable base or acid.
  • some of the compounds of the present invention contain a basic functional group such as R-NR 5 to form a pharmaceutically acceptable salt with a suitable acid.
  • the suitable acid may be a mineral acid or an organic acid.
  • pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, methanesulfonate, nitric acid, phosphate, acetate, oxalate, succinate, Tartrate, maleate, arginine, etc.
  • Some of the compounds of the present invention contain an acidic functional group such as R ⁇ -OH to form a pharmaceutically acceptable salt with a suitable base.
  • the suitable base may be an inorganic base or an organic base.
  • pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic ions, such as sodium salts, potassium salts, lithium salts, calcium salts, aluminum salts, zinc salts, ammonium salts, and the like; Salts such as methylamine salt, ethylamine salt, triethylamine salt, meglumine salt, tromethamine salt and the like.
  • a part of the compound of the present invention or a pharmaceutically acceptable salt thereof is crystallized or recrystallized from water or an organic solvent, and the solvent may be used in the crystal.
  • different crystallization conditions may result in different crystal forms of the compound. Therefore, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof containing a different chemical amount of the crystallization solvent and all the crystal forms is within the scope of the present invention.
  • the compound of the formula (I) of the present invention has one or more chiral centers, and thus may exist as a racemate, a racemic mixture, an enantiomeric monomer, a diastereomeric monomer, or a non- Enantiomeric mixtures and other forms.
  • tautomers such as, but not limited to, H, and thus a tautomer and a mixture of a plurality of tautomers are within the scope of the present invention.
  • the compound represented by the formula (I) may have a rotamer due to the restriction of free rotation of a certain group, and thus a certain form of rotamer and Mixtures of multiple rotamers are also within the scope of the invention.
  • R 3 is preferably -
  • R is especially chosen as H, .
  • Linear or branched alkyl, C 3 -7 cyclodecyl or -NR 4 R 5 ; m 0-2 integer;
  • R 4 and R 5 are each independently preferably an alkyl group
  • R 6 has the same definition as above.
  • R 1 and R 3 are each independently preferably Or -NR 4 R 5 ;
  • R 2 is preferably H or methyl
  • n is preferably 1 or 2;
  • n 0-2;
  • R 4 and R 5 are each independently preferably an alkyl group
  • R 6 has the same definition as above.
  • R 3 is preferably p-trifluoromethylbiphenyl-4-yl
  • R ⁇ CH ⁇ m- is preferably a linear or branched alkyl group of H, CM, cyclopropylmethyl or -CH 2 CH 2 NR 4 R 5 ;
  • R 4 and R 5 are each independently preferably methyl or ethyl. Most preferably ethyl;
  • R 1 and R 3 are each independently preferably ⁇ 0 ⁇ R or -N R 4 R 5 ;
  • R 2 is preferably H or methyl
  • n is preferably 1 or 2;
  • n 0-2;
  • R 4 and R 5 are each independently preferably methyl or ethyl
  • R 7 is preferably a methyl group substituted with a halogen atom, a methyl group or a halogen atom, and most preferably -CF 3 .
  • the pyrimidinone compound represented by the formula (I) may specifically be:
  • the compounds of the present invention are potent inhibitors of lipoprotein-associated phospholipase A2 and are potentially useful for clinical treatment, particularly for the treatment and prevention of acute and chronic coronary heart disease, such as by peripheral vascular and cerebrovascular atherosclerosis.
  • This type of event that is, the present invention provides a compound of the general formula (I) which can be used for clinical treatment.
  • the compound represented by the formula (I) of the present invention can inhibit the formation of lysophosphatidylcholine (Lyso-PC), and thus can be generally applied to diseases associated with endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, Angina and ischemic reperfusion. Furthermore, the compounds of the formula (I) can be generally applied to any condition involving the hydrolysis of oxidized lipids with the participation of Lp-PLA 2 , in addition to atherosclerosis, diabetes, etc. Ischemia, rheumatoid arthritis, stroke, brain inflammatory disease (such as Alzheimer's disease), myocardial infarction, reperfusion injury, sepsis, acute and chronic inflammatory diseases.
  • Lp-PLA 2 is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus the compounds of the general formula (I) of the present invention can be treated and inflammatory cell activation Applications in related conditions such as psoriasis.
  • the present invention provides the use of a compound represented by the general formula (I) for the treatment of a disease associated with activation of Lp-PLA 2 by inhibiting the enzymatic activity of Lp-PLA 2 .
  • diseases may be associated with the following events: activation of inflammatory cells; formation of lysophosphatidylcholine and oxidized free fatty acids; Lp-PLA 2 catalyzed lipid oxidation; endothelial cell dysfunction.
  • the compound of the formula (I) of the present invention can be used in combination with the following drugs in the treatment of the above diseases: hypolipidemic Medicine, anti-atherosclerotic drugs, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs, antihypertensive drugs or drugs that inhibit phospholipase A.
  • a statin that inhibits cholesterol synthesis an antioxidant probucol, an insulin sensitizer, a calcium channel antagonist, or a non-anti-inflammatory drug.
  • the compound of the formula (I) of the present invention is used in combination with a cholesterol lowering drug, such as a statin.
  • a statin is an HMG-CoA reductase inhibitor such as atorvastatin, swastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and the like. You can take both drugs at the same time or at different times as recommended by your doctor.
  • the compound of the formula (I) of the present invention can be used in combination with a hypoglycemic agent or an insulin sensitizer.
  • the insulin sensitizer used in combination is preferably a PPA- ⁇ agonist such as rosiglitazone or pioglitazone.
  • the compounds of the invention are typically administered in the form of a standard pharmaceutical composition. That is, the present invention provides a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I), and a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable excipient is a pharmaceutically acceptable carrier, excipient or sustained release agent, and the like.
  • the compounds and pharmaceutical compositions provided herein may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be presented in a suitable solid or liquid carrier or In the diluent.
  • the pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Odorants, flavoring agents and the like may also be included in the pharmaceutical composition.
  • the pharmaceutical composition contains a safely effective amount (e.g., 0.1 to 99.9 parts by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; A quantity of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition of the present invention contains the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an amount of from 0.1 to 99.9% by weight, based on the total weight, preferably from 1 to 90% by weight, based on the total weight; A pharmaceutically acceptable excipient wherein the total weight of the composition is 100% by weight.
  • a preferred ratio of the compound of the formula (I) to a pharmaceutically acceptable carrier, excipient or sustained release agent is that the formula (I) as the active ingredient accounts for more than 60% by weight of the total weight, and the balance is 0-40% by weight of the total weight, the rest
  • the amount of the moiety is preferably from 1 to 20%, most preferably from 1 to 10%.
  • the compound of the formula (I) or the pharmaceutical composition comprising the compound of the formula (I) of the present invention can be used clinically in mammals, including humans and animals, and the administration route can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract.
  • a preferred route of administration is oral. It is preferably in a unit dosage form, and each dose contains the active ingredient of 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, once or in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment. Usually starting with a small dose, gradually increase the dose until the most appropriate dose is found.
  • the pharmaceutical composition of the present invention can be administered orally and intravenously, intramuscularly or subcutaneously.
  • Preferred pharmaceutical compositions are solid compositions, especially tablets and solid filling or liquids, from the standpoint of ease of preparation and administration. Filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • the solid carrier includes: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin
  • the liquid carrier includes: sterile water, polyethylene glycol, nonionic surfactant and edible oil (such as corn oil). , peanut oil and sesame oil, etc., as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required.
  • Adjuvants which are usually used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oily solutions, suspensions, emulsions and the like. These formulations may also be formulated with parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable formulations can be sterilized by filtration in a filter that traps bacteria. These formulations may also be formulated with a bactericide which is dissolved or dispersed in an injectable medium or by other methods known in the art.
  • the compound of the present invention can be produced by one of the methods represented by Reaction Scheme 1 or Scheme 2. Unless otherwise defined, the definition of each substituent in the reaction scheme is the same as in the general formula (I). Reaction route 1
  • compound 1 Under the action of a base, compound 1 is condensed with hydroxylamine hydrochloride to form compound 2;
  • the base used includes an organic base and an inorganic base such as triethylamine, potassium carbonate, sodium hydroxide, etc.;
  • the reaction is carried out in a polar solvent such as methanol, Ethanol, DMF, water, etc. or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C.
  • the compound 2 is chlorinated to the compound 3 by an equivalent amount of NCS; the reaction solvent includes THF, DMF, etc.; and the reaction temperature is from 0 ° C to 60 ° C.
  • Compound 3 is dehydrochlorinated under the action of a base to form a 1,3-dipole ion, and then added with ethyl acrylate to form compound 4;
  • the base used is an organic base such as triethylamine, DIPEA, DBU, etc.; THF, DMF, etc.; reaction temperature between -40 ° C to room temperature.
  • the catalyst used in the reaction is palladium/carbon in an amount of 10% to 20% by mass of the compound 4; the reaction is carried out in a polar solvent such as methanol or ethanol; the reaction temperature is between 0 ° C Up to 80 ° C, the best room temperature.
  • Compound 5 reacts with DPPA under the action of a base to form compound 6;
  • the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and
  • the reaction solvent includes THF, CH 3 CN, DME
  • the equipolar aprotic solvent is preferably THF; the reaction temperature is between 0 ° C and 100 ° C, preferably the reflux temperature of the solvent used.
  • Compound 6 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 7 (Gololobov, Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst used for the hydrogenation reduction reaction is palladium.
  • the reaction is carried out in methanol, ethanol, EA or THF, the reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used in the Staudinger reaction is an excess of Ph 3 P, and the reaction is in THF-H 2 0 In progress, the temperature is between 0 ° C and 50 ° C.
  • R 8 is methyl or ethyl
  • the reaction is carried out in the presence of a dehydrating agent comprising molecular sieves, toluene azeotrope, Si(OEt) 4 or the like
  • the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.
  • the reaction temperature is from 0 ° C to 140 ° C, preferably the reflux temperature of the solvent used.
  • Compound 8 is condensed with more than one equivalent of isocyanate to form compound 9; the isocyanate includes
  • Compound 9 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 10; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
  • an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc.
  • the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.
  • Compound 10 and R 1 - (CH 2 ) m -LG are prepared under the action of a strong base, and LG represents a leaving group including a halogen atom, a trifluoromethylsulfonate (-OTf), a methanesulfonate (- OMs), etc., most preferably Cl, B, I;
  • the strong base includes NaH, n-BuLi, KOBu-t, etc., most preferably NaH;
  • the reaction solvent includes THF, DMF;
  • the reaction temperature is between -80 ° C to Room temperature, preferably from 0 ° C to room temperature.
  • R 8 is methyl or ethyl
  • the hydrochloride salt of compound 12 at least one is required.
  • Equivalent organic base such as triethylamine, DIPEA
  • the reaction is carried out in the presence of a dehydrating agent, including molecular sieve, toluene azeotrope, Si(OEt) 4, etc.
  • the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.
  • the reaction temperature is between 0 ° C and 140 ° C, preferably the reflux temperature of the solvent used.
  • Compound 13 is condensed with greater than one equivalent of isocyanate to form compound 14; the isocyanate includes
  • Compound 14 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 15; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
  • an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc.
  • the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.
  • Compound 15 undergoes alkaline hydrolysis to give compound 16;
  • the base used is an inorganic strong base such as LiOH, NaOH, KOH;
  • the reaction is carried out in an aqueous polar solvent including methanol, ethanol, dioxane, DMF, DMSO Isopropanol, THF, etc., preferably methanol or ethanol;
  • the reaction temperature is between 0 ° C and 50 ° C; after the hydrolysis reaction is completed, the reaction solution is subjected to acidification to precipitate the free compound 16, and acidification is usually carried out using hydrochloric acid and acetic acid.
  • Compound 16 and ( eH2 ) m or its hydrochloride form compound 17 under the action of a condensing agent;
  • the condensing agent used includes dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate/triphenyl Phosphorus, carbonyl diimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxy-benzo-triazole (EDCI/-(lH-benzo) Triazol-1-yl)-AWN', N'-tetramethylisourea boron tetrafluoride (TBTU) / organic base, etc.; when used For the hydrochloride, at least one equivalent of an organic base such as triethylamine or DIPEA is required; the reaction solvent includes non-alcoholic solvents such as DCM, DCE, acetonitrile, THF, toluene, DMF
  • the above compound 12 can be produced by one of two methods shown in Reaction Scheme 3 and Reaction Scheme 4. Hydrogenation reduction
  • compound 18 is condensed with sodium pyruvate to form compound 19; the reaction is carried out in methanol, ethanol, water, DCM or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C; It is purchased or prepared as known in the literature.
  • Compound 19 is prepared by esterification to produce compound 20; the acid catalyst in the reaction is formed in situ from acetyl chloride and ethanol; the reaction solvent is toluene; and the reaction temperature is between 0 ° C and 110 ° C.
  • the catalyst is palladium/carbon in an amount of 10% to 20% by mass of the compound 20; the reaction is carried out in a low polar solvent such as EA; and the reaction temperature is between 0 ° C and 80 ° C, The best is room temperature.
  • Compound 21 reacts with DPPA under the action of a base to form compound 22; the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and the reaction solvent includes THF, CH 3 CN, DME, etc.
  • a polar aprotic solvent most preferably THF; the reaction temperature is between 0 ° C and 100 ° C, most preferably the reflux temperature of the solvent used.
  • Compound 22 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 23 (Gololobov, YG Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst for the hydrogenation reduction reaction is palladium/carbon, and the reaction is carried out in methanol, ethanol, EA, THF.
  • the reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used for the Staudinger reaction is an excess of Ph 3 P, and the reaction is carried out in THF-H 2 0 at a temperature between 0 ° C and 50 ° C. .
  • Compound 12 can be prepared by the method shown in Scheme 4: wherein R 6 is as defined above.
  • Diethyl 2-acetamidomalonate is condensed with ( GH2 ) n
  • the base used includes NaH, KOBu-t, sodium ethoxide, etc., preferably sodium ethoxide;
  • reaction solvents include ethanol, DME, THF, DMF, etc., most commonly ethanol; reaction temperature is between 0 ° C and 80 ° C.
  • the compound 24 is hydrolyzed by 1 equivalent of NaOH, and then decarboxylated by heating to form the compound 25; the hydrolysis reaction is carried out in an aqueous alcohol solution at a reaction temperature of from 0 ° C to room temperature; and the decarboxylation reaction is refluxed in toluene.
  • Compound 25 is acid hydrolyzed to prepare compound 26; the reaction is carried out under reflux in dilute hydrochloric acid.
  • Compound 26 undergoes an esterification reaction involving thionyl chloride to form compound 24; the reaction is carried out under reflux in ethanol.
  • the numbering of the synthetic intermediate of the present invention begins with the English letters "A, B, C", such as the intermediate "A8"; and the final “example” begins with the word “example 18".
  • A6 2-[4-(p-trifluoromethylbiphenyl-4-yl)-1-ethoxy-1-pyrene-2-yl]amino-1-cyclopentenecarboxylate
  • the product obtained in the previous step was dissolved in 10 ml of absolute ethanol, and 195 ⁇ l of ethyl cyclopentanone-2-carboxylate and 590 ⁇ l of tetraethyl silicate were added, and the reaction was refluxed under nitrogen for 10 h.
  • the mixture was directly stirred into silica gel, and after spinning, it was separated by flash column chromatography to obtain 0.51 g of oil.
  • the dried DMF was heated at 140 ° C for 4 h, and the reaction was completed by TLC. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise. Then, 20 ml of EA and 10 ml of water were added and stirred for 10 min. The EA phase was separated, and the aqueous phase was extracted once with 10 ml of EA, and the organic phases were combined.
  • the above gum was dissolved in 3 ml of ethanol, and ice-bath, 0.5 ml of 10% aqueous NaOH solution was added dropwise, and the reaction was completed at room temperature for 2 hours. 20 ml of ice water was added to the flask, and the pH was adjusted to about 5 with 6N hydrochloric acid to precipitate a white precipitate. Add 5 ml of EA - stir for 10 min, collect the precipitate by filtration, wash with water, wash with EA, and dry to give 186 mg.
  • Example 2 monomethyl-TV-dimethylaminoethyl _ 2 _[ (2 _ p-fluorobenzylthio) _ 4 _ oxo_6, 7 _ dihydro _ 4 / _ cyclopentamethylpyrimidine -1(5H)-yl]-4-(p-trifluoro-4-yl)butanamide
  • A10 was suspended in 15 ml of anhydrous diethyl ether, placed in an ice bath, and 370 ⁇ l of phosphorus tribromide was added in portions, and then reacted at room temperature for 2 hours.
  • the flask was placed in an ice bath, and the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate.
  • the organic phase was separated, and the aqueous phase was extracted with diethyl ether.
  • the organic phase was combined and dried over magnesium sulfate. .
  • A14 3-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentamethylpyrimidine -1(5H)-yl]propionic acid
  • Example 7 1-[3-(p-trifluoromethylbiphenyl-4-yl)-l-(4-dimethylaminopiperidin-1-yl)-1-oxopropan-2-yl] -2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[-4(5H)-one
  • B2 2.0g was placed in 15 ml of 6N hydrochloric acid and refluxed for 5 h. The water was evaporated to dryness under reduced pressure, and then water was taken twice with toluene to give a solid residue as B3-4-diethylamino-2-aminobutyric acid salt.
  • the preparation method was the same as that of A7, except that the reaction was completed, and the sodium carbonate saturated solution was used instead of the sodium hydrogencarbonate saturated solution to quench.
  • 550 mg of the target product was obtained from 2.5 g of B5.
  • the preparation method was the same as that of A8, and 660 mg of the target product was obtained from 1.0 g of B6.
  • 'H-NMR (CDC1 3 , 300 MHz) ⁇ .92/1.13 (2x t, 9 ⁇ ), 2.07 (m, 2 ⁇ ), 2.25 (m, 1H), 2.46 (m, 8H), 2.86 (m, 3H) , 4.16 (m, 2H), 4.49 (q, 2H), 4.95/5.47 (2x m, 1H), 6.97 (t, 2H), 7.35 (m, 2H)
  • the solid was dissolved in 30 ml of DMF, and 0.5 g of NCS was first added to initiate the reaction, and the remaining 3.5 g of NCS was added in portions, and the rate of addition was such that the temperature of the solution did not exceed 40 ° C, and the reaction was stopped for 0.5 h.
  • the reaction solution was dissolved in 200ml EA, washed 5 times with a small amount of brine several times, dried MgS0 4, the solvent was evaporated to dryness to give C2, 8.0g solid.
  • the preparation method was the same as A8 except that C9 was substituted for A7.
  • 'H-NMR (CDC1 3 , 300 MHz, ca 3:1 rotamer) 52.05 (m, 2H), 2.70/2.44 (2x m, 4H), 2.86/2.96 (2x m, 1H), 3.05/3.26 (2x m, 1H), 4.50 (m, 2H), 5.40/4.90 (2x t, 1H), 5.00/5.04 (2x dd, 1H), 7.07/6.79 (2x s, 1H, -NH-), 6.95/ 6.99 (2x t, 2H), 7.34 (m, 4H), 7.63 (d, 2H), 7.65 (d, 2H), 7.70 (d, 2H).
  • Example 30 one (s) - trans -1-[2-oxo-1-p-fluorobenzyl
  • Substrates were detected using tritiated platelet activating factor ([ 3 H] PAF, Perkinelmer, Lot NET910).
  • the reaction was carried out in a 200 ⁇ l system (50 mmol/L hydroxyethylpiperazineethanesulfonic acid (HEPES) and B 150 mmol/L sodium chloride (NaCl), pH 7.4).
  • HEPES hydroxyethylpiperazineethanesulfonic acid
  • NaCl sodium chloride
  • the reaction was carried out at 37 ° C for 10 minutes, followed by vortexing by adding 600 ⁇ l of CHCl 3 /MeOH (2:1) to terminate the reaction. After standing for a while, it was centrifuged at 12,000 x g for 15 minutes, and the aqueous layer was transferred to a new tube, vortexed by adding 200 ⁇ l of chloroform, and allowed to stand or centrifuge for 2 minutes. The supernatant of the ⁇ aqueous layer was taken for determination of radioactivity.
  • Reaction buffer 180 170 170 Test compound 10 Dimethyl sulfoxide (solvent) 10 10
  • Inhibition rate 1- (test tube DPM value - blank tube DPM value) control tube DPM value - blank tube DPM value)
  • Example 3 NT 26 NT
  • Example 9 NT 91 34
  • Example 19 NT 27 NT
  • Example 20 NT 33 NT
  • Example 21 NT 72 ⁇
  • Example 25 99 93 67
  • Example 26 98 90 44
  • Example 27 99 96.0 76.8
  • Example 28 53.1 NT NT
  • Example 29 48.8 NT NT
  • Example 30 90 88.7 32.2
  • Example 31 91 73.2 ⁇
  • Example 32 90 69.4 ⁇
  • Example 33 93 78.6 13.3
  • Example 34 96 78.5 16.3
  • Example 39 80.4 21.8 1.6

Abstract

Disclosed are pyrimidinone compounds represented by general formula (I), their preparation methods, pharmaceutical compositions comprising this kind of compounds as active components and the uses in the manufacture of medicaments for treating diseases related to the activity of Lp-PLA2 enzyme. In formula (I), the definition of each substituent is described as the description.

Description

嘧啶酮类化合物、 其制备方法及药物组合物和用途 技术领域  Pyrimidinone compound, preparation method thereof, and pharmaceutical composition and use thereof
本发明涉及药物化学领域， 尤其涉及一类新颖的嘧啶酮类化合物及其制备方法， 以该类化合物为活性成分的药物组合物， 以及它们在制备治疗与 Lp-PLA2酶活性有关 疾病的药物中的应用。 The present invention relates to the field of medicinal chemistry, and in particular to a novel class of pyrimidinone compounds and a process for the preparation thereof, pharmaceutical compositions containing the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity Application in .
背景技术 Background technique
动脉粥样硬化是心脑血管疾病的病理生理基础， 粥样斑块破裂后形成血栓而导致 血管堵塞是心血管事件发生的主要原因。 因此防治动脉粥样硬化是目前医学领域急需 解决的一个重要课题。 目前临床上的标准用药方案为： 他汀类药物调节血脂、 降压药 控制血压， 同时服用抵抗血小板凝聚的药物。 但是， 即便是坚持长期应用该治疗方案 的病人， 尤其是高危病人依然存在着较高的复发风险。  Atherosclerosis is the pathophysiological basis of cardiovascular and cerebrovascular diseases. The formation of thrombus after rupture of atheromatous plaques leads to vascular occlusion, which is the main cause of cardiovascular events. Therefore, prevention and treatment of atherosclerosis is an important issue that needs to be solved urgently in the medical field. At present, the standard clinical drug regimen is: statins regulate blood lipids, antihypertensive drugs to control blood pressure, and take drugs that resist platelet aggregation. However, even patients who adhere to long-term use of the treatment regimen, especially high-risk patients, still have a higher risk of recurrence.
研究证实动脉粥样硬化不只是与血脂水平异常有关， 也是一种炎症相关性疾病， 抑制动脉粥样硬化的炎症因子是治疗该疾病的新途径。 氧化低密度脂蛋白 (ox-LDL)是 一种存在于血浆中的危险因子， 能促进炎症发生， 引起动脉粥样硬化。  Studies have shown that atherosclerosis is not only related to abnormal blood lipid levels, but also an inflammation-related disease. Inflammatory factors that inhibit atherosclerosis are new ways to treat the disease. Oxidized low-density lipoprotein (ox-LDL) is a risk factor present in plasma that promotes inflammation and causes atherosclerosis.
Zalewski A等报道 (Arterioscler Thromb Vase Biol, 2005, 25(5):923-931)脂蛋白相关 磷脂酶 A2(Lp-PLA2)在 ox-LDL的促炎症效应和引起动脉粥样硬化形成过程中起着重要 作用， 它是介导 ox-LDL产生以上生物学效应的一个关键性酶。 Zalewski A et al. (Arterioscler Thromb Vase Biol, 2005, 25(5): 923-931) pro-inflammatory effects of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) in ox-LDL and atherogenesis It plays an important role in mediating the above biological effects of ox-LDL.
Lp-PLA2是 PLA2超家族中的一员， 属于 VD型 PLA2。 Lp-PLA2也称血浆血小板激 活因子乙酰水解酶， 该酶含有 441个氨基酸， 相对分子质量为 45 kD。 人血浆中 70% 的 Lp-PLA2与 LDL结合， 30%的 Lp-PLA2与高密度脂蛋白 (HDL)结合， 这就意味着它 容易随着 LDL输送到血管壁内的损坏形成的部位。 Lp-PLA2能水解 PAF、 PAF类似的 磷脂和氧化修饰的磷脂酰胆碱等。 其酶活性不需要二价阳离子如钙离子的存在， 这与 其他许多 PLA2不同。 Lp-PLA2对磷脂的 sn-2位短链残基具有很强的特异性， 当 sn-2 位残基为乙酰基时具有最大水解活性， 而对 sn-2位为长链脂肪酸的磷脂底物没有酶活 性。 定点突变已鉴定出 Lp-PLA2中的 Ser-273， Asp-296和 His-351构成其酶活性中心。 Lp-PLA 2 is a member of the PLA 2 superfamily and belongs to VD type PLA 2 . Lp-PLA 2, also known as plasma platelet-activating factor acetylhydrolase, contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to LDL, and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL), which means that it is easily transported to the site of damage caused by LDL into the vessel wall. . Lp-PLA 2 can hydrolyze PAF, PAF-like phospholipids, and oxidatively modified phosphatidylcholines. Its enzymatic activity does not require the presence of divalent cations such as calcium ions, which is different from many other PLA 2s . Lp-PLA 2 has strong specificity for the short strand residues of the phosphonium at the sn-2 position, and has the maximum hydrolytic activity when the sn-2 residue is an acetyl group, and the phospholipid of a long chain fatty acid at the sn-2 position. The substrate has no enzymatic activity. Site-directed mutagenesis Ser-273, Asp-296 and His-351 in Lp-PLA 2 have been identified to constitute the center of their enzyme activity.
Maphee等人 (Macphee CH， Moores KE, Boyd HF， et al. Biochem J 1999; 338:479-87) 首先提出了 Lp-PLA2导致动脉粥样硬化的机理。 LDL的组分卵磷脂的 sn-2位长链经氧 化修饰縮短， 进入动脉血管内膜成为 Lp-PLA2的底物。 Lp-PLA2迅速水解将其水解， 产生溶血磷脂酰胆碱 (Lyso-PC)和氧化的游离脂肪酸 (OX-NEFA), 两者都具有很强的促 炎症作用。 这两个生物介质通过启动包括内皮细胞、 平滑肌细胞、 单核 /巨噬细胞、 T 细胞、 嗜中性粒细胞在内的多种细胞的发炎 /免疫反应而引起前动脉粥样硬化效应， 比 如上调粘附分子水平而使单核 /巨噬细胞向粥样斑块形成的区域汇集， 诱导细胞因子如 干扰素的表达， 活化白细胞、 诱导产生氧化应力， 诱导细胞膜通透和细胞凋亡等。 这 些效应进一步导致动脉粥样硬化斑块的生长和不稳定， 斑块坏死核心不断扩大， 血栓 帽变薄以至破裂， 最终发展成为临床上所见的心肌梗塞、 冠心病、 缺血性中风等疾病。 Maphee et al. (Macphee CH, Moores KE, Boyd HF, et al. Biochem J 1999; 338: 479-87) first proposed a mechanism by which Lp-PLA 2 causes atherosclerosis. The long strand of the sn-2 position of the component lecithin of LDL is shortened by oxidative modification, and enters the arterial intima to become a substrate of Lp-PLA 2 . Lp-PLA 2 hydrolyzes it to hydrolyze it, producing lysophosphatidylcholine (Lyso-PC) and oxidized free fatty acid (OX-NEFA), both of which have a strong pro-inflammatory effect. These two biological mediators cause anterior atherosclerotic effects by initiating inflammatory/immune responses to a variety of cells including endothelial cells, smooth muscle cells, monocytes/macrophages, T cells, neutrophils, such as Upregulate the level of adhesion molecules to bring mononuclear/macrophage to the area formed by atheromatous plaques, induce cytokines such as Interferon expression, activation of leukocytes, induction of oxidative stress, induction of cell membrane permeability and apoptosis. These effects further lead to the growth and instability of atherosclerotic plaque, the core of plaque necrosis continues to expand, the thrombus cap becomes thin and even ruptured, and eventually develops into clinically seen diseases such as myocardial infarction, coronary heart disease, ischemic stroke and the like. .
