WO2018166493A1 - 杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用 - Google Patents

杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2018166493A1
WO2018166493A1 PCT/CN2018/079086 CN2018079086W WO2018166493A1 WO 2018166493 A1 WO2018166493 A1 WO 2018166493A1 CN 2018079086 W CN2018079086 W CN 2018079086W WO 2018166493 A1 WO2018166493 A1 WO 2018166493A1
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group
compound
formula
heteroaryl
cycloalkyl
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PCT/CN2018/079086
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English (en)
French (fr)
Inventor
陆标
王胜蓝
沈晓冬
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to RU2019131111A priority Critical patent/RU2764655C2/ru
Priority to MX2019010354A priority patent/MX393395B/es
Priority to EP18766881.9A priority patent/EP3575301A4/en
Priority to CA3054976A priority patent/CA3054976A1/en
Priority to BR112019017108A priority patent/BR112019017108A2/pt
Priority to AU2018233367A priority patent/AU2018233367B2/en
Priority to JP2019548401A priority patent/JP7111733B2/ja
Priority to KR1020197025674A priority patent/KR20190129851A/ko
Priority to UAA201910243A priority patent/UA125592C2/uk
Priority to CN201880004302.2A priority patent/CN109963854B/zh
Priority to US16/492,273 priority patent/US11312705B2/en
Publication of WO2018166493A1 publication Critical patent/WO2018166493A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and relates to a heteroaryl[4,3-c]pyrimidine-5-amine derivative represented by the formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, and as therapeutic agents, in particular as a 2a receptor antagonists of use and manufacture of a medicament for the treatment of a disorder or condition through inhibition of a 2a receptors in ameliorated.
  • Adenosine is a naturally occurring purine nucleoside and is an endogenous regulator of many physiological functions. It plays an important role in the regulation of cardiovascular system, central nervous system, respiratory system, kidney, fat and platelets.
  • adenosine The action of adenosine is mediated by the G-protein coupled receptor family, and at least four subtypes of adenosine receptors are currently known, classified as A 1 , A 2a , A 2b and A 3 .
  • the A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, while the A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in the cells through which adenosine is widely regulated.
  • Physiological function The action of adenosine is mediated by the G-protein coupled receptor family, and at least four subtypes of adenosine receptors are currently known, classified as A 1 , A 2a , A 2b and A 3 .
  • the A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, while the A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating
  • the A 2a receptor (A 2a R) is widely distributed in the body, and is mainly expressed in the striatum in the central nervous system, and is also expressed in tissues such as the periphery, heart, liver, lung and kidney.
  • adenosine A 2a receptor antagonists have surprising efficacy in the treatment of neurodegenerative diseases, primarily Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29(11), 647-654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991, etc.). It can also be used to treat other central nervous system (CNS) related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety (Clin. Neuropharmacol.
  • CNS central nervous system
  • adenosine A 2a receptor antagonists have therapeutic potential as neuroprotective agents (see Jenner PJ Neuro 1.2000; 247 Supp 12: 1143-50).
  • a 2a receptors may play an important immunomodulatory role in many pathological processes such as ischemia, hypoxia, inflammation, trauma, transplantation, etc., which may be related to A 2a receptors in T cells and B cells. It is related to the high expression levels of various immune cells such as mononuclear macrophages and neutrophils.
  • the activation of A 2a receptor can promote the body to produce immune tolerance, and closely participate in the formation of "immune escape” or "immunosuppression” of tumor cells, which creates favorable conditions for the occurrence and development of tumors.
  • a 2a receptor knockout mice can enhance the anti-tumor immunity of CD8 + T cells, significantly inhibiting tumors proliferation. Therefore, A 2a receptor antagonists can also be used in the treatment of tumors.
  • adenosine A 1 receptor in tissue, ischemia, hypoxia, in the central, circulatory, digestive system and skeletal muscle, cells in the hypoxic and hypoxic stress environment extracellular accumulation of adenosine through activation a 1 starts the corresponding membrane receptor on protection mechanisms, thus increasing cellular tolerance to hypoxic hypoxia.
  • the A 1 receptor located on immune cells promotes a cellular immune response in a hypoxic environment.
  • the A 1 receptor also reduces free fatty acids and triglycerides and is involved in the regulation of blood sugar.
  • Adenosine A 3 (as described by Gessi S et al., Pharmacol. Ther.
  • a 3 Sustained blockade of the receptor may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina or heart failure.
  • the present invention provides a novel adenosine [4,3-c]pyrimidin-5-amine structure adenosine A 2a receptor antagonist, and found that a compound having such a structure has strong inhibitory activity and high selectivity. And the compound of such a structure has a low free drug concentration in the brain, a weak ability to pass through the blood-brain barrier, and a low side effect which may occur after the drug enters the brain.
  • G is N or CR 4 ;
  • Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;
  • R 1 is the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group. And heteroaryl;
  • R 2 is selected from the group consisting of alkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkoxy, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl. Substituting one or more substituents of aryl, heteroaryl, C(O)OR 5 and R b ;
  • R 3 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R b is a heterocyclylalkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally selected from the group consisting of an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, Substituted by one or more substituents of a cycloalkyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, and C(O)OR 5 ;
  • n 1, 2, 3 or 4.
  • the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R b is one or more substituents;
  • R & lt b is a heterocyclyl group, heterocyclylalkyl wherein said heterocyclyl is optionally substituted with one or more alkyl groups.
  • the compound of the formula (I) is a compound of the formula (II):
  • Ring B is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a heterocyclic ring.
  • Base aryl, heteroaryl, C(O)OR 5 and R 6 ;
  • s 0, 1, 2, 3 or 4;
  • Rings A, G, R 1 , R 3 , R 5 , R b and n are as defined in formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • R 6 are the same or different and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R b ;
  • R b is heterocyclylalkyl, wherein The heterocyclic group in the heterocyclylalkyl group is optionally substituted by one or more alkyl groups;
  • Ring A, Ring B, R 1 , R 3 , n and s are as defined in the formula (II).
  • the compound of the formula (I) is a compound of the formula (III'):
  • R 6 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, an oxo group, a cycloalkyl group, a heterocyclic group and R b ; and R b is a heterocycloalkyl group, Wherein the heterocyclic group in the heterocyclylalkyl group is optionally substituted by one or more alkyl groups;
  • s is 0, 1 , 2, 3 or 4; the rings A, R 1 , R 3 and n are as defined in the formula (I).
  • the compound of the formula (I), wherein the ring A is an aryl or heteroaryl group, preferably a phenyl or furyl group.
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a compound of the formula (IV):
  • X is a halogen
  • Rings A, G, R 1 , R 3 and n are as defined in formula (I).
  • Typical compounds of the invention include, but are not limited to:
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (II), the process comprising:
  • X is a halogen
  • Ring A, Ring B, G, R 1 , R 3 , R 6 , n and s are as defined in the general formula (I).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention or a tautomer thereof, a mesogen, a racemic form , enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting the A2a receptor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for the manufacture for treating a condition or disorder by a 2a receptors to inhibition of the improved medicament.
  • a condition ameliorated or disorder selected from cancer, depression, cognitive disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease Or amyotrophic lateral sclerosis, etc., attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addiction Behavior; preferably a tumor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic side) Somatorrhea, etc., attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior, preferably tumor Use in medicine.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating a tumor.
  • the invention also relates to a method of inhibiting an A2a receptor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate thereof , enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention further relates to a method of treating a condition or disorder by A 2a receptor inhibition and to improve the method comprising administering to a patient in need thereof a therapeutically effective amount of a Formula (I), or a tautomer thereof shown, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a Formula (I) or a tautomer thereof shown, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention relates to the treatment of tumors, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders , extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior, preferably a method of tumor, which includes administering a desired patient An effective amount of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
  • a method of tumor which includes administering a desired patient
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a medicament.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as an A2a receptor antagonist.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, which by the treatment of a disorder or condition a 2a receptor inhibition ameliorated.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the treatment of a tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or muscular atrophy) Sexual lateral sclerosis, etc., attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior, preferably Tumor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the treatment of a tumor.
  • the tumor described in the present invention is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma.
  • sarcoma osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia, leukemia, thyroid neoplasms, ureteral neoplasms, bladder Cancer, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer, and pediatric tumor; preferably lung cancer.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • the oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the injection or microemulsion is injected into the bloodstream of the patient by topical injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. Any blended fixed oil can be used for this purpose.
  • fatty acids can also be prepared as injections.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from a hydrogen atom, a halogen, an alkyl group, an alkane.
  • One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 Replaced.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group. Substituted by one or more substituents in the hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 groups.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 10 The carbon atom, more preferably contains 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • the cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, One or more substitutions in alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 Substituted by the base.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, High piperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from a hydrogen atom, a halogen, an alkyl group, One or more substitutions in alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 Substituted by the base.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups which are polycyclic rings having a conjugated ⁇ -electron system (ie, The ring group adjacent to a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkane.
  • substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 Replaced.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, One or more substitutions in alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)OR 5 Substituted by the base.
  • cycloalkyloxy refers to cycloalkyl-O-.
  • heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclic groups, wherein alkyl and heterocyclic groups are as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • R 5 is as defined in the formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphine).
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • X is a halogen
  • Ring A, Ring B, G, R 1 , R 3 , R 6 , n and s are as defined in the formula (II).
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (III-1) is reacted with hydrazine hydrate to obtain a compound of the formula (III-2);
  • a compound of the formula (IIIA) and a compound of the formula (V) are reacted under basic conditions to undergo a suzuki coupling reaction in the presence of a catalyst to obtain a compound of the formula (III).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphine).
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • X is a halogen
  • Ring A, Ring B, R 1 , R 3 , R 6 , n and s are as defined in the general formula (III).
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (III-1) is reacted with hydrazine hydrate to obtain a compound of the formula (III-2);
  • the compound of the formula (III-2) and the compound of the formula (V) are reacted under basic conditions to undergo a suzuki coupling reaction in the presence of a catalyst to obtain a compound of the formula (IIIB);
  • a compound of the formula (IIIB) is reacted with a compound of the formula (III-3) to give a compound of the formula (III);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphine).
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • X is a halogen
  • Ring A, Ring B, R 1 , R 3 , R 6 , n and s are as defined in the general formula (III).
  • the compound of the formula (III-1) is reacted with hydrazine hydrate to obtain a compound of the formula (III-2);
  • a compound of the formula (III'b) is reacted with a compound of the formula (III-3) to give a compound of the formula (III');
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphine).
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof;
  • X is a halogen
  • Rings A, R 1 , R 3 , R 6 , n and s are as defined in formula (III).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Rui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • the developing agent used for the reaction the column chromatography eluent system used for the purification of the compound
  • the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate / dichloromethane / n-hexane, H: ethyl acetate / dichloromethane / acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and acetic acid may also be added. Adjust with alkaline or acidic reagents.
  • 6-Bromo-8-methylquinoline 5b (444 mg, 2.00 mmol, prepared by a known method "Journal of Organic Chemistry, 2014, 79 (11), 5379-5385”) was added in an argon atmosphere, and 4 , 4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) 5a (508 mg, 2.00 mmol , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (292 mg, 0.40 mmol) and potassium acetate (588 mg, 6.00 mmol) were dissolved in 10 mL of ethylene glycol dimethyl ether solution Heat to 80 ° C and stir for 12 hours. The reaction was quenched, cooled to room temperature, filtered, EtOAc EtOAcjjjjjjjjjjjjjjjjjjjj The title compound 5c (320 mg, yield: 59.5%) was obtained.
  • 6-bromo-8-fluoroquinoline 7a (226 mg, 1.00 mmol, prepared by a known method "Journal of Medicinal Chemistry, 2010, 53 (10), 4066-4084”), compound 5a (in a argon atmosphere) was added.
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.20 mmol)
  • potassium acetate 294 mg, 3.00 mmol
  • the crude product 8d (1.5 g, 5.279 mmol) was added to 20 mL of ethyl (tri) orthoformate, and the reaction was stirred at 140 ° C for 15 minutes. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)EtOAc.
  • reaction solution was cooled to room temperature, and then added with 20 mL of water, and ethyl acetate (10mL ⁇ 3), and the organic phase was combined, the organic phase was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: Purification with ammonium hydrogencarbonate, water, EtOAc (EtOAc)
  • the crude compound 18c (16 g, 49.92 mmol) was dissolved in 250 mL of ethanol, 50 mL of 85% hydrazine hydrate was added, and the reaction was stirred for 17 hours. The reaction mixture was filtered, and the filtered cake was washed with ethyl acetate (20 mL, 2), hexane (20 mL ⁇ 2), and dried to give the title compound 18d (12 g, yield: 76.1%).
  • the crude compound 19b (1.9 g, 6.28 mmol) was dissolved in 30 mL of ethanol, and 85% hydrazine hydrate (125.61 mmol, 7.18 mL) was added and stirred at 60 ° C for 1 hour. The reaction mixture was filtered, and the filtered cake was washed with ethyl ether (20mL, 2), and then filtered to give the title compound 19c (1.7 g, yield: 90.8%).
  • the title compound 24 (32 mg) was obtained from the title compound.
  • 2-ethyl-6-methylpyridine 26a (1 g, 8.25 mmol, Suiyuan Technology Shanghai Co., Ltd.), compound 5a (2.31 g, 9.08 mmol), (1Z, 5Z)-cycloocta- were sequentially added.
  • reaction mixture was concentrated under reduced pressure and purified tolulululululululululululululululululululululululululululululululululu , 2-dioxaborolan-2-yl)pyridine 26b (809 mg, yield: 39.7%).
  • the first step starting compound 15b was replaced with (3-fluorophenyl)boronic acid 29a using the synthetic route of Example 15 to give the compound 8-bromo-7-(3-fluorophenyl)-[1,2,4]triazole. And [4,3-c]pyrimidine-5-amine 29b;
  • 6-Chloro-2-(methylthio)pyrimidine-4-amine 32a (2.0 g, 11.39 mmol, Shanghai Biotech Co., Ltd.) and (4-fluorophenyl)boronic acid (2.39 g, 17.08) under an argon atmosphere Methyl) was dissolved in 50 mL of toluene, and tetrakis(triphenylphosphine)palladium (657.60 mg, 569.35 ⁇ mmol) and sodium carbonate (2.41 g, 22.77 mmol) and 10 mL of water were sequentially added. Stir at 90 ° C for 3 hours.
