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WO2016180247A1 - Bicyclic compound used as an lp-pla2 inhibitor, and preparation method and pharmaceutical use thereof - Google Patents

Bicyclic compound used as an lp-pla2 inhibitor, and preparation method and pharmaceutical use thereof Download PDF

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Publication number
WO2016180247A1
WO2016180247A1 PCT/CN2016/080725 CN2016080725W WO2016180247A1 WO 2016180247 A1 WO2016180247 A1 WO 2016180247A1 CN 2016080725 W CN2016080725 W CN 2016080725W WO 2016180247 A1 WO2016180247 A1 WO 2016180247A1
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group
alkyl
compound
formula
alkoxy
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PCT/CN2016/080725
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French (fr)
Chinese (zh)
Inventor
沈建华
王逸平
陈鑫德
徐文伟
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中国科学院上海药物研究所
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Priority to CN201680016991.XA priority Critical patent/CN107709325B/en
Publication of WO2016180247A1 publication Critical patent/WO2016180247A1/en

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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to novel bicyclic compounds and preparation methods thereof, pharmaceutical compositions using the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity .
  • Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), also known as platelet-activating factor acetylhydrolase (PAF-AH), contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to low-density lipoprotein (LDL), and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL).
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Lp-PLA 2 can rapidly hydrolyze oxidized phosphatidylcholine into lysophosphatidylcholine (1yso-PC) and oxidized non-esterified fatty acid (ox-NEFA), while lyso-PC and ox-NEFA are very strong. It promotes inflammation and activates the inflammatory/immune response of various cells including endothelial cells, smooth muscle cells, monocytes/macrophages, T cells, and neutrophils.
  • Lp-PLA 2 inhibitors may be universally applicable to any condition in which the lipid involved in oxidation is hydrolyzed into two inflammatory traits with the participation of Lp-PLA 2 .
  • These include atherosclerosis, diabetes, diabetic eye disease, diabetic brain disease, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, ischemia and reperfusion, psoriasis, and brain inflammatory diseases (such as: Alzheimer's disease), various neuropsychiatric diseases (such as: schizophrenia), ischemia-reperfusion injury, sepsis, acute and chronic inflammatory diseases.
  • 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. Studies have shown that lyso-PC can promote the development of atherosclerotic plaque and eventually form a necrotic core. Experiments conducted on a diabetic high cholesterol pig model confirmed that Lp-PLA 2 inhibitors can affect the arteriosclerotic plaque volume, composition and gene expression of diabetic high cholesterol pigs, and effectively inhibit the continued growth of atherosclerotic plaques.
  • Lyso-PC acts as a pro-inflammatory factor that induces the release of multiple cytotoxic inflammatory cytokines, whereas Lp-PLA 2 inhibitors attenuate inflammatory responses by inhibiting the production of lyso-PC.
  • Lp-PLA 2 inhibitors can improve blood brain barrier (BBB) function, reduce blood-brain barrier (BBB) permeability, and alleviate beta-like protein in the brain. precipitation.
  • BBB blood brain barrier
  • BBB blood-brain barrier
  • Lp-PLA 2 inhibitors can inhibit lyso- The production of PC is used to treat diabetes-related tissue damage. Considering that local inflammatory reactions play an important role in the development of diabetic retinopathy, it is speculated that Lp-PLA 2 inhibitors can be used for the treatment of diabetic eye diseases.
  • BRB blood-retinal barrier
  • DME diabetic macular edema
  • Lp-PLA 2 inhibitors can reduce BRB permeability
  • studies have shown that Lp-PLA 2 inhibitors may Used in the treatment of diabetic macular edema.
  • Glaucoma and age-related macular degeneration are retinal neurodegenerative diseases, and studies have shown that inflammatory responses, including: TNF- ⁇ signaling pathway may play an important role in these two diseases.
  • Lp-PLA 2 inhibitors can block the release of inflammatory cytokines, it is speculated that Lp-PLA 2 inhibitors can be used in the treatment of glaucoma and AMD.
  • GlaxoSmithKline 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 bicyclo or pyridone group in the structure, and the representative compounds darapladib and rilapladib are currently in clinical research.
  • GlaxoSmithKline has also developed a class of Lp-PLA 2 inhibitors (US 2012/0142717, WO 2012/075917, WO 2012/037782, WO 2013/013503, WO 2013/014185, WO 2014/114248, WO 2014/114249 , WO 2014/114694), the structure is also characterized by a bicyclic group, which differs from the previous class of reversible inhibitors in that the structure is linear and the molecular weight is relatively small.
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein the C 1 -C 4 alkyl group, C 2 -C 4 alkenyl group a C 2 -C 4 alkynyl group, a C 3 -C 6 cycloalkyl group, a 3-8 membered heteroaryl group, a 3-6 membered heterocyclic group, and a phenyl group are optionally 1-4 groups selected from the group consisting of Substituted: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1
  • R 1 is -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-6 membered heteroaryl), wherein the 3-6 membered heteroaryl group
  • the phenyl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
  • R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrimidinyl, pyridyl, wherein the pyrazolyl, pyrimidinyl, Pyridyl, phenyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
  • R 2 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 2 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 2 is H or methyl;
  • R 3 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 3 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 3 is H;
  • X is O, S, -(CH 2 ) q - or -N(R 8 )-; preferably X is O or S;
  • n 0, 1, 2, 3 or 4; preferably n is 0, 1, 2 or 3; more preferably n is 0, 1 or 2;
  • Ar is a C 6 -C 10 aryl group or a 3-8 membered heteroaryl group, wherein the C 6 -C 10 aryl group or the 3-8 membered heteroaryl group is optionally 1-4 selected from the group consisting of Group substitution: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
  • Ar is phenyl, naphthyl or 5-6 membered heteroaryl, wherein the phenyl, naphthyl, 5-6 membered heteroaryl is optionally substituted with from 1 to 4 groups selected from the group consisting of :-CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
  • Ar is a phenyl group or a 5-6 membered heteroaryl group, wherein the phenyl group, a 5-6 membered heteroaryl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, C 1- C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy;
  • Ar is a phenyl group, wherein the phenyl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, Propyl;
  • Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(3-8 membered heteroaryl), wherein A is O, S, -(CH 2 ) o - or -N(R 9 )-, the C 6 -C 10 aryl, 3-8 membered heteroaryl is optionally substituted with 1-3 groups selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1- C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl;
  • Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O, said C 6 -C 10 aryl, 5-6
  • the heteroaryl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl;
  • Z is CH or N
  • R 4 to R 9 and R 1 ' to R 4 ' are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, -(CH 2 ) p -(C 1 - C 6 alkoxy), C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 8 cycloalkenyl; preferably, R 4 to R 9 And R 1 ' to R 4 ' are each independently selected from H, C 1 -C 3 alkyl;
  • the m, q, o, and p are each independently 0, 1, 2, or 3.
  • the compound of formula I has one or both of the following characteristics:
  • R 2 is H or C 1 -C 6 alkyl, preferably R 2 is H or C 1 -C 4 alkyl; most preferably, R 2 is H or methyl;
  • R 3 is H or C 1 -C 6 alkyl; preferably, R 3 is H or C 1 -C 4 alkyl; most preferably, R 3 is H;
  • n 0, 1, 2 or 3;
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic , -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein
  • R 4 , R 5 , R 3 ' and R 4 ' are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) p -(C 1 -C 6 alkoxy), C 3 -C 8 -cycloalkyl;
  • n and p are each independently 0, 1, 2 or 3.
  • the compound of formula I has one or both of the following characteristics:
  • Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group, a naphthyl group or a 5-6 membered hetero
  • the aryl group has from 1 to 4 substituents selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkoxy;
  • Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O or S; the C 6 -C 10 aryl group And the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of C 1 -C 4 alkyl, -CN, halogen, halogenated C 1 -C 6 alkyl.
  • Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group or a 5- to 6-membered heteroaryl group having 1-3 Substituents selected from the group consisting of -CN, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 Alkoxy.
  • Ar is a substituted or unsubstituted phenyl group, and the substitution means having 1-3 substituents selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl Base, methyl, ethyl or propyl.
  • A is O.
  • the C 6 -C 10 aryl group, the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of -CN, F, Cl, CF 3 .
  • the compound has the structure shown in formula (IA):
  • Ra and Rb are each independently H, halogen, -CN, trifluoromethyl or methyl;
  • Z is CH or N
  • n 0, 1, 2 or 3;
  • R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrazolyl, pyrimidinyl, pyridyl, wherein the phenyl, pyrazolyl,
  • R 2 is hydrogen or methyl
  • Ar' is a phenyl group, a pyridyl group or a pyrimidinyl group, wherein the phenyl group, pyridyl group or pyrimidinyl group is optionally substituted with one to three groups selected from the group consisting of trifluoromethyl, fluorine, chlorine, Cyano, methyl.
  • the compound of formula I is any of the compounds shown in the following table.
  • the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, a citrate, a methanesulfonate, a trifluoroacetate, or a Acid salts, oxalates, succinates, malates, tosylates, tartrates, fumarates, glutamates, glucuronates, lactates, glutarate, fine Alkaloid or maleate.
  • Z in the general formula I is CH, that is, a compound of the formula II, obtained by reacting a compound of the formula Ic with R 1 W, wherein W is Cl, Br or I;
  • preparation method comprises the following steps:
  • preparation method comprises the following steps:
  • Z in the formula I is CH, it is a compound of the formula II, which is obtained by reacting a compound of the formula IId with Y-Ar-(CH 2 ) n XH in the presence of a base;
  • preparation method comprises the following steps:
  • R 1 , R 2 , R 3 , Y, Ar, n, and X are as described in the first aspect.
  • a pharmaceutical composition comprising a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are provided.
  • a fourth aspect of the invention provides the use of a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect, for use in:
  • the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, stroke, myocardial infarction, ischemia-reperfusion injury, diabetic eye disease, diabetic encephalopathy, diabetic macular edema, various types Neurodegenerative diseases, Alzheimer's disease, acute inflammatory diseases, chronic inflammatory diseases, psoriasis or glaucoma macular degeneration.
  • the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, diabetic macular edema, diabetic encephalopathy or Alzheimer's disease.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 1 , R 2 , and R 3 are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • a method of inhibiting Lp-PLA 2 administering a safe and effective amount of a compound of formula I to a subject or to the environment.
  • a method of treating a condition associated with Lp-PLA 2 enzymatic activity wherein a safe and effective amount of a compound of formula I is administered to a subject in need thereof.
  • the desired subject comprises cells cultured in vitro, human or non-human mammals, preferably human, mouse or rat.
  • safety and effective amount means that the amount of the active ingredient (the compound of formula I) is sufficient to significantly improve the condition without causing serious side effects.
  • Figure 1 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 1 and 11 and the positive control compound darapladib to SD rats.
  • Figure 2 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 44 and 47 and the positive control compound darapladib to SD rats.
  • the inventors of the present application have extensively and intensively studied for the first time to develop a novel bicyclic compound which can be used as an Lp-PLA 2 inhibitor to prevent and/or treat and/or ameliorate Lp-PLA 2 enzyme activity.
  • Related diseases On the basis of this, the present invention has been completed.
  • C 1 -C 6 alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl. And butyl and the like; the term “C 1 -C 4 alkyl” has a similar meaning.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and having one double bond, and includes, without limitation, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group. , pentynyl and hexynyl.
  • halo C 1 -C 6 alkyl refers to an alkyl group substituted with one or more halogen atoms, such as -CH 2 F, -CF 3 , -CH 2 CHF 3 and the like.
  • C 1 -C 6 alkoxy means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group. Base, isopropoxy and butoxy, etc.; the term “C 1 -C 4 alkoxy” has a similar meaning.
  • C 3 -C 8 cycloalkyl means a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. , cyclohexyl, cycloheptyl, cyclooctyl, etc.; the term “C 3 -C 6 cycloalkyl” has a similar meaning.
  • C 3 -C 8 cycloalkenyl refers to a cyclic alkenyl group having from 3 to 8 carbon atoms in the ring, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl Wait.
  • aryl means a hydrocarbon group containing one or more aromatic rings such as a phenyl group or a naphthyl group and the like.
  • heteroaryl denotes an aromatic ring group containing from 1 to 4 heteroatoms selected from N, O, S, including, without limitation, pyrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, quinazolinyl, quinolyl, isoquinolyl and anthracenyl.
  • heterocyclyl means a cycloalkyl group containing from 1 to 4 hetero atoms selected from N, O, S, and includes, without limitation, pyrrolidinyl, morpholinyl, piperidinyl, thio. Morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiazolyl.
  • the compound of the formula I according to the invention, its stereoisomer or a pharmaceutically acceptable salt thereof can be prepared by the following method:
  • the boric acid or boron ester of R 1 is selected from
  • the base in the step (a), (g), (k) or (1) is selected from the group consisting of inorganic bases, organic bases, and combinations thereof; preferably, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and hydrogen.
  • the organic base is selected from the group consisting of sodium alkoxide, potassium alkoxide, butyl lithium, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, piperidine, pyrrolidine, morpholine, N-methyl Morpholine, quinoline, 4-dimethylaminopyridine, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, and combinations thereof; more preferably The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, barium carbon
  • the reaction solvent for the reaction is selected from the group consisting of aromatic hydrocarbons Solvent-like, ether soluble a halogenated hydrocarbon solvent and other solvents; preferably, the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, and combinations thereof; the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, and ethyl Diol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane and combinations thereof; the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, and Eth
  • the compounds of the invention are Lp-PLA 2 inhibitors. These compounds are therefore useful in the treatment, for example, in the treatment of conditions associated with the activity of Lp-PLA 2 . Accordingly, another aspect of the present invention relates to the treatment associated with Lp-PLA 2 activity is a disorder.
  • a particular disorder or treatment thereof can involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including one or more of the mechanisms described herein.
  • the compounds of the invention are useful in the treatment of any disease involving endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, angina pectoris, and conditions following ischemia and reperfusion.
  • the compounds of the invention are useful in the treatment of any disease involving lipid oxidation associated with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, such as rheumatoid arthritis, Stroke, brain inflammatory conditions such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • the compounds of the invention are useful in the treatment of diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA 2 , including diseases involving activated macrophages, typically Conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease, cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, Multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus.
  • the invention provides a method of treating a disease associated with Lp-PLA 2 activity comprising treating a subject in need of treatment with an effective amount of an Lp-PLA 2 inhibitor.
  • the disease may be associated with increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidized free fatty acids; associated with lipid oxidation of associated Lp-PLA 2 activity; Or related to endothelial dysfunction.
  • the compounds of the invention may be used for primary or secondary prevention of acute coronary events, for the prevention of combination therapy for restenosis or for delaying the development of diabetes or hypertensive renal insufficiency. A subject having a risk of such a condition is prevented and treated.
  • the compounds of the invention are useful in combination with an antihyperlipidemic agent, an antiatherogenic agent, an anti-diabetic agent, an anti-angina or an antihypertensive agent, or an agent for lowering lipoprotein a to treat the present invention.
  • an antihyperlipidemic agent such as statins; antioxidants, such as probucol; insulin sensitizers; calcium channel antagonists and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs.
  • the compounds of the invention are useful for treating a neurodegenerative disease in a subject.
  • the method comprises administering a pharmaceutical composition comprising a drug that inhibits Lp-PLA 2 activity to a subject in need of treatment.
  • exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease.
  • the neurodegenerative disease of the invention is associated with an abnormal blood-brain barrier.
  • the subject to whom the agent that inhibits Lp-PLA 2 activity is administered is a human.
  • the invention provides a method of treating a subject having or at risk of having vascular dementia.
  • the method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a compound of the invention.
  • the vascular dementia is associated with Alzheimer's disease.
  • the invention provides a method of treating a neurological disorder associated with abnormal blood-brain barrier function, inflammation, or microglial activation in a subject in need of treatment.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the abnormal blood brain barrier is a permeable blood brain barrier.
  • the disease is a neurodegenerative disease.
  • Such neurodegenerative diseases are, for example but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease.
  • the invention provides a method of treating a condition associated with blood-brain barrier leakage in a subject. Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease is vascular dementia.
  • the neurodegenerative disease is multiple sclerosis.
  • the invention provides a method of reducing beta amyloid accumulation in a brain of a subject.
  • the method comprises administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound of the invention.
  • the amyloid beta protein is A[beta]-42.
  • the method can further comprise treating another neurodegenerative disease or possibly a comorbidity that can be used to treat the subject being treated
  • the therapeutic agent is administered to the subject or may also include the simultaneous use of other therapies.
  • the neurodegenerative disease is similar to Alzheimer's disease
  • the subject may be treated with other agents or other therapies that target Alzheimer's disease, such as donepezil, tacrine, and lifan Smectin, galantamine, anti-amyloid vaccine, A ⁇ reduction therapy, thinking practice or stimulation.
  • the invention relates to a method of treating metabolic bone disease by administering an effective amount of a compound of the invention to a subject in need of treatment.
  • exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density including, but not limited to, osteoporosis and osteopenia related diseases.
  • Exemplary osteoporosis and osteopenia related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Parkid's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases.
  • the subject in need of treatment is a human.
  • some embodiments of the present invention provides a method of suppressing blocking activity of Lp-PLA 2 is.
  • a method of inhibiting Lp-PLA 2 by reducing and/or downregulating expression of Lp-PLA 2 RNA is provided.
  • bone loss and/or loss of bone density is prevented and/or reduced, thereby preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenia.
  • the method further comprises administering to the subject in need of treatment additional therapeutic agents for treating metabolic bone disease.
  • additional therapeutic agents for treating metabolic bone disease.
  • the metabolic bone disease is osteoporosis
  • other therapeutic agents such as bisphosphonate therapeutic agents can be used.
  • One aspect of the invention provides a method of treating an ocular condition by administering an effective amount of a compound of the invention.
  • the eye disease to which the present invention is applicable may be related to the destruction of the blood retinal barrier.
  • Exemplary ocular diseases involve diabetic ocular diseases and conditions including macular edema, diabetic retinopathy, and the like.
  • the present invention relates to a method to inhibit the Lp-PLA 2 for treating eye diseases by administration of the compounds of the present invention.
  • Exemplary ocular diseases include, but are not limited to, central retinal vein occlusion, retinal branch vein occlusion, I-plus syndrome, retinitis pigmentosa, flattening inflammation, shotgun-like retinal choroidal lesion, retinal outer membrane, choroidal neoplasm, Cystic macular edema, paracentral telangiectasia, traction macular disease, vitreoma macular traction syndrome, retinal detachment, optic nerve retinitis, idiopathic macular edema, etc.
  • some embodiments of the invention provide methods for treating diabetic macular edema in a subject.
  • the method comprises administering an effective amount of a compound of the invention to a subject in need of treatment.
  • the invention provides methods for treating a subject having macular edema or having a risk of macular edema.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the macular edema is associated with a diabetic eye disease, such as diabetic retinopathy.
  • the macular edema is associated with posterior uveitis.
  • the invention provides a method of treating glaucoma or macular degeneration.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the invention provides a method of treating a condition associated with disruption of the blood retinal barrier in a subject in need of treatment.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, system Lupus erythematosus, Fu-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, inflammatory granulomatous disease, etc.
  • the present invention relates to a method of treating uveitis or any of these systemic inflammatory diseases by administering an effective amount of a compound of the present invention.
  • the compounds and pharmaceutical compositions provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be present 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 safe or 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 according to the invention contains 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 of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; 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) can be used clinically in mammals, including humans and animals, and the route of administration can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract.
  • a preferred route of administration is oral.
  • it is a unit dosage form, and each dose contains 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, of the active ingredient, once or in divided doses.
  • the optimal dosage for the individual should be based on the particular 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 filled or liquid filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • the intermediate 1 (1.0 g, 1 eq.) was dissolved in dichloromethane, and then chlorosulfoxide (480 ⁇ l, 2 eq.) was added dropwise in an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 h, then evaporated and evaporated. Chlorosulfoxide gave 1.05 g of intermediate 2a which was used directly in the next step without purification.
  • Intermediate 10c was prepared by referring to the preparation method of Intermediate 1a, except that the starting material was Intermediate 10b and 4-chloro-3-trifluoromethylphenol.
  • the intermediate 11c was prepared by referring to the preparation method of the intermediate 1a, except that p-fluorobenzaldehyde was replaced with the intermediate 11b.
  • Intermediate 12 was prepared by referring to the preparation method of Intermediate 4, except that Intermediate 1a was used as a starting material.
  • N-methylpyrazole (1.0 g, 1 equivalent) was dissolved in N,N-dimethylformamide (2.8 ml, 3 eq.), and phosphorus oxychloride (1.3 ml, 1.2 eq.) was added dropwise at 90 ° C. The addition was completed in 1 h, and the reaction was continued for 2 h. After cooling, the reaction solution was poured into ice water, adjusted to pH 4 to 5 with 10% aqueous sodium hydroxide solution, extracted twice with dichloromethane, washed twice with water, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated 600 mg of intermediate 60a.
  • Oxalyl chloride (428 ⁇ L, 1.5 eq.) was dissolved in methylene chloride, EtOAc (EtOAc) EtOAc (EtOAc) After the addition, the mixture was stirred for 5 min, then the intermediate 60 d of dichloromethane solution was added, and the addition was completed in about 10 min. After the addition, the mixture was stirred for 5 min, then triethylamine (1.67 mL, 4 equivalents) was added, and the addition was completed in about 3 min. After stirring for 5 min, the reaction flask was taken out from the cold mash and allowed to react at room temperature for 5 min. Add water to quench The methylene chloride layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.
  • the intermediate 1 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 499 (M+1).
  • the intermediate 25 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 513 (M+1).
  • the intermediate 14 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 524 (MH).
  • the intermediate 13 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 517 (M+1).
  • the intermediate 26 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 533 (M + 1).
  • the intermediate 27 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 567 (M+1).
  • Example 2 The compound of Example 2 was prepared by referring to the production method of Example 1 except that Intermediate 28 and 2-methoxy-4-bromopyrimidine were used as starting materials.
  • Example 3 The compound of Example 3 was prepared by referring to the production method of Example 1 except that Intermediate 33 and 4-bromopyrimidine were used as starting materials.
  • Example 7 The compound of Example 7 was prepared by referring to the production method of Example 1 except that Intermediate 35 and 4-bromopyrimidine were used as starting materials.
  • Example 9 The compound of Example 9 was prepared by referring to the preparation method of Example 8 except that the intermediate 54 and p-methoxyphenylboronic acid were used as a starting material.
  • 1 H NMR 300 MHz, Chloroform-d
  • 7.63 - 7.28 m, 7H
  • 7.04 m, 5H
  • 5.49 s, 2H
  • Example 10 The compound of Example 10 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 4-bromopyrimidine were used as starting materials.
  • Example 11 The compound of Example 11 was prepared by referring to the preparation method of Example 1 except that Intermediate 34 and 4-bromopyrimidine were used as the starting materials.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 12 The compound of Example 12 was prepared by referring to the preparation method of Example 1 except that Intermediate 36 and 4-bromopyrimidine were used as the starting materials.
  • Example 13 The compound of Example 13 was prepared by referring to the preparation method of Example 8 except that Intermediate 58 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 14 was prepared by referring to the preparation method of Example 8 except that Intermediate 54 and 4-pyridine boronic acid were used as the starting materials.
  • Example 15 was prepared by referring to the preparation method of Example 1 except that Intermediate 28 and 3-bromopyridine were used as the starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 16 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 17 The compound of Example 17 was prepared by referring to the preparation method of Example 1 except that Intermediate 37 and 4-bromopyrimidine were used as the starting materials.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 18 was prepared by referring to the preparation method of Example 1 except that Intermediate 38 and 4-bromopyrimidine were used as starting materials.
  • Example 19 The compound of Example 19 was prepared by referring to the preparation method of Example 1 except that Intermediate 39 and 4-bromopyrimidine were used as starting materials.
  • Example 20 was prepared by referring to the preparation method of Example 1 except that Intermediate 40 and 4-bromopyrimidine were used as the starting materials.
  • Example 21 was prepared by referring to the preparation method of Example 1 except that Intermediate 41 and 4-bromopyrimidine were used as the starting materials.
  • Example 22 The compound of Example 22 was prepared by referring to the preparation method of Example 1 except that Intermediate 42 and 4-bromopyrimidine were used as starting materials.
  • Example 23 The compound of Example 23 was prepared by referring to the preparation method of Example 1 except that Intermediate 43 and 4-bromopyrimidine were used as starting materials.
  • Example 24 The compound of Example 24 was prepared by referring to the preparation method of Example 1 except that Intermediate 44 and 4-bromopyrimidine were used as starting materials.
  • Example 25 was prepared by referring to the preparation method of Example 1 except that Intermediate 31 and 4-bromopyrimidine were used as the starting materials.
  • Example 26 was prepared by referring to the preparation method of Example 6 except that Intermediate 8 and Intermediate 53 were used.
  • Example 27 was prepared by referring to the preparation method of Example 6 except that Intermediate 9 and Intermediate 53 were used.
  • Example 28 was prepared by referring to the preparation method of Example 6 except that Intermediate 10 and Intermediate 53 were used.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 was carried out to prepare the compound of Example 29.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 was carried out to prepare the compound of Example 30.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 31 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 2-methoxy-4-pyrimidineboronic acid were used as a starting material.
  • Example 32 The compound of Example 32 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 3-bromo-4-methylpyridine were used as starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 33 The compound of Example 33 was prepared by referring to the preparation method of Example 1 except that Intermediate 32 and 4-bromopyrimidine were used as a starting material.
  • Example 34 was prepared by referring to the preparation method of Example 1 except that Intermediate 30 and 4-bromopyrimidine were used as the starting materials.
  • Example 35 was prepared by referring to the preparation method of Example 8 except that Intermediate 57 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 36 The compound of Example 36 was prepared by referring to the preparation method of Example 1 except that Intermediate 45 and 4-bromopyrimidine were used as starting materials.
  • Example 37 The compound of Example 37 was prepared by referring to the preparation method of Example 1 except that Intermediate 46 and 4-bromopyrimidine were used as starting materials.
  • Example 38 was prepared by referring to the preparation method of Example 6 except that Intermediate 2 and Intermediate 53 were used.
  • Example 39 The compound of Example 39 was prepared by referring to the preparation method of Example 1 except that Intermediate 47 and 4-bromopyrimidine were used as starting materials.
  • Example 40 The compound of Example 40 was prepared by referring to the preparation method of Example 8 except that Intermediate 56 and 4-pyrimidineboronic acid were used as starting materials.
  • Example 41 was prepared by referring to the preparation method of Example 6 except that Intermediate 5 and Intermediate 53 were used.
  • 1H NMR 400MHz, Chloroform-d
  • Example 42 The compound of Example 42 was prepared by referring to the preparation method of Example 6 except that Intermediate 6 and Intermediate 53 were used.
  • Example 43 The compound of Example 43 was prepared by referring to the preparation method of Example 1 except that Intermediate 48 and 4-bromopyrimidine were used as starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 61 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 62 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 63 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 64 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 65 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 66 and 4-pyrimidineboronic acid as raw materials.
  • Example 1 The preparation method of Example 1 was referred to using Intermediate 67 as a raw material.
  • the reaction buffer was 0.1 M Tris-HCl, 1 mM EGTA, pH 7.2.
  • the concentration was 1.1 mg/ml with three distilled water, and an appropriate amount of 0.1 M NaOH was added until the DTNB just dissolved.
  • Lp-PLA 2 activity was determined using 2-sulfur-PAF as a substrate.
  • the thiol group produced after the hydrolysis of 2-sulfo-PAF can react with DTNB to form a yellow substance, and the optical density value can be detected at 414 nm to reflect the Lp-PLA 2 activity.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 2 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 1 ⁇ M, and some compounds showed an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 100 nM, wherein Example 16 showed in rabbit serum.