因此应用 Lp-PLA2抑制剂可能减少上述炎症反应的发生，是一种新的、非降脂策略 的动脉粥样硬化治疗方法。 在人体内观察到 Lp-PLA2的选择性抑制剂能够显著减少 ox-NEFA 的生成和 ox-LDL 引起的巨噬细胞的凋亡 (Rosenson RS, Vracar-Grabar M， Helenowski I. Cardiovasc Drugs Ther 2008; 22:55-8)。 在动物模型上进行的实验同样支持 Lp-PLA2抑制剂的作用， Wilensky等人 (Wilensky RL, Shi Y, Mohler ER， et al. Nat Med 2008; 14:1059-66)细致研究了 Lp-PLA2抑制剂 Darapladib影响糖尿病 /高胆固醇猪的动脉 硬化斑块体积、组成和基因表达的情况，发现能有效抑制动脉粥样硬化斑块的继续生长。 Therefore, the application of Lp-PLA 2 inhibitor may reduce the occurrence of the aforementioned inflammatory response, and is a new, non-lipid-lowering strategy for atherosclerosis. Selective inhibitors of Lp-PLA 2 were observed in humans to significantly reduce ox-NEFA production and ox-LDL-induced apoptosis in macrophages (Rosenson RS, Vracar-Grabar M, Helenowski I. Cardiovasc Drugs Ther 2008 22:55-8). Experiments performed on animal models also support the role of Lp-PLA 2 inhibitors, and Wilensky et al. (Wilensky RL, Shi Y, Mohler ER, et al. Nat Med 2008; 14:1059-66) studied Lp-PLA in detail. 2 Inhibitor Darapladib affects the volume, composition and gene expression of atherosclerotic plaque in diabetic/high cholesterol pigs and is found to be effective in inhibiting the continued growth of atherosclerotic plaque.
大量临床研究证明了心血管事件的发生率与 Lp-PLA2水平正相关。 Caslake 等 (Packard CJ， O'Reilly DS， Caslake MJ， et al. West of Scotland Coronary Prevention Group. N Engl J Med 2000; 343 :1148-55)对 580名曾发生心肌梗塞、缺血性再灌注或者冠心病相 关死亡的人群以及 1168名对照者做了一项名为 West of Scotland Coronary Prevention Study CWOSCOPS)巢式病例对照研究， 第一次证明了 Lp-PLA2水平与冠心病事件 (CHD) 的关系， 并指出 Lp-PLA2独立于传统危险因子和 C-反应蛋白而对冠心病事件有预测价 值。 Lp-PLA2水平每升高一个标准偏差， 冠心病事件发生率将增加 22%。 Lp-PLA2水平 最高的 1/5人群的发病风险两倍于水平最低的 1/5。 A large number of clinical studies have demonstrated that the incidence of cardiovascular events is positively correlated with Lp-PLA 2 levels. Caslake et al. (Packard CJ, O'Reilly DS, Caslake MJ, et al. West of Scotland Coronary Prevention Group. N Engl J Med 2000; 343: 1148-55) had a myocardial infarction, ischemic reperfusion, or 580 Coronary heart disease-related deaths and 1,168 controls underwent a nested case-control study called West of Scotland Coronary Prevention Study CWOSCOPS, which demonstrated the relationship between Lp-PLA 2 levels and coronary heart disease events (CHD) for the first time. And pointed out that Lp-PLA 2 is predictive of coronary heart disease events independent of traditional risk factors and C-reactive protein. For every one standard deviation of Lp-PLA 2 levels, the incidence of coronary heart disease events will increase by 22%. The risk of developing one-fifth of the highest Lp-PLA 2 levels is twice the lowest of the lowest level.
对目前健康但具有潜在心血管发病风险的病人所作的研究表明 Lp-PLA2应该作为 诊断指标对 LDL水平虽然较低但具有高度冠心病风险的病人提出预警。 "Rotterdam study"(Oei HH， van der Meer IM, Hofman A, et al. Circulation 2005; 111 :570-5)对 7983名 无冠心病史的且年龄大于 55岁的人群所做的研究表明在普遍的人群中， 不论胆固醇水 平高低， Lp-PLA2都是冠心病事件的预警因子， 同时也是缺血性脑猝中的预警因子。 Studies of patients who are currently healthy but at risk for potential cardiovascular risk have shown that Lp-PLA 2 should be used as a diagnostic indicator to alert patients with low LDL levels but at high risk of coronary heart disease. "Rotterdam study" (Oei HH, van der Meer IM, Hofman A, et al. Circulation 2005; 111 : 570-5) studies of 7,983 people with no history of coronary heart disease and older than 55 years of age indicate widespread Among the population, regardless of the level of cholesterol, Lp-PLA 2 is an early warning factor for coronary heart disease events and an early warning factor in ischemic cerebral palsy.
在二级预防的人群中， Lp-PLA2也是预测疾病周期性发生的危险因子。一项研究指 出（Brilakis ES， McConnell JP， Lennon RJ， Elesber AA, Meyer JG， Berger PB. Eur Heart J 2005; 26:137-144), 冠状动脉血管造影术的病人 Lp-PLA2水平每升高一个标准偏差， 冠 心病事件发生率将增加 30%。 Lp-PLA2的这种影响独立于传统的危险因子。 另外一项对 正在进行康复治疗的病人所作的研究发现， Lp-PLA2水平最高的 1/2人群发生心血管疾 病的几率是最低 1/2的两倍。 In the secondary prevention population, Lp-PLA 2 is also a risk factor for predicting the periodic occurrence of the disease. One study pointed out (Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Eur Heart J 2005; 26: 137-144), elevated Lp-PLA 2 levels in patients undergoing coronary angiography With a standard deviation, the incidence of coronary heart disease events will increase by 30%. This effect of Lp-PLA 2 is independent of traditional risk factors. Another study of patients undergoing rehabilitation therapy found that 1/2 of the people with the highest levels of Lp-PLA 2 had a cardiovascular disease rate that was twice as low as 1/2.
ox-LDL 的水解产物一溶血磷脂酰胆碱 (Lyso-PC)水平的增高被认为与动脉粥样 硬化病人的内皮功能紊乱有关， 而 Lp-PLA2抑制剂有可能改善这种病症。 对于其他表 现出内皮功能紊乱的疾病如糖尿病、 高血压、 心绞痛及缺血性区域之再灌流等， 都有 可能应用 Lp-PLA2抑制剂进行治疗。 An increase in the level of lysophosphatidylcholine (Lyso-PC), a hydrolysate of ox-LDL, is thought to be associated with endothelial dysfunction in patients with atherosclerosis, and Lp-PLA 2 inhibitors may improve this condition. For other diseases that exhibit endothelial dysfunction such as diabetes, hypertension, angina pectoris, and reperfusion of ischemic areas, Lp-PLA 2 inhibitors may be used for treatment.
Lp-PLA2在活化的炎症细胞 (巨噬细胞、淋巴细胞、 中性粒细胞和嗜酸性粒细胞等） 中表达， 因此 Lp-PLA2抑制剂可以在治疗与炎症细胞有关的病症中应用， 比如牛皮癣。 此外， Lp-PLA2抑制剂可能普遍适用于任何涉及到氧化的脂质在 Lp-PLA2的参与 下水解成为两个炎症特性物质这一过程的病症。 这就包括前述的动脉粥样硬化、 糖尿 病、 高血压、 心绞痛、 风湿性关节炎、 脑卒中、 心肌梗塞、 再灌流、 急性和慢性炎症 疾病。 Lp-PLA 2 in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.) In expression, Lp-PLA 2 inhibitors can therefore be used in the treatment of conditions associated with inflammatory cells, such as psoriasis. Furthermore, Lp-PLA 2 inhibitors may be universally applicable to any process involving the hydrolysis of lipids into the two inflammatory traits with the participation of Lp-PLA 2 . This includes the aforementioned atherosclerosis, diabetes, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, reperfusion, acute and chronic inflammatory diseases.
专利申请 W096/13484, W096/19451 , WO97/02242, W097/21765 , W097/21766, WO97/41098和 WO97/41099(SmithKline Beecham pic)公开了一系列单环 β内酰胺衍生 物， 它们是 Lp-PLA2的非可逆的、 乙酰化抑制剂 (Tew et al， Biochemistry, 37, 10087, 1998)。 Patent applications W096/13484, W096/19451, WO97/02242, W097/21765, W097/21766, WO97/41098 and WO97/41099 (SmithKline Beecham pic) disclose a series of monocyclic beta lactam derivatives which are Lp- A non-reversible, acetylation inhibitor of PLA 2 (Tew et al, Biochemistry, 37, 10087, 1998).
SmithKline Beecham pic开发了一类 Lp-PLA2的强效可逆抑制剂 (WO 99/24420, WO 01/60805 , WO 02/30911 , WO 03/016287, WO 03/042179, WO 03/042206, WO 08/048867 等）， 以结构中含有嘧啶酮或吡啶酮基团为特征。 其中， Lp-PLA2抑制剂 Darapladib(SB480848)处于 III期临床阶段。 SmithKline Beecham pic has developed a class of potent reversible inhibitors of Lp-PLA 2 (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08 /048867, etc., characterized by a pyrimidinone or pyridone group in the structure. Among them, the Lp-PLA 2 inhibitor Darapladib (SB480848) is in the phase III clinical stage.
韩国的研究者开发了 (US7642291)—类新颖的 0-乙酰化羟肟衍生物， 具有微摩尔 级别的活性。  Researchers in Korea have developed (US7642291) a novel class of 0-acetylated oxindole derivatives with micromolar activity.
我们发现了一类新颖的嘧啶酮类化合物， 药理实验证明它们是 Lp-PLA2的有效抑 制剂。 We have discovered a novel class of pyrimidinone compounds that have been shown to be potent inhibitors of Lp-PLA 2 by pharmacological experiments.
发明内容 Summary of the invention
本发明的一个目的在于提供通式 (I)所示的有药用价值的嘧啶酮类化合物、其对映异 构体、 非对映异构体、 外消旋体和混合物， 或其药学上可接受的盐。  An object of the present invention is to provide a pharmaceutically acceptable pyrimidinone compound represented by the formula (I), an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically thereof thereof Acceptable salt.
本发明的另一目的在于提供通式 (I)所示嘧啶酮类化合物、其对映异构体、非对映异 构体、 外消旋体和混合物， 或其药学上可接受的盐的制备方法。  Another object of the present invention is to provide a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof Preparation.
本发明的进一步目的在于提供通式 (I)所示的嘧啶酮类化合物、其对映异构体、非对 映异构体、外消旋体和混合物，或其药学上可接受的盐在制备 Lp-PLA2抑制剂的药物中 的用途，从而在制备用于预防、治疗或改善与 Lp-PLA2酶活性有关的疾病的药物中的用 途， 所述疾病如动脉粥样硬化， 脑中风， 心肌梗塞、 心绞痛、 心肌缺血、 再灌注损伤等 冠心病， 糖尿病， 风湿性关节炎， 急性和慢性炎症疾病。 A further object of the present invention is to provide a pyrimidinone compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof Use of a medicament for the preparation of an Lp-PLA 2 inhibitor, thereby for use in the preparation of a medicament for preventing, treating or ameliorating a disease associated with Lp-PLA 2 enzyme activity, such as atherosclerosis, stroke , myocardial infarction, angina pectoris, myocardial ischemia, reperfusion injury and other coronary heart disease, diabetes, rheumatoid arthritis, acute and chronic inflammatory diseases.
本发明的还一目的在于提供一种药物组合物，其包含一种或多种有效治疗剂量的通 式 (I)所示的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体和混合物， 或其 药学上可接受的盐， 以及药学上可接受的辅料。  It is still another object of the present invention to provide a pharmaceutical composition comprising one or more effective therapeutic doses of a pyrimidinone compound of the formula (I), an enantiomer thereof, a diastereomer A body, a racemate and a mixture, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
本发明所提供的嘧啶酮类化合物或其药学上可接受的盐如通式 (I)所示：
Figure imgf000006_0001
The pyrimidinone compound provided by the present invention or a pharmaceutically acceptable salt thereof is represented by the formula (I):
Figure imgf000006_0001
(I)  (I)
W代表 IA和 IB,  W stands for IA and IB,
(
Figure imgf000006_0002
(
Figure imgf000006_0002
(IA (IB: 1和 R3各自独立地选自： Η、 _1()的直链或支链烷基、 C„的环烷基、羟基、 -NR4R5、
Figure imgf000006_0003
、 或者五到七元的芳香或非芳香杂环， 所述杂环含有一个到三个氮原子， 并且非必须地被 d_3的烷基取代； (IA: IB: 1 and R 3 are each independently selected from the group consisting of: a straight or branched alkyl group of Η, _ 1 () , a cycloalkyl group of C, a hydroxyl group, -NR 4 R 5 ,
Figure imgf000006_0003
, Or five to seven yuan aromatic or non-aromatic heterocyclic ring containing one to three nitrogen atoms, and not necessarily be d_ 3 alkyl substituents;
R2为 H或 d_3的烷基； 或者 R 2 is an alkyl group of H or d 3 ;
R1-(CH2)m和 R2与其连接的 N共同组成五到七元的非芳香杂环， 且该非芳香杂环 非必须地被 d_3的烷基或 -NR4R5取代， 例如但不仅限于" 4-二甲氨基哌啶基"； R 1 —(CH 2 )m and R 2 together with the N to which they are bonded constitute a five- to seven-membered non-aromatic heterocyclic ring, and the non-aromatic heterocyclic ring is optionally substituted by an alkyl group of d_ 3 or —NR 4 R 5 , For example, but not limited to "4-dimethylaminopiperidinyl";
m=0-2的整数；  An integer of m=0-2;
n=0-2的整数；  An integer of n=0-2;
R4和 R5各自独立地选自： H或 d_3的烷基； R 4 and R 5 are each independently selected from: an alkyl group of H or d 3 ;
R6可以处于临位、 对位或间位， 选自 H、 卤素原子、 d_4
Figure imgf000006_0004
R 6 may be in the para, para or meta position, selected from H, a halogen atom, d_ 4
Figure imgf000006_0004
R7选自 H、 卤素原子、 d_2的烷基或者一个到三个卤素原子取代的 d_2的烷基。 R 7 is selected from H, a halogen atom, an alkyl group of d 2 or an alkyl group of d 2 substituted by three halogen atoms.
具体实施方式 detailed description
本发明中所述的"取代"表示被一个或多个基团所替代。当多个取代基从同一系列候 选取代基中选择时， 它们可以相同， 也可以不同。  "Substituted" as used in the present invention means replaced by one or more groups. When a plurality of substituents are selected from the same series of candidate substituents, they may be the same or different.
本发明中所述的"各自独立地"表示多个定义基团都可从同一系列候选基团中进行 选择， 它们互不影响， 即可以相同， 也可以不同。 本发明中所述的"有效治疗剂量"表示与没有接受该剂量治疗的对象相比，接受该剂 量治疗的对象的疾病、 紊乱、 副作用等得到治愈、 改善、 有效预防或者其发生率显著降 低。 此外， 它还包括增强正常生理功能的有效剂量。 The phrase "independently" as used in the present invention means that a plurality of defined groups can be selected from the same series of candidate groups, and they do not affect each other, that is, they may be the same or different. The "effective therapeutic dose" as used in the present invention means that the disease, disorder, side effect, and the like of the subject receiving the dose are cured, improved, effectively prevented, or the incidence thereof is significantly lowered as compared with the subject not receiving the dose. In addition, it also includes an effective dose that enhances normal physiological function.
本发明中所述的"浣基"等名词包括特定碳原子个数下所有支链和直链的异构体。代 表性的例子有但不仅限于： 甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基。  The term "mercapto" as used in the present invention includes all branched and straight chain isomers of a specific number of carbon atoms. Representative examples are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
本发明中所述的"环烷基 "代表特定碳原子个数下的非芳香性、饱和、环状的脂肪烃 基团。 代表性的例子有但不仅限于： 环丙基、 环丁基、 环戊基、 环己基。  The "cycloalkyl group" described in the present invention represents a non-aromatic, saturated, cyclic aliphatic hydrocarbon group at a specific number of carbon atoms. Representative examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
若非专门定义， 本发明中所述的"卤素"包括氟、 氯、 溴和碘。  The "halogen" as used in the present invention includes fluorine, chlorine, bromine and iodine unless specifically defined.
通式 (I)所示的嘧啶酮类化合物可能以药学上可接受的盐的形式存在，这是本发明范 围内特别重要的一部分。"药学上可接受的盐"表示式 (I)所示的化合物保持了期望的生物 活性且具有最小的毒副作用。该药学上可接受的盐可以直接在化合物的制备和纯化过程 中得到，也可以间接的通过该化合物的游离酸或游离碱与另外一种合适的碱或酸反应得 到。  The pyrimidinone compound represented by the formula (I) may exist in the form of a pharmaceutically acceptable salt, which is a particularly important part within the scope of the present invention. "Pharmaceutically acceptable salt" means that the compound of formula (I) retains the desired biological activity and has minimal toxic side effects. The pharmaceutically acceptable salt can be obtained directly during the preparation and purification of the compound, or it can be obtained indirectly by reacting the free acid or free base of the compound with another suitable base or acid.
具体地， 本发明的部分化合物含有碱性官能团， 如当 R -N R5时， 可以与合适的 酸形成药学上可接受的盐的。所述合适的酸可以是无机酸， 也可以是有机酸。 药学上可 接受的盐的代表性例子包括但不限于： 盐酸盐、 硫酸盐、 氢溴酸盐、 甲磺酸盐、 硝酸、 磷酸盐、 乙酸盐、 草酸盐、 丁二酸盐、 酒石酸盐、 马来酸盐、 精氨酸盐等。 Specifically, some of the compounds of the present invention contain a basic functional group such as R-NR 5 to form a pharmaceutically acceptable salt with a suitable acid. The suitable acid may be a mineral acid or an organic acid. Representative examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, methanesulfonate, nitric acid, phosphate, acetate, oxalate, succinate, Tartrate, maleate, arginine, etc.
本发明的部分化合物含有酸性官能团， 如当 R^-OH时， 可以与合适的碱形成药学 上可接受的盐。所述合适的碱可以是无机碱， 也可以是有机碱。 药学上可接受的盐的代 表性例子包括但不限于： 与无机离子形成的盐， 如钠盐、 钾盐、 锂盐、 钙盐、 铝盐、 锌 盐、 铵盐等； 与有机碱形成的盐， 如甲胺盐、 乙胺盐、 三乙胺盐、 葡甲胺盐、 氨基丁三 醇盐等。  Some of the compounds of the present invention contain an acidic functional group such as R^-OH to form a pharmaceutically acceptable salt with a suitable base. The suitable base may be an inorganic base or an organic base. Representative examples of pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic ions, such as sodium salts, potassium salts, lithium salts, calcium salts, aluminum salts, zinc salts, ammonium salts, and the like; Salts such as methylamine salt, ethylamine salt, triethylamine salt, meglumine salt, tromethamine salt and the like.
本发明的部分化合物或其药学上可接受的盐是从水或有机溶剂中结晶或重结晶而 来， 晶体中可能包含所使用的溶剂分子。此外， 不同的结晶条件可能导致化合物的晶型 不同。因此，含有不同化学剂量的结晶溶剂以及所有晶型的通式 (I)所示的化合物或其药 学上可接受的盐都在本发明的范围内。  A part of the compound of the present invention or a pharmaceutically acceptable salt thereof is crystallized or recrystallized from water or an organic solvent, and the solvent may be used in the crystal. In addition, different crystallization conditions may result in different crystal forms of the compound. Therefore, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof containing a different chemical amount of the crystallization solvent and all the crystal forms is within the scope of the present invention.
本发明通式 (I)所示的化合物中具有一个或多个手性中心， 因而可能存在外消旋体、 外消旋混合物、 对映异构单体、 非对映异构单体、 非对映异构混合物等多种形式。 通式 The compound of the formula (I) of the present invention has one or more chiral centers, and thus may exist as a racemate, a racemic mixture, an enantiomeric monomer, a diastereomeric monomer, or a non- Enantiomeric mixtures and other forms. general formula
(I)所示化合物的所有这些异构形式都在本发明的保护范围内。通式 (I)所示的化合物可能 HO All such isomeric forms of the compounds shown in (I) are within the scope of the invention. The compound represented by the formula (I) may be HO
以互变异构体的形式存在， 例如但不仅限于 H ， 因此某一种互变 异构体以及多种互变异构体的混合体都在本发明的保护范围内。通式 (I)所示的化合物的 可能由于某个基团自由旋转受限而存在旋转异构体，因此某一种形式的旋转异构体以及 多种旋转异构体的混合体也在本发明的保护范围内。 It exists in the form of tautomers such as, but not limited to, H, and thus a tautomer and a mixture of a plurality of tautomers are within the scope of the present invention. The compound represented by the formula (I) may have a rotamer due to the restriction of free rotation of a certain group, and thus a certain form of rotamer and Mixtures of multiple rotamers are also within the scope of the invention.
优选实施方案 Preferred embodiment
在通式 (I)所示化合物的取代基的定义范围内，如下对基团的更详细的定义是本发明 的优选方案：  Within the definition of the substituent of the compound of the formula (I), a more detailed definition of the group as follows is a preferred embodiment of the invention:
当 W是 IA时，  When W is IA,
R3优选为
Figure imgf000008_0001
-R 3 is preferably
Figure imgf000008_0001
-
R 尤选为 H、 。的直链或支链烷基、 C3_7的环垸基或 -NR4R5 ; m =0-2的整数； R is especially chosen as H, . Linear or branched alkyl, C 3 -7 cyclodecyl or -NR 4 R 5 ; m =0-2 integer;
R4和 R5各自独立地优选为 的烷基； R 4 and R 5 are each independently preferably an alkyl group;
R6的定义同上。 R 6 has the same definition as above.
或者，  Or,
当 W是 IB时，  When W is IB,
R1和 R3各自独立地优选为
Figure imgf000008_0002
或 -NR4R5； R 1 and R 3 are each independently preferably
Figure imgf000008_0002
Or -NR 4 R 5 ;
R2优选为 H或甲基； R 2 is preferably H or methyl;
m优选为 1或 2;  m is preferably 1 or 2;
n =0-2的整数；  An integer of n =0-2;
R4和 R5各自独立地优选为 的烷基； R 4 and R 5 are each independently preferably an alkyl group;
R6的定义同上。 R 6 has the same definition as above.
更优的方案为：  A better solution is:
当 W是 IA时，  When W is IA,
R3优选为对三氟甲基联苯 -4-基； R 3 is preferably p-trifluoromethylbiphenyl-4-yl;
R^CH^m-优选为 H、 CM的直链或支链烷基、 环丙甲基或 -CH2CH2NR4R5 ; R4和 R5各自独立地优选为甲基或乙基， 最优选为乙基； R^CH^m- is preferably a linear or branched alkyl group of H, CM, cyclopropylmethyl or -CH 2 CH 2 NR 4 R 5 ; R 4 and R 5 are each independently preferably methyl or ethyl. Most preferably ethyl;
或者，  Or,
当 W是 IB时，  When W is IB,
R1和 R3各自独立地优选为 ^0^^^R 或 -NR4R5； R 1 and R 3 are each independently preferably ^0^^^ R or -N R 4 R 5 ;
R2优选为 H或甲基； R 2 is preferably H or methyl;
m优选为 1或 2;  m is preferably 1 or 2;
n =0-2的整数；  An integer of n =0-2;
R4和 R5各自独立地优选为甲基或乙基； R 4 and R 5 are each independently preferably methyl or ethyl;
R7优选为卤素原子、 甲基或卤素原子取代的甲基， 最优选为 -CF3。 最优选地， 通式 (I)所示的嘧啶酮类化合物具体可以为： R 7 is preferably a methyl group substituted with a halogen atom, a methyl group or a halogen atom, and most preferably -CF 3 . Most preferably, the pyrimidinone compound represented by the formula (I) may specifically be:
甲基 二乙氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺；  Methyldiethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]-4 - (p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 二甲氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺；  Methyl dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]-4 - (p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 -N-(l-甲基哌啶 -4-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl-N-(l-methylpiperidin-4-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo -6,7-dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[1-氧代 -4- (对三氟甲基联苯 -4-基) -1-(N-甲基哌嗪 -1 基)丁烷 -2-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)-1-(N-methylpiperazin-1yl)butan-2-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
1-[1-氧代 -4- (对三氟甲基联苯 -4-基 )小(4-二甲氨基哌啶 -1-基)丁烷 -2-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-dimethylaminopiperidin-1-yl)butan-2-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
甲基 -N-[(1H-咪唑 -2-基)甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl-N-[(1H-imidazol-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4- Oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[3- (对三氟甲基联苯 -4-基 )小(4-二甲氨基哌啶 -1-基)小氧代丙烷 -2-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[3-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-dimethylaminopiperidin-1-yl)oxyxopropan-2-yl]-2-p-fluorobenzylthio- 6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
N-(l-甲基哌啶 -4-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  N-(l-methylpiperidin-4-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6 , 7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]butanamide;
N-二甲氨基乙基 -2-[(2-对氟苄硫基 )-4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 - 1 (5 )- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺；  N-dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta]pyrimidine-1 (5)-yl]-4 - (p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 -N-[(l-甲基 -1H-吡咯 -2-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫 基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1(5H)-基]丁酰胺；  Methyl-N-[(l-methyl-1H-pyrrol-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio) -4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H)-yl]butanamide;
Ν,Ν -二甲基 -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 - 5H)-基]丁酰胺；  Ν,Ν-dimethyl-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H - cyclopenta [ ]pyrimidine-5H)-yl]butanamide;
ΛΚ哌啶 -1-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环 戊 [ ]嘧啶 - 5H)-基]丁酰胺；  Piperidin-1-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-5H)-yl]butanamide;
甲基 -N-(2-羟乙基 )-4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl-N-(2-hydroxyethyl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7 - dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]butanamide;
甲基 [(吡啶 -2-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl [(pyridin-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6, 7-Dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
甲基 [(吡啶 -3-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl [(pyridin-3-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6, 7-Dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[1-氧代 -3- (对三氟甲基联苯 -4-基 )小(4-甲基哌嗪 -1-基)丙烷 -2-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-3-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-methylpiperazin-1-yl)propan-2-yl]-2-p-fluorobenzylthio -6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
甲基 二甲氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -3- (对三氟甲基联苯 -4-基)丙酰胺； Methyl dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)- Benzyl-3-(p-trifluoromethylbiphenyl-4-yl)propanamide;
甲基 二乙氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -3- (对三氟甲基联苯 -4-基)丙酰胺；  Methyldiethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]-3 - (p-trifluoromethylbiphenyl-4-yl)propanamide;
甲基 -Λ 对三氟甲基联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl-hydrazone p-trifluoromethylbiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 (对氯联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-chlorobiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentyl [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 -N-(对氯联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]戊酰胺；  Methyl-N-(p-chlorobiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H - cyclopenta [ ]pyrimidine-1(5H)-yl]pentanamide;
甲基 -Λ 对三氟甲基联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]戊酰胺；  Methyl-hydrazone p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-1(5H)-yl]pentanamide;
甲基 (对氟联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-fluorobiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentyl [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 (对甲基联苯 -4-基）甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-methylbiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclo Butyl [ ]pyrimidine-1(5H)-yl]butanamide;
(士) 式 -1-[2-氧代 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (士) Formula-1-[2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(士) -鑕式小[2-氧代 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (士) - 锧 small [2-oxo-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-二乙胺乙基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-diethylamine ethyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluoro Benzylthio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
式 -1-[(5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -1-[(5-Phenyl-2-oxo)B-pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta [pyrimidine]
-4(5H)-酮； -4(5H)-one;
(±)-鑕式 -1-[(5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±)-锧-1-((5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopentyl [ ]pyrimidine-4(5H)-one;
(士)—^式小[2-氧代 -1-对氟苄基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-p-fluorobenzyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士) 式 -1-[2-氧代 -N-(2-甲基丙基) -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士) Formula-1-[2-Oxo-N-(2-methylpropyl)-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2 -p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-正丁基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-n-butyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl sulfide Base-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-环丙甲基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-cyclopropanyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式 -1-[2-氧代 -1-乙基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6，7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮； (士)-^-1-(2-oxo-1-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2-p-fluorobenzyl Sulfur -6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-间三氟甲基苄基 -5-苯基吡咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-inter-trifluoromethylbenzyl-5-phenylpyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro- 1H-cyclopenta[]pyrimidin-4(5H)-one;
^-^式 -1-[(1-间氟苯甲基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H- 环戊 [ ]嘧啶 -4(5H)-酮；  ^-^式-1-[(1-m-fluorobenzyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-di Hydrogen-1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-对叔丁基苄基 -5-苯基 -2-氧代)吡咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±) Formula-1-[(1-P-Butylbenzyl-5-phenyl-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro -1H-cyclopenta[]pyrimidin-4(5H)-one;
(； ±)- ^式 -l-[0正十二烷基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H- 环戊 [ ]嘧啶 -4(5H)-酮；  (; ±)- ^-l-[0-n-dodecyl-5-phenyl-2-oxo) B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-正辛基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±) Formula-1-[(1-n-octyl-5-phenyl-2-oxo)Bpyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro- 1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-正丙基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±) Formula-1-[(1-n-propyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro- 1H-cyclopenta[]pyrimidin-4(5H)-one;
^-^式 -1-[(1-对氟苄基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环 戊 [ ]嘧啶 -4(5H)-酮；  ^-^式-1-[(1-p-fluorobenzyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro -1H-cyclopenta[]pyrimidin-4(5H)-one;
其对映异构体、 非对映异构体、 外消旋体和混合物， 或其药学上可接受的盐。 上述最优选的化合物的结构式示于下述的制备实施例中。  Its enantiomers, diastereomers, racemates and mixtures, or pharmaceutically acceptable salts thereof. The structural formula of the above most preferred compound is shown in the following Preparation Examples.