  • Example 17 Using the synthesis route of Example 17, the first starting material compound 17a is replaced by the compound 32b to obtain 8-bromo-7-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-amine 32c;
  • the title compound 34 (30.4 mg) was obtained from the title compound (1).
  • Example 15 Using the synthesis route of Example 15, the first starting material compound 15b was replaced with p-tolylboronic acid 35a (Shanghai Darui Chemical Co., Ltd.) to obtain 8-bromo-7-(p-tolyl)-[1,2, 4] Triazolo[4,3-c]pyrimidine-5-amine 35b;
  • the title compound 36 (45.9 mg) was obtained from the title compound.
  • the fourth step starting material compound 2d was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 37a. (Shanghai Bi De Pharmaceutical Technology Co., Ltd.), the title compound 37 (20 mg) was obtained.
  • the title compound 40 (40 mg) was obtained by the procedure of the procedure of Example 18, substituting the material of the first step 1c to compound 11a.
  • the title compound 42 (52 mg) was obtained by substituting the crude product of the crude material of the crude material of the crude material of the crude material of the crude material of the crude material of the crude product of the crude material of the product of the first step.
  • Example 4 Using the synthetic route of Example 4, the first starting material compound 4a was replaced by 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Based)pyridine-2(1H)-one 43a (prepared by the method "WO2011143426A1" disclosed in the patent application) to give the title compound 43 (31 mg).
  • the first step starting material compound 15b was replaced by (2-chloro-4-fluorophenyl)boronic acid ( ⁇ ) to obtain 8-bromo-7-(2-chloro- 4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 46a;
  • Example 22 Using the synthesis scheme of Example 22, the starting compound 22c was replaced with 4-((6-chloropyridin-2-yl)methyl)morpholine (prepared by the method disclosed in the patent application "US20150361100A1") to obtain the title compound. 47 (34.8%).
  • Example 15 Using the synthesis route of Example 15, the first step starting material compound 15b was replaced with (4-chloro-2-fluorophenyl)boronic acid ( ⁇ ) to obtain 8-bromo-7-(4-chloro- 2-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine 49a;
  • Example 15 Using the synthesis route of Example 15, the first step starting material compound 15b was replaced with (4-chloro-2-fluorophenyl)boronic acid (Suiyuan Technology Shanghai Co., Ltd.) to give the title compound 50 (30 mg).
  • reaction mixture was cooled to room temperature, filtered, and then evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the title compound 54 (47.5 mg) was obtained from the title compound.
  • Test Example 1 the compounds of the present invention for the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, A 2b adenosine receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway, adenosine a 1 receptor (adenosine a 1 receptor, a 1 R) cAMP signaling pathway and a 3 adenosine receptor (adenosine a 3 receptor, a 3 R) cAMP signaling pathway inhibitory activity of.
  • the following method was used to determine the inhibition of adenosine A 2a receptor cAMP signaling pathway, adenosine A 2b receptor cAMP signaling pathway, adenosine A 1 receptor cAMP signaling pathway and adenosine A 3 receptor cAMP signaling pathway by the compounds of the present invention. active.
  • the experimental method is briefly described as follows:
  • CHO-K1/A 2a R cells NM_000675.5
  • CHO-K1/A 2b R cells NM_000676.2
  • CHO-K1/A 1 R cells NM_000674.2
  • CHO-K1/A 3 R cells NM_000677.3
  • Adenosine deaminase (sigma, 10102105001)
  • CHO-K1/A 2a R cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 800 ⁇ g/ml bleomycin. The cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 10 6 /ml. Add 5 ⁇ l of cell suspension to each well in a 384-well plate, 2.5 ⁇ l of 4 ⁇ prepared with balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase.
  • test compound Concentration of test compound was incubated for 30 minutes at room temperature. Add 2.5 ⁇ l of each well to a 4 ⁇ concentration of ethyl carbazole prepared with 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well, incubate at room temperature 30 minutes.
  • the final concentrations of the compounds were: 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM and the final concentration of ethyl carbazole was 20 nM. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-Cryptate were separately diluted 1:4 with cAMP lysis buffer. 5 ⁇ l of the diluted cAMP-d2 was added to each well, and 5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added thereto, and the mixture was incubated at room temperature for 1 hour in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader.
  • the IC 50 values of the compound inhibitory activity were calculated using Graphpad Prism software, as shown in Table 1.
  • CHO-K1/A 1 R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 1 mg/ml G418.
  • the cells were digested with the cell separation buffer at the time of the experiment, and then the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 /ml.
  • 12.5 ⁇ l of cell suspension was added to each well in a 384-well plate, and 6.25 ⁇ l was prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase.
  • the concentration of the test compound was incubated for 30 minutes at room temperature. Add 4.25 ⁇ l of each well to a 4 ⁇ concentration of forskolin and N6-ring prepared with 20 ⁇ m HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well. Amyl adenosine was incubated for 30 minutes at room temperature. The final concentrations of the compounds were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin was 10 ⁇ M, and the final concentration of CPA was 10 nM. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted with cAMP lysis buffer at a ratio of 1:4. 12.5 ⁇ l of diluted cAMP-d2 was added to each well, and 12.5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added and incubated for 1 hour at room temperature in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values (Table 2).
  • CHO-K1/A 3 R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 10 ⁇ g/ml puromycin. The cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 /ml.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted with cAMP lysis buffer at a ratio of 1:4. 12.5 ⁇ l of diluted cAMP-d2 was added to each well, and 12.5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added and incubated for 1 hour at room temperature in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values (Table 2).
  • a 2b adenosine receptor (adenosine A 2b receptor, A 2b R)
  • CHO-K1/A 2b R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 1 mg/ml G418.
  • the cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 10 6 /ml.
  • test compound Concentration of test compound was incubated for 30 minutes at room temperature. Add 2.5 ⁇ l of each well to a 4 ⁇ concentration of ethyl carbazole (Torcis, prepared with 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well). 1691/10), incubate for 30 minutes at room temperature. The final concentrations of the compounds were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, and the final concentration of ethyl carbazole was 1 ⁇ M. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted 1:4 with cAMP lysis buffer. 5 ⁇ l of the diluted cAMP-d2 was added to each well, and 5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added thereto, and the mixture was incubated at room temperature for 1 hour in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values. See Table 3.
  • the compounds of the present invention have significant inhibitory activity on the adenosine A 2a receptor cAMP signaling pathway.
  • the compound of the present invention has a weak effect on the adenosine A 1 receptor and A 3 receptor inhibitory activity, indicating that the compound of the present invention has high selectivity to the A 2a receptor.
  • the compound of the present invention has a weak effect on adenosine A 2b receptor inhibitory activity, indicating that the compound of the present invention has high selectivity to the A 2a receptor.
  • Test Example 2 Determination of brain permeability of a compound of the present invention
  • the brain permeability of the compound of the present invention was determined by the following experimental method:
  • RED device (Device Inserts) (Thermo Scientific, QL21291110)
  • mice supplied by Jiesijie Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2013-0006.
  • mice Female, 12/12 hour light/dark adjustment, constant temperature of 24 ⁇ 3 °C, humidity 50-60%, free access to drinking water. After fasting overnight, they were administered by intragastric administration. The drug was administered at a dose of 20 mg/kg, and the drug-administered group was sacrificed at 0.5 h after administration (blood collection 0.5 ml). The blood sample was placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes, and recorded as plasma 1, and stored at -80 ° C. After the sacrifice, the heart of the animal was perfused with normal saline to remove excess blood from the brain tissue, and the brain tissue was taken. The residual blood was absorbed by the filter paper and recorded as brain tissue at 1,-80 ° C. Another 3 animals were taken for blank plasma and brain tissue 2, and the treatment method was the same as that of the administration group.
  • the RED device was inserted into the 96-well bottom plate.
  • 300 ⁇ l of the prepared plasma sample 2 containing the test substance and the corresponding blank plasma sample were placed in a red labeled well (plasma chamber).
  • 500 ⁇ l of pH 7.4 phosphate buffered saline was placed and placed in a red buffered buffer chamber. According to the above procedure, each compound has a concentration of 2 samples per sample.
  • the 96-well plate was covered with a sealing tape, and the entire substrate was placed in a thermomixer and equilibrated at 37 rpm for 4 h at 400 rpm. After the incubation, the 96-well bottom plate device was removed from the heat mixer to complete the equilibrium dialysis.