  • the best in vitro activity, the inhibition rate of Lp-PLA 2 can reach more than 70% at 100nM concentration.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 4 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 10 nM, wherein Example 16 and Example 31 showed the best in vitro activity in human recombinant enzyme at a concentration of 10 nM.
  • the inhibition rate to Lp-PLA 2 reached about 90%.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 6 showed good in vitro activity in rat serum, and all compounds inhibited Lp-PLA 2 by more than 50% at a concentration of 100 nM.
  • TRIS tris-hydroxymethyl aminomethane
  • a solution of MgCl 2 (100 mM) was prepared in 0.1 M Tris/HCl buffer, and stored at -20 ° C after dispensing. The incubation concentration of MgCl 2 was 5.0 mM.
  • NADPH NADPH
  • Human S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 10-fold with 0.1 M Tris/HCl, and rat S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 5-fold.
  • the incubation concentration of human and rat S9 was equivalent to the incubation concentration of the corresponding species of liver microsomes (the incubation concentration of human and rat liver microsomes was 0.33 mg/mL).
  • the compound was dissolved in DMSO to obtain a stock solution having a concentration of 10 mM. After diluting to 1 mM in DMSO, it was diluted with 0.1% BSA-water to obtain a working solution having a concentration of 2 ⁇ M. In the incubation system, 2 ⁇ M of the working solution was diluted 20-fold to a final concentration of 0.1 ⁇ M. The concentration of DMSO in the incubation system was ⁇ 0.01%.
  • VIVID stock solution purchased from Shanghai Baili Biotechnology Co., Ltd.
  • 2 mM VIVID stock solution purchased from Shanghai Baili Biotechnology Co., Ltd.
  • the mixed working solution of VIVID and the analyte is diluted 20 times.
  • S9 was incubated in 96-well plates at 450 ⁇ L per incubation system, 0.1 M Tris buffer (pH 7.4), MgCl 2 , S9 and +NADPH/-NADPH pre-incubated for 10 min at 37 ° C (600 rpm)
  • the test drug was added to initiate the reaction, and the reaction was stopped by adding the same volume of ice methanol at 0, 7, 17, 30, 60 min.

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Abstract

The present invention relates to a bicyclic compound used as an Lp-PLA2 inhibitor, a preparation method and pharmaceutical use thereof, and a pharmaceutical composition containing the compound. The structure of the bicyclic compound is shown in general formula I. The definitions of R1, R2, R3, X, Y, Z, Ar and n are shown in the description and claims. The compound shown in general formula I of the present invention can be used as an Lp-PLA2 inhibitor for preventing and/or treating and/or improving diseases related to the enzymatic activity of Lp-PLA2.

Description

用作Lp-PLA2抑制剂的双环类化合物、其制备方法及医药用途Bicyclic compound used as Lp-PLA2 inhibitor, preparation method thereof and medical use thereof 技术领域Technical field
本发明涉及药物化学领域，尤其涉及新颖的双环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 novel bicyclic compounds and preparation methods thereof, pharmaceutical compositions using the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity .
背景技术Background technique
脂蛋白相关的磷脂酶A2(Lp-PLA2)也称血小板激活因子乙酰水解酶(PAF-AH)，该酶含有441个氨基酸，相对分子质量为45kD。人血浆中70％的Lp-PLA2与低密度脂蛋白(LDL)结合，30％的Lp-PLA2与高密度脂蛋白(HDL)结合。Lp-PLA2能迅速地将氧化的磷脂酰胆碱水解成为溶血磷脂胆碱(1yso-PC)以及氧化非酯化脂肪酸(ox-NEFA)，而lyso-PC和ox-NEFA都具有很强的促炎症作用，能够启动包括内皮细胞、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。Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), also known as platelet-activating factor acetylhydrolase (PAF-AH), contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to low-density lipoprotein (LDL), and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL). Lp-PLA 2 can rapidly hydrolyze oxidized phosphatidylcholine into lysophosphatidylcholine (1yso-PC) and oxidized non-esterified fatty acid (ox-NEFA), while lyso-PC and ox-NEFA are very strong. It promotes inflammation and activates the inflammatory/immune response of various cells including endothelial cells, smooth muscle cells, monocytes/macrophages, T cells, and neutrophils.
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。这其中包括动脉粥样硬化、糖尿病、糖尿病眼部疾病、糖尿病脑部疾病、高血压、心绞痛、类风湿性关节炎、中风、心肌梗死、缺血和再灌注后、牛皮癣、脑部炎症疾病(如：阿尔茨海默症)、各类神经精神疾病(如：精神分裂症)、缺血再灌注损伤、败血症、急性和慢性炎症疾病。Lp-PLA 2 inhibitors may be universally applicable to any condition in which the lipid involved in oxidation is hydrolyzed into two inflammatory traits with the participation of Lp-PLA 2 . These include atherosclerosis, diabetes, diabetic eye disease, diabetic brain disease, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, ischemia and reperfusion, psoriasis, and brain inflammatory diseases ( Such as: Alzheimer's disease), various neuropsychiatric diseases (such as: schizophrenia), ischemia-reperfusion injury, sepsis, acute and chronic inflammatory diseases.
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。有研究表明，lyso-PC能够促进动脉粥样硬化斑块发展，并最终形成坏死核心。在糖尿病高胆固醇猪模型上进行的实验证实Lp-PLA2抑制剂能够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，并且有效抑制动脉粥样硬化斑块的继续生长。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. Studies have shown that lyso-PC can promote the development of atherosclerotic plaque and eventually form a necrotic core. Experiments conducted on a diabetic high cholesterol pig model confirmed that Lp-PLA 2 inhibitors can affect the arteriosclerotic plaque volume, composition and gene expression of diabetic high cholesterol pigs, and effectively inhibit the continued growth of atherosclerotic plaques.
有研究指出在所有的神经退行性疾病当中，比如：多发性硬化症、帕金森病、阿尔茨海默症等，均表现出了神经炎症。Lyso-PC作为一个前炎症因 子，能够诱导释放多种细胞毒性炎症细胞因子，而Lp-PLA2抑制剂能够通过抑制lyso-PC的产生来减弱炎症反应。Studies have shown that in all neurodegenerative diseases, such as: multiple sclerosis, Parkinson's disease, Alzheimer's disease, etc., have shown neuroinflammation. Lyso-PC acts as a pro-inflammatory factor that induces the release of multiple cytotoxic inflammatory cytokines, whereas Lp-PLA 2 inhibitors attenuate inflammatory responses by inhibiting the production of lyso-PC.
在糖尿病高胆固醇猪模型上进行的实验表明，Lp-PLA2抑制剂能够改善血脑屏障(blood brain barrier，BBB)功能，降低血脑屏障(BBB)渗透性，并且能够缓解脑中β样蛋白沉淀。这些研究结果表明Lp-PLA2抑制剂可能可以应用于与血脑屏障损伤相关联的疾病的治疗，比如糖尿病脑病，阿尔茨海默症。Experiments conducted on a diabetic high cholesterol pig model have shown that Lp-PLA 2 inhibitors can improve blood brain barrier (BBB) function, reduce blood-brain barrier (BBB) permeability, and alleviate beta-like protein in the brain. precipitation. These findings suggest that Lp-PLA 2 inhibitors may be applicable to the treatment of diseases associated with blood-brain barrier damage, such as diabetic encephalopathy, Alzheimer's disease.
由于lyso-PC参与白细胞激活、诱导细胞凋亡并且能够介导内皮细胞功能失调，而糖尿病能够引起持续的血管炎症并且增加活性氧的产生，因此普遍认为Lp-PLA2抑制剂可以通过抑制lyso-PC的产生，从而用于治疗糖尿病相关的组织损伤。考虑到局部的炎症反应在糖尿病视网膜病变的发生发展过程中起着重要作用，因此推测Lp-PLA2抑制剂可以应用于糖尿病性眼病的治疗。Since lyso-PC is involved in leukocyte activation, induces apoptosis and mediates endothelial dysfunction, and diabetes can cause sustained vascular inflammation and increase reactive oxygen species production, it is generally accepted that Lp-PLA 2 inhibitors can inhibit lyso- The production of PC is used to treat diabetes-related tissue damage. Considering that local inflammatory reactions play an important role in the development of diabetic retinopathy, it is speculated that Lp-PLA 2 inhibitors can be used for the treatment of diabetic eye diseases.
另外，血视网膜屏障(BRB)的破坏是糖尿病黄斑水肿(DME)患者的共同病理特征。正常情况下，BRB可通过主动和被动转运阻止血浆成份自由进入视网膜，维持视网膜内感受器细胞的自身稳定性。一旦BRB遭到破坏，将不能严格控制血浆内蛋白和水分进入视网膜实质层，导致视网膜细胞外间隙明显扩张，在黄斑区就表现为黄斑水肿。在链脲佐菌素(STZ)诱导的SD大鼠以及棕色挪威大鼠模型上进行的动物实验显示，Lp-PLA2抑制剂能够降低BRB渗透性，研究结果显示Lp-PLA2抑制剂可能可以应用于糖尿病黄斑水肿的治疗。In addition, destruction of the blood-retinal barrier (BRB) is a common pathological feature of patients with diabetic macular edema (DME). Under normal circumstances, BRB can prevent plasma components from entering the retina freely through active and passive transport, maintaining the stability of the sensor cells in the retina. Once the BRB is destroyed, it will not be able to strictly control the plasma protein and water into the retinal parenchyma, resulting in a significant expansion of the retinal extracellular space and macular edema in the macular area. Animal experiments on streptozotocin (STZ)-induced SD rats and brown Norwegian rat models have shown that Lp-PLA 2 inhibitors can reduce BRB permeability, and studies have shown that Lp-PLA 2 inhibitors may Used in the treatment of diabetic macular edema.
青光眼以及年龄相关的黄斑变性(AMD)均为视网膜神经退行性疾病，研究显示炎症反应，包括：TNF-α信号通路可能在这两种疾病当中起着重要的作用。考虑到Lp-PLA2抑制剂可以阻断炎症细胞因子的释放，因此推测Lp-PLA2抑制剂可以应用于青光眼以及AMD的治疗。Glaucoma and age-related macular degeneration (AMD) are retinal neurodegenerative diseases, and studies have shown that inflammatory responses, including: TNF-α signaling pathway may play an important role in these two diseases. Considering that Lp-PLA 2 inhibitors can block the release of inflammatory cytokines, it is speculated that Lp-PLA 2 inhibitors can be used in the treatment of glaucoma and AMD.
葛兰素史克开发了一类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)，以结构中含有双环或吡啶酮基团为特征，代表化合物darapladib以及rilapladib目前正处于临床研究阶段。GlaxoSmithKline 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 bicyclo or pyridone group in the structure, and the representative compounds darapladib and rilapladib are currently in clinical research.
葛兰素史克还开发了一类Lp-PLA2抑制剂(US 2012/0142717，WO 2012/075917，WO 2012/037782，WO 2013/013503，WO 2013/014185，WO 2014/114248，WO 2014/114249，WO 2014/114694)，结构也以双环基团为特 征，与之前一类可逆抑制剂的区别在于该类结构为线性结构，分子量也相对较小。GlaxoSmithKline has also developed a class of Lp-PLA 2 inhibitors (US 2012/0142717, WO 2012/075917, WO 2012/037782, WO 2013/013503, WO 2013/014185, WO 2014/114248, WO 2014/114249 , WO 2014/114694), the structure is also characterized by a bicyclic group, which differs from the previous class of reversible inhibitors in that the structure is linear and the molecular weight is relatively small.
本领域尚需对Lp-PLA2抑制剂进行深入的研究和开发。Intensive research and development of Lp-PLA 2 inhibitors is still needed in the art.
发明内容Summary of the invention
本发明的目的在于提供一种用作Lp-PLA2抑制剂的双环类化合物及其药物组合物。It is an object of the present invention to provide a bicyclic compound which is used as an Lp-PLA 2 inhibitor and a pharmaceutical composition thereof.
本发明的第一方面，提供一种通式I化合物或其药学上可以接受的盐：In a first aspect of the invention there is provided a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure PCTCN2016080725-appb-000001
Figure PCTCN2016080725-appb-000001
式中，R1为C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C3-C8环烯基、-(CH2)m-NR4R5、C6-C10芳基、-(CH2)m-(3-8元杂芳基)、或卤素，其中，所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烯基、3-8元杂芳基、3-8元杂环基、C6-C10芳基非必须地被1-4个选自下组的基团取代：-OH、-CN、＝O、C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷氧酰基、C1-C6烷酰基、C1-C6烷酰氧基、C3-C8环烷基、羧基、卤素、卤代C1-C6烷基、-S(O)R1’、-SO2R2’、-NO2、-NR3’R4’；Wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 3 - C 8 cycloalkenyl, -(CH 2 ) m -NR 4 R 5 , C 6 -C 10 aryl, -(CH 2 ) m -(3-8 membered heteroaryl), or halogen, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heteroaryl, The 3-8 membered heterocyclic group and the C 6 -C 10 aryl group are optionally substituted with 1 to 4 groups selected from the group consisting of -OH, -CN, =O, C 1 -C 6 alkyl, C 6- C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 3 -C 8 naphthenic a group, a carboxyl group, a halogen, a halogenated C 1 -C 6 alkyl group, -S(O)R 1 ', -SO 2 R 2 ', -NO 2 , -NR 3 'R 4 ';
优选地，R1为C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环基、-(CH2)m-NR4R5、苯基、-(CH2)m-(3-8元杂芳基)或卤素，其中，所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-8元杂芳基、3-6元杂环基、苯基非必须地被1-4个选自下组的基团所取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；Preferably, R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein the C 1 -C 4 alkyl group, C 2 -C 4 alkenyl group a C 2 -C 4 alkynyl group, a C 3 -C 6 cycloalkyl group, a 3-8 membered heteroaryl group, a 3-6 membered heterocyclic group, and a phenyl group are optionally 1-4 groups selected from the group consisting of Substituted: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl;
更优选地，R1为-(CH2)m-NR4R5、苯基、-(CH2)m-(3-6元杂芳基)，其中，所述3-6元杂芳基、苯基非必须地被1-3个选自下组的基团所取代：-CN、氟、氯、溴、甲氧基、三氟甲基、甲基、乙基或丙基；More preferably, R 1 is -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-6 membered heteroaryl), wherein the 3-6 membered heteroaryl group The phenyl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
更优选地，R1为-(CH2)-N(CH3)2、苯基、-(CH2)-吡唑基、嘧啶基、吡啶基，其中，所述吡唑基、嘧啶基、吡啶基、苯基非必须地被1-3个选自下组的基团所取代：-CN、氟、氯、溴、甲氧基、三氟甲基、甲基、乙基或丙基； More preferably, R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrimidinyl, pyridyl, wherein the pyrazolyl, pyrimidinyl, Pyridyl, phenyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
R2、R3独立地选自H、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基或-NR6R7，其中，所述C1-C6烷基、C3-C8环烷基、C1-C6烷氧基非必须地被1-4个选自下组的基团取代：-OH、-CN、＝O、C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷氧酰基、C1-C6烷酰基、C1-C6烷酰氧基、C3-C8环烷基、羧基、卤素、卤代C1-C6烷基、-S(O)R1’、-SO2R2’、-NO2、-NR3’R4’；R 2 and R 3 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy or -NR 6 R 7 , wherein said C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy are optionally substituted with from 1 to 4 groups selected from the group consisting of -OH, -CN, =O, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 3 -C 8 cycloalkyl, carboxyl, halogen, halogenated C 1 -C 6 alkyl, -S(O)R 1 ', -SO 2 R 2 ', -NO 2 , -NR 3 'R 4 ';
优选R2为H或C1-C6烷基，其中，所述所述C1-C6烷基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；更优选R2为H或C1-C4烷基，其中，所述所述C1-C4烷基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、甲氧基、三氟甲基、甲基、乙基或丙基；更优选R2为H或甲基；Preferably, R 2 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 2 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 2 is H or methyl;
优选R3为H或C1-C6烷基，其中，所述所述C1-C6烷基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；更优选R3为H或C1-C4烷基，其中，所述所述C1-C4烷基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、甲氧基、三氟甲基、甲基、乙基或丙基；更优选R3为H；Preferably, R 3 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 3 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 3 is H;
X为O、S、-(CH2)q-或-N(R8)-；优选X为O或S；X is O, S, -(CH 2 ) q - or -N(R 8 )-; preferably X is O or S;
n为0、1、2、3或4；优选n为0、1、2或3；更优选n为0、1或2；n is 0, 1, 2, 3 or 4; preferably n is 0, 1, 2 or 3; more preferably n is 0, 1 or 2;
Ar为C6-C10芳基或3-8元杂芳基，其中，所述C6-C10芳基或3-8元杂芳基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基、卤代C1-C6烷氧基；Ar is a C 6 -C 10 aryl group or a 3-8 membered heteroaryl group, wherein the C 6 -C 10 aryl group or the 3-8 membered heteroaryl group is optionally 1-4 selected from the group consisting of Group substitution: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
优选Ar为苯基、萘基或5-6元杂芳基，其中，所述苯基、萘基、5-6元杂芳基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基、卤代C1-C6烷氧基；Preferably, Ar is phenyl, naphthyl or 5-6 membered heteroaryl, wherein the phenyl, naphthyl, 5-6 membered heteroaryl is optionally substituted with from 1 to 4 groups selected from the group consisting of :-CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
更优选Ar为苯基或5-6元杂芳基，其中，所述苯基、5-6元杂芳基非必须地被1-3个选自下组的基团取代：-CN、C1-C4烷基、C1-C4烷氧基、卤素、羟基、卤代C1-C4烷基、卤代C1-C4烷氧基；More preferably, Ar is a phenyl group or a 5-6 membered heteroaryl group, wherein the phenyl group, a 5-6 membered heteroaryl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, C 1- C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy;
更优选Ar为苯基，其中，所述苯基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、三氟甲基、甲基、乙基、丙基；More preferably Ar is a phenyl group, wherein the phenyl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, Propyl;
Y为氢、-A-(C6-C10芳基)或-A-(3-8元杂芳基)，其中，A为O、S、-(CH2)o-或-N(R9)-，所述C6-C10芳基、3-8元杂芳基非必须地被1-3个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、卤代C1-C6烷基； Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(3-8 membered heteroaryl), wherein A is O, S, -(CH 2 ) o - or -N(R 9 )-, the C 6 -C 10 aryl, 3-8 membered heteroaryl is optionally substituted with 1-3 groups selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1- C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl;
优选地，Y为-A-(C6-C10芳基)或-A-(5-6元杂芳基)，其中，A为O，所述C6-C10芳基、5-6元杂芳基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、三氟甲基、甲基、乙基、丙基；Preferably, Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O, said C 6 -C 10 aryl, 5-6 The heteroaryl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl;
Z为CH或N；Z is CH or N;
所述R4至R9、以及R1’至R4’各自独立地选自H、C1-C6烷基、C1-C6烷酰基、-(CH2)p-(C1-C6烷氧基)、C3-C8环烷基、C2-C6烯基、C2-C6炔基、和C3-C8环烯基；优选地，R4至R9、以及R1’至R4’各自独立地选自H、C1-C3烷基；The R 4 to R 9 and R 1 ' to R 4 ' are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, -(CH 2 ) p -(C 1 - C 6 alkoxy), C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 8 cycloalkenyl; preferably, R 4 to R 9 And R 1 ' to R 4 ' are each independently selected from H, C 1 -C 3 alkyl;
所述m、q、o和p各自独立地为0、1、2或3。The m, q, o, and p are each independently 0, 1, 2, or 3.
在另一优选例中，所述通式I化合物具有以下一个或两个特征：In another preferred embodiment, the compound of formula I has one or both of the following characteristics:
(1)R2为H或C1-C6烷基，较佳地，R2为H或C1-C4烷基；最佳地，R2为H或甲基；(1) R 2 is H or C 1 -C 6 alkyl, preferably R 2 is H or C 1 -C 4 alkyl; most preferably, R 2 is H or methyl;
(2)R3为H或C1-C6烷基；较佳地，R3为H或C1-C4烷基；最佳地，R3为H；(2) R 3 is H or C 1 -C 6 alkyl; preferably, R 3 is H or C 1 -C 4 alkyl; most preferably, R 3 is H;
(3)n为0、1、2或3；(3) n is 0, 1, 2 or 3;
(4)X为O、S；(4) X is O, S;
在另一优选例中，R1为C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环基、-(CH2)m-NR4R5、苯基、-(CH2)m-(3-8元杂芳基)或卤素，其中，In another preferred embodiment, R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic , -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein
所述C1-C4烷基、3-6元杂环基、苯基、-(CH2)m-(3-8元杂芳基)非必须地被1-4个选自下组的基团取代：＝O、C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C3-C8环烷基、卤素、卤代C1-C6烷基或-NR3’R4’；The C 1 -C 4 alkyl group, the 3-6 membered heterocyclic group, the phenyl group, the —(CH 2 ) m —(3-8 membered heteroaryl group) are optionally 1-4 selected from the group consisting of Group substitution: =O, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, halogen, halogenated C 1 -C 6 Alkyl or -NR 3 'R 4 ';
R4、R5、R3’和R4’各自独立地选自H、C1-C6烷基、-(CH2)p-(C1-C6烷氧基)、C3-C8环烷基；R 4 , R 5 , R 3 ' and R 4 ' are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) p -(C 1 -C 6 alkoxy), C 3 -C 8 -cycloalkyl;
m和p各自独立地为0、1、2或3。m and p are each independently 0, 1, 2 or 3.
在另一优选例中，R1为C1-C4烷基、C2-C4烯基、C3-C6环烷基、3-6元杂环基、-(CH2)m-NR4R5、苯基、-(CH2)m-(3-6元杂芳基)或卤素，其中，所述C1-C4烷基、3-6元杂环基、苯基、-(CH2)m-(3-6元杂芳基)非必须地被选自下组的取代：＝O、C1-C4烷基、C6-C10芳基、C1-C4烷氧基、C3-C6环烷基、卤素、卤代C1-C4烷基或-NR3’R4’；R4、R5、R3’和R4’各自独立地选自H、C1-C4烷基、-(CH2)p-(C1-C4烷氧基)、C3-C6环烷基；m和p各自独立地为0或1。In another preferred embodiment, R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) m - NR 4 R 5 , phenyl, -(CH 2 ) m -(3-6 membered heteroaryl) or halogen, wherein the C 1 -C 4 alkyl group, the 3-6 membered heterocyclic group, the phenyl group, -(CH 2 ) m -(3-6 membered heteroaryl) is optionally substituted with a group selected from the group consisting of: =O, C 1 -C 4 alkyl, C 6 -C 10 aryl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, halo, halo-C 1 -C 4 alkyl or -NR 3 'R 4'; R 4, R 5, R 3 ' and R 4' are each independently It is selected from H, C 1 -C 4 alkyl, -(CH 2 ) p -(C 1 -C 4 alkoxy), C 3 -C 6 cycloalkyl; m and p are each independently 0 or 1.
在另一优选例中，R1为-(CH2)m-NR4R5、苯基、-(CH2)m-(3-6元杂芳基)，其中，所述苯基、-(CH2)m-(3-6元杂芳基)非必须地被选自下组的基团取代： ＝O、C1-C4烷基、苯基、C1-C4烷氧基、C3-C6环烷基、卤素、氟代C1-C4烷基或-NR3’R4’；R4、R5、R3’和R4’各自独立地选自甲基、乙基、丙基、-(CH2)2OCH3或环丙基；m为0或1。In another preferred embodiment, R 1 is -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-6 membered heteroaryl), wherein the phenyl group, (CH 2 ) m -(3-6 membered heteroaryl) is optionally substituted with a group selected from the group consisting of: =O, C 1 -C 4 alkyl, phenyl, C 1 -C 4 alkoxy , C 3 -C 6 cycloalkyl, halogen, fluoro C 1 -C 4 alkyl or -NR 3 'R 4 '; R 4 , R 5 , R 3 ' and R 4 ' are each independently selected from methyl , ethyl, propyl, -(CH 2 ) 2 OCH 3 or cyclopropyl; m is 0 or 1.
在另一优选例中，R1为-(CH2)-N(CH3)2、苯基、-(CH2)-吡唑基、吡唑基、嘧啶基、吡啶基，其中，所述苯基、吡唑基、嘧啶基非必须地被选自以下组的取代：＝O、甲基、乙基、苯基、甲氧基、乙氧基、环丙基、氟、氯、溴、三氟甲基；In another preferred embodiment, R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrazolyl, pyrimidinyl, pyridyl, wherein The phenyl, pyrazolyl, pyrimidinyl group is optionally substituted with a group selected from the group consisting of: =O, methyl, ethyl, phenyl, methoxy, ethoxy, cyclopropyl, fluoro, chloro, bromo, Trifluoromethyl;
在另一优选例中，所述通式I化合物具有以下一个或两个特征：In another preferred embodiment, the compound of formula I has one or both of the following characteristics:
(1)Ar为取代或未取代的苯基，取代或未取代的萘基，取代或未取代的5-6元杂芳基，所述取代是指苯基、萘基或5-6元杂芳基上具有1-4个选自下组的取代基：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基、卤代C1-C6烷氧基；(1) Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group, a naphthyl group or a 5-6 membered hetero The aryl group has from 1 to 4 substituents selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkoxy;
(2)Y为氢、-A-(C6-C10芳基)或-A-(5-6元杂芳基)，其中，A为O或S；所述C6-C10芳基、所述5-6元杂芳基上非必须地具有1-3个选自下组的取代基：C1-C4烷基、-CN、卤素、卤代C1-C6烷基。(2) Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O or S; the C 6 -C 10 aryl group And the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of C 1 -C 4 alkyl, -CN, halogen, halogenated C 1 -C 6 alkyl.
在另一优选例中，Ar为取代或未取代的苯基，取代或未取代的5-6元杂芳基，所述取代是指苯基或5-6元杂芳基上具有1-3个选自下组的取代基：-CN、C1-C4烷基、C1-C4烷氧基、卤素、羟基、卤代C1-C4烷基、卤代C1-C4烷氧基。In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group or a 5- to 6-membered heteroaryl group having 1-3 Substituents selected from the group consisting of -CN, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 Alkoxy.
在另一优选例中，Ar为取代或未取代的苯基，所述取代是指苯基上具有1-3个选自下组的取代基：-CN、氟、氯、溴、三氟甲基、甲基、乙基或丙基。In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, and the substitution means having 1-3 substituents selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl Base, methyl, ethyl or propyl.
在另一优选例中，A为O。在另一优选例中，所述C6-C10芳基、5-6元杂芳基上非必须地具有1-3个选自下组的取代基：-CN、F、Cl、CF3。In another preferred embodiment, A is O. In another preferred embodiment, the C 6 -C 10 aryl group, the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of -CN, F, Cl, CF 3 .
在另一优选例中，所述化合物具有式(IA)所示的结构：In another preferred embodiment, the compound has the structure shown in formula (IA):
Figure PCTCN2016080725-appb-000002
Figure PCTCN2016080725-appb-000002
其中，Ra和Rb各自独立地为H、卤素、-CN、三氟甲基或甲基；Wherein, Ra and Rb are each independently H, halogen, -CN, trifluoromethyl or methyl;
Z为CH或N；Z is CH or N;
n为0、1、2或3； n is 0, 1, 2 or 3;
R1为-(CH2)-N(CH3)2、苯基、-(CH2)-吡唑基、吡唑基、嘧啶基、吡啶基，其中，所述苯基、吡唑基、嘧啶基非必须地被选自以下组的取代：-CN、＝O、甲基、乙基、苯基、甲氧基、乙氧基、环丙基、氟、氯、溴、三氟甲基；R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrazolyl, pyrimidinyl, pyridyl, wherein the phenyl, pyrazolyl, The pyrimidinyl group is optionally substituted with a group selected from the group consisting of -CN, =O, methyl, ethyl, phenyl, methoxy, ethoxy, cyclopropyl, fluoro, chloro, bromo, trifluoromethyl ;
R2为氢或甲基；R 2 is hydrogen or methyl;
Ar’为苯基、吡啶基、嘧啶基，其中，所述苯基、吡啶基、嘧啶基非必须地被1-3个选自以下组的基团取代：三氟甲基、氟、氯、氰基、甲基。Ar' is a phenyl group, a pyridyl group or a pyrimidinyl group, wherein the phenyl group, pyridyl group or pyrimidinyl group is optionally substituted with one to three groups selected from the group consisting of trifluoromethyl, fluorine, chlorine, Cyano, methyl.
