WO2023216753A1 - 咪唑并哒嗪取代苯环类衍生物、制备方法、药物组合物及用途 - Google Patents
咪唑并哒嗪取代苯环类衍生物、制备方法、药物组合物及用途 Download PDFInfo
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- WO2023216753A1 WO2023216753A1 PCT/CN2023/084772 CN2023084772W WO2023216753A1 WO 2023216753 A1 WO2023216753 A1 WO 2023216753A1 CN 2023084772 W CN2023084772 W CN 2023084772W WO 2023216753 A1 WO2023216753 A1 WO 2023216753A1
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- Prior art keywords
- methoxy
- bromo
- mmol
- pain
- ethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
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- MJQSRSOTRPMVKB-UHFFFAOYSA-N 5h-imidazo[4,5-c]pyridazine Chemical group C1=NNC2=NC=NC2=C1 MJQSRSOTRPMVKB-UHFFFAOYSA-N 0.000 title 1
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- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 208000003251 Pruritus Diseases 0.000 claims description 3
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 claims description 3
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- 230000003412 degenerative effect Effects 0.000 claims description 3
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Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to imidazopyridazine-substituted phenyl ring derivatives with modulating function on GABA A receptors, their preparation methods, pharmaceutical compositions and their applications as medicines.
- GABA Gamma-aminobutyric acid
- GABA A R GABA A receptor
- GABA B R GABA B receptor
- GABA A receptor subunits in mammals have been found to include ⁇ 1-6, ⁇ 1-4, ⁇ 1-3, ⁇ , ⁇ , ⁇ and ⁇ 1-2 subunits, among which ⁇ subunit, ⁇ subunit and ⁇ subunit
- the base is essential for the formation of a complete functional GABA A receptor, while the alpha subunit is critical for the binding of benzodiazepines to the GABA A receptor.
- the drug bound at the allosteric binding position can be a positive allosteric modulator (or forward allosteric modulator) that increases receptor activity, or a negative allosteric modulator (or reverse allosteric modulator) that decreases receptor activity. ) or a neutral allosteric modulator that does not alter receptor activity (this refers to a compound that binds to an allosteric binding site but does not modulate receptor activity).
- GABA A receptors containing ⁇ 2 or ⁇ 3 subunits may be involved in certain pain states and that positive allosteric modulators of these receptors may be effective Analgesics (Mirza, NR and Munro, G., Drug News and Perspectives, 2010, 23(6), 351-360).
- the mainstream view is that the modulatory activity of GABA A receptors containing ⁇ 1 subunits is the main source of side effects (such as sedation, addiction, drowsiness, and forgetfulness) of current GABA A modulators (such as benzodiazepines) ( Nature Reviews: Drug Discovery, 2011, 10(9), 685-697) by Uwe Rudolph and Frederic Knoflach. Finding new compounds that interact with GABA A receptors and have fewer ⁇ 1-GABA A receptor-related side effects will have great therapeutic potential.
- the technical problem to be solved by the present invention is to provide an imidazopyridazine-substituted benzene ring compound as shown in formula (1), its derivatives, stereoisomers, tautomers, prodrugs, Pharmaceutically acceptable salts, amorphous forms, polymorphs or solvates:
- the R 1 is a fused group formed by a substituted or unsubstituted benzene ring and a heterocyclic ring;
- the R 2 is selected from H, halogen, OH, C1-C6 alkoxy or CN;
- the R 3 is selected from H, substituted or unsubstituted linear or branched C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl.
- substituted means that the specified group or moiety may have 1, 2, 3, 4, 5 or 6 substituents. When multiple substituents are possible on a group and multiple possible substituents are given, the substituents are independently selected and need not be the same.
- substituents When indicating the number of substituents, the term "one or more" means one substitution to the highest possible number of substitutions, ie, substitution of one hydrogen to substitution of all hydrogens with the substituent. Unless otherwise stated, 1, 2, 3, 4 or 5 substituents are preferred.
- substituted means that one or more hydrogens on the group are selected from C1-C4 alkyl, C1-C4 alkoxy, C1- C4 is halogen-substituted alkyl or halogen-substituted.
- halogen refers to fluorine, chlorine, bromine and iodine, with fluorine being preferred.
- the compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and steric isomers, as well as mixtures thereof, such as racemic mixtures, shall form part of the invention. In this article, when the stereochemistry of any particular chiral atom is not determined, all stereoisomers are considered. Furthermore, the invention relates to all geometric and positional isomers. The compounds of the invention may exist in different tautomeric forms, and all such forms are included within the scope of the invention. All stereoisomers of the compounds of the present invention are intended to include mixtures or pure or substantially pure forms. Resolution can be accomplished by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
- prodrug is a functional derivative of a compound of formula (1) that is readily converted to a compound of formula (1) in vivo. Suitable derivatives can be selected and prepared by conventional techniques well known to those skilled in the art, see for example Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.
- Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate , salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, mesylate and pamoate.
- “Pharmaceutically acceptable salt” may refer to the inclusion of another molecule such as maleate or other counterion. Counter ions stabilize the charge in the parent compound.
- a "pharmaceutically acceptable salt” can have more than one charged atom, and multiple charged atoms can have multiple counterions.
- the desired “pharmaceutically acceptable salt” can be prepared by a suitable method, for example, by treating the free base with the following inorganic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with The following organic acids: acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranosyl acids such as glucuronic acid or galacturonic acid, ⁇ -hydroxyl Acids such as citric acid or tartaric acid, amino acids such as glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.
- inorganic acids hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
- organic acids acetic acid, maleic acid, succinic acid, mande
- the desired "pharmaceutically acceptable salt” can be prepared by suitable methods, for example, by treating the free acid with an inorganic or organic base: an amine, an alkali metal hydroxide or an alkaline earth metal hydrogen Oxides etc.
- suitable salts include, but are not limited to, organic salts derived from amino acids, salts of primary, secondary and tertiary amines, and salts of cyclic amines such as piperidine, morpholine and piperazine, and salts derived from sodium, calcium, potassium Inorganic salts obtained from , magnesium, manganese, iron, copper, zinc, aluminum and lithium.
- the compounds of the present invention may exist in a continuum of solid states ranging from completely amorphous to completely crystalline.
- amorphous refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically, such materials do not give a distinct X-ray diffraction pattern and, while displaying solid properties, are more formally described as liquids.
- a change occurs from solid to liquid properties, characterized by a change of state, usually secondary ("glass transition").
- crystal refers to a solid phase in which the material has a regularly ordered internal structure at the molecular level and gives a defined peak unique X-ray diffraction pattern. Such materials will also behave like a liquid when heated sufficiently, but the change from solid to liquid is characterized by a phase transition, usually first order ("melting point").
- polymorph refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.
- solvate refers to a combination or complex of one or more solvent molecules with a compound of the invention.
- solvate-forming solvents include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.
- the compounds of the present invention can exist in unsolvated form or in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., so the present invention will include solvated and unsolvated forms.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- isotope has the same atomic number but an atomic mass or mass number different from that which predominates in nature. The atomic mass or mass number present.
- compounds can be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or C-14 (14C). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- Isotopic variants may offer certain therapeutic advantages, such as deuterium enrichment that can increase in vivo half-life or reduce dosage requirements, or may provide standard compounds that can be used for characterization of biological samples. Preparations may be made without undue experimentation by routine techniques well known to those skilled in the art, or by methods similar to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and/or intermediates. Isotopically enriched compounds within formula (1).
- the R 2 is selected from H, halogen, OH, C1-C6 alkoxy or CN; preferably, the R 2 is preferably H or halogen, more preferably H or F.
- the R 3 is selected from H, substituted or unsubstituted linear or branched C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl.
- the C1-C6 alkyl group can be a straight chain or a branched chain.
- Exemplary C1-C6 alkyl groups include methyl, ethyl, n-propyl (1-propyl), isopropyl (2-propyl, 1-methylethyl), n-butyl (1-butyl), sec-butyl (2-butyl, 1-methylpropyl), isobutyl (2-methyl Propyl) or Fe/F-butyl (1,1-dimethylethyl).
- One or more hydrogen atoms on the above-mentioned alkyl group can be substituted by methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, bromine, etc. replaced by base.
- cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group.
- exemplary C3-C5 cycloalkyl groups include cyclopropyl, cyclobutyl or cyclopentyl.
- exemplary C3-C6 cycloalkyl groups include 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methyl cyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl or 3-methylcyclopentyl.
- One or more hydrogen atoms on the above-mentioned cycloalkyl group can be replaced by methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, bromine, etc. substituted by substituents.
- alkoxy refers to an alkyloxy group.
- exemplary C1-C6 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , sec-butoxy, etc.
- One or more hydrogen atoms on the above-mentioned alkoxy group can be replaced by methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, bromine, etc. substituted by substituents.
- R 3 is selected from linear or branched C1-C6 alkyl, C1-C6 alkoxy, more preferably C2-C4 alkyl, more preferably ethyl or isopropyl .
- the R 1 is a fused group of a benzene ring and a heterocyclic ring
- the heterocyclic ring refers to a saturated or partially unsaturated monocyclic or polycyclic group with heteroatoms, and the heteroatoms are N, O or S.
- the two heterocycles are independently 3-7 membered saturated or partially unsaturated monocyclic or polycyclic groups containing 1-3 ring heteroatoms selected from N, O or S.
- S and O can be -SO or SO 2 exists.
- the heterocyclic ring forming the fused group represented by R1 is a 5-7 membered saturated or unsaturated ring containing 1-3 ring heteroatoms selected from N, O or S. Saturated monocyclic or bicyclic groups. More preferably, the heterocyclic ring is a 5-6 membered saturated or unsaturated monocyclic group containing 1, 2 or 3 ring heteroatoms selected from N and/or O, and more preferably it contains only N Or a heterocyclic ring containing both N and O as heteroatoms.
- the R 1 has the structure shown in the following formula (M):
- n 1, 2 or 3
- the A ring refers to a 5-7 membered saturated or partially unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, O or S.
- the A ring refers to a 5-7 membered saturated or partially unsaturated monocyclic ring containing at least one heteroatom selected from N, O or S; m is 1, 2 or 3, n is 1 or 2, Indicates the connection site.
- R 1 passed Connected to the phenyl group of the compound of formula (1).
- R 4 or R 5 is a substituent on the heterocyclic ring, which can be connected to a heteroatom or a carbon atom.
- the A ring is a 5-6 membered saturated or unsaturated monocyclic group containing 1-3 heteroatoms selected from at least one of N, O or S; specifically, when the When R 1 has the structure shown in formula (M), said R 1 has the structure shown in the following (a)-(e):
- the A ring when the R 1 has a structure shown in formula (M), the A ring can be selected from the following structures:
- the R 1 has the structure shown in the following formula (N):
- the A ring can be selected from the following structures:
- the R 4 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; the above groups can be optionally unsubstituted or mutually exclusive. 1-4 independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogenated C 1 -C 3 alkoxy substituted by at least one of the radicals.
- the R 4 is selected from hydrogen, C1-C3 alkyl or C1-C3 alkoxy; the above groups may be optionally unsubstituted or independently substituted by C1-C3 alkoxy or halogen.
- the R 4 is selected from methoxy C1-C3 alkyl or C1-C3 alkoxy; more preferably, it is methoxymethyl or methoxy.
- the heteroatom is selected from N, O or S.
- the R 5 is selected from hydrogen, halogen, hydroxyl, oxo, C1-C6 alkyl acyl, C1-C6 alkylamido, C1-C6 alkoxy imino, C1-C6 alkyl, C3-C6 ring Alkyl group, C1-C6 alkoxy group, C6-C10 aryl group, 5-7 membered heteroaryl group containing 1-3 heteroatoms or C3-C7 non-aromatic heteroaryl group containing 1-3 heteroatoms Ring; the above-mentioned groups are optionally unsubstituted or independently substituted by 1-4 C1-C3 alkyl groups respectively selected from halogen, hydroxyl, oxo, C1-C4 acyl, C1-C3 alkyl, and halogen. Substituted with at least one of C1-C3 alkoxy, halogenated C1-C3 alkoxy or sulfonyl.
- the R 5 is selected from hydrogen, halogen, oxo, C1-C3 alkyl acyl, C1-C3 alkylamido, C1-C3 alkoxy imino, C1-C3 alkyl, C3 -C4 cycloalkyl, C1-C3 alkoxy, C6-C8 aryl, 5-6 membered heteroaryl containing 1-2 heteroatoms or C4-C6 non-aromatic containing 1-2 heteroatoms Family heterocycle; the above groups are optionally unsubstituted or independently substituted by 1-2 C1-C3 alkyls selected from halogen, hydroxyl, oxo, C1-C3 acyl, C1-C3 alkyl, and halogen. Substituted with at least one of alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy or sulfonyl.
- the R 5 is selected from: H, oxo, methyl, ethyl, isopropyl, acetyl, methylmethoxy, ethyl Methoxy, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylamino, phenyl, or
- R 1 is selected from any one of the following structures:
- the R 4 is selected from H, C1-C3 alkoxy, or substituted or unsubstituted methoxy C1-C3 alkyl; preferably H, methylmethoxy, ethylmethoxy, methoxy or difluoromethoxy;
- the R 5 is selected from H, methyl, ethyl, acetyl, ethylmethoxy, methylmethoxy, methylcyclopropyl, phenyl, or
- the compound is selected from any one of the compounds in Table 1 below.
- the present invention also provides a pharmaceutical mixture, which contains two or more compounds selected from the following group: the compounds described in any one of the present invention or their stereoisomers and tautomers , prodrugs, pharmaceutically acceptable salts, amorphous substances, isotopomers, polymorphs or solvates.
- the present invention also provides a pharmaceutical composition, which contains the compound according to any one of the present invention or its stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous substance, At least one of isotopes, polymorphs or solvates, and optionally adding pharmaceutically acceptable carriers and/or auxiliaries.
- the compound of any one of the present invention or its stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous substance, polymorph, solvate, and the drug The mixture, or the use of the pharmaceutical composition in the preparation of a medicament for treating or preventing diseases related to GABA A receptors.
- the disease related to GABA A receptors is selected from at least one of the following: pain, Alzheimer's disease, multi-infarct dementia and stroke.
- the pain is neuropathic pain, inflammatory pain and cancer pain.
- the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, low back pain, Lower limb pain, musculoskeletal pain, vascular pain, gout, arthritic pain, visceral pain, pain due to infectious diseases, bony pain, sickle cell anemia, autoimmune diseases, pain related to multiple sclerosis or inflammation, injuries or chronic pain caused by surgery, nociceptive pain, diabetic pain, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, Pain related to cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infections, or degenerative osteoarthritis.
- the present invention also provides a method for treating or preventing diseases related to GABA A receptors, which involves administering to the patient an effective dose of the compound of any one of the present invention or its stereoisomers, tautomers, and precursors. body drugs, pharmaceutically acceptable salts, amorphous substances, polymorphs, solvates, said pharmaceutical mixtures, or said pharmaceutical compositions.
- the present invention also provides a method for treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke, by administering to the patient an effective dose of a compound according to any one of the present invention or a stereoisomer thereof, Tautomers, prodrugs, pharmaceutically acceptable salts, amorphous substances, polymorphs, solvates, said pharmaceutical mixtures, or said pharmaceutical compositions.
- the compound of formula (1) and its intermediate products can be prepared according to similar methods or according to the aforementioned methods.
- Starting materials known in the art may be obtained commercially or may be prepared according to methods known in the art or analogous to known methods.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier and/or auxiliary agent.
- the present invention also includes the use of the compounds or compositions as described above for the preparation of medicaments for the treatment or prevention of diseases related to ⁇ 2/3-GABA A receptors, especially the treatment or prevention of the following diseases: pain, epilepsy, Anxiety, itching, and depression.
- Pain is preferably treated or prevented.
- cancer pain refers to the pain that occurs during the development of malignant tumors. It is currently believed that there are three mechanisms for the occurrence of cancer pain, namely: pain caused directly by the development of cancer, pain caused after cancer treatment, and pain caused by cancer patients. Comorbid painful diseases.
- neurode pain is pain triggered or caused by primary damage and dysfunction of the nervous system.
- inflammatory pain is pain caused by local acute inflammation or chronic inflammation that stimulates nerves.
- treatment also includes prophylactic administration that alleviates or eliminates a condition once it has been established.
- a "patient” is defined as any warm-blooded animal, such as, but not limited to, a mouse, guinea pig, dog, horse, or human, preferably the patient is a human.
- acute pain is defined as pain caused by injury to the skin, body structures, or internal organs and/or noxious stimulation by the occurrence of disease, or pain caused by abnormal function of muscles or internal organs without actual tissue damage .
- chronic pain is defined as pain that persists beyond the usual course of the acute illness or a reasonable period of time for healing of the injury, or is associated with a chronic pathological process that causes persistent pain, or pain that recurs at regular intervals over months or years, if it should Pain that persists after healing has been achieved or beyond the usual course of treatment is considered chronic pain. The length of time the pain takes depends on the nature of the pain and the course of treatment associated with the pain. If the pain lasts longer than the usual course of treatment, the pain is chronic.
- Chronic pain includes, but is not limited to, headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, low back pain, lower extremity pain, musculoskeletal pain, pain associated with somatic disorders, visceral pain, and painful diabetes Sexual neuropathy, vascular pain, gout, arthritic pain, cancer pain, autonomic reflex pain, pain caused by infectious diseases (such as AIDS and herpes zoster), pain caused by autoimmune diseases (rheumatism), acute and chronic Pain due to inflammation, post-operative pain, and post-burn pain.
- infectious diseases such as AIDS and herpes zoster
- rheumatism rheumatism
- the medicines disclosed in the present invention can effectively treat chronic pain as defined above, and the medicines disclosed in the present invention can be used to treat pain sensitivity associated with other diseases, including hyperalgesia, allodynia, enhanced pain perception and enhanced pain memory.
- the invention will improve Treatment of its pain.
- headache can be divided into primary headaches, which include tension headaches, migraines, and cluster headaches, and secondary headaches, which are caused by other conditions.
- primary headaches which include tension headaches, migraines, and cluster headaches
- secondary headaches which are caused by other conditions.
- the pain-sensitive tissues of the head and face become diseased or irritated, they can cause various headaches. These pain-sensitive tissues are distributed in the scalp, face, mouth, and throat. Because they are mainly muscles or blood vessels of the head, they contain rich nerves. Fibers are more sensitive to pain, so when these tissues are injured they can cause headaches.
- facial pain includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial palsy, and hemifacial spasm.
- Trigeminal neuralgia is a unique chronic pain disease, also known as painful convulsions, which refers to the occurrence of brief, paroxysmal and recurring electric shock-like severe pain in the distribution area of the trigeminal nerve. Or accompanied by ipsilateral facial muscle spasm. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia means that no neurological signs are found clinically, and no organic disease is found in examination; secondary trigeminal neuralgia means that clinically There are neurological signs, and organic lesions such as tumors and inflammation are found on examination. Disease, etc.
- atypical facial pain refers to pain resulting from a variety of etiologies. It manifests as persistent burning pain that is non-intermittent and has nothing to do with special movements or triggering stimuli. The pain is mostly bilateral and often extends beyond the distribution range of the trigeminal nerve and even involves the skin of the neck. The cause can be caused by sinusitis, malignant tumors, jaw and skull base infections, etc. that may stimulate or damage the trigeminal nerve and cause pain.
- neck pain, back pain, and shoulder pain refers to pain caused by acute and chronic muscle strain, degeneration of bones and joints, and trauma.
- Common diseases that cause neck, shoulder and upper limb pain include cervicofacial myofasciitis, nuchal ligamentitis, cervical spondylosis, frozen shoulder, thoracic outlet syndrome, lateral epicondylitis, etc., or pain caused by autoimmune diseases.
- diseases such as rheumatoid arthritis, ankylosing spondylitis, and rheumatoid arthritis.
- Other diseases that may cause neck pain, back pain, and shoulder pain include neck and shoulder tumors, neuritis, arteriovenous diseases, and various diseases. infections and referred pain caused by thoracic and abdominal organ lesions.
- chest, abdominal and back pain refers to pain caused by diseases of the thoracic and abdominal viscera and thoracic and abdominal wall tissues, including but not limited to intercostal neuralgia, intercostal chondritis, angina, and abdominal pain (acute abdominal visceral pain) and low back myofascial syndrome.
- lumbar and lower extremity pain refers to pain in the lower back, lumbosacral, sacroiliac, hip, buttocks, and lower extremities. Pain in the waist and lower limbs is often not an independent disease, but a common feature of many diseases. The clinical manifestations are diverse and the causes are very complex. Degeneration and injury are the most common, including but not limited to lumbar disc herniation, acute lumbar sprain, and sciatica. , osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, tail pain and heel pain.
- muscle pain includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndrome.
- ⁇ pain caused by nerve damage complicating diabetes, which is caused at least in part by reduced blood flow and high blood sugar. Some patients with diabetes do not develop neuropathy, while others develop the disease early. Diabetic neuropathy pain can be divided into mononeuropathies involving one or more focal sites and generalized polyneuropathies, which can be diffuse and symmetrical. , usually primarily involving sensory modalities (Merrit's Textbook of Neurology, 9th ed., edited by LPRowland LP). Manifestations of diabetic neuropathy can include autonomic dysfunction, resulting in regulatory disorders including those of the heart, smooth muscles, and glands, causing hypotension, diarrhea, constipation, and sexual impotence.
- Diabetic neuropathy often develops in stages. In the early stage, it occurs in the nerve ending area. Autonomic neuropathy or sensory neuropathy occurs in the feet. Cranial neuropathy occurs in the face and around the eyes. Intermittent pain and tingling occur in subsequent stages. Pain is stronger and occurs more often, and finally, when pain sensation is lost in a certain area, painless neuropathy occurs, which greatly increases the risk of severe tissue damage since there is no pain as an indicator of damage.
- visceral pain includes, but is not limited to, irritable bowel syndrome (IBS), pain with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis .
- IBS irritable bowel syndrome
- CFS chronic fatigue syndrome
- IBD inflammatory bowel disease
- interstitial cystitis interstitial cystitis
- vascular pain is pain resulting from one or more of the following factors.
- Examples include, but are not limited to, arteriosclerosis obliterans, thromboangiitis obliterans, acute arterial occlusion, embolism, congenital arteriovenous aneurysm, vasospastic disease, Rayaud's disease, acrocyanosis, acute venous occlusion, thrombophlebitis, varicose veins and lymphedema.
- autonomic reflex pain refers to pain resulting from “reflex sympathetic atrophy”.
- Reflex sympathetic atrophy sign refers to severe spontaneous pain after the body suffers acute or chronic injury, hypersensitivity to touch and pain, and may be accompanied by edema and blood circulation disorder. Symptoms such as nutritional disorders and atrophy of skin and musculoskeletal may subsequently occur.
- postoperative pain refers to a complex physiological response of the body to tissue damage caused by the disease itself and surgery, which manifests itself as an unpleasant psychological and behavioral experience.