  • the established LC/MS/MS method was used to determine the peak area ratio of the brain homogeneous chamber and the buffer chamber to the internal standard, and calculate the free percentage (f u brain hom %).
  • the protein binding rate of the compound in mouse plasma and brain tissue was determined by equilibrium dialysis method to calculate the free percentage (f u plasma %, f u brain %);
  • Plasma free percentage C buffer /C plasma ⁇ 100%
  • the brain permeability index of the compounds of the invention is as follows:
  • Example number Blood brain permeability index (Kp-unbound) Example 18 0.010
  • Example 20 0.015
  • the compound of the present invention has a low free drug concentration in the brain, a weak ability to pass through the blood-brain barrier, and less drug into the brain, and may have low side effects.

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Abstract

一种杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用。具体而言,一种通式(I)所示的杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂,特别是作为A2a受体拮抗剂的用途和在制备用于治疗通过对A2a受体的抑制而改善的病况或病症的药物中的用途,其中通式(I)的各取代基与说明书中的定义相同。

Description

杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域,涉及一种通式(I)所示的杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂,特别是作为A 2a受体拮抗剂的用途和在制备用于治疗通过对A 2a受体的抑制而改善的病况或病症的药物中的用途。
背景技术
腺苷是天然存在的嘌呤核苷,是许多生理功能的内源性调节剂。在心血管系统、中枢神经、呼吸系统、肾脏、脂肪和血小板的功能调节中发挥重要作用。
腺苷的作用由G蛋白偶联受体家族介导,目前已知至少有四种亚型的腺苷受体,分类为A 1、A 2a、A 2b和A 3。其中A 1和A 3受体抑制酶腺苷酸环化酶的活性,而A 2a和A 2b受体刺激该酶的活性,由此调节细胞中环AMP水平,通过这些受体,腺苷调节广泛的生理功能。
A 2a受体(A 2aR)在机体分布较为广泛,在中枢神经系统主要表达于纹状体,在外周、心、肝、肺、肾等组织也均有表达。数个临床前研究表明,腺苷A 2a受体拮抗剂对于治疗神经变性疾病,主要是帕金森病、亨廷顿病或阿尔茨海默病具有惊人疗效(Trends in Neurosci.2006,29(11),647-654;Expert Opinion on Therapeutic Patents,2007,17,979-991等)。而且也可以用于治疗其他中枢神经系统(CNS)相关的疾病例如抑郁、多动综合征、睡眠障碍和焦虑症(Clin.Neuropharmacol.2010,33,55-60;J.Neurosci.2010,30(48),16284-16292;Parkinsonisn Relat.Disord.2010,16(6),423-426;及其中的参考献:Mov.Disorders,2010,25(2),S305)。此外,腺苷A 2a受体拮抗剂还具有作为神经保护剂的治疗潜力(参见Jenner P.J Neuro 1.2000;247Supp12:1143-50)。
近来研究表明,在缺血低氧、炎症、创伤、移植等诸多病理过程中,腺苷A 2a受体的激活可以发挥重要的免疫调节作用,这可能与A 2a受体在T细胞、B细胞、单核巨噬细胞、中性粒细胞等多种免疫细胞上表达水平较高有关。此外,A 2a受体的活化可以促使机体产生免疫耐受,密切参与了肿瘤细胞“免疫逃逸”或“免疫抑制”的形成,为肿瘤的发生发展创造了有利条件。Lokshin及其同事(Cancer Res.2006Augl;66(15):7758-65)证实自然杀伤细胞上的A 2a受体活化可以通过升高cAMP,激活PKA抑制自然杀伤细胞对肿瘤细胞的杀伤。还有研究表明,激活A 2a受体的活化可以促进黑色素瘤A375细胞、成纤维瘤NIH3T3细胞及嗜铬细胞瘤PC12细胞等肿瘤细胞的增殖,其可能与T细胞上A 2a受体的活化可以抑制T细胞活化、增殖、与肿瘤细胞的黏附及对肿瘤细胞产生细胞毒性作用相关;而A 2a受体基因敲除的小鼠则可 以加强CD8 +T细胞抗肿瘤的免疫作用,显著抑制肿瘤的增殖。因此,A 2a受体拮抗剂也可用于肿瘤的治疗。
尽管对多种腺苷受体亚型具有显著生物学活性的化合物可具有治疗作用,但它们可导致不想要的副作用。例如腺苷A 1受体在组织缺血/缺氧时,在中枢、循环、消化系统和骨骼肌中,细胞在处于缺氧和低氧的应激环境时,胞外聚集的腺苷通过激活胞膜上的A 1受体启动相应的保护机制,从而增加细胞对缺氧低氧的耐受。位于免疫细胞上的A 1受体在低氧环境中能促进细胞免疫应答。另外,A 1受体还能降低游离脂肪酸和甘油三酯,参与调节血糖。因此,A 1受体的持续阻断可能会引起机体组织中各种不良反应的发生(Chinese Pharmacological Bulletin,2008,24(5),573-576)。如有文献报道,在动物模型上,阻断A 1受体将会产生焦虑、觉醒等不良反应(Basic & Clinical Pharmacology & Toxicology,2011,109(3),203-7)。腺苷受体A 3(如Gessi S等人,Pharmacol.Ther.117(1),2008,123-140所述)在心肌缺血期间释放的腺苷在心脏中发挥强力的保护作用,A 3受体的持续阻断可能增加由任何预先存在的或正在发展的缺血性心脏病引起的并发症的可能性,所述缺血性心脏病诸如心绞痛或心衰。
目前,虽然已有许多化合物被开发为A 2a受体的拮抗剂用于治疗很多疾病,如WO2007116106、WO2009080197、WO2011159302、WO2011095625、WO2014101373、WO2015031221中所述。但仍有低溶解性、光敏性、低活性、低选择性和生物利用率较低等问题存在。
本发明提供一种新型杂芳基并[4,3-c]嘧啶-5-胺类结构的腺苷A 2a受体拮抗剂,并发现具有此类结构的化合物具有强抑制活性和高选择性,并且此类结构的化合物在脑中的游离药物浓度低,透过血脑屏障能力弱,对药物进脑后可能产生的副作用低。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物:
Figure PCTCN2018079086-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合 物形式或其可药用的盐,
其中:
G为N或CR 4
环A选自环烷基、芳基和杂芳基;
R 1相同或不同,各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
R 2选自烷氧基、羟基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;其中所述的烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、C(O)OR 5和R b中的一个或多个取代基所取代;
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
R 4选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
R 5选自氢原子、烷基、氨基、卤代烷基、环烷基、杂环基、芳基和杂芳基;
R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被选自烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基、杂环基、芳基、杂芳基和C(O)OR 5中的一个或多个取代基所取代;且
n为1、2、3或4。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物,其中所述的R 2选自氰基、环烷基、杂环基、芳基和杂芳基;其中所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b中的一个或多个取代基所取代;R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被一个或多个烷基所取代。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物为通式(II)所示的化合物:
Figure PCTCN2018079086-appb-000002
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B选自环烷基、杂环基、芳基和杂芳基;
R 6相同或不同,各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、C(O)OR 5和R 6
s为0、1、2、3或4;且
环A、G、R 1、R 3、R 5、R b和n如通式(I)中所定义。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物为通式(III)所示的化合物:
Figure PCTCN2018079086-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
R 6相同或不同,各自独立地选自卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b;R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被一个或多个烷基所取代;
环A、环B、R 1、R 3、n和s如通式(II)中所定义。
在本发明一个优选的实施方案中,所述的通式(II)所示的化合物,其中所述环B选自苯基、5至6元杂环基或5至10元杂芳基;优选苯基、吡啶基、吡唑基、吡啶-2-酮基、咪唑基、吡咯基、呋喃基、噻吩基、哌啶基、1,2,3,6-四氢吡啶基、异喹啉基、喹啉基、喹喔啉基、吲哚基、吲唑基、苯并呋喃基或苯并噻吩基。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物为通式(III’)所示的化合物:
Figure PCTCN2018079086-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
R 6相同或不同,各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b;R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被一个或多个烷基所取代;
s为0、1、2、3或4;环A、R 1、R 3和n如通式(I)中所定义。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物,其中所述的环A为芳基或杂芳基,优选为苯基或呋喃基。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物,其中所述的R 1选自氢原子、卤素或烷基。
在本发明一个优选的实施方案中,所述的通式(I)所示的化合物,其中所述的R 3选自氢原子、卤素或烷基。
本发明的典型化合物包括但不限于:
Figure PCTCN2018079086-appb-000005
Figure PCTCN2018079086-appb-000006
Figure PCTCN2018079086-appb-000007
Figure PCTCN2018079086-appb-000008
Figure PCTCN2018079086-appb-000009
Figure PCTCN2018079086-appb-000010
Figure PCTCN2018079086-appb-000011
Figure PCTCN2018079086-appb-000012
Figure PCTCN2018079086-appb-000013
Figure PCTCN2018079086-appb-000014
Figure PCTCN2018079086-appb-000015
Figure PCTCN2018079086-appb-000016
Figure PCTCN2018079086-appb-000017
Figure PCTCN2018079086-appb-000018
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。
本发明的另一方面涉及一种通式(IV)所示的化合物:
Figure PCTCN2018079086-appb-000019
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合 物形式或其可药用的盐,
其中:
X为卤素;
环A、G、R 1、R 3和n如通式(I)中所定义。
本发明的典型化合物包括但不限于:
Figure PCTCN2018079086-appb-000020
Figure PCTCN2018079086-appb-000021
Figure PCTCN2018079086-appb-000022
Figure PCTCN2018079086-appb-000023
本发明的另一方面涉及一种制备通式(II)所示的化合物的方法,该方法包括:
Figure PCTCN2018079086-appb-000024
通式(IV)的化合物和通式(V)的化合物反应,得到通式(II)的化合物,
其中:
X为卤素;
W为
Figure PCTCN2018079086-appb-000025
环A、环B、G、R 1、R 3、R 6、n和s如通式(I)中所定义。
本发明的另一方面涉及一种药物组合物,所述药物组合物含有治疗有效量的 本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备用于抑制A 2a受体的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备用于治疗通过对A 2a受体抑制而改善的病况或病症的药物中的用途。
在本发明中,通过对A 2a受体抑制而改善的病况或病症选自肿瘤、抑郁症、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为;优选为肿瘤。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备治疗肿瘤、抑郁症、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为,优选肿瘤的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备治疗肿瘤的药物中的用途。
本发明还涉及一种抑制A 2a受体的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物。
本发明还涉及一种治疗通过对A 2a受体抑制而改善的病况或病症的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物。
本发明涉及一种治疗肿瘤、抑郁症、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为,优选肿瘤的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消 旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用作药物。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物,其用作A 2a受体拮抗剂。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物,其治疗通过对A 2a受体抑制而改善的病况或病症。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物,其用于治疗肿瘤、抑郁症、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为,优选肿瘤。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物,其用于治疗肿瘤。
本发明中所述的肿瘤选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤;优选为肺癌。
含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物,此类组合物可含有一种或多种选自以下的成分:甜味剂、矫味剂、着色剂和防腐剂,以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂,造粒剂、崩解剂,粘合剂,和润滑剂,。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收,因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂,分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油,或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂,以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油,或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂,乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射,将注射液或微乳注入患者的血流中。或者,最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用任何调和固定油。此外,脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等;另外,最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基 团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,优选包含3至10个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至10个环原子,其中1-4是杂原子;更优选包含5至6个环原子;其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
Figure PCTCN2018079086-appb-000026
杂环基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,其为具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,优选为6至10元,例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
Figure PCTCN2018079086-appb-000027
芳基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,更优选为5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑 基、吡唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
Figure PCTCN2018079086-appb-000028
杂芳基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基和-C(O)OR 5中的一个或多个取代基所取代。
术语“氧代基”指
Figure PCTCN2018079086-appb-000029
术语“环烷基氧基”指环烷基-O-。
术语“杂环基烷基”指烷基被一个或多个杂环基取代,其中烷基和杂环基如上所定义。术语“卤代烷基”指烷基被一个或多个卤素取代,其中烷基如上所定义。
术语“羟基”指-OH。
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2
术语“氰基”指-CN。
术语“硝基”指-NO 2
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或 理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
其中:R 5如通式(I)中所定义。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
方案一
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
Figure PCTCN2018079086-appb-000030
通式(IV)的化合物和通式(V)的化合物反应在碱性条件下,在催化剂存在下发生suzuki偶联反应得到通式(II)的化合物,
其中:
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