在另一优选例中，所述通式I化合物为如下表所示的任一化合物。In another preferred embodiment, the compound of formula I is any of the compounds shown in the following table.
Figure PCTCN2016080725-appb-000003
Figure PCTCN2016080725-appb-000003
Figure PCTCN2016080725-appb-000004
Figure PCTCN2016080725-appb-000004
Figure PCTCN2016080725-appb-000005
Figure PCTCN2016080725-appb-000005
Figure PCTCN2016080725-appb-000006
Figure PCTCN2016080725-appb-000006
Figure PCTCN2016080725-appb-000007
Figure PCTCN2016080725-appb-000007
Figure PCTCN2016080725-appb-000008
Figure PCTCN2016080725-appb-000008
在另一优选例中，所述药学上可以接受的盐为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、甲磺酸盐、三氟乙酸盐、乙酸盐、草酸盐、丁二酸盐、苹果酸盐、甲苯磺酸盐、酒石酸盐、富马酸盐、谷氨酸盐、葡糖醛酸盐、乳酸盐、戊二酸盐、精氨酸盐或马来酸盐。In another preferred embodiment, the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, a citrate, a methanesulfonate, a trifluoroacetate, or a Acid salts, oxalates, succinates, malates, tosylates, tartrates, fumarates, glutamates, glucuronates, lactates, glutarate, fine Alkaloid or maleate.
本发明的第二方面，提供第一方面所述的通式I化合物或其药学上可以接受的盐的制备方法，包括以下步骤：In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, of the first aspect, comprising the steps of:
Figure PCTCN2016080725-appb-000009
Figure PCTCN2016080725-appb-000009
当通式I中Z为CH时，即为通式II化合物，由式Ic化合物与R1W反应得到，其中，W为Cl、Br或I；When Z in the general formula I is CH, that is, a compound of the formula II, obtained by reacting a compound of the formula Ic with R 1 W, wherein W is Cl, Br or I;
或者所述制备方法包括以下步骤：Or the preparation method comprises the following steps:
Figure PCTCN2016080725-appb-000010
Figure PCTCN2016080725-appb-000010
当通式I中Z为CH时，即为通式II化合物，由式Id化合物与
Figure PCTCN2016080725-appb-000011
或
Figure PCTCN2016080725-appb-000012
反应得到；When Z in the formula I is CH, it is a compound of the formula II, and a compound of the formula Id is
Figure PCTCN2016080725-appb-000011
or
Figure PCTCN2016080725-appb-000012
The reaction is obtained;
或者所述制备方法包括以下步骤：Or the preparation method comprises the following steps:
Figure PCTCN2016080725-appb-000013
Figure PCTCN2016080725-appb-000013
当通式I中Z为CH时，即为通式II化合物，由式IId化合物与Y-Ar-(CH2)nXH在碱存在下反应得到；When Z in the formula I is CH, it is a compound of the formula II, which is obtained by reacting a compound of the formula IId with Y-Ar-(CH 2 ) n XH in the presence of a base;
或者所述制备方法包括以下步骤：Or the preparation method comprises the following steps:
Figure PCTCN2016080725-appb-000014
Figure PCTCN2016080725-appb-000014
当通式I中Z为N时，即为通式III化合物，由式IIIe化合物与
Figure PCTCN2016080725-appb-000015
或
Figure PCTCN2016080725-appb-000016
反应得到；When Z in the formula I is N, it is a compound of the formula III, which is a compound of the formula IIIe and
Figure PCTCN2016080725-appb-000015
or
Figure PCTCN2016080725-appb-000016
The reaction is obtained;
其中，所述R1、R2、R3、Y、Ar、n、X的定义如第一方面所述。Wherein, the definitions of R 1 , R 2 , R 3 , Y, Ar, n, and X are as described in the first aspect.
本发明的第三方面，提供一种药物组合物，包含第一方面所述的通式I化合物或其药学上可以接受的盐；和药学上可接受的载体。According to a third aspect of the invention, a pharmaceutical composition comprising a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are provided.
本发明的第四方面，提供第一方面所述的通式I化合物或其药学上可以接受的盐或第三方面所述的药物组合物的用途，所述用途是用于：A fourth aspect of the invention provides the use of a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect, for use in:
(1)制备抑制Lp-PLA2的药物；(1) preparing a drug that inhibits Lp-PLA 2 ;
(2)制备预防和/或治疗和/或改善与Lp-PLA2酶活性有关的疾病的药物。(2) A medicament for preventing and/or treating and/or ameliorating a disease associated with Lp-PLA 2 enzyme activity.
在另一优选例中，所述与Lp-PLA2酶活性有关的疾病为动脉粥样硬化、中风、心肌梗死、缺血再灌注损伤、糖尿病眼部疾病、糖尿病脑病、糖尿病 黄斑水肿、各类神经退行性疾病、阿尔茨海默症、急性炎症疾病、慢性炎症疾病、牛皮癣或青光眼黄斑变性。In another preferred embodiment, the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, stroke, myocardial infarction, ischemia-reperfusion injury, diabetic eye disease, diabetic encephalopathy, diabetic macular edema, various types Neurodegenerative diseases, Alzheimer's disease, acute inflammatory diseases, chronic inflammatory diseases, psoriasis or glaucoma macular degeneration.
在另一优选例中，所述与Lp-PLA2酶活性有关的疾病为动脉粥样硬化、糖尿病黄斑水肿、糖尿病脑病或阿尔茨海默症。In another preferred embodiment, the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, diabetic macular edema, diabetic encephalopathy or Alzheimer's disease.
本发明的第五方面，提供通式I化合物的中间体，结构为：In a fifth aspect of the invention, there is provided an intermediate of a compound of formula I, the structure of which is:
Figure PCTCN2016080725-appb-000017
Figure PCTCN2016080725-appb-000017
其中，所述R2、R3、Y、Ar、n、X的定义如第一方面所述。Wherein R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
本发明的第六方面，提供通式I化合物的中间体，结构为：In a sixth aspect of the invention, there is provided an intermediate of a compound of formula I, the structure of which is:
Figure PCTCN2016080725-appb-000018
Figure PCTCN2016080725-appb-000018
其中，所述R2、R3、Y、Ar、n、X的定义如第一方面所述。Wherein R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
本发明的第七方面，提供通式I化合物的中间体，结构为：In a seventh aspect of the invention, there is provided an intermediate of the compound of formula I, the structure of which is:
Figure PCTCN2016080725-appb-000019
Figure PCTCN2016080725-appb-000019
其中，所述R2、R3、Y、Ar、n、X的定义如第一方面所述。Wherein R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
本发明的第八方面，提供通式I化合物的中间体，结构为：In an eighth aspect of the invention, there is provided an intermediate of the compound of formula I, the structure of which is:
Figure PCTCN2016080725-appb-000020
Figure PCTCN2016080725-appb-000020
其中，所述R1、R2、R3的定义如第一方面所述。Wherein R 1 , R 2 , and R 3 are as defined in the first aspect.
本发明的第九方面，提供通式I化合物的中间体，结构为： In a ninth aspect of the invention, there is provided an intermediate of the compound of formula I, the structure of which is:
Figure PCTCN2016080725-appb-000021
Figure PCTCN2016080725-appb-000021
其中，所述R2、R3、Y、Ar、n、X的定义如第一方面所述。Wherein R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
本发明的第十方面，提供一种抑制Lp-PLA2的方法，向所需要的对象或向环境中施用安全有效量的通式I化合物。In a tenth aspect of the invention, there is provided a method of inhibiting Lp-PLA 2 , administering a safe and effective amount of a compound of formula I to a subject or to the environment.
本发明的第十一方面，提供一种治疗与Lp-PLA2酶活性有关疾病的方法，向所需要的对象施用安全有效量的通式I化合物。In an eleventh aspect of the invention, there is provided a method of treating a condition associated with Lp-PLA 2 enzymatic activity, wherein a safe and effective amount of a compound of formula I is administered to a subject in need thereof.
在另一优选例中，所述需要的对象包括体外培养的细胞、人或非人哺乳动物，较佳地，为人、小鼠或大鼠。In another preferred embodiment, the desired subject comprises cells cultured in vitro, human or non-human mammals, preferably human, mouse or rat.
本发明中，“安全有效量”指的是：活性成分(通式I化合物)的量足以明显改善病情，而不至于产生严重的副作用。In the present invention, "safe and effective amount" means that the amount of the active ingredient (the compound of formula I) is sufficient to significantly improve the condition without causing serious side effects.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
附图说明DRAWINGS
图1为对SD大鼠口服给予实施例1和11的化合物和阳性对照化合物darapladib后大鼠血清Lp-PLA2活性图。Figure 1 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 1 and 11 and the positive control compound darapladib to SD rats.
图2为对SD大鼠口服给予实施例44和47的化合物和阳性对照化合物darapladib后大鼠血清Lp-PLA2活性图。Figure 2 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 44 and 47 and the positive control compound darapladib to SD rats.
具体实施方式detailed description
本申请的发明人经过广泛而深入地研究，首次研发出一种结构新颖的双环类化合物，可用作Lp-PLA2抑制剂，预防和/或治疗和/或改善与Lp-PLA2酶活性有关的疾病。在此基础上，完成了本发明。The inventors of the present application have extensively and intensively studied for the first time to develop a novel bicyclic compound which can be used as an Lp-PLA 2 inhibitor to prevent and/or treat and/or ameliorate Lp-PLA 2 enzyme activity. Related diseases. On the basis of this, the present invention has been completed.
术语the term
在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基和丁基等；术语“C1-C4烷基”具有类似的含义。术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、 戊炔基和己炔基。术语“卤代C1-C6烷基”是指被一个或多个卤原子取代的烷基，如-CH2F、-CF3、-CH2CHF3等。In the present invention, the term "C 1 -C 6 alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl. And butyl and the like; the term "C 1 -C 4 alkyl" has a similar meaning. The term "C 2 -C 6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and having one double bond, and includes, without limitation, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group. , pentynyl and hexynyl. The term "halo C 1 -C 6 alkyl" refers to an alkyl group substituted with one or more halogen atoms, such as -CH 2 F, -CF 3 , -CH 2 CHF 3 and the like.
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等；术语“C1-C4烷氧基”具有类似的含义。In the present invention, the term "C 1 -C 6 alkoxy" means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group. Base, isopropoxy and butoxy, etc.; the term "C 1 -C 4 alkoxy" has a similar meaning.
在本发明中，术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等；术语“C3-C6环烷基”具有类似的含义。术语“C3-C8环烯基”是指环上具有3至8个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基等。In the present invention, the term "C 3 -C 8 cycloalkyl" means a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. , cyclohexyl, cycloheptyl, cyclooctyl, etc.; the term "C 3 -C 6 cycloalkyl" has a similar meaning. The term "C 3 -C 8 cycloalkenyl" refers to a cyclic alkenyl group having from 3 to 8 carbon atoms in the ring, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl Wait.
本发明中，术语“芳基”表示包含一个或多个芳环的烃基，如苯基或萘基等。In the present invention, the term "aryl" means a hydrocarbon group containing one or more aromatic rings such as a phenyl group or a naphthyl group and the like.
术语“杂芳基”表示包含1-4个选自N、O、S的杂原子的芳环基团，非限制性地包括吡唑基、噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、吡咯基、噁唑基、异噁唑基、咪唑基、噻唑基、异噻唑基、喹唑啉基、喹啉基、异喹啉基和吲哚基。The term "heteroaryl" denotes an aromatic ring group containing from 1 to 4 heteroatoms selected from N, O, S, including, without limitation, pyrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, quinazolinyl, quinolyl, isoquinolyl and anthracenyl.
本发明中，术语“杂环基”表示包含1-4个选自N、O、S的杂原子的环烷基，非限制性地包括吡咯烷基、吗啉基、哌啶基、硫代吗啉基、哌嗪基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻唑基。In the present invention, the term "heterocyclyl" means a cycloalkyl group containing from 1 to 4 hetero atoms selected from N, O, S, and includes, without limitation, pyrrolidinyl, morpholinyl, piperidinyl, thio. Morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiazolyl.
制备方法Preparation
本发明的的通式I化合物、其立体异构体或其药学上可以接受的盐可通过如下方法制备：The compound of the formula I according to the invention, its stereoisomer or a pharmaceutically acceptable salt thereof can be prepared by the following method:
路线1： Route 1:
Figure PCTCN2016080725-appb-000022
Figure PCTCN2016080725-appb-000022
(a)式Ia-1或Ia-2化合物与Y-Ar-(CH2)nXH在碱存在下反应得到式Ib化合物；(a) a compound of the formula Ia-1 or Ia-2 is reacted with Y-Ar-(CH 2 ) n XH in the presence of a base to give a compound of the formula Ib;
(b)溴代乙醛与式Ib化合物发生关环反应生成式Ic；(b) bromoacetaldehyde and a compound of formula Ib undergo a ring closure reaction to form formula Ic;
(c)Ib化合物与
Figure PCTCN2016080725-appb-000023
发生关环反应生成式II；(c) Ib compounds and
Figure PCTCN2016080725-appb-000023
The ring closure reaction occurs to form formula II;
(d)式Ic化合物与N-溴代丁二酰亚胺反应得到式Id化合物；(d) reacting a compound of formula Ic with N-bromosuccinimide to provide a compound of formula Id;
(e)式Id化合物与R1的硼酸或硼酯发生Suzuki反应得到式II化合物；(e) a compound of formula Id with a R boronic acid or boron ester occurring Suzuki reaction to give the compound of formula II;
(f)式Ic化合物与R1W反应得到式II化合物，其中，所述W为Cl、Br或I；(f) a compound of formula Ic is reacted with R 1 W to give a compound of formula II, wherein W is Cl, Br or I;
路线2： Route 2:
Figure PCTCN2016080725-appb-000024
Figure PCTCN2016080725-appb-000024
(g)式Ia-1或Ia-2化合物与苄硫醇在碱存在下反应得到式IIa化合物；(g) a compound of the formula Ia-1 or Ia-2 is reacted with a benzyl mercaptan in the presence of a base to give a compound of the formula IIa;
(h)溴代乙醛与式IIa化合物发生关环反应生成式IIb；(h) bromoacetaldehyde and a compound of formula IIa undergo a ring closure reaction to form formula IIb;
(i)式IIb化合物与R1W在醋酸钯催化下反应得到式IIc化合物，其中，W为Cl、Br或I；(i) a compound of formula IIb and R 1 W are catalyzed by palladium acetate to give a compound of formula IIc, wherein W is Cl, Br or I;
(j)式IIc化合物由间氯过氧苯甲酸氧化得到式IId化合物；(j) a compound of formula IIc is oxidized from m-chloroperoxybenzoic acid to give a compound of formula IId;
(k)式IId化合物与Y-Ar-(CH2)nXH在碱存在下反应得到式II化合物；(k) reacting a compound of formula IId with Y-Ar-(CH 2 ) n XH in the presence of a base to give a compound of formula II;
路线3：Route 3:
Figure PCTCN2016080725-appb-000025
Figure PCTCN2016080725-appb-000025
(l)式IIIa化合物与Y-Ar-(CH2)nXH在碱存在下反应得到式IIIb化合物；(l) a compound of formula IIIa is reacted with Y-Ar-(CH 2 ) n XH in the presence of a base to give a compound of formula IIIb;
(o)式IIIb化合物与水合肼发生亲核取代生成式IIIc； (o) a compound of formula IIIb is nucleophilically substituted with hydrazine hydrate to form formula IIIc;
(p)式IIIc化合物与原甲酸三乙酯发生关环反应得到式IIId化合物；(p) a compound of formula IIIc is reacted with triethyl orthoformate to give a compound of formula IIId;
(q)式IIId化合物与N-溴代丁二酰亚胺反应得到式IIIe化合物；(q) reacting a compound of formula IIId with N-bromosuccinimide to provide a compound of formula IIIe;
(r)式IIIe化合物与R1的硼酸或硼酯发生Suzuki反应得到式III化合物；(r) a compound of formula IIIe is subjected to a Suzuki reaction with a boronic acid or a boronic ester of R 1 to give a compound of formula III;
在另一优选例中，所述R1的硼酸或硼酯选自
Figure PCTCN2016080725-appb-000026
Figure PCTCN2016080725-appb-000027
In another preferred embodiment, the boric acid or boron ester of R 1 is selected from
Figure PCTCN2016080725-appb-000026
Figure PCTCN2016080725-appb-000027
所述步骤(a)、(g)、(k)或(1)中的碱选自无机碱、有机碱和其组合；优选地，所述无机碱选自氢氧化钠、氢氧化钾、氢氧化锶、氢氧化锂、氢氧化钡、氢氧化钙、氢氧化铯、碳酸氢钠、碳酸氢钾、碳酸钾、碳酸钠、碳酸锶、碳酸铯、硫化钠、钠氢和其组合；所述有机碱选自醇钠、醇钾、丁基锂、1，8-二氮杂环[5，4，0]十一烯-7、吡啶、哌啶、吡咯烷、吗啉、N-甲基吗啉、喹啉、4-二甲氨基吡啶、三乙胺、二乙胺、三正丁胺、三丙基胺、二异丙基胺、二异丙基乙胺和其组合；更优选地，所述碱选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸氢钠、碳酸氢钾、碳酸钾、碳酸钠、碳酸铯、钠氢、甲醇钠、乙醇钠、叔丁醇钾、吡啶、哌啶、吡咯烷、吗啉、N-甲基吗啉、三乙胺、二乙胺、二异丙基胺、二异丙基乙胺和其组合；所述反应的反应溶剂选自芳烃类溶剂、醚类溶剂、卤代烃类溶剂和其他溶剂；优选地，所述芳烃类溶剂选自苯、甲苯、二甲苯、氯苯、硝基苯和其组合；所述醚类溶剂选自四氢呋喃、乙醚、乙二醇二甲醚、二乙二醇二甲醚、乙二醇单甲醚、二氧六环和其组合；所述卤代烃类溶剂选自二氯甲烷、氯仿、四氯化碳、二氯乙烷和其组合；所述其他溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮、六甲基磷酰胺、丙酮、乙腈、乙酸乙酯和其组合；优选地，所述反应的反应温度为-30℃～300℃，更优选-10℃～150℃；优选地，所述反应的反应时间为0.5～12小时。 The base in the step (a), (g), (k) or (1) is selected from the group consisting of inorganic bases, organic bases, and combinations thereof; preferably, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and hydrogen. Cerium oxide, lithium hydroxide, barium hydroxide, calcium hydroxide, barium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, barium carbonate, barium carbonate, sodium sulfide, sodium hydrogen, and combinations thereof; The organic base is selected from the group consisting of sodium alkoxide, potassium alkoxide, butyl lithium, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, piperidine, pyrrolidine, morpholine, N-methyl Morpholine, quinoline, 4-dimethylaminopyridine, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, and combinations thereof; more preferably The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogen, sodium methoxide, sodium ethoxide, potassium t-butoxide, and pyridine. , piperidine, pyrrolidine, morpholine, N-methylmorpholine, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine, and combinations thereof; the reaction solvent for the reaction is selected from the group consisting of aromatic hydrocarbons Solvent-like, ether soluble a halogenated hydrocarbon solvent and other solvents; preferably, the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, and combinations thereof; the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, and ethyl Diol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane and combinations thereof; the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, and Ethyl chloride and a combination thereof; the other solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphoramide, Acetone, acetonitrile, ethyl acetate and combinations thereof; preferably, the reaction temperature of the reaction is from -30 ° C to 300 ° C, more preferably from -10 ° C to 150 ° C; preferably, the reaction time of the reaction is from 0.5 to 12 hour.
用途use
本发明化合物是Lp-PLA2抑制剂。因此这些化合物可用于治疗，例如治疗与Lp-PLA2的活性有关的病症。因此，本发明的另一方面涉及治疗与Lp-PLA2的活性有关的病症。本领域技术人员可以理解，特定的病症或其治疗可以涉及与Lp-PLA2活性有关的一种或多种基础机制，包括一种或多种本文中描述的机制。The compounds of the invention are Lp-PLA 2 inhibitors. These compounds are therefore useful in the treatment, for example, in the treatment of conditions associated with the activity of Lp-PLA 2 . Accordingly, another aspect of the present invention relates to the treatment associated with Lp-PLA 2 activity is a disorder. One of skill in the art will appreciate that a particular disorder or treatment thereof can involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including one or more of the mechanisms described herein.
在具体实施方式中，本发明化合物可用于治疗涉及内皮机能障碍的任何疾病，例如，动脉粥样硬化、糖尿病、高血压、心绞痛和局部缺血和再灌注后的病症。In a specific embodiment, the compounds of the invention are useful in the treatment of any disease involving endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, angina pectoris, and conditions following ischemia and reperfusion.
在具体实施方式中，本发明化合物可用于治疗涉及与酶活性有关联的脂质氧化的任何疾病，例如，除了例如动脉粥样硬化和糖尿病等病症外的其他病症，例如类风湿性关节炎、中风、脑的炎性病症例如阿尔茨海默病、各种神经精神病症如精神分裂症、心肌梗死、局部缺血、再灌注损伤、败血症以及急性和慢性炎症。In a specific embodiment, the compounds of the invention are useful in the treatment of any disease involving lipid oxidation associated with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, such as rheumatoid arthritis, Stroke, brain inflammatory conditions such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
在具体实施方式中，本发明化合物可用于治疗涉及活化的单核细胞、巨噬细胞或淋巴细胞的疾病，因为所有这些细胞种类表达Lp-PLA2，包括涉及活化的巨噬细胞的疾病，典型的病症包括但不限于牛皮癣、类风湿性关节炎、伤口愈合、慢性阻塞性肺病、肝硬化、特应性皮炎、肺气肿、慢性胰腺炎、慢性胃炎、主动脉瘤、动脉粥样硬化、多发性硬化、阿尔茨海默病和自身免疫疾病如狼疮。In a specific embodiment, the compounds of the invention are useful in the treatment of diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA 2 , including diseases involving activated macrophages, typically Conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease, cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, Multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus.
在具体实施方式中，本发明提供治疗与Lp-PLA2活性有关的疾病的方法，其包括用有效量的Lp-PLA2抑制剂治疗需要治疗的受试者。所述疾病可以与单核细胞、巨噬细胞或淋巴细胞的参与增加有关；与溶血磷脂酰胆碱和氧化的游离脂肪酸的形成有关；与相关联的Lp-PLA2活性的脂质氧化有关；或与内皮机能障碍有关。In a specific embodiment, the invention provides a method of treating a disease associated with Lp-PLA 2 activity comprising treating a subject in need of treatment with an effective amount of an Lp-PLA 2 inhibitor. The disease may be associated with increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidized free fatty acids; associated with lipid oxidation of associated Lp-PLA 2 activity; Or related to endothelial dysfunction.
在其他实施方式中，本发明化合物可以用于急性冠状动脉事件的初级或次级预防，预防再狭窄的联合治疗或延迟糖尿病或高血压性肾功能不全的发展。预防和治疗具有这样病症的风险的受试者。In other embodiments, the compounds of the invention may be used for primary or secondary prevention of acute coronary events, for the prevention of combination therapy for restenosis or for delaying the development of diabetes or hypertensive renal insufficiency. A subject having a risk of such a condition is prevented and treated.
在一些实施方式中，本发明化合物可用于与抗高血脂剂、抗动脉粥样硬化剂、抗糖尿病剂、抗心绞痛剂或抗高血压剂或用于降低脂蛋白a的药剂结合来治疗本发明描述的疾病。上述药剂的例子包括但不限于，胆固醇合成抑 制剂，例如他汀类；抗氧化剂，例如丙丁酚；胰岛素致敏剂；钙通道拮抗剂和抗炎药，例如非甾体抗炎药。In some embodiments, the compounds of the invention are useful in combination with an antihyperlipidemic agent, an antiatherogenic agent, an anti-diabetic agent, an anti-angina or an antihypertensive agent, or an agent for lowering lipoprotein a to treat the present invention. Described disease. Examples of the above agents include, but are not limited to, cholesterol synthesis Formulations, such as statins; antioxidants, such as probucol; insulin sensitizers; calcium channel antagonists and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs.
在一个实施方式中，本发明化合物可用于治疗受试者的神经退行性疾病。所述方法包括将含有抑制Lp-PLA2活性的药物的药物组合物给药于需要治疗的受试者。示例性的神经退行性疾病包括但不限于，阿尔茨海默病、血管性痴呆、帕金森病和亨廷顿舞蹈症。在一个具体实施方式中，本发明所述神经退行性疾病与异常的血脑屏障有关。在一个实施方式中，给药抑制Lp-PLA2活性的药剂的受试者是人。In one embodiment, the compounds of the invention are useful for treating a neurodegenerative disease in a subject. The method comprises administering a pharmaceutical composition comprising a drug that inhibits Lp-PLA 2 activity to a subject in need of treatment. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In a specific embodiment, the neurodegenerative disease of the invention is associated with an abnormal blood-brain barrier. In one embodiment, the subject to whom the agent that inhibits Lp-PLA 2 activity is administered is a human.
在一个实施方式中，本发明提供治疗患有血管性痴呆或具有血管性痴呆风险的受试者的方法。所述方法包括将含有有效量的本发明化合物的药物组合物给药于受试者。在一具体实施方式中，所述血管性痴呆与阿尔茨海默病有关。In one embodiment, the invention provides a method of treating a subject having or at risk of having vascular dementia. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a compound of the invention. In a specific embodiment, the vascular dementia is associated with Alzheimer's disease.
在具体实施方式中，本发明提供治疗需要治疗的受试者中与异常血脑屏障功能、炎症或小神经胶质活化有关的神经系统病症的方法。所述方法包括将有效量的本发明化合物给药于受试者。在另一个实施方式中，所述异常血脑屏障是渗透性血脑屏障。在另一个实施方式中，所述疾病是神经退行性疾病。这类神经退行性疾病例如但不限于，血管性痴呆、阿尔茨海默病、帕金森病和亨廷顿舞蹈病。在一个实施方式中，本发明提供治疗受试者的与血脑屏障泄露有关的疾病的方法。示例性的疾病包括但不限于，脑出血、脑淀粉样血管病。在一个实施方式中，所述神经退行性疾病是阿尔茨海默病。在一个实施方式中，所述神经退行性疾病是血管性痴呆。在一个实施方式中，所述神经退行性疾病是多发性硬化症。In a specific embodiment, the invention provides a method of treating a neurological disorder associated with abnormal blood-brain barrier function, inflammation, or microglial activation in a subject in need of treatment. The method comprises administering an effective amount of a compound of the invention to a subject. In another embodiment, the abnormal blood brain barrier is a permeable blood brain barrier. In another embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are, for example but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In one embodiment, the invention provides a method of treating a condition associated with blood-brain barrier leakage in a subject. Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In one embodiment, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis.
在具体实施方式中，本发明提供降低受试者脑中β淀粉样蛋白积聚的方法。所述方法包括将含有有效量的本发明化合物的药物组合物给药于需要治疗的受试者。在另一个实施方式中，所述β淀粉样蛋白是Aβ-42。In a specific embodiment, the invention provides a method of reducing beta amyloid accumulation in a brain of a subject. The method comprises administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound of the invention. In another embodiment, the amyloid beta protein is A[beta]-42.