本发明的化合物是脂蛋白相关的磷脂酶 A2的有效抑制剂并有可能用于临床治疗， 特别是用于急性和慢性冠心病的治疗和预防，比如由外周血管和脑血管动脉粥样硬化引 起的该类事件； 也就是说， 本发明提供了一个通式 (I)所示的可用于临床治疗的化合物。  The compounds of the present invention are potent inhibitors of lipoprotein-associated phospholipase A2 and are potentially useful for clinical treatment, particularly for the treatment and prevention of acute and chronic coronary heart disease, such as by peripheral vascular and cerebrovascular atherosclerosis. This type of event; that is, the present invention provides a compound of the general formula (I) which can be used for clinical treatment.
本发明通式 (I)所示的化合物可以抑制溶血磷脂酰胆碱 (Lyso-PC)的生成， 因此可以 普遍适用于与内皮功能紊乱有关的疾病， 比如动脉粥样硬化、 糖尿病、 高血压、 心绞 痛及缺血性再灌流等。 此外， 通式 (I)所示的化合物可以普遍适用于任何涉及到氧化脂 质在 Lp-PLA2的参与下发生水解这一过程的病症， 除了动脉粥样硬化、 糖尿病外， 这 些病症还包括局部缺血、风湿性关节炎、 中风、脑部炎症疾病 (比如阿兹海默氏症)、 心 肌梗塞、 再灌注损伤、 败血症、 急性及慢性炎症疾病。 The compound represented by the formula (I) of the present invention can inhibit the formation of lysophosphatidylcholine (Lyso-PC), and thus can be generally applied to diseases associated with endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, Angina and ischemic reperfusion. Furthermore, the compounds of the formula (I) can be generally applied to any condition involving the hydrolysis of oxidized lipids with the participation of Lp-PLA 2 , in addition to atherosclerosis, diabetes, etc. Ischemia, rheumatoid arthritis, stroke, brain inflammatory disease (such as Alzheimer's disease), myocardial infarction, reperfusion injury, sepsis, acute and chronic inflammatory diseases.
Lp-PLA2在活化的炎症细胞 (巨噬细胞、淋巴细胞、 中性粒细胞和嗜酸性粒细胞等） 中表达， 因此本发明通式 (I)所示的化合物可以在治疗与炎症细胞活化有关的病症中应 用， 比如牛皮癣。 Lp-PLA 2 is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus the compounds of the general formula (I) of the present invention can be treated and inflammatory cell activation Applications in related conditions such as psoriasis.
也就是说， 本发明提供了通式 (I)所示的化合物通过抑制 Lp-PLA2的酶活性进而治 疗与 Lp-PLA2活化相关的疾病的用途。 这些疾病可能与如下事件相关： 炎症细胞的活 化； 溶血磷脂胆碱和氧化的游离脂肪酸的形成； Lp-PLA2催化的脂质氧化； 内皮细胞 功能紊乱。 That is, the present invention provides the use of a compound represented by the general formula (I) for the treatment of a disease associated with activation of Lp-PLA 2 by inhibiting the enzymatic activity of Lp-PLA 2 . These diseases may be associated with the following events: activation of inflammatory cells; formation of lysophosphatidylcholine and oxidized free fatty acids; Lp-PLA 2 catalyzed lipid oxidation; endothelial cell dysfunction.
本发明通式 (I)所示的化合物在治疗上述疾病的时候可以与以下药物联用： 降血脂 药、 抗动脉粥样硬化药、 降糖药、 抗心绞痛药、 抗炎药、 降压药或抑制磷脂酶 A的药 物。 例如抑制胆固醇合成的他汀类药物、 抗氧化药普罗布考、 胰岛素增敏剂、 钙离子 通道拮抗剂或非 体抗炎药。 The compound of the formula (I) of the present invention can be used in combination with the following drugs in the treatment of the above diseases: hypolipidemic Medicine, anti-atherosclerotic drugs, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs, antihypertensive drugs or drugs that inhibit phospholipase A. For example, a statin that inhibits cholesterol synthesis, an antioxidant probucol, an insulin sensitizer, a calcium channel antagonist, or a non-anti-inflammatory drug.
优选本发明通式 (I)所示的化合物与降低胆固醇的药物联用， 比如他汀。 他汀类药 物是 HMG-CoA还原酶抑制剂， 例如阿托法他汀、 思伐他汀、 普伐他汀、 西立伐他汀、 氟伐他汀、 洛伐他汀、 匹伐他汀等。 可以依照医生的建议同时或分时间服用两种药物。  Preferably, the compound of the formula (I) of the present invention is used in combination with a cholesterol lowering drug, such as a statin. The statin is an HMG-CoA reductase inhibitor such as atorvastatin, swastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and the like. You can take both drugs at the same time or at different times as recommended by your doctor.
多达 30%的高胆固醇病人对他汀治疗无效。 本发明通式 (I)所示的化合物的进一步 应用可能是适用于该部分病人。  Up to 30% of patients with high cholesterol do not respond to statin therapy. Further use of the compounds of formula (I) of the present invention may be applicable to such patients.
由于心血管事件是导致糖尿病人死亡的主要原因，所以，本发明通式 (I)所示的化合 物可与降糖药或胰岛素增敏剂联用。 联用的胰岛素增敏剂优选 PPA -γ激动剂， 比如罗 格列酮或吡格列酮。  Since the cardiovascular event is the main cause of death of a diabetic person, the compound of the formula (I) of the present invention can be used in combination with a hypoglycemic agent or an insulin sensitizer. The insulin sensitizer used in combination is preferably a PPA-γ agonist such as rosiglitazone or pioglitazone.
在用于治疗时，本发明的化合物通常以一种标准药物组合物的形式给药。也就是说， 本发明提供了一种药物组合物，其中包含一种或多种有效治疗剂量的通式 (I)所示的化合 物， 以及药学上可接受的辅料。所述药学上可接受的辅料为药学上可接受的载体、赋形 剂或缓释剂等。  When used in therapy, the compounds of the invention are typically administered in the form of a standard pharmaceutical composition. That is, the present invention provides a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I), and a pharmaceutically acceptable adjuvant. The pharmaceutically acceptable excipient is a pharmaceutically acceptable carrier, excipient or sustained release agent, and the like.
本发明所提供的化合物和药物组合物可以是多种形式， 如片剂、 胶囊剂、 散剂、 糖 浆剂、 溶液剂、 混悬剂和气雾剂等， 并可以存在于适宜的固体或液体载体或稀释液中。 本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。该药物组合物中还 可包含气味剂、 香味剂等。  The compounds and pharmaceutical compositions provided herein may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be presented in a suitable solid or liquid carrier or In the diluent. The pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Odorants, flavoring agents and the like may also be included in the pharmaceutical composition.
在本发明中， 所述的药物组合物含有安全有效量 (如 0.1-99.9重量份， 优选 1-90重 量份)的式 (I)所示的化合物或其药学上可接受的盐； 以及余量的药学上可接受的辅料， 其中组合物的总重量为 100 重量份。 或者， 本发明所述的药物组合物含有占总重量 0.1-99.9重量％，优选占总重量 1-90重量％的式 (I)所示的化合物或其药学上可接受的盐； 以及余量的药学上可接受的辅料， 其中组合物的总重量为 100重量％。  In the present invention, the pharmaceutical composition contains a safely effective amount (e.g., 0.1 to 99.9 parts by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; A quantity of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight. Alternatively, the pharmaceutical composition of the present invention contains the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an amount of from 0.1 to 99.9% by weight, based on the total weight, preferably from 1 to 90% by weight, based on the total weight; A pharmaceutically acceptable excipient wherein the total weight of the composition is 100% by weight.
式 (I)化合物与药学上可接受的载体、赋形剂或缓释剂的优选比例是，式 (I)作为活性 成分占总重量 60%以上， 其余部分占总重量 0-40%， 其余部分的量优选为 1-20%， 最优 选为 1-10%。  A preferred ratio of the compound of the formula (I) to a pharmaceutically acceptable carrier, excipient or sustained release agent is that the formula (I) as the active ingredient accounts for more than 60% by weight of the total weight, and the balance is 0-40% by weight of the total weight, the rest The amount of the moiety is preferably from 1 to 20%, most preferably from 1 to 10%.
本发明式 (I)所示的化合物或包含式 (I)化合物的药物组合物可对哺乳动物临床使 用， 包括人和动物， 给药途径可以包括口服、 鼻腔吸入、 透皮吸收、 肺部给药或胃肠道 等。 优选的给药途径为口服。 优选为单位剂型， 且每剂包含有效成分 0.01mg-200mg， 优选 0.5mg-100mg， 一次或分次服用。 不管用何种服用方法， 个人的最佳剂量应根据具 体治疗而定。 通常情况下是从小剂量开始， 逐渐增加剂量一直到找到最合适的剂量。  The compound of the formula (I) or the pharmaceutical composition comprising the compound of the formula (I) of the present invention can be used clinically in mammals, including humans and animals, and the administration route can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract. A preferred route of administration is oral. It is preferably in a unit dosage form, and each dose contains the active ingredient of 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, once or in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment. Usually starting with a small dose, gradually increase the dose until the most appropriate dose is found.
本发明的药物组合物可通过口服以及静脉内、 肌内或皮下等途径给药。 从易于制 备和给药的立场看， 优选的药物组合物是固态组合物， 尤其是片剂和固体填充或液体 填充的胶囊。 药物组合物的口服给药是优选的。 The pharmaceutical composition of the present invention can be administered orally and intravenously, intramuscularly or subcutaneously. Preferred pharmaceutical compositions are solid compositions, especially tablets and solid filling or liquids, from the standpoint of ease of preparation and administration. Filled capsules. Oral administration of the pharmaceutical composition is preferred.
固态载体包括： 淀粉、 乳糖、 磷酸二钙、 微晶纤维素、 蔗糖和白陶土等， 而液态 载体包括： 无菌水、 聚乙二醇、 非离子型表面活性剂和食用油 (如玉米油、 花生油和 芝麻油)等， 只要适合活性成分的特性和所需的特定给药方式。 在制备药物组合物中 通常使用的佐剂也可有利地被包括， 例如调味剂、 色素、 防腐剂和抗氧化剂如维生素 E、 维生素 C、 BHT和 BHA。  The solid carrier includes: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and the liquid carrier includes: sterile water, polyethylene glycol, nonionic surfactant and edible oil (such as corn oil). , peanut oil and sesame oil, etc., as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required. Adjuvants which are usually used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
可注射的制剂包括， 但不局限于， 无菌的、 可注射的、 含水的、 含油的溶液、 悬浊 液、乳液等。这些制剂还可以被配置胃肠外合适的稀释剂、分散剂、润湿剂、悬浮剂等。 这样可注射的制剂可以通过在截留细菌的过滤器中过滤灭菌。这些制剂还可以用杀菌剂 配置， 所述的杀菌剂溶解或分散在可注射的介质中或用本领域已知的其他方法。  Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oily solutions, suspensions, emulsions and the like. These formulations may also be formulated with parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable formulations can be sterilized by filtration in a filter that traps bacteria. These formulations may also be formulated with a bactericide which is dissolved or dispersed in an injectable medium or by other methods known in the art.
制备方法 Preparation
縮写  Abbreviation
DBU—— 1,8-二氮杂环 [5，4，0] ^—烯 -7  DBU—— 1,8-diazaheterocycle [5,4,0] ^-ene-7
DCE——二氯乙烷  DCE - dichloroethane
DCM——二氯甲烷  DCM - dichloromethane
DIPEA ~二异丙基乙胺  DIPEA ~ diisopropylethylamine
DMAP—— 4-二甲氨基吡啶  DMAP—— 4-dimethylaminopyridine
DME——乙二醇二甲醚  DME - ethylene glycol dimethyl ether
DMF—— N，N-二甲基甲酰胺  DMF - N,N-dimethylformamide
DPPA ~叠氮磷酸二苯酯  DPPA ~ diphenylphosphoryl azide
EA ~乙酸乙酯  EA ~ ethyl acetate
EDCI— 1-(3-二甲氨基丙基 )-3-乙基碳二亚胺盐酸盐  EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOBt—— 1-羟基苯并*** HOBt - 1-hydroxybenzotriazole
NCS _ N-氯代丁二酰亚胺 NCS _ N-chlorosuccinimide
PE——石油醚 PE - petroleum ether
THF—四氢呋喃 THF-tetrahydrofuran
TUTU—— 0-( 1H-苯并***- 1 - )-NMN',N'-四甲基异脲四氟化硼  TUTU——0-( 1H-benzotriazole-1 - )-NMN', N'-tetramethylisourea boron tetrafluoride
Trans 反式  Trans trans
Cis 顺式  Cis cis
合成路线  synthetic route
本发明所述的化合物可以通过反应路线 1 或反应路线 2所表示的方法中的一种制 备。 除非专门定义， 反应路线中各取代基的定义与通式 (I)相同。
Figure imgf000014_0001
反应路线 1 The compound of the present invention can be produced by one of the methods represented by Reaction Scheme 1 or Scheme 2. Unless otherwise defined, the definition of each substituent in the reaction scheme is the same as in the general formula (I).
Figure imgf000014_0001
Reaction route 1
当 W是 IA时， 通式 (I)化合物可由反应路线 1所示的方法制备： 其中， R R3和 m的定义与上述相同； When W is IA, the compound of the formula (I) can be produced by the method shown in Reaction Scheme 1: wherein the definitions of RR 3 and m are the same as described above;
在碱的作用下， 化合物 1与盐酸羟胺縮合生成化合物 2; 所用的碱包括有机碱和无 机碱， 如三乙胺、碳酸钾、氢氧化钠等； 反应在极性溶剂中进行， 如甲醇、 乙醇、 DMF、 水等或其混合溶剂； 反应温度介于 0°C到 30°C。  Under the action of a base, compound 1 is condensed with hydroxylamine hydrochloride to form compound 2; the base used includes an organic base and an inorganic base such as triethylamine, potassium carbonate, sodium hydroxide, etc.; the reaction is carried out in a polar solvent such as methanol, Ethanol, DMF, water, etc. or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C.
化合物 2经等当量的 NCS氯化成为化合物 3; 反应溶剂包括 THF、 DMF等； 反应 温度介于 0°C到 60°C。  The compound 2 is chlorinated to the compound 3 by an equivalent amount of NCS; the reaction solvent includes THF, DMF, etc.; and the reaction temperature is from 0 ° C to 60 ° C.
化合物 3在碱的作用下脱去氯化氢生成 1，3-偶极离子，然后与丙烯酸乙酯加成生成 化合物 4; 所用的碱为有机碱， 如三乙胺、 DIPEA、 DBU等； 反应溶剂包括 THF、 DMF 等； 反应温度介于 -40°C到室温。 化合物 4氢化还原得到化合物 5 ; 该反应所用的催化剂为钯 /碳， 用量为化合物 4 质量的 10%-20%； 反应在极性溶剂中进行， 如甲醇、 乙醇； 反应温度介于 0°C到 80°C， 最佳为室温。 Compound 3 is dehydrochlorinated under the action of a base to form a 1,3-dipole ion, and then added with ethyl acrylate to form compound 4; the base used is an organic base such as triethylamine, DIPEA, DBU, etc.; THF, DMF, etc.; reaction temperature between -40 ° C to room temperature. Hydrogenation of compound 4 to give compound 5; the catalyst used in the reaction is palladium/carbon in an amount of 10% to 20% by mass of the compound 4; the reaction is carried out in a polar solvent such as methanol or ethanol; the reaction temperature is between 0 ° C Up to 80 ° C, the best room temperature.
化合物 5在碱的作用下与 DPPA反应生成化合物 6;所用的碱为有机碱，如三乙胺、 DIPEA、 DBU、 DMAP等， 最优为 DBU和 DMAP; 反应溶剂包括 THF、 CH3CN、 DME 等极性非质子溶剂， 最优为 THF; 反应温度介于 0°C到 100°C， 最佳为所用溶剂的回流 温度。 Compound 5 reacts with DPPA under the action of a base to form compound 6; the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and the reaction solvent includes THF, CH 3 CN, DME The equipolar aprotic solvent is preferably THF; the reaction temperature is between 0 ° C and 100 ° C, preferably the reflux temperature of the solvent used.
化合物 6经过氢化还原反应或 Staudinger反应得到化合物 7(Gololobov， Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437)；氢化还原反应所用的催化剂为钯 Compound 6 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 7 (Gololobov, Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst used for the hydrogenation reduction reaction is palladium.
/碳， 反应在甲醇、 乙醇、 EA或 THF中进行， 反应温度介于 0°C到 80°C， 最佳为室温； Staudinger反应所用试剂为过量的 Ph3P，反应在 THF-H20中进行，温度介于 0°C到 50°C。 /carbon, the reaction is carried out in methanol, ethanol, EA or THF, the reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used in the Staudinger reaction is an excess of Ph 3 P, and the reaction is in THF-H 2 0 In progress, the temperature is between 0 ° C and 50 ° C.
化合物 7与一个当量的 R8取代的环戊酮羧酸酯縮合生成化合物 8， R8为甲基或乙 基； 反应在脱水剂的存在下进行， 所述脱水剂包括分子筛、 甲苯共沸、 Si(OEt)4等； 反 应溶剂包括甲醇、 乙醇、 甲苯、 乙酸等； 反应温度介于 0°C到 140°C， 最佳为所用溶剂 的回流温度。 Compound 7 is condensed with one equivalent of R 8 -substituted cyclopentanone carboxylate to form compound 8, R 8 is methyl or ethyl; the reaction is carried out in the presence of a dehydrating agent comprising molecular sieves, toluene azeotrope, Si(OEt) 4 or the like; the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.; the reaction temperature is from 0 ° C to 140 ° C, preferably the reflux temperature of the solvent used.
化合物 8与大于 1当量的异氰酸酯縮合生成化合物 9; 所述异氰酸酯包括  Compound 8 is condensed with more than one equivalent of isocyanate to form compound 9; the isocyanate includes
0 0  0 0
Me3Si CS、 EtG^NCS、 Ph CS等， 最优为 Me3Si CS， 通常用量为 3.5当量； 反应无 需溶剂或者在 DMF中进行； 反应温度介于 100°C到 160°C， 最佳为 140°C。 Me 3 Si CS, EtG ^ NCS , Ph CS and the like, most of M e 3 Si CS, usually in an amount of 3.5 equivalents; the reaction without solvent or in DMF; the reaction temperature is between 100 ° C to 160 ° C, most Good for 140 ° C.
化合物 9与对氟苄溴或对氟苄氯反应生成化合物 10; 反应中加入大于一个当量的 有机碱或无机碱， 如三乙胺、 DBU、 DIPEA、 碳酸钾、 碳酸钠等； 反应可加入催化剂， 如碘化钾、 四丁基碘化铵等； 反应溶剂包括乙腈、 丙酮、 DME、 DCM、 DCE、 EA、 乙 醇、 甲醇、 THF等； 反应温度介于 0°C到 80°C， 最佳为所用溶剂的回流温度。  Compound 9 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 10; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
化合物 10与 R1- (CH2)m-LG在强碱的作用下制备化合物 11， LG代表离去基团， 包 括卤素原子、 三氟甲基磺酸根 (-OTf)、 甲磺酸根 (-OMs)等， 最优为 Cl、 B、 I； 所述强碱 包括 NaH、 n-BuLi、 KOBu-t等， 最佳为 NaH; 反应溶剂包括 THF、 DMF; 反应温度介 于 -80°C到室温， 最佳为 0°C到室温。 Compound 10 and R 1 - (CH 2 ) m -LG are prepared under the action of a strong base, and LG represents a leaving group including a halogen atom, a trifluoromethylsulfonate (-OTf), a methanesulfonate (- OMs), etc., most preferably Cl, B, I; the strong base includes NaH, n-BuLi, KOBu-t, etc., most preferably NaH; the reaction solvent includes THF, DMF; the reaction temperature is between -80 ° C to Room temperature, preferably from 0 ° C to room temperature.
Figure imgf000016_0001
反应路线 2
Figure imgf000016_0001
Reaction route 2
当 W是 IB时， 通式 (I)化合物可由反应路线 2所示的方法制备： 其中， R R2、 R3、 m和 n的定义与上述相同； When W is IB, the compound of the formula (I) can be produced by the method shown in Reaction Scheme 2 : wherein RR 2 , R 3 , m and n have the same definitions as above;
化合物 12或其盐酸盐与一个当量的 R8取代的环戊酮羧酸酯縮合生成化合物 13， R8为甲基或乙基； 当使用化合物 12的盐酸盐时， 需要加入至少 1个当量的有机碱， 如 三乙胺、 DIPEA; 反应在脱水剂的存在下进行， 所述脱水剂包括分子筛、 甲苯共沸、 Si(OEt)4等； 反应溶剂包括甲醇、 乙醇、 甲苯、 乙酸等； 反应温度介于 0°C到 140°C， 最 佳为所用溶剂的回流温度。 Compound 12 or its hydrochloride is condensed with one equivalent of R 8 -substituted cyclopentanone carboxylate to form compound 13, R 8 is methyl or ethyl; when using the hydrochloride salt of compound 12, at least one is required. Equivalent organic base, such as triethylamine, DIPEA; the reaction is carried out in the presence of a dehydrating agent, including molecular sieve, toluene azeotrope, Si(OEt) 4, etc.; the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc. The reaction temperature is between 0 ° C and 140 ° C, preferably the reflux temperature of the solvent used.
化合物 13 与大于 1 当量的异氰酸酯縮合生成化合物 14 ; 所述异氰酸酯包括  Compound 13 is condensed with greater than one equivalent of isocyanate to form compound 14; the isocyanate includes
0 0  0 0
Me3Si CS、 EtG^NCS、 Ph CS等， 最优为 Me3Si CS， 用量通常为 3.5当量； 反应无 需溶剂或者在 DMF中进行； 反应温度介于 100°C到 160°C， 最佳为 140°C。 Me 3 Si CS, EtG ^ NCS , Ph CS and the like, most of M e 3 Si CS, an amount of usually 3.5 equivalents; the reaction without solvent or in DMF; the reaction temperature is between 100 ° C to 160 ° C, most Good for 140 ° C.
化合物 14与对氟苄溴或对氟苄氯反应生成化合物 15 ; 反应中加入大于一个当量的 有机碱或无机碱， 如三乙胺、 DBU、 DIPEA, 碳酸钾、 碳酸钠等； 反应可加入催化剂， 如碘化钾、 四丁基碘化铵等； 反应溶剂包括乙腈、 丙酮、 DME、 DCM、 DCE、 EA、 乙 醇、 甲醇、 THF等； 反应温度介于 0°C到 80°C， 最佳为所用溶剂的回流温度。  Compound 14 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 15; more than one equivalent of an organic or inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate, etc. is added to the reaction; Such as potassium iodide, tetrabutylammonium iodide, etc.; the reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; reaction temperature is between 0 ° C and 80 ° C, the best for use The reflux temperature of the solvent.