所述的催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚苄基丙酮)钯、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯)]钯、[1,1′-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1′-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素;
W为
Figure PCTCN2018079086-appb-000031
环A、环B、G、R 1、R 3、R 6、n和s如通式(II)中所定义。
方案二
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
Figure PCTCN2018079086-appb-000032
第一步,通式(III-1)的化合物和水合肼反应得到通式(III-2)的化合物;
第二步,通式(III-2)的化合物和通式(III-3)的化合物反应得到通式(IIIA)的化合物;
第三步,通式(IIIA)的化合物和通式(V)的化合物反应在碱性条件下,在催化剂存在下发生suzuki偶联反应得到通式(III)的化合物,
其中:
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
所述的催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚苄基丙酮)钯、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯)]钯、[1,1′-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1′-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素;
W为
Figure PCTCN2018079086-appb-000033
环A、环B、R 1、R 3、R 6、n和s如通式(III)中所定义。
方案三
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
Figure PCTCN2018079086-appb-000034
第一步,通式(III-1)的化合物和水合肼反应得到通式(III-2)的化合物;
第二步,通式(III-2)的化合物和通式(V)的化合物反应在碱性条件下,在催化剂存在下发生suzuki偶联反应得到通式(IIIB)的化合物;
第三步,通式(IIIB)的化合物和通式(III-3)的化合物反应得到通式(III)的化合物;
其中:
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
所述的催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚苄基丙酮)钯、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯)]钯、[1,1′-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1′-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素;
W为
Figure PCTCN2018079086-appb-000035
环A、环B、R 1、R 3、R 6、n和s如通式(III)中所定义。
方案四
本发明通式(III’)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
Figure PCTCN2018079086-appb-000036
第一步,通式(III-1)的化合物和水合肼反应得到通式(III-2)的化合物;
第二步,通式(III-2)的化合物和通式(III’a)的化合物反应在碱性条件下,在催化剂存在下发生suzuki偶联反应得到通式(III’b)的化合物;
第三步,通式(III’b)的化合物和通式(III-3)的化合物反应得到通式(III’)的化合物;
其中:
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
所述的催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚苄基丙酮)钯、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯)]钯、[1,1′-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1′-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素;
W为
Figure PCTCN2018079086-appb-000037
环A、R 1、R 3、R 6、n和s如通式(III)中所定义。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d 6),氘代氯仿(CDCl 3),氘代甲醇(CD 3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
手性HPLC分析测定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH &Co.KG,Acros Organics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂,纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括:A:二氯甲烷/甲醇体系,B:正己烷/乙酸乙酯体系,C:石油醚/乙酸乙酯体系,D:丙酮,E:二氯甲烷/丙酮体系,F:乙酸乙酯/二氯甲烷体系,G:乙酸乙酯/二氯甲烷/正己烷,H:乙酸乙酯/二氯甲烷/丙酮,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺1
Figure PCTCN2018079086-appb-000038
第一步
4-氯-5-碘-6-苯基嘧啶-2-胺1b
将4-氯-6-苯基嘧啶-2-胺1a(2g,9.75mmol,采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2011,21(8),2497-2501”制备而得)和N-碘代丁二酰亚胺(2.6g,11.7mmol)溶于30mL乙酸中,加毕,反应16小时。反应液中加入200mL饱和碳酸氢钠,用乙酸乙酯萃取(100mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤(100mL),无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,残余物用硅胶色谱法以洗脱剂体系B纯化,得标题化合物1b(2.88g,产率:89%)。
MS m/z(ESI):332.2[M+1]
第二步
4-氯-5-(2-甲基-6-(三氟甲基)吡啶-4-基)-6-苯基嘧啶-2-胺1d
在氮气氛下,依次加入化合物1b(2.88g,8.7mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-6-(三氟甲基)吡啶1c(2.7g,9.17mmol,采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(0.64g,0.87mmol)和碳酸钾(3.6g,26.1mmol)溶解于66mL 1,4-二氧六环和水(V/V=10∶1)的混合溶液中,加热至83℃,搅拌3小时。停止反应,冷却至室温,过滤,滤液中加入200mL乙酸乙酯,再用饱和氯化钠溶液洗涤(100mL),无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,残余物用硅胶色谱法以洗脱剂体系B纯化,得标题化合物1d(2.4g,产率:76%)。
MS m/z(ESI):365.4[M+1]
第三步
4-肼基-5-(2-甲基-6-(三氟甲基)吡啶-4-基)-6-苯基嘧啶-2-胺1e
依次加入化合物1d(100mg,0.275mmol)和85%水合肼(62mg,2.747mmol)溶于10mL乙醇中,回流条件下,搅拌反应17小时。停止反应,冷却至室温,反应液中加入30mL水,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤(50mL×2),无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,得粗品标题化合物1e(85mg),其不经纯化直接用于下一步反应。
MS m/z(ESI):361.4[M+1]
第四步
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺1
依次将粗品1e(85mg,0.275mmol)加入2mL原甲酸(三)乙酯,140℃条件下,搅拌反应0.5小时。停止反应,冷却至室温,反应液减压浓缩,所得残余物用高效液相色谱法纯化,得标题化合物1(6mg,产率:6.9%)。
MS m/z(ESI):371.4[M+1]
1H NMR(400MHz,DMSO-d 6)9.38(s.1H),8.42(brs.2H),7.59(s,1H),7.42(s,1H),7.35-7.31(m,5H),2.48(s,3H)。
实施例2
7-苯基-8-(1H-吡唑-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺2
Figure PCTCN2018079086-appb-000039
Figure PCTCN2018079086-appb-000040
第一步
5-溴-4-氯-6-苯基嘧啶-2-胺2a
将化合物1a(500mg,2.431mmol)和N-溴代丁二酰亚胺(519mg,2.918mmol)溶于16mL N,N-二甲基甲酰胺中,加毕,反应1小时。反应液中加入50mL水,用乙酸乙酯萃取(50mL×3),合并有机相,有机相依次用水(100mL×3)和饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,得粗品标题化合物2a(698mg),其不经纯化直接用于下一步反应。
MS m/z(ESI):284.2[M+1]
第二步
5-溴-4-肼基-6-苯基嘧啶-2-胺2b
依次将粗品2a(692mg,2.432mmol)和85%水合肼(1.432mg,24.32mmol)溶于20mL乙醇中,回流条件下,搅拌反应1小时。反应液冷却至室温,搅拌反应0.5小时。过滤,滤饼依次用乙醇(3mL×2)和乙醚(3mL×2)洗涤,收集滤饼,滤饼干燥,得粗品标题化合物2b(480mg),其不经纯化直接用于下一步反应。
MS m/z(ESI):280.3[M+1]
第三步
8-溴-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺2c
将粗品2b(480mg,1.713mmol)加入5mL的原甲酸(三)乙酯中,140℃条件下,搅拌反应15分钟。停止反应,冷却至室温,过滤,滤饼依次用乙醇(3mL×3)和乙醚(5mL×3)洗涤,收集滤饼,滤饼干燥,得标题化合物2c(348mg,产率:62.4%)。MS m/z(ESI):290.3[M+1]
第四步
7-苯基-8-(1H-吡唑-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺2
在氩气氛下,依次将化合物2c(120mg,0.414mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑2d(120mg,0.620mmol,采用公知的方法“Journal of the American Chemical Society,2014,136(11),4287-4299”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.041mmol)和碳酸钾(171mg,1.241mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×3),有机相减压浓缩,残余物高效液相色谱法纯化,得标题化合物2(33mg,产率:28.7%)。
MS m/z(ESI):278.4[M+1]
1H NMR(400MHz,DMSO-d 6)12.79(brs,1H),9.32(s,1H),7.98(brs,2H), 7.41-7.37(m,7H)。
实施例3
7-苯基-8-(喹啉-6-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺3
Figure PCTCN2018079086-appb-000041
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉3a(106mg,0.414mmol,采用公知的方法“Journal of the American Chemical Society,2013,135(50),18730-18733”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌2小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(50mL×3),有机相减压浓缩,残余物用硅胶色谱法以洗脱剂体系A纯化,得标题化合物3(49mg,产率:41.9%)。
MS m/z(ESI):339.2[M+1]
1H NMR(400MHz,DMSO-d 6)9.38(s,1H),8.88-8.87(m,1H),8.29-8.27(m,1H),8.20(brs,2H),8.05-8.04(m,1H),7.88-7.85(m,1H),7.54-7.50(m,2H),7.37-7.34(m,2H),7.24-7.20(m,3H)。
实施例4
8-(2-氯-6-甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺4
Figure PCTCN2018079086-appb-000042
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、2-氯-6-甲基-4-(4,4,5,5- 四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶4a(105mg,0.414mmol,采用公知的方法“Organic Syntheses,2005,82,126-133”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034mmol)溶解于10mL 1,4-二氧六环和水(V/V=4∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×4),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物4(20.7mg,产率:17.8%)。
MS m/z(ESI):337.4[M+1]
1H NMR(400MHz,DMSO-d 6)9.36(s,1H),8.38(brs,2H),7.36-7.32(m,5H),7.19-7.14(m,2H),2.35(s,3H)。
实施例5
8-(8-甲基喹啉-6-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺5
Figure PCTCN2018079086-appb-000043
第一步
8-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉5c
在氩气氛下依次加入6-溴-8-甲基喹啉5b(444mg,2.00mmol,采用公知的方法“Journal of Organic Chemistry,2014,79(11),5379-5385”制备而得)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-二(1,3,2-二氧杂环戊硼烷)5a(508mg,2.00mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(292mg,0.40mmol)和乙酸钾(588mg,6.00mmol)溶解于10mL乙二醇二甲醚溶液中,加热至80℃,搅拌12小时。停止反应,冷却至室温,过滤,滤液加入20mL乙酸乙酯,依次用水(10mL)洗涤,饱和氯化钠溶液(10mL)洗涤,用无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用薄层色谱法以展开剂体系B纯化,得到标题化合物5c(320mg,产率:59.5%)。
MS m/z(ESI):270.1[M+1]
第二步
8-(8-甲基喹啉-6-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺5
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、5c(130mg,0.482mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034 mmol)溶解于5mL 1,4-二氧六环和水(V/V=4∶1)的混合溶液中,加热至90℃,搅拌2小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×3),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物5(32mg,产率:26.4%)。MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,DMSO-d 6)19.37(s,1H),8.90-8.89(m,1H),8.21-8.19(m,3H),7.78(s,1H),7.51-7.49(m,2H),7.37-7.36(m,2H),7.22-7.20(m,3H),2.60(s,3H)。
实施例6
8-(7-氟-1H-吲唑-5-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺6
Figure PCTCN2018079086-appb-000044
第一步
7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吲唑6b
在氩气氛下依次加入5-溴-7-氟-1H-吲唑6a(1.27g,5.90mmol,采用专利申请“WO2012037410”公开的方法制备而得)、化合物5a(2.25g,8.86mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(432mg,0.56mmol)和乙酸钾(1.74g,17.7mmol)溶解于40mL乙二醇二甲醚溶液中,加热至80℃,搅拌12小时。停止反应,冷却至室温,加入10mL乙酸乙酯,过滤,滤液减压蒸馏,残余物用硅胶色谱法以洗脱剂体系B纯化,得到标题化合物6b(1.178g,产率:76.0%)。
MS m/z(ESI):263.2[M+1]
第二步
8-(7-氟-1H-吲唑-5-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺6
在氩气氛下,依次将化合物2c(117mg,0.348mmol)、6b(100mg,0.382mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.035mmol)和碳酸钾(192mg,1.387mmol)溶解于10mL 1,4-二氧六环和水(V/V=4∶1)的混合溶液中,加热至90℃,搅拌2小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×3),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物6(13mg,产率:10.8%)。
MS m/z(ESI):346.4[M+1]
1H NMR(400MHz,DMSO-d 6)13.65(brs,1H),9.34(s,1H),8.13-8.11(m,3H),7.55(s,1H),7.35-7.33(m,2H),7.23-7.22(m,3H),7.05-7.02(m,1H)。
实施例7
8-(8-氟喹啉-6-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺7
Figure PCTCN2018079086-appb-000045
第一步
8-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉7b
在氩气氛下依次加入6-溴-8-氟喹啉7a(226mg,1.00mmol,采用公知方法“Journal of Medicinal Chemistry,2010,53(10),4066-4084”制备而得)、化合物5a(305mg,1.20mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(146mg,0.20mmol)和乙酸钾(294mg,3.00mmol)溶解于10mL乙二醇二甲醚溶液中,加热至80℃,搅拌12小时。停止反应,冷却至室温,过滤,滤液减压蒸馏,残余物用CombiFlash快速制备仪以洗脱剂体系B纯化,得到标题化合物7b(220mg,产率:80.1%)。
MS m/z(ESI):274.1[M+1]
第二步
8-(8-氟喹啉-6-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺7
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、7b(100mg,0.414mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(40mL×4),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物7(20mg,产率:16.3%)。
MS m/z(ESI):357.2[M+1]
1H NMR(400MHz,DMSO-d 6)9.38(s,1H),8.94-8.93(m,1H),8.35-8.33(m,1H),8.26(brs,2H),7.86(s,1H),7.62-7.59(m,1H),7.40-7.36(m,3H),7.26-7.24(m,3H)。
实施例8
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-(5-甲基呋喃-2-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺8
Figure PCTCN2018079086-appb-000046
第一步
5-溴-4-氯-6-(5-甲基呋喃-2-基)嘧啶-2-胺8c