在具体实施方式中，当向受试者给药有效量的本发明化合物时，所述方法还可以包括将可用于治疗正在治疗的受试者的神经变性疾病或可能是合并症的另一种治疗剂给药于受试者，或者还可以包括同时采用其他疗法。例如，当所述神经变性疾病类似于阿尔茨海默症时，受试者可用靶向阿尔茨海默病的其他药剂或其他疗法治疗，所述药剂或疗法例如多奈哌齐、他克林、利凡斯的明、加兰他敏、抗淀粉样蛋白疫苗、Aβ降低疗法、思维练习或刺激。 In a specific embodiment, when an effective amount of a compound of the invention is administered to a subject, the method can further comprise treating another neurodegenerative disease or possibly a comorbidity that can be used to treat the subject being treated The therapeutic agent is administered to the subject or may also include the simultaneous use of other therapies. For example, when the neurodegenerative disease is similar to Alzheimer's disease, the subject may be treated with other agents or other therapies that target Alzheimer's disease, such as donepezil, tacrine, and lifan Smectin, galantamine, anti-amyloid vaccine, Aβ reduction therapy, thinking practice or stimulation.
在具体实施方式中，本发明涉及通过将有效量的本发明化合物给药于需要治疗的受试者治疗代谢性骨病的方法。示例性的代谢性骨病包括与骨质和骨密度损失有关的疾病，包括但不限于骨质疏松症和骨质减少相关疾病。示例性的骨质疏松症和骨质减少相关疾病包括但不限于，骨髓异常、血脂异常、帕吉特氏病、II型糖尿病、代谢综合征、胰岛素抵抗、甲状旁腺亢进和相关疾病。在另一个实施方式中，需要治疗的受试者是人。In a specific embodiment, the invention relates to a method of treating metabolic bone disease by administering an effective amount of a compound of the invention to a subject in need of treatment. Exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density including, but not limited to, osteoporosis and osteopenia related diseases. Exemplary osteoporosis and osteopenia related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Parkid's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In another embodiment, the subject in need of treatment is a human.
通常认为预防本文描述的骨质疏松症和/或骨质减少疾病的方法可能受到抑制Lp-PLA2的表达和/或抑制Lp-PLA2的蛋白活性的影响。因此，本发明的一些实施方式提供阻断酶活性来抑制Lp-PLA2的方法。在另一个实施方式中，提供了通过降低和/或下调Lp-PLA2RNA的表达从而抑制Lp-PLA2的方法。在另一个实施方式中，预防和/或降低骨质损失和/或骨密度损失，从而预防或减少与代谢性骨病例如骨质疏松症和/或骨质减少疾病有关的症状。It is generally believed that methods of preventing osteoporosis and/or osteopenia diseases described herein may be affected by inhibition of Lp-PLA 2 expression and/or inhibition of Lp-PLA 2 protein activity. Accordingly, some embodiments of the present invention provides a method of suppressing blocking activity of Lp-PLA 2 is. In another embodiment, a method of inhibiting Lp-PLA 2 by reducing and/or downregulating expression of Lp-PLA 2 RNA is provided. In another embodiment, bone loss and/or loss of bone density is prevented and/or reduced, thereby preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenia.
在具体实施方式中，所述方法还包括将用于治疗代谢性骨病的其他治疗剂给药于需要治疗的受试者。例如，当所述代谢性骨病是骨质疏松症时，可以使用其他治疗剂，例如双磷酸盐类治疗剂。In a specific embodiment, the method further comprises administering to the subject in need of treatment additional therapeutic agents for treating metabolic bone disease. For example, when the metabolic bone disease is osteoporosis, other therapeutic agents such as bisphosphonate therapeutic agents can be used.
本发明的一方面提供通过给药有效量的本发明化合物治疗眼病的方法。本发明适用的眼病可以与血视网膜内屏障的破坏有关。示例性的眼病涉及糖尿病性眼病和包括黄斑水肿、糖尿病性视网膜病等的病症。此外，在一个实施方式中，本发明涉及通过给药本发明化合物以抑制Lp-PLA2治疗眼病的方法。示例性的眼病包括但不限于，视网膜中央静脉阻塞、视网膜分枝静脉阻塞、伊-加综合征、色素性视网膜炎、平坦部炎、鸟枪弹样视网膜脉络膜病变、视网膜外层膜、脉络膜肿瘤、囊性黄斑水肿、旁中心凹毛细血管扩张、牵引性黄斑病、玻璃体黄斑牵引综合征、视网膜剥离、视神经视网膜炎、特发性黄斑水肿等。One aspect of the invention provides a method of treating an ocular condition by administering an effective amount of a compound of the invention. The eye disease to which the present invention is applicable may be related to the destruction of the blood retinal barrier. Exemplary ocular diseases involve diabetic ocular diseases and conditions including macular edema, diabetic retinopathy, and the like. Further, in one embodiment, the present invention relates to a method to inhibit the Lp-PLA 2 for treating eye diseases by administration of the compounds of the present invention. Exemplary ocular diseases include, but are not limited to, central retinal vein occlusion, retinal branch vein occlusion, I-plus syndrome, retinitis pigmentosa, flattening inflammation, shotgun-like retinal choroidal lesion, retinal outer membrane, choroidal neoplasm, Cystic macular edema, paracentral telangiectasia, traction macular disease, vitreoma macular traction syndrome, retinal detachment, optic nerve retinitis, idiopathic macular edema, etc.
此外，本发明的一些实施方式提供用于治疗受试者的糖尿病黄斑水肿的方法。所述方法包括将有效量的本发明化合物给药于需要治疗的受试者。在具体实施方式中，本发明提供用于治疗患有黄斑水肿或具有黄斑水肿风险的受试者的方法。所述方法包括将有效量的本发明化合物给药于受试者。在另一个实施方式中，所述黄斑水肿与糖尿病性眼病例如糖尿病视网膜病有关。在另一个实施方式中，所述黄斑水肿与后葡萄膜炎有关。Moreover, some embodiments of the invention provide methods for treating diabetic macular edema in a subject. The method comprises administering an effective amount of a compound of the invention to a subject in need of treatment. In a specific embodiment, the invention provides methods for treating a subject having macular edema or having a risk of macular edema. The method comprises administering an effective amount of a compound of the invention to a subject. In another embodiment, the macular edema is associated with a diabetic eye disease, such as diabetic retinopathy. In another embodiment, the macular edema is associated with posterior uveitis.
在具体实施方式中，本发明提供治疗青光眼或黄斑变性的方法。所述方法包括将有效量的本发明化合物给药于受试者。 In a specific embodiment, the invention provides a method of treating glaucoma or macular degeneration. The method comprises administering an effective amount of a compound of the invention to a subject.
在一个实施方式中，本发明提供治疗需要治疗的受试者的与血视网膜内屏障破坏有关的疾病的方法。所述方法包括将有效量的本发明化合物给药于受试者。In one embodiment, the invention provides a method of treating a condition associated with disruption of the blood retinal barrier in a subject in need of treatment. The method comprises administering an effective amount of a compound of the invention to a subject.
在一个实施方式中，全身性炎性疾病例如青少年类风湿性关节炎、炎性肠病、川崎病、多发性硬化、结节病、多动脉炎、牛皮癣性关节炎、反应性关节炎、系统性红斑狼疮、伏-小柳-原田综合征、莱姆病、贝赫切特病、强直性脊柱炎、炎性肉芽肿性疾病等。本发明涉及通过给药有效量的本发明化合物治疗后葡萄膜炎或这些全身炎性疾病中的任一种的方法。In one embodiment, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, system Lupus erythematosus, Fu-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, inflammatory granulomatous disease, etc. The present invention relates to a method of treating uveitis or any of these systemic inflammatory diseases by administering an effective amount of a compound of the present invention.
使用方法Instructions
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 by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be present 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 safe or 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 according to the invention contains 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 of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; 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) can be used clinically in mammals, including humans and animals, and the route of administration can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract. A preferred route of administration is oral. Preferably, it is a unit dosage form, and each dose contains 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, of the active ingredient, once or in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the particular 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. From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and solid filled or liquid filled capsules. Oral administration of the pharmaceutical composition is preferred.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York：Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. The suggested conditions. Percentages and parts are by weight unless otherwise stated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的优选实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.
制备实施例Preparation example
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。本发明中用到的起始原料未经特别说明，均购自百灵威、泰坦科技、韶远化学、达瑞化学、国药等等。The invention will be further illustrated in the following examples. These examples are for illustrative purposes only and are not intended to limit the invention in any way. The starting materials used in the present invention are not specifically described, and are all purchased from Billingway, Titan Technology, Suiyuan Chemical, Dari Chemical, Sinopharm, and the like.
中间体1——(4-(4-氯-3-(三氟甲基)苯氧基)苯基)甲醇Intermediate 1 - (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol
Figure PCTCN2016080725-appb-000028
Figure PCTCN2016080725-appb-000028
将4-氯-3-(三氟甲基)苯酚(6.5g，1当量)，对氟苯甲醛(3.9ml，1.1当量)以及无水碳酸钾(6g，1.3当量)溶于N，N-二甲基甲酰胺中，氮气保护，120℃搅拌2h，冷却，加水，乙酸乙酯萃取两次，饱和食盐水洗三次，无水硫酸镁干燥，过滤，蒸干溶剂得11g中间体1a。MS(ESI)：301(M+H)。4-Chloro-3-(trifluoromethyl)phenol (6.5 g, 1 equivalent), p-fluorobenzaldehyde (3.9 ml, 1.1 equivalents) and anhydrous potassium carbonate (6 g, 1.3 equivalents) were dissolved in N,N- The dimethylformamide was purged with nitrogen, stirred at 120 ° C for 2 h, cooled, water was added, and ethyl acetate was evaporated. MS (ESI): 301 (M + H).
将中间体1a(4.0g，1当量)溶于50ml无水乙醇，冰浴下加入硼氢化钠(493mg，1当量)，然后室温搅拌1h。加入氯化铵水溶液淬灭反应，蒸干溶剂，加入水，乙酸乙酯提取两次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得4g中间体1。MS(ESI)：285(M-17)。Intermediate 1a (4.0 g, 1 eq.) was dissolved in 50 mL EtOAc. The reaction was quenched by the addition of aqueous ammonium chloride solution, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. MS (ESI): 285 (M-17).
中间体2——(4-(4-氯-3-(三氟甲基)苯氧基)苯基)甲硫醇 Intermediate 2 - (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methylmercaptan
Figure PCTCN2016080725-appb-000029
Figure PCTCN2016080725-appb-000029
将中间体1(1.0g，1当量)溶于重蒸二氯甲烷中，冰浴下滴加二氯亚砜(480μl，2当量)，滴加完成后室温搅拌2h，然后蒸干溶剂及二氯亚砜，得1.05g中间体2a，不需纯化直接用于下一步。The intermediate 1 (1.0 g, 1 eq.) was dissolved in dichloromethane, and then chlorosulfoxide (480 μl, 2 eq.) was added dropwise in an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 h, then evaporated and evaporated. Chlorosulfoxide gave 1.05 g of intermediate 2a which was used directly in the next step without purification.
将中间体2a(210mg，1当量)与硫脲(70mg，1.4当量)混于2ml无水乙醇中，回流4h，冷却至室温，加入10N氢氧化钠水溶液(2ml)，回流3h，冷却至室温，加4N盐酸水溶液调节PH至5，乙酸乙酯萃取3次，饱和食盐水洗1次，无水硫酸镁干燥，过滤，蒸干溶剂，无需纯化直接用于下一步。MS(ESI)：285(M-33)。Intermediate 2a (210 mg, 1 eq.) was combined with thiourea (70 mg, 1.4 eq.) in EtOAc (EtOAc) The pH was adjusted to 5 with 4N aqueous hydrochloric acid, extracted with ethyl acetate (3×), brine, and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated. MS (ESI): 285 (M-33).
中间体3——(4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苯基)甲醇Intermediate 3 - (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol
Figure PCTCN2016080725-appb-000030
Figure PCTCN2016080725-appb-000030
将4-氯-3-(三氟甲基)苯酚(4.67g，1当量)，3，4，5-三氟苯甲醛(4.0g，1.05当量)以及无水碳酸钾(4.27g，1.3当量)溶于N，N-二甲基甲酰胺中，氮气保护，120℃搅拌2h，冷却，加水，乙酸乙酯萃取两次，饱和食盐水洗三次，硫酸镁干燥，过滤，蒸干溶剂得8.0g中间体3a。MS(ESI)：337(M+H)。4-Chloro-3-(trifluoromethyl)phenol (4.67 g, 1 eq.), 3,4,5-trifluorobenzaldehyde (4.0 g, 1.05 eq.) and anhydrous potassium carbonate (4.27 g, 1.3 eq. Dissolved in N,N-dimethylformamide, protected with nitrogen, stirred at 120 ° C for 2 h, cooled, added water, extracted with EtOAc EtOAc EtOAc. Intermediate 3a. MS (ESI): 337 (M + H).
中间体3a(4.0g，1当量)溶于50ml无水乙醇，冰浴下加入硼氢化钠(440mg，1当量)，然后室温搅拌1h。加入氯化铵水溶液淬灭反应，蒸干溶剂，加入水，乙酸乙酯提取两次，饱和食盐水洗一次，无水硫酸钠干燥，柱层析分离得4g中间体3。MS(ESI)：321(M-17)。Intermediate 3a (4.0 g, 1 eq.) was dissolved in EtOAc (EtOAc)EtOAc. The reaction was quenched by the addition of aqueous ammonium chloride solution, and the solvent was evaporated to dryness. MS (ESI): 321 (M-17).
中间体4——2-(4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苯基)乙烷-1-醇Intermediate 4 - 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)ethane-1-ol
Figure PCTCN2016080725-appb-000031
Figure PCTCN2016080725-appb-000031
将氢化钠(950mg，4当量)置于烧瓶中，冰浴下，依次加入超干四氢呋喃，甲基三苯基溴化磷(2.54g，1.2当量)，0℃搅拌1h，然后加入中间体3a(2g，1当量)，室温搅拌2h。反应完成后，柱层析分离得730mg中间体4a。Sodium hydride (950 mg, 4 eq.) was placed in a flask, and then, under ice-cooling, EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) (2 g, 1 equivalent), stirred at room temperature for 2 h. After completion of the reaction, column chromatography gave 730 mg of Intermediate 4a.
将中间体4a(730mg，1当量)溶于超干四氢呋喃，氮气保护，冰浴下加入1N硼烷四氢呋喃溶液(2.2ml，1.2当量)，室温搅拌1h，然后冰浴下缓慢滴加2ml甲醇淬灭多余硼烷，分批加入氢氧化钠(350mg，4当量)，继而加入过氧化氢(3.1ml，30％水溶液，14当量)，加料完成后60℃反应2h，亚硫酸钠水溶液淬灭反应，乙酸乙酯萃取三次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得600mg中间体4。MS(ESI)：348(M-17)。The intermediate 4a (730 mg, 1 eq.) was dissolved in EtOAc (EtOAc) (EtOAc m. Excess borane was added, sodium hydroxide (350 mg, 4 equivalents) was added in portions, followed by hydrogen peroxide (3.1 ml, 30% aqueous solution, 14 equivalents). After the addition was completed, the reaction was carried out at 60 ° C for 2 h, and the aqueous solution of sodium sulfite was quenched. The ethyl ester was extracted three times, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. MS (ESI): 348 (M-17).
中间体5——4-(4-氯-3-(三氟甲基)苯氧基)苯酚Intermediate 5 - 4-(4-chloro-3-(trifluoromethyl)phenoxy)phenol
Figure PCTCN2016080725-appb-000032
Figure PCTCN2016080725-appb-000032
中间体1a(200mg，1当量)溶于氯仿，冰浴下，加入间氯过氧苯甲酸(246mg，1.5当量，70％)，室温搅拌24h，加入碳酸氢钠水溶液，剧烈搅拌一段时间，分出氯仿层，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得150mg中间体5。MS(ESI)：289(M+1)。Intermediate 1a (200 mg, 1 eq.) was dissolved in chloroform, EtOAc (EtOAc: EtOAc. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. MS (ESI): 289 (M+1).
中间体6——3-(4-(4-氯-3-(三氟甲基)苯氧基)苯基)丙烷-1-醇Intermediate 6 - 3-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)propan-1-ol
Figure PCTCN2016080725-appb-000033
Figure PCTCN2016080725-appb-000033
4-氯-3-(三氟甲基)苯酚(200mg，1当量)，对二碘苯(336mg，1当量)，磷酸钾(432mg，2当量)，碘化亚铜(19mg，0.1当量)以及四丁基溴化铵(33mg，0.1当量)混于N，N-二甲基甲酰胺中，150℃反应22h。加水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得150mg中间体6a。 4-Chloro-3-(trifluoromethyl)phenol (200 mg, 1 eq.), p-diiodobenzene (336 mg, 1 eq.), potassium phosphate (432 mg, 2 eq.), cuprous iodide (19 mg, 0.1 eq.) And tetrabutylammonium bromide (33 mg, 0.1 equivalent) was mixed in N,N-dimethylformamide, and reacted at 150 ° C for 22 h. Add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filtered, and evaporated to dryness.
中间体6a(150mg，1当量)，丙烯醇(33mg，1.5当量)，碳酸氢钠(79mg，2.5当量)，四丁基氯化铵(105mg，1当量)以及醋酸钯(2mg，0.02当量)混于N，N-二甲基甲酰胺中，60℃搅拌5h。加水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得65mg中间体6b。Intermediate 6a (150 mg, 1 eq.), propylene alcohol (33 mg, 1.5 eq.), sodium bicarbonate (79 mg, 2.5 eq.), tetrabutylammonium chloride (105 mg, 1 eq.) and palladium acetate (2 mg, 0.02 eq.) It was mixed with N,N-dimethylformamide and stirred at 60 ° C for 5 h. After adding water, ethyl acetate extraction, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.
中间体6b(65mg，1当量)溶于无水乙醇中，冰浴下，加入硼氢化钠(7.6mg，1当量)，室温反应30min。蒸干溶剂，加水，乙酸乙酯提取两次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得60mg中间体6。Intermediate 6b (65 mg, 1 eq.) was dissolved in dry ethyl ether. EtOAc (EtOAc) The solvent was evaporated to dryness. EtOAc was evaporated, evaporated, evaporated.
中间体7——(3-氟-4-((5-(三氟甲基)吡啶-2-基)氧基)苯基)甲醇Intermediate 7 - (3-fluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)methanol
Figure PCTCN2016080725-appb-000034
Figure PCTCN2016080725-appb-000034
除了以2-氯-5-(三氟甲基)吡啶与3-氟-4羟基苯甲醛为初始原料以外，参照中间体1的制备方法制备中间体7。Intermediate 7 was prepared by referring to the preparation method of Intermediate 1, except that 2-chloro-5-(trifluoromethyl)pyridine and 3-fluoro-4-hydroxybenzaldehyde were used as starting materials.
中间体8——(4-((4-(三氟甲基)噻唑-2-基)氧基)苯基)甲醇Intermediate 8 - (4-((4-(Trifluoromethyl)thiazol-2-yl)oxy)phenyl)methanol
Figure PCTCN2016080725-appb-000035
Figure PCTCN2016080725-appb-000035
3-溴-1，1，1-三氟丙烷-2-酮(5g，1当量)与硫脲(2.98g，1.5当量)溶于无水乙醇中，55℃反应3h。蒸干溶剂，加水，以氢氧化钠水溶液调节PH≈10，二氯甲烷提取四次，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得3.9g中间体8a。3-Bromo-1,1,1-trifluoropropan-2-one (5 g, 1 eq.) and thiourea (2.98 g, 1.5 eq.) were dissolved in anhydrous ethanol and reacted at 55 ° C for 3 h. The solvent was evaporated to dryness, and water was added, and the mixture was stirred with EtOAc EtOAc EtOAc EtOAc.
中间体8a(1.5g，1当量)与氯化铜(1.78g，1.5当量)溶于乙腈中，缓慢滴加入亚硝酸叔丁酯(1.6mL，1.5当量)，滴加完成后，反应0.5h，然后蒸掉大部分乙腈，加入稀盐酸，乙醚提取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂得1.0g中间体8b。 Intermediate 8a (1.5 g, 1 eq.) and copper chloride (1.78 g, 1.5 eq.) were dissolved in acetonitrile, and t-butyl nitrite (1.6 mL, 1.5 eq.) was slowly added dropwise. After the addition was completed, the reaction was carried out for 0.5 h. Then, most of the acetonitrile was distilled off, diluted with hydrochloric acid, extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated.
中间体8b(1g，1当量)，对羟基苯甲醛(0.65g，1.3当量)与碳酸钾(0.96g，1.3当量)混于N，N-二甲基甲酰胺中，85℃反应6h。反应完成后，加水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得0.65g中间体8c。Intermediate 8b (1 g, 1 eq.), p-hydroxybenzaldehyde (0.65 g, 1.3 eq.) and potassium carbonate (0.96 g, 1.3 eq.) were mixed in N,N-dimethylformamide and reacted at 85 ° C for 6 h. After completion of the reaction, water was added, and ethyl acetate was evaporated.
除了将中间体1a替换成中间体8c以外，参照从中间体1a到中间体1的制备方法来制备中间体8。Intermediate 8 was prepared with reference to the preparation of Intermediate 1a to Intermediate 1 except that Intermediate 1a was replaced with Intermediate 8c.
中间体9——(1-(3，4-二氯苄基)-1H-吡唑-4-基)甲醇Intermediate 9 - (1-(3,4-dichlorobenzyl)-1H-pyrazol-4-yl)methanol
Figure PCTCN2016080725-appb-000036
Figure PCTCN2016080725-appb-000036
氢化钠(0.6g，1.5当量)混悬于四氢呋喃中，冰浴，氮气保护下缓慢加入吡唑(760mg，1.1当量)，5min后加入1，2-二氯-4-(氯甲基)苯(1.38mL，1当量)，50℃反应过夜。氯化铵水溶液淬灭反应，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得2.08g中间体9a。Sodium hydride (0.6 g, 1.5 eq.) was suspended in tetrahydrofuran, and the mixture was stirred in an ice bath under a nitrogen atmosphere, and the pyrazole (760 mg, 1.1 eq.) was slowly added. After 5 min, 1,2-dichloro-4-(chloromethyl)benzene was added. (1.38 mL, 1 eq.), reacted at 50 ° C overnight. The ammonium chloride aqueous solution was quenched, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated.
中间体9a(1.0g，1当量)溶于干燥N，N-二甲基甲酰胺中，90℃～100℃下，逐滴加入三氯氧磷(0.45mL，1.1当量)，滴加完成后再继续反应2h。冷却后，冰浴下加入水淬灭反应，10％氢氧化钠水溶液调节PH≈9，乙酸乙酯萃取，饱和食盐水洗3次，无水硫酸钠干燥，过滤，蒸干溶剂得1.0g中间体9b。Intermediate 9a (1.0 g, 1 equivalent) was dissolved in dry N,N-dimethylformamide, and phosphorus oxychloride (0.45 mL, 1.1 eq.) was added dropwise at 90 ° C to 100 ° C. The reaction was continued for another 2 hours. After cooling, the reaction was quenched by adding water to an ice-bath, and the mixture was adjusted to pH ≈9 with 10% aqueous sodium hydroxide, and extracted with ethyl acetate. 9b.
除了将中间体1a替换成中间体9b以外，参照从中间体1a到中间体1的制备方法制备中间体9。Intermediate 9 was prepared with reference to the preparation of Intermediate 1a to Intermediate 1 except that Intermediate 1a was replaced with Intermediate 9b.
中间体10——(2-(4-氯-3-(三氟甲基)苯氧基)恶唑-5-基)甲醇 Intermediate 10 - (2-(4-chloro-3-(trifluoromethyl)phenoxy)oxazol-5-yl)methanol
Figure PCTCN2016080725-appb-000037
Figure PCTCN2016080725-appb-000037
溴丙酮酸乙酯(5mL，1当量)与尿素(3.22g，1.5当量)溶于无水乙醇中，回流反应5h，蒸干溶剂，加水，碳酸钠水溶液调节PH≈9，有白色固体析出，过滤收集沉淀，水洗，乙醇洗，干燥得2.8g中间体10a。Ethyl bromopyruvate (5 mL, 1 eq.) and urea (3.22 g, 1.5 eq.) were dissolved in absolute ethanol, refluxed for 5 h, and the solvent was evaporated to dryness. The precipitate was collected by filtration, washed with water, and washed with ethanol, and then evaporated
亚硝酸叔丁酯(3.22mL，1.5当量)与氯化铜(3.58g，1.5当量)溶于乙腈中，60℃下分批加入中间体10a(2.8g，1当量)，加完后升温至80℃反应1.5h，蒸掉大部分乙腈，加入水，二氯甲烷提取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干，柱层析分离得2.13g中间体10b。Tert-butyl nitrite (3.22 mL, 1.5 eq.) and copper chloride (3.58 g, 1.5 eq.) were dissolved in acetonitrile. Intermediate 10a (2.8 g, 1 eq.) was added portionwise at 60 ° C. The mixture was reacted at 80 ° C for 1.5 h, and most of the acetonitrile was evaporated. Water was added, dichloromethane was evaporated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.
除了初始原料为中间体10b与4-氯-3三氟甲基苯酚以外，参照中间体1a的制备方法制备中间体10c。Intermediate 10c was prepared by referring to the preparation method of Intermediate 1a, except that the starting material was Intermediate 10b and 4-chloro-3-trifluoromethylphenol.
除了将中间体1a替换成中间体10c以外，参照从中间体1a到中间体1的制备方法制备中间体10。 Intermediate 10 was prepared with reference to the preparation of Intermediate 1a to Intermediate 1 except that Intermediate 1a was replaced with Intermediate 10c.
中间体11——(6-(4-氯-3-(三氟甲基)苯氧基)-5氟吡啶-3-基)甲醇Intermediate 11 - (6-(4-chloro-3-(trifluoromethyl)phenoxy)-5-fluoropyridin-3-yl)methanol
Figure PCTCN2016080725-appb-000038
Figure PCTCN2016080725-appb-000038
2-氯-3-氟-5-甲基吡啶(200mg，1当量)，N-溴代丁二酰亚胺(734mg，3当量)以及过氧化苯甲酰(67mg，0.2当量)混于四氯化碳中，85℃反应 8.5h。蒸干溶剂，加水，乙酸乙酯萃取，饱和食盐水洗3次，无水硫酸钠干燥，过滤，蒸干溶剂得240mg中间体11a的粗品。2-Chloro-3-fluoro-5-methylpyridine (200 mg, 1 equivalent), N-bromosuccinimide (734 mg, 3 equivalents) and benzoyl peroxide (67 mg, 0.2 equivalent) mixed in four 85 ° C reaction in carbon chloride 8.5h. The solvent was evaporated to dryness, evaporated, evaporated, evaporated, evaporated,
中间体11a(240mg，1当量)与硝酸银(538mg，4当量)混于乙醇(2ml)和水(2ml)的混合溶液，100℃反应1h，过滤，蒸掉部分溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得60mg中间体11b。Intermediate 11a (240 mg, 1 eq.) and silver nitrate (538 mg, 4 eq.) were mixed with a mixture of ethanol (2 ml) and water (2 ml), and reacted at 100 ° C for 1 h, filtered, evaporated and evaporated. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.
除了将对氟苯甲醛替换成中间体11b以外，参照中间体1a的制备方法制备中间体11c。The intermediate 11c was prepared by referring to the preparation method of the intermediate 1a, except that p-fluorobenzaldehyde was replaced with the intermediate 11b.