- arthritic pain includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendonitis, bursa Pain caused by diseases such as inflammation, bone damage, and joint soft tissue inflammation.
- postherpetic neuralgia refers to severe pain that persists under the skin in the area of the original rash after the shingles rash has healed.
- nociceptive pain is pain caused by tissue damaging processes that stimulate nociceptor afferents, or pain caused by prolonged excitation of nociceptors. Pain caused by prolonged excitation of nociceptors can be due to persistent noxious stimulation of nociceptors or their sensitization or both, or they can be caused by these factors and caused by their persistence, various reflex mechanisms, and other factors And extended.
- the present invention provides the use of pharmaceutical compounds containing a therapeutically effective amount of ⁇ 2/3-GABA A positive allosteric modulator.
- the therapeutic ⁇ 2/3-GABA A positive allosteric modulator may be administered as a raw compound, but preferably the active ingredient, optionally in the form of a physiologically acceptable salt, together with one or more additives, Excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients are mixed together to form pharmaceutical compositions.
- the present invention provides a pharmaceutical composition containing an ⁇ 2/3-GABA A positive allosteric modulator, wherein the ⁇ 2/3-GABA A positive allosteric modulator is combined with one or more pharmaceutically acceptable Received carrier, and optionally mixed with other therapeutic and/or prophylactic components known or used in the art.
- the carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the compounds used in the present invention can therefore be formulated into pharmaceutical compositions and unit dosage forms thereof together with conventional additives, or diluents.
- Such forms include solids (especially tablets, filled capsules, powders and pill forms), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all oral Forms of administration: suppositories for rectal administration, and sterile injectable solutions for parenteral administration.
- Pharmaceutical compositions such as these and unit dosage forms thereof may contain the conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable active ingredient commensurate with the desired daily application dosage range. amount of active ingredient.
- the compounds used in the present invention can be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
- pharmaceutically acceptable carriers may be solid or liquid.
- Solid form preparations include powders, tablets, tablets, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.
- the carrier is a finely divided solid which is mixed with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary binding properties in appropriate proportions and compressed into the desired shape and size.
- Powders and tablets preferably contain from 5% or 10% to about 70% active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point waxes , cocoa butter, etc.
- the term "preparation" includes active compounds formulated with encapsulating materials as carriers which provide encapsulations in which the active ingredient, with or without carriers, is surrounded by such carriers so as to be associated therewith.
- formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets and lozenges may be used as solid forms suitable for oral administration.
- a low-melting wax such as a slurry of fatty acid glycerides or cocoa butter
- the active ingredient is then uniformly dispersed therein by stirring.
- This molten homogeneous mixture is then poured into appropriately sized molds and allowed to cool and thereby solidify.
- compositions suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, suitable carriers known in the art. .
- Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions.
- liquid preparations for parenteral injection may be formulated as water-polyethylene glycol solutions.
- the compounds used in the present invention may therefore be formulated for parenteral administration (eg injection, such as bolus injection or continuous infusion), and may be presented in unit dose form in ampoules, preservatives, with an added preservative. In filled syringes, small volume infusion bags, or in multi-dose containers.
- the compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation ingredients such as suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form, which may be obtained by aseptic isolation from a sterile solid or by lyophilization from a solution for constitution with a suitable vehicle, such as sterile, pyrogen-free water, before use.
- Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the desired coloring, flavoring, stabilizing and thickening agents.
- Aqueous suspensions suitable for oral administration may be prepared by dispersing the finely divided active ingredient in a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending substances. prepared in water.
- a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending substances. prepared in water.
- liquid dosage forms designed for conversion shortly before use to liquid dosage forms for oral administration.
- Such liquid preparations include solutions, suspensions and emulsions.
- such preparations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.
- the compounds of the invention may be formulated as ointments, creams or lotions or as transdermal patches.
- ointments and creams may be formulated with an aqueous or oily base plus suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and often also contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents, or coloring agents.
- compositions suitable for topical administration to the oral cavity include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia gum or tragacanth; in an inert base such as gelatin and glycerol or sucrose and acacia gum. tablets (pastiules) containing the active ingredient; and mouthwashes containing the active ingredient in a suitable liquid carrier.
- Solutions or suspensions may be applied directly to the nasal cavity by conventional methods, such as with a dropper, pipette or spray.
- the composition can be a single dose or multi-dose form.
- Administration to the respiratory tract may also be achieved by aerosols in which the active ingredient is contained in a pressurized package with a suitable propellant including chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane Methane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. Aerosols may also suitably contain surfactants such as lecithin.
- the dose of the drug can be controlled by a metering valve.
- the active ingredient may be in the form of a dry powder, for example a powder mixture of the compound with a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP).
- a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the powder carrier allows for easy gel formation in the nasal cavity.
- Powder compositions may be presented in unit dose form, for example in capsules or cartridges (eg, gelatin capsules or cartridges), or in blister packs in which the powder may be administered via an inhaler.
- compositions for administration to the respiratory tract typically the compounds will have a small particle size, for example on the order of 5 microns or less.
- particle sizes can be obtained using methods known in the art, such as by micronization.
- compositions suitable for sustained release of the active ingredient may be used.
- compositions are preferably in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient.
- the unit dosage form may be an encapsulated preparation containing discrete quantities of the preparation in sealed packages, such as encapsulated tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form may be a capsule, tablet, tablet, or lozenge itself, or it may be an appropriate quantity of any of the above capsules, tablets, or the like in encapsulated form.
- Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
- the amount of active ingredient in a unit dose formulation may vary depending on the specific application and the potency of the active ingredient, and may be adjusted from 0.01 mg to about 0.1 g.
- the drug may be administered in capsules of 0.01 to about 100 mg three times a day, and the composition may also contain other compatible therapeutic agents if necessary.
- the compounds used in the present invention are used at starting doses of 0.001 mg/kg to 10 mg/kg body weight per day.
- these dosages may vary depending on the needs of the patient, the severity of the condition being treated, and the compound used.
- treatment is initiated with smaller doses that are less than the optimal dose of the compound and thereafter the dosage is increased in small increments to the maximum dose.
- the total daily dose can be subdivided into divided doses throughout the day if necessary.
- the pharmaceutical composition of the present invention can also be used in combination with other drugs for treating pain, epilepsy, anxiety and depression, including but not limited to morphine, gabapentin, etc. Therefore, the present invention provides a drug for treating pain, epilepsy, anxiety and depression, which is not only effective but also has no obvious side effects.
- Another object of the present invention is to provide a drug for special patient groups, such as the elderly, A highly safe drug for patients with liver or kidney function decline, or cardiovascular disease.
- the present invention also provides a method for treating or preventing diseases, which involves administering an effective dose of a compound or composition as described above to a patient.
- the present invention also provides a method for treating or preventing diseases related to GABA A receptors, which involves administering an effective dose of a compound as described above or a composition as described above to a patient.
- the present invention also provides the use of a compound or composition as described above in the preparation of a medicament for the treatment or prevention of the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke.
- the pain described is neuropathic pain, inflammatory pain and cancer pain.
- the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, low back pain, lower limb pain, muscle and bone pain, vascular pain, gout, arthritis pain, visceral pain Pain, pain due to infectious diseases, bony pain, sickle cell anemia, autoimmune diseases, pain related to multiple sclerosis or inflammation, chronic pain due to injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia , lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infection, or degenerative bone Arthropathy-related pain.
- the present invention also provides a method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke by administering to a patient an effective dose of a compound as described or a composition as described above.
- the present invention also relates to a method for preparing the imidazopyridazine-substituted benzene ring compound represented by formula (1) as described above, which includes:
- R3 is ethyl or isopropyl and the experimental operations are the same.
- the compounds of the present invention and their pharmaceutically acceptable salts or prodrugs have important pharmacological properties and are ⁇ 2/3-GABA A receptor positive allosteric modulators.
- the compound of the present invention has excellent affinity activity and positive regulatory activity for ⁇ 2/3-GABA A receptor, and has good genotoxic safety and druggability. Therefore, the compounds of the present invention and their pharmaceutically acceptable salts or prodrugs thereof can be used alone Used or combined with other drugs for the treatment or prevention of diseases related to ⁇ 2/3-GABA A.
- the solvent ratio used in the purification steps is a volume ratio.
- the experimental operation is the same as Example 1, with 5-bromo-4-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2, 3] Triazole (70 mg, 0.22 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (75 mg, 0.26 mmol) as raw material to obtain the title compound (65 mg, 61%).
- the experimental operation is the same as in Example 1, with 8-bromo-7-methoxy-4-methyl-3,4-dihydrobenzo[f][1,4]oxaza-5(2H)-one ( 100mg, 0.35mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (100mg, 0.35mmol) as raw material, The title compound (25 mg, 16%) was obtained as an off-white solid.
- Example 4 The experimental operation is the same as in Example 4, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (100mg, 0.35mmol), 6-bromo-7-methoxy-3-methylbenzo[d]oxazole-2(3H )-ketone (90 mg, 0.35 mmol) was used as starting material to obtain the title compound (10 mg, 7%) as a white solid.
- Example 8 The experimental operation is the same as in Example 1, with 7-bromo-2-ethyl-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one ( 2.0g, 6.7mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (1.9g, 6.7mmol) is Starting material, the title compound (1.0 g, 33%) was obtained as an off-white solid. After further chiral resolution, Example 8 (first peak, 10 mg, white solid) and Example 9 (second peak, 10 mg, white solid) were obtained.
- LC-MS: m/z[M+1] + 462.
- LC-MS: m/z[M+1] + 462.
- the experimental operation was the same as Example 1, with 5-bromo-1-ethyl-4-(methoxymethyl)-1H-benzo[d][1,2,3]triazole (1100 mg, 4.07 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (932 mg, 3.26 mmol) was used as raw material to obtain the title compound as a white solid ( 545 mg, 31%).
- the experimental operation was the same as Example 1, with 6-bromo-5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)benzo[d]oxazole-2(3H)-one (68 mg ,0.2mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl )-7H-imidazo[4,5-c]pyridazine (75 mg, 0.2 mmol) was used as raw material to obtain the title compound (30 mg, 33%).
- Example 2 The experimental operation is the same as Example 1, using 7-chloro-8-methoxy-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4] Oxazin-1-one (50 mg, 0.2 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (112 mg ,0.4mmol) as raw material to obtain the title compound (10mg, 11%).
- the experimental operation is the same as in Example 1, using 7-bromo-6-methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4 ]oxazin-3(4H)-one (130mg, 0.17mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (130 mg, 0.35 mmol) was used as starting material to obtain the title compound (100 mg, 54%).
- the experimental operation is the same as in Example 1, with 7-bromo-6-methoxy-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazine -3(4H)-one (100mg, 0.28mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (100 mg, 0.28 mmol) was used as raw material to obtain the title compound (46 mg, 32%).
- the experimental operation is the same as in Example 7, with 7-bromo-6-methoxy-4-(2-morpholino)-2H-benzo[b][1,4]oxazin-3(4H)-one (80mg, 0.22mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) -7H-imidazo[4,5-c]pyridazine (100 mg, 0.27 mmol) was used as raw material to obtain the title compound (35 mg, 24%).
- Example 2 The experimental operation is the same as Example 1, using 7-bromo-4-(2,2-difluoroethyl)-6-methoxy-2H-benzo[b][1,4]oxazine-3(4H) -one (92 mg, 0.29 mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- (base)phenyl)-7H-imidazo[4,5-c]pyridazine (90 mg, 0.24 mmol) was used as raw material to obtain the title compound (70 mg, 63%).
- 6-Bromo-5-(methoxymethyl)benzo[d]oxazol-2(3H)-one (431 mg, 1.67 mmol) was suspended in a solution of dimethyl sulfoxide (10.0 mL). Add methyl iodide (3.1 mL, 50.1 mmol) and potassium carbonate (461.1 mg, 3.34 mmol) at room temperature, and react at room temperature for 16 hours. After adding water (100 mL) to quench, extract with ethyl acetate (50 mLx3), and then Wash once with saturated brine (50 mL) and spin dry to obtain a crude product. After HPLC preparative purification, the title product (267.7 mg, white solid) was obtained with a yield of 59%.
- the experimental operation is the same as in Example 7, with 7-bromo-4-(2-(dimethylamino)ethyl)-6-methoxy-2H-benzo[b][1,4]oxazine-3( 4H)-one (150 mg, 0.38 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (140 mg, 0.38 mmol) was used as raw material to obtain the title compound (120 mg, 56%).
- the experimental operation is the same as in Example 7, with 7-bromo-4-(2-(dimethylamino)ethyl)-6-methoxy-2H-benzo[b][1,4]oxazine-3( 4H)-one (120 mg, 0.36 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (133 mg, 0.36 mmol) was used as raw material to obtain the title compound (24 mg, 14%) as a white solid.
- the experimental operation is the same as in Example 7, with 7-bromo-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazine-3(4H)- Ketone (60 mg, 0.22 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) )-phenyl)-7H-imidazo[4,5-c]pyridazine (81 mg, 0.22 mmol) was used as raw material to obtain the title compound (10 mg, 10%) as a yellow solid.
- Example 7 The experimental operation was the same as Example 7, with 7-bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.39 mmol), 7-ethyl -4-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4, 5-c]pyridazine (144 mg, 0.39 mmol) was used as raw material to obtain the title compound (68 mg, 42%).
- the experimental operation is the same as in Example 1, using 7-bromo-6-methoxy-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H) -one (97 mg, 0.32 mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- (100 mg, 0.27 mmol) was used as raw material to obtain the title compound (57 mg, 46%).
- the experimental operation was the same as Example 1, with 2-(5-bromo-6-ethoxypyridin-2-yl)-5-methyl-1,3,4-oxadiazole (92 mg, 0.32 mmol) and 7- Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[ 4,5-c]pyridazine (100 mg, 0.27 mmol) was used as raw material to obtain the title compound (60 mg, 50%).
- the experimental operation is the same as in Example 1, with 7-bromo-4-cyclobutyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.32 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)- 7H-Imidazo[4,5-c]pyridazine (117 mg, 0.32 mmol) was used as raw material to obtain the title compound (17 mg, 11%) as a yellow solid.
- the experimental operation was the same as Example 1, with 6-bromo-5-methoxy-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one (70 mg, 0.23 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl-7H-imidazo [4,5-c]pyridazine (66.28 mg, 0.23 mmol) was used as raw material to obtain the title compound (43 mg, yield 40%).
- the experimental operation is the same as in Example 7, with 7-bromo-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazine-3(4H)- Ketone (200 mg, 0.70 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) )-phenyl)-7H-imidazo[4,5-c]pyridazine (258 mg, 0.70 mmol) was used as raw material to obtain the title compound (72 mg, 23%) as a yellow solid.
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (120mg, 0.33mmol), 6-bromo-3-ethyl-5-methoxybenzo[d]thiazole-2(3H) - Ketone (100 mg, 0.33 mmol) was used as starting material to obtain the title compound (16 mg, 11%) as a white solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (129mg, 0.35mmol), 6-bromo-5-methoxy-3-(2-methoxyethyl)benzo[d ] Thiazol-2(3H)-one (110 mg, 0.35 mmol) was used as raw material to obtain the title compound (125 mg, 74%) as a white solid.
- 6-bromo-5-methoxybenzo[d]oxazol-2(3H)-one 100 mg, 0.4 mmol was dissolved in N-methylpyrrolidone (10 mL).
- sodium cyanide 40 mg, 1.0 mmol
- 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (200mg, 0.82mmol) was added to dimethyl sulfoxide (20mL), and iodomethane (1.53mL, 24.59mmol) was added.
- Cesium carbonate (534 mg, 1.64 mmol), stirred at 80°C for 3 hours.
- Example 2 The experimental operation was the same as Example 1, with 7-bromo-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (151 mg, 0.55 mmol) and 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H -Imidazo[4,5-c]pyridazine (141 mg, 0.37 mmol) was used as raw material to obtain the title compound (140 mg, 85%).
- the experimental operation was the same as Example 1, with 5-bromo-4-methoxy-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (120 mg, 0.43 mmol), 7-ethyl-4 -(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5- c] Pyridazine (158 mg, 0.43 mmol) was used as raw material to obtain the title compound (40 mg, 21%) as a white solid.
- Example 2 The experimental operation is the same as in Example 1, with ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (100mg, 0.27mmol) and 5-bromo-2-(trifluoromethyl)quinoline (74mg, 0.27mmol) as raw materials to obtain the title
- the compound was a white solid (68 mg, 55.31%).
- Example 40 and Example 41 were obtained by SFC chiral resolution.
- Example 40 The title product (7.2 mg, white solid, second peak) was obtained.
- Example 41 The title product (6.2 mg, white solid, first peak) was obtained.
- LC-MS: m/z[M+H] + 500.
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -(yl)phenyl)-7H-imidazo[4,5-c]pyridazine (70mg, 0.19mmol), 6-bromo-5-methoxy-2,3-dimethylbenzo[b]thiophene (103 mg, 0.19 mmol) was used as raw material to obtain the title compound as a white solid (11 mg, 13%).
- the experimental operation is the same as the synthesis method of 40-1 in Example 40, using 4-((5-bromo-4-methoxy-2-nitrobenzylidene)amino)-3,3-difluoropiperidine- 1-tert-butylcarboxylate (950 mg, 2.0 mmol) was used as raw material to obtain the title compound as a blue-brown solid (500 mg, yield 56%).
- LC-MS: m/z[M+H] + 446.
- Example 46 rel-(S)-4-(3-(2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole-5 -base)-4-fluorophenyl)-7-ethyl Base-7H-imidazo[4,5-c]pyridazine
- Example 46 The title compound (275 mg, first peak) was obtained.
- LC-MS: m/z[M+H] + 522.
- Example 47 The title compound (273 mg, second peak) was obtained.
- LC-MS:m/z[M +H] + 522.
- LC-MS:m/z[M+H] + 241,243 .
- LC-MS:m/z[M+H] + 241,243 .
- the experimental operation was the same as in Example 1, with 5-bromo-6-methoxy-2-methyl-2H-indazole (52 mg, 0.22 mmol) and 4-(4-fluoro-3-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (68.8mg, 0.18 mmol) as raw material to obtain the title compound (45 mg, 60%).
- the experimental operation was the same as in Example 1, with 5-bromo-1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazole (58mg, 0.22mmol) and 4-( 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[ 4,5-c]pyridazine (68.8 mg, 0.18 mmol) was used as raw material to obtain the title compound (45 mg, 60%).
- 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one 500mg, 2.05mmol
- copper acetate 102mg, 0.51mmol
- 1,10-phenanthroline 56mg, 0.15mmol
- potassium carbonate 566mg, 4.10mmol
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (220mg, 0.6mmol), 6-bromo-5-methoxy-3-methylbenzo[d]thiazole-2(3H) - Ketone (160 mg, 0.6 mmol) was used as starting material to obtain the title compound (118 mg, 45%) as a white solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (136mg, 0.37mmol), 6-bromo-7-methoxy-1-methylquinolin-2(1H)-one (99mg ,0.37mmol) as raw material to obtain the title compound (90mg, 57%) as a white solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (129mg, 0.35mmol), 5-bromo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl) -1H-indazole (110 mg, 0.35 mmol) was used as raw material to obtain the title compound (50 mg, 30%) as a white solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )Phenyl)-7H-imidazo[4,5-c]pyridazine (77mg, 0.21mmol), (6-bromo-5-methoxy-3-methylbenzofuran-2-yl) (pyrrole Alk-1-yl)methanone (70 mg, 0.21 mmol) was used as starting material to obtain the title compound (15 mg, 14%) as a white solid.
- the experimental operation was the same as in Example 1, with 5-bromo-1-(ethylsulfonyl)-6-methoxyindoline (40 mg, 0.125 mmol), 7-ethyl-4-(4-fluoro-3 -(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (46mg, 0.125 mmol) as starting material to obtain the title compound (20 mg, 33%).
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )Phenyl)-7H-imidazo[4,5-c]pyridazine (78mg, 0.21mmol), 6-bromo-2-ethyl-7-methoxyisoquinolin-1(2H)-one ( 60 mg, 0.21 mmol) as starting material to obtain the title compound (50 mg, 54%) as a white solid.
- the experimental operation is the same as the synthesis method of 40-1 and 40-2 in Example 40, using 5-bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol), tert-butyl (3S, 4R )-4-amino-3-fluoroperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.29 mmol) was used as raw material to obtain the title compound (250 mg, 51%) as a light yellow oily liquid.
- LC-MS: m/z[M+H] + 428,430.
- the experimental operation was the same as Example 1, with 5-bromo-2-((3S, 4R)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (150 mg, 0.439mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) -7H-imidazo[4,5-c]pyridazine (162 mg, 0.439 mmol) was used as raw material to obtain the title compound (18 mg, 8%) as a brown solid.
- the experimental operation is the same as the synthesis method of 40-1 and 40-2 in Example 40, with 5-bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol), tert-butyl (3S, 4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (500mg, 2.29mmol) was used as raw material to obtain the title compound as a light yellow oily liquid (280mg, 57% ).
- LC-MS: m/z[M+H] + 428,430.
- the experimental operation was the same as Example 1, with 5-bromo-2-((3S, 4S)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (170 mg, 0.497mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) -7H-Imidazo[4,5-c]pyridazine (183 mg, 0.497 mmol) was used as raw material to obtain the title compound (89 mg, 36%) as an off-white solid.
- the experimental operation is the same as the synthesis method of 40-1 and 40-2 in Example 40, using 5-bromo-4-methoxy-2-nitrobenzaldehyde (500 mg, 1.92 mmol), tert-butyl (3S, 4R )-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (783 mg, 3.84 mmol) was used as raw material to obtain the title compound (760 mg, 95%) as a light yellow oily liquid.
- LC-MS: m/z[M+H] + 414,416.
- the experimental operation was the same as Example 1, with 5-bromo-2-((3S, 4R)-4-fluoro-1-methylpyrrolidin-3-yl)-6-methoxy-2H-indazole (150 mg, 0.46mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) -7H-imidazo[4,5-c]pyridazine (169 mg, 0.46 mmol) was used as raw material to obtain the title compound (60 mg, 27%) as a brown solid.
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (72mg, 0.19mmol), 2-(azetidin-1-yl)-6-bromo-5-methoxybenzo [d] Oxazole (55 mg, 0.19 mmol) was used as raw material to obtain the title compound (40 mg, 48%) as a white solid.
- the experimental operation was the same as in Example 1, with 5-bromo-2-(3,3-difluorocyclobutyl)-6-methoxy-2H-indazole (150 mg, 0.475 mmol), 7-ethyl-4- (4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c ] Pyridazine (175 mg, 0.475 mmol) was used as raw material to obtain the title compound (120 mg, 53%) as a white solid.