化合物 15发生碱性水解生成化合物 16; 所用碱为无机强碱， 如 LiOH、 NaOH、 KOH; 反应在含水的极性溶剂中进行， 所述溶剂包括甲醇、 乙醇、 二氧六环、 DMF、 DMSO、 异丙醇、 THF等， 最佳为甲醇、 乙醇； 反应温度介于 0°C到 50°C ; 水解反应完 成后， 反应液需经过酸化析出游离的化合物 16， 酸化通常使用盐酸和乙酸。 H Compound 15 undergoes alkaline hydrolysis to give compound 16; the base used is an inorganic strong base such as LiOH, NaOH, KOH; the reaction is carried out in an aqueous polar solvent including methanol, ethanol, dioxane, DMF, DMSO Isopropanol, THF, etc., preferably methanol or ethanol; the reaction temperature is between 0 ° C and 50 ° C; after the hydrolysis reaction is completed, the reaction solution is subjected to acidification to precipitate the free compound 16, and acidification is usually carried out using hydrochloric acid and acetic acid. H
R N— 2 RN- 2
化合物 16与 、(eH2)m 或其盐酸盐在縮合剂的作用下生成化合物 17; 所用縮合 剂包括二环己基碳二亚胺 (DCC)、 偶氮二羧酸二乙酯 /三苯基磷、碳酰二咪唑、 1-(3-二甲 氨基丙基) -3-乙基碳二亚胺盐酸盐 /1-羟基-苯并-三氮唑 (EDCI/ -(lH-苯并*** -1- 基) -AWN',N'-四甲基异脲四氟化硼 (TBTU)/有机碱等； 当使用
Figure imgf000017_0001
的盐酸盐时， 需要加入至少 1个当量的有机碱， 如三乙胺、 DIPEA; 反应溶剂包括 DCM、 DCE、 乙 腈、 THF、 甲苯、 DMF等非醇溶剂， 最常用为 DCM、 乙腈、 甲苯或其混合溶剂； 反应 温度 ° 120 °C。
Figure imgf000017_0002
可以购买得到或按文献已知的方法制备 (；如 WO2000066567, 其公开 的全部内容通过引用的方式并入到本申请中)。 Compound 16 and ( eH2 ) m or its hydrochloride form compound 17 under the action of a condensing agent; the condensing agent used includes dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate/triphenyl Phosphorus, carbonyl diimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxy-benzo-triazole (EDCI/-(lH-benzo) Triazol-1-yl)-AWN', N'-tetramethylisourea boron tetrafluoride (TBTU) / organic base, etc.; when used
Figure imgf000017_0001
For the hydrochloride, at least one equivalent of an organic base such as triethylamine or DIPEA is required; the reaction solvent includes non-alcoholic solvents such as DCM, DCE, acetonitrile, THF, toluene, DMF, etc., most commonly DCM, acetonitrile, toluene Or a mixed solvent thereof; reaction temperature ° 120 °C.
Figure imgf000017_0002
It can be purchased or prepared by methods known in the literature (as in WO2000066567, the entire disclosure of which is incorporated herein by reference).
其中， 上述的化合物 12可由反应路线 3和反应路线 4所示的两种方法之一进行制 备。 氢化还原
Figure imgf000017_0003
Among them, the above compound 12 can be produced by one of two methods shown in Reaction Scheme 3 and Reaction Scheme 4. Hydrogenation reduction
Figure imgf000017_0003
Figure imgf000017_0004
由 反应路线 3所示的方法制备： 其中， R6的定义同上。
Figure imgf000017_0004
Prepared by the method shown in Reaction Scheme 3: wherein R 6 is as defined above.
在氢氧化钾的作用下， 化合物 18与丙酮酸钠縮合生成化合物 19; 反应在甲醇、 乙 醇、 水、 DCM或其混合溶剂中进行； 反应温度介于 0°C到 30°C ; 化合物 18可以购买得 到或按文献已知的方法制备。  Under the action of potassium hydroxide, compound 18 is condensed with sodium pyruvate to form compound 19; the reaction is carried out in methanol, ethanol, water, DCM or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C; It is purchased or prepared as known in the literature.
化合物 19通过酯化反应制备化合物 20; 反应中的酸催化剂由乙酰氯和乙醇原位生 成； 反应溶剂为甲苯； 反应温度介于 0°C到 110°C。  Compound 19 is prepared by esterification to produce compound 20; the acid catalyst in the reaction is formed in situ from acetyl chloride and ethanol; the reaction solvent is toluene; and the reaction temperature is between 0 ° C and 110 ° C.
化合物 20 氢化还原得到化合物 21 ; 催化剂为钯 /碳， 用量为化合物 20 质量的 10%-20%； 反应在低极性溶剂中进行， 如 EA; 反应温度介于 0°C到 80°C， 最佳为室温。 化合物 21在碱的作用下与 DPPA反应生成化合物 22;所用碱为有机碱，如三乙胺、 DIPEA、 DBU、 DMAP等， 最优为 DBU和 DMAP; 反应溶剂包括 THF、 CH3CN、 DME 等极性非质子溶剂， 最优为 THF; 反应温度介于 0°C到 100°C， 最佳为所用溶剂的回流 温度。 Hydrogenation of compound 20 to give compound 21; the catalyst is palladium/carbon in an amount of 10% to 20% by mass of the compound 20; the reaction is carried out in a low polar solvent such as EA; and the reaction temperature is between 0 ° C and 80 ° C, The best is room temperature. Compound 21 reacts with DPPA under the action of a base to form compound 22; the base used is an organic base such as triethylamine, DIPEA, DBU, DMAP, etc., most preferably DBU and DMAP; and the reaction solvent includes THF, CH 3 CN, DME, etc. A polar aprotic solvent, most preferably THF; the reaction temperature is between 0 ° C and 100 ° C, most preferably the reflux temperature of the solvent used.
化合物 22经过氢化还原反应或 Staudinger反应得到化合物 23(Gololobov， Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437)； 氢化还原反应的催化剂为钯 /碳， 反应在甲醇、乙醇、 EA、 THF中进行，反应温度介于 0°C到 80°C，最佳为室温； Staudinger 反应所用试剂为过量的 Ph3P， 反应在 THF-H20中进行， 温度介于 0°C到 50°C。 Compound 22 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 23 (Gololobov, YG Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437); the catalyst for the hydrogenation reduction reaction is palladium/carbon, and the reaction is carried out in methanol, ethanol, EA, THF. The reaction temperature is between 0 ° C and 80 ° C, preferably room temperature; the reagent used for the Staudinger reaction is an excess of Ph 3 P, and the reaction is carried out in THF-H 2 0 at a temperature between 0 ° C and 50 ° C. .
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000018_0002
化合物 12可由反应路线 4所 示的方法制备： 其中， R6的定义同上。
Figure imgf000018_0002
Compound 12 can be prepared by the method shown in Scheme 4: wherein R 6 is as defined above.
Cl\ ^\ , Cl \ ^\ ,
2-乙酰氨基丙二酸二乙酯在碱的作用下与 （GH2)n |¾ 縮合得到化合物 24; 所 用碱包括 NaH、 KOBu-t、 乙醇钠等， 最佳为乙醇钠； 反应可加入催化剂， 如碘化钾； 反应溶剂包括乙醇、 DME、 THF、 DMF等， 最常用为乙醇； 反应温度介于 0°C到 80°C。 Diethyl 2-acetamidomalonate is condensed with ( GH2 ) n | 3⁄4 under the action of a base to obtain a compound 24; the base used includes NaH, KOBu-t, sodium ethoxide, etc., preferably sodium ethoxide; Such as potassium iodide; reaction solvents include ethanol, DME, THF, DMF, etc., most commonly ethanol; reaction temperature is between 0 ° C and 80 ° C.
化合物 24被 1当量的 NaOH水解， 再加热脱羧生成化合物 25 ; 水解反应在醇水溶 液中进行， 反应温度介于 0°C到室温； 脱羧反应在甲苯中回流。  The compound 24 is hydrolyzed by 1 equivalent of NaOH, and then decarboxylated by heating to form the compound 25; the hydrolysis reaction is carried out in an aqueous alcohol solution at a reaction temperature of from 0 ° C to room temperature; and the decarboxylation reaction is refluxed in toluene.
化合物 25酸性水解制备化合物 26; 反应在稀盐酸中回流进行。  Compound 25 is acid hydrolyzed to prepare compound 26; the reaction is carried out under reflux in dilute hydrochloric acid.
化合物 26经过氯化亚砜参与的酯化反应生成化合物 24; 反应在乙醇中回流进行。  Compound 26 undergoes an esterification reaction involving thionyl chloride to form compound 24; the reaction is carried out under reflux in ethanol.
具体实施例 Specific embodiment
以下将以实施例进一步说明本发明。 需要特别指出的是， 这些实施例只用于举例 说明本发明， 而不以任何方式限制本发明。 实例中的所有参数及其余说明， 除另加说明 外， 都是以质量为依据的。 柱层析分离所用填料若未说明均为硅胶。 制备实施例 The invention will be further illustrated by the following examples. It is to be understood that the examples are only illustrative of the invention and are not intended to limit the invention in any way. All parameters and remaining descriptions in the examples are based on quality unless otherwise stated. The filler used for column chromatography separation is silica gel unless otherwise stated. Preparation example
本发明的合成中间体的编号以英文字母" A、 B、 C"开头， 如中间体" A8"; 而最终 实 "例"字开头， 如"例 18"。  The numbering of the synthetic intermediate of the present invention begins with the English letters "A, B, C", such as the intermediate "A8"; and the final "example" begins with the word "example 18".
Figure imgf000019_0001
Figure imgf000019_0001
A1—— (对三氟甲基联苯 -4-基)甲醛  A1——(p-trifluoromethylbiphenyl-4-yl)formaldehyde
4-三氟甲基苯硼酸 (3.80g， 1当量)， 对溴苯甲醛 (3.7g， 1当量)， 醋酸钯 (0.225g， 0.05 当量)以及浓度为 2 mol/L的 Na2C03溶液 (20ml， 2当量)于 40ml DME中， 氮气置换排尽 空气， 回流 3h， TLC监测反应完毕。 趁热过滤除去不溶物， 且以 EA洗涤， 转移至分 液漏斗， 分出有机相， 水相再以 EA萃取两次， 合并有机相， 以饱和食盐水洗涤两次后 硫酸镁干燥， 柱层析分离之或以***-石油醚重结晶。 4-trifluoromethylbenzeneboronic acid (3.80 g, 1 equivalent), p-bromobenzaldehyde (3.7 g, 1 equivalent), palladium acetate (0.225 g, 0.05 eq.), and a 2 mol/L Na 2 C0 3 solution (20 ml, 2 eq.) In 40 ml of DME, the air was purged with nitrogen and refluxed for 3 h. The reaction was monitored by TLC. The insoluble material was removed by hot filtration, washed with EA, transferred to a separating funnel, and the organic phase was separated. The aqueous phase was extracted twice with EA. The organic phase was combined, washed twice with brine and dried over magnesium sulfate. The precipitate is separated or recrystallized from diethyl ether-petroleum ether.
A2—— (E)- 2-氧代 -4- (对三氟甲基联苯 -4-基) -3-丁烯酸钾盐 A2——(E)-2-oxo-4-(p-trifluoromethylbiphenyl-4-yl)-3-butenoic acid potassium salt
(对三氟甲基联苯 -4-基)甲醛 2.5g和丙酮酸钠 1.16g于 50ml甲醇中且置于冰浴，搅拌 下投入 1.12g KOH颗粒， 待其全部溶解后再置于室温反应过夜。 加入 50ml水和 50ml 二氯甲烷一起搅拌 0.5h， 过滤收集沉淀， 经水洗和二氯甲烷后干燥，得 2.67g黄色固体。  (p-trifluoromethylbiphenyl-4-yl)carboxaldehyde 2.5 g and sodium pyruvate 1.16 g in 50 ml of methanol and placed in an ice bath, and 1.12 g of KOH pellets were added with stirring, and after being completely dissolved, it was allowed to react at room temperature. overnight. After adding 50 ml of water and 50 ml of dichloromethane, the mixture was stirred for 0.5 hr, and the precipitate was collected by filtration, washed with water and dichloromethane and then evaporated
A3—— (E)- 2-氧代- 4- (对三氟甲基联苯 -4-基) -3-丁烯酸乙酯 A3——(E)-2-oxo- 4-(p-trifluoromethylbiphenyl-4-yl)-3-butenoic acid ethyl ester
2.0g A2悬浮于 10ml无水乙醇中，置于冰浴， 2min滴加 1.3ml乙酰氯，再加入 10ml 甲苯， 回流 5h， 反应完毕。 蒸出溶剂至少量， 向剩余物中加入 20ml水， CH2C12 提取 两次， 合并有机相再食盐水洗涤两次， 无水硫酸钠干燥， 蒸干溶剂后以无水乙醇重结晶 得 1.40g黄色晶体。 1H-NMR (CDC13, 300 MHz) 51.43 (t， 3H, J=7.2), 4.41 (q， 2H, J=7.2), 7.42 (d, 1H， J=15.9), 7.66 (d, 2H, J=8.4), 7.72 (m， 6H)， 7.90 (d, 1H， J=15.9). 2.0 g of A2 was suspended in 10 ml of absolute ethanol, placed in an ice bath, 1.3 ml of acetyl chloride was added dropwise over 2 min, and 10 ml of toluene was added thereto, and refluxed for 5 hours, and the reaction was completed. The solvent was distilled off to a minimum amount, 20 ml of water was added to the residue, and the CH 2 C1 2 was extracted twice. The organic phase was combined and washed twice with brine, dried over anhydrous sodium sulfate and evaporated to dryness. g yellow crystals. 1H-NMR (CDC1 3 , 300 MHz) 51.43 (t, 3H, J = 7.2), 4.41 (q, 2H, J = 7.2), 7.42 (d, 1H, J = 15.9), 7.66 (d, 2H, J =8.4), 7.72 (m, 6H), 7.90 (d, 1H, J=15.9).
A4—— 4- (对三氟甲基联苯 -4-基) -2-羟基丁酸乙酯 A4—— 4-(p-trifluoromethylbiphenyl-4-yl)-2-hydroxybutyrate
A3 1.31g, 10%的钯 /碳加氢催化剂 130mg于 lOml EA中， 压力为 1 个大气压加氢 反应 3h完毕。 过滤除去催化剂， 滤液经快速柱色谱分离得 0.64g 白色固体。 1H-NMR (CDC13, 400 MHz) 51.30 (t, 3H, J=7.2), 2.00 (m， 1H), 2.16 (m， 1H), 2.82 (m， 2H), 2.88 (d, 1H, -OH), 4.23 (m， 3H), 7.32 (d, 2H, J=8.0)， 7.53 (d, 2H, J=8.0)， 7.68 (s, 4H). A3 1.31g, 10% palladium on carbon hydrogenation catalyst 130mg in 10ml EA, the pressure is 1 atmosphere hydrogenation reaction 3h. The catalyst was removed by filtration, and the filtrate was subjected to flash column chromatography to yield white crystals. 1H-NMR (CDC1 3 , 400 MHz) 51.30 (t, 3H, J=7.2), 2.00 (m, 1H), 2.16 (m, 1H), 2.82 (m, 2H), 2.88 (d, 1H, -OH ), 4.23 (m, 3H), 7.32 (d, 2H, J=8.0), 7.53 (d, 2H, J=8.0), 7.68 (s, 4H).
Figure imgf000020_0001
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0002
A5—— 4- (对三氟甲基联苯 -4-基) -2-叠氮基丁酸乙酯 A5—— 4-(p-trifluoromethylbiphenyl-4-yl)-2-azidobutanoic acid ethyl ester
氮气保护下， A4 0.63g(l当量)， DPPA 0.5ml(1.3当量）以及 DBU 0.35ml(1.3当量) 于 lOml THF中回流 lh， TLC检测反应完毕。 冷却后， 将反应液投到氯化铵饱和液中， EA提取，食盐水洗涤两次，干燥后经快速柱色谱分离得 0.52g油。 1H-NMR (CDC13， 400 MHz) 51.32 (t， 3H, J=7.2), 2.10 (m， 1H), 2.19 (m， 1H), 2.82 (m， 2H), 3.85 (dd， 1H), 4.25 (q， 2H), 7.31 (d， 2H), 7.55 (d， 2H), 7.68 (s, 4H). Under a nitrogen atmosphere, A4 0.63 g (1 eq.), DPPA 0.5 ml (1.3 eq.) and DBU 0.35 ml (1.3 eq.) were refluxed for 1 h in 10 ml of THF. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with EA, washed twice with brine, dried and then purified by flash column chromatography. 1H-NMR (CDC1 3 , 400 MHz) 51.32 (t, 3H, J=7.2), 2.10 (m, 1H), 2.19 (m, 1H), 2.82 (m, 2H), 3.85 (dd, 1H), 4.25 (q, 2H), 7.31 (d, 2H), 7.55 (d, 2H), 7.68 (s, 4H).
A6—— 2-[4- (对三氟甲基联苯 -4-基) -1-乙氧基 -1-氧丁烷 -2-基】氨基 -1-环戊烯羧酸乙酯  A6——2-[4-(p-trifluoromethylbiphenyl-4-yl)-1-ethoxy-1-pyrene-2-yl]amino-1-cyclopentenecarboxylate
0.50g A5溶于 THF-H2O(10-0.5mml)， 加入 520mg Ph3P室温反应 4h， 完毕。拌入硅 胶， 旋干后硅胶柱层析分离， PE/EA =1 :1洗脱得 4- (对三氟甲基联苯 -4-基) -2-氨基丁酸 乙酯和三苯基氧膦的混合物， 直接向下反应。 0.50 g of A5 was dissolved in THF-H 2 O (10-0.5 mm), and 520 mg of Ph 3 P was added to react at room temperature for 4 h, and was completed. Stir in silica gel, spin dry and separate by silica gel column chromatography, eluting with PE/EA = 1:1 to give ethyl 4-(p-trifluoromethylbiphenyl-4-yl)-2-aminobutanoate and triphenyl A mixture of phosphine oxides, which reacts directly downward.
将上一步得到的产物溶于 10ml无水乙醇中，加入 195μ1环戊酮 -2-羧酸乙酯和 590μ1 硅酸四乙酯， 氮气保护下回流反应 10h停止。 直接拌入硅胶， 旋干后经快速柱色谱分离 得 0.51g油。 1H-NMR (CDC13, 300 MHz) 51.28 (m， 6H)， 1.81 (m， 2H), 2.08 (m， 1H)， 2.20 (m， 1H), 2.41 (m， 2H), 2.53 (t， 2H), 2.79 (m， 2H), 3.93 (m， 1H)， 4.18 (2x q， 4H)， 7.28 (d, 2H), 7.52 (d, 2H), 7.67 (m， 5H). The product obtained in the previous step was dissolved in 10 ml of absolute ethanol, and 195 μl of ethyl cyclopentanone-2-carboxylate and 590 μl of tetraethyl silicate were added, and the reaction was refluxed under nitrogen for 10 h. The mixture was directly stirred into silica gel, and after spinning, it was separated by flash column chromatography to obtain 0.51 g of oil. 1H-NMR (CDC1 3 , 300 MHz) 51.28 (m, 6H), 1.81 (m, 2H), 2.08 (m, 1H), 2.20 (m, 1H), 2.41 (m, 2H), 2.53 (t, 2H) ), 2.79 (m, 2H), 3.93 (m, 1H), 4.18 (2x q, 4H), 7.28 (d, 2H), 7.52 (d, 2H), 7.67 (m, 5H).
A7—— 1-[1-乙氧基 -1-氧代 -4- (对三氟甲基联苯 -4-基)丁烷 -2-基】 -5,6-三亚甲基 -2-硫尿嘧 干燥的 DMF于 140°C加热 4h， TLC检测反应完毕。 冷去后将烧瓶置于冰浴中， 滴加饱 和碳酸氢钠溶液淬灭， 再加入 20ml EA和 10ml水一起搅拌 10min， 分出 EA相， 水相 再以 10ml EA萃取一次，合并有机相，干燥同时活性炭脱色，经快速柱色谱分离得 340mg 固体。 1H-NMR (CDC13, 300 MHz, ca 1.5:1 旋转异构体） 51.28 (t， 3H, J=7.2), 1.98 (m， 2H), 2.20 (m， 1H)， 2.51-2.84 (m， 6H)， 3.03 (m， 1H)， 4.25 (q， 2H, J=7.2), 7.16/4.36 (2x m， 1H)， 7.28 (d, 2H, J=8.1), 7.50 (d, 2H), 7.64 (d, 2H, J=8.7), 7.68 (d, 2H, J=8.7), 9.69/9.42 (2x s， 1H); MS (ESI): 501 (M-l). A7——1-[1-Ethoxy-1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)butan-2-yl]-5,6-trimethylene-2- Thiourea The dried DMF was heated at 140 ° C for 4 h, and the reaction was completed by TLC. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise. Then, 20 ml of EA and 10 ml of water were added and stirred for 10 min. The EA phase was separated, and the aqueous phase was extracted once with 10 ml of EA, and the organic phases were combined. The mixture was dried while decolorizing the activated carbon, and 340 mg of a solid was obtained by flash column chromatography. 1H-NMR (CDC1 3 , 300 MHz, ca 1.5:1 rotamer) 51.28 (t, 3H, J=7.2), 1.98 (m, 2H), 2.20 (m, 1H), 2.51-2.84 (m, 6H), 3.03 (m, 1H), 4.25 (q, 2H, J=7.2), 7.16/4.36 (2x m, 1H), 7.28 (d, 2H, J=8.1), 7.50 (d, 2H), 7.64 (d, 2H, J=8.7), 7.68 (d, 2H, J=8.7), 9.69/9.42 (2x s, 1H); MS (ESI): 501 (Ml).
A9—— 4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7二氢 -4H-环戊 [ί ]嘧啶 -1(5H)-基】丁酸  A9—— 4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta [ί ] Pyrimidine-1(5H)-yl]butyric acid
A7 320mg(l 当量)， 对氟苄溴 85μ1(1.05 当量)和无水碳酸钾 176mg(2当量)于 5ml 丙酮中回流 0.5h反应完毕。过滤除去无机物， 滤液经快速柱色谱分离得 240mg胶状物， 为中间体 A8— 4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酸乙酯。  A7 320 mg (l equivalent), fluorobenzyl bromide 85 μl (1.05 eq.) and anhydrous potassium carbonate 176 mg (2 eq.) were refluxed in 5 ml of acetone for 0.5 h. The inorganic substance was removed by filtration, and the filtrate was separated by flash column chromatography to give 240 mg of the crude compound as intermediate A8-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio) 4-Oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]butyrate ethyl ester.
将上述胶状物溶于 3ml乙醇中， 冰浴， 滴加 0.5ml 10%的 NaOH水溶液， 再室温反 应 2h完毕。 向烧瓶中加入 20ml冰水， 以 6N盐酸调节 pH值约为 5， 析出白色沉淀。 加入 5ml EA—起搅拌 10min，过滤收集沉淀，水洗， EA洗，干燥后得 186mg。 1H-NMR (de-DMSO, 300 MHz, ca 1.2:1 旋转异构体） 51.88 (m， 2H), 2.20-3.00 (m， 8H)， 4.39/4.45 (2x s， 2H), 5.19/4.97 (2x t， 1H)， 7.10 (m， 2H), 7.20 (m， 2H), 7.46 (dd， 2H, J=8.1, 5.4)， 7.54/7.60 (2x d， 2H, J=7.8), 7.81 (m， 4H)， 13.54 (vbrs, 1H).  The above gum was dissolved in 3 ml of ethanol, and ice-bath, 0.5 ml of 10% aqueous NaOH solution was added dropwise, and the reaction was completed at room temperature for 2 hours. 20 ml of ice water was added to the flask, and the pH was adjusted to about 5 with 6N hydrochloric acid to precipitate a white precipitate. Add 5 ml of EA - stir for 10 min, collect the precipitate by filtration, wash with water, wash with EA, and dry to give 186 mg. 1H-NMR (de-DMSO, 300 MHz, ca 1.2:1 rotamer) 51.88 (m, 2H), 2.20-3.00 (m, 8H), 4.39/4.45 (2x s, 2H), 5.19/4.97 ( 2x t, 1H), 7.10 (m, 2H), 7.20 (m, 2H), 7.46 (dd, 2H, J=8.1, 5.4), 7.54/7.60 (2x d, 2H, J=7.8), 7.81 (m , 4H), 13.54 (vbrs, 1H).
例 i一 甲基 -TV-二乙氨基乙基 _2_[(2_对氟节硫基) _4_氧代 _6，7_二氢 _4 /_环戊 M嘧啶 -1(5H)-基】 -4- (对三氟 -4-基)丁酰胺 Example i-Methyl-TV-diethylaminoethyl _ 2 _[ (2 _ fluorofluoro) _ 4 _ oxo_6, 7 _ dihydro _ 4 / _ cyclopenta M pyrimidine-1 (5H )-based -4-(p-trifluoro-4-yl)butanamide
Figure imgf000021_0001
Figure imgf000021_0001
20mg A9(l当量)于 2ml CH2C12中，加入 8.5mg EDCI(1.3当量)， 6mg HOBt(1.3当量) 和 6μ1(1.1 当量) N，N-二乙基 -W-甲基乙二胺， 室温反应 lh 完毕。 制备 TLC , 以 CH2Cl2/MeOH =15:1展开， 刮取目标产物色带， 以 CH2Cl2/MeOH =15:1的溶液浸提得 15mg固体。 1H-NMR (CDC13， 300 MHz, ca 5:1 旋转异构体） δΐ.83/0.91 (2x t， 6H， J=6.9), 〜2.00 (m， 3H), 2.40 (m， 1H), 2.60-2.95 (m， 12H), 2.83/3.01 (2x s， 3H), 3.00/3.20 (2x m， 1H)， 3.56/3.73 (2x m， 1H), 4.50 (s, 2H), 5.16 (m， 1H), 6.92 (t, 2H, J=8.4)， 7.22 (d, 2H, J=7.8), 7.31 (m， 2H), 7.46 (d， 2H, J=7.8), 7.64 (m， 4H). 20 mg of A9 (1 equivalent) in 2 ml of CH 2 C1 2 , 8.5 mg of EDCI (1.3 equivalents), 6 mg of HOBt (1.3 equivalents) and 6 μl (1.1 equivalents) of N,N-diethyl-W-methylethylenediamine , room temperature reaction lh is completed. TLC prepared to CH 2 Cl 2 / MeOH = 15 : 1 to expand, the desired product is scraped off ribbon to CH 2 Cl 2 / MeOH = 15 : 1 solution leached solid 15mg. 1H-NMR (CDC1 3 , 300 MHz, ca 5:1 rotamer) δ ΐ.83/0.91 (2x t, 6H, J=6.9), 〜2.00 (m, 3H), 2.40 (m, 1H), 2.60-2.95 (m, 12H), 2.83/3.01 (2x s, 3H), 3.00/3.20 (2x m, 1H), 3.56/3.73 (2x m, 1H), 4.50 (s, 2H), 5.16 (m, 1H), 6.92 (t, 2H, J=8.4), 7.22 (d, 2H, J=7.8), 7.31 (m, 2H), 7.46 (d, 2H, J=7.8), 7.64 (m, 4H).