除了将中间体1a替换成中间体11c以外，参照从中间体1a到中间体1的制备方法制备中间体11。MS(ESI)：322(M+1)。Intermediate 11 was prepared by referring to the preparation method from Intermediate 1a to Intermediate 1, except that Intermediate 1a was replaced with Intermediate 11c. MS (ESI): 322 (M+1).
中间体12——2-(4-(4-氯-3-(三氟甲基)苯氧基)苯基)乙烷-1-醇Intermediate 12 - 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)ethane-1-ol
Figure PCTCN2016080725-appb-000039
Figure PCTCN2016080725-appb-000039
除了以中间体1a为原料以外，参照中间体4的制备方法制备中间体12。Intermediate 12 was prepared by referring to the preparation method of Intermediate 4, except that Intermediate 1a was used as a starting material.
参考下表，除了采用“原料”一栏所述的原料替代相应的原料以外，参照中间体1的制备方法制备以下中间体13-27。Referring to the table below, the following intermediates 13-27 were prepared by referring to the preparation method of Intermediate 1, except that the raw materials described in the column of "raw materials" were used instead of the corresponding raw materials.
Figure PCTCN2016080725-appb-000040
Figure PCTCN2016080725-appb-000040
Figure PCTCN2016080725-appb-000041
Figure PCTCN2016080725-appb-000041
Figure PCTCN2016080725-appb-000042
Figure PCTCN2016080725-appb-000042
中间体28——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)咪唑[1，2-a]嘧啶Intermediate 28 - 7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000043
Figure PCTCN2016080725-appb-000043
中间体1(3.0g，1.5当量)溶于四氢呋喃，冰浴下加入氢化钠(0.8g，60％，3当量)，冰浴下搅拌30min，加入4-氯-2氨基嘧啶(0.85g，1当量)，室温反应过夜。反应完成后，冰浴下加入氯化铵水溶液淬灭反应，乙酸乙酯萃取3次，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得2.4g中间体28a。Intermediate 1 (3.0 g, 1.5 eq.) was dissolved in tetrahydrofuran, sodium hydride (0.8 g, 60%, 3 eq.). Equivalent), reacted overnight at room temperature. After completion of the reaction, the reaction was quenched with aqueous EtOAc (EtOAc)EtOAc.
溴代乙醛二甲基乙缩醛(2.4mL，8当量)与溴化氢水溶液(850μL，3当量，48％)溶于95％乙醇中，80℃水解6h，冷却，分批加入碳酸氢钠(1.0g，5当量)，然后加入中间体28a(1.0g，1当量)，置于70℃反应2h。反应完成后，蒸干溶剂，加入二氯甲烷，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得310mg产品中间体28。MS(ESI)：420(M+H)。Bromoacetaldehyde dimethyl acetal (2.4 mL, 8 equivalents) and aqueous hydrogen bromide (850 μL, 3 equivalents, 48%) were dissolved in 95% ethanol, hydrolyzed at 80 ° C for 6 h, cooled, and hydrogen carbonate was added in portions. Sodium (1.0 g, 5 eq.) was then added to intermediate 28a (1.0 g, 1 eq.). After completion of the reaction, the solvent was evaporated to dryness. MS (ESI): 420 (M + H).
参考下表，除了采用“原料”一栏所述的原料替代相应的原料以外，参照中间体28的制备方法制备以下中间体29-51。Referring to the table below, the following intermediates 29-51 were prepared by reference to the preparation of Intermediate 28, except that the starting materials described in the "Materials" column were used in place of the corresponding starting materials.
Figure PCTCN2016080725-appb-000044
Figure PCTCN2016080725-appb-000044
Figure PCTCN2016080725-appb-000045
Figure PCTCN2016080725-appb-000045
Figure PCTCN2016080725-appb-000046
Figure PCTCN2016080725-appb-000046
Figure PCTCN2016080725-appb-000047
Figure PCTCN2016080725-appb-000047
Figure PCTCN2016080725-appb-000048
Figure PCTCN2016080725-appb-000048
中间体52——7-(苄基硫基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Intermediate 52——7-(Benzylthio)-3-(pyrimidin-5-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000049
Figure PCTCN2016080725-appb-000049
中间体49(685mg，1当量)，4-溴嘧啶(496mg，1.1当量)，醋酸钾(556mg，2当量)与醋酸钯(64mg，0.1当量)混于N，N-二甲基乙酰胺中，氮气置换，140℃反应2h。冷却，过滤，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得370mg中间体52。MS(ESI)：320(M+1)。Intermediate 49 (685 mg, 1 eq.), 4-bromopyrimidine (496 mg, 1.1 eq.), potassium acetate (556 mg, 2 eq.) and palladium acetate (64 mg, 0.1 eq.) in N,N-dimethylacetamide , nitrogen substitution, reaction at 140 ° C for 2 h. After cooling, filtration, ethyl acetate extraction, brine, dried over anhydrous sodium sulfate, filtered, evaporated. MS (ESI): 320 (M+1).
中间体53——7-(苄基磺酰基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Intermediate 53 - 7-(Benzylsulfonyl)-3-(pyrimidin-5-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000050
Figure PCTCN2016080725-appb-000050
中间体52(370mg，1当量)溶于重蒸二氯甲烷，冰浴下加入间氯过氧苯甲酸(715mg，2.5当量，70％)，冰浴下反应3h。碳酸氢钠水溶液淬灭反应，二氯甲烷提取，饱和碳酸氢钠水溶液洗，饱和食盐水洗，无水硫酸镁干燥，过滤，蒸干溶剂得240mg中间体53。MS(ESI)：352(M+1)。 Intermediate 52 (370 mg, 1 eq.) was dissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was quenched with EtOAc EtOAc m. MS (ESI): 352 (M+1).
中间体54——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)咪唑[1，2-a]嘧啶Intermediate 54 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000051
Figure PCTCN2016080725-appb-000051
中间体28(560mg，1当量)溶于四氢呋喃中，冰浴下加入N-溴代丁二酰亚胺(262mg，1.1当量)，然后室温反应1h。反应完成后，直接柱层析分离得240mg中间体54。MS(ESI)：498(M+1)。Intermediate 28 (560 mg, 1 eq.) was dissolved in tetrahydrofuran. N-bromosuccinimide (262 mg, 1.1 eq. After completion of the reaction, direct column chromatography gave 240 mg of Intermediate 54. MS (ESI): 498 (M+1).
中间体55——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)咪唑[1，2-a]嘧啶Intermediate 55 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)imidazole [1,2 -a]pyrimidine
Figure PCTCN2016080725-appb-000052
Figure PCTCN2016080725-appb-000052
除了以中间体29为原料以外，参照中间体54的制备方法制备中间体55。MS(ESI)：534(M+1)。Intermediate 55 was prepared by reference to the preparation of Intermediate 54 except that Intermediate 29 was used. MS (ESI): 534 (M+1).
中间体56——3-溴-7-(4-(4-氯-3-(三氟甲基)苯氧基)苯乙氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 56 - 3-bromo-7-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenylethoxy)-[1,2,4]triazole [4, 3-a]pyrimidine
Figure PCTCN2016080725-appb-000053
Figure PCTCN2016080725-appb-000053
中间体12(1g，1当量)与氢化钠(506mg，4当量，60％)混于N，N-二甲基甲酰胺中，冰浴下搅拌10min，加入2，4，-二氯嘧啶，室温反应30min。氯化铵水溶液淬灭反应，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得1.22g中间体56a。Intermediate 12 (1 g, 1 eq.) was combined with sodium hydride (506 mg, 4 eq, 60%) in N,N-dimethylformamide, stirred for 10 min. The reaction was carried out for 30 min at room temperature. The ammonium chloride aqueous solution was quenched, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated.
中间体56a(1.22g，1当量)溶于水合肼(7mL)中，回流反应1h。蒸干溶剂，得1.3g中间体56b，不需纯化，直接用于下一步反应。Intermediate 56a (1.22 g, 1 eq.) was dissolved in EtOAc (7 mL). The solvent was evaporated to dryness to give EtOAc (md.
中间体56b(1.3g，1当量)溶于原甲酸三乙酯(10mL)中，120℃反应3h。蒸干溶剂，柱层析分离得1.14g中间体56c。Intermediate 56b (1.3 g, 1 eq.) was dissolved in triethyl orthoformate (10 mL). The solvent was evaporated to dryness.
中间体56c(1.14g，1当量)溶于重蒸二氯甲烷中，加入N-溴代丁二酰亚胺(1027mg，2.2当量)，40℃反应过夜，直接柱层析分离得1.2g中间体56。MS(ESI)：513(M+1)。Intermediate 56c (1.14 g, 1 eq.) was dissolved in EtOAc (EtOAc) (EtOAc) Body 56. MS (ESI): 513 (M+1).
中间体57——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 57 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-[1,2 , 4] triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000054
Figure PCTCN2016080725-appb-000054
除了以中间体3为原料以外，参照中间体56的制备方法制备中间体57。MS(ESI)：535(M+1)。Intermediate 57 was prepared by reference to the preparation of Intermediate 56, except that Intermediate 3 was used as the starting material. MS (ESI): 535 (M+1).
中间体58——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-5-甲基咪唑[1，2-a]嘧啶Intermediate 58 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-5-methylimidazole [1,2-a Pyrimidine
Figure PCTCN2016080725-appb-000055
Figure PCTCN2016080725-appb-000055
除了以中间体50为原料以外，参照中间体54的制备方法制备中间体58。MS(ESI)：498(M+1)。MS(ESI)：512(M+1)。Intermediate 58 was prepared by reference to the preparation of Intermediate 54 except that Intermediate 50 was used. MS (ESI): 498 (M+1). MS (ESI): 512 (M + 1).
中间体59——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5二氟苄基)氧基)-5-甲基咪唑[1，2-a]嘧啶Intermediate 59——3-Bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-5-methylimidazole [1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000056
Figure PCTCN2016080725-appb-000056
除了以中间体51为原料以外，参照中间体54的制备方法制备中间体59。MS(ESI)：548(M+1)。Intermediate 59 was prepared by reference to the preparation of Intermediate 54 except that Intermediate 51 was used as a material. MS (ESI): 548 (M+1).
中间体60——2-溴-3-(1-甲基-1H-吡唑-4-基)丙烷Intermediate 60 - 2-bromo-3-(1-methyl-1H-pyrazol-4-yl)propane
Figure PCTCN2016080725-appb-000057
Figure PCTCN2016080725-appb-000057
N-甲基吡唑(1.0g，1当量)溶于N，N-二甲基甲酰胺(2.8ml，3当量)，90℃下滴加三氯氧磷(1.3ml，1.2当量)，约1h滴加完成，再继续反应2h。冷却，反应液倾倒入冰水中，10％氢氧化钠水溶液调节PH至4～5，二氯甲烷萃取4次，水洗两次，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得600mg中间体60a。N-methylpyrazole (1.0 g, 1 equivalent) was dissolved in N,N-dimethylformamide (2.8 ml, 3 eq.), and phosphorus oxychloride (1.3 ml, 1.2 eq.) was added dropwise at 90 ° C. The addition was completed in 1 h, and the reaction was continued for 2 h. After cooling, the reaction solution was poured into ice water, adjusted to pH 4 to 5 with 10% aqueous sodium hydroxide solution, extracted twice with dichloromethane, washed twice with water, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated 600 mg of intermediate 60a.
中间体60a(600mg，1当量)溶于二氧六环(16mL)中，室温下，依次加入碳酸铯(4.0g，2当量)，磷酸乙酸三甲酯(1.1g，2当量)，二甲基亚砜(4mL)，置于100℃反应过夜。加水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得650mg中间体60b。Intermediate 60a (600 mg, 1 eq.) was dissolved in dioxane (16 mL). EtOAc (4.0 g, 2 eq.). The sulfoxide (4 mL) was reacted at 100 ° C overnight. After adding water, ethyl acetate extraction, washing with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
中间体60b(650mg，1当量)溶于无水乙醇中，加入10％Pd/C(65mg)，氢气环境下，40℃反应过夜。冷却，过滤，蒸干溶剂得500mg中间体60c。Intermediate 60b (650 mg, 1 eq.) was dissolved in dry ethanol, and 10% Pd/C (65 mg) was added and reacted at 40 ° C overnight under hydrogen atmosphere. Cool, filter and evaporate the solvent to give aq.
中间体60c(500mg，1当量)溶于四氢呋喃中，冰浴下缓慢加入氢化锂铝(113mg，1当量)，室温反应1h。反应完成后，依次加入一定量的乙酸乙酯，碳酸氢钠水溶液，水，然后过滤，四氢呋喃洗滤饼，滤液蒸干得435mg中间体60d。Intermediate 60c (500 mg, 1 eq.) was dissolved in THF. EtOAc (EtOAc m. After completion of the reaction, a certain amount of ethyl acetate, aqueous sodium hydrogencarbonate solution and water were successively added, then filtered, and the filter cake was washed with tetrahydrofuran, and the filtrate was evaporated to give 435 mg of intermediate 60d.
草酰氯(428μL，1.5当量)溶于二氯甲烷，氮气保护，至于-60℃冷肼，缓慢加入二甲基亚砜(0.64mL，3当量)的二氯甲烷(2mL)溶液，约5min加完，加完后搅拌5min，然后加入中间体60d的二氯甲烷溶液，约10min加完，加完后搅拌5min，然后加入三乙胺(1.67mL，4当量)，约3min加完，加完后搅拌5min后从冷肼中取出反应瓶，置于室温反应5min。加水淬灭反 应，分出二氯甲烷层，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得100mg中间体60e。Oxalyl chloride (428 μL, 1.5 eq.) was dissolved in methylene chloride, EtOAc (EtOAc) EtOAc (EtOAc) After the addition, the mixture was stirred for 5 min, then the intermediate 60 d of dichloromethane solution was added, and the addition was completed in about 10 min. After the addition, the mixture was stirred for 5 min, then triethylamine (1.67 mL, 4 equivalents) was added, and the addition was completed in about 3 min. After stirring for 5 min, the reaction flask was taken out from the cold mash and allowed to react at room temperature for 5 min. Add water to quench The methylene chloride layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.
中间体60e(70mg，1当量)，N-溴代丁二酰亚胺(99mg，1.1当量)与L-脯氨酸(11.5mg，0.2当量)溶于二氯甲烷中，室温反应2h，饱和食盐水洗，无水硫酸镁干燥，过滤，蒸干溶剂，柱层析分离得60mg中间体60。Intermediate 60e (70 mg, 1 eq.), N-bromosuccinimide (99 mg, 1.1 eq.) and L-valine (11.5 mg, 0.2 eq.) dissolved in dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated.
中间体61——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 61 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-[1,2,4]triazole [ 4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000058
Figure PCTCN2016080725-appb-000058
以中间体1为原料，参照中间体56的制备方法。MS(ESI)：499(M+1)。The intermediate 1 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 499 (M+1).
中间体62——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-甲基苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 62 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-methylbenzyl)oxy)-[1,2,4 Triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000059
Figure PCTCN2016080725-appb-000059
以中间体25为原料，参照中间体56的制备方法。MS(ESI)：513(M+1)。The intermediate 25 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 513 (M+1).
中间体63——5-(((3-溴-[1，2，4]三氮唑[4，3-a]嘧啶-7-基)氧基)甲基)-2-(4-氯-3-(三氟甲基)苯氧基)苯甲腈Intermediate 63——5-(((3-Bromo-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)oxy)methyl)-2-(4-chloro -3-(trifluoromethyl)phenoxy)benzonitrile
Figure PCTCN2016080725-appb-000060
Figure PCTCN2016080725-appb-000060
以中间体14为原料，参照中间体56的制备方法。MS(ESI)：524(M+1)。The intermediate 14 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 524 (MH).
中间体64——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-氟苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 64 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-fluorobenzyl)oxy)-[1,2,4] Triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000061
Figure PCTCN2016080725-appb-000061
以中间体13为原料，参照中间体56的制备方法。MS(ESI)：517(M+1)。 The intermediate 13 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 517 (M+1).
中间体65——3-溴-7-((3-氯-4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 65 - 3-bromo-7-((3-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-[1,2,4] Triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000062
Figure PCTCN2016080725-appb-000062
以中间体26为原料，参照中间体56的制备方法。MS(ESI)：533(M+1)。The intermediate 26 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 533 (M + 1).
中间体66——3-溴-7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-(三氟甲基)苄基)氧基)-[1，2，4]三氮唑[4，3-a]嘧啶Intermediate 66 - 3-bromo-7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzyl)oxy)-[1 , 2,4]triazole [4,3-a]pyrimidine
以中间体27为原料，参照中间体56的制备方法。MS(ESI)：567(M+1)。The intermediate 27 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 567 (M+1).
Figure PCTCN2016080725-appb-000063
Figure PCTCN2016080725-appb-000063
中间体67——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-6-甲基咪唑[1，2-a]嘧啶Intermediate 67——7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-6-methylimidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000064
Figure PCTCN2016080725-appb-000064
以中间体1和4-氯-5-甲基嘧啶-2-胺为原料，参照中间体28的制备方法。MS(ESI)：434(M+1)。Starting from Intermediate 1 and 4-chloro-5-methylpyrimidin-2-amine, reference is made to the preparation method of Intermediate 28. MS (ESI): 434 (M+1).
实施例1——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 1 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1,2- a]pyrimidine
Figure PCTCN2016080725-appb-000065
Figure PCTCN2016080725-appb-000065
中间体28(100mg，1当量)，4-溴嘧啶(42mg，1.1当量)，醋酸钾(44mg，2当量)与醋酸钯(6mg，0.1当量)混于N，N-二甲基乙酰胺中，氮气置换，140℃反应2h，冷却，过滤，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得60mg白色固体的实施例1化合物。1H NMR(400MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.33(d，J＝7.4Hz，1H)，7.76(s，1H)，7.54(d，J＝8.6Hz，2H)，7.45(d，J＝8.8Hz，1H)，7.34(d，J＝2.9Hz， 1H)，7.10(dd，J＝8.8，2.8Hz，1H)，7.04(d，J＝8.6Hz，2H)，6.61(d，J＝7.4Hz，1H)，5.55(s，2H).MS(ESI)：498(M+H)。Intermediate 28 (100 mg, 1 eq.), 4-bromopyrimidine (42 mg, 1.1 eq.), potassium acetate (44 mg, 2 eq.) and palladium acetate (6 mg, 0.1 eq.) in N,N-dimethylacetamide The mixture was purged with nitrogen, dried at 140 ° C for 2 h, cooled, filtered, ethyl acetate evaporated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. 1 H NMR (400MHz, Chloroform- d) δ9.27 (s, 1H), 8.93 (s, 2H), 8.33 (d, J = 7.4Hz, 1H), 7.76 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.10 (dd, J = 8.8, 2.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H). MS (ESI): 498 (M+H).
实施例2——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(2-甲氧基嘧啶-5-基)咪唑[1，2-a]嘧啶Example 2 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(2-methoxypyrimidin-5-yl)imidazole [1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000066
Figure PCTCN2016080725-appb-000066
除了以中间体28和2-甲氧基-4溴嘧啶为原料以外，参照实施例1的制备方法制备实施例2化合物。1H NMR(300MHz，Chloroform-d)δ8.65(s，2H)，8.19(d，J＝7.4Hz，1H)，7.63(d，J＝10.0Hz，1H)，7.54(d，J＝8.5Hz，2H)，7.44(d，J＝8.7Hz，1H)，7.34(d，J＝2.8Hz，1H)，7.09(dd，J＝8.7，2.8Hz，1H)，7.02(d，J＝8.2Hz，2H)，6.57(d，J＝7.1Hz，1H)，5.53(s，2H)，4.10(s，3H).MS(ESI)：528(M+H)。The compound of Example 2 was prepared by referring to the production method of Example 1 except that Intermediate 28 and 2-methoxy-4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ8.65 (s, 2H), 8.19 (d, J = 7.4Hz, 1H), 7.63 (d, J = 10.0Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.7, 2.8 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.57 (d, J = 7.1 Hz, 1H), 5.53 (s, 2H), 4.10 (s, 3H). MS (ESI): 528 (M+H).
实施例3——7-(4-(4-氯-3-(三氟甲基)苯氧基)苯乙氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 3 - 7-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)phenylethoxy)-3-(pyrimidin-5-yl)imidazole [1,2-a] Pyrimidine
Figure PCTCN2016080725-appb-000067
Figure PCTCN2016080725-appb-000067
除了以中间体33和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例3化合物。1H NMR(400MHz，Chloroform-d)δ9.26(s，1H)，8.92(s，2H)，8.30(d，J＝7.4Hz，1H)，7.72(s，1H)，7.42(d，J＝8.8Hz，1H)，7.32(m，3H)，7.06(d，J＝9.0Hz，1H)，6.98(d，J＝8.0Hz，2H)，6.54(d，J＝8.3Hz，1H)，4.74(t，J＝6.5Hz，2H)，3.16(t，J＝6.4Hz，2H).MS(ESI)：512(M+H)。The compound of Example 3 was prepared by referring to the production method of Example 1 except that Intermediate 33 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.26 (s, 1H), 8.92 (s, 2H), 8.30 (d, J = 7.4Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.32 (m, 3H), 7.06 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 8.3 Hz, 1H), 4.74 (t, J = 6.5 Hz, 2H), 3.16 (t, J = 6.4 Hz, 2H). MS (ESI): 512 (M+H).
实施例4——1-(7-(4-(4-氯-3-(三氟甲基)苯氧基)苯乙氧基)咪唑[1，2-a]嘧啶-3-基)-N，N-二甲基甲胺Example 4 - 1-(7-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenylethoxy)imidazo[1,2-a]pyrimidin-3-yl)- N,N-dimethylmethylamine
Figure PCTCN2016080725-appb-000068
Figure PCTCN2016080725-appb-000068
将中间体33(30mg，1当量)，N，N-二甲基碘烯亚胺(15mg，1.2当量)溶于乙腈中，回流反应1.5h，蒸干溶剂，柱层析分离得20mg产品，即实施例4的化合物。1H NMR(400MHz，Chloroform-d)δ8.43(d，J＝7.3Hz，1H)，7.41(d，J＝8.7Hz，1H)，7.32(m，4H)，7.05(dd，J＝8.8，2.9Hz，1H)，6.96(d，J＝8.6Hz，2H)，6.38(d，J＝7.3Hz，1H)，4.68(t，J＝6.9Hz，2H)，3.62(s，2H)，3.12(t，J＝6.8Hz，2H)，2.21(s，6H).MS(ESI)：491(M+H)。 The intermediate 33 (30 mg, 1 eq.), N,N-dimethyliodoenimine (15 mg, 1.2 eq.) was dissolved in acetonitrile, refluxed for 1.5 h, and the solvent was evaporated to dryness. That is, the compound of Example 4. 1 H NMR (400MHz, Chloroform- d) δ8.43 (d, J = 7.3Hz, 1H), 7.41 (d, J = 8.7Hz, 1H), 7.32 (m, 4H), 7.05 (dd, J = 8.8 , 2.9 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.38 (d, J = 7.3 Hz, 1H), 4.68 (t, J = 6.9 Hz, 2H), 3.62 (s, 2H), 3.12 (t, J = 6.8 Hz, 2H), 2.21. (s, 6H). MS (ESI): 491 (M+H).
实施例5——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-((1-甲基-1H-吡唑-4-基)甲基)咪唑[1，2-a]嘧啶Example 5 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-((1-methyl-1H-pyrazole-4) -yl)methyl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000069
Figure PCTCN2016080725-appb-000069
中间体60(16mg，1当量)溶于乙醇(1mL)和水(1mL)的混合溶剂中，加入中间体28a，70℃反应7h。蒸干溶剂，柱层析分离得3mg产品，即实施例5化合物。1H NMR(400MHz，Chloroform-d)δ7.91(d，J＝7.4Hz，1H)，7.51(d，J＝8.6Hz，2H)，7.43(d，J＝8.6Hz，1H)，7.35(s，1H)，7.34(d，J＝2.1Hz，2H)，7.10(s，1H)，7.08(dd，J＝8.9，2.9Hz，1H)，7.02(d，J＝8.5Hz，2H)，6.41(d，J＝7.3Hz，1H)，5.49(s，2H)，4.01(s，2H)，3.84(s，3H).MS(ESI)：514(M+H)。Intermediate 60 (16 mg, 1 eq.) was dissolved in a mixed solvent of ethanol (1 mL) and water (1 mL). Intermediate 28a was added and reacted at 70 ° C for 7 h. The solvent was evaporated to dryness. 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.35 ( s, 1H), 7.34 (d, J = 2.1 Hz, 2H), 7.10 (s, 1H), 7.08 (dd, J = 8.9, 2.9 Hz, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 7.3 Hz, 1H), 5.49 (s, 2H), 4.01 (s, 2H), 3.84 (s, 3H). MS (ESI): 514 (M+H).
实施例6——7-(苄基氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 6 - 7-(Benzyloxy)-3-(pyrimidin-5-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000070
Figure PCTCN2016080725-appb-000070
苯甲醇(23mg，1.5当量)与氢化钠(17mg，3当量)于0℃搅拌30min，加入中间体53(50mg，1当量)，室温反应过夜。加入氯化铵水溶液淬灭反应，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得40mg产品，即实施例6化合物。1H NMR(300MHz，Chloroform-d)δ9.25(s，1H)，8.92(s，2H)，8.31(d，J＝7.4Hz，1H)，7.73(s，1H)，7.51(dd，J＝7.9，1.6Hz，2H)，7.44-7.35(m，3H)，6.59(d，J＝7.4Hz，1H)，5.55(s，2H).MS(ESI)：304(M+H)。The benzyl alcohol (23 mg, 1.5 eq.) and sodium hydride (17 mg, 3 eq.) were stirred at 0 ° C for 30 min. The reaction was quenched by the addition of aq. EtOAc. EtOAc EtOAc. 1 H NMR (300MHz, Chloroform- d) δ9.25 (s, 1H), 8.92 (s, 2H), 8.31 (d, J = 7.4Hz, 1H), 7.73 (s, 1H), 7.51 (dd, J = 7.9, 1.6 Hz, 2H), 7.44 - 7.35 (m, 3H), 6.59 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H). MS (ESI): 304 (M+H).
实施例7——2-(4-氯-3-(三氟甲基)苯氧基)-5-(((3-(嘧啶-5-基)咪唑[1，2-a]嘧啶-7-基)氧基)甲基)苯甲腈Example 7 - 2-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-(((3-(pyrimidin-5-yl))imidazo[1,2-a]pyrimidine-7 -yl)oxy)methyl)benzonitrile
Figure PCTCN2016080725-appb-000071
Figure PCTCN2016080725-appb-000071
除了以中间体35和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例7化合物。1H NMR(300MHz，Chloroform-d)δ9.28(s，1H)，8.93(s，2H)，8.36(d，J＝7.4Hz，1H)，7.85(d，J＝1.8Hz，1H)，7.75(s，1H)，7.71(dd，J＝8.6，2.0Hz，1H)，7.54(d，J＝8.8Hz，1H)，7.42(d，J＝2.8Hz，1H)，7.20(dd，J＝8.7，2.7Hz，1H)，6.94(d，J＝8.6Hz，1H)，6.63(d，J＝7.4Hz，1H)，5.56(s，2H).MS(ESI)：523(M+H)。 The compound of Example 7 was prepared by referring to the production method of Example 1 except that Intermediate 35 and 4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.28 (s, 1H), 8.93 (s, 2H), 8.36 (d, J = 7.4Hz, 1H), 7.85 (d, J = 1.8Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J = 8.6, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.20 (dd, J = 8.7, 2.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.56 (s, 2H). MS (ESI): 523 (M+H ).