- the experimental operation was the same as Example 1, with 5-bromo-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)-2H-indazole (50 mg, 0.16 mmol), 7-ethyl Base-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4 ,5-c]pyridazine (59 mg, 0.16 mmol) was used as raw material to obtain the title compound (12 mg, 16%) as a yellow solid.
- 6-Bromo-7-methoxy-1-tosyl-1H-indazole (327mg, 0.858mmol) was added to methanol (6ml), magnesium chips (42mg, 1.716mmol) was added, under argon protection, 0 °C reaction for 3 hours.
- LC-MS: m/z[M+H] + 227,229.
- 6-Bromo-7-methoxy-1H-indazole (135mg, 0.595mmol), methyl iodide (85mg, 0.595mmol), cesium carbonate (395mg, 1.190mmol) were added to N,N-dimethylformamide ( 2ml), react at 25°C for 15 minutes.
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -(yl)phenyl)-7H-imidazo[4,5-c]pyridazine (61mg, 0.166mmol), 6-bromo-7-methoxy-2-methyl-indazole (40mg, 0.166mmol) As raw material, the title compound was obtained as a light yellow solid (25 mg, 37%).
- Example 2 The experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -(yl)phenyl)-7H-imidazo[4,5-c]pyridazine (61mg, 0.166mmol), 6-bromo-7-methoxy-1-methyl-indazole (40mg, 0.166mmol) As raw material, the title compound was obtained as a light yellow solid (14 mg, 21%).
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (100mg, 0.27mmol), 6-bromo-5-methoxy-2-morpholinebenzo[d]oxazole (100mg, 0.27 mmol) as starting material to obtain the title compound (42 mg, 33%) as a brown solid.
- the experimental operation is the same as the synthesis method of 40-1 and 40-2 in Example 40, using 5-bromo-4-methoxy-2-nitrobenzaldehyde (275 mg, 1.06 mmol), 4-amino-3,3 - Difluoropiperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.06 mmol) was used as raw material to obtain the title compound (330 mg, 70%) as a light yellow oily liquid.
- LC-MS: m/z[M+H] + 446,448.
- the experimental operation was the same as Example 1, with 5-bromo-2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (150 mg, 0.42 mmol) ,7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H- Imidazo[4,5-c]pyridazine (155 mg, 0.42 mmol) was used as raw material to obtain the title compound (37 mg, 17%) as an off-white solid.
- the experimental operation was the same as in Example 1, with 4-bromo-2-(difluoromethyl)-5-methoxybenzo[d]oxazole (60 mg, 0.215 mmol) and 7-ethyl-4-(4- Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (67 mg, 0.17 mmol) was used as starting material to obtain the title compound (40 mg, 54%).
- the experimental operation is the same as the synthesis method of 40-1 and 40-2 in Example 40, using 5-bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol), 4-amino-3-fluoro Piperidine-1-carboxylic acid tert-butyl ester (377 mg, 1.73 mmol) was used as raw material to obtain the title compound (400 mg, 81%) as a light yellow oily liquid.
- LC-MS: m/z[M+H] + 428,430.
- Example 46 The experimental operation was the same as in Example 46, the synthesis method of 46-4, using 5-bromo-2-(3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (290 mg, 0.80 mmol) as raw material to obtain the title compound (100 mg, 37%) as a colorless oily liquid.
- LC-MS: m/z[M+H] + 342,346.
- the experimental operation was the same as Example 1, with 5-bromo-2-(3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (100 mg, 0.29 mmol), 7- Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[ 4,5-c]pyridazine (95 mg, 0.29 mmol) was used as raw material to obtain the title compound (68 mg, 46%) as a yellow solid.
- Example 46 The experimental operation is the same as in Example 46, the synthesis method of 46-4, using 5-bromo-6-methoxy-2-(piperidin-4-yl)-2H-indazole hydrochloride (280 mg, 0.81 mmol), and oxetan-3-one (62 mg, 1.62 mmol) was used as raw material to obtain the title compound (170 mg, 58%) as a yellow solid.
- LC-MS: m/z[M+H] + 366,368.
- the experimental operation was the same as Example 1, with 5-bromo-6-methoxy-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazole (70 mg, 0.19 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)- 7H-Imidazo[4,5-c]pyridazine (70 mg, 0.19 mmol) was used as raw material to obtain the title compound (28 mg, 28%) as a white solid.
- the experimental operation was the same as Example 1, with 5-bromo-6-methoxy-2-(1-methyl-1H-imidazol-2-yl)-2H-indazole (50 mg, 0.16 mmol), 7-ethyl -4-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4, 5-c]pyridazine (59 mg, 0.16 mmol) was used as raw material to obtain the title compound (6 mg, 8%) as a yellow solid.
- the experimental operation was the same as Example 1, with 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,5-dimethylisoxazole (200 mg, 0.62 mmol), 7- Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[ 4,5-c]pyridazine (228 mg, 0.62 mmol) was used as raw material to obtain the title compound (28 mg, 9%) as a white solid.
- the experimental operation was the same as in Example 1, with 5-bromo-2-(difluoromethyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole (30 mg, 0.1 mmol), 7-ethyl Base-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4 ,5-c]pyridazine (37 mg, 0.1 mmol) was used as raw material to obtain the title compound (2 mg, 4%) as a yellow solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )Phenyl)-7H-imidazo[4,5-c]pyridazine (90mg, 0.24mmol), 5-bromo-4-methoxy-1-methyl-1H-benzo[d][1, 2,3]triazole (60 mg, 0.24 mmol) was used as raw material to obtain the title compound (48 mg, 48%) as a brown solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (90mg, 0.24mmol), 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (66mg ,0.24mmol) as raw material to obtain the title compound (47mg, 49%) as a brown solid.
- Example 83 Example 84
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (80mg, 0.22mmol), 2-(5-bromo-6-methoxy-2H-indazol-2-yl)-1- (pyrrolidin-1-yl)ethyl-1-one (70 mg, 0.22 mmol) was used as starting material to obtain the title compound (70 mg, 64%) as a brown solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (80mg, 0.22mmol), 2-(5-bromo-6-methoxy-1H-indazol-1-yl)-1- (pyrrolidin-1-yl)ethyl-1-one (70 mg, 0.22 mmol) was used as starting material to obtain the title compound (46 mg, 42%) as a brown solid.
- Example 85 Example 85, Example 86
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (80mg, 0.22mmol), 3-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl )-5-methylisoxazole (70 mg, 0.22 mmol) was used as raw material to obtain the title compound (29 mg, 27%) as a white solid.
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (80mg, 0.22mmol), 3-((5-bromo-6-methoxy-1H-indazol-1-yl)methyl )-5-methylisoxazole (70 mg, 0.22 mmol) was used as raw material to obtain the title compound (38 mg, 35%) as a brown solid.
- the experimental operation was the same as in Example 1, with 5-bromo-2-cyclopropyl-4-methoxy-1-methyl-1H-benzo[d]imidazole (120 mg, 0.43 mmol), 7-ethyl-4 -(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5- c] Pyridazine (158 mg, 0.43 mmol) was used as raw material to obtain the title compound (17 mg, 9%) as a white solid.
- the experimental operation was the same as Example 1, with 2-(8-bromoquinolin-5-yl)-5-cyclopropyl-1,3,4-oxadiazole (23 mg.0.06mmol) and 7-ethyl-4 -(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5- c] Pyridazine (23 mg, 0.06 mmol) was used as raw material to obtain the title compound (13 mg, 45%).
- the experimental operation is the same as in Example 1, with 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )phenyl)-7H-imidazo[4,5-c]pyridazine (80mg, 0.22mmol), 5-bromo-6-(difluoromethoxy)-1-methyl-1H-indazole (75mg ,0.22mmol) as raw material to obtain the title compound (25mg, 27%) as a brown solid.
- Example 2 The experimental operation was the same as Example 1, with 8-bromo-4-(methylamino)-N-propylcinnoline-3-carboxamide (53 mg, 0.16 mmol), 7-ethyl-4-(4-fluoro- 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (50mg ,0.13mmol) as raw material to obtain the title compound (26mg, 40%).
- 8-bromo-4-(methylamino)-N-propylcinnoline-3-carboxamide 53 mg, 0.16 mmol
- 7-ethyl-4-(4-fluoro- 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine 50mg ,0.13mmol
- Example 2 The experimental operation was the same as Example 1, with 6-bromo-5-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole (50 mg, 0.16 mmol), 7-ethyl Base-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4 ,5-c]pyridazine (50 mg, 0.13 mmol) was used as raw material to obtain the title compound (12 mg, 19%).
- the experimental operation is the same as in Example 1, with 5-bromo-6-methoxy-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-indazole (60 mg, 0.16 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) Phenyl)-7H-imidazo[4,5-c]pyridazine (59 mg, 0.16 mmol) was used as raw material to obtain the title compound (35 mg, 42%) as a yellow solid.
- the operation method is the same as 94-2, using 2-(azetidin-3-yl)-5-bromo-6-methoxy-2H-indazole hydrochloride (80 mg, 0.25 mmol) as raw material to obtain light
- the title compound was a yellow oily liquid (50 mg, 55%).
- LC-MS: m/z[M+H] + 364,366.
- the experimental operation is the same as in Example 1, with 5-bromo-6-methoxy-2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-indazole (50 mg, 0.14 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) Phenyl)-7H-imidazo[4,5-c]pyridazine (52 mg, 0.14 mmol) was used as raw material to obtain the title compound (35 mg, 48%) as a yellow solid.
- Example 2 The experimental operation was the same as Example 1, with 4-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl)tetrahydro-2H-pyran-4-ol (50 mg, 0.15 mmol) ), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H -Imidazo[4,5-c]pyridazine (55 mg, 0.15 mmol) was used as raw material to obtain the title compound (8 mg, 11%) as a yellow solid.
- the experimental operation was the same as in Example 1, with 1-(3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidin-1-yl)ethan-1-one (60 mg ,0.19mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl )-7H-imidazo[4,5-c]pyridazine (70 mg, 0.19 mmol) was used as raw material to obtain the title compound (30 mg, 33%) as a yellow solid.
- the experimental operation was the same as in Example 1, with 1-(3-(5-bromo-6-methoxy-2H-indazol-2-yl)azetidin-1-yl)ethan-1-one (50 mg ,0.15mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl )-7H-imidazo[4,5-c]pyridazine (55 mg, 0.15 mmol) was used as raw material to obtain the title compound (20 mg, 27%) as a yellow solid.
- the experimental operation was the same as Example 1, with 5-bromo-6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazole (200 mg, 0.62 mmol), 7-ethyl-4 -(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-7H-imidazo[4,5- c] Pyridazine (228 mg, 0.62 mmol) was used as raw material to obtain the title compound (160 mg, 53%) as a white solid.
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Abstract
本发明涉及咪唑并哒嗪类衍生物、其制备方法、药物组合物和用途。本发明提供一种式(1)所示化合物、其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物。含有该化合物的药物组合物以及所述化合物作为GABAA受体调节剂的用途。
Description
相关申请的交叉引用
本申请要求在2022年5月10日提交中国专利局、申请号为202210542611.3、发明名称为“咪唑并哒嗪取代苯环类衍生物、制备方法、药物组合物及用途”的中国专利申请的优先权,其全部内容通过引用的方式并入本文中。
本发明涉及对GABAA受体具有调节功能的咪唑并哒嗪取代苯环类衍生物、其制备方法、药物组合物和它们作为药物的应用。
γ-氨基丁酸(GABA)是哺乳动物中枢神经系统中重要的抑制性神经递质。调节GABA能神经传导的物质,被广泛地用于治疗各种病症,诸如癫痫症、焦虑症和抑郁症。自然界中,有两类GABA受体,一类是GABAA受体(GABAAR),该类受体为配体门控离子通道超家族的成员,另一类是GABAB受体(GABABR),该类受体是为G蛋白偶联受体超家族的成员。哺乳动物中的GABAA受体亚基已发现的有α1-6、β1-4、γ1-3、δ、ε、θ和ρ1-2等亚基,其中α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的,而α亚基对苯二氮卓类化合物与GABAA受体的结合是至关重要的。
在别构结合位置上结合的药物可为增加受体活性的阳性别构调节剂(或正向别构调节剂)、降低受体活性性的阴性别构调节剂(或反向别构调节剂)或不改变受体活性的中性别构调节剂(该指与别构结合位置结合但不调节受体活性的化合物)。最近的证据示意包含α2或α3亚基的GABAA受体(在本文称为α2/3-GABAA受体)可能涉及某些疼痛状态,且这些受体的阳性别构调节剂可能为有效的镇痛剂(Mirza,N.R.和Munro,G.,Drug News and Perspectives,2010,23(6),351-360)。
国际专利申请案PCT/GB01/04948(公告为WO2002/038568)和PCT/GB02/03114(公告为WO2003/008418)描述7-苯基咪唑并[1,2-b][1,2,4]三嗪衍生物,其对α2、α3和/或α5亚基具有亲和性。国际专利申请案PCT/US99/14935(公告为WO2000/001697)尤其公开了4-苯基-7H-咪唑并[4,5-c]哒嗪衍生物,其为促肾上腺皮质素释放因子拮抗剂。国际专利申请案PCT/IB2013/060631(公告为WO2014/091368)和PCT/IB2015/054200(公告号为WO2015/189744)和Robert M.Owen的文章(Robert M.Owen的J.Med.Chem.2019,62,5773-5796)描述4-(联苯-3-基)-7H-咪唑并[4,5-c]哒嗪衍生物与α2/3-GABAA受体具有相互作用,用于治疗包括疼痛等多种疾病。该类化合物还被用于瘙痒症(国际专利申请案PCT/US2019/033598,公告号为WO2019/26820A1)以及癫痫(Duveau,V.的CNS Neurosci Ther.2019.25(2):p.255-260.)的治疗。
主流观点认为对含有α1亚基的GABAA受体的调节活性,是目前GABAA调节剂(诸如苯并二氮杂卓类)的副作用(诸如镇静、成瘾性、嗜睡、健忘)主要来源(Uwe Rudolph和Frederic Knoflach的Nature Reviews:Drug Discovery,2011,10(9),685-697)。寻找与GABAA受体相互作用且α1-GABAA受体相关副作用更少的新化合物将有巨大的治疗潜力。
发明内容
为此,本发明所要解决的技术问题在于提供一种如式(1)所示咪唑并哒嗪取代苯环类化合物、其衍生物、立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物或溶剂合物:
其中,
所述R1为取代或者未取代的苯环与杂环形成的稠合基;
所述R2选自H、卤素、OH、C1-C6烷氧基或CN;
所述R3选自H、取代或者未取代的直链或者支链C1-C6烷基或取代或者未取代的C3-C6环烷基。
除特别指明外,下列定义用于说明和定义在本文中用于描述本发明时使用的各种术语的意义和范围。
无论是单独出现还是组合出现,一般术语的下列定义均适用。
本申请中使用的命名规则是基于AutoNomTM 2000,用于产生IUPAC系统命名的Beilstein Institute计算机化的系统。在本文中给出的结构中的碳、氧、硫或氮原子上出现的任何开放价键表明存在氢原子。
除特别说明外,术语“取代的”是指指定的基团或部分可以具有1、2、3、4、5或6个取代基。当基团上可以具有多个取代基并且给出了多种可能的取代基时,所述取代基独立选择,不必是相同的。
术语“未取代的”是指指定的基团上不具有取代基。
术语“任选取代的”是指指定的基团是未取代的或者是被一个或多个独立选自可能的取代基所取代的。