例 2一 甲基 -TV-二甲氨基乙基 _2_[(2_对氟苄硫基) _4_氧代 _6，7_二氢 _4 /_环戊 M嘧啶 -1(5H)-基】 -4- (对三氟 -4-基)丁酰胺 Example 2 monomethyl-TV-dimethylaminoethyl _ 2 _[ (2 _ p-fluorobenzylthio) _ 4 _ oxo_6, 7 _ dihydro _ 4 / _ cyclopentamethylpyrimidine -1(5H)-yl]-4-(p-trifluoro-4-yl)butanamide
Figure imgf000022_0001
Figure imgf000022_0001
按照例 1的方法制备，除了以 N，W-三甲基乙二胺代替 N，N-二乙基 甲基乙二胺。 1H-NMR (CDC13, 400 MHz, ca 3.5: 1 旋转异构体） 51.97 (m， 4H)， 2.37/2.08 (2x s， 6H)， 2.55-2.68 (m， 6H)， 2.75/2.98 (2x s， 3H), 2.87 (m， 2H), 2.89/3.18 (2x m， 1H),3.61 (m， 1H)， 4.43 (m, 2H), 5.10 (m, 1H), 6.90 (t, 2H, J=8.4), 7.22 (d, 2H, J=8.0)， 7.30 (m, 2H), 7.45 (d, 2H: J=8.0)， 7.60 (d, 2H, J=8.4), 7.67(d, 2H, J=8.0). Prepared according to the procedure of Example 1 except that N,N-diethylmethyldiamine was replaced by N,W-trimethylethylenediamine. 1H-NMR (CDC1 3 , 400 MHz, ca 3.5: 1 rotamer) 51.97 (m, 4H), 2.37/2.08 (2x s, 6H), 2.55-2.68 (m, 6H), 2.75/2.98 (2x s, 3H), 2.87 (m, 2H), 2.89/3.18 (2x m, 1H), 3.61 (m, 1H), 4.43 (m, 2H), 5.10 (m, 1H), 6.90 (t, 2H, J =8.4), 7.22 (d, 2H, J=8.0), 7.30 (m, 2H), 7.45 (d, 2H : J=8.0), 7.60 (d, 2H, J=8.4), 7.67(d, 2H, J=8.0).
例 3—— ^V-甲基 - V-(1-甲基哌啶 -4-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧 代 -6,7-二氢 -4H-环戊 -1(5H)-基】丁酰胺 Example 3 - ^V-methyl-V-(1-methylpiperidin-4-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzyl) Thio)-4-oxo-6,7-dihydro-4H-cyclopenta-1(5H)-yl]butanamide
Figure imgf000022_0002
Figure imgf000022_0002
按照例 1的方法制备， 除了以 (N-甲基哌啶 -4-基)甲胺盐酸盐代替 N，N-二乙基 甲 基乙二胺， 并加入 1.2当量的三乙胺。 1H-NMR (CDC13， 300 MHz, ca 1.1 : 1 旋转异构体) 51.47 (m， 2H), 1.65-2.00 (m， 8H)， 2.47/2.21 (2x s， 3H), 2.63/2.86 (2x s， 3H), 2.38 (m， 1H)， 2.68 (m， 5H)， 2.88/3.11 (2x m， 2H), 3.67/3.32 (2x m， 1H), 4.44 (m， 2H), 4.99/4.55 (2x t， 1H)， 6.92 (m， 2H), 7.20 (d, 2H, J=8.1), 7.26/7.34 (2x m， 2H), 7.46 (d, 2H, J=8.4), 7.60 (d, 2H, J=8.1), 7.68(d, 2H, J=8.4). Prepared according to the procedure of Example 1 except that (N-methylpiperidin-4-yl)methylamine hydrochloride was substituted for N,N-diethylmethyldiamine, and 1.2 equivalents of triethylamine was added. 1H-NMR (CDC1 3 , 300 MHz, ca 1.1 : 1 rotamer) 51.47 (m, 2H), 1.65-2.00 (m, 8H), 2.47/2.21 (2x s, 3H), 2.63/2.86 (2x s, 3H), 2.38 (m, 1H), 2.68 (m, 5H), 2.88/3.11 (2x m, 2H), 3.67/3.32 (2x m, 1H), 4.44 (m, 2H), 4.99/4.55 ( 2x t, 1H), 6.92 (m, 2H), 7.20 (d, 2H, J=8.1), 7.26/7.34 (2x m, 2H), 7.46 (d, 2H, J=8.4), 7.60 (d, 2H , J=8.1), 7.68(d, 2H, J=8.4).
例 4—— 1-[1-氧代 -4- (对三氟甲基联苯 -4-基) -1-( V-甲基哌嗪 -1基)丁烷 -2-基】 -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ -4(5H)-酮 Example 4 - 1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)-1-(V-methylpiperazin-1yl)butan-2-yl]-2 -p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[-4(5H)-one
Figure imgf000022_0003
按照例 1的方法制备，除了以 N-甲基哌嗪代替 N，N-二乙基 -W-甲基乙二胺。 1H-NMR (CDC13, 300 MHz) δΐ.80-2.10 (m， 4H)， 2.22 (m， 2H), 2.25 (s， 3H), 2.50 (m， 1H), 2.69 (m， 5H)， 2.89 (m， 2H), 3.15 (m， 2H), 3.60 (m， 1H)， 3.75 (m， 1H)， 4.43 (2x d， 2H, J=13.2), 5.00 (t， 1H), 6.93 (t， 2H, J=8.4), 7.22 (d, 2H, J=8.1), 7.31 (dd, 2H, J=8.4, 5.7), 7.47 (d, 2H, J=8.1), 7.60 (d， 2H, J=8.1), 7.68 (d， 2H, J=8.1).
Figure imgf000022_0003
Prepared according to the procedure of Example 1 except that N,N-diethyl-W-methylethylenediamine was replaced by N-methylpiperazine. 1H-NMR (CDC1 3 , 300 MHz) δΐ.80-2.10 (m, 4H), 2.22 (m, 2H), 2.25 (s, 3H), 2.50 (m, 1H), 2.69 (m, 5H), 2.89 (m, 2H), 3.15 (m, 2H), 3.60 (m, 1H), 3.75 (m, 1H), 4.43 (2x d, 2H, J=13.2), 5.00 (t, 1H), 6.93 (t, 2H, J=8.4), 7.22 (d, 2H, J=8.1), 7.31 (dd, 2H, J=8.4, 5.7), 7.47 (d, 2H, J=8.1), 7.60 (d, 2H, J= 8.1), 7.68 (d, 2H, J=8.1).
例 5一 1-[1-氧代 -4- (对三氟甲基联苯 -4-基) -l-(4-二甲氨基哌啶 -1-基)丁烷 -2-基】 -2-对氟 苄硫基 -6,7-二氢 -1H- -4(5H)-酮 Example 5 - 1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)-l-(4-dimethylaminopiperidin-1-yl)butan-2-yl] 2-p-fluorobenzylthio-6,7-dihydro-1H- -4(5H)-one
Figure imgf000023_0001
Figure imgf000023_0001
按照例 1 的方法制备， 除了以 4-二甲氨基哌啶代替 N，N-二乙基 甲基乙二胺。 1H-NMR (CDC13, 400 MHz) δΙ.45/1.65 (m， 2H), 1.80-2.10 (m， 5H)， 2.18 (s， 3H), 2.29 (s， 3H), 2.30 (m， 1H), 2.68 (m， 6H)， 2.87 (m， 3H), 3.44 (t， 1H), 4.35/4.51 (2x d， 2H, J=13.2), 4.54 (t, 1H), 5.05 (m， 1H), 6.92 (t, 2H, J=8.4)， 7.22 (d, 2H, J=8.0)， 7.33 (m， 2H), 7.47 (d, 2H, J=8.0), 7.60 (d, 2H, J=8.0), 7.68 (d, 2H, J=8.4). Prepared as in Example 1, except that 4-dimethylaminopiperidine was substituted for N,N-diethylmethylethylenediamine. 1H-NMR (CDC1 3 , 400 MHz) δΙ.45/1.65 (m, 2H), 1.80-2.10 (m, 5H), 2.18 (s, 3H), 2.29 (s, 3H), 2.30 (m, 1H) , 2.68 (m, 6H), 2.87 (m, 3H), 3.44 (t, 1H), 4.35/4.51 (2x d, 2H, J=13.2), 4.54 (t, 1H), 5.05 (m, 1H), 6.92 (t, 2H, J=8.4), 7.22 (d, 2H, J=8.0), 7.33 (m, 2H), 7.47 (d, 2H, J=8.0), 7.60 (d, 2H, J=8.0) , 7.68 (d, 2H, J=8.4).
例 6—— 甲基 - V-[(1H-咪唑 -2-基)甲基】 -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4- 氧代 -6,7-二氢 -4H-环戊 -1(5H)-基】丁酰胺 Example 6 - Methyl-V-[(1H-imidazol-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio) -4-oxo-6,7-dihydro-4H-cyclopenta-1(5H)-yl]butanamide
Figure imgf000023_0002
Figure imgf000023_0002
按照例 1的方法制备， 除了以 (1H-咪唑 -2-基)甲胺代替 N，N-二乙基 甲基乙二胺。 1H-NMR (CDC13, 400 MHz) 51.94 (m， 2H), 2.14 (m， 1H), 2.66 (m， 5H)， 2.82 (m， 2H), 2.92(s: 3H), 4.40 (s， 2H), 4.58/4.76 (2x d， 2H), 5.10 (t， 1H), 6.89 (t， 2H, J=8.4)， 7.00 (s， 2H), 7.15 (d， 2H, J=8.0), 7.26 (m， 2H), 7.44 (d， 2H, J=8.0), 7.59 (d， 2H, J=8.4), 7.67(d, 2H, J=8.0).
Figure imgf000024_0001
Prepared according to the procedure of Example 1 except that (1H-imidazol-2-yl)methylamine was substituted for N,N-diethylmethyldiamine. 1H-NMR (CDC1 3 , 400 MHz) 51.94 (m, 2H), 2.14 (m, 1H), 2.66 (m, 5H), 2.82 (m, 2H), 2.92 (s : 3H), 4.40 (s, 2H) ), 4.58/4.76 (2x d, 2H), 5.10 (t, 1H), 6.89 (t, 2H, J=8.4), 7.00 (s, 2H), 7.15 (d, 2H, J=8.0), 7.26 ( m, 2H), 7.44 (d, 2H, J=8.0), 7.59 (d, 2H, J=8.4), 7.67 (d, 2H, J=8.0).
Figure imgf000024_0001
All—— (对三氟甲基联苯 -4-基)甲基溴 All——(p-trifluoromethylbiphenyl-4-yl)methyl bromide
2.0g原料 A1于 15ml无水乙醇中， 冰浴中加入 150mg硼氢化钠， 再室温反应 lh 完毕。减压蒸出乙醇， 向剩余物中加入 10ml冰水和 10ml CH2Cl2， 边搅拌边逐滴加入浓 盐酸， 直至不再有大量气泡生成， 再以 10ml碳酸氢钠饱和液淬灭。 分出有机相， 水相 再以 CH2C12提取一次，合并有机相以硫酸镁干燥，蒸出溶剂后得白色固体，为 A10— 对三氟甲基联苯 -4-基)甲醇。 2.0 g of the starting material A1 was placed in 15 ml of absolute ethanol, 150 mg of sodium borohydride was added to the ice bath, and the reaction was completed at room temperature for 1 hour. Ethanol was distilled off under reduced pressure, and 10 ml of ice water and 10 ml of CH 2 Cl 2 were added to the residue, and concentrated hydrochloric acid was added dropwise with stirring until a large amount of bubbles were not formed, and then quenched with 10 ml of sodium hydrogencarbonate saturated solution. The organic phase was separated and the aqueous phase was extracted with CH 2 C1 2 .
将 A10悬于 15ml无水***中， 置于冰浴， 分批加入 370μ1三溴化磷， 再室温反应 2h完毕。 将烧瓶置于冰浴中， 滴加碳酸氢钠饱和液淬灭， 分出有机相， 水相再以*** 萃取一次， 合并有机相硫酸镁干燥， 蒸出溶剂后得白色固体 2.4g， 为 All。  A10 was suspended in 15 ml of anhydrous diethyl ether, placed in an ice bath, and 370 μl of phosphorus tribromide was added in portions, and then reacted at room temperature for 2 hours. The flask was placed in an ice bath, and the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The organic phase was combined and dried over magnesium sulfate. .
A12—— 3- (对三氟甲基联苯 - -基) -2-氨基丙酸乙酯盐酸盐 A12—— 3-(p-trifluoromethylbiphenyl--yl)-2-aminopropionic acid ethyl ester hydrochloride
Figure imgf000024_0002
Figure imgf000024_0002
方法同于下述的从 B0 制备 B4， 除了以 Al l 代替 2-二乙氨基乙基氯。 1H-NMR (de-DMSO, 400 MHz) 51.12 (t， 3H, J=7.2), 3.14 (dd， 1H， J=14.0, 8.4)， 3.25 (dd， 1H， J=14.0, 5.6), 4.14 (q, 2H), 4.31 (t, 1H, J=6.8), 7.40 (d, 2H, J=8.4), 7.73 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.90 (d, 2H, J=8.4), 8.65 (s, 3H).  The procedure was the same as the preparation of B4 from B0 below, except that Al l was substituted for 2-diethylaminoethyl chloride. 1H-NMR (de-DMSO, 400 MHz) 51.12 (t, 3H, J=7.2), 3.14 (dd, 1H, J=14.0, 8.4), 3.25 (dd, 1H, J=14.0, 5.6), 4.14 ( q, 2H), 4.31 (t, 1H, J=6.8), 7.40 (d, 2H, J=8.4), 7.73 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.90 (d, 2H, J=8.4), 8.65 (s, 3H).
A13—— 2-[3- (对三氟甲基联苯 -4- -1-乙氧基 -1-氧丙烷 -2-基】氨基 -1-环戊烯羧酸乙酯  A13——2-[3-(p-Trifluoromethylbiphenyl-4--1-ethoxy-1-oxopropan-2-yl]amino-1-cyclopentenecarboxylate
Figure imgf000024_0003
Figure imgf000024_0003
0.83g (1当量) Α12， 325μ1(1当量)环戊酮 -2-羧酸乙酯， 960μ1(2当量)硅酸四乙酯， 450μ1(1.5当量)三乙胺于 10ml无水乙醇中回流 24h，减压蒸出乙醇，剩余物溶于 CH2C12 中，食盐水洗涤三次，干燥，经快速柱色谱分离得 0.68g 油。 1H-NMR (CDC13， 300 MHz) 51.24 (m， 6H)， 1.70 (m， 2H), 1.25/2.34 (2x m， 2H), 2.46 (t, 2H), 3.03/3.16 (2x dd， 2H), 3.87 (m， 1H)， 4.18 (m， 4H)， 7.30 (d， 2H), 7.53 (d， 2H), 7.67 (m， 5H) 0.83 g (1 equivalent) Α12, 325 μl (1 equivalent) of ethyl cyclopentanone-2-carboxylate, 960 μl (2 equivalents) of tetraethyl silicate, 450 μl (1.5 equivalents) of triethylamine refluxed in 10 ml of absolute ethanol After 24 h, ethanol was evaporated under reduced pressure. the residue was dissolved in CH 2 C1 2 and washed three times with brine, dried, and then evaporated. 1H-NMR (CDC1 3 , 300 MHz) 51.24 (m, 6H), 1.70 (m, 2H), 1.25/2.34 (2x m, 2H), 2.46 (t, 2H), 3.03/3.16 (2x dd, 2H), 3.87 (m, 1H), 4.18 ( m, 4H), 7.30 (d, 2H), 7.53 (d, 2H), 7.67 (m, 5H)
A14—— 3- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 M嘧啶 -1(5H)-基】丙酸  A14—— 3-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentamethylpyrimidine -1(5H)-yl]propionic acid
Figure imgf000025_0001
Figure imgf000025_0001
方法同于从 A6制备 A9，除了以 A13代替 A6。1H-NMR (d6-DMSO, 300 MHz, ca 1.2:1 旋转异构体） δΐ.41-2.38 (m， 4H)， 2.49-3.57 (m， 4H)， 4.50/4.15 (2x d， 1H， J=13.8, -SCH-), 4.58/4.22 (2x d， 1H, J=14.5, -SCH-), 5.29/5.54 (2x dd， 1H, J=14.5, 4.8)， 6.85-7.88 (m， 12H); MS (ESI): 567 (M-l). The procedure was identical to the preparation of A9 from A6 except that A13 was substituted for A6. 1H-NMR (d 6 -DMSO, 300 MHz, ca 1.2:1 rotamer) δ ΐ.41-2.38 (m, 4H), 2.49-3.57 ( m, 4H), 4.50/4.15 (2x d, 1H, J=13.8, -SCH-), 4.58/4.22 (2x d, 1H, J=14.5, -SCH-), 5.29/5.54 (2x dd, 1H, J=14.5, 4.8), 6.85-7.88 (m, 12H); MS (ESI): 567 (Ml).
例 7—— 1-[3- (对三氟甲基联苯 -4-基) -l-(4-二甲氨基哌啶 -1-基) -1-氧代丙烧 -2-基】 -2-对氟 苄硫基 -6,7-二氢 -1H-环戊 [ -4(5H)-酮 Example 7—— 1-[3-(p-trifluoromethylbiphenyl-4-yl)-l-(4-dimethylaminopiperidin-1-yl)-1-oxopropan-2-yl] -2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[-4(5H)-one
Figure imgf000025_0002
Figure imgf000025_0002
除了以 A14和 4-二甲氨基哌啶为原料，按照例 1的方法制备。 1H-NMR (CDC13, 400 MHz) δΙ.45/1.60 (m， 2H), 2.00 (m， 4H)， 2.23/2.34 (2x s， 6H)， 2.39 (m， 1H), 2.76 (m， 5H)， 3.06 (m， 2H), 3.43 (m， 1H), 3.65 (m， 1H), 4.26 (m， 1H), 4.53 (m， 2H), 5.27 (m， 1H), 6.93 (m， 2H), 7.29 (m， 4H)， 7.51 (d， 2H, J=8.0), 7.65 (d， 2H, J=8.40), 7.69 (d， 2H, J=8.4). 下列化合物亦按照例 1的方法制备 Prepared according to the procedure of Example 1 except that A14 and 4-dimethylaminopiperidine were used as starting materials. 1H-NMR (CDC1 3 , 400 MHz) δΙ.45/1.60 (m, 2H), 2.00 (m, 4H), 2.23/2.34 (2x s, 6H), 2.39 (m, 1H), 2.76 (m, 5H) ), 3.06 (m, 2H), 3.43 (m, 1H), 3.65 (m, 1H), 4.26 (m, 1H), 4.53 (m, 2H), 5.27 (m, 1H), 6.93 (m, 2H) , 7.29 (m, 4H), 7.51 (d, 2H, J = 8.0), 7.65 (d, 2H, J = 8.40), 7.69 (d, 2H, J = 8.4). The following compounds were also prepared according to the method of Example 1.
Figure imgf000026_0001
例 12—— (哌啶 -1-基) -4- (对三
Figure imgf000026_0001
Example 12 - (piperidin-1-yl)-4- (for three
氟甲基联苯 -4-基) -2-[(2-对氟苄硫 A9， 1-氨 基) -4-氧代 -6,7-二氢 -4H-环戊 [ί J 基哌啶 嘧啶 -1(5H)-基】丁酰胺 Fluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylsulfide A9, 1-amino)-4-oxo-6,7-dihydro-4H-cyclopenta[ί J-piperidine Pyrimidine-1(5H)-yl]butanamide
例 13—— N-甲基 - V-(2-羟乙 Example 13 - N-methyl - V- (2-hydroxyethyl)
基）-4-(对三氟甲基联苯 -4-Base)-4-(p-trifluoromethylbiphenyl-4-
A9， N-甲 基) -2-[(2-对氟苄硫基) -4-氧代 A9, N-methyl)-2-[(2-p-fluorobenzylthio)-4-oxo
基乙醇胺 -6,7-二氢 -4H-环戊 [ί J嘧啶 -1(5H)- 基】丁酰胺  Ethanolamine-6,7-dihydro -4H-cyclopenta [ί J pyrimidine -1(5H)-yl]butanamide
例 I4—— ^V-甲基 -TV- [(吡啶 _2-基) Example I 4 - ^V-methyl-TV- [(pyridine- 2 -yl)
甲基】 -4- (对三氟甲基联苯 -4-Methyl]-4-(p-trifluoromethylbiphenyl-4-
A9， （吡啶 基) -2-[(2-对氟苄硫基) -4-氧代 A9, (pyridyl)-2-[(2-p-fluorobenzylthio)-4-oxo
-2-基)甲胺 -6,7-二氢 -4H-环戊 [ί J嘧啶 -1(5H)- 基】丁酰胺  -2-yl)methylamine-6,7-dihydro -4H-cyclopenta [ί J pyrimidine -1(5H)-yl]butanamide
例 IS—— ^V-甲基 -TV- [(吡啶 -3-基) Example IS - ^V-methyl-TV- [(pyridin-3-yl)
甲基】 -4- (对三氟甲基联苯 -4-Methyl]-4-(p-trifluoromethylbiphenyl-4-
A9， （吡啶 基) -2-[(2-对氟苄硫基) -4-氧代 A9, (pyridyl)-2-[(2-p-fluorobenzylthio)-4-oxo
-3-基)甲胺 -6,7-二氢 -4H-环戊 [ί J嘧啶 -1(5H)- 基】丁酰胺 -3-yl)methylamine-6,7-dihydro -4H-cyclopenta [ί J pyrimidine -1(5H)-yl]butanamide
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000027_0001
Figure imgf000028_0001
NHAc NHAc
Et02C C02EtEt0 2 C C0 2 Et
Figure imgf000029_0001
Figure imgf000029_0001
BO B1 B2  BO B1 B2
Figure imgf000029_0002
Figure imgf000029_0002
Bl—— 2-二乙氨基乙基 -2-乙酰氨基丙二酸二乙酯  Bl——2-Diethylaminoethyl-2-acetylaminomalonate diethyl ester
2-二乙氨基乙基氯盐酸盐 7g溶于 50ml水中， 以碳酸钠溶液调节 pH值大于 10， CH2C12萃取 5次， 合并有机相， 无水硫酸镁干燥过夜， 蒸干溶剂得淡黄色油 4.5g。 7 g of 2-diethylaminoethyl chloride hydrochloride was dissolved in 50 ml of water, adjusted to pH value greater than 10 with sodium carbonate solution, extracted 5 times with CH 2 C1 2 , combined with organic phase, dried over anhydrous magnesium sulfate overnight, evaporated to dryness Light yellow oil 4.5g.
760mg(l.l当量)金属钠全部溶解于 30ml无水乙醇中，再加入 6.51g(l当量) B0—— 2- 乙酰氨基丙二酸二乙酯， 60mg碘化钾和 0.1ml干燥的 DMF, 于 50°C加热 20min得白 色悬浊液。 然后加入上面制备的 2-二乙氨基乙基氯 4.5g(l.l当量)继续反应 20h， 停止。 冷却后过滤除去不溶物，滤液硅胶柱层析， CH2Cl2/MeOH =20:1洗脱得 3.0g油。 1H-NMR (CDC13, 300 MHz) 50.99 (t， 6H)， 1.26 (t， 6H)， 2.02 (s, 3H), 2.43 (m， 4H)， 2.49 (q， 4H)， 7.58 (s， 1H)。 760 mg (ll equivalent) of sodium metal was dissolved in 30 ml of absolute ethanol, and then added 6.51 g (l equivalent) of B0-diacetylaminomalonate diethyl ester, 60 mg of potassium iodide and 0.1 ml of dry DMF at 50°. C was heated for 20 min to give a white suspension. Then, 4.5 g (ll equivalent) of 2-diethylaminoethyl chloride prepared above was added to continue the reaction for 20 hours, and the reaction was stopped. After cooling, the insoluble material was removed by filtration, and the filtrate was subjected to silica gel column chromatography, eluting with CH 2 Cl 2 /MeOH = 20:1 to give 3.0 g of oil. 1H-NMR (CDC1 3 , 300 MHz) 50.99 (t, 6H), 1.26 (t, 6H), 2.02 (s, 3H), 2.43 (m, 4H), 2.49 (q, 4H), 7.58 (s, 1H) ).
B2—— 4-二乙氨基 -2-乙酰氨基丁酸乙酯  B2——ethyl 4-diethylamino-2-acetylaminobutyrate
Bl 3.0g(l当量)溶于 20ml乙醇中，冰浴中滴加 380mg(l当量)氢氧化钠的 5ml水溶 液， 再于室温反应 16h。 减压蒸出大部分乙醇， 向剩余物中加入 15ml水， 以盐酸调节 pH =4-5, 再减压蒸干水分得淡黄色固体。 继续向烧瓶中加入 20ml甲苯， 回流 2h并分 出残留的水分。 蒸出甲苯， 以 CH2C12浸提， 过滤除去无机盐， 滤液蒸干得 2.0g 油。 1H-NMR (CDC13, 300 MHz) δΙ.03/1.26 (2x t， 9Η)， 1.87/2.01 (2χ m， 2Η), 1.98 (s, 3Η), 2.43/2.57 (2χ m， 6Η)， 4.18 (q， 2Η, J=6.9)， 4.54 (m， 1H), 8.20 (d， 1H). Bl 3.0 g (1 equivalent) was dissolved in 20 ml of ethanol, and 380 mg (1 equivalent) of a 5 ml aqueous solution of sodium hydroxide was added dropwise in an ice bath, and then reacted at room temperature for 16 h. Most of the ethanol was distilled off under reduced pressure, and 15 ml of water was added to the residue, and pH was adjusted to 4-5 with hydrochloric acid. Further, 20 ml of toluene was added to the flask, refluxed for 2 hours, and residual water was separated. The toluene was distilled off, extracted with CH 2 C 2 2 , and the inorganic salt was removed by filtration, and the filtrate was evaporated to dryness to give 2.0 g of oil. 1H-NMR (CDC1 3 , 300 MHz) δΙ.03/1.26 (2x t, 9Η), 1.87/2.01 (2χ m, 2Η), 1.98 (s, 3Η), 2.43/2.57 (2χ m, 6Η), 4.18 (q, 2Η, J=6.9), 4.54 (m, 1H), 8.20 (d, 1H).
B5—— 2-[4-二乙氨基 -1-乙氧基 -1-氧丁烷 -2-基】氨基 -1-环戊烯羧酸甲酯 B5——2-[4-Diethylamino-1-ethoxy-1-pyrene-2-yl]amino-1-cyclopentenecarboxylate
B2 2.0g置于 15ml 6N盐酸中， 回流 5h停止。 减压蒸干水分， 再以甲苯带水两次， 得固体剩余物， 为 B3— 4-二乙氨基 -2-氨基丁酸盐酸盐。  B2 2.0g was placed in 15 ml of 6N hydrochloric acid and refluxed for 5 h. The water was evaporated to dryness under reduced pressure, and then water was taken twice with toluene to give a solid residue as B3-4-diethylamino-2-aminobutyric acid salt.
将此固体溶于 20ml无水乙醇中， 置于冰浴， 滴加 0.89ml氯化亚砜， 再回流 3h停 止。 减压蒸出溶剂， 再以甲苯带两次除去残留的氯化亚砜， 得胶状固体， 为 B4— 4- 二乙氨基 -2-氨基丁酸乙酯盐酸盐。 This solid was dissolved in 20 ml of absolute ethanol, placed in an ice bath, and 0.89 ml of thionyl chloride was added dropwise, followed by reflux for 3 h. The solvent is distilled off under reduced pressure, and the residual thionyl chloride is removed twice with toluene to obtain a colloidal solid, which is B4-4- Diethylamino-2-aminobutyric acid ethyl ester hydrochloride.