实施例8——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(4-氟苯基)咪唑[1，2-a]嘧啶Example 8 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(4-fluorophenyl)imidazole [1,2- a]pyrimidine
Figure PCTCN2016080725-appb-000072
Figure PCTCN2016080725-appb-000072
中间体54(37mg，1当量)，对氟苯硼酸(12mg，1.1当量)，二(三苯基磷)二氯化钯(2.6mg，0.05当量)与碳酸钠(23.5mg，3当量)混于二氧六环(5mL)与水(1mL)的混合溶液中，150℃微波反应30min。蒸掉部分溶剂，加水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，蒸干溶剂，柱层析分离得15mg产品，即实施例8化合物。1H NMR(300MHz，Chloroform-d)δ8.30(d，J＝7.4Hz，1H)，7.48(dd，J＝28.2，8.5Hz，6H)，7.33(s，1H)，7.21(t，J＝8.5Hz，2H)，7.13-6.93(m，3H)，6.51(d，J＝6.6Hz，1H)，5.51(s，2H).MS(ESI)：514(M+H)。Intermediate 54 (37 mg, 1 eq.), p-fluorophenylboronic acid (12 mg, 1.1 eq.), bis(triphenylphosphine)palladium dichloride (2.6 mg, 0.05 eq.) and sodium carbonate (23.5 mg, 3 eq.) In a mixed solution of dioxane (5 mL) and water (1 mL), microwave reaction was carried out at 150 ° C for 30 min. A part of the solvent was evaporated, water was added, ethyl acetate was evaporated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. 1 H NMR (300MHz, Chloroform- d) δ8.30 (d, J = 7.4Hz, 1H), 7.48 (dd, J = 28.2,8.5Hz, 6H), 7.33 (s, 1H), 7.21 (t, J = 8.5 Hz, 2H), 7.13 - 6.93 (m, 3H), 6.51 (d, J = 6.6 Hz, 1H), 5.51 (s, 2H). MS (ESI): 514 (M+H).
实施例9——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(4-甲氧基苯基)咪唑[1，2-a]嘧啶Example 9 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(4-methoxyphenyl)imidazole [1, 2-a]pyrimidine
Figure PCTCN2016080725-appb-000073
Figure PCTCN2016080725-appb-000073
除了以中间体54和对甲氧基苯硼酸为原料以外，参照实施例8的制备方法制备实施例9化合物。1H NMR(300MHz，Chloroform-d)δ8.30(d，J＝7.3Hz，1H)，7.63-7.28(m，7H)，7.04(m，5H)，6.49(d，J＝6.8Hz，1H)，5.49(s，2H)，3.86(s，3H).MS(ESI)：526(M+H)。The compound of Example 9 was prepared by referring to the preparation method of Example 8 except that the intermediate 54 and p-methoxyphenylboronic acid were used as a starting material. 1 H NMR (300 MHz, Chloroform-d) δ 8.30 (d, J = 7.3 Hz, 1H), 7.63 - 7.28 (m, 7H), 7.04 (m, 5H), 6.49 (d, J = 6.8 Hz, 1H) ), 5.49 (s, 2H), 3.86 (s, 3H). MS (ESI): 526 (M+H).
实施例10——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 10 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-3-(pyrimidin-5-yl) Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000074
Figure PCTCN2016080725-appb-000074
除了以中间体29和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例10化合物。1H NMR(300MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.37(d，J＝7.4Hz，1H)，7.76(s，1H)，7.42(d，J＝8.8Hz，1H)，7.30(d，J＝2.9Hz，1H)，7.20(d，J＝8.1Hz，2H)，7.03(dd，J＝8.7，2.7Hz，1H)，6.65(d，J＝7.4Hz，1H)，5.56(s，2H).MS(ESI)：534(M+H)。 The compound of Example 10 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.37 (d, J = 7.4Hz, 1H), 7.76 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.03 (dd, J = 8.7, 2.7 Hz, 1H), 6.65 (d, J) = 7.4 Hz, 1H), 5.56 (s, 2H). MS (ESI): 534 (M+H).
实施例11——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 11 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-fluorobenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [ 1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000075
Figure PCTCN2016080725-appb-000075
除了以中间体34和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例11化合物。1H NMR(300MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.35(d，J＝7.4Hz，1H)，7.75(s，1H)，7.48-7.35(m，2H)，7.34-7.29(m，2H)，7.13(t，J＝8.2Hz，1H)，7.05(dd，J＝8.8，2.5Hz，1H)，6.63(d，J＝7.4Hz，1H)，5.56(s，2H).MS(ESI)：516(M+H)。The compound of Example 11 was prepared by referring to the preparation method of Example 1 except that Intermediate 34 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (300 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.93 (s, 2H), 8.35 (d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.48-7.35 (m) , 2H), 7.34 - 7.29 (m, 2H), 7.13 (t, J = 8.2 Hz, 1H), 7.05 (dd, J = 8.8, 2.5 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H) , 5.56 (s, 2H). MS (ESI): 516 (M+H).
实施例12——7-((4-(3，4-二氟苯基氧基)-3-氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a1嘧啶Example 12——7-((4-(3,4-Difluorophenyloxy)-3-fluorobenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1,2-a1 Pyrimidine
Figure PCTCN2016080725-appb-000076
Figure PCTCN2016080725-appb-000076
除了以中间体36和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例12化合物。1H NMR(300MHz，Chloroform-d)δ9.27(s，1H)，8.92(s，2H)，8.33(d，J＝7.5Hz，1H)，7.77(s，1H)，7.35(d，J＝11.0Hz，1H)，7.29(s，1H)，7.08(td，J＝8.7，5.5Hz，2H)，6.80(ddd，J＝10.0，6.5，3.2Hz，1H)，6.74-6.66(m，1H)，6.62(d，J＝7.5Hz，1H)，5.54(s，2H).MS(ESI)：450(M+H)。The compound of Example 12 was prepared by referring to the preparation method of Example 1 except that Intermediate 36 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.27 (s, 1H), 8.92 (s, 2H), 8.33 (d, J = 7.5Hz, 1H), 7.77 (s, 1H), 7.35 (d, J =11.0 Hz, 1H), 7.29 (s, 1H), 7.08 (td, J = 8.7, 5.5 Hz, 2H), 6.80 (ddd, J = 10.0, 6.5, 3.2 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.62 (d, J = 7.5 Hz, 1H), 5.54 (s, 2H). MS (ESI): 450 (M+H).
实施例13——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-5-甲基-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 13 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-5-methyl-3-(pyrimidin-5-yl)imidazole [1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000077
Figure PCTCN2016080725-appb-000077
除了以中间体58和4-嘧啶硼酸为原料以外，参照实施例8的制备方法制备实施例13化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.84(s，2H)，7.57-7.48(m，3H)，7.44(d，J＝8.8Hz，1H)，7.34(d，J＝2.8Hz，1H)，7.09(dd，J＝8.7，2.8Hz，1H)，7.03(d，J＝8.6Hz，2H)，6.31(s，1H)，5.53(s，2H)，2.20(s，3H).MS(ESI)：512(M+H)。The compound of Example 13 was prepared by referring to the preparation method of Example 8 except that Intermediate 58 and 4-pyrimidineboronic acid were used as a starting material. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.84 (s, 2H), 7.57-7.48 (m, 3H), 7.44 (d, J = 8.8Hz, 1H), 7.34 (d , J = 2.8 Hz, 1H), 7.09 (dd, J = 8.7, 2.8 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.31 (s, 1H), 5.53 (s, 2H), 2.20 (s, 3H). MS (ESI): 512 (M+H).
实施例14——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(吡啶-4-基)咪唑[1，2-a]嘧啶 Example 14 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyridin-4-yl)imidazole [1,2- a]pyrimidine
Figure PCTCN2016080725-appb-000078
Figure PCTCN2016080725-appb-000078
除了以中间体54和4-吡啶硼酸为原料以外，参照实施例8的制备方法制备实施例14。1H NMR(400MHz，Chloroform-d)δ8.75(d，J＝5.1Hz，2H)，8.55(d，J＝4.4Hz，1H)，7.87(s，1H)，7.57-7.47(m，4H)，7.44(d，J＝8.7Hz，1H)，7.33(d，J＝2.6Hz，1H)，7.09(dd，J＝8.6，2.7Hz，1H)，7.03(d，J＝8.3Hz，2H)，6.63(d，J＝7.4Hz，1H)，5.55(s，2H).MS(ESI)：497(M+H)。Example 14 was prepared by referring to the preparation method of Example 8 except that Intermediate 54 and 4-pyridine boronic acid were used as the starting materials. 1 H NMR (400MHz, Chloroform- d) δ8.75 (d, J = 5.1Hz, 2H), 8.55 (d, J = 4.4Hz, 1H), 7.87 (s, 1H), 7.57-7.47 (m, 4H ), 7.44 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 8.6, 2.7 Hz, 1H), 7.03 (d, J = 8.3 Hz, 2H) ), 6.63 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H). MS (ESI): 495 (M+H).
实施例15——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(吡啶-3-基)咪唑[1，2-a]嘧啶Example 15 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyridin-3-yl)imidazole [1,2- a]pyrimidine
Figure PCTCN2016080725-appb-000079
Figure PCTCN2016080725-appb-000079
除了以中间体28和3-溴吡啶为原料以外，参照实施例1的制备方法制备实施例15化合物。1H NMR(400MHz，Chloroform-d)δ8.80(s，1H)，8.69(d，J＝4.2Hz，1H)，8.35(d，J＝7.4Hz，1H)，7.82(d，J＝8.1Hz，1H)，7.70(s，1H)，7.54(d，J＝8.5Hz，2H)，7.49-7.42(m，2H)，7.34(d，J＝2.8Hz，1H)，7.09(dd，J＝8.8，3.0Hz，1H)，7.03(d，J＝8.6Hz，2H)，6.56(d，J＝7.4Hz，1H)，5.53(s，2H).MS(ESI)：497(M+H)。The compound of Example 15 was prepared by referring to the preparation method of Example 1 except that Intermediate 28 and 3-bromopyridine were used as the starting materials. 1 H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.49-7.42 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.8, 3.0 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 7.4 Hz, 1H), 5.53 (s, 2H). MS (ESI): 497 (M+H ).
实施例16——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-5-甲基-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 16 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-5-methyl-3-( Pyrimidin-5-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000080
Figure PCTCN2016080725-appb-000080
除了以中间体59和4-嘧啶硼酸为原料以外，参照实施例8的制备方法制备实施例16化合物。1H NMR(300MHz，Chloroform-d)δ9.29(s，1H)，8.84(s，2H)，7.56(s，1H)，7.41(d，J＝8.7Hz，1H)，7.29(s，1H)，7.18(d，J＝8.1Hz，2H)，7.01(d，J＝8.4Hz，1H)，6.36(s，1H)，5.54(s，2H)，2.23(s，3H).MS(ESI)：548(M+H)。The compound of Example 16 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 4-pyrimidineboronic acid were used as a starting material. 1 H NMR (300MHz, Chloroform- d) δ9.29 (s, 1H), 8.84 (s, 2H), 7.56 (s, 1H), 7.41 (d, J = 8.7Hz, 1H), 7.29 (s, 1H ), 7.18 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 5.54 (s, 2H), 2.23 (s, 3H). MS (ESI) ): 548 (M+H).
实施例17——7-((3，5-二氟-4-(4-氟-3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 17 - 7-((3,5-Difluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl) Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000081
Figure PCTCN2016080725-appb-000081
除了以中间体37和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例17化合物。1H NMR(300MHz，Chloroform-d)δ9.31(s，1H)，8.96(s，2H)，8.39(d，J＝7.2Hz，1H)，7.81(s，1H)，7.17(m，5H)，6.73(d，J＝7.3Hz，1H)，5.58(s，2H).MS(ESI)：518(M+H)。MS(ESI)：518(M+H)。The compound of Example 17 was prepared by referring to the preparation method of Example 1 except that Intermediate 37 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (300 MHz, Chloroform-d) δ 9.31 (s, 1H), 8.96 (s, 2H), 8.39 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.17 (m, 5H) ), 6.73 (d, J = 7.3 Hz, 1H), 5.58 (s, 2H). MS (ESI): 518 (M+H). MS (ESI): 518 (M + H).
实施例18——7-((3，5-二氟-4-(3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 18 - 7-((3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1 , 2-a] pyrimidine
Figure PCTCN2016080725-appb-000082
Figure PCTCN2016080725-appb-000082
除了以中间体38和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例18化合物。1H NMR(300MHz，Chloroform-d)δ9.30(s，1H)，8.95(s，2H)，8.39(d，J＝6.1Hz，1H)，7.80(s，1H)，7.38(m，2H)，7.21(m，3H)，7.12(d，J＝8.0Hz，1H)，6.71(d，J＝6.0Hz，1H)，5.58(s，2H).MS(ESI)：500(M+H)。The compound of Example 18 was prepared by referring to the preparation method of Example 1 except that Intermediate 38 and 4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.30 (s, 1H), 8.95 (s, 2H), 8.39 (d, J = 6.1Hz, 1H), 7.80 (s, 1H), 7.38 (m, 2H ), 7.21 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 6.0 Hz, 1H), 5.58 (s, 2H). MS (ESI): 500 (M+H) ).
实施例19——7-((3，5-一二氟-4-((6-甲基吡啶-3-基)氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 19 - 7-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-3-(pyrimidin-5-yl) Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000083
Figure PCTCN2016080725-appb-000083
除了以中间体39和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例19化合物。1H NMR(300MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.38(d，J＝7.4Hz，1H)，8.23(d，J＝2.6Hz，1H)，7.77(s，1H)，7.34(d，J＝7.1Hz，1H)，7.21(d，J＝8.2Hz，3H)，6.66(d，J＝7.4Hz，1H)，5.55(s，2H)，2.62(s，3H).MS(ESI)：447(M+H)。The compound of Example 19 was prepared by referring to the preparation method of Example 1 except that Intermediate 39 and 4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.38 (d, J = 7.4Hz, 1H), 8.23 (d, J = 2.6Hz, 1H), 7.77(s,1H), 7.34(d,J=7.1Hz,1H), 7.21(d,J=8.2Hz,3H),6.66(d,J=7.4Hz,1H),5.55(s,2H), 2.62 (s, 3H). MS (ESI): 447 (M+H).
实施例20——7-((4-((6-氯吡啶-3-基)氧基)-3，5-二氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 20 - 7-((4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [ 1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000084
Figure PCTCN2016080725-appb-000084
除了以中间体40和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例20化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.37(d，J＝7.4Hz，1H)，8.14(d，J＝2.8Hz，1H)，7.76(s，1H)，7.25(m，2H)，7.20(d，J＝8.1Hz，2H)，6.65(d，J＝7.4Hz，1H)，5.56(s，2H).MS(ESI)：467(M+H)。 The compound of Example 20 was prepared by referring to the preparation method of Example 1 except that Intermediate 40 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.37 (d, J = 7.4Hz, 1H), 8.14 (d, J = 2.8Hz, 1H), 7.76 (s, 1H), 7.25 (m, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 7.4 Hz, 1H), 5.56 (s, 2H). MS (ESI): 467 (M+H).
实施例21——7-((4-(3-氯-4-甲基苯氧基)-3，5-二氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 21 - 7-((4-(3-chloro-4-methylphenoxy)-3,5-difluorobenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1 , 2-a] pyrimidine
Figure PCTCN2016080725-appb-000085
Figure PCTCN2016080725-appb-000085
除了以中间体41和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例21化合物。1H NMR(400MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.36(d，J＝7.3Hz，1H)，7.75(s，1H)，7.16(d，J＝7.9Hz，2H)，7.13(d，J＝8.5Hz，1H)，6.96-6.90(m，1H)，6.80-6.74(m，1H)，6.64(d，J＝7.4Hz，1H)，5.54(s，2H)，2.31(s，3H).MS(ESI)：480(M+H)。The compound of Example 21 was prepared by referring to the preparation method of Example 1 except that Intermediate 41 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.27 (s, 1H), 8.93 (s, 2H), 8.36 (d, J = 7.3Hz, 1H), 7.75 (s, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 6.96-6.90 (m, 1H), 6.80-6.74 (m, 1H), 6.64 (d, J = 7.4 Hz, 1H), 5.54 (s, 2H), 2.31 (s, 3H). MS (ESI): 480 (M+H).
实施例22——4-(2，6-二氟-4-(((3-(嘧啶-5-基)咪唑[1，2-a]嘧啶-7-基)氧基)甲基)苯氧基)-2-氟苯甲腈Example 22——4-(2,6-Difluoro-4-((3-(pyrimidin-5-yl)imidazo[1,2-a]pyrimidin-7-yl)oxy)methyl)benzene Oxy)-2-fluorobenzonitrile
Figure PCTCN2016080725-appb-000086
Figure PCTCN2016080725-appb-000086
除了以中间体42和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例22化合物。1H NMR(300MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.38(d，J＝7.2Hz，1H)，7.77(s，1H)，7.58(t，J＝7.6Hz，1H)，7.23(d，J＝8.2Hz，2H)，6.81(dd，J＝21.1，9.7Hz，2H)，6.66(d，J＝7.2Hz，1H)，5.57(s，2H).MS(ESI)：475(M+H)。The compound of Example 22 was prepared by referring to the preparation method of Example 1 except that Intermediate 42 and 4-bromopyrimidine were used as starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.38 (d, J = 7.2Hz, 1H), 7.77 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.81 (dd, J = 21.1, 9.7 Hz, 2H), 6.66 (d, J = 7.2 Hz, 1H), 5.57 (s, 2H) MS (ESI): 475 (M+H).
实施例23——7-((3，5-二氟-4-(4-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a1嘧啶Example 23 - 7-((3,5-Difluoro-4-(4-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1 , 2-a1 pyrimidine
Figure PCTCN2016080725-appb-000087
Figure PCTCN2016080725-appb-000087
除了以中间体43和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例23化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.38(d，J＝7.4Hz，1H)，7.77(s，1H)，7.57(d，J＝8.6Hz，2H)，7.24-7.17(m，2H)，7.02(d，J＝8.6Hz，2H)，6.66(d，J＝7.4Hz，1H)，5.56(s，2H).MS(ESI)：500(M+H)。The compound of Example 23 was prepared by referring to the preparation method of Example 1 except that Intermediate 43 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.38 (d, J = 7.4Hz, 1H), 7.77 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.24 - 7.17 (m, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 7.4 Hz, 1H), 5.56 (s, 2H). MS (ESI) ): 500 (M + H).
实施例24——7-((4-(3，4-二氯苯氧基)-3，5-二氟苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶 Example 24 - 7-((4-(3,4-Dichlorophenoxy)-3,5-difluorobenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1,2 -a]pyrimidine
Figure PCTCN2016080725-appb-000088
Figure PCTCN2016080725-appb-000088
除了以中间体44和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例24化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.94(s，2H)，8.37(d，J＝7.4Hz，1H)，7.76(s，1H)，7.36(d，J＝8.9Hz，1H)，7.19(d，J＝8.0Hz，2H)，7.04(d，J＝3.2Hz，1H)，6.84(dd，J＝9.0，2.8Hz，1H)，6.65(d，J＝7.5Hz，1H)，5.56(s，2H).MS(ESI)：500(M+H)。The compound of Example 24 was prepared by referring to the preparation method of Example 1 except that Intermediate 44 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.94 (s, 2H), 8.37 (d, J = 7.4Hz, 1H), 7.76 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 3.2 Hz, 1H), 6.84 (dd, J = 9.0, 2.8 Hz, 1H), 6.65 (d, J) = 7.5 Hz, 1H), 5.56 (s, 2H). MS (ESI): 500 (M+H).
实施例25——7-((3-氟-4-((5-(三氟甲基)吡啶-2-基)氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 25 - 7-((3-Fluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)oxy)-3-(pyrimidin-5-yl) Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000089
Figure PCTCN2016080725-appb-000089
除了以中间体31和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例25化合物。1H NMR(300MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.39(s，1H)，8.34(d，J＝7.4Hz，1H)，7.94(dd，J＝8.5，2.0Hz，1H)，7.75(s，1H)，7.37(t，J＝8.2Hz，2H)，7.30-7.21(m，1H)，7.12(d，J＝8.7Hz，1H)，6.62(d，J＝7.4Hz，1H)，5.57(s，2H).MS(ESI)：483(M+H)。The compound of Example 25 was prepared by referring to the preparation method of Example 1 except that Intermediate 31 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.27 (s, 1H), 8.93 (s, 2H), 8.39 (s, 1H), 8.34 (d, J = 7.4Hz, 1H), 7.94 (dd, J = 8.5, 2.0 Hz, 1H), 7.75 (s, 1H), 7.37 (t, J = 8.2 Hz, 2H), 7.30 - 7.21 (m, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 5.57 (s, 2H). MS (ESI): 48 (M+H).
实施例26——2-(4-(((3-(嘧啶-5-基)咪唑[1，2-a]嘧啶-7-基)氧基)甲基)苯氧基)-4-(三氟甲基)噻唑Example 26 - 2-(4-((3-(pyrimidin-5-yl))imidazo[1,2-a]pyrimidin-7-yl)oxy)methyl)phenoxy)-4-( Trifluoromethyl)thiazole
除了以中间体8和中间体53为原料以外，参照实施例6的制备方法制备实施例26化合物。1H NMR(300MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.34(d，J＝7.4Hz，1H)，7.75(s，1H)，7.60(d，J＝8.5Hz，2H)，7.36(d，J＝8.6Hz，2H)，7.29(s，1H)，6.61(d，J＝7.4Hz，1H)，5.58(s，2H).MS(ESI)：455(M+H)。The compound of Example 26 was prepared by referring to the preparation method of Example 6 except that Intermediate 8 and Intermediate 53 were used. 1 H NMR (300MHz, Chloroform- d) δ9.27 (s, 1H), 8.93 (s, 2H), 8.34 (d, J = 7.4Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.29 (s, 1H), 6.61 (d, J = 7.4 Hz, 1H), 5.58 (s, 2H). MS (ESI): 455 (M+H).
实施例27——7-((1-(3，4-二氯苄基)-1H-吡唑-4-基)甲氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶 Example 27 - 7-((1-(3,4-Dichlorobenzyl)-1H-pyrazol-4-yl)methoxy)-3-(pyrimidin-5-yl)imidazole [1,2 -a]pyrimidine
Figure PCTCN2016080725-appb-000091
Figure PCTCN2016080725-appb-000091
除了以中间体9和中间体53为原料以外，参照实施例6的制备方法制备实施例27化合物。1H NMR(400MHz，Chloroform-d)δ9.26(s，1H)，8.92(s，2H)，8.30(d，J＝7.4Hz，1H)，7.73(s，1H)，7.70(s，1H)，7.68(s，1H)，7.41(d，J＝8.2Hz，1H)，7.30(d，J＝1.9Hz，1H)，7.07(dd，J＝8.3，1.9Hz，1H)，6.53(d，J＝7.4Hz，1H)，5.46(s，2H).MS(ESI)：452(M+H)。The compound of Example 27 was prepared by referring to the preparation method of Example 6 except that Intermediate 9 and Intermediate 53 were used. 1 H NMR (400MHz, Chloroform- d) δ9.26 (s, 1H), 8.92 (s, 2H), 8.30 (d, J = 7.4Hz, 1H), 7.73 (s, 1H), 7.70 (s, 1H ), 7.68 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.3, 1.9 Hz, 1H), 6.53 (d) , J = 7.4 Hz, 1H), 5.46 (s, 2H). MS (ESI): 452 (M+H).
实施例28——2-(4-氯-3-(三氟甲基)苯氧基)-4-(((3-(嘧啶-5-y1)咪唑[1，2-a]嘧啶-7-基)氧基)甲基)恶唑Example 28 - 2-(4-Chloro-3-(trifluoromethyl)phenoxy)-4-(((3-(pyrimidin-5-y1))imidazo[1,2-a]pyrimidine-7 -yl)oxy)methyl)oxazole
Figure PCTCN2016080725-appb-000092
Figure PCTCN2016080725-appb-000092
除了以中间体10和中间体53为原料以外，参照实施例6的制备方法制备实施例28化合物。1H NMR(400MHz，Chloroform-d)δ9.26(s，1H)，8.92(s，2H)，8.32(d，J＝7.4Hz，1H)，7.74(d，J＝3.8Hz，2H)，7.59-7.55(m，3H)，6.59(d，J＝7.4Hz，1H)，5.39(s，2H).MS(ESI)：489(M+H)。The compound of Example 28 was prepared by referring to the preparation method of Example 6 except that Intermediate 10 and Intermediate 53 were used. 1 H NMR (400 MHz, Chloroform-d) δ 9.26 (s, 1H), 8.92 (s, 2H), 8.32 (d, J = 7.4 Hz, 1H), 7.74 (d, J = 3.8 Hz, 2H), 7.59-7.55 (m, 3H), 6.59 (d, J = 7.4 Hz, 1H), 5.39 (s, 2H). MS (ESI): 489 (M+H).
实施例29——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(1-甲基-1H-吡唑-4-基)咪唑[1，2-a]嘧啶Example 29 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(1-methyl-1H-pyrazole-4- Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000093
Figure PCTCN2016080725-appb-000093
除了以中间体28和1-甲基-4-(4，4，5，5-四甲基-1，3，2-二氧硼戊环-2-基)吡唑为原料以外，参照实施例8的制备方法制备实施例29化合物。1H NMR(400MHz，Chloroform-d)δ8.21(d，J＝7.4Hz，1H)，7.67(s，1H)，7.58(s，1H)，7.53(d，J＝8.4Hz，2H)，7.49(s，1H)，7.44(d，J＝8.8Hz，1H)，7.37-7.31(m，1H)，7.08(dd，J＝8.4，2.1Hz，1H)，7.03(d，J＝8.2Hz，2H)，6.50(d，J＝7.4Hz，1H)，5.52(s，2H)，4.01(s，3H).MS(ESI)：500(M+H)。 Except for the intermediate 28 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, the reference was carried out. The preparation method of Example 8 was carried out to prepare the compound of Example 29. 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 7.4 Hz, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.08 (dd, J = 8.4, 2.1 Hz, 1H), 7.03 (d, J = 8.2 Hz) , 2H), 6.50 (d, J = 7.4 Hz, 1H), 5.52 (s, 2H), 4.01 (s, 3H). MS (ESI): 500 (M+H).
实施例30——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-3-(1-甲基-1H-吡唑-4-基)咪唑[1，2-a]嘧啶Example 30 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-3-(1-methyl- 1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000094
Figure PCTCN2016080725-appb-000094
除了以中间体29和1-甲基-4-(4，4，5，5-四甲基-1，3，2-二氧硼戊环-2-基)吡唑为原料以外，参照实施例8的制备方法制备实施例30化合物。1H NMR(300MHz，Chloroform-d)δ8.25(d，J＝7.4Hz，1H)，7.88-7.46(m，3H)，7.40(d，J＝8.6Hz，1H)，7.28(s，1H)，7.18(d，J＝8.5Hz，2H)，6.99(s，1H)，6.60(d，J＝31.3Hz，1H)，5.51(s，2H)，4.00(s，3H).MS(ESI)：536(M+H)。Except for the intermediate 29 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, the reference was carried out. The preparation of Example 8 was carried out to prepare the compound of Example 30. 1 H NMR (300 MHz, Chloroform-d) δ 8.25 (d, J = 7.4 Hz, 1H), 7.88-7.46 (m, 3H), 7.40 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H) ), 7.18 (d, J = 8.5 Hz, 2H), 6.99 (s, 1H), 6.60 (d, J = 31.3 Hz, 1H), 5.51 (s, 2H), 4.00 (s, 3H). MS (ESI) ): 536 (M+H).