当指明取代基的数目时,术语“一个或多个”是指一个取代至取代的最多可能的数目,即取代一个氢至所有的氢均被取代基取代。除特别指明外,优选1、2、3、4或5个取代基。
具体的,R1和R3的基团定义中,“取代的”意为所述基团上一个或多个氢被选自C1-C4的烷基、C1-C4的烷氧基、C1-C4的卤素取代烷基或者卤素取代。
术语“卤素”是指氟、氯、溴和碘,优选氟。
本发明的化合物可以含有不对称中心或手性中心,并且因此存在不同的立体异构体形式。本发明化合物的所有立体异构体形式,包括但不局限于,非对映体、对映体和位阻异构体,以及它们的混合物例如外消旋混合物,将形成本发明的一部分。在本文中,当任何特定手性原子的立体化学未确定时,所有立体异构体均被考虑。此外,本发明涉及所有的几何和位置异构体。本发明化合物可以以不同的互变异构体形式存在,并且所有这些形式均包括在本发明范围内。本发明化合物的所有立体异构体预期包括混合物形式或纯的或基本上纯的形式。可以通过物理方法例如分步结晶、非对映体衍生物的分离或结晶、或者通过手性柱层析分离来拆分。
术语“前体药物”是式(1)的化合物的功能性衍生物,该衍生物在体内容易转化成式(1)的化合物。可以通过本领域技术人员众所周知的常规技术选择和制备合适该衍生物,例如参见Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985。
本文所用术语“药学上可接受的盐”,是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括但是不局限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、酸式硫酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、甲酸盐、甲磺酸盐和巴莫酸盐。“药学上可接受的盐”可涉及包括另一分子例如马来酸盐或其他平衡离子。平衡离子在母体化合物中稳定电荷。“药学上可接受的盐”可以有多于一个的荷电原子,多个荷电原子可具有多个平衡离子。
如果本发明化合物是碱,需要的“药学上可接受的盐”可通过适宜的方法制备,例如,用以下的无机酸处理该游离碱:盐酸、氢溴酸、硫酸、硝酸、磷酸;或者用如下的有机酸:乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如谷氨酸、芳香族酸如苯甲酸或肉桂酸、磺酸如甲磺酸或对甲苯磺酸。
如果本发明化合物是酸,需要的“药学上可接受的盐”可通过适宜的方法制备,例如,用如下的无机碱或者有机碱处理该游离酸:胺、碱金属氢氧化物或碱土金属氢氧化物等。适宜的盐的示例性的示例包括但是不限于由氨基酸得到的有机盐,伯、仲、叔胺盐,以及环状胺例如哌啶、吗啉和哌嗪的盐,以及由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到的无机盐。
本发明的化合物可以以从完全无定形到完全结晶的连续固态存在。术语“无定形”是指材料在分子水平上缺少长程有序性的状态,并且取决于温度,可以表现出固体或液体的物理性质。典型地,这样的材料不给出明显的X射线衍射图案,并且在显示出固体性质的同时,更正式地描述为液体。在加热时,发生从固体性质到液体性质的变化,其特征在于状态的变化,通常是二级(“玻璃化转变”)。术语“晶体”指的是一种固相,其中材料在分子水平上具有规则有序的内部结构,并给出具有确定峰
的独特的X射线衍射图。这样的材料在充分加热时也将表现出液体的性质,但是从固体到液体的变化的特征在于相变,通常是一级(“熔点”)。
本文所用术语“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
本文所用术语“溶剂合物”是指一个或多个溶剂分子与本发明化合物的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。本发明化合物可以以非溶剂化形式存在,也可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式存在,所以本发明将包括溶剂化和非溶剂化的形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素,术语“同位素体”具有相同的原子数,但是其原子质量或质量数不同于在自然界中占优势地存在的原子质量或质量数。例如,可用放射性同位素标记化合物,比如氘(2H)、氚(3H)、碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。同位素变体可能会提高某些治疗优点,比如氘富集可以增加体内半衰期或减少剂量需求,或者可以提供可用作生物样品的表征的标准品化合物。通过本领域技术人员众所周知的常规技术,或者通过与在本文的路线和实施例中所述的那些类似的方法,使用适当的同位素富集的试剂和/或中间体,无需过多实验,可以制备式(1)内的同位素富集的化合物。
[R2]
在本发明所述化合物中,所述R2选自H、卤素、OH、C1-C6烷氧基或CN;优选的,所述R2优选为H或卤素,更优选为H或F。
[R3]
在本发明所述化合物中,所述R3选自H、取代或者未取代的直链或者支链C1-C6烷基或取代或者未取代的C3-C6环烷基。在R3中,所述C1-C6烷基可以是直链,也可以是支链,示例性的C1-C6烷基包括甲基、乙基、正丙基(1-丙基)、异丙基(2-丙基,1-甲基乙基)、正丁基(1-丁基)、仲丁基(2-丁基,1-甲基丙基)、异丁基(2-甲基丙基)或Fe/F-丁基(1,1-二甲基乙基)。上述烷基上1至多个氢原子可以被甲基、乙基、正丙基、甲氧基、乙氧基、丙氧基、氟代甲基、氟代乙基、氟、氯、溴等取代基所取代。
术语“环烷基”是指单价饱和的环状烃基,在R3中,示例性的C3-C5环烷基包括环丙基、环丁基或环戊基。
在R3中,示例性的C3-C6环烷基包括1-甲基环丙基、2-甲基环丙基、1-甲基环丁基、2-甲基环丁基、3-甲基环丁基、1-甲基环戊基、2-甲基环戊基或3-甲基环戊基。上述环烷基上1至多个氢原子可以被甲基、乙基、正丙基、甲氧基、乙氧基、丙氧基、氟代甲基、氟代乙基、氟、氯、溴等取代基所取代。
术语“烷氧基”是指烷基氧基,在R3中,示例性的C1-C6烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基等。上述烷氧基上1至多个氢原子可以被甲基、乙基、正丙基、甲氧基、乙氧基、丙氧基、氟代甲基、氟代乙基、氟、氯、溴等取代基所取代。
在本发明一种优选地实施方案中,R3选自直链或者支链C1-C6烷基、C1-C6烷氧基,更优选为C2-C4烷基,更优选乙基或异丙基。
[R1]
在本发明方案中,所述R1为苯环与杂环的稠合基,所述杂环是指具有杂原子的饱和或部分不饱和的单环或多环基团,所述杂原子为N、O或S。优选地,两个杂环独立地为含有1-3个选自N、O或S的环杂原子的3-7元饱和或部分不饱和的单环或多环基团,S和O可以以-SO或者SO2存在。
作为优选的结构,本发明所述化合物中,形成所述R1所示稠合基的杂环为含有1-3个选自N、O或S的环杂原子的5-7元饱和或不饱和的单环基或双环基团。更优选地,所述杂环为含有1个、2个或3个选自N和/或O的环杂原子的5-6元饱和或不饱和的单环基,更优选的为仅含N或者同时含N和O为杂原子的杂环。
优选的,所述R1具有如下式(M)所示的结构:
其中,m为1、2或3,n为1或2,表示连接位点;
所述A环是指含有选自N、O或S中至少一种杂原子的5-7元饱和或部分不饱和的单环或双环。
所述A环是指含有选自N、O或S中至少一种杂原子的5-7元饱和或部分不饱和的单环;m为1、2或3,n为1或2,表示连接位点。
R1通过与式(1)化合物的苯基连接。
R4或者R5为杂环上的取代基,可以与杂原子连接,也可以与碳原子连接。
作为更为优选的结构,所述A环为含有1-3个选自N、O或S中至少一种杂原子的5-6元饱和或不饱和的单环基;具体的,当所述R1具有如式(M)所示结构时,所述R1具有如下(a)-(e)所示的结构:
更优选的,对于上述A环结构中,当所述R1具有如式(M)所示结构时,所述A环可选自如下结构:
作为可选的结构,所述R1具有如下式(N)所示的结构:
作为可选择的结构,当所述R1具有如式(N)所示结构时,所述A环可选自如下结构:
对于前述R1的可选结构中,所述R4选自氢、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基、;上述基团可选择的未被取代或者彼此独立的被1-4个分别选自卤素、羟基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或者卤代C1-C3烷氧基中的至少一种所取代。
优选的,所述R4选自氢、C1-C3烷基或C1-C3烷氧基;上述基团可选择的未被取代或者彼此独立的被C1-C3烷氧基或卤素取代。
更优选的,所述R4选自甲氧基C1-C3烷基或C1-C3烷氧基;更优选为甲氧基甲基或者甲氧基。
对于前述R1的可选结构中,R5基团中,杂原子选自N、O或S。
所述R5选自氢、卤素、羟基、氧代、C1-C6烷基酰基、C1-C6烷基酰胺基、C1-C6烷氧基亚胺基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C6-C10的芳基、含有1-3个杂原子的5-7元的杂芳基或者含有1-3个杂原子的C3-C7的非芳族杂环;上述基团可选择的未被取代或者彼此独立的被1-4个分别选自卤素、羟基、氧代、C1-C4酰基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基或者磺酰基中的至少一种所取代。
作为优选的结构,所述R5选自氢、卤素、氧代、C1-C3烷基酰基、C1-C3烷基酰胺基、C1-C3烷氧基亚胺基、C1-C3烷基、C3-C4环烷基、C1-C3烷氧基、C6-C8芳基、含有1-2个杂原子的5-6元的杂芳基或者含有1-2个杂原子的C4-C6的非芳族杂环;上述基团可选择的未被取代或者彼此独立的被1-2个分别选自卤素、羟基、氧代、C1-C3酰基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基或者磺酰基中的至少一种所取代。
作为更优选的结构,所述R5选自:H、氧代、甲基、乙基、异丙基、乙酰基、甲基甲氧基、乙
基甲氧基、环丙基、甲基环丙基、乙基环丙基、甲基环丁基、甲基胺基、苯基、
或者
本发明所述化合物中,所述R1选自如下结构中的任意一种:
并且,
所述R4选自H、C1-C3烷氧基、或者取代或未取代的甲氧基C1-C3烷基;优选为H、甲基甲氧基、乙基甲氧基、甲氧基或者二氟代甲氧基;
所述R5选自H、甲基、乙基、乙酰基、乙基甲氧基、甲基甲氧基、甲基环丙基、苯基、
或者
最优选的结构中,所述化合物选自如下表1中化合物中的任意一种。
表1优选化合物
本发明还提供了一种药物混合物,所述药物混合物包含选自下组的两种或两种以上的化合物:本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物。
本发明还提供了一种药物组合物,其包含本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物中的至少一种,并可选择的添加药学上可接受的载体和/或辅助剂。
本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物在制备治疗或预防与GABAA受体有关的疾病的药物中的用途。
进一步地,所述与GABAA受体有关的疾病选自如下至少一种:疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风。
进一步地,所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。
进一步地,所述的疼痛选自:头痛,面部痛、颈痛、肩痛、背痛、胸痛、腹痛、背部痛、腰痛、
下肢痛、肌肉与骨骼疼痛、血管疼痛、痛风、关节炎疼痛、内脏疼痛、感染性疾病导致的疼痛、多骨疼痛、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛,损伤或手术引起的慢性疼痛、伤害感受性疼痛、糖尿病性疼痛、三叉神经痛、腰部或子宫颈神经根病痛、舌咽神经痛、自主神经反射性疼痛、反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染或退行性骨关节病有关的疼痛。
本发明还提供了一种治疗或预防与GABAA受体有关的疾病的方法,向患者施用有效剂量的本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物。
本发明还提供了一种治疗或预防疼痛、阿尔茨海默氏病、多梗塞性痴呆或中风的方法,向患者施用有效剂量的本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物。
如果没有在实施例中描述其制备方法,那么式(1)化合物及其中间体产物可以根据类似的方法或者根据前述方法制备。本领域已知的原料可以得自商业,或者可以根据本领域已知的方法或已知方法的类似方法制备。
可以理解,本发明的式(1)化合物可以在官能团上衍生,从而得到能够在体内再转化为母体化合物的衍生物。
因此,本发明还涉及药用组合物,该药用组合物包括如上文所定义的化合物或其药学上可以接受的盐或其前药和药学上可接受的载体和/或辅助剂。
同样,本发明还包括如上所述的化合物或者组合物,用作制备治疗或预防与α2/3-GABAA受体有关的疾病的药物的用途,尤其是治疗或预防下列疾病:疼痛、癫痫、焦虑、瘙痒和抑郁。
优选治疗或预防疼痛。
特别优选治疗或预防神经病理性痛、炎性疼痛和癌性痛。
如本文所用,“癌性痛”是指恶性肿瘤在其发展过程中出现的疼痛,癌性痛发生目前认为有三种机制,即:癌症发展直接造成的疼痛、癌症治疗后造成的疼痛和癌症患者并发疼痛性疾病。
如本文所用,“神经病理性痛”是为由神经系统原发性损害和功能障碍所激发或引起的疼痛。
如本文所用,“炎性疼痛”是局部急性炎症或是慢性炎症刺激神经所致的疼痛。
如本文所用,“治疗”也包括预防性给药,一旦所述病症建立后缓解或消除所述病症。
如本文所用,“患者”定义为任何温血动物,例如不限于小鼠、豚鼠、狗、马或人,所述患者最好是人。
如本文所用,“急性疼痛”定义为由皮肤、身体结构或内脏的损伤和/或疾病发生的有害刺激而引起的疼痛,或由不产生实际组织损害的肌肉或内脏的异常功能而引起的疼痛。
如本文所用,“慢性疼痛”定义为持续超出急性疾病通常的病程或损伤治愈的合理时间,或与引起持续疼痛的慢性病理过程有关,或疼痛以一定间隔复发数月或数年,如果在应该已经达到治愈后或超过通常的治疗过程后仍存在疼痛,则认为是慢性疼痛。在疼痛需要经过的时间长度取决于疼痛的性质和与疼痛有关的治疗过程,如果疼痛超过通常的治疗过程,则疼痛是慢性的。慢性疼痛包括但不限于头痛、面部痛、颈痛、肩痛、胸痛、腹痛、背部痛、腰痛、下肢痛、肌与骨骼疼痛、与躯体病样精神障碍有关的疼痛、内脏痛、疼痛性糖尿病性神经病、血管疼痛、痛风、关节炎性疼痛、癌症疼痛、自主神经反射性疼痛、感染性疾病(如艾滋病和带状疱疹)导致的疼痛、自身免疫性疾病(风湿)导致的疼痛、急慢性炎症导致的疼痛、手术后疼痛和烧伤后疼痛。
本发明揭示的药物能有效地治疗如上定义的慢性疼痛,而且本发明揭示的药物可用于治疗伴随其他病症的痛敏,包括痛觉过敏、异常性疼痛、痛觉增强和疼痛记忆增强,该发明将改善对其疼痛的治疗。
如本文所用,“头痛”可分为原发性头痛和继发性头痛,原发性头痛包括紧张性头痛、偏头痛和丛集性头痛,而继发性头痛是由于其他疾病引起的。头面部的痛敏感组织发生病变或受到刺激时,可引起各种头痛,这些痛敏感组织包括分布于头皮、面部、口腔及咽喉等,由于它们主要是头部的肌肉或血管,含有丰富的神经纤维,对疼痛比较敏感,所以当这些组织受到伤害时可引起头痛。
如本文所用,“面部痛”包括但不限于三叉神经痛、非典型面痛、面神经麻痹和面肌痉挛。
如本文所用,“三叉神经痛”是一种独特的慢性疼痛性疾病,又称痛性抽搐,是指在三叉神经分布区域出现短暂的、阵发性的和反复发作的电击样剧烈性疼痛,或伴有同侧面肌痉挛。三叉神经痛分为原发性和继发性两种类型,原发性三叉神经痛是指临床上未发现神经系统体征,检查未发现器质性病变;继发性三叉神经痛是指在临床上有神经系统体征,检查发现有器质性病变,如肿瘤和炎
症等。
如本文所用,“非典型面痛”是指由多种病因引起的疼痛。表现为持续性烧灼样疼痛、无间歇性、与特殊的动作或触发刺激无关,疼痛多为双侧、疼痛常常超出三叉神经的分布范围甚至累及颈部皮肤。病因可由鼻窦炎、恶性肿瘤、颌及颅底感染等原因刺激或损伤三叉神经而引起疼痛。
如本文所用,“颈痛、背痛、肩痛”是指由于急慢性肌肉劳损及骨关节的退行性变和外伤等导致的疼痛。引起颈、肩及上肢疼痛的常见疾病有颈肩肌筋膜炎、项韧带炎、颈椎病、肩周炎、胸廓出口综合症、肱骨外上髁炎等,或由自身免疫性疾病引起的疼痛常见于类风湿性关节炎、强直性脊柱炎和风湿性关节炎等疾病,其他可能引起颈痛、背痛、肩痛的疾病还有颈、肩部的肿瘤、神经炎、动静脉疾病和各种感染以及胸、腹腔脏器病变引起的牵涉痛等。
如本文所用,“胸、腹及背部痛”指由于胸腹部内脏、胸腹壁组织的疾病导致的疼痛,包括但不限于肋间神经痛、肋间软骨炎、心绞痛、腹痛(急性腹部内脏痛)和腰背部肌筋膜综合征。
如本文所用,“腰、下肢痛”是指下腰、腰骶、骶髂、髋、臀及下肢痛。腰和下肢痛往往并不是独立的疾病,而是多种疾病的共有特征,临床表现多样,病因十分复杂,以退行性和损伤为多,包括但不限于腰椎间盘突出、急性腰扭伤、坐骨神经痛、骨质疏松症、第三腰椎横突综合症、梨状肌综合症、膝关节骨性关节炎、尾痛症和足跟痛等涉及的疼痛。
如本文所用,“肌与骨骼疼痛”包括但不限于肌筋膜疼痛、创伤引发的疼痛和慢性区域性疼痛综合症。
如本文所用,“疼痛性糖尿病”是指糖尿病并发的神经损伤而引起的疼痛,糖尿病中的神经损伤至少部分是由于血流减少和高血糖引起的。某些糖尿病患者不发生神经病变,而其他患者早期就发生该疾病,糖尿病性神经病痛可以分为涉及一个或者多个病灶部位的单神经病和全身性多神经病,所述多神经病可以是扩散和对称的,通常主要涉及感觉方式(Merrit’s Textbook of Neurology,第9版,LPRowland LP编辑)。糖尿病性神经病的表现可以包括植物神经功能障碍,导致包括心脏、平滑肌和腺体在内的调节障碍,引起低血压、腹泻、便秘和性无能。糖尿病神经病往往分阶段发展,早期在神经末梢区,植物神经病或感觉神经病的时发生在足部,脑神经病时发生在面部和眼周围,出现间歇性疼痛和麻刺感,在随后的阶段中,疼痛更强和经常发生,最后,当某一区域痛觉丧失时,发生为无痛性神经病,由于没有疼痛作为损伤的指示,大大增加了发生严重组织损伤的风险。
如本文所用,“内脏疼痛”包括但不限于刺激性肠综合征(IBS),伴有或不伴有慢性疲劳综合征(CFS)、炎性肠病(IBD)和间质性膀胱炎的疼痛。
如本文所用,“血管疼痛”是由以下一种或多种因素产生的疼痛。第一,组织的灌注不当。引起暂时或连续的局部缺血,诸如在运动期间发生肢体肌肉中的局部缺血;第二,迟发性变化。例如在皮肤或腹部内脏中的溃疡或坏疽;第三,大血管口径的突然或加速变化。例如动脉瘤发生的变化;第四,主动脉破裂。结果是血液溢出,刺激腹膜或胸膜壁层中的伤害感受纤维;第五,由于动脉内注射严重刺激动脉内皮而引起的强痉挛;第六,静脉血回流的损害,结果是迅速扩张筋膜隔室的大量水肿(Bonica等,The Management of Pain,第一卷(第二版),Philadelphia;Lea&Feboger,1990)。实例包括但不限于闭塞性动脉硬化、闭塞性血栓脉管炎、急性动脉闭合、栓塞、先天性动静脉瘤、血管痉挛性疾病、Rayaud病、手足发绀、急性静脉闭合、血栓静脉炎、静脉曲张和淋巴水肿。
如本文所用,“自主神经反射性疼痛”是指由“反射性交感神经萎缩征”导致的疼痛。反射性交感神经萎缩征是指机体遭受急慢性损伤后,有剧烈的自发疼痛,对触觉和痛觉过敏,可伴有浮肿和血行障碍,随后可出现皮肤及肌肉骨骼的营养障碍和萎缩等症状。
如本文所用,“术后疼痛”是指机体对疾病本身和手术造成的组织损伤的一种复杂的生理反应,它表现为心理和行为上的一种不愉快的经历。
如本文所用,“关节炎性疼痛”包括但不限于骨关节炎、类风湿性关节炎、关节强直性脊椎炎、牛皮癣性关节病、痛风、假痛风、传染性关节炎、腱炎、粘液囊炎、骨损害和关节软组织炎症等疾病导致的疼痛。
如本文所用,“带状疱疹后的神经痛”是指带状疱疹的皮疹愈合后,在原来皮疹区的皮下长期存在的剧烈疼痛。
如本文所用,“伤害感受性疼痛”是由刺激伤害性感受器传入的组织损害过程引起的疼痛,或是由伤害性感受器延长的兴奋引起的疼痛。由伤害感受器延长的兴奋引起的疼痛可以是由于伤害感受器的持久有害刺激或其敏化或这两者共同引起,或它们可以由这些因素引起,并由其持久性、各种反射机制和其他因素而延长。
本发明提供含治疗有效量的α2/3-GABAA正向别构调节剂的药物化合物的用途。尽管用于本发
明治疗的α2/3-GABAA正向别构调节剂可以原料化合物的形式给药,但优选将活性成分,任选地以生理上可接受的盐的形式,与一种或多种添加剂、赋形剂、载体、缓冲剂、稀释剂和/或其它常规的药物辅料一起混合成药物组合物。
在优选的实施方案中,本发明提供含α2/3-GABAA正向别构调节剂的药物组合物,其中α2/3-GABAA正向别构调节剂与一种或多种药学上可接受的载体、和任选地与其它本领域已知的或使用的治疗性的和/或预防性的组份混合。该载体必须是“可接受的”,即与制剂中的其它成分相容且不会对其接受者有害。
因此可将用于本发明的化合物与常规的添加剂、或稀释剂一起制成药物组合物及其单位剂量的形式。诸如此类的形式包括固体(尤其是片剂、填充胶囊、粉末以及丸剂的形式)、和液体(尤其是水溶液或非水溶液、混悬液、乳剂、酏剂)、和填充上述形式的胶囊、所有口服给药的形式、直肠给药的栓剂、以及肠胃外给药的无菌可注射的溶液。诸如此类药物组合物及其单位剂量形式可包括常规比例的常规成分、含或不含另外的活性化合物或成分,这类单位剂量形式可含与所需的每日应用剂量范围相当的任何合适的有效量的活性成分。
用于本发明的化合物可以各种的口服的和胃肠外的剂型给药。对本说领域的技术人员来说下述的剂型可含作为活性成分的本发明的化合物或其药学上可接受的盐。
为将用于本发明的化合物制成药物组合物,药学上可接受的载体可以是固体或者液体。固体形式的制剂包括粉末、片剂、九剂、胶囊、扁囊剂、栓剂、以及可分散的颗粒剂。固体载体可以是一种或多种还起稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂、或囊化材料作用的物质。
粉末中,载体为细分的固体,它与细分的活性成分混合。
片剂中,活性成分与具有必要的粘合性能的载体以适当的比例混合并压缩成所需的形状和大小。
粉末和片剂优选地含5%或10%到约7 0%的活性化合物。合适的载体为碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点的蜡、可可脂等等。术语“制剂”包括含与作为载体的囊化材料配制的活性化合物,囊化材料提供囊,其中含或不含载体的活性成分被载体包围,这样与其结合在一起。同样地,制剂包括扁囊剂和锭剂(lozenges)。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以用作适合于口服给药的固体形式。
为制备栓剂,首先将低熔点的蜡,如脂肪酸甘油酯或可可脂的泥合物熔化,然后通过搅拌将活性成分均匀地分散于其中。然后将该熔化的均匀混合物倒入适当大小模具中,让其冷却并由此固化。
适合于阴道给药的组合物可以阴道栓剂、棉塞、乳膏剂、凝胶剂、糊剂、泡沫或喷雾剂的形式存在,组合物除含活性成分外还含本领域已知的合适的载体。
液体制剂包括溶液、混悬液和乳剂,例如,水溶液或水-丙二醇溶液。例如,肠胃外注射液体制剂可以配制成水-聚乙二醇的溶液。
因此用于本发明的化合物可配制成用于肠胃外给药(例如注射,如快速浓注或连续输注)的制剂,和可以与添加的防腐剂一起以单位剂量的形式存在于安瓿、预填充的注射器、小体积的输液袋中或多剂量容器中。该组合物可采取油性或水性载体的混悬液、溶液或乳剂的形式,并可含制剂成分,如悬浮剂、稳定剂和/或分散剂。另外,活性成分可以是粉末的形式,可由灭菌的固体无菌分离或由溶液冻干获得,用于临用前与合适的载体如无菌的、无热原的水重建。
适合于口服给药的水溶液可通过将活性成分溶解于水中和加入所需的着色剂、调味剂、稳定剂和增稠剂来制备。
适合于口服给药的水悬浮液可通过将细分的活性成分分散于含粘性物质,如天然的或合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠、或其它公知的悬浮剂的水中而制备。
还包括为在临用前不久转化为用于口服给药的液态制剂而设计的固体制剂。这类液体制剂包括溶液、混悬液和乳剂。除活性成分之外,这类制剂可含着色剂、调味剂、稳定剂、缓冲剂、人造的和天然的甜味剂、分散剂增稠剂、增溶剂等。
为了局部施用到表皮,可将本发明的化合物配制成软膏剂、乳膏剂或洗剂或透皮贴剂。例如,软膏剂和乳膏剂可用水性或油性基质外加合适的增稠剂和/或胶凝剂配制而成。洗剂可用水性或油性基质配制而成,且通常还含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。
适合于口腔局部给药的组合物包括在调味基质通常为蔗糖和金合欢胶或西黄蓍胶中含有活性成分的锭剂(lozenges);在惰性的基质如明胶和甘油或蔗糖和金合欢胶中含活性成分的锭剂(pastiIles);以及在合适的液体载体中含活性成分的漱口药。
可将溶液或混悬液用常规方法例如用滴管、吸管或喷雾器直接应用到鼻腔。该组合物可以是单
剂量或多剂量的形式。
呼吸道给药也可以通过气雾剂实现,其中活性成分与合适的推进剂一起装在加压的包装中,合适的推进剂包括氟氯化碳(CFC)例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷,二氧化碳或其它合适的气体。气雾剂还可适当地含表面活性剂,如卵磷脂。药物的剂量可通过量阀控制。
另外活性成分可以是干粉的形式,例如化合物与合适粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP)的粉末混合物。粉末载体可方便地在鼻腔内形成凝胶。粉末组合物可以单位剂量的形式存在,例如存在于胶囊或药筒(如明胶的胶裘或药筒)中,或存在于粉末可经吸入器给药的泡罩包装中。
在用于呼吸道给药的组合物(包括鼻内用的组合物)中,通常化合物具有小的粒度,例如为5微米或更小数量级的粒度。这样的粒度可以用本领域已知的方法,例如通过微粉化获得。
需要时,可以应用适于活性成分缓释的组合物。
药物制剂优选为单位剂量形式。这类形式中,制剂被细分成合适量活性成分的单位剂量。单位剂量形式可以是封装的制剂,其中密封包装中含分离的大量制剂,如封装的片剂、胶囊和装入小瓶或安瓿中的粉末。此外,单位剂量形式可以是胶囊、片剂、扁裘剂或锭剂(lozenge)本身,或可以是任何封装形式的适量上述胶囊、片剂等。
用于口服给药的片剂或胶囊和用于静脉给药的液体以及连续的输液为优选的组合物。
关于制剂和给药技术的更详细的资料可以在Remington's Pharmaceutical Sciences(雷明顿药物科学)(Maack Publishing Co.,Easton,PA)的最新的版本上见到。
单位剂量制剂中活性组份的量可根据具体的应用和活性组份的效力而变化,可调节自0.01mg至约0.1g。例如,在医药用途中,该药物可以0.01至约100mg的胶囊每天给药三次,必要时该组合物还可以含其他相容的治疗剂。
在治疗用途中,用于本发明的化合物以起始剂量每天0.001mg/kg至10mg/kg体重。但是,这些剂量可以根据患者的需要、被治疗病症的严重性以及使用的化合物而变化,一般来说,开始以小于该化合物最佳剂量的较小剂量治疗,此后,小量增加此剂量达到最佳效果,方便起见,如果需要可将总日剂量再细分为一天内分次给药。
本发明的药物组合物还可同时与其它治疗疼痛、癫痫、焦虑和抑郁的药物联合使用,包括但不限于吗啡、加巴喷丁等。因此,本发明提供了一种用于治疗疼痛、癫痫、焦虑和抑郁的药物,该药物不仅有效,而且没有明显的副作用,本发明的另一个目的是提供一种对于特殊病人群体,如老人、患有肝或肾功能衰退、或心脏血管性疾病的病人,具有高度安全性的药物。
本发明还提供了一种治疗或预防疾病的方法,向患者施用有效剂量的如上所述的化合物或组合物。
本发明还提供了一种治疗或预防与GABAA受体有关的疾病的方法,向患者施用有效剂量的如上所述的化合物或如上所述的组合物。
本发明还提供了一种如上所述的化合物或组合物在制备治疗或预防下列疾病的药物中的用途:疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风。
所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。优选地,所述疼痛选自:头痛,面部痛、颈痛、肩痛、背痛、胸痛、腹痛、背部痛、腰痛、下肢痛、肌肉与骨骼疼痛、血管疼痛、痛风、关节炎疼痛、内脏疼痛、感染性疾病导致的疼痛、多骨疼痛、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛,损伤或手术引起的慢性疼痛、伤害感受性疼痛、疼痛性糖尿病、三叉神经痛、腰部或子宫颈神经根病痛、舌咽神经痛、自主神经反射性疼痛、反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染或退行性骨关节病有关的疼痛。
本发明还提供了一种治疗或预防疼痛、阿尔茨海默氏病、多梗塞性痴呆或中风的方法,向患者施用有效剂量的如商所述的化合物或如上所述的组合物。
本发明还涉及如上所述的式(1)所示咪唑并哒嗪取代苯环类化合物的制备方法如下,包括:
注:R3为乙基或者异丙基实验操作相同。
Z-1a:5-氯-N3-乙基哒嗪-3,4-二胺
将3,5-二氯哒嗪-4-胺(80.5g,0.5mol)和乙胺醇溶液(30%,600ml)放在高压釜中,150摄氏度反应16小时。反应液降至室温后有固体析出,过滤,滤饼用二氯甲烷洗(300ml),母液浓缩(不蒸干),有固体析出,再过滤,反复3次,收集所有的滤饼得到粗产物(含乙胺盐酸盐)。粗产物中加水搅拌打浆,过滤,滤饼旋干得到65g(76.5%产率)淡黄色固体目标产物。LC-MS:m/z[M+H]+=173.