将此固体溶于 20ml无水乙醇， 加入 1.2ml环戊酮 -2-酸酸甲酯， 4ml硅酸四乙酯和 2.7ml三乙胺， 回流 4h反应完毕。 蒸出乙醇， 剩余物溶于 30ml EA， 食盐水洗涤两次， 干燥后经快速柱色谱分离， 得 1.3g油。 'H-NMR (CDC13, 300 MHz) 51.00 (t， 6H， J=7.2), 1.26 (t， 3H, J=7.2), 1.81 (m， 3H), 2.00 (m， 1H), 2.52 (m， 10H), 3.68 (s， 3H), 4.10 (m， 1H)， 4.18 (q, 2H, J=7.2), 7.58 (d, 1H， -NH-). This solid was dissolved in 20 ml of absolute ethanol, and 1.2 ml of methyl cyclopentanone-2-acid acid, 4 ml of tetraethyl silicate and 2.7 ml of triethylamine were added, and the reaction was completed under reflux for 4 hours. Ethanol was distilled off, and the residue was dissolved in 30 ml of EA, washed twice with brine, dried and then purified by flash column chromatography. 'H-NMR (CDC1 3 , 300 MHz) 51.00 (t, 6H, J=7.2), 1.26 (t, 3H, J=7.2), 1.81 (m, 3H), 2.00 (m, 1H), 2.52 (m , 10H), 3.68 (s, 3H), 4.10 (m, 1H), 4.18 (q, 2H, J=7.2), 7.58 (d, 1H, -NH-).
B6—— 1-[4-二乙氨基 -1-乙氧基 -1-氧丁烷 -2-基】 -5,6-三亚甲基 -2-硫尿嘧啶  B6——1-[4-Diethylamino-1-ethoxy-1-pyrene-2-yl]-5,6-trimethylene-2-thiouracil
制备方法同于 A7， 只不过反应完成后以碳酸钠饱和液代替碳酸氢钠饱和液淬灭。 以 2.5g B5为原料得到 550mg目标产物。 1H-NMR (CDC13， 300 MHz) 50.97 (m， 6H)， 1.27 (t， 3H, J=6.9), 2.10 (m， 2H), 2.37 (m， 1H), 2.51 (m， 5H)， 2.68 (q, 2H), 2.80 (t， 2H), 2.89 (m， 1H), 3.35 (m， 1H)， 4.22 (q, 2H, J=7.2), 4.77 (t， 2H, J=6.3), 7.01 (s, 1H). The preparation method was the same as that of A7, except that the reaction was completed, and the sodium carbonate saturated solution was used instead of the sodium hydrogencarbonate saturated solution to quench. 550 mg of the target product was obtained from 2.5 g of B5. 1H-NMR (CDC1 3 , 300 MHz) 50.97 (m, 6H), 1.27 (t, 3H, J=6.9), 2.10 (m, 2H), 2.37 (m, 1H), 2.51 (m, 5H), 2.68 (q, 2H), 2.80 (t, 2H), 2.89 (m, 1H), 3.35 (m, 1H), 4.22 (q, 2H, J=7.2), 4.77 (t, 2H, J=6.3), 7.01 (s, 1H).
B7—— 4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 嘧啶 -1(5H)-基】丁酸 乙酯 B7——4-Diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentadienyl-1(5H)-yl]butyrate B Ester
制备方法同于 A8， 以 l.Og B6为原料得到 660mg目标产物。 'H-NMR (CDC13, 300 MHz) δΟ.92/1.13 (2x t, 9Η)， 2.07 (m， 2Η), 2.25 (m， 1H), 2.46 (m， 8H)， 2.86 (m， 3H), 4.16 (m， 2H), 4.49 (q， 2H), 4.95/5.47 (2x m， 1H), 6.97 (t， 2H), 7.35 (m， 2H) The preparation method was the same as that of A8, and 660 mg of the target product was obtained from 1.0 g of B6. 'H-NMR (CDC1 3 , 300 MHz) δΟ.92/1.13 (2x t, 9Η), 2.07 (m, 2Η), 2.25 (m, 1H), 2.46 (m, 8H), 2.86 (m, 3H) , 4.16 (m, 2H), 4.49 (q, 2H), 4.95/5.47 (2x m, 1H), 6.97 (t, 2H), 7.35 (m, 2H)
B8—— 4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1(5H)-基】丁酸 B8—— 4-Diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H)-yl]butyric acid
B7 650mg溶于 5ml乙醇， 冰浴中滴加 1ml 10%的 NaOH水溶液， 再室温搅拌 lh完 毕。 以盐酸调节至中性， 减压蒸干溶剂， 在以甲苯带出残留的水分。 剩余固体以 10ml 无水乙醇浸提， 滤除无机物， 蒸干溶剂得 570mg固体。 1H-NMR Cd6-DMSO， 300 MHz) 50.95 (t， 6H， J=7.2), 1.89 (m， 3H), 2.57 (m， 9H)， 2.79 (t， 2H), 4.37 (s, 2H), 4.65 (m， 1H), 7.12 (t， 2H, J=8.7), 7.32 (m， 2H); MS (ESI) found (M-l) =432. B7 650 mg was dissolved in 5 ml of ethanol, and 1 ml of 10% aqueous NaOH solution was added dropwise to the ice bath, and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to neutral with hydrochloric acid, and the solvent was evaporated to dryness under reduced pressure to give residual water. The remaining solid was extracted with 10 ml of dry ethanol, the organics were filtered, and evaporated to dryness. 1H-NMR Cd 6 -DMSO, 300 MHz) 50.95 (t, 6H, J = 7.2), 1.89 (m, 3H), 2.57 (m, 9H), 2.79 (t, 2H), 4.37 (s, 2H), 4.65 (m, 1H), 7.12 (t, 2H, J=8.7), 7.32 (m, 2H); MS (ESI) found (Ml) =432.
例 19—— TV-甲基 -TV- (对三氟甲基联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1(5 -基】丁酰胺 Example 19 - TV-Methyl-TV-(p-trifluoromethylbiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo -6,7-dihydro-4H-cyclopenta[pyrimidin-1(5-yl)butanamide
Figure imgf000030_0001
Figure imgf000030_0001
(；对三氟甲基联苯 -4-基)甲醛 500mg(l 当量)， 甲胺醇溶液 580μ1(2 当量)以及 50mg 钯 /碳加氢催化剂于 10ml EA-EtOH(l :l)混合溶液中， 室温下加氢反应 6h完毕。 滤除不 溶物， 蒸干溶剂得 500mg淡黄色固体， 为 N-甲基 (对三氟甲基联苯 -4-基)甲胺。 (; p-trifluoromethylbiphenyl-4-yl)carboxaldehyde 500mg (l equivalent), methylamine solution 580μ1 (2 equivalents) and 50mg The palladium/carbon hydrogenation catalyst was hydrogenated in a mixed solution of 10 ml of EA-EtOH (l:l) at room temperature for 6 h. The insoluble material was filtered off, and the solvent was evaporated to dryness to give the crystals of s.
22mg B8(l 当量）， N-甲基 (对三氟甲基联苯 -4-基）甲胺 15mg(1.15 当量）， TBTU 20mg(1.2当量)和 DIPEA 14μ1(1.5当量)于 1.5ml 乙腈中回流 lh， 再加入 2ml甲苯， 升 高温度至 110°C反应 2h停止。 减压蒸出溶剂， 剩余物以 5ml CH2C12溶解， 食盐水洗涤 两次， 干燥。制备 TLC， 以 CH2Cl2/MeOH =15: l展开， 得 12mg固体。 1H-NMR (CDC13， 300 MHz, ca 2:1 旋转异构体） 51.05 (m， 6H)， 1.95 (m， 3H), 2.68 (m， 11H), 2.79/3.03 (2x s, 3H), 4.50 (m， 4H)， 5.47/5.58 (2x dd， 1H), 7.32/6.91 (2x d， 2H), 6.96 (m， 2H), 7.36 (m， 2H), 7.53/7.43 (2x d， 2H), 7.68 (m， 4H); MS (ESI) found (M+l) =681. 22 mg of B8 (1 eq.), N-methyl(p-trifluoromethylbiphenyl-4-yl)methylamine 15 mg (1.15 eq.), TBTU 20 mg (1.2 eq.) and DIPEA 14 </ RTI> (1.5 eq.) in 1.5 ml of acetonitrile After refluxing for 1 h, 2 ml of toluene was added, and the temperature was raised to 110 ° C to react for 2 h to stop. The solvent was evaporated under reduced pressure, and the residue was dissolved in 5 ml of CH 2 C1 2 and washed twice with brine. TLC was prepared, in CH 2 Cl 2 / MeOH = 15 : l to expand, to give 12mg solid. 1H-NMR (CDC1 3 , 300 MHz, ca 2:1 rotamer) 51.05 (m, 6H), 1.95 (m, 3H), 2.68 (m, 11H), 2.79/3.03 (2x s, 3H), 4.50 (m, 4H), 5.47/5.58 (2x dd, 1H), 7.32/6.91 (2x d, 2H), 6.96 (m, 2H), 7.36 (m, 2H), 7.53/7.43 (2x d, 2H) , 7.68 (m, 4H); MS (ESI) found (M+l) =681.
例 20—— N-甲基 -TV- (对氯联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ί J嘧啶 -1(5//)-基】 Example 20 - N-methyl-TV-(p-chlorobiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6, 7-Dihydro-4H-cyclopenta [ί J pyrimidine-1(5//)-yl]
Figure imgf000031_0001
Figure imgf000031_0001
方法同于例 19的制备， 除了以 N-甲基 (对氯联苯 -4-基)甲胺代替 N-甲基 (对三氟甲 基联苯 -4-基）甲胺。 1H-NMR (CDC13, 300 MHz, ca 2:1 旋转异构体） 50.99 (m， 6H)， 1.89 (m， 3H), 2.68 (m， 11H), 2.79/3.00 (2x s, 3H), 4.57 (m， 4H)， 5.44/5.56 (2x dd， 1H), 6.96 (m， 2H), 7.23-7.35 (m， 4H)， 7.39-7.50 (m， 6H)。 The procedure was identical to the preparation of Example 19 except that N-methyl(p-chlorobiphenyl-4-yl)methylamine was substituted for N-methyl(p-trifluoromethylbiphenyl-4-yl)methylamine. 1H-NMR (CDC1 3 , 300 MHz, ca 2:1 rotamer) 50.99 (m, 6H), 1.89 (m, 3H), 2.68 (m, 11H), 2.79/3.00 (2x s, 3H), 4.57 (m, 4H), 5.44/5.56 (2x dd, 1H), 6.96 (m, 2H), 7.23-7.35 (m, 4H), 7.39-7.50 (m, 6H).
例 21—— ^V-甲基 -TV- (对氯联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ί J嘧啶 -1(5H)-基】戊酰胺 Example 21 - ^V-methyl-TV-(p-chlorobiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6 ,7-dihydro-4H-cyclopenta[ί J pyrimidine-1(5H)-yl]pentanamide
Figure imgf000032_0001
Figure imgf000032_0001
方法同于从 B0制备例 20，除了以 3-二甲氨基丙基氯盐酸盐代替 2-二乙氨基乙基氯 盐酸盐为起始原料。 1H-NMR (CDCl3，300 MHz，ca 3: l 旋转异构体） δ1.50-3.00 (m， 12H), 2.36 (s, 6H)， 2.78/3.02 (2x s, 3H), 4.50 (m， 4H)， 5.24/5.32 (2x m， 1H), 6.97/ 6.90 (2x t， 2H), 7.27/7.13 (2x d， 2H), 7.35-7.50 (m， 6H)。 The procedure was the same as in Preparation 20 from B0 except that 3-dimethylaminoethyl chloride hydrochloride was used instead of 2-diethylaminoethyl chloride hydrochloride. 1H-NMR (CDCl 3 , 300 MHz, ca 3: l rotamer) δ 1.50-3.00 (m, 12H), 2.36 (s, 6H), 2.78/3.02 (2x s, 3H), 4.50 (m , 4H), 5.24/5.32 (2x m, 1H), 6.97/ 6.90 (2x t, 2H), 7.27/7.13 (2x d, 2H), 7.35-7.50 (m, 6H).
例 22—— 甲基 -TV- (对三氟甲基联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ί J嘧啶 -1( -基】戊酰胺 Example 22 - Methyl-TV-(p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6 ,7-dihydro-4H-cyclopenta[ί J pyrimidine-1(-yl)pentanamide
Figure imgf000032_0002
Figure imgf000032_0002
方法同于从 B0制备例 19，除了以 3-二甲氨基丙基氯盐酸盐代替 2-二乙氨基乙基氯 盐酸盐为起始原料。 1H-NMR (CDCl3，300 MHz，ca 3: l 旋转异构体） δ1.50-3.00 (m， 12H), 2.27/2.40 (2x s, 6H)， 2.80/3.04 (2x s, 3H), 4.50 (m， 4H)， 5.30 (m， 1H), 6.97/6.93 (2x t， 2H), 7.29/7.11 (2x d， 2H), 7.36 (m， 2H), 7.53/7.45 (2x d， 2H), 7.68 (m， 4H); MS (ESI) found (M+l) =667. 下列化合物亦按照例 19的方法制备 实施例名称 原料 The procedure was the same as in Preparation Example 19 from B0 except that 3-dimethylaminoethyl chloride hydrochloride was used instead of 2-diethylaminoethyl chloride hydrochloride. 1H-NMR (CDCl 3 , 300 MHz, ca 3: l rotamer) δ 1.50-3.00 (m, 12H), 2.27/2.40 (2x s, 6H), 2.80/3.04 (2x s, 3H), 4.50 (m, 4H), 5.30 (m, 1H), 6.97/6.93 (2x t, 2H), 7.29/7.11 (2x d, 2H), 7.36 (m, 2H), 7.53/7.45 (2x d, 2H) , 7.68 (m, 4H); MS (ESI) found (M+l) = 667. The following compounds were also prepared according to the procedure of Example 19. Example name raw material
例 2 Example 2
甲 (对氟 基) - 甲胺  A (p-fluoro)-methylamine
例 example
基) (；对甲 基) - )甲胺
Figure imgf000033_0001
C3—— 3- (对三氟甲基联苯 -4-基) -4,5-二氢异恶唑 -5-羧酸甲酯 Base) (;p-methyl)-)methylamine
Figure imgf000033_0001
C3——3-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydroisoxazole-5-carboxylic acid methyl ester
(对三氟甲基联苯 -4-基）甲醛 7.2g(l 当量）， 盐酸羟胺 2.16g(l . l 当量)于 150ml EtOH-H20(l : 1)中， 置于冰浴， 缓慢滴加 14.4ml NaOH水溶液 (；浓度为 5M)， 0.5h滴完， 再室温反应过夜。 置于冰浴中， 以浓盐酸调节 pH值约为 5， 析出大量固体， 过滤收集 之， 水洗数次， 干燥后得 7.2 g Cl。 (p-trifluoromethylbiphenyl-4-yl)carboxaldehyde 7.2 g (1 eq.), hydroxylamine hydrochloride 2.16 g (1.1 eq.) in 150 ml of EtOH-H 2 0 (l: 1), placed in an ice bath. 14.4 ml of NaOH aqueous solution (concentration: 5 M) was slowly added dropwise, and the mixture was dropped at 0.5 h, and allowed to react at room temperature overnight. It was placed in an ice bath, adjusted to a pH of about 5 with concentrated hydrochloric acid, and a large amount of solid was precipitated, collected by filtration, washed with water several times, and dried to give 7.2 g of Cl.
将此固体溶于 30ml DMF，先加入 0.5g NCS引发反应，再分批加入剩余的 3.5g NCS， 加入速度以使溶液温度不超过 40°C为宜， 再反应 0.5h停止。 将反应液溶于 200ml EA， 食盐水少量多次洗涤 5次， MgS04干燥， 蒸干溶剂得 C2， 8.0g固体。 The solid was dissolved in 30 ml of DMF, and 0.5 g of NCS was first added to initiate the reaction, and the remaining 3.5 g of NCS was added in portions, and the rate of addition was such that the temperature of the solution did not exceed 40 ° C, and the reaction was stopped for 0.5 h. The reaction solution was dissolved in 200ml EA, washed 5 times with a small amount of brine several times, dried MgS0 4, the solvent was evaporated to dryness to give C2, 8.0g solid.
上述 8.0g固体溶于 100ml干燥的 THF， 氮气保护， 置于 -40°C冷阱中， 以注射器缓 慢滴加 4.2ml三乙胺， 0.5h滴完， 产生白色沉淀。 剧烈搅拌 20min， 然后滴加 2.7ml丙 烯酸乙酯， 停止制冷缓慢升温， 继续搅拌 6h后完毕。 以氯化铵饱和液淬灭反应， EA提 取， 依次用稀盐酸、 食盐水、 NaHC03饱和液洗涤， 干燥， 蒸干溶剂得 C3， 7.2g固体， 纯度较好可直接用于下一步反应。 1H-NMR (CDC13, 400 MHz) 53.69 (dd， 2H), 3.84 (s， 3H): 5.23 (dd, 1H)， 7.65 (d, 2H, J=8.0), 7.71(s, 4H)， 7.78 (d, 2H, J=8.4). The above 8.0 g of the solid was dissolved in 100 ml of dry THF, protected with nitrogen, placed in a cold trap at -40 ° C, and slowly added dropwise with a solution of 4.2 ml of triethylamine in a syringe over 0.5 h to give a white precipitate. Stir vigorously for 20 min, then add 2.7 ml of ethyl acrylate dropwise, stop the cooling and slowly heat up, and continue to stir for 6 h. Saturated ammonium chloride solution to quench the reaction, extracted EA, washed with dilute hydrochloric acid, brine, washed with saturated NaHC0 3 solution, dried and the solvent evaporated to dryness to give C3, 7.2g solid, the purity is preferably used directly in the next reaction. 1H-NMR (CDC1 3 , 400 MHz) 53.69 (dd, 2H), 3.84 (s, 3H) : 5.23 (dd, 1H), 7.65 (d, 2H, J=8.0), 7.71(s, 4H), 7.78 (d, 2H, J=8.4).
C4—— 5- (对三氟甲基联苯 -4-基) -3-羟基 -2-吡咯烷酮 C4—— 5-(p-trifluoromethylbiphenyl-4-yl)-3-hydroxy-2-pyrrolidone
7.2g C3溶于 60ml无水乙醇， 加入 l .Og 10%的钯 /碳加氢催化剂， 压力为 lpsi， 室 温加氢反应过夜， 产生大量白色固体， TLC 检测反应完毕。 将反应液加热至回流使白 色固体全溶， 趁热过滤除去不溶物， 再以热乙醇洗涤， 滤液放冷后析出白色晶体， 过滤 收集之， 冷乙醇洗涤， 干燥。母液浓縮后又有固体析出， 共得 5.0g。 1H-NMR (d6-DMSO, 300 MHz, ca 1.2: 1 旋转异构体） 51.58 (dt, 1H, J=12.3, 9.3), 2.13 (ddd, 1.2H, J=13.2, 7.8, 4.2), 2.31 (ddd, 1.2H, J=13.5, 8.1， 6.6)， 2.76 (ddd, 1H, J=12.6, 8.1， 6.3), 4.15 (m， 2.2H), 4.55 (dd, 1H, J=9.3, 6.6)， 4.76 (dd, 1.2H, J=8.1， 3.9), 5.58 (d， 1H, -OH), 5.55 (d, 1.2H, -OH), 7.40 (d, 2.4H, J=8.1), 7.46 (d, 2H, J=8.4)， 7.73 (d, 2.4H, J=8.4)， 7.75 (d, 2H, J=8.1), 7.80 (m， 4.4H), 7.89 (m， 4.4H), 8.25 (s， 1H), 8.33 (s， 1.2H)； MS (ESI) found (M+l) =322. 7.2 g of C3 was dissolved in 60 ml of absolute ethanol, and 1.0 g of a palladium on carbon hydrogenation catalyst was added thereto at a pressure of 1 psi. The reaction was hydrogenated at room temperature overnight to produce a large amount of white solid, and the reaction was completed by TLC. The reaction solution was heated to reflux to completely dissolve the white solid. The insoluble material was removed by hot filtration, and then washed with hot ethanol. The filtrate was allowed to cool to precipitate white crystals, collected by filtration, washed with cold ethanol, and dried. After the mother liquor was concentrated, solids were precipitated, and a total of 5.0 g was obtained. 1H-NMR (d 6 -DMSO, 300 MHz, ca 1.2: 1 rotamer) 51.58 (dt, 1H, J = 12.3, 9.3), 2.13 (ddd, 1.2H, J = 13.2, 7.8, 4.2), 2.31 (ddd, 1.2H, J=13.5, 8.1, 6.6), 2.76 (ddd, 1H, J=12.6, 8.1, 6.3), 4.15 (m, 2.2H), 4.55 (dd, 1H, J=9.3, 6.6 ), 4.76 (dd, 1.2H, J=8.1, 3.9), 5.58 (d, 1H, -OH), 5.55 (d, 1.2H, -OH), 7.40 (d, 2.4H, J=8.1), 7.46 (d, 2H, J=8.4), 7.73 (d, 2.4H, J=8.4), 7.75 (d, 2H, J=8.1), 7.80 (m, 4.4H), 7.89 (m, 4.4H), 8.25 (s, 1H), 8.33 (s, 1.2H); MS (ESI) found (M+l) = 322.
Figure imgf000034_0001
Figure imgf000034_0001
(士) -及式-和 (士) -赝式 -5- (对三氟甲基联苯 -4-基) -3-叠氮 -2-吡咯烷酮  (士) - and - and - (士) - - -5- (p-trifluoromethylbiphenyl-4-yl)-3-azido-2-pyrrolidone
氮气保护下， C4 3.0g(l当量)， DPPA 2.62ml(1.3当量)和 DBU 2.09ml(1.5当量)于 20ml Under nitrogen protection, C4 3.0g (1 equivalent), DPPA 2.62ml (1.3 equivalents) and DBU 2.09ml (1.5 equivalents) in 20ml
THF中回流 5h， TLC检测反应完毕。冷却后将反应液投入氯化铵饱和液中， EA提取两 次， 合并有机相再以食盐水洗涤两次， 干燥后， 硅胶柱层析分离， PE/EA =2: 1 洗脱得 C5—— (士) 式 -5- (对三氟甲基联苯 -4-基) -3-叠氮 -2-吡咯烷酮， 1.25g白色晶体， 1H-NMR (CDC13, 300 MHz) 52.30 (ddd, 1H), 2.49 (ddd, 1H), 4.28 (dd， 1H), 4.88 (dd， 1H), 6.36 (s， 1H), 7.36 (d, 2H, J=8.4), 7.61 (d, 2H, J=8.1), 7.68 (m， 4H); 再 PE/EA =1 :2 洗脱得 C6—— (±)-/ 式 -5- (；对三氟甲基联苯 -4-基) -3-叠氮 -2-吡咯烷酮， 0.81g白色晶体， 1H-NMR (CDC13, 400 MHz) 51.88 (ddd, 1H， J=13.2, 9.6， 8.4)， 2.89 (ddd, 1H， J=13.2, 8.4， 6.8)， 4.27 (t， 1H, J=9.2)， 4.71 (t， 1H, J=7.2), 6.67 (s, 1H), 7.41 (d, 2H, J=8.4)， 7.61 (d， 2H, J=8.0)， 7.66 (d， 2H, J= =8.8); 二者的相对构型通过一维 NOE加以指证。 The mixture was refluxed for 5 h in THF, and the reaction was completed by TLC. After cooling, the reaction solution was poured into a saturated solution of ammonium chloride, and the EA was extracted twice. The organic phase was combined and washed twice with brine. After drying, it was separated by silica gel column chromatography and eluted with PE/EA = 2:1 C5——(士) Formula-5-(p-trifluoromethylbiphenyl-4-yl)-3-azido-2-pyrrolidone, 1.25g white crystal, 1H-NMR (CDC1 3 , 300 MHz) 52.30 ( Ddd, 1H), 2.49 (ddd, 1H), 4.28 (dd, 1H), 4.88 (dd, 1H), 6.36 (s, 1H), 7.36 (d, 2H, J=8.4), 7.61 (d, 2H, J = 8.1), 7.68 (m, 4H); then PE / EA = 1: 2 elutes C6 - (±) - / formula - 5 - (; p-trifluoromethylbiphenyl-4-yl) - 3-azido-2-pyrrolidone, 0.81 g of white crystals, 1H-NMR (CDC1 3 , 400 MHz) 51.88 (ddd, 1H, J = 13.2, 9.6, 8.4), 2.89 (ddd, 1H, J = 13.2, 8.4 , 6.8), 4.27 (t, 1H, J=9.2), 4.71 (t, 1H, J=7.2), 6.67 (s, 1H), 7.41 (d, 2H, J=8.4), 7.61 (d, 2H, J = 8.0), 7.66 (d, 2H, J = = 8.8); The relative configuration of the two is demonstrated by a one-dimensional NOE.
Figure imgf000035_0001
Figure imgf000035_0001
C7—— (士) -及式 -5- (对三氟甲基联苯 -4-基) -3-氨基 -2-吡咯烷酮  C7——(士)-and -5-(p-trifluoromethylbiphenyl-4-yl)-3-amino-2-pyrrolidone
C5 1.24g(l当量)于 10ml THF中， 加入 1ml水和 1.41g三苯基膦 (1.5当量)， 室温搅 拌 3h， 反应完毕。 直接拌入适量硅胶， 旋干后上一根短的硅胶柱， 先用 EA洗去低极性 的三苯基膦和三苯基氧膦， 再以甲醇洗脱收集目标产物部分， 蒸干甲醇， 剩余物以 CH2Cl2/MeOH =15:1混合液溶解， 滤除不溶的硅胶， 蒸干溶剂得 l.Olg固体。 1H-NMR (CDC13, 400 MHz) 51.69 (s, 2H), 2.41 (m， 2H), 3.71 (dd， 1H, J=14.4, 7.2), 4.85 (dd， 1H, J=7.6, 3.6), 6.41 (s, 1H)， 7.36 (d, 2H, J=8.4)， 7.59 (d, 2H, J=8.4)， 7.66 (d, 2H, J=8.8)， 7.69 (d 2H，J=8.8)。 C5 1.24 g (1 eq.) in 10 ml of THF, 1 ml of water and 1.41 g of triphenylphosphine (1.5 eq.) were added and stirred at room temperature for 3 h. Stir directly into the appropriate amount of silica gel, spin dry and put on a short silica gel column, first wash off the low polarity triphenylphosphine and triphenylphosphine oxide with EA, then elute with methanol to collect the target product part, and evaporate the methanol. The residue was dissolved in a mixture of CH 2 Cl 2 /MeOH = 15:1, and the insoluble silica gel was filtered off. 1H-NMR (CDC1 3 , 400 MHz) 51.69 (s, 2H), 2.41 (m, 2H), 3.71 (dd, 1H, J = 14.4, 7.2), 4.85 (dd, 1H, J=7.6, 3.6), 6.41 (s, 1H), 7.36 (d, 2H, J=8.4), 7.59 (d, 2H, J=8.4), 7.66 (d, 2H, J=8.8), 7.69 (d 2H, J=8.8).