在氩气氛下依次加入5-溴-4,6-二氯嘧啶-2-胺8a(5g,20.585mmol,采用专利申请“US20100331294”公开的方法制备而得)、4,4,5,5-四甲基-2-(5-甲基呋喃-2-基)-1,3,2-二氧杂戊硼烷8b(4.283g,20.585mmol,采用公知的方法“Organometallics,2015,34(7),1307-1320”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(1.506g,2.058mmol)和碳酸钾(8.535g,61.756mmol)溶解于150mL 1,4-二氧六环和水(V/V=4∶1)的混合溶液中,搅拌2小时。停止反应,反应液中加入200mL水,乙酸乙酯萃取(200mL×3),有机相加入100-200目二氧化硅,减压浓缩,残余物用CombiFlash快速制备仪以洗脱剂体系B纯化,得标题化合物8c(2.0g,产率:33.7%)。
MS m/z(ESI):288.2[M+1]
第二步
5-溴-4-肼基-6-(5-甲基呋喃-2-基)嘧啶-2-胺8d
依次将化合物8c(1.88g,6.516mmol)和15mL 85%水合肼溶于120mL乙醇中,搅拌反应17小时。停止反应,过滤,干燥滤饼,得粗品标题化合物8d(1.5g),其不经纯化直接用于下一步反应。
MS m/z(ESI):284.3[M+1]
第三步
8-溴-7-(5-甲基呋喃-2-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺8e
依次将粗品8d(1.5g,5.279mmol)加入20mL的原甲酸(三)乙酯中,140℃条件下,搅拌反应15分钟。停止反应,冷却至室温,过滤,滤饼用正己烷洗涤(20mL×2),干燥,得粗品标题化合物8e(1.13g,产率:72.8%)。
MS m/z(ESI):294.3[M+1]
第四步
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-(5-甲基呋喃-2-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺8
在氩气氛下,依次将粗品8e(140mg,0.476mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-6-(三氟甲基)吡啶8f(205mg,0.714mmol,采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.048mmol)和碳酸钾(197mg,1.428mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌2.5小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(50mL×3),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物8(80mg,产率:44.9%)。
MS m/z(ESI):375.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.30(s,1H),8.26(brs,2H),7.68(s,1H),7.64(s,1H),6.70-6.69(m,1H),6.20-6.19(m,1H),2.60(s,3H),2.03(s,3H)。
实施例9
7-苯基-8-(7-(三氟甲基)-1H-吲唑-5-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺9
Figure PCTCN2018079086-appb-000047
第一步
5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-7-(三氟甲基)-1H-吲唑9b
在氩气氛下依次加入5-溴-7-(三氟甲基)-1H-吲唑9a(0.5g,1.88mmol,采用专利申请“WO2012056372”公开的方法制备而得)、化合物5a(575mg,2.26mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(275mg,0.38mmol)和乙酸钾(554mg,5.66mmol)溶解于10mL乙二醇二甲醚溶液中,加热至80℃,搅拌2小时。停止反应,冷却至室温,过滤,滤液减压蒸馏,残余物用CombiFlash快速制备仪以洗脱剂体系C纯化,得到标题化合物9b(270mg,产率:45.9%)。
MS m/z(ESI):313.2[M+1]
第二步
7-苯基-8-(7-(三氟甲基)-1H-吲唑-5-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺9
在氩气氛下,依次将化合物2c(117mg,0.348mmol)、9b(35mg,0.11mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.035mmol)和碳酸钾(192mg,1.387mmol)溶解于5mL 1,4-二氧六环和水(V/V=4∶1)的混合溶液中,加热至90℃,搅拌 2小时。停止反应,反应液中加入10mL水,二氯甲烷和甲醇(V/V=8∶1)混合溶液萃取(20mL×3),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物6(10mg,产率:22%)。
MS m/z(ESI):396.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ13.66(s,1H),9.36(s,1H),8.25-8.09(m,4H),7.53(s,1H),7.33-7.31(m,2H),7.25-7.23(m,3H)。
实施例10
8-(1H-吲唑-5-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺10
Figure PCTCN2018079086-appb-000048
在氩气氛下,依次将化合物2c(140mg,0.482mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吲唑10a(141mg,0.579mmol,采用公知方法“Journal of Medicinal Chemistry,2014,57(9),3856-3873”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.048mmol)和碳酸钾(200mg,1.448mmol)溶解于12mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,二氯甲烷和水(V/V=8∶1)混合溶液萃取(30mL×3),有机相减压浓缩,残余物用高效液相色谱法纯化,得标题化合物10(8.6mg,产率:5.4%)。
MS m/z(ESI):328.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ13.05(brs,1H),9.33(s,1H),8.05-8.01(m,3H),7.75(s,1H),7.53-7.41(m,1H),7.35-7.33(m,2H),7.20-7.07(m,4H)。
实施例11
8-(2,6-二甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺11
Figure PCTCN2018079086-appb-000049
Figure PCTCN2018079086-appb-000050
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶11a(91mg,0.414mmol,采用公知的方法“Organic Letters,2009,11(16),3586-3589”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×3),有机相减压浓缩,残余物高效液相色谱法纯化,得标题化合物11(27mg,产率:24.8%)。
MS m/z(ESI):317.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.25(brs,2H),7.32-7.30(m,5H),6.97(s,2H),2.32(s,6H)。
实施例12
8-(2-甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺12
Figure PCTCN2018079086-appb-000051
在氩气氛下,依次将化合物2c(100mg,0.345mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶12a(91mg,0.414mmol,采用公知的方法“Journal of the American Chemical Society,2014,136(11),4133-4136”制备而得)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(25mg,0.034mmol)和碳酸钾(143mg,1.034mmol)溶解于6mL 1,4-二氧六环和水(V/V=5∶1)的混合溶液中,加热至90℃,搅拌3小时。停止反应,反应液中加入50mL水,乙酸乙酯萃取(30mL×3),有机相减压浓缩,残余物高效液相色谱法纯化,得标题化合物12(6.8mg,产率:6.5%)。
MS m/z(ESI):303.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.29-8.26(m,3H),7.32-7.25(m,6H),6.99(s,1H),2.39(s,3H)。
实施例13
5-氨基-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-8-甲腈13
Figure PCTCN2018079086-appb-000052
氩气氛下将化合物2c(1.0g,3.45mmol)、氰化锌(484mg,4.13mmol)、锌(22mg,0.34mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(124mg,0.17mmol)和三(二亚苄基丙酮)二钯(156mg,0.17mmol)溶于30mL N,N-二甲基甲酰胺,60℃条件下,反应12小时。反应结束,硅藻土过滤,滤饼用甲醇洗涤,滤液中加入30mL水,二氯甲烷和甲醇(V/V=8∶1)混合溶液萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂A体系纯化,得标题化合物13(650mg,产率:80.0%)。
MS m/z(ESI):237.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.24(brs,1H),8.83(brs,1H),8.64(s,1H),7.92-7.89(m,2H),7.59-7.57(m,3H)。
实施例14
7-(4-氯苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺14
Figure PCTCN2018079086-appb-000053
Figure PCTCN2018079086-appb-000054
第一步
5-溴-4-氯-6-(4-氯苯基)嘧啶-2-胺14b
将4-氯-6-(4-氯苯基)嘧啶-2-胺14a(11g,38.03mmol,采用专利申请“DE102006008880A1”公开的方法制备而得)和N-溴代丁二酰亚胺(7.11g,39.93mmol)溶于300mL N,N-二甲基甲酰胺中,加毕,搅拌反应2小时。反应液中加入1L水,用乙酸乙酯萃取(300mL×4),合并有机相,有机相依次用水(100mL×3)和饱和氯化钠溶液(200mL×2)洗涤,无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,得粗品标题化合物14b(12g),产物不经纯化直接用于下一步反应。
MS m/z(ESI):318.2[M+1]
第二步
5-溴-4-(4-氯苯基)-6-肼基嘧啶-2-胺14c
依次将粗品化合物14b(12g,37.62mmol)和40mL 85%水合肼溶于400mL乙醇中,搅拌反应17小时。反应液过滤,滤饼依次用乙醇(50mL)和正己烷(100mL×2)洗涤,收集滤饼,滤饼干燥,得粗品标题化合物14c(10.28g),产物不经纯化直接用于下一步反应。
MS m/z(ESI):314.3[M+1]
第三步
8-溴-7-(4-氯苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺14d
将粗品化合物14c(2g,6.36mmol)和1.16mL的原甲酸(三)乙酯(1.04g,6.99mmol)加入50mL乙醇中,回流条件下,搅拌反应4小时。反应液冷却至室温,减压浓缩,残余物中加入51mL乙醇和正己烷(V/V=1∶50)混合溶液搅拌,过滤,收集滤饼,得标题化合物14d(2g,产率:96.9%)。
MS m/z(ESI):324.3[M+1]
第四步
7-(4-氯苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺14
氩气氛下,依次将化合物14d(250mg,770.27μmol)、化合物1c(265.36mg,924.32μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(56.36mg,77.03μmol)、碳酸钾(319.36mg,2.31mmol)加入10mL 1,4-二氧六环和水(V/V=4∶1)的混合溶剂中,加热至90℃,搅拌2小时。反应液冷却至室温,减压浓缩,残余物用CombiFlash快速制备仪以洗脱剂体系B纯化,所得粗品用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物14(64.4mg,产 率:20.7%)。
MS m/z(ESI):405.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.46(brs,2H),7.58(s,1H),7.49(s,1H),7.43-7.35(m,4H),2.50(s,3H)。
实施例15
8-(2-氯-6-甲基吡啶-4-基)-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺15
Figure PCTCN2018079086-appb-000055
第一步
4-氯-6-(4-氟苯基)嘧啶-2-胺15c
在氩气氛下,依次将4,6-二氯嘧啶-2-胺15a(10g,60.98mmol,阿达马斯试剂有限公司)、(4-氟苯基)硼酸15b(8.53g,60.98mmol,韶远科技上海有限公司)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(4.46g,6.10mmol)和碳酸钾(16.83g,121.96mmol)加入250mL 1,4-二氧六环和水(V/V=4∶1)的混合溶剂中,加热至60℃,搅拌3小时。反应液冷却至室温,加入300mL水,用乙酸乙酯(150mL×3)萃取,合并有机相,有机相减压浓缩,残余物用硅胶色谱法以洗脱剂体系B纯化,得到标题化合物15c(11.0g,产率:76.0%)。
MS m/z(ESI):224.3[M+1]
第二步
5-溴-4-氯-6-(4-氟苯基)嘧啶-2-胺15d
将化合物15c(11.0g,49.19mmol)溶于100mL N,N-二甲基甲酰胺中,分批加入N-溴代丁二酰亚胺(8.75g,49.19mmol),搅拌1小时。反应液中加入400mL水,用乙酸乙酯萃取(100mL×3),合并有机相,有机相依次用水(100mL×3)和饱和氯化钠溶液(200mL)洗涤,无水硫酸钠干燥,过滤,收集滤液,滤液减压浓缩,得粗品标题化合物15d(6.0g),产品不经纯化直接用于下一步反应。
MS m/z(ESI):301.9[M+1]
第三步
5-溴-4-(4-氟苯基)-6-肼基嘧啶-2-胺15e
依次将粗品化合物15d(5.5g,18.18mmol)和10mL 85%水合肼溶于20mL乙醇中,回流条件下,搅拌反应1小时。反应液冷却至室温,搅拌反应0.5小时。过滤,滤饼依次用乙醇(3mL×2)和乙醚(3mL×2)洗涤,收集滤饼,真空干燥,得粗品标题化合物15e(4.4g),产品不经纯化直接用于下一步反应。
MS m/z(ESI):298.1[M+1]
第四步
8-溴-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺15f
依次将粗品化合物15e(500mg,1.68mmol)和原甲酸(三)乙酯(497mg,3.35mmol)加入20mL乙醇中,回流3小时。反应液冷却至室温,过滤,滤饼2mL乙醇洗涤一次,收集滤饼,得粗品标题化合物15f(460mg),产物不经纯化直接下一步反应。
MS m/z(ESI):307.9[M+1]
第五步
8-(2-氯-6-甲基吡啶-4-基)-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺15
氩气氛下,将粗品化合物15f(120mg,389.47μmol)、化合物4a(138.24mg,545.26μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(28.50mg,38.95μmol)、碳酸钾(161.48mg,1.17mmol)加入6.0mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至90℃,搅拌2小时。反应液冷却至室温,加入50mL水,用乙酸乙酯萃取(30mL×3),合并有机相,有机相减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物15(22mg,产率:15.9%)。
MS m/z(ESI):355.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.38(brs,2H),7.40-7.37(m,2H),7.20-7.18(m,4H),2.37(s,3H)。
实施例16
7-(4-氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺16
Figure PCTCN2018079086-appb-000056
氩气氛下,依次将化合物15f(100mg,324.56μmol)、化合物1c(111.81mg,389.47μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(23.73mg,32.46μmol)、碳酸钾(89.71mg,649.12μmol)加入6.0mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至90合,搅拌2小时。反应液冷却至室温,加入20mL水,用乙酸乙酯萃取(10mL×3),合并有机相,有机相减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物16(34mg,产率:26.9%)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.40(brs,2H),7.56(s,1H),7.43(s,1H),7.34-7.37(m,2H),7.13-7.17(m,2H),2.49(s,3H)。
实施例17
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-苯基咪唑并[1,2-c]嘧啶-5-胺17
Figure PCTCN2018079086-appb-000057
第一步
5-溴-2-(甲硫基)-6-苯基嘧啶-4-胺17b
依次将2-(甲硫基)-6-苯基嘧啶-4-胺17a(1.2g,5.5mmol,采用公知的方法“Chemical & Pharmaceutical Bulletin,1981,29(4),948-54”)和N-溴代丁二酰亚胺 (1.1g,6.1mmol)加入20mL N,N-二甲基甲酰胺中,搅拌反应1小时。加入水,用乙酸乙酯萃取3次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得粗品标题化合物17b(550mg),产物不经纯化直接用于下一步反应。
MS m/z(ESI):296.0[M+1]
第二步
8-溴-5-(甲硫基)-7-苯基咪唑并[1,2-c]嘧啶17c
将粗品化合物17b(250mg,0.84mmol)溶于10mL 1,4-二氧六环,滴加氯乙醛(249mg,1.27mmol),90℃条件下,搅拌36小时。反应液冷却至室温,加入饱和碳酸氢钠溶液,用乙酸乙酯萃取3次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用薄层色谱法以展开剂体系A纯化,得标题化合物17c(195mg,产率:72%)。
MS m/z(ESI):320.1[M+1]
第三步
8-溴-5-(甲基磺酰基)-7-苯基咪唑并[1,2-c]嘧啶17d
将化合物17c(195mg,0.61mmol)溶于10mL二氯甲烷中,分批加入间氯过氧苯甲酸(316mg,1.83mmol),搅拌反应3小时。反应液中加入饱和碳酸氢钠溶液,用乙酸乙酯萃取3次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得粗品标题化合物17d(210mg),产物不经纯化直接用于下一步反应。
MS m/z(ESI):352.1[M+1]
第四步
8-溴-7-苯基咪唑并[1,2-c]嘧啶-5-胺17e
将粗品化合物17d(210mg,0.59mmol)溶于10mL 1,4-二氧六环,滴加1mL30%氨水,搅拌反应1小时。反应液中加入水,用二氯甲烷和甲醇(V/V=10∶1)混合溶液萃取3次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用薄层色谱法以展开剂体系A纯化,得标题化合物17e(172mg,产率:46%)。
MS m/z(ESI):289.1[M+1]
第五步
8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-苯基咪唑并[1,2-c]嘧啶-5-胺17
氩气氛下,依次将化合物17e(80mg,0.28mmol)、化合物1c(95mg,0.332mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(20mg,28μmol)、碳酸钾(87mg,0.56mmol)加入10mL 1,4-二氧六环和水(V/V=4∶1)的混合溶剂中,加热至90℃,搅拌3小时。反应液冷却至室温,加入水,用二氯甲烷和甲醇(V/V=8∶1)混合溶液萃取3次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用薄层色谱法以展开剂体系A纯化,得标题化合物17(15 mg,产率:14%)。