Z-2a:4-氯-7-乙基-7H-咪唑并[4,5-c]哒嗪
将5-氯-N3-乙基哒嗪-3,4-二胺(30g,0.17mol)加入原甲酸三甲酯(600ml)中。120摄氏度反应4小时。反应液直接旋干得到粗产物,粗产物加二氯甲烷甲醇溶解拌样过柱子(二氯甲烷,二氯甲烷/甲醇=50/1,V/V).得到20g(63%yield)黄色固体目标产物LC-MS:m/z[M+H]+=183.
Z-3a:4-(3-氯-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
将4-氯-7-乙基-7H-咪唑并[4,5-c]哒嗪(20g,108mmol),(3-氯-4-氟苯基)硼酸(19.08g,108mmol),碳酸钠(24g,216mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(9.2g,10.8mmol)加入1,4-二氧六环/水(160ml/40ml)中,90摄氏度反应2小时。反应液直接柱层层析纯化(石油醚/乙酸乙酯=10/1,5/1,1/1,乙酸乙酯,V/V.)得到黄色固体标题化合物(26g,85.7%yield).LC-MS:m/z[M+H]+=277.
Z-4a-1:7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)-7H-咪唑并[4,5-c]
哒嗪
将4-(3-氯-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪(15g,54mmol),联硼酸频那醇酯(27.6g,108mmol),乙酸钠(13g,163mmol),2-二环己基磷-2,4,6-三异丙基联苯(2.7g,5.4mmol),三(二亚芐基丙酮)二钯(5g,5.4mmol)加入无水1,4-二氧六环(150ml)中,110摄氏度搅拌过夜。反应液直接柱层层析纯化(二氯甲烷/无水甲醇=50/1)得到淡黄色固体标题化合物(12g,60%yield)。1H NMR(400MHz,CHLOROFORM-d)ppm 1.40(s,12H)1.69(t,J=7.09Hz,3H)4.58(q,J=7.34Hz,2H)7.26(d,J=6.36Hz,1H)8.29(s,1H)8.45(d,J=1.96Hz,2H)9.39(s,1H).LC-MS:m/z[M+H]+=287,369.
Z-4a-2:(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸
将7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(12g,32.5mmol)溶于200mL盐酸水溶液(2M)中,室温下搅拌2小时,冻干得标题化合物(9.3g,粗品),外观为白色固体。
本发明的化合物及其药学上可接受的盐或其前药具有重要的药理学性质,为α2/3-GABAA受体正向别构调节剂。本发明的化合物对α2/3-GABAA受体具有优异的亲和活性、正向调控活性,且具有良好的遗传毒安全性和成药性。因此,本发明化合物及其药学上可接受的盐或其前药可以单独使
用或与其他药物组合使用,用于治疗或预防与α2/3-GABA A有关的疾病。
下面对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。其中,下述实施例中纯化步骤(例如制备薄层色谱、柱层析等)采用的溶剂比例为体积比。
实施例1
1-1:4-甲氧基-2-(甲氨基)苯甲酸
在25℃下,将2-氨基-4-甲氧基苯甲酸(2g,12mmol,1.0eq)溶解于甲醇(20mL)中,加入37%甲醛溶液(1mL,13.2mmol,1.1eq),搅拌分批加入氰基硼氢化钠(791mg,12.6mmol,1.05eq),并将混合物搅拌2小时。LCMS检测完全,反应液倒入100mL水中,乙酸乙酯(100mL×2)萃取,水洗与盐水洗有机相后干燥浓缩旋干,得到粗品4-甲氧基-2-(甲氨基)苯甲酸(2.2g,100%)。LC-MS:m/z[M+H]+=182。
1-2:5-溴-4-甲氧基-2-(甲氨基)苯甲酸
将4-甲氧基-2-(甲氨基)苯甲酸(1.5g,8.3mmol,1.0eq)溶解于醋酸(20mL)中,滴加自制1.4M溴醋酸溶液(6.2mL,8.7mmol,1.05eq),并将混合物25℃反应3小时。倒入100mL水中,乙酸乙酯萃取干燥旋干,得粗品5-溴-4-甲氧基-2-(甲氨基)苯甲酸(2.05g,100%)。LC-MS:m/z[M+H]+=261。
1-3:(5-溴-4-甲氧基-2-(甲氨基)苯基)甲醇
在25℃下,将5-溴-4-甲氧基-2-(甲氨基)苯甲酸(2.05g,7.7mmol,1.0eq)溶解于四氢呋喃(40mL)中,加入2M硼烷二甲硫醚四氢呋喃溶液(20mL)。将混合物在65℃下搅拌16小时。倒入150mL水中,乙酸乙酯(100mL×2)萃取,旋蒸除去一半左右溶剂,剩余有机相无水硫酸钠干燥,备得含产物的有机相(200mL),旋干了会变蓝色非常不稳定。LC-MS:m/z[M+H]+=248。
1-4:5-溴-4-甲氧基-2-(甲氨基)苯甲醛
在25℃下,将粗品(5-溴-4-甲氧基-2-(甲氨基)苯基)甲醇(50mL)加入到二氯甲烷(50mL)中,再加入戴斯马丁氧化剂(cas:87413-09-0,3g)。将混合物在25℃搅拌4小时。反应液过滤,滤液中加入二甲苯(50mL)后旋蒸除去乙酸乙酯等低沸点溶剂后,无水硫酸钠干燥。得到含产物的干燥二甲苯溶液(50mL,计500mg粗品,100%)。LC-MS:m/z[M+H]+=244。
1-5:3-乙酰基-6-溴-7-甲氧基-1-甲基喹啉-2(1H)-酮
在25℃下,将含粗品5-溴-4-甲氧基-2-(甲氨基)苯甲醛(20mL,计200mg含量)加入2,2,6-三甲基-4H-1,3-二噁英-4-酮(1.13g,8mmol,10.0eq)。将混合物在120℃搅拌2小时。蒸除去大量二甲苯后,柱层析(二氯甲烷:甲醇=10:1),得到粗品标题产物(150mg,60%)。LC-MS:m/z[M+H]+=311。
1:3-乙酰-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-1-甲基喹啉-2(1H)-酮
将3-乙酰基-6-溴-7-甲氧基-1-甲基喹啉-2(1H)-酮(150mg,0.48mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(138mg,0.48mmol),[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(cas:95408-45-0,32mg,0.05mmol),碳酸铯(325mg,1.0mmol)加入1,4-二氧六环/水(3ml/0.3ml)中。氩气保护下,100℃反应2小时。反应液送HPLC制备,冻干后得标题化合物(100mg,21%)。
1H NMR(400MHz,DMSO-d6)9.59(s,1H),8.89(s,1H),8.52(dd,J=9.2,5.9Hz,2H),8.47(s,1H),
8.00(s,1H),7.54(t,J=9.0Hz,1H),7.12(s,1H),4.51(q,J=7.2Hz,2H),4.00(s,3H),3.77(s,3H),2.63(s,3H),1.56(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=474。
实施例2
2-1:(3-氟-2-硝基苯基)甲醇
3-氟-2-硝基苯甲酸甲酯(1g,5.02mmol)和硼氢化钠(570mg,15.06mmol)加到四氢呋喃/甲醇(10/10mL)得混合溶剂中,室温搅拌1小时。将反应液柱层析(二氯甲烷/甲醇=20/1)得到标题化合物(800mg,93%)。
2-2:(3-(甲氨基)-2-硝基苯基)甲醇
(3-氟-2-硝基苯基)甲醇(600mg,3.51mmol)和甲胺的醇溶液(5mL),闷罐100℃搅拌过夜。将反应液柱层析(二氯甲烷/甲醇=20/1)得到标题化合物(500mg,78%)。
2-3:(6-溴-3-(甲氨基)-2-硝基苯基)甲醇
将(3-(甲氨基)-2-硝基苯基)甲醇(500mg,2.74mmol),N-溴代丁二酰亚胺(439mg,2.47mmol))加到乙腈(20mL)中,室温搅拌2小时。反应液加水(150ml),然后用乙酸乙酯萃取(200ml×2),乙酸乙酯用水洗一次,再用饱和食盐水洗一次,然后浓缩得到红色固体标题化合物(600mg,84%)。LC-MS:m/z[M+H]+=243。
2-4:(2-氨基-6-溴-3-(甲氨基)苯基)甲醇
(6-溴-3-(甲氨基)-2-硝基苯基)甲醇(600mg,2.3mmol),雷尼镍(68mg)加到甲醇(20ml)中,反应体系处于氢气氛围下,室温搅拌2小时。反应液过滤,滤饼用甲醇洗两次,然后将滤液浓缩得到黄色固体标题化合物(500mg,94%)。LC-MS:m/z[M+H]+=231。
2-5:(5-溴-1-甲基-1H-苯并[d]咪唑-4-基)甲醇
(2-氨基-6-溴-3-(甲氨基)苯基)甲醇(500mg,2.16mmol)加到原甲酸三甲酯(10ml)中,90摄氏度搅拌过夜。反应液直接薄层层析(石油醚/乙酸乙酯=1/1)得到黄色油状标题化合物(400mg,76%)。LC-MS:m/z[M+H]+=241。
2-6:5-溴-4-(甲氧基甲基)-1-甲基-1H-苯并[d]咪唑
将(5-溴-1-甲基-1H-苯并[d]咪唑-4-基)甲醇(400mg,1.65mmol)加到四氢呋喃(10mL)中,然后氢化钠(119mg,4.95mmol)加入反应体系中,常温搅拌10分钟后加入碘甲烷(1171mg,8.25mmol),室温搅拌1小时。反应液中加乙酸乙酯(200ml),然后用水洗(100ml×2),再用饱和食盐水洗一次,然后用无水硫酸钠干燥,浓缩后得到黄色油状标题化合物(240mg,57%)LC-MS:m/z[M+H]+=255。
2:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-1-甲基-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-1-甲基-1H-苯并[d]咪唑(100mg,0.39mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(112mg,0.39mmol)为原料,得到黄色固体标题化合物(14mg,9%)。
1H NMR(400MHz,CHLOROFORM-d)ppm 1.68(t,J=7.34Hz,3H)3.33(s,3H)3.89(s,3H)4.57(q,J=7.34Hz,2H)4.83(br.s.,2H)7.33-7.41(m,2H)7.43-7.49(m,1H)7.97(s,1H)8.27(s,1H)8.31(d,J=7.34Hz,1H)8.37-8.44(m,1H)9.40(s,1H)。LC-MS:m/z[M+H]+=417。
实施例3
3-1:(2-硝基-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇
(3-氟-2-硝基苯基)甲醇(500mg,2.92mmol)和四氢-2H-吡喃-4-胺(570mg,5.84mmol)加到无水乙醇中(10ml)100℃闷罐搅拌过夜。将反应液直接上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(680mg,92%)。LC-MS:m/z[M+H]+=253。
3-2:(6-溴-2-硝基-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇
实验操作同实施例2中,2-3的合成方法,以(2-硝基-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇(600mg,2.4mmol)为原料,得标题化合物(300mg,38%)。LC-MS:m/z[M+H]+=331,333。
3-3:(2-氨基-6-溴-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇
实验操作同实施例2中,2-4的合成方法,以(6-溴-2-硝基-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇(300mg,0.9mmol)为原料,得标题化合物(220mg,82%)。LC-MS:m/z[M+H]+=301,303。
3-4:(5-溴-1-(四氢-2H-吡喃-4-基)-1H-苯并[d][1,2,3]三唑-4-基)甲醇
(2-氨基-6-溴-3-((四氢-2H-吡喃-4-基)氨基)苯基)甲醇(200mg,0.67mol),亚硝酸钠(231mg,3.35mmol)加到盐酸溶液(1M,8ml)中,室温搅拌两小时,将反应液加入乙酸乙酯萃取,有机相制备薄层色谱分离纯化(石油醚/乙酸乙酯=1/1)得到标题化合物(150mg,72%)。LC-MS:m/z[M+H]+=312,314。
3-5:5-溴-4-(甲氧基甲基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d][1,2,3]三唑
实验操作同实施例2中,2-6的合成方法,以(5-溴-1-(四氢-2H-吡喃-4-基)-1H-苯并[d][1,2,3]三唑-4-基)甲醇(150mg,0.48mmol)为原料,得到标题化合物(140mg,90%)。LC-MS:m/z[M+H]+=326,328。
3:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d][1,2,3]三唑-5)-基)苯
基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d][1,2,3]三唑(70mg,0.22mmol)和(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(75mg,0.26mmol)为原料,得标题化合物(65mg,61%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H),8.42(br.s.,1H),8.35(d,J=6.8Hz,1H),8.27(s,1H),7.65(d,J=8.3Hz,1H),7.55(d,J=8.3Hz,1H),7.40(t,J=8.8Hz,1H),5.06-4.89(m,3H),4.58(q,J=7.0Hz,2H),4.24(d,J=9.8Hz,2H),3.69(t,J=11.5Hz,2H),3.40(s,3H),2.63-2.50(m,2H),2.17(d,J=13.2Hz,2H),1.72-1.67(m,3H)。LC-MS:m/z[M+H]+=488。
实施例4
4-1:3-(5-氯-4-甲氧基-2-硝基苯氧基)丙-1-醇
1-氯-5-氟-2-甲氧基-4-硝基苯(1g,4.86mmol),1,3-丙二醇(740mg,9.72mmol),碳酸铯(3.17g,9.72mmol)加到N,N-二甲基甲酰胺(5ml)中,120℃反应3小时。反应液倒入水(30ml)中,二氯甲烷萃取(30ml×3),有机相合并,饱和氯化钠水溶液(30ml)洗,有机相浓缩,拌样,柱色谱(石油醚/乙酸乙酯=4/1)得标题化合物白色固体(648mg,51%)。
1H NMR(400MHz,CHLOROFORM-d)d=7.54(s,1H),7.20(s,1H),4.24(t,J=5.9Hz,2H),3.94-3.89(m,5H),2.11(quin,J=5.5Hz,2H)。
4-2:3-(5-氯-4-甲氧基-2-硝基苯氧基)丙酸
琼斯试剂(2.5M,2ml)加到丙酮(4ml)中,3-(5-氯-4-甲氧基-2-硝基苯氧基)丙-1-醇(200mg,0.76mmol)溶于丙酮(4ml)中,缓慢滴加至反应液,室温搅拌30分钟。反应液倒入水(30ml)中,二氯甲烷萃取(30ml×3)有机相合并,无水硫酸钠干燥,浓缩得标题化合物淡黄色固体(178mg,84.97%)。
1H NMR(400MHz,CHLOROFORM-d)d=7.49(s,1H),7.22(s,1H),4.36(t,J=6.1Hz,2H),3.93(s,3H),2.93(t,J=6.1Hz,2H)。
4-3:8-氯-7-甲氧基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮
3-(5-氯-4-甲氧基-2-硝基苯氧基)丙酸(170mg,0.62mmol)铁粉(69mg,1.24mmol)加到乙酸(3ml)中,110℃反应过夜。反应液倒入饱和碳酸氢钠水溶液(30ml),抽滤得标题化合物白色固体(120mg,85%)。LC-MS:m/z[M+H]+=228,230.
4-4:8-氯-7-甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮
8-氯-7-甲氧基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮(60mg,0.26mmol)加到四氢呋喃(2ml)中,氢化钠(12mg,0.40mmol)加到反应液,室温搅拌5分钟后,碘甲烷(55mg,0.39mmol)缓慢加到反应液,室温搅拌30分钟。反应液缓慢倒入水(30ml)中,二氯甲烷萃取(30ml×3),有机相合并,无水硫酸钠干燥,浓缩,制备薄层色谱(二氯甲烷/甲醇=30/1)得标题化合物灰色固体(40mg,64%)。LC-MS:m/z[M+H]+=242,244。
4:8-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-5-甲基-2,3-二氢苯并[b][1.4]氧
氮杂-4(5H)-酮
8-氯-7-甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮(30mg,0.12mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(34mg,0.12mmol),碳酸铯(78mg,0.24mmol),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(Xphos-Pd-G3,cas:1445085-55-1,10mg,0.01mmol)加到1,4-二氧六环(2ml)中。氩气保护,100℃下反应两小时。反应液制备薄层色谱(二氯甲烷/甲醇=15/1)得标题化合物棕色固体(11mg,20%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.28(s,3H),7.37-7.35(m,1H),7.16(s,1H),6.80(s,1H),4.58(br.s.,2H),4.45(br.s.,2H),3.83(s,3H),3.42(s,3H),2.73(s,2H),1.71-1.70(m,3H).LC-MS:m/z[M+H]+=448。
实施例5
5-1:3-(3-溴-4-甲氧基苯氧基)丙酸乙酯
在25℃下,将3-溴-4-甲氧基苯酚(10g,49mmol)加入丙烯酸乙酯(70mL)中,添加催化量的4-二甲氨基吡啶(0.5g),将该溶液在100℃下搅拌24小时。LCMS检测后。旋蒸出去丙烯酸乙酯,然后乙酸乙酯溶解拌样,柱层析(石油醚:乙酸乙酯=3:1)纯化得到产物(7g,47%)类白色固体。LC-MS:m/z[M+H]+=303。
5-2:3-(3-溴-4-甲氧基苯氧基)丙酸
将3-(3-溴-4-甲氧基苯氧基)丙酸乙酯(600mg,2mmol)加入浓盐酸(5mL),并将混合物加热100℃回流2小时。加入水中稀释,然后乙酸乙酯(2×100mL)萃取。合并的有机相用水和盐水洗涤。然后经无水硫酸钠干燥并真空浓缩。然后通过柱色谱纯化(石油醚:乙酸乙酯=1:2)获得产物(400mg,72%)类白色固体。LC-MS:m/z[M+H]+=276。
5-3:7-溴-6-甲氧基色满-4-酮
在25℃下,将3-(3-溴-4-甲氧基苯氧基)丙酸(400mg,1.45mmol)添加到多聚磷酸(5mL)中,将混合物在80℃下搅拌2小时。倒入20mL水中搅拌30分钟,混合物用乙酸乙酯萃取(2×50毫升)。合并的有机相经无水硫酸钠干燥并真空浓缩,得到粗品产物(500mg,100%)黄色固体。LC-MS:m/z[M+H]+=257。
5-4:(Z)-7-溴-6-甲氧基色满-4-酮肟
在25℃下,将7-溴-6-甲氧基色满-4-酮(500mg,1.94mmol),溶解于乙醇(7mL)中,添加羟胺盐酸盐(404mg,5.82mmol),再滴加2M氢氧化钠溶液(5mL)。将混合物在25℃搅拌16小时。倒入水中,乙酸乙酯萃取干燥旋干得到粗品产物(240mg,45%)黄色固体。LC-MS:m/z[M+H]+=273。
5-5:8-溴-7-甲氧基-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-酮
在25℃下,将(Z)-7-溴-6-甲氧基色满-4-酮肟(240mg,0.22mmol),溶解于多聚磷酸(5mL)中,将混合物在100℃搅拌3小时。倒入水中,乙酸乙酯萃取干燥旋干。得到粗品产物(180mg,75%)。LC-MS:m/z[M+H]+=273。
5-6:8-溴-7-甲氧基-4-甲基-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-酮
在25℃下,将8-溴-7-甲氧基-3,4-二氢苯并[f][1,4]噁嗪-5(2H)-酮(180mg,0.36mmol),溶解于N,N-二甲基甲酰胺(5mL)中,分批加入NaH(23mg,0.55mmol)搅拌30min后,加入碘甲烷(142mg,1mmol),将混合物在25℃搅拌2小时。倒入水中,乙酸乙酯萃取干燥旋干得到粗品产物(100mg,96%)黄色固体。LC-MS:m/z[M+H]+=287。
5:8-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-4-甲基-3,4-二氢苯并[f][1,4]氧
氮杂-5(2H)-酮
实验操作同实施例1,以8-溴-7-甲氧基-4-甲基-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-酮(100mg,0.35mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(100mg,0.35mmol)为原料,得标题化合物(25mg,16%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.56(s,1H),8.86(s,1H),8.47(t t,J=7.3,2.3Hz,2H),7.57–7.45(m,1H),7.31(s,1H),7.07(s,1H),4.51(q,J=7.3Hz,2H),4.35(t,J=5.1Hz,2H),3.78(s,3H),3.59(t,J=5.2Hz,2H),3.13(s,3H),1.56(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=448。
实施例6
6-1:2-氨基-6-甲氧基苯酚
将2-硝基-6-甲氧基苯酚(CAS:15969-08-1 900mg,5.3mmol)溶于10mL甲醇中,加入雷尼镍(1g),氢气保护下,室温搅拌30分钟,过滤,浓缩反应液得到黄色固体标题化合物(600mg,80%)。LC-MS:m/z[M+H]+=140。
6-2:6-氨基-3-溴-2-甲氧基苯酚
将2-氨基-6-甲氧基苯酚(600mg,4.3mmol)溶于10mL二氯甲烷中冷却至0摄氏度,加入N-溴代丁二酰亚胺(613mg,3.45mmol),保持0摄氏度搅拌30分钟,浓缩,柱层析纯化(石油醚:乙酸乙酯=5:1)得到黄色固体标题化合物(110mg,12%)。LC-MS:m/z[M+H]+=218。
6-3:6-溴-7-甲氧基苯并[d]噁唑-2(3H)-酮
将6-氨基-3-溴-2-甲氧基苯酚(100mg,0.46mmol)溶于10mL四氢呋喃中,加入三光气(273mg,0.92mmol),室温搅拌2小时,浓缩,制备板纯化(二氯甲烷:甲醇=20:1)得到白色固体标题化合物(100mg,89%)。LC-MS:m/z[M+H]+=244。
6-4:6-溴-7-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮
将6-溴-7-甲氧基苯并[d]噁唑-2(3H)-酮(100mg,0.41mmol)溶于10mL乙腈中,加入碘甲烷(116mg,0.82mmol)和碳酸铯(270mg,0.82mmol),室温搅拌2小时,过滤固体,浓缩,得到黄色固体标题化合物(100mg,94%)。LC-MS:m/z[M+H]+=258。
6:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮
实验操作同实施例4,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.35mmol),6-溴-7-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮(90mg,0.35mmol)为原料,得到白色固体标题化合物(10mg,7%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.26-8.37(m,3H)7.40(s,1H)7.08(d,J=8.31Hz,1H)6.82(d,J=8.80Hz,1H)4.60(d,J=7.34Hz,2H)4.04(s,3H)3.16(s,3H)1.70(t,J=7.58Hz,3H)。LC-MS:m/z[M+H]+=420。
实施例7
7-1:(2-氨基-5-溴-4-甲氧基苯基)甲醇
将2-氨基-5-溴-4-甲氧基苯甲酸甲酯(500mg,1.92mmol)加到四氢呋喃(10mL)中,然后氢化铝锂(291mg,7.68mmol)加入反应体系中,常温搅拌2小时。反应液直接薄层层析(二氯甲烷/甲醇=20/1)得到黄色油状标题化合物(380mg,85%)。LC-MS:m/z[M+H]+=213.9。
7-2:6-溴-7-甲氧基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮
(2-氨基-5-溴-4-甲氧基苯基)甲醇(380mg,1.64mmol),双(三氯甲基)碳酸酯(1947mg,6.56mmol)加到四氢呋喃(10ml)中,室温搅拌2小时。反应液直接浓缩,然后用薄层析纯化(二氯甲烷/甲醇20/1)得到黄色固体标题化合物(180mg,42%)。LC-MS:m/z[M+H]+=258。
7-3:6-溴-7-甲氧基-1-甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮
将6-溴-7-甲氧基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮(150mg,0.58mmol),碳酸钾(80mg,0.58mol),碘甲烷(247mg,1.74mmol)加入甲醇(5ml)中,40摄氏度搅拌过夜。反应液直接薄层层析(石油醚/乙酸乙酯=5/1)得到黄色固体标题化合物(150mg,95%)。LC-MS:m/z[M+H]+=272。
7:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-1-甲基-1,4-二氢-2H-苯并[d][1,3]
噁嗪-2-酮
将6-溴-7-甲氧基-1-甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮(90mg,0.33mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(122mg,0.33mmol),二(三苯基膦)二氯化钯(23mg,0.033mmol),碳酸钠(70mg,0.66mmol)加入四氢呋喃/水(5ml/1ml)中。氩气保护下,80摄氏度,反应过夜。反应液直接薄层析纯化(二氯甲烷/甲醇=20/1)得到黄色固体标题化合物(28mg,19%)。
1H NMR(400MHz,CHLOROFORM-d)ppm 1.68-1.73(m,3H)3.47(s,3H)3.89(s,3H)4.54-4.63(m,2H)5.22(s,2H)7.15(s,1H)7.34(t,J=9.29Hz,1H)7.64-7.72(m,1H)8.19(d,J=6.85Hz,1H)8.28(s,2H)9.39(br.s.,1H)。LC-MS:m/z[M+H]+=434。
实施例8、实施例9
8-1:2-乙基-6-甲氧基-2H-苯并[b][1,4]恶嗪-3(4H)-酮
在氮气保护下将2-氨基-4-甲氧基苯酚(1.9g,13.8mmol)和2-溴-丁酸乙酯(3g,15.2mmol)溶解在20mL N,N-二甲基甲酰胺中,再加入碳酸铯(9g,27.6mmol),95℃反应16小时。反应结束后加入50ml水中,乙酸乙酯萃取(50mL×3),水反洗(30ml×3),旋干有机相,柱层析(石油醚/乙酸乙酯=5/1),得到标题化合物(1g,35%)白色固体。LC-MS:m/z[M+H]+=208。
8-2:7-溴-2-乙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将2-乙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(3.4g,16.4mmol),溶解于二甲基甲酰胺(40mL)中,再分批次加入N-溴代丁二酰亚胺(5.8g,32.8mmol)室温反应2h。反应完全后将体系倒入冰水中,乙酸乙酯(3×50ml)萃取,无水硫酸钠干燥,prep-HPLC制备纯化得到标题产物,旋干得到7-溴-2-乙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(2.1g,45%)黄色固体。LC-MS:m/z[M+1]+=208。
8-3:7-溴-2-乙基-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-2-乙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮1c(2.1g,7.4mmol)溶解在四氢呋喃(30ml)中,搅拌10分钟。在0℃下加入氢化钠(596mg,14.8mmol),搅拌20分钟后入碘甲烷(2.1g,14.8mmol),撤走冰水浴,室温下反应2h。将反应液倒入冰水(20ml)中,乙酸乙酯(3×50ml)萃取,无水硫酸钠干燥,HPLC制备纯化,旋干得到标题化合物(2.0g,油状液体,产率91%)。LCMS:m/z[M+1]+=301。
8:rel-(S)-2-乙基-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-甲基-2H-苯并
[b][1,4]恶嗪-3(4H)-酮
9:rel-(R)-2-乙基-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-甲基-2H-苯并
[b][1,4]恶嗪-3(4H)-酮
实验操作同实施例1,以7-溴-2-乙基-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(2.0g,6.7mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(1.9g,6.7mmol)为原料,得到标题化合物(1.0g,33%)类白色固体。再经过手性拆分,得到实施例8(第一个峰,10mg,白色固体)和实施例9(第二个峰,10mg,白色固体)。
拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:Afor CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
实施例8:1H NMR(400MHz,DMSO-d6)9.55(s,1H),8.86(s,1H),8.44(d,J=6.0Hz,2H),7.48(t,J=9.4Hz,1H),7.05(s,1H),6.92(s,1H),4.51(d,J=7.2Hz,3H),3.81(s,3H),3.39(s,3H),1.83(ddd,J=21.7,14.2,6.8Hz,2H),1.56(t,J=7.3Hz,3H),1.01(s,3H)。LC-MS:m/z[M+1]+=462。
实施例9:1H NMR(400MHz,DMSO-d6)9.37(s,1H),8.34–8.24(m,2H),8.19(dd,J=6.9,2.1Hz,1H),7.33(t,J=9.0Hz,1H),7.05(s,1H),6.62(s,1H),4.58(q,J=7.3Hz,2H),4.48(dd,J=8.5,4.4Hz,1H),3.83(s,3H),3.43(s,3H),2.11–1.83(m,3H),1.69(t,J=7.3Hz,4H),1.09(t,J=7.4Hz,3H)。LC-MS:m/z[M+1]+=462。
实施例10
10-1:5-(4-氯-2-氟-5-甲氧基苯基)-1-甲基-1H-吡唑-4-羧酸乙酯
实验操作同实施例1,以5-溴-1-甲基-1H-吡唑-4-羧酸甲酯(300mg,1.37mmol),4-氯-2-氟-5-甲氧
基苯基)硼酸(279mg,1.37mmol)为原料,得标题化合物(200mg,47%)收率黄色固体。LC-MS:m/z[M+1]+=313。
10-2:(5-(4-氯-2-氟-5-甲氧基苯基)-1-甲基-1H-吡唑-4-基)甲醇
将5-(4-氯-2-氟-5-甲氧基苯基)-1-甲基-1H-吡唑-4-羧酸乙酯(400mg,1.28mmol)溶解在四氢呋喃(40ml)中,降温至0℃,再加入硼氢化锂(84mg,3.84mmol)。反应在室温条件下反应3小时。反应完全后,将反应液倒入冰水(20ml)中,乙酸乙酯(3×50ml)萃取,无水硫酸钠干燥,HPLC制备纯化,旋干得到标题化合物(150mg,43%)油状液体。LC-MS:m/z[M+1]+=272。
10-3:7-氯-8-甲氧基-1-甲基-1,4-二氢色烯并[4,3-c]吡唑
将(5-(4-氯-2-氟-5-甲氧基苯基)-1-甲基-1H-吡唑-4-基)甲醇(200mg,0.74mmol)溶解在二甲基亚砜(10ml)中,再加入碳酸钾(200mg),加热至165设施度反应3小时。反应完全后,将反应液倒入冰水(20ml)中,乙酸乙酯(3×50ml)萃取,无水硫酸钠干燥,HPLC制备纯化,旋干得到标题化合物(75mg,油状液体,产率40%)。LC-MS:m/z[M+1]+=251。
10:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-8-甲氧基-1-甲基-1,4-二氢色基[4,3-c]吡
唑
实验操作同实施例1,以7-氯-8-甲氧基-1-甲基-1,4-二氢色烯并[4,3-c]吡唑(20.0mg,0.08mmol),(5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(23mg,0.08mmol)为原料,类白色固体的
(8mg,22%)。
1H NMR(400MHz,CDCl3)9.39(s,1H),8.29(s,2H),8.24–8.17(m,1H),7.35(t,J=9.0Hz,2H),7.17(s,1H),7.10(s,1H),5.22(s,2H),4.58(q,J=7.2Hz,2H),4.22(s,3H),3.86(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+1]+=457。
实施例11
11-1:(3-(乙氨基)-2-硝基苯基)甲醇
(3-氟-2-硝基苯基)甲醇(1000mg,5.84mmol),乙氨水溶液(50%,4ml)加入乙醇(10ml)中,100摄氏度封管搅拌过夜。反应液直接柱层析(二氯甲烷/甲醇=30/1)得到红色固体标题化合物(1100mg,96%)。LC-MS:m/z[M+H]+=197。
11-2:(6-溴-3-(乙基氨基)-2-硝基苯基)甲醇
实验操作同实施例2中,2-3的合成方法,以(3-(乙氨基)-2-硝基苯基)甲醇(1100mg,5.61mmol)为原料,得到红色固体标题化合物(1500mg,97%)。LC-MS:m/z[M+H]+=275。
11-3:(2-氨基-6-溴-3-(乙氨基)苯基)甲醇
实验操作同实施例2中,2-4的合成方法,以(6-溴-3-(乙基氨基)-2-硝基苯基)甲醇(1500mg,5.47mmol),得到黄色固体标题化合物(1300mg,97%)。LC-MS:m/z[M+H]+=245。
11-4:(5-溴-1-乙基-1H-苯并[d][1,2,3]三唑-4-基)甲醇
实验操作同实施例3中,3-4的合成方法,以(2-氨基-6-溴-3-(乙氨基)苯基)甲醇(1300mg,5.3mmol)为原料,得到棕色固体标题化合物(1100mg,81%)。LC-MS:m/z[M+H]+=256。
11-5:5-溴-1-乙基-4-(甲氧基甲基)-1H-苯并[d][1,2,3]三唑
实验操作同实施例2中,2-6的合成方法,以(5-溴-1-乙基-1H-苯并[d][1,2,3]三唑-4-基)甲醇(1100mg,4.3mmol)为原料,得到黄色油状标题化合物(1100mg,95%)。LC-MS:m/z[M+H]+=270。
11:7-乙基-4-(3-(1-乙基-4-(甲氧基甲基)-1H-苯并[d][1,2,3]三唑-5-基)-4-氟苯基)-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-1-乙基-4-(甲氧基甲基)-1H-苯并[d][1,2,3]三唑(1100mg,4.07mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(932mg,3.26mmol)为原料,得到白色固体标题化合物(545mg,31%)。
1H NMR(400MHz,DMSO-d6)1.54(s,6H)3.12(s,3H)4.46-4.54(m,2H)4.76-4.85(m,4H)7.55-7.62(m,2H)7.96-8.00(m,1H)8.52-8.59(m,2H)8.83-8.86(m,1H)9.53-9.56(m,1H)。LC-MS:m/z[M+H]+=432.2。
实施例12
12-1:6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将2-氨基-4-甲氧基苯酚(10000mg,71.68mmol),碳酸钾(19860mg,147.72mmol)和氯乙酰氯(8120mg,71.68mmol)依次加到乙腈(80mL)中,在90℃下搅拌16小时。反应液加入水(200mL),将析出的固体过滤后浓缩得紫色固体标题化合物(12000mg,93%)。LC-MS:m/z[M+H]+=259,261。
12-2:7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(12000mg,66.98mmol),氢溴酸乙酸溶液(33wt%)(24633mg,100.47mmol)依次加到乙酸(80mL)中,在室温下搅拌0.5小时后,再加入过氧化氢(2278mg,66.98mmol),在室温下搅拌2小时。反应液加入水(200mL),将析出的固体过滤后浓缩得紫色固体标题化合物(10000mg,46%)。LC-MS:m/z[M+H]+=259,261。
12-3:7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-硫酮
在氮气保护下,将五硫化二磷(947.3mg,4.26mmol),碳酸钾(802.9mg,5.81mmol),TEBA(44.1mg,0.19mmol)悬浮于1,2-二氯乙烷(40mL)中,并于100℃搅拌2小时,冷却至40℃左右,将7-
溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(1.0g,3.87mmol)加入反应液中,并于100℃反应15分钟。热过滤,滤饼用二氯甲烷洗三次,滤液浓缩,柱层析(二氯甲烷/乙酸乙酯=3/1)纯化得到标题产物(0.51g,48%)黄色固体。LC-MS:m/z[M+H]+=275。
12-4:(Z)-7-溴-3-肼基-6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪
在氮气保护下,将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-硫酮(470mg,1.7mmol)溶解在20mL乙醇中,并加入水合肼(103mg,2.1mmol),室温下反应2h,加入水(100mL),搅拌30分钟后过滤,滤饼用水洗三次,真空干燥后得到标题产物(290mg,褐色固体)产率62%。LC-MS:m/z[M+H]+=273。
12-5:7-溴-8-甲氧基-4H-苯并[b][1,2,4]三唑并[4,3-d][1,4]噁嗪
在氮气保护下,将(Z)-7-溴-3-肼基-6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪(290mg,1.07mmol)悬浮在12mL原甲酸三甲酯中,并于125℃搅拌2小时后,柱层析(二氯甲烷/乙酸乙酯=3/1)纯化得到标题产物(202mg,67%)白色固体。LC-MS:m/z[M+H]+=283。
12:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-8-甲氧基-4H-苯并[b][1,2,4]三唑并
[4,3-d][1,4]噁嗪
实验操作同实施例1,以7-溴-8-甲氧基-4H-苯并[b][1,2,4]三唑并[4,3-d][1,4]噁嗪(100.0mg,0.35mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基-7H-咪唑并[4,5-c]哒嗪(100.1mg,0.35mmol)为原料,得标题化合物(23mg,15%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.57(s,1H),9.47(s,1H),8.87(s,1H),8.47(d,J=6.7Hz,2H),7.72(s,1H),7.51(t,J=9.5Hz,1H),7.27(s,1H),5.50(s,2H),4.51(dd,J=14.5,7.3Hz,2H),3.85(s,3H),1.56(t,J=7.2Hz,3H)。LC-MS:m/z[M+H]+=444。
实施例13
13-1:5-甲氧基苯并[d]噁唑-2(3H)-酮
将2-氨基-4-甲氧基苯酚(5.01g,35.93mmol),溶于无水二氯甲烷(100.0mL)中,并分批加入N,N-羰基二咪唑(6.41g,39.53mmol),室温搅拌16h,用水(100mL)淬灭后,分层,收集有机层,水相再用二氯甲烷(100mLx3)萃取,旋干后得到一粗品,柱层析(二氯甲烷:乙酸乙酯)纯化后得到标题产物(4.51g,褐色固体)产率76%。LC-MS:m/z[M+H]+=166。
13-2:6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮
5-甲氧基苯并[d]噁唑-2(3H)-酮(1g,6.06mmol)和氢溴酸的醋酸溶液(33%,3.71g,15.1mmol)溶到醋酸中(8mL),0摄氏度下,滴加双氧水(30%,0.895g,7.88mmol),室温搅拌2小时。往反应体系中加水,有粉红色固体析出,将固体滤出浓缩得到得标题化合物(500mg,34%)。1H NMR(400MHz,DMSO-d6)11.78(s,1H),7.59(s,1H),6.86(s,1H),3.84(s,3H)。LC-MS:m/z[M+H]+=244,244。
13-3:6-溴-5-甲氧基-3-(2-(吡咯烷-1-基)乙基)苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(100mg,0.41mmol),碳酸钾(170mg,1.23mmol)和1-(2-氯乙基)吡咯烷盐酸盐(104.6mmol,0.61mmol)溶于二甲基亚砜中(4mL)80℃搅拌过夜。将反应液用乙酸乙酯和水萃取3次,有机相浓缩薄层色谱板纯化(二氯甲烷/甲醇=20/1)得到标题化合物(70mg,50%)。LC-MS:m/z[M+H]+=341,343。
13:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-(2-(吡咯烷-1-基)乙基)苯并[d]
噁唑-2(3H)-酮
实验操作同实施例1,以6-溴-5-甲氧基-3-(2-(吡咯烷-1-基)乙基)苯并[d]噁唑-2(3H)-酮(68mg,0.2mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(75mg,0.2mmol)为原料,得到标题化合物(30mg,33%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.30-8.17(m,3H),7.34(t,J=9.0Hz,1H),7.23(s,1H),7.00(br.s.,1H),4.58(q,J=7.2Hz,2H),4.17(br.s.,2H),3.87(s,3H),3.08(br.s.,2H),2.85(br.s.,4H),1.92(br.s.,4H),1.72-1.68(m,3H)。LC-MS:m/z[M+H]+=448。
实施例14
14-1:5-((2-溴-5-氯-4-甲氧基苯氧基)甲基)吡咯烷-2-酮
在25℃下,将1-溴-4-氯-2-氟-5-甲氧基苯(500mg,2.0mmol,1.0eq)溶解于二甲基亚砜(4mL)中,加入5-(羟甲基)吡咯烷-2-酮(350mg,3.0mmol,1.5eq),再加入碳酸铯(500mg,1.5mmol,0.77eq),置换气体后,将混合物于微波100℃反应2小时。LCMS检测,将该溶液过滤后反向HPLC纯化。冻干得到5-((2-溴-5-氯-4-甲氧基苯氧基)甲基)吡咯烷-2-酮(200mg,30%)。LC-MS:m/z[M+H]+=334。
14-2:7-氯-8-甲氧基-2,3,3a,4-四氢-1H-苯并[b]吡咯并[1,2-d][1,4]噁嗪-1-酮
将5-((2-溴-5-氯-4-甲氧基苯氧基)甲基)吡咯烷-2-酮(150mg,0.45mmol,1.0eq)溶解于甲苯(3mL)中,加入1,1'-联萘-2,2'-双二苯膦(150mg,0.24mmol,0.5eq),再加入碳酸铯(300mg,0.92mmol,2.0eq)加醋酸钯(60mg,0.2mmol,0.45eq)。置换氮气后微波100℃反应1.5小时。LCMS检测后,反应液过滤后反向HPLC纯化,冻干得7-氯-8-甲氧基-2,3,3a,4-四氢-1H-苯并[b]吡咯并[1,2-d][1,4]噁嗪-1-酮(70mg,61%)。LC-MS:m/z[M+H]+=254。
14:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-8-甲氧基-2,3,3a,4-四氢-1H-苯并[b]吡咯
并[1,2-d][1,4]噁嗪-1-酮
实验操作同实施例1,以7-氯-8-甲氧基-2,3,3a,4-四氢-1H-苯并[b]吡咯并[1,2-d][1,4]噁嗪-1-酮(50mg,0.2mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(112mg,0.4mmol)为原料,得标题化合物(10mg,11%)。
1H NMR(400MHz,DMSO-d6)9.54(s,1H),8.86(s,1H),8.43(t,J=6.4Hz,2H),8.29(s,1H),7.47(t,J=9.3Hz,1H),6.98(s,1H),4.52(dt,J=14.7,5.2Hz,3H),4.06(d,J=9.5Hz,1H),3.77(t,J=10.3Hz,1H),3.70(s,3H),2.77–2.57(m,1H),2.44–2.31(m,1H),2.24(t,J=13.7Hz,1H),1.79–1.62(m,1H),1.55(t,J=7.2Hz,3H)。LC-MS:m/z[M+H]+=460。
实施例15
15-1:6-甲氧基-4-(2-(2-氧代吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,1.12mmol),碳酸铯(730mg,2.24mmol)和1-(2-氯乙基)吡咯烷-2-酮(248mg,1.68mmol)加到乙腈(8mL)中60℃搅拌过夜。将反应液浓缩,上制备板分离纯化(石油醚/乙酸乙酯=1/1)得标题化合物(220mg,38%)。
15-2:7-溴-6-甲氧基-4-(2-(2-氧代吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
6-甲氧基-4-(2-(2-氧代吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.69mmol),HBr(0.3mL)和双氧水(0.1mL)加到醋酸中(10mL)中室温搅拌一个小时。将反应加入大量水,产物从反应体系中析出,将反应液过滤浓缩得标题化合物(140mg,55%)。
15:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-(2-(2-氧代吡咯烷-1-基)乙
基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