C8—— (士) -及式 -2-[2-氧代 -5- (对三氟甲基联苯 -4-基)吡咯烧 -3-基】氨基 -1-环戊烯羧酸乙 酯  C8——(士)-and-2-(2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)pyrrole-3-yl]amino-1-cyclopentenecarboxylic acid B Ester
l.Olg C7， 0.56ml环戊酮 -2-羧酸乙酯和 1.56ml硅酸四乙酯于 10ml无水乙醇中， 氮 气保护下回流反应 3h完毕。冷却后析出固体， 过滤收集之，冷乙醇洗涤，干燥得 1.20g。 1H-NMR (CDC13, 300 MHz) 51.24 (t, 3H, J=6.9)， 1.83 (m， 2H), 2.51 (m， 5H)， 2.82 (m， 1H)， 4.11 (q， 2H, J=7.2), 4.21 (dd， 1H, J=17.1, 8.4)， 4.90 (dd， 1H，J=8.1， 2.7), 6.64 (s， 1H)， 7.37 (d， 2H, J=8.1), 7.62 (d， 2H, J=8.1), 7.69 (m， 5H). l.Olg C7, 0.56 ml of ethyl cyclopentanone-2-carboxylate and 1.56 ml of tetraethyl silicate in 10 ml of absolute ethanol were refluxed under nitrogen for 3 h. After cooling, the solid was precipitated, collected by filtration, washed with cold ethanol and dried to yield 1.20 g. 1H-NMR (CDC1 3 , 300 MHz) 51.24 (t, 3H, J=6.9), 1.83 (m, 2H), 2.51 (m, 5H), 2.82 (m, 1H), 4.11 (q, 2H, J= 7.2), 4.21 (dd, 1H, J=17.1, 8.4), 4.90 (dd, 1H, J=8.1, 2.7), 6.64 (s, 1H), 7.37 (d, 2H, J=8.1), 7.62 (d , 2H, J=8.1), 7.69 (m, 5H).
C9—— (士) -及式 -5， 6-三亚甲基 -l-[2-氧代 -5- (对三氟甲基联苯 -4-基)吡咯烷 -3-基】 -2-硫尿 嘧啶  C9——(士)- and formula-5,6-trimethylene-l-[2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)pyrrolidin-3-yl]-2 -thiouracil
C8 1.2g(l当量)， 三甲基硅基异硫氰酸酯 1.3ml(3.5当量)于 2ml DMF中， 氮气保护 下于 140°C反应 3.5h完毕。将烧瓶置于冰浴，滴加碳酸氢钠饱和液淬灭，再加入 10ml EA 和 10ml水一起搅拌 2h， 过滤收集析出的沉淀， 水洗， EA洗涤， 干燥后得 0.9g白色固 体。 1H-NMR (de-DMSO, 300 MHz, ca 4:3 旋转异构体） 52.01 (m， 2H), 2.20-3.30 (m， 6H)， 5.01/4.93 (2x dd， 1H， J=7.2, 3.9), 6.89/5.06 (2x dd， 1H， J=10.8， 6.9)， 7.43/7.54 (2x d， 2H, J=8.1), 7.74-7.94 (m， 6H)， 9.00/8.53 (2x s， 1H)， 12.77/12.49 (2x s， 1H); MS (ESI) found (M-l) =470. C8 1.2 g (1 equivalent), trimethylsilyl isothiocyanate 1.3 ml (3.5 eq.) was dissolved in 2 ml of DMF under a nitrogen atmosphere at 140 ° C for 3.5 h. The flask was placed in an ice bath, diluted with sodium bicarbonate saturated solution, and then added with 10 ml of EA and 10 ml of water and stirred for 2 h. The precipitate was collected by filtration, washed with water, washed with EA, and dried to give a white solid. Body. 1H-NMR (de-DMSO, 300 MHz, ca 4:3 rotamer) 52.01 (m, 2H), 2.20-3.30 (m, 6H), 5.01/4.93 (2x dd, 1H, J=7.2, 3.9 ), 6.89/5.06 (2x dd, 1H, J=10.8, 6.9), 7.43/7.54 (2x d, 2H, J=8.1), 7.74-7.94 (m, 6H), 9.00/8.53 (2x s, 1H) , 12.77/12.49 (2x s, 1H); MS (ESI) found (Ml) =470.
例 25—— (士) -反式 -l-[2-氧代 -5- (对三氟甲基联苯 -4-基)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7- 二氢 -1H-环戊 M嘧啶 -4(5H)- Example 25 - (士) - trans-l-[2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)pyrrolidin-3-yl]-2-p-fluorobenzylthio- 6,7-Dihydro-1H-cyclopentamethylpyrimidine-4(5H)-
Figure imgf000036_0001
Figure imgf000036_0001
制备方法同于 A8， 除了以 C9代替 A7。 'H-NMR (CDC13， 300 MHz, ca 3:1 旋转异 构体) 52.05 (m， 2H), 2.70/2.44 (2x m， 4H)， 2.86/2.96 (2x m， 1H), 3.05/3.26 (2x m， 1H), 4.50 (m， 2H), 5.40/4.90 (2x t， 1H), 5.00/5.04 (2x dd， 1H), 7.07/6.79 (2x s, 1H, -NH-), 6.95/6.99 (2x t， 2H), 7.34 (m， 4H)， 7.63 (d， 2H), 7.65 (d， 2H), 7.70 (d， 2H). The preparation method was the same as A8 except that C9 was substituted for A7. 'H-NMR (CDC1 3 , 300 MHz, ca 3:1 rotamer) 52.05 (m, 2H), 2.70/2.44 (2x m, 4H), 2.86/2.96 (2x m, 1H), 3.05/3.26 (2x m, 1H), 4.50 (m, 2H), 5.40/4.90 (2x t, 1H), 5.00/5.04 (2x dd, 1H), 7.07/6.79 (2x s, 1H, -NH-), 6.95/ 6.99 (2x t, 2H), 7.34 (m, 4H), 7.63 (d, 2H), 7.65 (d, 2H), 7.70 (d, 2H).
CIO—— (士) -赝式 -5,6-三亚甲基 -l-[2-氧代 -5- (对三氟甲基联苯 -4-基)吡咯烧 -3-基】 -2-硫尿 嘧啶  CIO——(士)-赝-5-6-trimethylene-l-[2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)pyrrole-3-yl] -2 -thiouracil
Figure imgf000036_0002
Figure imgf000036_0002
方法同于从 C5制备 C9， 除了以 C6代替 C5。 1H-NMR (d6-DMSO, 300 MHz, ca 2:1 旋转异构体） 52.00 (m， 2H), 2.45-3.20 (m， 6H)， 4.91/4.72 (2x dd， 1H)， 6.86/5.01 (2x dd， 1H)， 7.52/7.64 (2x d， 2H, J=8.1), 7.81 (m, 4H), 7.91 (d, 2H, J=8.0), 8.84/8.38 (2x s, 1H, -CONH-), 12.57 (s， 1H,-CSNH-). 例 26一 (士) -赝式 -1-[2-氧代 -5- (对三氟甲基联苯 -4-基)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7- 二氢 -1H-环戊 M嘧啶 -4(5H)- The procedure was the same as preparing C9 from C5 except that C6 was substituted for C5. 1H-NMR (d 6 -DMSO, 300 MHz, ca 2:1 rotamer) 52.00 (m, 2H), 2.45-3.20 (m, 6H), 4.91/4.72 (2x dd, 1H), 6.86/5.01 (2x dd, 1H), 7.52/7.64 (2x d, 2H, J=8.1), 7.81 (m, 4H), 7.91 (d, 2H, J=8.0), 8.84/8.38 (2x s, 1H, -CONH -), 12.57 (s, 1H, -CSNH-). Example 26- (士)-赝-1-(2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6 ,7-Dihydro-1H-cyclopentamethylpyrimidine-4(5H)-
Figure imgf000037_0001
Figure imgf000037_0001
0.63g C10, 185μ1对氟苄溴和 370mg碳酸钾于 5ml丙酮中回流 lh， 反应完毕。 冷 却后， 向烧瓶中加入 10ml水， 搅拌 20min， 过滤收集沉淀， 干燥得 520mg。 1H-NMR (de-DMSO, 400 MHz, ca 2:1 旋转异构体） 51.97 (m， 3H), 2.40-2.60 (m， 2H), 2.96 (m， 3H), 4.45 (m， 2H), 4.85/4.74 (2x dd， 1H), 5.47/5.21 (2x dd， 1H), 7.17/7.09 (2x t， 2H), 7.48/7.52 (2xd, 2H), 7.52/7.42 (2x dd， 2H), 7.78/7.71 (2x d， 2H), 7.80-7.91 (m， 4H)， 8.95/8.77 (2x s， 1H, -NH-).  0.63 g of C10, 185 μl of fluorobenzyl bromide and 370 mg of potassium carbonate were refluxed in 5 ml of acetone for 1 h, and the reaction was completed. After cooling, 10 ml of water was added to the flask, stirred for 20 min, and the precipitate was collected by filtration and dried to yield 520 mg. 1H-NMR (de-DMSO, 400 MHz, ca 2:1 rotamer) 51.97 (m, 3H), 2.40-2.60 (m, 2H), 2.96 (m, 3H), 4.45 (m, 2H), 4.85/4.74 (2x dd, 1H), 5.47/5.21 (2x dd, 1H), 7.17/7.09 (2x t, 2H), 7.48/7.52 (2xd, 2H), 7.52/7.42 (2x dd, 2H), 7.78 /7.71 (2x d, 2H), 7.80-7.91 (m, 4H), 8.95/8.77 (2x s, 1H, -NH-).
例 27—— (士) -及式 -l-[2-氧代 -1-二乙胺乙基 -5- (对三氟甲基联苯 -4-基)吡咯烧 -3-基】 -2-对 氟苄硫基 -6,7-二氢 -1H-环戊 [ί -4(5H)-酮 Example 27 - (士) - and -1-[2-oxo-1-diethylamine ethyl-5-(p-trifluoromethylbiphenyl-4-yl)pyrrole-3-yl] - 2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[ί -4(5H)-one
Figure imgf000037_0002
Figure imgf000037_0002
冰浴中， 9mg钠氢 (以 55-65%的含量分散在油中)于 1.5ml干燥的 DMF， 氮气保护 下加入 64mg (1当量)例 25， 搅拌 15min， 再加入 30mg (2当量) 2-二乙氨基乙基氯， TLC 监测反应进程。反应完成后， 以氯化铵饱和液淬灭， EA提取，食盐水洗涤，无水 Na2S04 干燥， 制备 TLC， CH2Cl2/MeOH =15:l展开， 得 45mg白色固体。 1H-NMR (CDC13， 300 MHz, ca 2:1 旋转异构体） 51.03 (t， 6H)， 2.10 (m， 2H), 2.60 (m， 5H)， 2.84 (m， 5H)， 2.99-3.3 l(m, 3H), 3.95/4.25 (2x m, 1H), 4.44-4.71 (m， 2H), 5.12 (t， 1H), 5.51/5.25 (2x t, 1H)， 6.97 (m， 2H), 7.23-7.52 (m， 4H)， 7.69 (m， 6H); MS (ESI) found (M+l) =679. In an ice bath, 9 mg of sodium hydrogen (dispersed in oil at 55-65%) in 1.5 ml of dry DMF, added 64 mg (1 equivalent) of Example 25 under nitrogen, stirred for 15 min, then added 30 mg (2 equivalents) 2 -Diethylaminoethyl chloride, TLC was used to monitor the progress of the reaction. After completion of the reaction, the solution was quenched with saturated ammonium chloride, extracted EA, washed with brine, dried over anhydrous Na 2 S0 4, was prepared TLC, CH 2 Cl 2 / MeOH = 15: l to expand, to give a white solid 45mg. 1H-NMR (CDC1 3 , 300 MHz, ca 2:1 rotamer) 51.03 (t, 6H), 2.10 (m, 2H), 2.60 (m, 5H), 2.84 (m, 5H), 2.99-3.3 l(m, 3H), 3.95/4.25 (2x m, 1H), 4.44-4.71 (m, 2H), 5.12 (t, 1H), 5.51/5.25 (2x t, 1H), 6.97 (m, 2H), 7.23-7.52 (m, 4H), 7.69 (m, 6H); MS (ESI) found (M+l) =679.
例 28—— (士) -反式 -l-[(5-苯基 -2-氧代)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7-二氢 -IH-环戊 嘧 啶 -4(5H)-酮 Example 28 - (士) -trans-l-[(5-phenyl-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-IH- Cyclopenta-4-(5H)-one
Figure imgf000038_0001
Figure imgf000038_0001
方法同于从 A4制备例 25，除了以苯甲醛代替 A4为起始原料。 1H-NMR (d6-DMSO, 300 MHz, ca 2.4: 1 旋转异构体） 51.97 (m， 2H), 2.30-3.10 (m， 6H)， 4.38/4.48 (q/s, 2H), 4.90/4.4.86 (2x dd， 1H), 5.30/5.17 (2x t， 1H), 7.10-7.50 (m， 9H)， 9.01/8.84(2x s, 1H); MS (ESI) found (M+l) =436 o The procedure was the same as in Preparation 25 from A4 except that benzaldehyde was used instead of A4 as a starting material. 1H-NMR (d 6 -DMSO, 300 MHz, ca 2.4: 1 rotamer) 51.97 (m, 2H), 2.30-3.10 (m, 6H), 4.38/4.48 (q/s, 2H), 4.90/ 4.4.86 (2x dd, 1H), 5.30/5.17 (2x t, 1H), 7.10-7.50 (m, 9H), 9.01/8.84 (2x s, 1H); MS (ESI) found (M+l) = 436 o
例 29—— (士) -赝式 -l-[(5-苯基 -2-氧代)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7-二氢 -IH-环戊 嘧 啶 -4(5H)-酮 Example 29 - (士) -赝-l-[(5-Phenyl-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-IH- Cyclopenta-4-(5H)-one
Figure imgf000038_0002
Figure imgf000038_0002
方法同于从 A4制备例 26，除了以苯甲醛代替 A4为起始原料。 1H-NMR (d6-DMSO: 300 MHz, ca 2: 1 旋转异构体） 51.98 (m， 3H), 2.50 (m， 2H), 2.93 (m， 3H), 4.44 (m， 2H): 4.78/4.4.66 (2x t, 1H, J=7.8), 5.44/5.19 (2x t, 1H, J=10.2), 7.05-7.55 (m, 9H), 8.88/8.70(2x s: 1H); MS (ESI) found (M+l) =436。 下列化合物亦按照例 27的方法制备 实施例名称 原料 The procedure was the same as in Preparation 26 from A4 except that benzaldehyde was used in place of A4. 1H-NMR (d 6 -DMSO : 300 MHz, ca 2: 1 rotamer) 51.98 (m, 3H), 2.50 (m, 2H), 2.93 (m, 3H), 4.44 (m, 2H) : 4.78 /4.4.66 (2x t, 1H, J=7.8), 5.44/5.19 (2x t, 1H, J=10.2), 7.05-7.55 (m, 9H), 8.88/8.70 (2x s : 1H); MS ( ESI) found (M+l) = 436. The following compounds were also prepared according to the method of Example 27. Example name raw material
例 30一 (士) -反式 -1-[2-氧代 -1-对氟苄基 Example 30 one (s) - trans -1-[2-oxo-1-p-fluorobenzyl
-5- (对三氟甲基联苯 -4-基)吡咯烷 -3-基】 -2-对 例 25， 对 氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)- 酮 -5-(p-trifluoromethylbiphenyl-4-yl)pyrrolidin-3-yl]-2-pair 25, p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[pyrimidine- 4(5H)- ketone
例 31—— (士) -及式 -1-[2-氧代 - V-(2-甲基丙 Example 31 - (士) - and -1-[2-oxo-V-(2-methylpropane)
基) -5- (对三氟甲基联苯 -4-基)吡咯烧 -3-基】 -2- 例 25， 溴 对氟苄硫基 -6,7-二氢 -1H-环戊 M嘧啶 代异丁烷 -4(5H)-酮 -5-(p-trifluoromethylbiphenyl-4-yl)pyrrole-3-yl]-2-Example 25, bromo-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta M Pyrimidine isobutane-4(5H)-one
例 32—— (士) -及式 -1-[2-氧代 -1-正丁基 -5- (对 Example 32 - (士) - and -1-[2-oxo-1-n-butyl-5- (pair
例 25， 碘 三氟甲基联苯 -4-基)吡咯烷 -3-基】 -2-对氟苄  Example 25, Iodotrifluoromethylbiphenyl-4-yl)pyrrolidine-3-yl]-2-p-fluorobenzyl
代正丁烷 硫基 -6,7-二氢 -1H-环戊 M嘧啶 -4(5H)-酮
Figure imgf000039_0001
正-n-butanethio-6,7-dihydro-1H-cyclopenta-pyrimidin-4(5H)-one
Figure imgf000039_0001
Figure imgf000040_0001
O
Figure imgf000040_0001
O
例 37 (士) -反式 -1-[(1-对叔丁基苄基 -5-苯 例 28， 对 基 -2-氧代)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7- N— ( 叔丁基苄 二氢 -1H-环戊 M嘧啶 -4(5H)-酮 Example 37 (s) - trans-1-[(1-p-tert-butylbenzyl-5-benzene 28,p-yl-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylsulfide -6,7-N-(tert-butylbenzyldihydro-1H-cyclopentamethylpyrimidin-4(5H)-one
o 例 38 (±) -及式 -1-[(1-正十二烷基 -5-苯基 o Example 38 (±) - and -1-[(1-n-dodecyl-5-phenyl
例 28， 氯 -2-氧代)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7-二  Example 28, chloro-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-di
代十二烷 氢 -1H-环戊 [ί ]嘧啶 -4(5H)-酮 μ」、  Decadodecane Hydrogen -1H-cyclopenta [ί ]pyrimidine -4(5H)-one μ",
C12H25  C12H25
O 例 39—— (士) -及式 -1-[(1-正辛基 -5-苯基 -2-氧 O Example 39 - (士) - and -1-[(1-n-octyl-5-phenyl-2-oxo
例 28， 氯 代)吡咯烧 -3-基】 -2-对氟苄硫基 -6,7-二氢 -1H- 代辛烷 环戊 嘧啶 -4(5H)-酮 μ」...  Example 28, Chloro)pyrrole-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-octane Cyclopentylpyrimidine -4(5H)-one μ"...
O 例 40—— (士) -及式 -1-[(1-正丙基 -5-苯基 -2-氧 O Example 40 - (士) - and -1-[(1-n-propyl-5-phenyl-2-oxo
例 28， 碘 代)吡咯烧 -3-基】 -2-对氟苄硫基 -6,7-二氢 -1H- 丙烷 环戊 嘧啶 -4(5H)-酮  Example 28, iodo)pyrrole-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-propane Cyclopentylpyrimidine -4(5H)-one
C3H; C 3 H;
0 例 41 (士) -及式 -1-[(1-对氟苄基 -5-苯基 -2- 例 28， 对 氧代)吡咯烷 -3-基】 -2-对氟苄硫基 -6,7-二氢 0 Example 41 (士) - and formula-1-[(1-p-fluorobenzyl-5-phenyl-2-case 28, p-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio -6,7-dihydrogen
氟苄溴 -1H-环戊 [ί J嘧啶 -4(5H)-酮
Figure imgf000041_0001
药理实施例 Fluobenzyl bromide-1H-cyclopenta[ί J pyrimidine-4(5H)-one
Figure imgf000041_0001
Pharmacological embodiment
化合物对兔血清为酶源的 Lp-PLA2抑制活性的测定 (体外） Determination of Lp-PLA 2 inhibitory activity of compounds against rabbit serum by enzyme source (in vitro)
1、 实验方法  1, experimental methods
使用氚标记的血小板激活因子 （[3H] PAF， Perkinelmer, Lot NET910) 为底物进行 检测。 反应在 200μ1体系（50 mmol/L羟乙基哌嗪乙磺酸（HEPES ) 禾 B 150 mmol/L氯 化钠 （NaCl) ， pH为 7.4) 中进行。 首先， ΙΟμΙ兔血清与 ΙΟμΙ用二甲基亚砜溶解的下 述各实施例化合物于 37°C预孵育 10分钟。然后加入 20 nM [3H] PAF启动反应（反应体 系见表 1 ) 。 反应在 37°C进行 10分钟， 接着加入 600μ1 CHCl3/MeOH (2: 1)涡旋混匀终 止反应。 静置片刻后于 12，000xg离心 15分钟， 水层上清移于新管， 加入 200μ1氯仿涡 旋， 静置或离心 2分钟。 取 ΙΟΟμΙ水层上清液用于放射性强度测定。 Substrates were detected using tritiated platelet activating factor ([ 3 H] PAF, Perkinelmer, Lot NET910). The reaction was carried out in a 200 μl system (50 mmol/L hydroxyethylpiperazineethanesulfonic acid (HEPES) and B 150 mmol/L sodium chloride (NaCl), pH 7.4). First, ΙΟμΙ rabbit serum and the following examples of compounds in which ΙΟμΙ was dissolved in dimethyl sulfoxide were preincubated for 10 minutes at 37 °C. Then start the reaction by adding 20 nM [ 3 H] PAF (see Table 1 for the reaction system). The reaction was carried out at 37 ° C for 10 minutes, followed by vortexing by adding 600 μl of CHCl 3 /MeOH (2:1) to terminate the reaction. After standing for a while, it was centrifuged at 12,000 x g for 15 minutes, and the aqueous layer was transferred to a new tube, vortexed by adding 200 μl of chloroform, and allowed to stand or centrifuge for 2 minutes. The supernatant of the ΙΟΟμΙ aqueous layer was taken for determination of radioactivity.
表 1 : 反应体系列表  Table 1: List of reaction systems
空白管 对照管 测定管  Blank tube
反应缓冲液 180 170 170 待测化合物 10 二甲基亚砜 （溶剂） 10 10  Reaction buffer 180 170 170 Test compound 10 Dimethyl sulfoxide (solvent) 10 10
底物 （[¾] PAF) 10 10 10 酶源 （兔血清） 10 10 抑制率计算公式：  Substrate ([3⁄4] PAF) 10 10 10 Enzyme source (rabbit serum) 10 10 Inhibition rate calculation formula:
抑制率 =1- (测试管 DPM值-空白管 DPM值) 对照管 DPM值-空白管 DPM值) Inhibition rate =1- (test tube DPM value - blank tube DPM value) control tube DPM value - blank tube DPM value)
(注： DPM为放射性强度单位。 )  (Note: DPM is the unit of radioactivity.)
2、 实验结果见下表 2。 2. The experimental results are shown in Table 2 below.
表 2: 部分化合物在各浓度条件下对兔血清为酶源的 Lp-PLA2的抑制活性 Table 2: Inhibitory activity of some compounds on Lp-PLA 2 enzymatically derived from rabbit serum at various concentrations
抑制率（o/o) Inhibition rate (o /o )
化合物编号  Compound number
ΙΟΟμΜ 10μΜ ΙμΜ 例 3 NT 26 NT 例 9 NT 91 34 例 19 NT 27 NT 例 20 NT 33 NT 例 21 NT 72 ― 例 25 99 93 67 例 26 98 90 44 例 27 99 96.0 76.8 例 28 53.1 NT NT 例 29 48.8 NT NT 例 30 90 88.7 32.2 例 31 91 73.2 ― 例 32 90 69.4 ― 例 33 93 78.6 13.3 例 34 96 78.5 16.3 例 39 80.4 21.8 1.6ΙΟΟμΜ 10μΜ ΙμΜ Example 3 NT 26 NT Example 9 NT 91 34 Example 19 NT 27 NT Example 20 NT 33 NT Example 21 NT 72 ― Example 25 99 93 67 Example 26 98 90 44 Example 27 99 96.0 76.8 Example 28 53.1 NT NT Example 29 48.8 NT NT Example 30 90 88.7 32.2 Example 31 91 73.2 ― Example 32 90 69.4 ― Example 33 93 78.6 13.3 Example 34 96 78.5 16.3 Example 39 80.4 21.8 1.6
"一"， 未检测到活性； "NT"， 未测试。 "One", no activity detected; "NT", not tested.

Claims

权利要求 Rights request
1、 通式 (I)所示的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体和混 合物， 或其药学上可接受的盐；  A pyrimidinone compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof;
W代表 IA和 IB, W stands for IA and IB,
(
Figure imgf000044_0001
(
Figure imgf000044_0001
( I A ( I B :  ( I A ( I B :
其巾 : Its towel :
1和 R3各自独立地选自： Η、 _1()的直链或支链烷基、 C„的环烷基、羟基、 -NR4R5、
Figure imgf000044_0002
、 或者五到七元的芳香或非芳香杂环， 所述杂环含有一个到三个氮原子， 并且非必须地被 d_3的烷基取代； 1 and R 3 are each independently selected from the group consisting of: a straight or branched alkyl group of Η, _ 1 () , a cycloalkyl group of C „, a hydroxyl group, —NR 4 R 5 ,
Figure imgf000044_0002
, Or five to seven yuan aromatic or non-aromatic heterocyclic ring containing one to three nitrogen atoms, and not necessarily be d_ 3 alkyl substituents;
R2为 H或 d_3的烷基； 或者 R 2 is an alkyl group of H or d 3 ;
R1-(CH2)m和 R2与其连接的 N共同组成五到七元的非芳香杂环， 且该非芳香杂环 非必须地被 d_3的烷基或 -NR4R5取代； R 1 —(CH 2 )m and R 2 together with the N to which they are bonded form a five- to seven-membered non-aromatic heterocyclic ring, and the non-aromatic heterocyclic ring is optionally substituted with a d- 3 alkyl group or —NR 4 R 5 ;
m =0-2的整数；  An integer of m =0-2;
n =0-2的整数；  An integer of n =0-2;
R4和 R5各自独立地选自： R 4 and R 5 are each independently selected from:
R6选自 H、 卤素原子、 d_4
Figure imgf000044_0003
R 6 is selected from H, a halogen atom, d 4
Figure imgf000044_0003
R7选自 H、 卤素原子、 d_2的烷基或者一个到三个卤素原子取代的 d_2的烷基。 R 7 is selected from H, a halogen atom, an alkyl group of d 2 or an alkyl group of d 2 substituted by three halogen atoms.
2、 根据权利要求 1所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消 旋体和混合物， 或其药学上可接受的盐， 其中， 通式 (I)中：
Figure imgf000045_0001
The pyrimidinone compound, the enantiomer, the diastereomer, the racemate and the mixture thereof, or a pharmaceutically acceptable salt thereof, according to Claim 1, wherein )in:
Figure imgf000045_0001
1^为11、 。的直链或支链烷基、 C3_7的环烷基或 -NR4R5; 1^ is 11,. Linear or branched alkyl, C 3 _ 7 cycloalkyl or -NR 4 R 5 ;
m =0-2的整数；  An integer of m =0-2;
R4和 R5各自独立地为 d_3的烷基； R 4 and R 5 are each independently an alkyl group of d 3 ;
R6的定义同权利要求 1 ; R 6 is defined in the same manner as in claim 1;
或者，  Or,
当 W是 IB时，  When W is IB,
R1和 R3各自独立地为
Figure imgf000045_0002
或 -NR4R5； R 1 and R 3 are each independently
Figure imgf000045_0002
Or -NR 4 R 5 ;
R2为 H或甲基； R 2 is H or methyl;
m为 1或 2;  m is 1 or 2;
n =0-2的整数；  An integer of n =0-2;
R4和 R5各自独立地为 d_3的烷基； R 4 and R 5 are each independently an alkyl group of d 3 ;
R6的定义同权利要求 1。 R 6 is defined in the same manner as in claim 1.