实施例31——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-3-(2-甲氧基嘧啶-5-基)-5-甲基咪唑[1，2-a]嘧啶Example 31 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-3-(2-methoxy) Pyrimidin-5-yl)-5-methylimidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000095
Figure PCTCN2016080725-appb-000095
除了以中间体59和2-甲氧基-4-嘧啶硼酸为原料以外，参照实施例8的制备方法制备实施例31化合物。1H NMR(300MHz，Chloroform-d)δ8.59(s，2H)，7.41(d，J＝8.8Hz，1H)，7.35-7.26(m，2H)，7.18(d，J＝7.5Hz，2H)，7.01(d，J＝10.1Hz，1H)，6.38(d，J＝35.6Hz，1H)，5.54(s，2H)，4.10(s，3H)，2.24(s，3H).MS(ESI)：578(M+H)。The compound of Example 31 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 2-methoxy-4-pyrimidineboronic acid were used as a starting material. 1 H NMR (300MHz, Chloroform- d) δ8.59 (s, 2H), 7.41 (d, J = 8.8Hz, 1H), 7.35-7.26 (m, 2H), 7.18 (d, J = 7.5Hz, 2H ), 7.01 (d, J = 10.1 Hz, 1H), 6.38 (d, J = 35.6 Hz, 1H), 5.54 (s, 2H), 4.10 (s, 3H), 2.24 (s, 3H). MS (ESI ): 578 (M+H).
实施例32——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-3-(4-甲基吡啶-3-基)咪唑[1，2-a]嘧啶Example 32 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-3-(4-methylpyridine -3-yl)imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000096
Figure PCTCN2016080725-appb-000096
除了以中间体29和3-溴-4-甲基吡啶为原料以外，参照实施例1的制备方法制备实施例32化合物。1H NMR(400MHz，Chloroform-d)δ8.61(d，J＝5.1Hz，1H)，8.58(s，1H)，7.95(d，J＝7.3Hz，1H)，7.61(s，1H)，7.44(d，J＝8.7Hz，1H)，7.35(d，J＝5.2Hz，1H)，7.33(d，J＝2.9Hz，1H)，7.25-7.19(m，2H)，7.05(dd，J＝9.1，2.9Hz，1H)，6.57(d，J＝7.4Hz，1H)，5.58(s，2H)，2.28(s，3H).MS(ESI)：547(M+H)。The compound of Example 32 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 3-bromo-4-methylpyridine were used as starting materials. 1 H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 5.1 Hz, 1H), 8.58 (s, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.61 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 2.9 Hz, 1H), 7.25-7.19 (m, 2H), 7.05 (dd, J = 9.1, 2.9 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 5.58 (s, 2H), 2.28 (s, 3H). MS (ESI): 547 (M+H).
实施例33——7-((6-(4-氯-3-(三氟甲基)苯氧基)-5-氟吡啶-3-基)甲氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶 Example 33 - 7-((6-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-fluoropyridin-3-yl)methoxy)-3-(pyrimidine-5- Imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000097
Figure PCTCN2016080725-appb-000097
除了以中间体32和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例33化合物。1H NMR(300MHz，Chloroform-d)δ9.28(s，1H)，8.93(s，2H)，8.35(d，J＝7.4Hz，1H)，8.06(s，1H)，7.74(m，2H)，7.54(m，2H)，7.33(dd，J＝8.7，2.6Hz，1H)，6.60(d，J＝7.4Hz，1H)，5.55(s，2H).MS(ESI)：517(M+H)。The compound of Example 33 was prepared by referring to the preparation method of Example 1 except that Intermediate 32 and 4-bromopyrimidine were used as a starting material. 1 H NMR (300MHz, Chloroform- d) δ9.28 (s, 1H), 8.93 (s, 2H), 8.35 (d, J = 7.4Hz, 1H), 8.06 (s, 1H), 7.74 (m, 2H ), 7.54 (m, 2H), 7.33 (dd, J = 8.7, 2.6 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H). MS (ESI): 517 (M +H).
实施例34——7-(4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苯基乙氧基)-3-(嘧啶-5-基)咪唑[1，2-a1嘧啶Example 34 - 7-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenylethoxy)-3-(pyrimidin-5-yl) Imidazole [1,2-a1 pyrimidine
Figure PCTCN2016080725-appb-000098
Figure PCTCN2016080725-appb-000098
除了以中间体30和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例34化合物。1H NMR(300MHz，Chloroform-d)δ9.27(s，1H)，8.92(s，2H)，8.31(d，J＝7.4Hz，1H)，7.74(s，1H)，7.41(d，J＝8.8Hz，1H)，7.27(d，J＝3.0Hz，1H)，7.05-6.95(m，3H)，6.55(d，J＝7.4Hz，1H)，4.76(t，J＝6.5Hz，2H)，3.16(t，J＝6.4Hz，2H).MS(ESI)：548(M+H)。The compound of Example 34 was prepared by referring to the preparation method of Example 1 except that Intermediate 30 and 4-bromopyrimidine were used as the starting materials. 1 H NMR (300MHz, Chloroform- d) δ9.27 (s, 1H), 8.92 (s, 2H), 8.31 (d, J = 7.4Hz, 1H), 7.74 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 3.0 Hz, 1H), 7.05-6.95 (m, 3H), 6.55 (d, J = 7.4 Hz, 1H), 4.76 (t, J = 6.5 Hz, 2H) ), 3.16 (t, J = 6.4 Hz, 2H). MS (ESI): 548 (M+H).
实施例35——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3，5-二氟苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 35 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-3-(pyrimidin-5-yl) )-[1,2,4]triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000099
Figure PCTCN2016080725-appb-000099
除了以中间体57和4-嘧啶硼酸为原料以外，参照实施例8的制备方法制备实施例35化合物。1H NMR(400MHz，Chloroform-d)δ9.56(s，2H)，9.33(s，1H)，8.67(d，J＝7.2Hz，1H)，7.43(d，J＝8.7Hz，1H)，7.29(d，J＝2.7Hz，1H)，7.20(d，J＝8.0Hz，2H)，7.04(dd，J＝8.7，3.1Hz，1H)，6.75(d，J＝7.3Hz，1H)，5.59(s，2H).MS(ESI)：535(M+H)。The compound of Example 35 was prepared by referring to the preparation method of Example 8 except that Intermediate 57 and 4-pyrimidineboronic acid were used as a starting material. 1 H NMR (400MHz, Chloroform- d) δ9.56 (s, 2H), 9.33 (s, 1H), 8.67 (d, J = 7.2Hz, 1H), 7.43 (d, J = 8.7Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 8.7, 3.1 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 5.59 (s, 2H). MS (ESI): 535 (M+H).
实施例36——7-((3，5-二氟-4-((6-(三氟甲基)吡啶-3-基)氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 36 - 7-((3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-3-(pyrimidine-5) -based imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000100
Figure PCTCN2016080725-appb-000100
除了以中间体45和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例36化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.93(s，2H)，8.49(d，J＝2.7Hz，1H)，8.37(d，J＝7.4Hz，1H)，7.76(s，1H)，7.64(d，J＝8.7Hz，1H)，7.32(dd，J＝8.6，2.8Hz，1H)，7.23(d，J＝8.0Hz，2H)，6.65(d，J＝7.4Hz，1H)，5.57(s，2H).MS(ESI)：501(M+H)。The compound of Example 36 was prepared by referring to the preparation method of Example 1 except that Intermediate 45 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.93 (s, 2H), 8.49 (d, J = 2.7Hz, 1H), 8.37 (d, J = 7.4Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.6, 2.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.65 (d, J) = 7.4 Hz, 1H), 5.57 (s, 2H). MS (ESI): 501 (M+H).
实施例37——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-甲基苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 37 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-methylbenzyl)oxy)-3-(pyrimidin-5-yl)imidazole [1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000101
Figure PCTCN2016080725-appb-000101
除了以中间体46和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例37化合物。1H NMR(400MHz，Methanol-d4)δ9.19(s，1H)，9.09(s，2H)，8.79(d，J＝7.4Hz，1H)，7.78(s，1H)，7.53(m，2H)，7.42(dd，J＝8.2，1.8Hz，1H)，7.25(d，J＝2.9Hz，1H)，7.06(dd，J＝8.8，2.9Hz，1H)，6.99(d，J＝8.3Hz，1H)，6.72(d，J＝7.4Hz，1H)，5.52(s，2H)，2.21(s，3H).MS(ESI)：512(M+H)。The compound of Example 37 was prepared by referring to the preparation method of Example 1 except that Intermediate 46 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Methanol- d 4) δ9.19 (s, 1H), 9.09 (s, 2H), 8.79 (d, J = 7.4Hz, 1H), 7.78 (s, 1H), 7.53 (m, 2H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.06 (dd, J = 8.8, 2.9 Hz, 1H), 6.99 (d, J = 8.3) Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 5.52 (s, 2H), 2.21. (s, 3H). MS (ESI): 512 (M+H).
实施例38——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)硫基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 38 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)thio)-3-(pyrimidin-5-yl)imidazole [1,2- a]pyrimidine
Figure PCTCN2016080725-appb-000102
Figure PCTCN2016080725-appb-000102
除了以中间体2和中间体53为原料以外，参照实施例6的制备方法制备实施例38化合物。1H NMR(400MHz，Chloroform-d)δ9.28(s，1H)，8.93(s，2H)，8.24(d，J＝7.2Hz，1H)，7.83(s，1H)，7.51(d，J＝8.6Hz，2H)，7.42(d，J＝8.8Hz，1H)，7.32(d，J＝2.9Hz，1H)，7.06(dd，J＝8.8，2.8Hz，1H)，6.96(d，J＝8.6Hz，2H)，6.80(d，J＝7.2Hz，1H)，4.61(s，2H).MS(ESI)：514(M+H)。The compound of Example 38 was prepared by referring to the preparation method of Example 6 except that Intermediate 2 and Intermediate 53 were used. 1 H NMR (400MHz, Chloroform- d) δ9.28 (s, 1H), 8.93 (s, 2H), 8.24 (d, J = 7.2Hz, 1H), 7.83 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.9 Hz, 1H), 7.06 (dd, J = 8.8, 2.8 Hz, 1H), 6.96 (d, J) = 8.6 Hz, 2H), 6.80 (d, J = 7.2 Hz, 1H), 4.61 (s, 2H). MS (ESI): 514 (M+H).
实施例39——7-((3-氯-4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a1嘧啶Example 39 - 7-((3-Chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)imidazole [ 1,2-a1 pyrimidine
Figure PCTCN2016080725-appb-000103
Figure PCTCN2016080725-appb-000103
除了以中间体47和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例39化合物。1H NMR(400MHz，Chloroform-d)δ9.27(s，1H)，8.94(s， 2H)，8.37(d，J＝7.4Hz，1H)，7.77(s，1H)，7.65(d，J＝1.8Hz，1H)，7.44(m，2H)，7.29(d，J＝2.9Hz，1H)，7.07(d，J＝8.3Hz，1H)，7.01(dd，J＝8.8，2.8Hz，1H)，6.65(d，J＝7.4Hz，1H)，5.55(s，2H).MS(ESI)：532(M+H)。The compound of Example 39 was prepared by referring to the preparation method of Example 1 except that Intermediate 47 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.27 (s, 1H), 8.94 (s, 2H), 8.37 (d, J = 7.4Hz, 1H), 7.77 (s, 1H), 7.65 (d, J =1.8 Hz, 1H), 7.44 (m, 2H), 7.29 (d, J = 2.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.8, 2.8 Hz, 1H) ), 6.65 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H). MS (ESI): 532 (M+H).
实施例40——7-(4-(4-氯-3-(三氟甲基)苯氧基)苯基乙氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 40 - 7-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)phenylethoxy)-3-(pyrimidin-5-yl)-[1,2,4 Triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000104
Figure PCTCN2016080725-appb-000104
除了以中间体56和4-嘧啶硼酸为原料以外，参照实施例8的制备方法制备实施例40化合物。1H NMR(400MHz，Chloroform-d)δ9.41(s，1H)，9.24(s，2H)，8.33(d，J＝7.5Hz，1H)，7.45(d，J＝8.7Hz，1H)，7.35-7.31(m，3H)，7.09(dd，J＝8.7，2.7Hz，1H)，7.01(d，J＝8.5Hz，2H)，6.62(d，J＝7.5Hz，1H)，4.81(t，J＝6.9Hz，2H)，3.19(t，J＝6.8Hz，2H).MS(ESI)：513(M+H)。The compound of Example 40 was prepared by referring to the preparation method of Example 8 except that Intermediate 56 and 4-pyrimidineboronic acid were used as starting materials. 1 H NMR (400MHz, Chloroform- d) δ9.41 (s, 1H), 9.24 (s, 2H), 8.33 (d, J = 7.5Hz, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.35-7.31 (m, 3H), 7.09 (dd, J = 8.7, 2.7 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 7.5 Hz, 1H), 4.81 (t , J = 6.9 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H). MS (ESI): 513 (M+H).
实施例41——7-(4-(4-氯-3-(三氟甲基)苯氧基)苯氧基)-3-(嘧啶-5-基)咪唑[1，2-a1嘧啶Example 41 - 7-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)phenoxy)-3-(pyrimidin-5-yl)imidazole [1,2-a1 pyrimidine
Figure PCTCN2016080725-appb-000105
Figure PCTCN2016080725-appb-000105
除了以中间体5和中间体53为原料以外，参照实施例6的制备方法制备实施例41化合物。1H NMR(400MHz，Chloroform-d)δ9.31(s，1H)，8.97(s，2H)，8.48(d，J＝7.4Hz，1H)，7.78(s，1H)，7.49(d，J＝8.8Hz，1H)，7.43(d，J＝2.7Hz，1H)，7.31(d，J＝8.9Hz，2H)，7.16(dd，J＝8.8，2.7Hz，1H)，7.10(d，J＝8.9Hz，2H)，6.83(d，J＝7.3Hz，1H).MS(ESI)：484(M+H)。The compound of Example 41 was prepared by referring to the preparation method of Example 6 except that Intermediate 5 and Intermediate 53 were used. 1H NMR (400MHz, Chloroform-d) δ 9.31 (s, 1H), 8.97 (s, 2H), 8.48 (d, J = 7.4 Hz, 1H), 7.78 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 7.16 (dd, J = 8.8, 2.7 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 7.3 Hz, 1H). MS (ESI): 484 (M+H).
实施例42——7-(3-(4-(4-氯-3-(三氟甲基)苯氧基)苯基)丙氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 42 - 7-(3-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)phenyl)propoxy)-3-(pyrimidin-5-yl)imidazole [1 , 2-a] pyrimidine
Figure PCTCN2016080725-appb-000106
Figure PCTCN2016080725-appb-000106
除了以中间体6和中间体53为原料以外，参照实施例6的制备方法制备实施例42化合物。1H NMR(400MHz，Chloroform-d)δ9.26(s，1H)，8.92(s，2H)，8.30(d，J＝7.4Hz，1H)，7.72(s，1H)，7.42(d，J＝8.8Hz，1H)，7.31(d，J＝2.9Hz，1H)，7.23(d，J＝8.5Hz，2H)，7.05(dd，J＝8.7，2.9Hz，1H)，6.95(d，J＝ 8.5Hz，2H)，6.55(d，J＝7.4Hz，1H)，4.54(t，J＝6.5Hz，2H)，2.85-2.78(m，2H)，2.25-2.20(m，2H).MS(ESI)：526(M+H)。The compound of Example 42 was prepared by referring to the preparation method of Example 6 except that Intermediate 6 and Intermediate 53 were used. 1 H NMR (400MHz, Chloroform- d) δ9.26 (s, 1H), 8.92 (s, 2H), 8.30 (d, J = 7.4Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.9 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.05 (dd, J = 8.7, 2.9 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 7.4 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 2.85-2.78 (m, 2H), 2.25-2.20 (m, 2H). (ESI): 526 (M+H).
实施例43——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-(三氟甲基)苄基)氧基)-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 43 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzyl)oxy)-3-(pyrimidine-5 -based imidazo[1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000107
Figure PCTCN2016080725-appb-000107
除了以中间体48和4-溴嘧啶为原料以外，参照实施例1的制备方法制备实施例43化合物。1H NMR(400MHz，Chloroform-d)δ9.27(s，1H)，8.93(s，2H)，8.36(d，J＝7.4Hz，1H)，7.85(d，J＝1.7Hz，1H)，7.75(s，1H)，7.69(dd，J＝8.5，1.8Hz，1H)，7.48(d，J＝8.8Hz，1H)，7.37(d，J＝2.9Hz，1H)，7.11(dd，J＝8.8，2.8Hz，1H)，6.99(d，J＝8.5Hz，1H)，6.63(d，J＝7.4Hz，1H)，5.59(s，2H).MS(ESI)：566(M+H)。The compound of Example 43 was prepared by referring to the preparation method of Example 1 except that Intermediate 48 and 4-bromopyrimidine were used as starting materials. 1 H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.93 (s, 2H), 8.36 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J = 8.5, 1.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.9 Hz, 1H), 7.11 (dd, J = 8.8, 2.8 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.59 (s, 2H). MS (ESI): 566 (M+H ).
实施例44——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 44 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)-[1,2, 4] Triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000108
Figure PCTCN2016080725-appb-000108
以中间体61和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.25(s，1H)，9.03(s，2H)，7.77(d，J＝6.6Hz，1H)，7.50(d，J＝8.8Hz，1H)，7.43(d，J＝6.6Hz，1H)，7.39(d，J＝2.7Hz，1H)，7.33(d，J＝8.5Hz，2H)，7.16(dd，J＝8.7，2.6Hz，1H)，7.02(d，J＝8.5Hz，2H)，5.56(s，2H).MS(ESI)：m/z 499(M+H)。The preparation method of Example 8 was referred to using Intermediate 61 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.25 (s, 1H), 9.03 (s, 2H), 7.77 (d, J = 6.6Hz, 1H), 7.50 (d, J = 8.8Hz, 1H), 7.43 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.16 (dd, J = 8.7, 2.6 Hz, 1H), 7.02 (d, J = 8.5 Hz, 2H), 5.56 (s, 2H). MS (ESI): m/z 499 (M+H).
实施例45——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-甲基苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 45 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-methylbenzyl)oxy)-3-(pyrimidin-5-yl)- [1,2,4]triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000109
Figure PCTCN2016080725-appb-000109
以中间体62和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.39(s，1H)，9.23(s，2H)，8.35(d，J＝7.5Hz，1H)，7.45-7.43(m，1H)，7.41(d，J＝8.8Hz，1H)，7.36(dd，J＝8.3，2.0Hz，1H)， 7.26(s，1H)，6.98(dd，J＝8.8，2.9Hz，1H)，6.94(d，J＝8.2Hz，1H)，5.57(s，2H)，2.25(s，3H).MS(ESI)：m/z 513(M+H)。The preparation method of Example 8 was referred to using Intermediate 62 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.39 (s, 1H), 9.23 (s, 2H), 8.35 (d, J = 7.5Hz, 1H), 7.45-7.43 (m, 1H), 7.41 (d , J = 8.8 Hz, 1H), 7.36 (dd, J = 8.3, 2.0 Hz, 1H), 7.26 (s, 1H), 6.98 (dd, J = 8.8, 2.9 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.57 (s, 2H), 2.25 (s, 3H). MS (ESI): m/z 513 (M+H).
实施例46——2-(4-氯-3-(三氟甲基)苯氧基)-5-(((3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶-7-基)氧基)甲基)苯甲腈Example 46 - 2-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-(((3-(pyrimidin-5-yl)-[1,2,4]triazole) [4,3-a]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure PCTCN2016080725-appb-000110
Figure PCTCN2016080725-appb-000110
以中间体63和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.41(s，1H)，9.23(s，2H)，8.37(d，J＝7.5Hz，1H)，7.86(d，J＝2.0Hz，1H)，7.72(dd，J＝8.6，2.1Hz，1H)，7.55(d，J＝8.7Hz，1H)，7.42(d，J＝2.7Hz，1H)，7.21(dd，J＝8.6，2.8Hz，1H)，6.95(d，J＝8.6Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.60(s，2H).MS(ESI)：m/z 524(M+H)。The preparation method of Example 8 was referred to using Intermediate 63 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.41 (s, 1H), 9.23 (s, 2H), 8.37 (d, J = 7.5Hz, 1H), 7.86 (d, J = 2.0Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.21 (dd, J = 8.6, 2.8 Hz, 1H) , 6.95 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.60 (s, 2H). MS (ESI): m/z 524 (M+H).
实施例47——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-氟苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 47 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-fluorobenzyl)oxy)-3-(pyrimidin-5-yl)-[ 1,2,4]triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000111
Figure PCTCN2016080725-appb-000111
以中间体64和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.43(s，1H)，9.25(s，2H)，8.38(d，J＝7.5Hz，1H)，7.46(d，J＝8.9Hz，1H)，7.42(dd，J＝10.9，1.8Hz，1H)，7.33(d，J＝3.1Hz，2H)，7.16(t，J＝8.2Hz，1H)，7.08(dd，J＝8.8，2.9Hz，1H)，6.71(d，J＝7.5Hz，1H)，5.62(s，2H).MS(ESI)：m/z 517(M+H)。The preparation method of Example 8 was referred to using Intermediate 64 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.43 (s, 1H), 9.25 (s, 2H), 8.38 (d, J = 7.5Hz, 1H), 7.46 (d, J = 8.9Hz, 1H), 7.42 (dd, J = 10.9, 1.8 Hz, 1H), 7.33 (d, J = 3.1 Hz, 2H), 7.16 (t, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.8, 2.9 Hz, 1H) ), 6.71 (d, J = 7.5 Hz, 1H), 5.62 (s, 2H). MS (ESI): m/z 517 (M+H).
实施例48——7-((3-氯-4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 48 - 7-((3-Chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-3-(pyrimidin-5-yl)-[ 1,2,4]triazole [4,3-a]pyrimidine
Figure PCTCN2016080725-appb-000112
Figure PCTCN2016080725-appb-000112
以中间体65和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.40(s，1H)，9.23(s，2H)，8.35(d，J＝7.5Hz，1H)，7.66(d，J＝2.0Hz，1H)，7.45(d，J＝8.8Hz，2H)，7.29(d，J＝2.9Hz，1H)， 7.07(d，J＝8.3Hz，1H)，7.02(dd，J＝8.8，2.9Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.59(s，2H).MS(ESI)：m/z 533(M+H)。The preparation method of Example 8 was referred to using Intermediate 65 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.40 (s, 1H), 9.23 (s, 2H), 8.35 (d, J = 7.5Hz, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 2.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.8, 2.9 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.59 (s, 2H). MS (ESI): m/z 533 (M+H).
实施例49——7-((4-(4-氯-3-(三氟甲基)苯氧基)-3-(三氟甲基)苄基)氧基)-3-(嘧啶-5-基)-[1，2，4]三氮唑[4，3-a]嘧啶Example 49 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzyl)oxy)-3-(pyrimidine-5 -yl)-[1,2,4]triazole [4,3-a]pyrimidine
以中间体66和4-嘧啶硼酸为原料以外，参照实施例8的制备方法。1H NMR(400MHz，chloroform-d)δ9.40(s，1H)，9.23(s，2H)，8.36(d，J＝7.5Hz，1H)，7.86(d，J＝1.7Hz，1H)，7.70(dd，J＝8.4，1.7Hz，1H)，7.49(d，J＝8.8Hz，1H)，7.37(d，J＝2.9Hz，1H)，7.12(dd，J＝8.7，2.9Hz，1H)，7.00(d，J＝8.4Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.63(s，2H).MS(ESI)：m/z 567(M+H)。The preparation method of Example 8 was referred to using Intermediate 66 and 4-pyrimidineboronic acid as raw materials. 1 H NMR (400MHz, chloroform- d) δ9.40 (s, 1H), 9.23 (s, 2H), 8.36 (d, J = 7.5Hz, 1H), 7.86 (d, J = 1.7Hz, 1H), 7.70 (dd, J = 8.4, 1.7 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.9 Hz, 1H), 7.12 (dd, J = 8.7, 2.9 Hz, 1H) ), 7.00 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.63 (s, 2H). MS (ESI): m/z 567 (M+H).
Figure PCTCN2016080725-appb-000113
Figure PCTCN2016080725-appb-000113
实施例50——7-((4-(4-氯-3-(三氟甲基)苯氧基)苄基)氧基)-6-甲基-3-(嘧啶-5-基)咪唑[1，2-a]嘧啶Example 50 - 7-((4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-6-methyl-3-(pyrimidin-5-yl)imidazole [1,2-a]pyrimidine
Figure PCTCN2016080725-appb-000114
Figure PCTCN2016080725-appb-000114
以中间体67为原料以外，参照实施例1的制备方法。1H NMR(400MHz，chloroform-d)δ9.28(s，1H)，8.93(s，2H)，8.15(s，1H)，7.73(s，1H)，7.56(d，J＝8.5Hz，2H)，7.45(d，J＝8.8Hz，1H)，7.35(d，J＝2.6Hz，1H)，7.10(dd，J＝8.6，2.8Hz，1H)，7.04(d，J＝7.3Hz，2H)，5.58(s，2H)，2.26(s，3H).MS(ESI)：m/z 512(M+H)。The preparation method of Example 1 was referred to using Intermediate 67 as a raw material. 1 H NMR (400MHz, chloroform- d) δ9.28 (s, 1H), 8.93 (s, 2H), 8.15 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 8.5Hz, 2H ), 7.45 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.10 (dd, J = 8.6, 2.8 Hz, 1H), 7.04 (d, J = 7.3 Hz, 2H) ), 5.58 (s, 2H), 2.26 (s, 3H). MS (ESI): m/z 512 (M+H).
药理实施例Pharmacological embodiment
药理实施例1：体外抑制活性实验Pharmacological Example 1: In vitro inhibitory activity experiment
试剂Reagent
1)反应缓冲液1) Reaction buffer
反应缓冲液为0.1M Tris-HCl，1mM EGTA，PH 7.2。The reaction buffer was 0.1 M Tris-HCl, 1 mM EGTA, pH 7.2.
2)磷脂酰胆碱的硫酯类似物(2-硫-PAF，2-thio-PAF，Cayman，Lot 60945)2) Thioester analogs of phosphatidylcholine (2-sulfo-PAF, 2-thio-PAF, Cayman, Lot 60945)
用无水乙醇溶解，配置25mg/ml母液，并分装，保存于-80℃。稀释900倍后使用(浓度约为50μM)。Dissolved in absolute ethanol, and placed 25 mg/ml mother liquor, and dispensed and stored at -80 °C. It was diluted 900 times and used (concentration was about 50 μM).
3)DTNB(5，5’-二硫-双-(2-硝基苯甲酸)，5，5’-dithio-bis-(2-nitrobenzoic acid)，Sigma，Lot D8130) 3) DTNB (5,5'-dithio-bis-(2-nitrobenzoic acid), 5,5'-dithio-bis-(2-nitrobenzoic acid), Sigma, Lot D8130)
使用时才配制。用三蒸水配制成浓度为1.1mg/ml，加入适量0.1M NaOH至DTNB刚好溶解。Formulated when used. The concentration was 1.1 mg/ml with three distilled water, and an appropriate amount of 0.1 M NaOH was added until the DTNB just dissolved.
4)化合物用DMSO溶解至适宜浓度。4) The compound was dissolved in DMSO to a suitable concentration.
实验原理Experimental principle
以2-硫-PAF为底物测定Lp-PLA2活性。2-硫-PAF水解后产生的巯基可与DTNB反应，生成黄色物质，可在414nm检测光密度值，从而反映Lp-PLA2活性。Lp-PLA 2 activity was determined using 2-sulfur-PAF as a substrate. The thiol group produced after the hydrolysis of 2-sulfo-PAF can react with DTNB to form a yellow substance, and the optical density value can be detected at 414 nm to reflect the Lp-PLA 2 activity.