实验操作同实施例1,以7-溴-6-甲氧基-4-(2-(2-氧代吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(130mg,0.17mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(130mg,0.35mmol)为原料,得标题化合物(100mg,54%)。
1H NMR(CHLOROFORM-d,400MHz)9.36(s,1H),8.23-8.29(m,2H),8.19(d,J=5.9Hz,1H),7.33(t,J=8.8Hz,1H),7.14(s,1H),7.04(s,1H),4.61(s,2H),4.55-4.60(m,2H),4.16(t,J=7.1Hz,2H),3.92(s,3H),3.59(t,J=7.1Hz,2H),3.50(t,J=7.1Hz,2H),2.36(t,J=8.1Hz,2H),1.99-2.06(m,2H),1.68-1.72ppm(m,3H)。LC-MS:m/z[M+H]+=531。
实施例16
16-1:(5-溴-1-甲基-1H-苯并[d][1,2,3]三唑-4-基)甲醇
实验操作同实施例3中,3-4的合成方法,以(2-氨基-6-溴-3-(甲基氨基)苯基)甲醇(200mg,0.87mol)为原料,得到标题化合物(170mg,81%)。
16-2:5-溴-4-(甲氧基甲基)-1-甲基-1H-苯并[d][1,2,3]三唑
实验操作同实施例2中,2-6的合成方法,以(5-溴-1-甲基-1H-苯并[d][1,2,3]三唑-4-基)甲醇(150mg,0.69mmol)为原料,得到标题化合物(140mg,88%)。
16:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)苯基)-7H-咪唑[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-1-甲基-1H-苯并[d][1,2,3]三唑(101mg,0.4mmol)和
7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(120mg,0.33mmol)为原料,得标题化合物(80mg,58%)。
1H NMR(400MHz,CHLOROFORM-d)9.41(s,1H),8.45-8.39(m,1H),8.35(d,J=5.9Hz,1H),8.28(s,1H),7.57(s,2H),7.40(t,J=9.0Hz,1H),4.95(br.s.,2H),4.58(q,J=7.0Hz,2H),4.36(s,3H),3.38(s,3H),1.72-1.67(m,3H)。LC-MS:m/z[M+H]+=418。
实施例17
17-1:7-溴-6-甲氧基-4-(2-(吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.77mmol),1-(2-氯乙基)吡咯烷盐酸盐(262mg,1.54mmol)和碳酸铯(753mg,2.31mmol)加到乙腈(10mL)中,在80℃下搅拌0.5小时后,再加入2-溴-N,N-二甲基乙胺盐酸盐(360mg,1.54mmol),在室温下搅拌2小时。反应液过滤后浓缩,制备薄层色谱(二氯甲烷/甲醇=10/1)分离得标题化合物(110mg,40%)。LC-MS:m/z[M+H]+=356,358。
17:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-(2-(吡咯烷-1-基)乙基)-2H苯
并[b][1,4]噁嗪-3(4H)-酮
实验操作同实施例1,以将7-溴-6-甲氧基-4-(2-(吡咯烷-1-基)乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(100mg,0.28mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.28mmol)为原料,得标题化合物(46mg,32%)。
1H NMR(400MHz,CHLOROFORM-d)9.35(s,1H),8.31-8.21(m,2H),8.19(d,J=6.4Hz,1H),7.32(t,J=8.8Hz,1H),7.05(d,J=6.4Hz,2H),4.62-4.53(m,4H),4.43(br.s.,2H),3.93(s,3H),3.10(br.s.,6H),2.03(br.s.,4H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=517。
实施例18
18-1:7-溴-6-甲氧基-4-(2-吗啉代基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.77mmol),碳酸铯(752.6mg,2.31mmol)和4-(2-氯乙基)吗啉(172.8mg,1.16mmol)加到乙腈(6mL)60℃搅拌过夜。反应直接上制备板分离纯化(二氯甲烷/甲醇=20/1)得标题化合物(190mg,66%)。
18:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-(2-吗啉乙基)-2H-苯并[b]
[1,4]噁嗪-3(4H)-酮
实验操作同实施例7,以7-溴-6-甲氧基-4-(2-吗啉代基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(80mg,
0.22mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.27mmol)为原料,得标题化合物(35mg,24%)。
1HNMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.28(s,2H),8.19(d,J=6.8Hz,1H),7.34(t,J=8.8Hz,1H),7.05(s,1H),6.78(s,1H),4.61(s,2H),4.60-4.55(m,2H),4.13(t,J=6.8Hz,2H),3.82(s,3H),3.73(br.s.,4H),2.68(t,J=6.8Hz,2H),2.59(br.s.,4H),1.69(s,3H)。LC-MS:m/z[M+H]+=533。
实施例19
19-1:7-溴-4-(2,2-二氟乙基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(100mg,0.39mmol),碳酸铯(381mg,1.17mmol)和2,2-二氟乙基三氟甲磺酸酯(36mg,0.09mmol)加到乙腈(6mL)60℃搅拌过夜。反应直接上制备板分离纯化(二氯甲烷/甲醇=20/1)得标题化合物(90mg,72%)。
19:4-(2,2-二氟乙基)-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并[b]
[1,4]噁嗪-3(4H)-酮
实验操作同实施例1,以7-溴-4-(2,2-二氟乙基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(92mg,0.29mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(90mg,0.24mmol)为原料,得标题化合物(70mg,63%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.28(s,2H),8.19(d,J=6.8Hz,1H),7.34(t,J=9.0Hz,1H),7.08(s,1H),6.79(s,1H),6.31-5.98(m,1H),4.66(s,2H),4.58(q,J=7.3Hz,2H),4.37-4.27(m,2H),3.83(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=484。
实施例20
20-1:4-((4-甲氧基苄基)氧基)-3-硝基苯甲醛
将4-羟基-3-硝基苯甲醛(5.0g,29.92mmol),1-(氯甲基)-4-甲氧基苯(7.03g,44.88mmol),碳酸铯(19.50g,59.84mmol)加入N,N-二甲基甲酰胺(100mL)中,65℃搅拌16h。将反应液倒入水(200mL)中,用乙酸乙酯(100mL×3)萃取,分别用5%氯化锂,饱和食盐水洗涤后,无水硫酸钠干燥,浓缩后得标题化合物(7.0g,黄色油状物,产率:81%)。
1H NMR(400MHz,DMSO-d6)9.94(s,1H),8.42(d,J=2.0Hz,1H),8.18(dd,J=8.7,2.1Hz,1H),7.67(d,J=8.8Hz,1H),7.45–7.37(m,2H),7.01–6.95(m,2H),5.35(s,2H),3.76(s,3H)。
20-2:(4-((4-甲氧基苄基)氧基)-3-硝基苯基)甲醇
将4-((4-甲氧基苄基)氧基)-3-硝基苯甲醛(7.0g,24.37mmol)溶于甲醇(150mL)中,并于室温下缓慢加入硼氢化钠(4.63g,121.84mmol),室温搅拌16h,将反应液倒入水(200mL)中,用乙酸乙酯(100mL×3)萃取,用饱和食盐水洗涤后,无水硫酸钠干燥,浓缩后得标题化合物(7.0g,黄色油状物,产率:99%)。
1H NMR(400MHz,CDCl3)7.84(d,J=2.1Hz,1H),7.49(dd,J=8.6,2.1Hz,1H),7.37(d,J=8.7Hz,2H),7.11(d,J=8.6Hz,1H),6.93–6.89(m,2H),5.17(s,2H),4.67(s,2H),3.81(s,3H)。
20-3:1-((4-甲氧基苄基)氧基)-4-(甲氧基甲基)-2-硝基苯
将(4-((4-甲氧基苄基)氧基)-3-硝基苯基)甲醇(6.7g,23.16mmol),碘甲烷(2.2mL,34.74mmol)溶于无水N,N-二甲基甲酰胺(134mL)中,并于氮气下缓慢加入60%氢化钠(1.39g,34.74mmol),室温搅拌16h,将反应液倒入饱和氯化铵(200mL)中,用乙酸乙酯(100mL×3)萃取,分别用5%氯化锂,饱和食盐水洗涤后,无水硫酸钠干燥,浓缩后得标题化合物(6.8g,黄色油状物,产率:97.1%)。
1H NMR(400MHz,CDCl3)7.82(d,J=2.1Hz,1H),7.46(dd,J=8.6,2.2Hz,1H),7.37(d,J=8.7Hz,2H),7.10(d,J=8.6Hz,1H),6.93–6.90(m,2H),5.17(s,2H),4.41(s,2H),3.81(s,3H),3.39(s,3H)。
20-4:4-(甲氧基甲基)-2-硝基苯酚
将1-((4-甲氧基苄基)氧基)-4-(甲氧基甲基)-2-硝基苯(7.0g,23.08mmol)溶于二氯甲烷(100ml)中,并加入三氟乙酸(10.0mL),室温搅拌16h,将反应液倒入水(100mL)中,用二氯甲烷(100mL×3)萃取,用10%碳酸钾(50mL×5)洗涤后,收集水相,水相用乙酸乙酯(50mL×3)洗涤后,用浓盐酸调节PH=1,然后用乙酸乙酯(100mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,浓缩得标题化合物(3.4g,黄色油状物,产率:81%)。
1H NMR(400MHz,CDCl3)10.50(s,1H),8.01(d,J=2.0Hz,1H),7.50(dd,J=8.6,2.1Hz,1H),7.09(d,J=8.6Hz,1H),4.36(s,2H),3.34(s,3H)。
20-5:2-氨基-4-(甲氧基甲基)苯酚
将4-(甲氧基甲基)-2-硝基苯酚(3.5g,19.10mmol)溶于乙醇(70mL)中,并加入二氧化铂(350mg),此反应于氢气氛(1atm)下室温搅拌16h,过滤,滤液浓缩得标题化合物(2.1g,褐色固体,产率:72%)。
20-6:5-(甲氧基甲基)苯并[d]噁唑-2(3H)-酮
将2-氨基-4-(甲氧基甲基)苯酚(2.1g,13.71mmol),溶于无水二氯甲烷(100.0mL)中,并分批加入N,N'-羰基二咪唑(2.45g,15.08mmol),室温搅拌16h,用水(100mL)淬灭后,分层,收集有机层,水相再用二氯甲烷(100mLx3)萃取,旋干后得到一粗品,正相(二氯甲烷:乙酸乙酯)纯化后得到标题产物(1.7g,褐色固体)产率69%。1H NMR(400MHz,DMSO-d6)7.23(d,1H),7.01(m,2H),4.40(s,2H),3.27(s,3H).LCMS:m/z[M+1]+=180.0.
20-7:6-溴-5-(甲氧基甲基)苯并[d]噁唑-2(3H)-酮
将5-(甲氧基甲基)苯并[d]噁唑-2(3H)-酮(500mg,2.79mmol)溶于冰醋酸(12.5mL)溶液中,加入(33%)氢溴酸/醋酸(1.72g,6.98mmol),并于室温下搅拌30分钟,冷却至10度,并缓慢滴加(30%)双氧水(284.6mg,2.51mmol),控制温度不要超过10度,并于10度~室温反应2h,将反应液倒入100mL水中,用乙酸乙酯(50mLx3)萃取,浓缩,prep-HPLC(0.5%HCOOH~乙腈)纯化得到标题化合物(415.0mg,白色固体,产率57.6%)。
1H NMR(400MHz,DMSO-d6)11.82(s,1H),7.63(s,1H),7.15(s,1H),4.43(s,2H),3.36(s,3H)。
20-8:6-溴-5-(甲氧基甲基)-3-甲基苯并[d]噁唑-2(3H)-酮
将6-溴-5-(甲氧基甲基)苯并[d]噁唑-2(3H)-酮(431mg,1.67mmol),悬浮于二甲基亚砜(10.0mL)的溶液中,室温下加入碘甲烷(3.1mL,50.1mmol),碳酸钾(461.1mg,3.34mmol),并于室温下反应16h,加入水(100mL)淬灭后,用乙酸乙酯(50mLx3)萃取,再用饱和食盐水(50mL)洗一次,旋干后得一粗品,HPLC制备纯化后得到标题产物(267.7mg,白色固体)产率59%。
1H NMR(400MHz,DMSO-d6)7.68(s,1H),7.34(s,1H),4.47(s,2H),3.39(s,3H),3.34(s,3H)。
20:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-(甲氧基甲基)-3-甲基苯并[d]噁唑-2(3H)
-酮
实验操作同实施例1,以6-溴-5-(甲氧基甲基)-3-甲基苯并[d]噁唑-2(3H)-酮(100.0mg,0.37mmol),(2-氟-5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)苯基)硼酸(105.1mg,0.37mmol)为原料,得到标题化合物(82mg,白色固体)产率52%。
1H NMR(400MHz,DMSO-d6)9.57(s,1H),8.87(s,1H),8.53(m,1H),8.46(m,1H),7.56(t,1H),7.40(m,2H),4.51(q,J=7.3Hz,2H),4.33(s,2H),3.41(s,3H),3.19(s,3H),1.56(t,J=7.3Hz,3H)。LCMS:m/z[M+1]+=434。
实施例21
21-1:7-溴-6-甲氧基-4-(3-(4-甲基哌嗪-1-基)丙基)-3,4-二氢-2H-1,4-苯并噁嗪-3-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.77mmol)1-(3-氯丙基)-4-甲基哌嗪盐酸盐(380mg,1.54mmol)和碳酸铯(750mg,2.31mmol)依次加到乙腈(5mL)中,在80℃下搅拌2小时。反应液过滤后浓缩,制备薄层色谱(二氯甲烷/甲醇=10/1)分离得标题化合物(200mg,65%)。LC-MS:m/z[M+H]+=399,401。
21:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-(3-(4-甲基哌嗪-1-基)丙
基)-3,4-二氢-2H-1,4-苯并噁嗪-3-酮
实验操作同实施例7,以7-溴-4-(2-(二甲基氨基)乙基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(150mg,0.38mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(140mg,0.38mmol)为原料,得标题化合物(120mg,56%)。
1H NMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.29(s,1H),8.28-8.22(m,1H),8.19(d,J=5.4Hz,1H),7.33(t,J=9.0Hz,1H),7.04(s,1H),6.70(s,1H),4.62-4.54(m,4H),4.06(t,J=7.1Hz,2H),3.81(s,3H),2.60(br.s.,8H),2.51(t,J=6.8Hz,2H),2.38(s,3H),1.98-1.89(m,2H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=560。
实施例22
22-1:7-溴-4-(2-(二甲基氨基)乙基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.77mmol)加到四氢呋喃(10mL)中,在冰浴下加入氢化钠(92mg,3.85mmol),在室温下搅拌0.5小时后,再加入2-溴-N,N-二甲基乙胺盐酸盐(360mg,1.54mmol),在室温下搅拌2小时。反应液过滤后浓缩,制备薄层色谱(乙酸乙酯)分离得标题化合物(120mg,47%)。LC-MS:m/z[M+H]+=330,332。
22:4-(2-(二甲氨基)乙基)-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并
并[b][1,4]噁嗪-3(4H)-酮
实验操作同实施例7,以7-溴-4-(2-(二甲基氨基)乙基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(120mg,0.36mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(133mg,0.36mmol)为原料,得白色固体标题化合物(24mg,14%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.28(s,2H),8.20(d,J=6.4Hz,1H),7.34(t,J=8.8Hz,1H),7.05(s,1H),6.93(br.s.,1H),4.62-4.56(m,4H),4.23(br.s.,2H),3.87(s,3H),2.77(br.s.,2H),2.50(br.s.,6H),1.70(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=491。
实施例23
23-1:7-溴-6-甲氧基-4-(2-甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(300mg,1.16mmol),1-溴-2-甲氧基乙烷(322mg,2.32mmol)和碳酸钾(481mg,3.48mmol)依次加到甲醇(5mL)中,在45℃下搅拌16小时。反应液反应液过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得黄色固体标题化合物(40mg,11%)。LC-MS:m/z[M+H]+=317,319。
23:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-(2-甲氧基乙基)-2H-苯并[b]
[1,4]噁嗪-3(4H)-酮
实验操作同实施例7,以7-溴-6-甲氧基-4-(2-甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(60mg,0.22mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(81mg,0.22mmol)为原料,得黄色固体标题化合物(10mg,10%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(br.s.,1H),8.34-8.22(m,2H),8.18(d,J=6.4Hz,1H),7.33(t,J=8.8Hz,1H),7.05(s,1H),6.54(s,1H),4.62-4.52(m,3H),4.50(s,2H),3.80(s,3H),2.62(br.s.,2H),2.55-2.42(m,2H),1.86(d,J=8.3Hz,2H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=474。
实施例24
24:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-
酮
实验操作同实施例7,以7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(100mg,0.39mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(144mg,0.39mmol)为原料,得标题化合物(68mg,42%)。
1H NMR(400MHz,CHLOROFORM-d)10.76(s,1H),9.50(s,1H),8.83(s,1H),8.41-8.35(m,2H),7.43(s,1H),6.95(s,1H),6.66(s,1H),4.54(s,2H),4.51-4.43(m,2H),3.67(s,3H),1.51(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=420。
实施例25
25-1:1-(4-甲氧基-2-硝基苯氧基)环丙烷-1-羧酸甲酯
1-氟-4-甲氧基-2-硝基苯(1g,5.85mmol),钠氢(420mg,17.52mmol)和1-羟基环丙烷-1-羧酸甲酯(1.06g,8.76mmol)加到四氢呋喃中(10ml)0℃搅拌两小时。将反应液浓缩上制备板分离纯化(石油醚/乙酸乙酯=3/1))得标题化合物(1.1g,71%)。
25-2:6-甲氧基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮
1-(4-甲氧基-2-硝基苯氧基)环丙烷-1-羧酸甲酯(1g,3.74mmol)和Fe(1.04g,18.7mmol)加到乙酸中(6ml)80℃搅拌一小时。将反应液浓缩加适量甲醇上制备板分离纯化(石油醚/乙酸乙酯=1/1)得标题化合物(550mg,71%)。
25-3:6-甲氧基-4-甲基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮
6-甲氧基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮(550mg,2.65mmol),碳酸铯(2.59g,7.95mmol)和碘甲烷(2.59mg,7.95mmol)加到甲醇中(8ml)室温搅拌过夜。将反应液过滤浓缩,母液上制备板分离纯化(石油醚/乙酸乙酯=1/1)得标题化合物(400mg,68.22%)。
25-4:7-溴-6-甲氧基-4-甲基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮
6-甲氧基-4-甲基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮(200mg,0.9mmol),HBr(0.3mL)和双氧水(0.1mL)加到醋酸中(10mL)中室温搅拌一个小时。将反应加入大量水,产物从反应体系中析出,将反应液过滤浓缩得标题化合物(110mg,41%)。
25:7-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-甲基螺[苯并[b][1,4]噁嗪
-2,1'-环丙烷]-3(4H)-酮
实验操作同实施例1,以7-溴-6-甲氧基-4-甲基螺[苯并[b][1,4]噁嗪-2,1'-环丙烷]-3(4H)-酮(97mg,0.32mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.27mmol)为原料,得标题化合物(57mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)9.36(br.s.,1H),8.31-8.23(m,2H),8.18(d,J=6.8Hz,1H),7.33(t,J=9.0Hz,1H),6.94(s,1H),6.64(s,1H),4.58(q,J=7.3Hz,2H),3.85(s,3H),3.49-3.41(m,3H),1.73-1.68(m,3H),1.45-1.38(m,2H),1.25-1.21(m,2H)。LCMS:m/z[M+H]+=460.