3、 根据权利要求 2所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消 旋体和混合物， 或其药学上可接受的盐， 其中， 通式 (I)中：  The pyrimidinone compound, the enantiomer, the diastereomer, the racemate and the mixture thereof, or a pharmaceutically acceptable salt thereof, according to Claim 2, wherein ):
当 W是 IA时，  When W is IA,
R3为对三氟甲基联苯 -4-基； R 3 is p-trifluoromethylbiphenyl-4-yl;
R^C ^ -为 H、 d_4的直链或支链烷基、 环丙甲基或 -CH2CH2NR4R5 ; R^C ^ - is a linear or branched alkyl group of H, d_ 4 , cyclopropylmethyl or -CH 2 CH 2 NR 4 R 5 ;
R4和 R5各自独立地为甲基或乙基； R 4 and R 5 are each independently methyl or ethyl;
或者，  Or,
当 W是 IB时，  When W is IB,
R1和 R3各自独立地为
Figure imgf000045_0003
或 -NR4R5; R 1 and R 3 are each independently
Figure imgf000045_0003
Or -NR 4 R 5 ;
R2为 H或甲基； R 2 is H or methyl;
m为 1或 2;  m is 1 or 2;
n =0-2的整数；  An integer of n =0-2;
R4和 R5各自独立地为甲基或乙基； R 4 and R 5 are each independently methyl or ethyl;
R7为卤素原子、 甲基或卤素原子取代的甲基。 R 7 is a methyl group substituted with a halogen atom, a methyl group or a halogen atom.
4、 根据权利要求 1所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消 旋体和混合物， 或其药学上可接受的盐， 其中， 所述化合物为以下化合物：  The pyrimidinone compound according to claim 1, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is The following compounds:
甲基 二乙氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺； Methyldiethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta]pyrimidine-1(5H)- -4-(p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 二甲氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺；  Methyl dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]-4 - (p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 -N-(l-甲基哌啶 -4-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl-N-(l-methylpiperidin-4-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo -6,7-dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[1-氧代 -4- (对三氟甲基联苯 -4-基) -1-(N-甲基哌嗪 -1 基)丁烷 -2-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)-1-(N-methylpiperazin-1yl)butan-2-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
1-[1-氧代 -4- (对三氟甲基联苯 -4-基 )小(4-二甲氨基哌啶 -1-基)丁烷 -2-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-4-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-dimethylaminopiperidin-1-yl)butan-2-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
甲基 -N-[(1H-咪唑 -2-基)甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl-N-[(1H-imidazol-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4- Oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[3- (对三氟甲基联苯 -4-基 )小(4-二甲氨基哌啶 -1-基)小氧代丙烷 -2-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[3-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-dimethylaminopiperidin-1-yl)oxyxopropan-2-yl]-2-p-fluorobenzylthio- 6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
N-(l-甲基哌啶 -4-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  N-(l-methylpiperidin-4-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6 , 7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]butanamide;
N-二甲氨基乙基 -2-[(2-对氟苄硫基 )-4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 - 1 (5 )- 基] -4- (对三氟甲基联苯 -4-基)丁酰胺；  N-dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta]pyrimidine-1 (5)-yl]-4 - (p-trifluoromethylbiphenyl-4-yl)butanamide;
甲基 -N-[(l-甲基 -1H-吡咯 -2-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫 基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1(5H)-基]丁酰胺；  Methyl-N-[(l-methyl-1H-pyrrol-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio) -4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H)-yl]butanamide;
Ν,Ν -二甲基 -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 - 5H)-基]丁酰胺；  Ν,Ν-dimethyl-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H - cyclopenta [ ]pyrimidine-5H)-yl]butanamide;
ΛΚ哌啶 -1-基) -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环 戊 [ ]嘧啶 - 5H)-基]丁酰胺；  Piperidin-1-yl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-5H)-yl]butanamide;
甲基 -N-(2-羟乙基 )-4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl-N-(2-hydroxyethyl)-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6,7 - dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]butanamide;
甲基 [(吡啶 -2-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl [(pyridin-2-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6, 7-Dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
甲基 [(吡啶 -3-基）甲基] -4- (对三氟甲基联苯 -4-基) -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ 嘧啶 -1C5H)-基]丁酰胺；  Methyl [(pyridin-3-yl)methyl]-4-(p-trifluoromethylbiphenyl-4-yl)-2-[(2-p-fluorobenzylthio)-4-oxo-6, 7-Dihydro-4H-cyclopenta[pyrimidin-1C5H)-yl]butanamide;
1-[1-氧代 -3- (对三氟甲基联苯 -4-基 )小(4-甲基哌嗪 -1-基)丙烷 -2-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  1-[1-oxo-3-(p-trifluoromethylbiphenyl-4-yl)succinyl(4-methylpiperazin-1-yl)propan-2-yl]-2-p-fluorobenzylthio -6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
甲基 二甲氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -3- (对三氟甲基联苯 -4-基)丙酰胺；  Methyl dimethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[]pyrimidin-1(5H)-yl]-3 - (p-trifluoromethylbiphenyl-4-yl)propanamide;
甲基 二乙氨基乙基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)- 基] -3- (对三氟甲基联苯 -4-基)丙酰胺； Methyldiethylaminoethyl-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta]pyrimidine-1(5H)- Benzyl-3-(p-trifluoromethylbiphenyl-4-yl)propanamide;
甲基 -Λ 对三氟甲基联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl-hydrazone p-trifluoromethylbiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 (对氯联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-chlorobiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentyl [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 -N-(对氯联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]戊酰胺；  Methyl-N-(p-chlorobiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H - cyclopenta [ ]pyrimidine-1(5H)-yl]pentanamide;
甲基 -Λ 对三氟甲基联苯 -4-基)甲基 -5-二甲氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二 氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]戊酰胺；  Methyl-hydrazone p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro- 4H-cyclopenta [ ]pyrimidine-1(5H)-yl]pentanamide;
甲基 (对氟联苯 -4-基)甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H- 环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-fluorobiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentyl [ ]pyrimidine-1(5H)-yl]butanamide;
甲基 (对甲基联苯 -4-基）甲基 -4-二乙氨基 -2-[(2-对氟苄硫基) -4-氧代 -6,7-二氢 -4H-环戊 [ ]嘧啶 -1(5H)-基]丁酰胺；  Methyl (p-methylbiphenyl-4-yl)methyl-4-diethylamino-2-[(2-p-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclo Butyl [ ]pyrimidine-1(5H)-yl]butanamide;
(士) 式 -1-[2-氧代 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (士) Formula-1-[2-oxo-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(士) -鑕式小[2-氧代 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (士) - 锧 small [2-oxo-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-二乙胺乙基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-diethylamine ethyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluoro Benzylthio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
式 -1-[(5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -1-[(5-Phenyl-2-oxo)B-pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta [pyrimidine]
-4(5H)-酮； -4(5H)-one;
(±)-鑕式 -1-[(5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±)-锧-1-((5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopentyl [ ]pyrimidine-4(5H)-one;
(士)—^式小[2-氧代 -1-对氟苄基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-p-fluorobenzyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士) 式 -1-[2-氧代 -N-(2-甲基丙基) -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄 硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士) Formula-1-[2-Oxo-N-(2-methylpropyl)-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2 -p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-正丁基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-n-butyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl sulfide Base-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-环丙甲基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫 基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^ Small [2-oxo-1-cyclopropanyl-5-(p-trifluoromethylbiphenyl-4-yl) B-pyrrol-3-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式 -1-[2-氧代 -1-乙基 -5- (对三氟甲基联苯 -4-基) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ 嘧啶 -4(5H)-酮；  (士)-^-1-(2-oxo-1-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)B-pyrrol-3-yl]-2-p-fluorobenzyl Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;
(士)—^式小[2-氧代 -1-间三氟甲基苄基 -5-苯基吡咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [J]嘧啶 -4(5H)-酮； (士)-^ Small [2-oxo-1-inter-trifluoromethylbenzyl-5-phenylpyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro -1H-cyclopenta[J]pyrimidin-4(5H)-one;
^-^式 -1-[(1-间氟苯甲基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6，7-二氢 -1H- 环戊 [ ]嘧啶 -4(5H)-酮；  ^-^式-1-[(1-m-fluorobenzyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-di Hydrogen-1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-对叔丁基苄基 -5-苯基 -2-氧代)吡咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±) Formula-1-[(1-P-Butylbenzyl-5-phenyl-2-oxo)pyrrolidin-3-yl]-2-p-fluorobenzylthio-6,7-dihydro -1H-cyclopenta[]pyrimidin-4(5H)-one;
(； ±)- ^式 -l-[0正十二烷基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H- 环戊 [ ]嘧啶 -4(5H)-酮；  (; ±)- ^-l-[0-n-dodecyl-5-phenyl-2-oxo) B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7- Dihydro-1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-正辛基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮；  (±) Formula-1-[(1-n-octyl-5-phenyl-2-oxo)Bpyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro- 1H-cyclopenta[]pyrimidin-4(5H)-one;
(±) 式 -1-[(1-正丙基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环戊 [ ]嘧啶 -4(5H)-酮； 或  (±) Formula-1-[(1-n-propyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro- 1H-cyclopenta[]pyrimidin-4(5H)-one; or
^-^式 -1-[(1-对氟苄基 -5-苯基 -2-氧代) B比咯烷 -3-基] -2-对氟苄硫基 -6,7-二氢 -1H-环 戊 [ ]嘧啶 -4(5H)-酮。  ^-^式-1-[(1-p-fluorobenzyl-5-phenyl-2-oxo)B-pyrrol-3-yl]-2-p-fluorobenzylthio-6,7-dihydro -1H-cyclopenta [ ]pyrimidine-4(5H)-one.
5、 一类嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体和混合物， 或 其药学上可接受的盐的制备方法， 其中， 采用下述反应路线中的一种： A method for producing a pyrimidine ketone compound, an enantiomer thereof, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the following reaction scheme is employed One kind:
Figure imgf000049_0001
反应路线 1
Figure imgf000049_0001
Reaction route 1
其中， R R3和 m的定义与权利要求 1相同； Wherein the definitions of RR 3 and m are the same as in claim 1;
在碱的作用下， 化合物 1与盐酸羟胺縮合生成化合物 2; 所用的碱为三乙胺、 碳酸 钾或氢氧化钠；反应所用溶剂为甲醇、乙醇、 DMF、水或其混合溶剂；反应温度介于 0°C 到 30°C ;  Under the action of a base, compound 1 is condensed with hydroxylamine hydrochloride to form compound 2; the base used is triethylamine, potassium carbonate or sodium hydroxide; the solvent used for the reaction is methanol, ethanol, DMF, water or a mixed solvent thereof; From 0 ° C to 30 ° C ;
化合物 2经 NCS氯化成为化合物 3; 反应溶剂为 THF或 DMF; 反应温度介于 0°C 到 60°C ;  Compound 2 is chlorinated to compound 3 by NCS; the reaction solvent is THF or DMF; the reaction temperature is between 0 ° C and 60 ° C;
化合物 3在碱的作用下脱去氯化氢生成 1，3-偶极离子，然后与丙烯酸乙酯加成生成 化合物 4; 所用的碱为三乙胺、 DIPEA或 DBU; 反应溶剂为 THF或 DMF; 反应温度介 于 -40 °C到室温；  Compound 3 is dehydrochlorinated under the action of a base to form a 1,3-dipolar ion, and then added with ethyl acrylate to form compound 4; the base used is triethylamine, DIPEA or DBU; the reaction solvent is THF or DMF; Temperature between -40 ° C and room temperature;
化合物 4氢化还原得到化合物 5; 该反应所用的催化剂为钯 /碳， 用量为化合物 4 质量的 10%-20%; 反应溶剂为甲醇或乙醇； 反应温度介于 0°C到 80°C ; 化合物 5在碱的作用下与 DPPA反应生成化合物 6; 所用的碱为三乙胺、 DIPEA、 DBU或 DMAP;反应溶剂为 THF、 CH3CN、 DME的极性非质子溶剂；反应温度介于 0°C 到 100°C ; Hydrogenation of compound 4 to give compound 5; the catalyst used in the reaction is palladium/carbon in an amount of compound 4 10%-20% of mass; reaction solvent is methanol or ethanol; reaction temperature is between 0 ° C and 80 ° C; compound 5 reacts with DPPA under the action of a base to form compound 6; the base used is triethylamine, DIPEA , DBU or DMAP; the reaction solvent is a polar aprotic solvent of THF, CH 3 CN, DME; the reaction temperature is between 0 ° C and 100 ° C ;
化合物 6经过氢化还原反应或 Staudinger反应得到化合物 7; 氢化还原反应所用的 催化剂为钯 /碳， 反应在甲醇、 乙醇、 EA或 THF中进行， 反应温度介于 0°C到 80°C ; Staudinger反应所用试剂为过量的 Ph3P，反应在 THF-H20中进行，温度介于 0°C到 50°C ; 化合物 7与 R8取代的环戊酮羧酸酯縮合生成化合物 8， R8为甲基或乙基； 反应在 脱水剂的存在下进行， 所述脱水剂为分子筛、 甲苯共沸或 Si(OEt)4 ; 反应溶剂为甲醇、 乙醇、 甲苯或乙酸； 反应温度介于 0°C到 140°C ; Compound 6 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 7; the catalyst used for the hydrogenation reduction reaction is palladium on carbon, and the reaction is carried out in methanol, ethanol, EA or THF at a reaction temperature of from 0 ° C to 80 ° C; Staudinger reaction The reagent used is an excess of Ph 3 P, the reaction is carried out in THF-H 2 0 at a temperature between 0 ° C and 50 ° C; compound 7 is condensed with R 8 -substituted cyclopentanone carboxylate to give compound 8, R 8 Is a methyl or ethyl; the reaction is carried out in the presence of a dehydrating agent, which is molecular sieve, toluene azeotrope or Si(OEt) 4 ; the reaction solvent is methanol, ethanol, toluene or acetic acid; the reaction temperature is between 0 ° C to 140 ° C;
0 化合物 8与异氰酸酯縮合生成化合物 9; 所述异氰酸酯为 Me3SiNCS、 EtC^NCS或0 Compound 8 is condensed with isocyanate to form compound 9; the isocyanate is Me 3 SiNCS, EtC^NCS or
0 0
Ph GS， 用量为 3.5当量； 反应无需溶剂或者在 DMF中进行； 反应温度介于 100°C到 160 °C ; Ph GS, the amount is 3.5 equivalent; the reaction is carried out without solvent or in DMF; the reaction temperature is between 100 ° C and 160 ° C ;
化合物 9与对氟苄溴或对氟苄氯反应生成化合物 10; 反应中加入大于一个当量的 三乙胺、 DBU、 DIPEA、 碳酸钾或碳酸钠； 反应非必须地加入碘化钾或四丁基碘化铵催 化剂； 反应溶剂为乙腈、 丙酮、 DME、 DCM、 DCE、 EA、 乙醇、 甲醇或 THF; 反应温 度介于 0°C到 80 °C ;  Compound 9 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 10; more than one equivalent of triethylamine, DBU, DIPEA, potassium carbonate or sodium carbonate is added to the reaction; the reaction is optionally added with potassium iodide or tetrabutyl iodide. Ammonium catalyst; reaction solvent is acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol or THF; reaction temperature is between 0 ° C and 80 ° C;
化合物 10与 R1- (CH2)m-LG在强碱的作用下制备化合物 11， LG代表离去基团， 为卤素原子、 三氟甲基磺酸根 -OTf 或甲磺酸根 -OMs; 所述强碱为 NaH、 n-BuLi 或 KOBu-t; 反应溶剂为 THF或 DMF; 反应温度介于 -80°C到室温； Compound 10 and R 1 - (CH 2 ) m -LG are prepared by the action of a strong base, and LG represents a leaving group, which is a halogen atom, a trifluoromethylsulfonate-OTf or a methanesulfonate-OMs; The strong base is NaH, n-BuLi or KOBu-t; the reaction solvent is THF or DMF; the reaction temperature is between -80 ° C and room temperature;
或者， or,
Figure imgf000051_0001
反应路线 2
Figure imgf000051_0001
Reaction route 2
其中， R R2、 R3、 m和 n的定义与权利要求 1相同； Wherein, the definitions of RR 2 , R 3 , m and n are the same as in claim 1;
化合物 12或其盐酸盐与 R8取代的环戊酮羧酸酯縮合生成化合物 13， R8为甲基或 乙基； 当使用化合物 12 的盐酸盐时， 需要加入至少 1 个当量的有机碱， 为三乙胺或 DIPEA; 反应在脱水剂的存在下进行， 所述脱水剂为分子筛、 甲苯共沸或 Si(OEt)4 ; 反 应溶剂为甲醇、 乙醇、 甲苯或乙酸； 反应温度介于 0°C到 140°C ; Compound 12 or its hydrochloride is condensed with R 8 -substituted cyclopentanone carboxylate to give compound 13, R 8 is methyl or ethyl; when using the hydrochloride salt of compound 12, at least one equivalent of organic is required. The base is triethylamine or DIPEA; the reaction is carried out in the presence of a dehydrating agent, which is molecular sieve, toluene azeotrope or Si(OEt) 4 ; the reaction solvent is methanol, ethanol, toluene or acetic acid; 0 ° C to 140 ° C ;
0 化合物 13与异氰酸酯縮合生成化合物 14;所述异氰酸酯为 Me3SiNCS、 EtC^NCS或0 Compound 13 is condensed with isocyanate to form compound 14; the isocyanate is Me 3 SiNCS, EtC^NCS or
0 0
Ph GS， 用量为 3.5当量； 反应无需溶剂或者在 DMF中进行； 反应温度介于 100°C到 160 °C ; Ph GS, the amount is 3.5 equivalent; the reaction is carried out without solvent or in DMF; the reaction temperature is between 100 ° C and 160 ° C ;
化合物 14与对氟苄溴或对氟苄氯反应生成化合物 15 ; 反应中加入大于一个当量的 有机碱或无机碱， 为三乙胺、 DBU、 DIPEA, 碳酸钾或碳酸钠； 反应非必须地加入催化 剂， 为碘化钾或四丁基碘化铵； 反应溶剂为乙腈、 丙酮、 DME、 DCM、 DCE、 EA、 乙 醇、 甲醇或 THF; 反应温度介于 0°C到 80°C ;  Compound 14 is reacted with p-fluorobenzyl bromide or p-fluorobenzyl chloride to form compound 15; more than one equivalent of an organic or inorganic base is added to the reaction, which is triethylamine, DBU, DIPEA, potassium carbonate or sodium carbonate; the reaction is optionally added The catalyst is potassium iodide or tetrabutylammonium iodide; the reaction solvent is acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol or THF; the reaction temperature is between 0 ° C and 80 ° C;
化合物 15发生碱性水解生成化合物 16; 所用的碱为无机强碱， 为 LiOH、 NaOH 或 KOH; 反应在含水的极性溶剂中进行， 所述溶剂为甲醇、 乙醇、 二氧六环、 DMF、 Compound 15 undergoes alkaline hydrolysis to form compound 16; the base used is an inorganic strong base, which is LiOH, NaOH or KOH; the reaction is carried out in an aqueous polar solvent such as methanol, ethanol, dioxane, DMF,
DMSO、 异丙醇或 THF; 反应温度介于 0°C到 50°C ; 水解反应完成后， 反应液需经过酸 化析出游离的化合物 16， 酸化使用盐酸和乙酸； DMSO, isopropanol or THF; the reaction temperature is between 0 ° C and 50 ° C; after the completion of the hydrolysis reaction, the reaction solution is subjected to acidification to precipitate the free compound 16, acidification using hydrochloric acid and acetic acid;
H  H
R1\ / N R2 R1 \ / N R 2
化合物 16与 （eH2)m 或其盐酸盐在縮合剂的作用下生成化合物 17;所用縮合 剂为二环己基碳二亚胺 DCC、 偶氮二羧酸二乙酯 /三苯基磷、 碳酰二咪唑、 1-(3-二甲氨 基丙基 )-3-乙基碳二亚胺盐酸盐 /1-羟基-苯并-三氮唑 EDCI/HOBt、 或者 0-(lH-苯并*** Compound 16 and ( eH2 ) m or its hydrochloride salt form compound 17 under the action of a condensing agent; condensation used The agent is dicyclohexylcarbodiimide DCC, diethyl azodicarboxylate/triphenylphosphine, carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride/1-hydroxy-benzo-triazole EDCI/HOBt, or 0-(lH-benzotriazole
Η  Η
R1\ / N R2 R1 \ / N R 2
-1-基) -AWN',N'-四甲基异脲四氟化硼 TBTU/有机碱； 当使用 （GH2)m 的盐酸盐时， 需要加入至少 1个当量的有机碱， 为三乙胺或 DIPEA; 反应溶剂为 DCM、 DCE、 乙腈、 THF、 甲苯或 DMF或其混合物； 反应温度介于 0°C到 120°C。 -1-yl)-AWN', N'-tetramethylisourea boron tetrafluoride TBTU/organic base; when using ( GH2 ) m hydrochloride, it is necessary to add at least one equivalent of organic base, three Ethylamine or DIPEA; The reaction solvent is DCM, DCE, acetonitrile, THF, toluene or DMF or a mixture thereof; the reaction temperature is between 0 ° C and 120 ° C.
6、 根据权利要求 5所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消 旋体和混合物， 或其药学上可接受的盐的制备方法， 其中， 所述化合物 12由以下反应 路线 一种制备：  The method for producing a pyrimidinone compound, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 5, wherein Compound 12 was prepared by one of the following reaction schemes:
Figure imgf000052_0001
Figure imgf000052_0001
应路线 3所示的方法制备： 其中， R6的定义同权利要求 1 ; Prepared according to the method shown in Scheme 3: wherein R 6 is as defined in claim 1;
在氢氧化钾的作用下， 化合物 18与丙酮酸钠縮合生成化合物 19; 反应在甲醇、 乙 醇、 水、 DCM或其混合溶剂中进行； 反应温度介于 0°C到 30°C ;  Under the action of potassium hydroxide, compound 18 is condensed with sodium pyruvate to form compound 19; the reaction is carried out in methanol, ethanol, water, DCM or a mixed solvent thereof; the reaction temperature is between 0 ° C and 30 ° C;
化合物 19通过酯化反应制备化合物 20; 反应中的酸催化剂由乙酰氯和乙醇原位生 成； 反应溶剂为甲苯； 反应温度介于 0°C到 110°C ;  Compound 19 is prepared by esterification to produce compound 20; the acid catalyst in the reaction is formed in situ from acetyl chloride and ethanol; the reaction solvent is toluene; and the reaction temperature is between 0 ° C and 110 ° C;
化合物 20氢化还原得到化合物 21 ; 反应中所用的催化剂为钯 /碳， 用量为化合物 20质量的 10%-20%； 反应在低极性溶剂 EA中进行； 反应温度介于 0°C到 80°C；  Hydrogenation of compound 20 to give compound 21; the catalyst used in the reaction is palladium/carbon in an amount of 10% to 20% by mass of the compound 20; the reaction is carried out in a low polar solvent EA; the reaction temperature is between 0 ° C and 80 ° C;
化合物 21在碱的作用下与 DPPA反应生成化合物 22; 所用碱为三乙胺、 DIPEA、 DBU或 DMAP; 反应溶剂为 THF、 CH3CN或 DME; 反应温度介于 0°C到 100 °C； 化合物 22经过氢化还原反应或 Staudinger反应得到化合物 23 ; 氢化还原反应所用 的催化剂为钯 /碳， 反应在甲醇、 乙醇、 EA或 THF中进行， 反应温度介于 0°C到 80°C ; Staudinger反应所用试剂为过量的 Ph3P，反应在 THF-H20中进行，温度介于 0°C到 50°C ; 或者，
Figure imgf000053_0001
Compound 21 is reacted with DPPA under the action of a base to form compound 22; the base used is triethylamine, DIPEA, DBU or DMAP; the reaction solvent is THF, CH 3 CN or DME; the reaction temperature is between 0 ° C and 100 ° C; Compound 22 is subjected to a hydrogenation reduction reaction or a Staudinger reaction to obtain a compound 23; the catalyst used in the hydrogenation reduction reaction is palladium on carbon, and the reaction is carried out in methanol, ethanol, EA or THF at a reaction temperature of from 0 ° C to 80 ° C; Staudinger reaction The reagent used is an excess of Ph 3 P, and the reaction is carried out in THF-H 2 0 at a temperature between 0 ° C and 50 ° C; or
Figure imgf000053_0001
Figure imgf000053_0002
化合物 12可由反应路线 4所 示的方法制备： 其中， R6的定义同权利要求 1 ;
Figure imgf000053_0002
Compound 12 can be prepared by the method shown in Reaction Scheme 4: wherein R 6 is as defined in Claim 1;
Cl\ ^\ , Cl \ ^\ ,
2-乙酰氨基丙二酸二乙酯在碱的作用下与 （GH2)n |¾ 縮合得到化合物 24; 所 用碱为 NaH、 KOBu-t或乙醇钠； 反应非必须地加入催化剂， 为碘化钾； 反应溶剂为乙 醇、 DME、 THF或 DMF; 反应温度介于 0°C到 80°C； Diethyl 2-acetamidomalonate is condensed with ( GH2 ) n | 3⁄4 under the action of a base to obtain compound 24; the base used is NaH, KOBu-t or sodium ethoxide; the reaction is optionally added to the catalyst, which is potassium iodide; The solvent is ethanol, DME, THF or DMF; the reaction temperature is between 0 ° C and 80 ° C;
化合物 24被 NaOH水解，再加热脱羧生成化合物 25;水解反应在醇水溶液中进行， 反应温度介于 0°C到室温； 脱羧反应在甲苯中回流；  Compound 24 is hydrolyzed by NaOH and then decarboxylated by heating to form compound 25; the hydrolysis reaction is carried out in an aqueous alcohol solution at a reaction temperature of from 0 ° C to room temperature; and the decarboxylation reaction is refluxed in toluene;
化合物 25酸性水解制备化合物 26; 反应在稀盐酸中回流进行；  Compound 25 is acid hydrolyzed to prepare compound 26; the reaction is carried out in refluxing with dilute hydrochloric acid;
化合物 26经过氯化亚砜参与的酯化反应生成化合物 24; 反应在乙醇中回流进行。 Compound 26 undergoes an esterification reaction involving thionyl chloride to form compound 24; the reaction is carried out under reflux in ethanol.
7、 权利要求 1所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体 和混合物， 或其药学上可接受的盐在制备 Lp-PLA2抑制剂的药物中的用途。 7. The pyrimidinone compound of claim 1, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing an Lp-PLA 2 inhibitor Use of the drug.
8、 权利要求 1所述的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体 和混合物，或其药学上可接受的盐在制备预防、治疗或改善与 Lp-PLA2酶活性有关的疾 病的药物中的用途。 8. The pyrimidinone compound of claim 1, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, for the prophylaxis, treatment or amelioration of Use of a drug for a disease associated with Lp-PLA 2 enzyme activity.
9、 根据权利要求 8所述的用途， 其中， 所述的疾病包括动脉粥样硬化、 脑中风、 冠心病、 糖尿病、 风湿性关节炎、 以及急性和慢性炎症疾病。  9. The use according to claim 8, wherein the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, rheumatoid arthritis, and acute and chronic inflammatory diseases.
10、 一种药物组合物， 其包含一种或多种有效治疗剂量的权利要求 1 中的通式 (I) 所示的嘧啶酮类化合物、 其对映异构体、 非对映异构体、 外消旋体和混合物， 或其药学 上可接受的盐， 以及药学上可接受的辅料。  10. A pharmaceutical composition comprising one or more effective therapeutic doses of a pyrimidinone compound of the formula (I) according to claim 1, an enantiomer thereof, a diastereomer thereof , racemates and mixtures, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
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