MS m/z(ESI):370.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.99(brs,2H),7.57(s,1H),7.55(s,1H),7.43(s,1H),7.30(brs,5H),2.45(s,3H)。
实施例18
7-(2,4-二氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺
Figure PCTCN2018079086-appb-000058
第一步
4-氯-6-(2,4-二氟苯基)嘧啶-2-胺18b
在氩气氛下,依次将化合物15a(11g,63.72mmol)、(2,4-二氟苯基)硼酸18a(10.06g,63.72mmol,上海书亚科技有限公司)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(4.66g,6.37mmol)和碳酸钾(26.42g,191.17mmol)加入500mL 1,4-二氧六环和水(V/V=4∶1)的混合溶剂中,90℃条件下,搅拌反应2小时。反应液过滤,滤液分液,水相用乙酸乙酯萃取(200mL×2),合并有机相,减压浓缩,残余物用硅胶色谱法以洗脱剂体系B纯化,得标题化合物18b(14.04g,产率:91.2%)。
MS m/z(ESI):242.3[M+1]
第二步
5-溴-4-氯-6-(2,4-二氟苯基)嘧啶-2-胺18c
将化合物18b(14.04g,58.11mmol)溶于300mL的N,N-二甲基甲酰胺中,加入N-溴代丁二酰亚胺(11.38g,63.92mmol),搅拌反应1小时。反应液倒入1L水中,搅拌30分钟,过滤,收集滤饼,真空干燥,得粗品标题化合物18c(16g),产品不经纯化直接进行下一步反应。
MS m/z(ESI):320.0[M+1]
第三步
5-溴-4-(2,4-二氟苯基)-6-肼基嘧啶-2-胺18d
将粗品化合物18c(16g,49.92mmol)溶于250mL乙醇中,加入50mL 85%水合肼,搅拌反应17小时。反应液过滤,滤饼依次用乙醇(20mL×2)、正己烷(20mL×2)洗涤,干燥滤饼,得标题化合物18d(12g,产率:76.1%)。
MS m/z(ESI):316.0[M+1]
第四步
8-溴-7-(2,4-二氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺18e
将化合物18d(4g,12.65mmol)和原甲酸(三)乙酯(2.25g,15.18mmol)溶解于50mL乙醇中,回流条件下,搅拌反应2小时。停止反应,冷却至室温,反应液减压浓缩,所得残余物用5mL乙醇打浆0.5小时,过滤,滤饼用无水乙醚(10mL×2)洗涤,干燥滤饼,得标题化合物18e(3.85g,产率:93.4%)。
MS m/z(ESI):326.2[M+1]
第五步
7-(2,4-二氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺18
氩气氛下,依次将化合物18e(110mg,337.32μmol)、化合物1c(145.26mg,505.98μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(24.7mg,33.73μmol)、碳酸钾(93.1mg,674.64μmol)加入12mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至90℃,搅拌3小时。反应冷却至室温,加入水,用乙酸乙酯萃取(20mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物18(31mg,产率:22.6%)。
MS m/z(ESI):407.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.50(brs,2H),7.55(brs,2H),7.44(s,1H),7.20-7.18(m,2H),2.49(s,3H)。
实施例19
8-(2,6-二甲基吡啶-4-基)-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺19
Figure PCTCN2018079086-appb-000059
Figure PCTCN2018079086-appb-000060
第一步
5-溴-4-氯-6-(2,4-二氟苯基)嘧啶-2-胺19b
将4-氯-6-(2-氟苯基)嘧啶-2-胺19a(1.5g,6.71mmol,采用专利申请的公开的方法“WO 2014162039A1”制备而得)溶于20mL的N,N-二甲基甲酰胺中,加入N-溴代丁二酰亚胺(1.31g,7.38mmol),搅拌反应1小时。反应液中加入120mL水,搅拌,过滤,收集滤饼,真空干燥,得粗品标题化合物19b(1.9g),产品不经纯化直接进行下一步反应。
MS m/z(ESI):301.9[M+1]
第二步
5-溴-4-(2-氟苯基)-6-肼基嘧啶-2-胺19c
将粗品化合物19b(1.9g,6.28mmol)溶于30mL乙醇中,加入85%水合肼(125.61mmol,7.18mL),60℃条件下,搅拌1小时。反应液过滤,滤饼用乙醇(20mL×2)洗涤,干燥滤饼,得标题化合物19c(1.7g,产率:90.8%)。
MS m/z(ESI):297.8[M+1]
第三步
8-溴-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺19d
将化合物19c(1.7g,5.70mmol)加入10mL原甲酸(三)乙酯中,130℃条件下,搅拌0.5小时。反应液冷却至室温,过滤,滤饼中加入乙酸乙酯,搅拌,过滤,干燥滤饼,得标题化合物19d(1.1g,产率:62.6%)。
MS m/z(ESI):307.9[M+1]
第四步
8-(2,6-二甲基吡啶-4-基)-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺19
氩气氛下,依次将化合物19d(200mg,649.12μmol)、化合物11a(151.32mg,649.12μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(47.45mg,64.91μmol)、碳酸钾(179.16mg,1.30mmol)加入12mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至80℃,搅拌3小时。反应液冷却至室温,加入水,用乙酸乙酯萃取(20mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物19(26mg,产率:12%)。
MS m/z(ESI):335.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.30(s,2H),7.41(brs,2H),7.19-7.22 (m,1H),7.09-7.13(m,1H),6.91(s,2H),2.29(s,6H)。
实施例20
8-(2-(二氟甲基)-6-甲基吡啶-4-基)-7-(2,4-二氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺
Figure PCTCN2018079086-appb-000061
氩气氛下,依次将2-(二氟甲基)-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶20a(247.56mg,919.96μmol,采用专利申请“WO2011095625A1”公开的方法制备而得)、化合物18e(200mg,613.31μmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(44.88mg,61.33μmol)、碳酸钾(254.29mg,1.84mmol)加入12mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至90℃,搅拌2小时。反应液冷却至室温,减压浓缩,残余物用CombiFlash快速制备仪以洗脱剂体系B纯化,所得粗品用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物20(26mg,产率:12%)。
MS m/z(ESI):389.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.44(brs,2H),7.54(s,1H),7.40-7.18(m,4H),6.96-6.69(m,1H),2.44(s,3H)。
实施例21
8-(2,6-二甲基吡啶-4-基)-2-甲基-7-苯基咪唑并[1,2-c]嘧啶-5-胺21
Figure PCTCN2018079086-appb-000062
Figure PCTCN2018079086-appb-000063
第一步
2-((2-(甲硫基)-6-苯基嘧啶-4-基)氨基)丙-1-醇21b
将4-氯-2-甲硫基-6-苯基-嘧啶21a(1.5g,6.34mmol,采用公知的方法“Tetrahedron,1994,50(34),10299-308”制备而得)溶于40mL乙腈中,加入2-氨基丙-1-醇(713.91mg,9.50mmol)和N,N-二异丙基乙胺(1.64g,12.67mmol),75℃条件下,反应72小时。反应液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化,得标题化合物21b(1.5g,产率:86%)。
MS m/z(ESI):276.2[M+1]
第二步
2-((5-溴-2-(甲硫基)-6-苯基嘧啶-4-基)氨基)丙-1-醇21c
将化合物21b(1.5g,5.45mmol)溶于30mL N,N-二甲基甲酰胺中,分批加入N-溴代丁二酰亚胺(969.50mg,5.45mmol),搅拌反应1小时。加入150mL水,用二氯甲烷和甲醇混合溶液(V/V=8∶1)萃取3次,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化,得标题化合物21c(1.2g,产率:62.2%)。
MS m/z(ESI):354.1[M+1]
第三步
8-溴-2-甲基-5-(甲硫基)-7-苯基-2,3-二氢咪唑并[1,2-c]嘧啶21d
将化合物21c(2.3g,6.49mmol)溶于40mL二氯甲烷中,加入三乙胺(983.59mg,9.74mmol),滴加甲磺酰氯(892.44mg,7.79mmol),搅拌过夜。加入饱和碳酸氢钠溶液,二氯甲烷萃取三次(30mL×3),合并有机相,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化,得标题化合物21d(1.2g,产率:55%)。
MS m/z(ESI):336.0[M+1]
第四步
8-溴-2-甲基-5-(甲硫基)-7-苯基咪唑并[1,2-c]嘧啶21e
将化合物21d(1.2g,3.57mmol)加入1,4二氧六环中,加入二氧化锰(3.14g,35.69mmol),90℃条件下,反应36小时。反应液冷却至室温,垫硅藻土过滤,滤饼用甲醇洗涤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化,得标题化合物21e(750mg,产率:62.9%)。
MS m/z(ESI):334.1[M-1]
第五步
8-溴-2-甲基-5-(甲磺酰基)-7-苯基咪唑并[1,2-c]嘧啶21f
将化合物21e(320mg,957.41μmmol)溶于5mL三氟乙酸,滴加过氧化氢(0.5mL 957.41μmmol),搅拌1小时。反应液用饱和碳酸钠溶液中和,二氯甲烷萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物21f(350mg),产物不经纯化直接用于下一步反应。
第六步
8-溴-2-甲基-7-苯基咪唑并[1,2-c]嘧啶-5-胺21g
将粗品化合物21f(350mg,955.68μmmol)溶于10mL 1,4-二氧六环,加入一水合氨(1.0mL,955.68μmmol,),40℃条件下,反应1小时。反应液减压浓缩,加入水,二氯甲烷和甲醇混合溶液(V/V=8∶1)萃取三次,合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用薄层色谱法以展开剂体系A纯化,得标题化合物21g(215mg,产率:74.2%)。
第七步
8-(2,6-二甲基吡啶-4-基)-2-甲基-7-苯基咪唑并[1,2-c]嘧啶-5-胺21
氩气氛下,依次将化合物21g(215mg,709.20μmmol)、化合物11a(247.99mg,1.06mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(51.84mg,70.92μmmol)、碳酸氢钠(131.06mg,1.56mmol)加入12mL 1,4-二氧六环和水(V/V=5∶1)的混合溶剂中,加热至80℃,搅拌2小时。反应液冷却至室温,加入水,乙酸乙酯萃取(20mL×3),合并有机相,饱和氯化钠溶液洗涤,硫酸钠干燥,过滤,滤液减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物21(45mg,产率:19.3%)。
MS m/z(ESI):330.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.68(s,1H),7.65(s,2H),7.28(s,2H),7.24(s,3H),6.89(s,2H),2.31(s,6H),2.27(s,3H)。
实施例22
8-(2-甲基-6-((4-甲基哌嗪-1-基)甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺22
Figure PCTCN2018079086-appb-000064
第一步
1-甲基-4-((6-甲基吡啶-2-基)甲基)哌嗪22c
将2-(氯甲基)-6-甲基吡啶22b(1g,7.06mmol)和碳酸钾(1.46g,10.59mmol)溶于40mL乙腈,加入1-甲基哌嗪22a(848.57mg,8.47mmol,939.72uL),80℃条件下,反应17小时。反应液用硅胶柱色谱法以洗脱剂体系A纯化,得标题化合物22c(1g,产率:69%)。
MS m/z(ESI):206.4[M+1]
第二步
1-甲基-4-((6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)甲基)哌嗪22d
氩气氛下,将化合物22c(1g,4.87mmol)、化合物5a(146.13μmmol)、甲氧基(环辛二烯)铱(I)二聚体(78.44mg,292.26μmmol)溶于40mL正己烷。80℃条件下,反应17小时。反应液减压浓缩,反应液用硅胶柱色谱法以洗脱剂体系B纯化,得标题化合物22d(217mg,产率:13.5%)。
采用实施例5合成路线,将第一步原料5b替换为22d,制得标题化合物22(27.6mg)。
MS m/z(ESI):415.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.26(brs,2H),7.32-7.28(m,6H),6.85(s,1H),3.38(s,2H),2.54(s,3H),2.43(s,3H),2.19-2.09(m,8H)。
实施例23
8-(2-氯-6-(三氟甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺23
Figure PCTCN2018079086-appb-000065
采用实施例4合成路线,将第一步原料化合物4a替换为2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-6-(三氟甲基)吡啶23a(采用公知的方法“Research on Chemical Intermediates,2013,39(4),1917-1926”制备而得),制得标题化合物23(11.8mg)。
MS m/z(ESI):391.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.58(brs,2H),7.82(s,1H),7.65(s,1H),7.40-7.36(m,5H)。
实施例24
8-(2-氯-6-甲基吡啶-4-基)-7-苯基咪唑并[1,2-c]嘧啶-5-胺24
Figure PCTCN2018079086-appb-000066
采用实施例17合成路线,将第五步原料化合物1c替换为化合物4a,制得标题化合物24(32mg)。
MS m/z(ESI):336.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.00(s,1H),7.93(s,2H),7.55(s,1H),7.31(s,5H),7.14(d,2H),2.33(s,3H)。
实施例25
8-(2-甲氧基-6-甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺25
Figure PCTCN2018079086-appb-000067
采用实施例4合成路线,将第一步原料化合物4a替换为2-甲氧基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶25a(采用公知的方法“Chemistry-A European Journal,2017,23(24),5663-5667”制备而得),制得标题化合物25(11.8mg)。
MS m/z(ESI):333.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.33(s,1H),8.24(brs,2H),7.36-7.29(m,5H),6.76(s,1H),6.48(s,1H),3.77(s,3H),2.29(s,3H)。
实施例26
8-(2-乙基-6-甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺26
Figure PCTCN2018079086-appb-000068
在氩气氛下,依次加入2-乙基-6-甲基吡啶26a(1g,8.25mmol,韶远科技上海有限公司)、化合物5a(2.31g,9.08mmol)、(1Z,5Z)-cycloocta-1,5-diene;iridium;methyloxonium(164.10mg,247.57μmmol)和4-叔丁基-2-(4-叔丁基-2-吡啶基)吡啶(588mg,6.00mmol)于40mL正己烷溶液中,加热至80℃,搅拌17小时。反应液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系B纯化,得到2-乙基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶26b(809mg,产率:39.7%)。
MS m/z(ESI):248.2[M+1]
采用实施例4合成路线,将第一步原料化合物4a替换为26b,制得标题化合物26(136.6mg)。
MS m/z(ESI):331.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.25(brs,2H),7.32-7.28(m,5H),7.12(s,1H),6.80(s,1H),2.57-2.55(m,2H),2.37(s,3H),1.03-1.00(m,3H)。
实施例27
8-(2-氯-6-甲基吡啶-4-基)-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺27
Figure PCTCN2018079086-appb-000069
采用实施例19合成路线,将第四步原料化合物11a替换为化合物4a,制得标题产物27(73mg)。
MS m/z(ESI):355.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.39(s,1H),8.44(s,2H),7.49-7.45(m,2H),7.28-7.24(m,1H),7.17-7.14(m,2H),7.11(s,1H),2.33(s,3H)。
实施例28
8-(2,6-二甲基吡啶-4-基)-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺28
Figure PCTCN2018079086-appb-000070
采用实施例15合成路线,将第五步原料化合物4a替换为化合物11a,制得标题产物28(38mg)。
MS m/z(ESI):335.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.24(brs,2H),7.39-7.35(m,2H),7.16-7.11(m,2H),6.95(s,2H),2.33(s,6H)。
实施例29
7-(3-氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺29
Figure PCTCN2018079086-appb-000071
采用实施例15合成路线将第一步原料化合物15b替换为(3-氟苯基)硼酸29a,得到化合物8-溴-7-(3-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺29b;
将实施例15的第五步原料化合物4a替换为化合物1c,制得标题化合物29(28mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.46(brs,2H),7.60(s,1H),7.48(s,1H),7.36-7.34(m,1H),7.23-7.19(m,2H),7.10-7.08(m,1H),2.49(s,3H)。
实施例30
8-(2-环丙基-6-甲基吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺30
Figure PCTCN2018079086-appb-000072
采用实施例11合成路线,将第一步原料化合物11a替换为2-环丙基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶30a(采用专利申请“WO2011070131A1”公开的方法制备而得),制得标题化合物30(43mg)。
MS m/z(ESI):343.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.23(brs,2H),7.47-7.31(m,5H),6.92-6.87(m,2H),2.28(s,3H),1.98-1.90(m,1H),0.84-0.72(m,4H)。
实施例31
8-(2,6-二甲基吡啶-4-基)-7-苯基咪唑并[1,2-c]嘧啶-5-胺31
Figure PCTCN2018079086-appb-000073