1.1化合物对兔血清为酶源的Lp-PLA2抑制活性的测定(体外)1.1 Determination of inhibitory activity of Lp-PLA 2 by enzymes in rabbit serum (in vitro)
1.1.1实验方法1.1.1 Experimental methods
1)按表1加入相应试剂，并振荡混合均匀1) Add the corresponding reagent according to Table 1 and mix well by shaking
表1：反应体系列表Table 1: List of reaction systems
Figure PCTCN2016080725-appb-000115
Figure PCTCN2016080725-appb-000115
2)每孔加入10μL DTNB。2) Add 10 μL of DTNB to each well.
3)每孔加入150μL2-硫-PAF，在酶标仪上振荡15s，使孔内液体混匀。414nM检测10分钟，每分钟检测一次，测定斜率。按下列公式计算抑制率3) Add 150 μL of 2-sulfur-PAF to each well and shake it on a microplate reader for 15 s to mix the liquid in the well. The 414 nM was tested for 10 minutes, once every minute, and the slope was measured. Calculate the inhibition rate according to the following formula
抑制率＝1-(斜率样品孔-斜率空白孔)/(斜率对照孔-斜率空白孔)×100％Inhibition rate = 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) × 100%
1.1.2实验结果见下表2。1.1.2 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抑制活性Table 2: Lp-PLA 2 inhibitory activity of some compounds on rabbit serum as enzyme source under various concentration conditions
Figure PCTCN2016080725-appb-000116
Figure PCTCN2016080725-appb-000116
Figure PCTCN2016080725-appb-000117
Figure PCTCN2016080725-appb-000117
“NT”表示未测试。"NT" means not tested.
表2中所列化合物在1μM浓度下对Lp-PLA2抑制率均大于50％，部分化合物在100nM浓度下对Lp-PLA2抑制率大于50％，其中，实施例16在兔血清中显示出了最好的体外活性，在100nM浓度下对Lp-PLA2抑制率可达到70％以上。The compounds listed in Table 2 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 1 μM, and some compounds showed an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 100 nM, wherein Example 16 showed in rabbit serum. The best in vitro activity, the inhibition rate of Lp-PLA 2 can reach more than 70% at 100nM concentration.
1.2化合物对人源重组酶为酶源的Lp-PLA2抑制活性的测定(体外)1.2 Determination of Lp-PLA 2 inhibitory activity of human recombinant enzyme as an enzyme source (in vitro)
1.2.1实验方法1.2.1 Experimental methods
1)按表3加入相应试剂，并振荡混合均匀1) Add the corresponding reagent according to Table 3, and mix well by shaking
表3：反应体系列表Table 3: List of reaction systems
Figure PCTCN2016080725-appb-000118
Figure PCTCN2016080725-appb-000118
2)每孔加入10μL DTNB。2) Add 10 μL of DTNB to each well.
3)每孔加入150μL 2-硫-PAF，在酶标仪上振荡15s，使孔内液体混匀。414nM检测10分钟，每分钟检测一次，测定斜率。按下列公式计算抑制率3) Add 150 μL of 2-sulfur-PAF to each well and shake it on a microplate reader for 15 s to mix the liquid in the well. The 414 nM was tested for 10 minutes, once every minute, and the slope was measured. Calculate the inhibition rate according to the following formula
抑制率＝1-(斜率样品孔-斜率空白孔)/(斜率对照孔-斜率空白孔)×100％Inhibition rate = 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) × 100%
1.2.2实验结果见下表4。1.2.2 The experimental results are shown in Table 4 below.
表4：部分化合物对人源重组酶为酶源的Lp-PLA2的抑制活性Table 4: Inhibitory activity of some compounds on Lp-PLA 2 with human recombinant enzyme as enzyme source
Figure PCTCN2016080725-appb-000119
Figure PCTCN2016080725-appb-000119
Figure PCTCN2016080725-appb-000120
Figure PCTCN2016080725-appb-000120
表4中所列化合物在10nM浓度下对Lp-PLA2抑制率均大于50％，其中，实施例16、实施例31在人源重组酶中显示出了最好的体外活性，在10nM浓度下对Lp-PLA2抑制率达到约90％。The compounds listed in Table 4 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 10 nM, wherein Example 16 and Example 31 showed the best in vitro activity in human recombinant enzyme at a concentration of 10 nM. The inhibition rate to Lp-PLA 2 reached about 90%.
1.3化合物对大鼠血清为酶源的Lp-PLA2抑制活性的测定(体外)1.3 Determination of inhibitory activity of Lp-PLA 2 by enzymes in rat serum (in vitro)
1.3.1实验方法1.3.1 Experimental methods
1)按表5加入相应试剂，并振荡混合均匀1) Add the corresponding reagent according to Table 5, and mix well by shaking
表5：反应体系列表Table 5: List of reaction systems
  空白孔Blank hole 样品孔Sample hole 对照孔Control hole
反应缓冲液Reaction buffer 30μL30μL 20μL20μL 20μL20μL
大鼠血清(酶源)Rat serum (enzyme source)   10μL10μL 10μL10μL
DMSODMSO 10μL10μL   10μL10μL
样品(DMSO溶解)Sample (DMSO dissolved)   10L10L  
2)每孔加入10μL DTNB。2) Add 10 μL of DTNB to each well.
3)每孔加入150μL2-硫-PAF，在酶标仪上振荡15s，使孔内液体混匀。414nM检测10分钟，每分钟检测一次，测定斜率。按下列公式计算抑制率 3) Add 150 μL of 2-sulfur-PAF to each well and shake it on a microplate reader for 15 s to mix the liquid in the well. The 414 nM was tested for 10 minutes, once every minute, and the slope was measured. Calculate the inhibition rate according to the following formula
抑制率＝1-(斜率样品孔-斜率空白孔)/(斜率对照孔-斜率空白孔)×100％Inhibition rate = 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) × 100%
1.3.2实验结果见下表6。1.3.2 The experimental results are shown in Table 6 below.
表6：部分化合物对大鼠血清为酶源的Lp-PLA2的抑制活性Table 6: Inhibitory activity of some compounds on rat serum-derived Lp-PLA 2
Figure PCTCN2016080725-appb-000121
Figure PCTCN2016080725-appb-000121
“NT”表示未测试。"NT" means not tested.
表6中所列化合物，在大鼠血清中显示出了的不错的体外活性，所有化合物在100nM浓度下对Lp-PLA2抑制率均大于50％。The compounds listed in Table 6 showed good in vitro activity in rat serum, and all compounds inhibited Lp-PLA 2 by more than 50% at a concentration of 100 nM.
药理实施例2：S9体外代谢稳定性实验Pharmacological Example 2: S9 in vitro metabolic stability experiment
2.1.试剂2.1. Reagents
2.1.1Tris/HCl(0.1M，pH 7.4)缓冲液配制2.1.1 Tris/HCl (0.1M, pH 7.4) buffer preparation
称取12.12g TRIS(三羟甲基氨基甲烷，tris-hydroxymethyl aminomethane)，溶解于800mL水中，用HCl(2M)调节pH至7.4，然后用水定容至1000mL。12.12 g of TRIS (tris-hydroxymethyl aminomethane) was weighed, dissolved in 800 mL of water, adjusted to pH 7.4 with HCl (2M), and then made up to 1000 mL with water.
2.1.2MgCl2配制2.1.2MgCl 2 preparation
用0.1M Tris/HCl缓冲液配成MgCl2(100mM)溶液，分装后存放于-20℃。MgCl2的孵育浓度为5.0mM。A solution of MgCl 2 (100 mM) was prepared in 0.1 M Tris/HCl buffer, and stored at -20 ° C after dispensing. The incubation concentration of MgCl 2 was 5.0 mM.
2.1.3NADPH配制 2.1.3 NADPH preparation
用0.1M Tris/HCl缓冲液配成NADPH(10mM)溶液，分装后存放于-20℃。NADPH的孵育浓度为1.0mM。A solution of NADPH (10 mM) was prepared in 0.1 M Tris/HCl buffer, and stored at -20 ° C after dispensing. The incubation concentration of NADPH was 1.0 mM.
2.1.4S9配制2.1.4S9 preparation
用0.1M Tris/HCl将人S9(购自瑞德肝脏疾病研究(上海)有限公司)稀释10倍，大鼠S9(购自瑞德肝脏疾病研究(上海)有限公司)稀释5倍。使得人、大鼠S9的孵育浓度相当于相应种属肝微粒体的孵育浓度(人、大鼠肝微粒体的孵育浓度均为0.33mg/mL)。Human S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 10-fold with 0.1 M Tris/HCl, and rat S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 5-fold. The incubation concentration of human and rat S9 was equivalent to the incubation concentration of the corresponding species of liver microsomes (the incubation concentration of human and rat liver microsomes was 0.33 mg/mL).
2.1.5待测化合物配制2.1.5 Preparation of test compounds
用DMSO溶解化合物获得浓度为10mM的储备液。以DMSO稀释至1mM后再以0.1％BSA-水稀释获得浓度为2μM的工作溶液。孵育体系中，2μM的工作溶液稀释20倍，终浓度为0.1μM。孵育体系中的DMSO浓度≤0.01％。The compound was dissolved in DMSO to obtain a stock solution having a concentration of 10 mM. After diluting to 1 mM in DMSO, it was diluted with 0.1% BSA-water to obtain a working solution having a concentration of 2 μM. In the incubation system, 2 μM of the working solution was diluted 20-fold to a final concentration of 0.1 μM. The concentration of DMSO in the incubation system was < 0.01%.
2.1.6阳性对照化合物配制2.1.6 Preparation of positive control compounds
使用2μM的待测物工作液将2mM VIVID储备液(购自上海拜力生物科技有限公司)稀释50倍。孵育体系中，VIVID和待测物的混合工作溶液稀释20倍。2 mM VIVID stock solution (purchased from Shanghai Baili Biotechnology Co., Ltd.) was diluted 50 times using 2 μM of the test substance working solution. In the incubation system, the mixed working solution of VIVID and the analyte is diluted 20 times.
2.2实验方法2.2 Experimental methods
S9孵育于96孔板中进行，每个孵育体系体积为450μL，0.1M Tris缓冲液(pH 7.4)、MgCl2、S9和+NADPH/-NADPH在37℃下预孵10min后(转速为600rpm)，加入受试药物起始反应，分别在0、7、17、30、60min后加入同体积的冰甲醇终止反应。S9 was incubated in 96-well plates at 450 μL per incubation system, 0.1 M Tris buffer (pH 7.4), MgCl 2 , S9 and +NADPH/-NADPH pre-incubated for 10 min at 37 ° C (600 rpm) The test drug was added to initiate the reaction, and the reaction was stopped by adding the same volume of ice methanol at 0, 7, 17, 30, 60 min.
2.3实验结果见下表7。2.3 The experimental results are shown in Table 7 below.
表7：部分化合物在人、大鼠S9中的代谢稳定性Table 7: Metabolic stability of some compounds in human and rat S9
Figure PCTCN2016080725-appb-000122
Figure PCTCN2016080725-appb-000122
Figure PCTCN2016080725-appb-000123
Figure PCTCN2016080725-appb-000123
“-”表示化合物在测试体系中稳定，无法测定半衰期。"-" indicates that the compound is stable in the test system and the half-life cannot be determined.
表7中所列化合物，实验结果显示代谢稳定性相比于目前处于临床研究阶段的化合物darapladib具有优势，且人与大鼠代谢性质显示出较好的种属一致性。The compounds listed in Table 7, the experimental results show that the metabolic stability is superior to the compound darapladib currently in the clinical research stage, and the metabolic properties of human and rat show better species consistency.
药理实施例3：SD大鼠体内抑制Lp-PLA2活性实验Pharmacological Example 3: Inhibition of Lp-PLA 2 activity in SD rats
2.1实验方法2.1 Experimental methods
每组5只SD大鼠，口服给药25mg/kg，Darapladib用ddH20溶解，实施例化合物溶剂为0.5％羧甲基纤维素钠(CMC钠)。于给药前0h、给药后1h、3h、5h、7h、24h眼眶采血，室温放置30分钟后离心，取血清，测定血清中Lp-PLA2活性。Five SD rats in each group were orally administered with 25 mg/kg, and Darapladib was dissolved in ddH20. The solvent of the example compound was 0.5% sodium carboxymethylcellulose (sodium CMC). Blood was collected from the eyelids at 0 h before administration, 1 h, 3 h, 5 h, 7 h, and 24 h after administration. After standing at room temperature for 30 minutes, the cells were centrifuged, and serum was taken to measure the activity of Lp-PLA 2 in the serum.
2.2实验结果2.2 Experimental results
根据体外活性的测试结果，选取了部分化合物进行了SD大鼠体内的Lp-PLA2抑制活性测试，实验结果如图1和图2所示。According to the test results of in vitro activity, some compounds were selected for Lp-PLA 2 inhibitory activity test in SD rats. The experimental results are shown in Fig. 1 and Fig. 2.
结果表明，单次给药后，选取的实施例化合物1、11、44和47，均能够显著抑制SD大鼠血清中Lp-PLA2的活性，并且表现出与阳性对照化合物darapladib相当的体内抑制活性。体内实验结果显示，口服实施例化合物，在大鼠体内展现出了相当不错的Lp-PLA2抑制活性，表明实施例化合物具备很好的开发前景。The results showed that after a single administration, the selected compounds 1, 11, 44 and 47 were able to significantly inhibit the activity of Lp-PLA 2 in the serum of SD rats and showed comparable inhibition in vivo to the positive control compound darapladib. active. In vivo experiments showed that the oral administration of the compound exhibited a relatively good Lp-PLA 2 inhibitory activity in rats, indicating that the compound of the example has a good development prospect.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (10)

  1. 一种通式I化合物或其药学上可以接受的盐：A compound of formula I or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2016080725-appb-100001
    Figure PCTCN2016080725-appb-100001
    式中，R1为C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C3-C8环烯基、-(CH2)m-NR4R5、C6-C10芳基、-(CH2)m-(3-8元杂芳基)、或卤素，其中，所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烯基、3-8元杂芳基、3-8元杂环基、C6-C10芳基非必须地被选自下组的基团取代：-OH、-CN、＝O、C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷氧酰基、C1-C6烷酰基、C1-C6烷酰氧基、C3-C8环烷基、羧基、卤素、卤代C1-C6烷基、-S(O)R1’、-SO2R2’、-NO2、-NR3’R4’；Wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 3 - C 8 cycloalkenyl, -(CH 2 ) m -NR 4 R 5 , C 6 -C 10 aryl, -(CH 2 ) m -(3-8 membered heteroaryl), or halogen, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heteroaryl, The 3-8 membered heterocyclic group, C 6 -C 10 aryl group is optionally substituted with a group selected from the group consisting of -OH, -CN, =O, C 1 -C 6 alkyl, C 6 -C 10 Aryl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 3 -C 8 cycloalkyl, carboxy, Halogen, halogenated C 1 -C 6 alkyl, -S(O)R 1 ', -SO 2 R 2 ', -NO 2 , -NR 3 'R 4 ';
    R2、R3独立地选自H、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基或-NR6R7，其中，所述C1-C6烷基、C3-C8环烷基、C1-C6烷氧基非必须地被选自下组的基团取代：-OH、-CN、＝O、C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷氧酰基、C1-C6烷酰基、C1-C6烷酰氧基、C3-C8环烷基、羧基、卤素、卤代C1-C6烷基、-S(O)R1’、-SO2R2’、-NO2、-NR3’R4’；R 2 and R 3 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy or -NR 6 R 7 , wherein said C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy is optionally substituted with a group selected from the group consisting of -OH, -CN, =O, C 1 -C 6 alkane , C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 3 -C 8 -cycloalkyl, carboxy, halogen, halogenated C 1 -C 6 alkyl, -S(O)R 1 ', -SO 2 R 2 ', -NO 2 , -NR 3 'R 4 ';
    X为O、S、-(CH2)q-或-N(R8)-；X is O, S, -(CH 2 ) q - or -N(R 8 )-;
    n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
    Ar为C6-C10芳基或3-8元杂芳基，其中，所述C6-C10芳基或3-8元杂芳基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基、卤代C1-C6烷氧基；Ar is a C 6 -C 10 aryl group or a 3-8 membered heteroaryl group, wherein the C 6 -C 10 aryl group or the 3-8 membered heteroaryl group is optionally 1-4 selected from the group consisting of Group substitution: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
    Y为氢、-A-(C6-C10芳基)或-A-(3-8元杂芳基)，其中，A为O、S、-(CH2)o-或-N(R9)-，所述C6-C10芳基、3-8元杂芳基非必须地被1-3个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、卤代C1-C6烷基；Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(3-8 membered heteroaryl), wherein A is O, S, -(CH 2 ) o - or -N(R 9 )-, the C 6 -C 10 aryl, 3-8 membered heteroaryl is optionally substituted with 1-3 groups selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1- C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl;
    Z为CH或N；Z is CH or N;
    所述R4至R9、以及R1’至R4’各自独立地选自H、C1-C6烷基、C1-C6烷酰基、-(CH2)p-(C1-C6烷氧基)、C3-C8环烷基、C2-C6烯基、C2-C6炔基、3-8元杂环基、C3-C8环烯基和C6-C10芳基；The R 4 to R 9 and R 1 ' to R 4 ' are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, -(CH 2 ) p -(C 1 - C 6 alkoxy), C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered heterocyclic, C 3 -C 8 cycloalkenyl and C 6- C 10 aryl;
    所述m、q、o和p各自独立地为0、1、2或3。The m, q, o, and p are each independently 0, 1, 2, or 3.
  2. 根据权利要求1所述的化合物或其药学上可以接受的盐， The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
    式中，R1为C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环基、-(CH2)m-NR4R5、苯基、-(CH2)m-(3-8元杂芳基)或卤素，其中，所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-8元杂芳基、3-6元杂环基、苯基非必须地被选自下组的基团所取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；Wherein R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein the C 1 -C 4 alkyl group, C 2 -C 4 alkenyl group , C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-8 membered heteroaryl, 3-6 membered heterocyclyl, phenyl are optionally substituted with a group selected from the group consisting of: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl;
    R2为H或C1-C6烷基，其中，所述所述C1-C6烷基非必须地被选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；R 2 is H or a C 1 -C 6 alkyl group, wherein the C 1 -C 6 alkyl group is optionally substituted with a group selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl;
    R3为H或C1-C6烷基，其中，所述所述C1-C6烷基非必须地被选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基；R 3 is H or a C 1 -C 6 alkyl group, wherein the C 1 -C 6 alkyl group is optionally substituted with a group selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl;
    X为O或S；X is O or S;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    Ar为苯基、萘基或5-6元杂芳基，其中，所述苯基、萘基、5-6元杂芳基非必须地被1-4个选自下组的基团取代：-CN、C1-C6烷基、C1-C6烷氧基、卤素、羟基、卤代C1-C6烷基、卤代C1-C6烷氧基；Ar is phenyl, naphthyl or 5-6 membered heteroaryl, wherein the phenyl, naphthyl, 5-6 membered heteroaryl is optionally substituted with from 1 to 4 groups selected from the group consisting of: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkoxy;
    Y为-A-(C6-C10芳基)或-A-(5-6元杂芳基)，其中，A为O，所述C6-C10芳基、5-6元杂芳基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、三氟甲基、甲基、乙基、丙基；Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O, the C 6 -C 10 aryl group, 5-6 membered heteroaryl The base is optionally substituted with 1-3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl;
    Z为CH或N；Z is CH or N;
    所述R4和R5各自独立地选自H、C1-C6烷基、C1-C6烷酰基、-(CH2)p-(C1-C6烷氧基)、C3-C8环烷基、C2-C6烯基、C2-C6炔基、3-8元杂环基、C3-C8环烯基和C6-C10芳基；The R 4 and R 5 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, -(CH 2 ) p -(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered heterocyclyl, C 3 -C 8 cycloalkenyl and C 6 -C 10 aryl;
    所述m和p各自独立地为0、1、2或3。The m and p are each independently 0, 1, 2 or 3.
  3. 根据权利要求1所述的化合物或其药学上可以接受的盐，The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
    式中，R1为-(CH2)m-NR4R5、苯基或-(CH2)m-(3-6元杂芳基)；Wherein R 1 is -(CH 2 ) m -NR 4 R 5 , phenyl or -(CH 2 ) m -(3-6 membered heteroaryl);
    R2为H或甲基；R 2 is H or methyl;
    R3为H；R 3 is H;
    X为O或S；X is O or S;
    n为0、1或2；n is 0, 1 or 2;
    Ar为苯基，所述苯基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、三氟甲基、甲基、乙基或丙基； Ar is a phenyl group which is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl or propyl;
    Y为-A-(C6-C10芳基)或-A-(5-6元杂芳基)，其中，A为O，所述C6-C10芳基、5-6元杂芳基非必须地被1-3个选自下组的基团取代：-CN、氟、氯、溴、三氟甲基、甲基、乙基、丙基；Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O, the C 6 -C 10 aryl group, 5-6 membered heteroaryl The base is optionally substituted with 1-3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl;
    Z为CH或N；Z is CH or N;
    所述R4和R5各自独立地选自H、C1-C3烷基；The R 4 and R 5 are each independently selected from H, C 1 -C 3 alkyl;
    所述m为0、1、2或3。The m is 0, 1, 2 or 3.
  4. 根据权利要求1所述的化合物或其药学上可以接受的盐，其中，所述化合物具有式(IA)所示的结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure represented by the formula (IA):
    Figure PCTCN2016080725-appb-100002
    Figure PCTCN2016080725-appb-100002
    其中，Ra和Rb各自独立地为H、卤素、-CN、三氟甲基或甲基；Wherein, Ra and Rb are each independently H, halogen, -CN, trifluoromethyl or methyl;
    Z为CH或N；Z is CH or N;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    R1为-(CH2)-N(CH3)2、苯基、-(CH2)-吡唑基、吡唑基、嘧啶基、吡啶基，其中，所述苯基、吡唑基、嘧啶基非必须地被选自以下组的取代：-CN、＝O、甲基、乙基、苯基、甲氧基、乙氧基、环丙基、氟、氯、溴、三氟甲基；R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrazolyl, pyrimidinyl, pyridyl, wherein the phenyl, pyrazolyl, The pyrimidinyl group is optionally substituted with a group selected from the group consisting of -CN, =O, methyl, ethyl, phenyl, methoxy, ethoxy, cyclopropyl, fluoro, chloro, bromo, trifluoromethyl ;
    R2为氢或甲基；R 2 is hydrogen or methyl;
    Ar’为苯基、吡啶基、嘧啶基，其中，所述苯基、吡啶基、嘧啶基非必须地被1-3个选自以下组的基团取代：三氟甲基、氟、氯、氰基、甲基。Ar' is a phenyl group, a pyridyl group or a pyrimidinyl group, wherein the phenyl group, pyridyl group or pyrimidinyl group is optionally substituted with one to three groups selected from the group consisting of trifluoromethyl, fluorine, chlorine, Cyano, methyl.
  5. 根据权利要求1所述的化合物或其药学上可以接受的盐，其中，所述通式I化合物为如下表所示的任一化合物：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of the formula I is any one of the compounds shown in the following table:
    Figure PCTCN2016080725-appb-100003
    Figure PCTCN2016080725-appb-100003
    Figure PCTCN2016080725-appb-100004
    Figure PCTCN2016080725-appb-100004
    Figure PCTCN2016080725-appb-100005
    Figure PCTCN2016080725-appb-100005
    Figure PCTCN2016080725-appb-100006
    Figure PCTCN2016080725-appb-100006
    Figure PCTCN2016080725-appb-100007
    Figure PCTCN2016080725-appb-100007
    Figure PCTCN2016080725-appb-100008
    Figure PCTCN2016080725-appb-100008
  6. 根据权利要求1所述的化合物或其药学上可以接受的盐，其中，所述药学上可以接受的盐为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、甲磺酸盐、三氟乙酸盐、乙酸盐、草酸盐、丁二酸盐、苹果酸盐、甲 苯磺酸盐、酒石酸盐、富马酸盐、谷氨酸盐、葡糖醛酸盐、乳酸盐、戊二酸盐、精氨酸盐或马来酸盐。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, a citrate, Methanesulfonate, trifluoroacetate, acetate, oxalate, succinate, malate, A A besylate, a tartrate, a fumarate, a glutamate, a glucuronate, a lactate, a glutarate, an arginine or a maleate.
  7. 根据权利要求1所述的通式I化合物或其药学上可以接受的盐的制备方法，包括以下步骤：A process for the preparation of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of:
    Figure PCTCN2016080725-appb-100009
    Figure PCTCN2016080725-appb-100009
    当通式I中Z为CH时，即为通式II化合物，由式Ic化合物与R1W反应得到，其中，W为Cl、Br或I；When Z in the general formula I is CH, that is, a compound of the formula II, obtained by reacting a compound of the formula Ic with R 1 W, wherein W is Cl, Br or I;
    或者所述制备方法包括以下步骤：Or the preparation method comprises the following steps:
    Figure PCTCN2016080725-appb-100010
    Figure PCTCN2016080725-appb-100010
    当通式I中Z为CH时，即为通式II化合物，由式Id化合物与
    Figure PCTCN2016080725-appb-100011
    Figure PCTCN2016080725-appb-100012
    反应得到；    When Z in the formula I is CH, it is a compound of the formula II, and a compound of the formula Id is
    Figure PCTCN2016080725-appb-100011
    Figure PCTCN2016080725-appb-100012
    The reaction is obtained;
    或者所述制备方法包括以下步骤：Or the preparation method comprises the following steps:
    Figure PCTCN2016080725-appb-100013
    Figure PCTCN2016080725-appb-100013
    当通式I中Z为CH时，即为通式II化合物，由式IId化合物与Y-Ar-(CH2)nXH在碱存在下反应得到；When Z in the formula I is CH, it is a compound of the formula II, which is obtained by reacting a compound of the formula IId with Y-Ar-(CH 2 ) n XH in the presence of a base;
    或者所述制备方法包括以下步骤： Or the preparation method comprises the following steps:
    Figure PCTCN2016080725-appb-100014
    Figure PCTCN2016080725-appb-100014
    当通式I中Z为N时，即为通式III化合物，由式IIIe化合物与
    Figure PCTCN2016080725-appb-100015
    Figure PCTCN2016080725-appb-100016
    反应得到；    When Z in the formula I is N, it is a compound of the formula III, which is a compound of the formula IIIe and
    Figure PCTCN2016080725-appb-100015
    Figure PCTCN2016080725-appb-100016
    The reaction is obtained;
    其中，所述R1、R2、R3、Y、Ar、n、X的定义与权利要求1中的定义相同。Wherein, the definitions of R 1 , R 2 , R 3 , Y, Ar, n, and X are the same as defined in claim 1.
  8. 一种药物组合物，包含根据权利要求1所述的通式I化合物或其药学上可以接受的盐；和药学上可接受的载体。A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  9. 根据权利要求1所述的通式I化合物或其药学上可以接受的盐或者权利要求8所述的药物组合物的用途，所述用途是用于：Use of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 for:
    (1)制备抑制Lp-PLA2的药物；或者(1) preparing a drug that inhibits Lp-PLA 2 ; or
    (2)制备预防和/或治疗和/或改善与Lp-PLA2酶活性有关的疾病的药物。(2) A medicament for preventing and/or treating and/or ameliorating a disease associated with Lp-PLA 2 enzyme activity.
  10. 一种根据权利要求1所述的通式I化合物的中间体，其结构为：An intermediate of the compound of formula I according to claim 1 having the structure:
    Figure PCTCN2016080725-appb-100017
    Figure PCTCN2016080725-appb-100017
    Figure PCTCN2016080725-appb-100018
    Figure PCTCN2016080725-appb-100018
    其中，所述R1、R2、R3、Y、Ar、n、X的定义与权利要求1中所述的相同。 Wherein, the definitions of R 1 , R 2 , R 3 , Y, Ar, n, and X are the same as those described in claim 1.
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