采用实施例17合成路线,将第五步原料化合物1c替换为化合物11a,值得标题化合物31(40mg)。
MS m/z(ESI):316.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.00(s,1H),7.99(s,2H),7.51(d,1H),7.31-7.29(m,2H),7.26-7.25(m,3H),6.91(s,2H),2.30(s,6H)。
实施例32
8-(2,6-二甲基吡啶-4-基)-7-(4-氟苯基)咪唑并[1,2-c]嘧啶-5-胺32
Figure PCTCN2018079086-appb-000074
Figure PCTCN2018079086-appb-000075
氩气氛下,将6-氯-2-(甲硫基)嘧啶-4-胺32a(2.0g,11.39mmol,上海毕得科技有限公司)和(4-氟苯基)硼酸(2.39g,17.08mmol)溶于50mL甲苯中,依次加入四(三苯基膦)钯(657.60mg,569.35μmmol)和碳酸钠(2.41g,22.77mmol)和10mL水。90℃,搅拌3小时。加入水,乙酸乙酯萃取三次(50mL×3),合并有机相,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物中加入甲醇搅拌,过滤,收集滤饼,得6-(4-氟苯基)-2-(甲硫基)嘧啶-4-胺32b(1.3g,产率:48.5%)。
采用实施例17合成路线,第一步原料化合物17a替换为化合物32b,制得8-溴-7-(4-氟苯基)咪唑并[1,2-c]嘧啶-5-胺32c;
将实施例17的第五步原料化合物1c替换为化合物11a,制得标题化合物32(70mg)。
MS m/z(ESI):334.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.98(d,1H),7.82(s,2H),7.52(d,1H),7.35-7.32(m,2H),7.28-7.08(m,2H),6.92(s,2H),2.32(s,6H)。
实施例33
7-(2-氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺33
Figure PCTCN2018079086-appb-000076
采用实施例19的合成路线,将第四步原料化合物11a替换为化合物1c,制得标题化合物33(25mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.48(brs,2H),7.55(s,1H),7.50-7.44(m,2H),7.42(s,1H),7.28-7.26(m,1H),7.15-7.12(m,1H),2.46(s,3H)。
实施例34
8-(2-氯-6-甲基吡啶-4-基)-7-(2,4-二氟苯基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺34
Figure PCTCN2018079086-appb-000077
采用实施例18合成路线,将第五步原料化合物1c替换为化合物4a,制得标题化合物34(30.4mg)。
MS m/z(ESI):373.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.46(brs,2H),7.55-7.54(m,1H),7.25-7.14(m,4H),2.36(s,3H)。
实施例35
8-(2-氯-6-甲基吡啶-4-基)-7-(p-甲基苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺35
采用实施例15合成路线,将第一步原料化合物15b替换为对甲苯基硼酸35a(上海达瑞化学有限公司),制得8-溴-7-(p-甲苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺35b;
将实施例15第五步原料化合物15f替换为化合物35b,制得标题化合物35(21.3mg)。
MS m/z(ESI):351.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.33(brs,2H),7.26-7.13(m,6H),2.36(s,3H),2.30(s,3H)。
实施例36
8-(2-氯-6-甲基吡啶-4-基)-7-(4-氯苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺36
Figure PCTCN2018079086-appb-000079
采用实施例14合成路线,将第四步原料化合物1c替换为化合物4a,制得标题化合物36(45.9mg)。
MS m/z(ESI):371.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.40(brs,2H),7.43-7.35(m,4H),7.20-7.18(m,2H),2.38(s,3H)。
实施例37
7-苯基-8-(吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺37
Figure PCTCN2018079086-appb-000080
采用实施例2合成路线,将第四步原料化合物2d替换为4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶37a(上海毕得医药科技有限公司),制得标题化合物37(20mg)。
MS m/z(ESI):289.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.47-8.46(m,2H),8.29(brs,2H),7.33-7.29(m,7H)。
实施例38
8-(2-氯吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺38
Figure PCTCN2018079086-appb-000081
采用实施例2合成路线,将第四步原料化合物2d替换为2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶38a(阿达马斯试剂有限公司),制得标题化合物 38(20mg)。
MS m/z(ESI):323.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.40(brs,2H),8.28-8.27(m,1H),7.47(s,1H),7.38-7.31(m,5H),7.23-7.22(m,1H)。
实施例39
8-(2-氯-6-(三氟甲基)吡啶-4-基)-7-(2,4-二氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺39
Figure PCTCN2018079086-appb-000082
采用实施例18合成路线,将第五步原料1c替换为2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-6-(三氟甲基)吡啶(采用公知的方法“Research on Chemical Intermediates,2013,39(4),1917-1926”制备而得),制得标题化合物39(19.8mg)。
MS m/z(ESI):427.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.80(brs,2H),7.80(s,1H),7.70(s,1H),7.65-7.59(m,1H),7.29-7.22(m,2H)。
实施例40
7-(2,4-二氟苯基)-8-(2,6-二甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺40
Figure PCTCN2018079086-appb-000083
采用实施例18合成路线,将第五步原料1c替换为化合物11a,制得标题化合物40(40mg)。
MS m/z(ESI):353.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),8.43(brs,2H),7.51-7.45(m,1H),7.21-7.10(m,2H),6.92(s,2H),2.31(s,6H)。
实施例41
7-(2,4-二氟苯基)-8-(2-甲氧基-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺41
Figure PCTCN2018079086-appb-000084
采用实施例18合成路线,将第五步原料1c替换为化合物25a,制得标题化合物41(10.6mg)。
MS m/z(ESI):369.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),8.33(brs,2H),7.50-7.48(m,1H),7.22-7.13(m,2H),6.76(s,1H),6.45(s,1H),3.76(s,3H),2.30(s,3H)。
实施例42
3-甲基-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺42
Figure PCTCN2018079086-appb-000085
采用实施例1合成路线,将第四步原料原甲酸(三)乙酯替换为原乙酸三乙酯,制得标题化合物42(52mg)。
MS m/z(ESI):385.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.69(brs,2H),7.55(s,1H),7.41(s,1H),7.35-7.31(m,5H),2.96(s,3H),2.46(s,3H)。
实施例43
5-(5-氨基-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-8-基)-1-异丙基吡啶-2(1H)-酮43
Figure PCTCN2018079086-appb-000086
采用实施例4合成路线,将第一步原料化合物4a替换为1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2(1H)-酮43a(采用专利申请公开的方法“WO2011143426A1”制备而得),制得标题化合物43(31mg)。
MS m/z(ESI):347.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.33(s,1H),8.13(brs,2H),7.47-7.33(m,7H),6.38-6.35(m,1H),4.97-4.90(m,1H),0.99-0.97(m,6H)。
μmmol μmmol
实施例44
8-(2-环丙基-6-甲基吡啶-4-基)-7-(2,4-二氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺44
Figure PCTCN2018079086-appb-000087
采用实施例18合成路线,将第五步原料1c替换为化合物30a,制得标题化合物44(79.4mg)。
MS m/z(ESI):379.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.33(brs,2H),7.52-7.46(m,1H),7.21-7.11(m,2H),6.90-6.85(m,2H),2.28(s,3H),1.95-1.85(m,1H),0.85-0.83(m,2H),0.72-0.70(m,2H)。
实施例45
7-(2,4-二氟苯基)-8-(2-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺45
Figure PCTCN2018079086-appb-000088
采用实施例18合成路线,将第五步原料1c替换为化合物12a,制得标题化合物45(79.4mg)。
MS m/z(ESI):339.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.40(brs,2H),8.31-8.30(m,1H),7.53-7.47(m,1H),7.22-7.11(m,3H),6.98-6.97(m,1H),2.39(s,3H)。
实施例46
7-(2-氯-4-氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺46
Figure PCTCN2018079086-appb-000089
采用实施例15合成路线,将第一步原料化合物15b替换为(2-氯-4-氟苯基)硼酸(韶远科技上海有限公司),制得8-溴-7-(2-氯-4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺46a;
将实施例15的第五步原料化合物4a替换为化合物1c,制得标题化合物46(32mg)。
MS m/z(ESI):423.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.54(brs,2H),7.54(s,1H),7.53-7.49(m,2H),7.47(s,1H),7.40-7.28(m,1H),2.47(s,3H)。
实施例47
8-(2-氯-6-(吗啉甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺47
采用实施例22合成路线,将原料化合物22c替换为4-((6-氯吡啶-2-基)甲基)吗啉(采用专利申请“US20150361100A1”公开的方法制备而得),制得标题化合物47(34.8%)。
MS m/z(ESI):422.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),7.58(s,1H),7.48-7.33(m,5H),7.05(s,1H),3.35-3.28(m,6H),2.11(s,2H),1.90-1.87(m,4H)。
实施例48
8-(2-甲基-6-(吗啉甲基)吡啶-4-基)-7-苯基-[1,2,4]三唑并[4,3-c]嘧啶-5-胺48
Figure PCTCN2018079086-appb-000091
采用实施例43合成路线,将第一步原料化合物43a替换为吗啉48a,制得标题化合物48(30.8mg)。
MS m/z(ESI):402.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.23(brs,2H),7.35-7.28(m,6H),6.85(s,1H),3.42-3.35(m,6H),2.44(s,3H),2.13-2.05(m,4H)。
实施例49
7-(4-氯-2-氟苯基)-8-(2-甲基-6-(三氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺
Figure PCTCN2018079086-appb-000092
采用实施例15合成路线,将第一步原料化合物15b替换为(4-氯-2-氟苯基)硼酸(韶远科技上海有限公司),制得8-溴-7-(4-氯-2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺49a;
将实施例15的第五步原料化合物4a替换为化合物1c,制得标题化合物49(20mg)。
MS m/z(ESI):422.7[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.54(brs,2H),7.56-7.52(m,2H),7.45(s,1H),7.42-7.38(m,2H),2.48(s,3H)。
实施例50
7-(4-氯-2-氟苯基)-8-(2-氯-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺50
Figure PCTCN2018079086-appb-000093
采用实施例15合成路线,将第一步原料化合物15b替换为(4-氯-2-氟苯基)硼酸(韶远科技上海有限公司),制得标题化合物50(30mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.47(brs,2H),7.54-7.50(m,1H),7.44-7.39(m,2H),7.18(s,1H),7.14(s,1H),2.36(s,3H)。
实施例51
8-(2-(二氟甲基)-6-甲基吡啶-4-基)-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺51
Figure PCTCN2018079086-appb-000094
氩气氛下,依次将化合物15f(1.00g,3.25mmol)、化合物20a(1.05g,3.90mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(238mg,324.6μmol)、碳酸氢钠(682mg,8.11mmol)加入55mL 1,4-二氧六环和水(V/V=9∶2)的混合溶剂中,加热至95℃,搅拌17小时。反应液冷却至室温,过滤,滤液减压浓缩,残余物用高效液相色制备(Waters 2767-SQ Detecor2,洗脱体系:碳酸氢铵,水,乙腈)纯化,得标题化合物51(50mg)。
MS m/z(ESI):371.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),8.38(brs,2H),7.44(s,1H),7.39-7.36(m,2H),7.32(s,1H),7.19-7.14(m,2H),6.98-6.70(m,1H),2.46(s,3H)。
实施例52
7-(4-氯苯基)-8-(2-(二氟甲基)-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺52
Figure PCTCN2018079086-appb-000095
采用实施例14合成路线,将原料化合物1c替换为化合物20a,制得标题化合物52(32mg)。
MS m/z(ESI):387.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),8.39(brs,2H),7.40-7.43(m,2H),7.33-7.38(m,4H),6.84(t,1H),2.46(s,3H)。
实施例53
7-(4-氯苯基)-8-(2-(氟甲基)-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺53
Figure PCTCN2018079086-appb-000096
采用实施例14合成路线,将原料化合物1c替换为化合物2-(氟甲基)-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶53a(采用专利申请“WO201195625A1”公开的方法制备而得),制得标题化合物53(4mg)。
MS m/z(ESI):369.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.36(brs,2H),7.42-7.32(m,3H),7.19(s,1H),5.42-5.30(m,2H),7.19-7.14(m,2H),2.40(s,3H)。
实施例54
7-(4-氯苯基)-8-(2,6-二甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺54
Figure PCTCN2018079086-appb-000097
采用实施例14合成路线,将原料化合物1c替换为化合物11a,制得标题化合物54(47.5mg)。
MS m/z(ESI):351.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.27(brs,2H),7.39-7.33(m,4H),6.96(s,2H),2.34(s,6H)。
实施例55
8-(2-(氟甲基)-6-甲基吡啶-4-基)-7-(4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺55
Figure PCTCN2018079086-appb-000098
采用实施例15合成路线,将原料化合物4a替换为化合物53a,制得标题化合物55(20mg)。
MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.31(brs,2H),7.40-7.36(m,2H),7.20-7.13(m,4H),5.42-5.31(m,2H),2.41(s,3H)。
实施例56
8-(2-(二氟甲基)-6-甲基吡啶-4-基)-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺56
Figure PCTCN2018079086-appb-000099
采用实施例19合成路线,将原料化合物11a替换为化合物20a,制得标题化合物56(105.6mg)。
MS m/z(ESI):371.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.50(brs,2H),7.47-7.42(m,2H),7.37(s,1H),7.31(s,1H),7.26-7.24(m,1H),7.13-7.11(m,1H),6.94-6.66(m,1H),2.41(s, 3H)。
实施例57
8-(2-(氟甲基)-6-甲基吡啶-4-基)-7-(2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺57
Figure PCTCN2018079086-appb-000100
采用实施例19合成路线,将原料化合物11a替换为化合物53a,制得标题化合物57(58mg)。
MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,METHANOL-d 4)δ9.29(s,1H),7.51-7.48(m,1H),7.43-7.41(m,1H),7.26-7.21(m,3H),7.04-6.99(m,1H),5.37-5.25(m,2H),2.45(s,3H)。
实施例58
7-(2,4-二氟苯基)-8-(2-(氟甲基)-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺58
Figure PCTCN2018079086-appb-000101
采用实施例18合成路线,将原料化合物1c替换为化合物53a,制得标题化合物58(30mg)。
MS m/z(ESI):371.1[M+1]
1H NMR(400MHz,CD 3OD)δ9.29(s,1H),7.59-7.55(m,1H),7.27-7.25(m,2H),7.06-7.02(m,1H),6.91-6.86(m,1H),5.40-5.28(m,2H),2.48(s,3H)。
实施例59
7-(4-氯-2-氟苯基)-8-(2-(二氟甲基)-6-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺59
Figure PCTCN2018079086-appb-000102
采用实施例49合成路线,将原料化合物1c替换为化合物20a,制得标题化合物59(49.1mg)。
MS m/z(ESI):405.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),7.54-7.50(m,1H),7.40-7.30(m,4H),6.97-6.69(m,1H),3.43(brs,2H),2.44(s,3H)。
测试例:
生物学评价
测试例1、本发明化合物对腺苷A 2a受体(adenosine A 2a receptor,A 2aR)cAMP信号通路,腺苷A 2b受体(adenosine A 2b receptor,A 2bR)cAMP信号通路,腺苷A 1受体(adenosine A 1receptor,A 1R)cAMP信号通路和腺苷A 3受体(adenosine A 3 receptor,A 3R)cAMP信号通路抑制活性的测定。
以下方法用来测定本发明化合物对腺苷A 2a受体cAMP信号通路,腺苷A 2b受体cAMP信号通路,腺苷A 1受体cAMP信号通路和腺苷A 3受体cAMP信号通路的抑制活性。实验方法简述如下:
一、实验材料及仪器
1.CHO-K1/A 2aR细胞(NM_000675.5)或CHO-K1/A 2bR细胞(NM_000676.2)或CHO-K1/A 1R细胞(NM_000674.2)或CHO-K1/A 3R细胞(NM_000677.3)
2.胎牛血清(Gibco,10099-141)
3.博来霉素(Thermo,R25001)或G418(ENZO,ALX-380-013-G005)或嘌呤霉素(Thermo,10687-010)
4.DMEM/F12培养基(GE,SH30023.01)
5.细胞分离缓冲液(Thermo Fisher,13151014)
6.HEPES(Gibco,42360-099)
7.牛血清白蛋白(MP Biomedicals,219989725)
8.咯利普兰(sigma,R6520-10MG)
9.腺苷脱氨酶(sigma,10102105001)
10.毛喉素(sigma,F6886)
11.2Cl-IB-MECA(Tocrics,1104/10)
12.N6-环戊基腺苷(Tocris,1702/50)
13.平衡盐缓冲液(Thermo,14025-092)
14.cAMP动态2试剂盒(cAMP dynamic 2 kit)(Cisbio,62AM4PEB)
15.384孔板(Corning,4514)或(Nunc,267462#)
16.乙基咔唑(Torcis,1691/10)
17.PHERAstar多功能酶标仪(Cisbio,62AM4PEB)
二、实验步骤
2.1 腺苷A 2a受体
CHO-K1/A 2aR细胞用含有10%胎牛血清和800μg/ml博来霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡盐缓冲液重悬细胞并计数,将细胞密度调整为10 6个/ml。在384孔板中每孔加入5μl细胞悬液,2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物,室温孵育30分钟。每孔再加入2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的乙基咔唑,室温孵育30分钟。化合物终浓度是:10000,2000,400,80,16,3.2,0.64,0.128,0.0256,0.00512,0.001024nM,乙基咔唑终浓度是20nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按1∶4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物(Anti-cAMP-Eu-Cryptate)。每孔加入5μl稀释后的cAMP-d2,再加入5μl稀释后的抗cAMP-Eu-穴状化合物,室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值,见表1。
2.2 腺苷A 1受体
CHO-K1/A 1R用含有10%胎牛血清和1mg/mlG418的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞,然后用含有20mM HEPES和0.1%牛血清白蛋白的平衡盐缓冲液重悬细胞并计数,将细胞密度调整为5×10 5个/ml。在384孔板中每孔加入12.5μl细胞悬液,6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物,室温孵育30分钟。每孔再加入6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和N6-环戊基腺苷,室温孵育30分钟。化合物终浓度是:100000,10000,1000,100,10,1,0.1和0nM,毛喉素的终浓度是10μM,CPA的终浓度是10nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1∶4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μl稀释后的cAMP-d2,再加入12.5μl稀释后的抗cAMP-Eu-穴状化合物,室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值,见表2。
2.3 腺苷A 3受体
CHO-K1/A 3R用含有10%胎牛血清和10μg/ml嘌呤霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡盐缓冲液重悬细胞并计数,将细胞密度调整为5×10 5/ml。在384孔板中每孔加入12.5μl细胞悬液,6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受 试化合物,室温孵育30分钟。每孔再加入6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和2Cl-IB-MECA,室温孵育30分钟。化合物终浓度是:100000,10000,1000,100,10,1,0.1和0nM,毛喉素的终浓度是10μM,2Cl-IB-MECA的终浓度是5nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1∶4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μl稀释后的cAMP-d2,再加入12.5μl稀释后的抗cAMP-Eu-穴状化合物,室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值,见表2。
2.4 腺苷A 2b受体(adenosine A 2b receptor,A 2bR)
CHO-K1/A 2bR用含有10%胎牛血清和1mg/ml G418的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡盐缓冲液重悬细胞并计数,将细胞密度调整为10 6个/ml。在384孔板中每孔加入5μl细胞悬液,2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物,室温孵育30分钟。每孔再加入2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的乙基咔唑(Torcis,1691/10),室温孵育30分钟。化合物终浓度是:100000,10000,1000,100,10,1,0.1和0nM,乙基咔唑终浓度是1μM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按1∶4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入5μl稀释后的cAMP-d2,再加入5μl稀释后的抗cAMP-Eu-穴状化合物,室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值。见表3。
表1 本发明化合物对腺苷A 2a受体cAMP信号通路抑制活性的IC 50
实施例编号 IC 50/nM(A 2aR)
1 0.23
3 0.07
4 0.08
5 0.09
6 0.14
7 0.16
8 0.18
9 0.25
10 0.26
11 0.15
12 0.63
14 1.56
15 0.17
16 0.63
17 0.75
18 3.96
19 0.96
20 2.33
21 2.46
23 0.23
24 0.27
25 0.32
26 0.42
27 0.5
28 0.52
29 0.55
30 0.77
31 0.93
32 1
33 1.77
34 2.04
35 0.18
36 3.47
37 2.11
38 2.18
40 1.75
43 0.2
50 3.55
51 0.36
52 0.48
53 0.35
54 0.48
55 1.04
56 1.68
57 2.59
59 3.05
结论:本发明化合物对腺苷A 2a受体cAMP信号通路具有明显的抑制活性。
表2 本发明化合物对腺苷A 1受体cAMP信号通路和A 3受体cAMP信号通路抑制活性的IC 50
实施例 IC 50/nM IC 50/nM IC 50比率 IC 50/nM IC 50比率
编号 (A 2aR) (A 1R) (A 1R/A 2aR) (A 3R) (A 3R/A 2aR)
3 0.07 18 257 2×10 3 2.9×10 4
4 0.08 37 463 >10 4 >1.3×10 5
5 0.09 12 133 1.4×10 3 1.5×10 4
7 0.16 16 100 5×10 3 3.1×10 4
11 0.15 102 680 >10 4 >6.7×10 4
18 3.96 409 103 >10 4 >2.5×10 3
19 0.96 173 180 >10 4 >10 4
20 2.33 519 223 >10 4 >4.3×10 3
27 0.5 71 142 >10 4 >2×10 4
28 0.52 66 127 >10 4 >1.9×10 4
51 0.36 418 1161 >10 4 >10 4
52 0.48 41 85 >10 4 >10 4
55 1.04 222.5 214 >10 4 >10 3
56 1.68 248 148 >10 4 >10 3
57 2.59 302.4 117 >10 4 >10 3
59 3.05 1009 330 >10 4 >10 3
结论:本发明化合物对腺苷A 1受体和A 3受体抑制活性作用较弱,说明本发明化合物对A 2a受体具有高选择性。
表3 本发明化合物对腺苷A 2b受体cAMP信号通路抑制活性的IC 50
Figure PCTCN2018079086-appb-000103
Figure PCTCN2018079086-appb-000104
结论:本发明化合物对腺苷A 2b受体抑制活性作用较弱,说明本发明化合物对A 2a受体具有高选择性。
测试例2、本发明化合物小鼠脑通透性的测定
本发明化合物小鼠脑通透性采用如下实验方法测定:
一.实验材料与仪器
1.RED装置(Device Inserts)(Thermo Scientific,QL21291110)
2.API 4000 Q-trap线性离子阱质谱仪(Applied Biosystems)
3.LC-30A超高压液相色谱系统(岛津)
4.pH7.4 PBS(100mM,4℃冰箱保存)
5.C57小鼠,由杰思捷实验动物有限公司提供,动物生产许可证号SCXK(沪)2013-0006。
二.实验动物操作
C57小鼠4只,雌性,12/12小时光/暗调节,温度24±3℃恒温,湿度50-60%,自由进食饮水。禁食一夜后分别灌胃给药。给药剂量20mg/kg,给药组于给药后0.5h采血后处死(采血量0.5ml),血样置于肝素化试管中,3500rpm离心10min分离血浆,记为血浆1,于-80℃保存;处死后的动物心脏灌流生理盐水,去除脑组织中多余血液,取脑组织,滤纸吸干残留的血液,记为脑组织1,-80℃保存。另取3只动物取空白血浆和脑组织2,处理方法同给药组。
三.血浆蛋白结合平衡透析过程
3.1 样品制备
用DMSO溶解药物化合物至20mM,得到储备液I;移取适量储备液I,用甲醇稀释得到200μM稀释储备液II;移取10μl储备液II于1.5ml Eppendorf管中,加入990μl空白血浆,混匀得到2μM血浆样品2(DMSO含量≤0.2%),用于该浓度血浆蛋白结合率的测定。移取上述配好的50μl血浆样品,记为T 0,置于-4℃冰箱保存待测。
3.2 实验过程
取RED装置将平衡透析管插至于96孔的底板中。取上述配制好的含待测物血浆样品2及相应空白血浆样品300μl,置于红色标记的孔中(plasma chamber)。取500μl pH 7.4磷酸缓冲盐溶液,置于并排红色标记的另一孔中(buffer chamber)。按上述步骤处理方法,每个化合物每一个浓度为2个样本。完毕用封条(sealing tape)覆盖96孔板,并将整块底板放至热混仪中,以400rpm转速,于37℃平衡4h。孵化结束后,从热混仪中取出96孔底板装置,完成平衡透析。取25μl平衡 后的血浆样品或透析液样品,加入25μl相对应的未平衡的不含药的空白磷酸盐缓冲液或不含药的空白血浆,加入内标(乙腈配制)200μl,涡旋混合5min,离心10min(4000rpm),取上清液进行LC/MS/MS分析。T 0样品不经孵化,直接采用上述建立的LC/MS/MS法分别测定总药物(plasma chamber)及游离药物(buffer chamber)与内标物色谱峰面积比,计算游离百分率(f u plasma%)。
四.脑组织蛋白结合平衡透析过程
脑组织蛋白结合平衡透析过程:空白脑组织2按照稀释因子=11的比例用pH7.4PBS将脑组织制成空白脑匀浆,加入化合物配制成2μM脑匀浆,其余与血浆蛋白结合的操作相同,采用建立的LC/MS/MS法分别测定总药物(brain homo chamber)及游离药物(buffer chamber)与内标物色谱峰面积比,计算游离百分率(f brain hom%)。
五.脑通透试验数据计算方法
5.1 采用建立的LC/MS/MS法分别测定小鼠给药后0.5h的血浆1和脑组织1中的药物浓度,此为总浓度(C total,p和C total,b);
5.2 采用RED Device Inserts装置,用平衡透析法分别测定化合物在小鼠血浆和脑组织中的蛋白结合率,从而计算出游离百分率(f u plasma%,f u brain%);
血浆游离百分率(f u plasma%)=C buffer/C plasma×100%;
脑匀浆游离百分率(f u brain hom%)=C buffer/C brain hom×100%;
脑组织游离百分率(f u brain%)=f u brain hom/(Df-(Df-1)×f u brain hom)×100%;此处Df=11
5.3 采用以下公式计算血脑通透指数Kp-unbound。
Figure PCTCN2018079086-appb-000105
六.试验结果与讨论
本发明化合物的脑通透指数如下:
实施例编号 血脑通透指数(Kp-unbound)
实施例18 0.010
实施例20 0.015
结论:本发明化合物在脑中的游离药物浓度低,透过血脑屏障能力弱,较少药物进脑,可能产生的副作用低。

Claims (17)

  1. 一种通式(I)所示的化合物:
    Figure PCTCN2018079086-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
    其中:
    G为N或CR 4
    环A选自环烷基、芳基和杂芳基;
    R 1相同或不同,各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
    R 2选自烷氧基、羟基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;其中所述的烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、C(O)OR 5和R b中的一个或多个取代基所取代;
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
    R 4选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基;
    R 5选自氢原子、烷基、氨基、卤代烷基、环烷基、杂环基、芳基和杂芳基;
    R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被选自烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基、杂环基、芳基、杂芳基和C(O)OR 5中的一个或多个取代基所取代;且
    n为1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物,其中所述的R 2选自氰基、环烷基、杂环基、芳基和杂芳基;其中所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b中的一个或多个取代基所取代;R b为杂环基烷基,其中所述的杂环基烷基中 的杂环基任选被一个或多个烷基所取代。
  3. 根据权利要求1所述的通式(I)所示的化合物,其为通式(II)所示的化合物:
    Figure PCTCN2018079086-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
    其中:
    环B选自环烷基、杂环基、芳基和杂芳基;
    R 6相同或不同,各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、C(O)OR 5和R b
    s为0、1、2、3或4;且
    环A、G、R 1、R 3、R 5、R b和n如权利要求1中所定义。
  4. 根据权利要求1~3中任一项所述的通式(I)所示的化合物,其为通式(III)所示的化合物:
    Figure PCTCN2018079086-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
    其中:
    环B选自环烷基、杂环基、芳基和杂芳基;R 6相同或不同,各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b;R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被一个或多个烷基所取代;
    s为0、1、2、3或4;且
    环A、R 1、R 3和n如权利要求1中所定义。
  5. 根据权利要求3或4中任一项所述的通式(II)所示的化合物,其中所述环B选自:苯基、吡啶基、吡唑基、吡啶-2-酮基、咪唑基、吡咯基、呋喃基、噻吩基、哌啶基、四氢吡啶基、异喹啉基、喹啉基、喹喔啉基、吲哚基、吲唑基、苯并呋喃基或苯并噻吩基。
  6. 根据权利要求1~5中任一项所述的通式(I)所示的化合物,其为通式(III’)所示的化合物:
    Figure PCTCN2018079086-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
    其中:
    R 6相同或不同,各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、氧代基、环烷基、杂环基和R b;R b为杂环基烷基,其中所述的杂环基烷基中的杂环基任选被一个或多个烷基所取代;
    s为0、1、2、3或4;
    环A、R 1、R 3和n如权利要求1中所定义。
  7. 根据权利要求1~6中任一项所述的通式(I)所示的化合物,其中所述的环A为芳基或杂芳基,优选为苯基或呋喃基。
  8. 根据权利要求1~7中任一项所述的通式(I)所示的化合物,其中所述的R 1选自氢原子、卤素或烷基。
  9. 根据权利要求1~8中任一项所述的通式(I)所示的化合物,其中所述的 R 3选自氢原子、卤素或烷基。
  10. 根据权利要求1~9中任一项所述的通式(I)所示的化合物,其选自:
    Figure PCTCN2018079086-appb-100005
    Figure PCTCN2018079086-appb-100006
    Figure PCTCN2018079086-appb-100007
  11. 一种通式(IV)所示的化合物:
    Figure PCTCN2018079086-appb-100008
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合 物形式或其可药用的盐,
    其中:
    X为卤素;
    环A、G、R 1、R 3和n如权利要求1中所定义。
  12. 根据权利要求11所述的通式(IV)所示的化合物,其选自:
    Figure PCTCN2018079086-appb-100009
  13. 一种制备根据权利要求3所述的通式(II)所示的化合物的方法,该方法包括:
    Figure PCTCN2018079086-appb-100010
    通式(IV)的化合物和通式(V)的化合物反应,得到通式(II)的化合物,
    其中:
    X为卤素;
    W为
    Figure PCTCN2018079086-appb-100011
    环A、环B、G、R 1、R 3、R 6、n和s如权利要求3中所定义。
  14. 一种药物组合物,所述药物组合物含有治疗有效量的根据权利要求1~10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  15. 根据权利要求1~10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求14所述的药物组合物在制备用于抑制A 2a受体的药物中的用途。
  16. 根据权利要求1~10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求14所述的药物组合物在制备用于治疗通过对A 2a受体的抑制而改善的病况或病症的药物中的用途。
  17. 根据权利要求16所述的用途,其中所述的通过对A 2a受体的抑制而改善的病况或病症选自肿瘤、抑郁症、认知功能病症、神经退行性病症、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为;优选为肿瘤。
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