实施例26
26-1:6-甲氧基-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
2-氨基-4-甲氧基苯酚(500mg,3.59mmol),碳酸铯(2.34g,7.18mmol)和2-溴丙酸乙酯(650mg,3.59mmol)加到N,N-二甲基甲酰胺中(8mL)95℃搅拌过夜。反应液用乙酸乙酯和水萃取三次,有机相浓缩直接上制备板分离纯化(石油醚/乙酸乙酯=1/1)得标题化合物(500mg,72.09%)。
26-2:6-甲氧基-2,4-二甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
6-甲氧基-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(500mg,2.59mmol),碳酸铯(2.53g,7.77mmol)和碘甲烷(1.85mg,12.95mmol)加到甲醇中(20mL)室温搅拌过夜。反应直接上制备板分离纯化(二氯甲烷/甲醇=30/1)得标题化合物(400mg,74.6%)。
26-3:7-溴-6-甲氧基-2,4-二甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
6-甲氧基-2,4-二甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(400mg,1.93mmol),HBr(0.5mL)和双氧水(0.2mL)加到醋酸中(20mL)中室温搅拌一个小时。将反应加入大量水,产物从反应体系中析出,将反应液过滤浓缩得标题化合物(190mg,34%)。
26:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2,4-二甲基-2H-苯并[b][1,4]噁
嗪-3(4H)-酮
实验操作同实施例1,以2-(5-溴-6-乙氧基吡啶-2-基)-5-甲基-1,3,4-噁二唑(92mg,0.32mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.27mmol)为原料,得标题化合物(60mg,50%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.30-8.25(m,2H),8.19(d,J=6.8Hz,1H),7.34(t,J=9.0Hz,1H),7.05(s,1H),6.63(s,1H),4.67-4.62(m,1H),4.59(d,J=7.3Hz,2H),3.84(s,3H),3.44(s,3H),1.72-1.69(m,3H),1.60(d,J=6.8Hz,3H)。LC-MS:m/z[M+H]+=448。
实施例27
27-1:7-溴-4-环丁基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(300mg,1.16mmol),环丁基溴(235mg,1.74mmol)和碳酸钾(481mg,3.48mmol)依次加到N,N-二甲基甲酰胺(5mL)中,在80℃下搅拌2小时。反应液反应液过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得白色固体标题化合物(110mg,30%)。LCMS:m/z[M+H]+=313,315。
27:4-环丁基-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例1,以将7-溴-4-环丁基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(100mg,0.32mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(117mg,0.32mmol)为原料,得黄色固体标题化合物(17mg,11%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.40(br.s.,1H),8.34-8.22(m,2H),8.18(d,J=6.4Hz,1H),7.33(t,J=8.8Hz,1H),7.05(s,1H),6.54(s,1H),4.62-4.52(m,3H),4.50(s,2H),3.80(s,3H),2.62(br.s.,2H),2.55-2.42(m,2H),1.86(d,J=8.3Hz,2H),1.69(t,J=7.3Hz,3H)。LCMS:m/z[M+H]+=474。
实施例28
28-1:6-溴-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(200mg,0.82mmol)加入N,N-二甲基甲酰胺(10mL)中,加碳酸钾(113mg,0.82mmol),1-溴-2-甲氧基乙烷(0.77mL,0.82mmol),80℃搅拌5h。反应液倒入水中,用乙酸乙酯(100mLx3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=2:1)纯化得标题化合物为白色固体(70mg,产率57%)。LCMS:m/z[M+H]+=302。
28:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噁唑
-2(3H)-酮
实验操作同实施例1,以6-溴-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噁唑-2(3H)-酮(70mg,0.23mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基-7H-咪唑并[4,5-c]哒嗪(66.28mg,0.23mmol)为原料,得标题化合物(43mg,产率40%)。
1H NMR(400MHz,DMSO-d6)9.56(s,1H),8.86(s,1H),8.45(m,2H),7.47(m,1H),7.37–7.32(m,1H),7.24(s,1H),4.52(m,2H),4.08(m,2H),3.81(s,3H),3.71(m,2H),1.56(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=464.2。
实施例29
29-1:6-溴-3-环丁基-5-甲氧基苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(100mg,0.41mmol)加入N,N-二甲基甲酰胺(10mL)中,加溴代环丁烷(1.11g,8.19mmol),碳酸钾(113.27mg,0.82mmol),加热到80℃搅拌5h。反应液倒入水中,用乙酸乙酯(50mLx3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=2:1)纯化得标题化合物为粉色固体(130mg)。LC-MS:m/z[M+H]+=298。
29:3-环丁基-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑-2(3H)-
酮
实验操作同实施例1,以6-溴-3-环丁基-5-甲氧基苯并[d]噁唑-2(3H)-酮(130mg,0.44mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(124.74mg,0.44mmol)为原料,得标题化合物(45mg,产率22%)。
1H NMR(400MHz,DMSO-d6)9.59(s,1H),8.91(s,1H),8.56–8.35(m,2H),7.50(t,1H),7.39(s,1H),7.22(s,1H),4.95–4.74(m,1H),4.52(q,J=7.3Hz,2H),3.84(s,3H),2.84(m,2H),2.42–2.30(m,2H),1.99–1.75(m,2H),1.56(t,J=7.2Hz,3H)。LC-MS:m/z[M+H]+=460。
实施例30
30-1:7-溴-4-环丙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(500mg,1.94mmol),醋酸铜(352mg,1.94mmol),碳酸铯(316mg,0.97mmol),环丙基硼酸(330mg,3.88mmol)和联吡啶(460mg,5.82mmol)依次加到甲苯(10mL)中,在110℃下搅拌2小时。反应液过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(190mg,33%)。LC-MS:m/z[M+H]+=299,231。
30:4-环丙基-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例7,以7-溴-4-环丙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(190mg,0.70mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(258mg,0.70mmol)为原料,得白色固体标题化合物(99mg,33%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.31-8.22(m,2H),8.18(d,J=6.4Hz,1H),7.33(t,J=9.0Hz,1H),7.00(br.s.,2H),4.63-4.51(m,4H),3.83(s,3H),2.80(br.s.,1H),1.69(t,J=7.1Hz,3H),1.26-1.19(m,4H)。LC-MS:m/z[M+H]+=434。
实施例31
31-1:7-溴-4-乙基-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(500mg,1.94mmol),碘乙烷(454mg,2.91mmol)
和碳酸钾(804mg,5.82mmol)依次加到甲醇(5mL)中,在45℃下搅拌16小时。反应液过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(200mg,36%)。LC-MS:m/z[M+H]+=287,289。
31:4-乙基-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例7,以7-溴-6-甲氧基-4-(2-甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(200mg,0.70mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(258mg,0.70mmol)为原料,得黄色固体标题化合物(72mg,23%)。
1H NMR(400MHz,CHLOROFORM-d)9.34(s,1H),8.31-8.20(m,2H),8.17(d,J=6.8Hz,1H),7.31(t,J=8.8Hz,1H),7.02(s,1H),6.64(s,1H),4.61-4.50(m,4H),4.02(q,J=6.8Hz,2H),3.81(s,3H),1.66(t,J=7.3Hz,3H),1.33(t,J=6.8Hz,3H)。LC-MS:m/z[M+H]+=448。
实施例32
32-1:3-乙基-5-甲氧基苯并[d]噻唑-2(3H)-酮
将5-甲氧基-2,3-二氢-1,3-苯并噻唑-2-酮(CAS:15193-51-8 300mg,1.7mmol)溶于10mL甲醇中,加入碘乙烷(1.3g,8.3mmol)和碳酸钾(0.5g,3.3mmol)加热至40摄氏度搅拌2小时,过滤碳酸钾,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到黄色固体标题化合物(200mg,57%)。LC-MS:m/z[M+H]+=210。
32-2:6-溴-3-乙基-5-甲氧基苯并[d]噻唑-2(3H)-酮
将3-乙基-5-甲氧基苯并[d]噻唑-2(3H)-酮(200mg,0.96mmol)溶于2mL醋酸中,加入33%氢溴酸醋酸溶液(588mg,2.4mmol)室温搅拌30分钟后冷却至0摄氏度,加入双氧水(163mg,1.44mmol)后升至室温搅拌2小时,加入水,大量固体析出,过滤,干燥,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到白色固体标题化合物(100mg,36%)。LC-MS:m/z[M+H]+=288。
32:3-乙基-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噻唑-2(3H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(120mg,0.33mmol),6-溴-3-乙基-5-甲氧基苯并[d]噻唑-2(3H)-酮(100mg,0.33mmol)为原料,得到白色固体标题化合物(16mg,11%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(br.s.,1H)8.18-8.34(m,3H)7.41(s,1H)7.34(t,J=8.80Hz,1H)6.72(s,1H)4.59(q,J=6.85Hz,2H)4.03-4.12(m,2H)3.89(s,3H)1.67-1.70(m,3H)1.41(t,J=6.85Hz,3H)。LC-MS:m/z[M+H]+=450。
实施例33
33-1:5-甲氧基-3-(2-甲氧基乙基)苯并[d]噻唑-2(3H)-酮
将5-甲氧基-2,3-二氢-1,3-苯并噻唑-2-酮(CAS:15193-51-8 300mg,1.7mmol)溶于10mL乙腈中,加入1-溴-2-甲氧基乙烷(346mg,2.5mmol)和碳酸铯(1.1g,03.3mmol)加热至60摄氏度搅拌过夜,过滤碳酸铯,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到黄色固体标题化合物(200mg,50%)。LC-MS:m/z[M+H]+=241。
33-2:6-溴-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噻唑-2(3H)-酮
将5-甲氧基-3-(2-甲氧基乙基)苯并[d]噻唑-2(3H)-酮(200mg,0.96mmol)溶于2mL醋酸中,加入33%氢溴酸醋酸溶液(588mg,2.4mmol)室温搅拌30分钟后冷却至0摄氏度,加入双氧水(163mg,1.44mmol)后升至室温搅拌2小时,加入水,大量固体析出,过滤,干燥,浓缩,制备板纯化(石油醚:乙酸乙酯=2:1)得到白色固体标题化合物(120mg,39%)。LC-MS:m/z[M+H]+=318。
33:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噻唑
-2(3H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(129mg,0.35mmol),6-溴-5-甲氧基-3-(2-甲氧基乙基)苯并[d]噻唑-2(3H)-酮(110mg,0.35mmol)为原料,得到白色固体标题化合物(125mg,74%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H)8.20-8.32(m,3H)7.31-7.40(m,2H)6.95(s,1H)4.59(q,J=7.34Hz,2H)4.19(t,J=5.14Hz,2H)3.87(s,3H)3.74(t,J=5.14Hz,2H)3.38(s,3H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=480。
实施例34
34-1:6-溴-3-(环丙基甲基)-5-甲氧基苯并[d]噁唑-2(3H)-酮
在氮气的惰性气氛下,将6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(100mg,0.4mmol)用N-甲基吡咯烷酮(10mL)溶解后,在0℃下加入氰化钠(40mg,1.0mmol),加完室温搅拌15分钟后,加(溴甲基)环丙烷(108mg,0.8mmol)搅拌2小时。反应液倒入冰水(50mL)中,用乙酸乙酯(100mLx3)萃取,旋干后柱层析(石油醚:乙酸乙酯=4:1)纯化得到标题产物(110g,产率90%)黄色固体。LC-MS:m/z[M+H]+=298.0。
34:3-(环丙基甲基)-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑
-2(3H)–酮
实验操作同实施例1,以6-溴-3-(环丙基甲基)-5-甲氧基苯并[d]噁唑-2(3H)-酮(75mg,0.25mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(86mg,0.3mmol)为原料,得标题化合物(30mg,产率26%)白色固体。
1H NMR(400MHz,CDCl3)9.40(s,1H),8.35(s,1H),8.31–8.22(m,2H),7.35(t,1H),7.24(s,1H),6.73(s,1H),4.59(q,J=7.3Hz,2H),3.86(s,3H),3.77(d,J=7.0Hz,2H),1.70(t,J=7.3Hz,3H),1.28(m,1H),0.70–0.60(m,2H),0.49(m,2H)。LC-MS:m/z[M+H]+=460。
实施例35
35-1:6-溴-5-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(200mg,0.82mmol)加入二甲亚砜(20mL)中,加碘甲烷(1.53mL,24.59mmol),碳酸铯(534mg,1.64mmol),80℃搅拌3h。反应液倒入水中,乙酸乙酯(40mLx3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=2:1)纯化得标题化合物为紫色固体(130mg,产率49%)。
1H NMR(400MHz,DMSO-d6)7.64(s,1H),7.19(s,1H),3.88(s,3H),3.35(s,3H)。LC-MS:m/z[M+H]+=258。
35:6-(2-氟-5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)苯基)-5-甲氧基-3-甲基苯并[d]噁唑-2(3H)-
酮
实验操作同实施例1,以6-溴-5-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮(30mg,0.12mmol),(2-氟-5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)苯基)硼酸(44mg,0.12mmol)为原料,得标题化合物(40mg,产率77%)。LC-MS:m/z[M+H]+=434.2。
1H NMR(400MHz,DMSO-d6)9.60(s,1H),8.99(s,1H),8.70–8.40(m,2H),7.61–7.45(m,1H),7.38(s,1H),7.21(s,1H),5.11(m,1H),3.82(s,3H),3.42(s,3H),1.68(m,6H)。
实施例36
36-1:6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(500mg,2.8mmol),碳酸铯(2.8g,8.4mmol)和碘甲烷(800mg,5.6mmol)依次加入到20mL甲醇中,加热至35摄氏度搅拌2小时,过滤碳酸铯,浓缩,制备板纯化(二氯甲烷:甲醇=30:1),得到棕色固体标题化合物(400mg,74%)。LC-MS:m/z[M+H]+=194。
36-2:7-溴-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(400mg,2mmol),溶于5mL的醋酸中,加入3M溴化氢醋酸溶液2mL室温搅拌30分钟后冷却至0摄氏度,加入双氧水1mL后升至室温搅拌2小时,加水,大量固体析出,用二氯甲烷萃取,干燥,浓缩,制备板纯化(二氯甲烷:甲醇=30:1),得到白色固体标题化合物(180mg,32%)。LC-MS:m/z[M+H]+=272。
36:7-(2-氟-5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)苯基)-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例1,以7-溴-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(151mg,0.55mmol)和4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-7-异丙基-7H-咪唑并[4,5-c]哒嗪(141mg,0.37mmol)为原料,得标题化合物(140mg,85%)。
1H NMR(400MHz,DMSO-d6)9.53(s,1H),8.92(s,1H),8.42(d,J=7.3Hz,2H),7.47(t,J=9.0Hz,1H),7.03(s,1H),6.92(s,1H),5.13-5.08(m,1H),4.67-4.62(m,2H),3.80(s,3H),3.37(s,3H),1.66(d,J=6.8Hz,6H)。LC-MS:m/z[M+H]+=448。
实施例37
37-1:4-溴-3-甲氧基-2-甲基苯胺
将3-甲氧基-2-甲基苯胺(5.48g,40.0mmol),加入到N,N-二甲基甲酰胺(50mL)中。然后分批加入N-溴代丁二酰亚胺(7.2g,40.0mmol),室温条件下反应2h。反应液倒入水(200mL)中,乙酸乙酯(100mL x 3)萃取,有机相旋干后柱层析分离(石油醚/乙酸乙酯=4:1),得到灰色标题化合物固体(3.5g,产率41%)。LCMS:m/z[M+H]+=216.1。
37-2:4-溴-3-甲氧基-2-甲基苯磺酰氯
将4-溴-3-甲氧基-2-甲基苯胺(2.0g,9.3mmol)溶解于盐酸(8mL)、醋酸(4mL)和乙腈(30mL)混合溶液中,搅拌10分钟后降至0℃滴加亚硝酸钠(5N,2mL)并反应30分钟,滴加饱和的二氧化硫醋酸溶液(5mL),控制温度不超过5℃并保持10分钟.再滴加氯化铜水溶液(2.4g,2mL/g)并恢复至室温反应16h,倒入水(100mL)中,乙酸乙酯(100mL x 3)萃取,有机相用盐水洗,饱和碳酸氢钠洗至弱碱性,干燥,浓缩得到灰色标题化合物粗品1.5g。LCMS:m/z[M+H]+=298.9。
37-3:4-溴-3-甲氧基-N,2-二甲基苯磺酰胺
将4-溴-3-甲氧基-2-甲基苯磺酰氯(200mg,0.67mmol)和甲胺盐酸盐(90mg,1.33mmol)依次加入到二氯甲烷(10mL)中。然后,逐滴加入三乙胺(203mg,2.01mmol),室温条件下反应2h。反应液倒入水(50mL)中,乙酸乙酯(50mL x 3)萃取旋干得到灰色标题化合物固体(200mg)。1H NMR(400MHz,CDCl3)7.64(d,J=8.5Hz,1H),7.58–7.50(m,1H),3.83(s,3H),2.66(d,J=4.5Hz,3H),2.61(s,3H)。LCMS:m/z[M+H]+=294。
37-4:4-溴-2-(溴甲基)-3-甲氧基-N-甲基苯磺酰胺
将原料4-溴-3-甲氧基-N,2-二甲基苯磺酰胺(200mg,0.67mmol)与过氧化二苯甲酰(100mg,0.41mmol)加入到四氯化碳(10mL)与二氯甲烷(4mL)混合溶液中。将原料N-溴代丁二酰亚胺(145mg,0.81mmol)分批加入到反应液中。90℃下反应过夜。反应液中加水(100mL),乙酸乙酯(50mL×3)萃取浓缩,柱层析纯化(石油醚/乙酸乙酯=20%~30%),得白色标题化合物固体(110mg,产率44%)。1H NMR(400MHz,DMSO-d6)7.94–7.84(m,2H),7.55(t,J=12.4Hz,1H),4.96(s,2H),4.04–3.97(m,3H),2.49(s,3H)。LCMS:m/z[M+H]+=373。
37-5:5-溴-4-甲氧基-2-甲基-2,3-二氢苯并[d]异噻唑1,1-二氧化物
将4-溴-2-(溴甲基)-3-甲氧基-N-甲基苯磺酰胺(110mg,0.29mmol)加入到N,N-二甲基甲酰胺(10mL)中。常温下加入氢化钠(14mg,0.35mmol)反应1小时。倒入水(50mL)中,乙酸乙酯(50mL x 3)萃取旋干,TLC板纯化(石油醚/乙酸乙酯=4:1),得到白色标题化合物固体(10mg,产率11.8%)。1H NMR(400MHz,CDCl3)7.65(m,1H),7.49–7.30(m,1H),4.29(s,2H),3.86(s,3H),2.89(s,3H)。LCMS:m/z[M+H]+=292。
37:5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-4-甲氧基-2-甲基-2,3-二氢苯并[d]异噻唑
1,1-二氧化物
实验操作同实施例1,以5-溴-4-甲氧基-2-甲基-2,3-二氢苯并[d]异噻唑1,1-二氧化物(10mg,0.034mmol)和(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(10mg,0.035mmol)为原料,得到白色标题化合物固体(2.7mg,产率18%)。
1H NMR(400MHz,DMSO-d6)9.59(s,1H),8.88(s,1H),8.57(t,2H),7.74(d,1H),7.68(d,1H),7.60(t,1H),4.63(s,2H),4.52(q,J=7.2Hz,2H),3.72(s,3H),2.89(s,3H),1.56(t,J=7.3Hz,3H)。LCMS:m/z[M+1]+=454。
实施例38
38-1:6,7-二氢苯并[b]噻吩-4-(5H)-酮
将4-(噻吩-2-基)丁酸(5000mg,29.37mmol)和三氟乙酸酐(18510mg,88.11mmol)依次加到三氟乙酸(40mL)中,在室温下搅拌2小时。把反应液浓缩,加入水(40mL),水相经乙酸乙酯(30mL x 3)萃取,合并有机相,饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得得棕色液体标题化合物(5400mg,粗产物)。1H NMR(400MHz,CHLOROFORM-d)δ=7.39(d,J=5.4Hz,1H),7.07(d,J=5.4Hz,1H),3.04(t,J=5.9Hz,2H),2.59(t,J=6.4Hz,2H),2.22(q,J=6.2Hz,2H)。
38-2:5,5-二溴-6,7-二氢苯并[b]噻吩-4-(5H)-酮
将乙酸乙酯(20mL),6,7-二氢苯并[b]噻吩-4-(5H)-酮(5000mg,32.85mmol)和溴化铜(14670mg,65.7mmol)依次加到氯仿(20mL)中,在80℃下敞口搅拌16小时。反应液过滤,滤出的固体经硅胶柱纯化(石油醚:乙酸乙酯=100:1)得产物缩得棕色固体标题化合物(1500mg,15%)。1H NMR(400MHz,CHLOROFORM-d)δ=7.47(d,J=4.9Hz,1H),7.16(d,J=4.9Hz,1H),3.15(s,4H)。
38-3:5-溴苯并[b]噻吩-4-醇
将5,5-二溴-6,7-二氢苯并[b]噻吩-4-(5H)-酮(1400mg,4.52mmol)和碳酸锂(1000mg,13.56mmol)依次加到N,N-二甲基甲酰胺(20mL)中,在100℃下搅拌3小时。反应液加入水(50mL),水相经乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得白色固体标题化合物(1000mg,94%)。1H NMR(400MHz,CHLOROFORM-d)δ=7.52(d,J=5.4Hz,1H),7.40-7.35(m,2H),7.34-7.30(m,1H),6.32(br.s.,1H)。
38-4:5-溴-4-甲氧基苯并[b]噻吩
将5-溴苯并[b]噻吩-4-醇(1000mg,4.37mmol),硫酸二甲酯(1650mg,13.11mmol)和碳酸钾(1810mg,13.11mmol)依次加到丙酮(40mL)中,在50℃下搅拌16小时。反应液过滤,滤渣经丙酮(5mL x 3)洗涤,滤液减压浓缩后,加甲醇(20mL)溶解,加入氢氧化钠(600mg),在室温下搅拌0.5h淬灭多余的硫酸二甲酯。然后过滤,把滤液减压浓缩得棕色固体标题化合物(1000mg,97%)。1H NMR(400MHz,CHLOROFORM-d)δ=7.52-7.42(m,4H),4.00(s,3H)。
38-5:5-溴-4-甲氧基苯并[b]噻吩1,1-二氧化物
将5-溴-4-甲氧基苯并[b]噻吩(600mg,2.47mmol)和过硫酸氢钾(4555mg,7.41mmol)依次加
到甲醇(5mL)四氢呋喃(5mL)水(5mL)的混合溶剂中,在40℃下搅拌16小时。反应液加入水(100mL)稀释,过滤烘干得白色固体标题化合物(500mg,74%)。LC-MS:m/z[M+H]+=276,278。
38-6:5-溴-4-甲氧基-2,3-二氢苯并[b]噻吩1,1-二氧化物
将5-溴-4-甲氧基苯并[b]噻吩1,1-二氧化物(200mg,0.73mmol)和氰基硼氢化钠(55mg,1.46mmol)依次加到乙醇(10mL)中,在室温下搅拌2小时。反应液加入盐酸水溶液(1M)调至弱酸,加入水(20mL)稀释,分液,水相经二氯甲烷(20mL×3)萃取,合并有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩除去溶剂得白色固体标题化合物(150mg,74%)。LC-MS:m/z[M+H]+=278,280.
38:5-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-4-甲氧基-2,3-二氢苯并[b]噻吩-1,1-二
氧化物
实验操作同实施例1,以5-溴-4-甲氧基-2,3-二氢苯并[b]噻吩1,1-二氧化物(120mg,0.43mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(158mg,0.43mmol)为原料,得白色固体标题化合物(40mg,21%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.40(br.s.,1H),8.38-8.28(m,3H),7.64-7.52(m,2H),7.41(t,J=8.8Hz,1H),4.59(q,J=7.3Hz,2H),3.63(s,3H),3.60-3.52(m,2H),3.51-3.42(m,2H),1.70(t,J=7.1Hz,3H).LC-MS:m/z[M+H]+=439.
实施例39
39:5-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-2-(三氟甲基)喹啉
实验操作同实施例1,以乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.27mmol),5-溴-2-(三氟甲基)喹啉(74mg,0.27mmol)为原料,得标题化合物白色固体(68mg,55.31%)。
1H NMR(400MHz,CHLOROFORM-d)d=9.41(s,1H),8.42-8.22(m,5H),7.94(t,J=7.8Hz,1H),7.81-7.70(m,2H),7.49(t,J=8.8Hz,1H),4.60(q,J=7.0Hz,2H),1.70(t,J=7.3Hz,3H).LC-MS:m/z[M+H]+=438.
实施例40、实施例41
40-1:1-(5-溴-4-甲氧基-2-硝基苯基)-N-(1-甲基哌啶-4-基)甲胺
将5-溴-4-甲氧基-2-硝基苯甲醛(780mg,3.0mmol),1-甲基哌啶-4-胺(342mg,3.0mmol)加入甲苯(50mL)中,110℃搅拌16小时。将反应液浓缩得标题化合物为黄褐色色油状物(1.0g,产率94%)。LC-MS:m/z[M+H]+=356
40-2:5-溴-6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑
将1-(5-溴-4-甲氧基-2-硝基苯基)-N-(1-甲基哌啶-4-基)甲胺(1.0g,2.8mmol)用磷酸三乙酯(20mL)溶解,150℃反应2小时后。反应液直接柱层析(二氯甲烷:甲醇=12:1)纯化得标题化合物为黄色固体(650mg,产率71%)。LC-MS:m/z[M+H]+=324
40-3:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑(324mg,1.0mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基-7H-咪唑并[4,5-c]哒嗪(286g,1.0mmol)为原料,得到黄褐色固体(200mg,产率37%)。LC-MS:m/z[M+H]+=486。
实施例40:rel-(R)-4-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2
-yl)-1-甲基哌啶-2-酮
实施例41:rel-(S)-4-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2
-yl)-1-甲基哌啶-2-酮
将7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪(175mg,0.36mmol)用四氢呋喃(20mL)溶解,加入碳酸氢钠(303mg,3.6mmol)单质碘(916mg,3.6mmol)和水(8mL),30℃下搅拌24小时后,将反应液倒入水(50mL)中,乙酸乙酯萃取(50mLx3),干燥,浓缩,柱层析分离(二氯甲烷:甲醇=10:1)得到黄色固体(120mg),HPLC制备纯化得到白色固体(60mg)。然后,SFC手性拆分得实施例40和实施例41。拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:A for CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
实施例40:得到标题产物(7.2mg,白色固体,第二个峰)。1H NMR(400MHz,CDCl3)9.43(brs,1H),8.35(m,2H),8.23(d,1H),7.92(s,1H),7.62(s,1H),7.35(t,1H),7.11(s,1H),4.91(m,1H),4.59(d,J=7.1Hz,2H),3.87(s,3H),3.43(m,1H),3.35(m,1H),3.09(m,2H),3.02(s,3H),2.56(m,1H),2.49(m,1H),1.70(t,J=7.0Hz,3H)。LC-MS:m/z[M+H]+=500。
实施例41:得标题产物(6.2mg,白色固体,第一个峰)。1H NMR(400MHz,CDCl3)9.41(brs,1H),8.31(m,2H),8.21(d,1H),7.91(s,1H),7.62(s,1H),7.34(t,1H),7.11(s,1H),4.89(m,1H),4.59(q,J=7.1Hz,2H),3.87(s,3H),3.53–3.39(m,1H),3.39–3.28(m,1H),3.19–3.05(m,2H),3.02(s,3H),2.67–2.52(m,1H),2.48(s,1H),1.69(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=500。
实施例42
42:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(220mg,0.6mmol),7-溴-6-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(160mg,0.6mmol)
为原料,得到棕色固体标题化合物(97mg,37%)。
1H NMR(400MHz,CHLOROFORM-d)9.54(s,1H)8.86(s,1H)8.37-8.46(m,2H)7.43-7.51(m,1H)7.04(s,1H)6.93(s,1H)4.65(s,2H)4.50(d,J=7.34Hz,2H)3.81(s,3H)3.38(s,3H)1.55(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=434。
实施例43
43-1:5-甲氧基-2,3-二甲基苯并[b]噻吩
4-甲氧基苯硫酚(501mg,3.57mmol)加入反应瓶中,0℃搅拌15分钟。氢氧化钠(285mg,7.14mmol)溶于水(3ml)中缓慢加入反应液,加完后0℃搅拌30分钟。3-溴-2-丁酮(1g,6.62mmol)缓慢加至反应液,加完后室温搅拌1小时。反应液倒入水(30ml)中,二氯甲烷萃取,有机相无水硫酸钠干燥,浓缩得粗品中间体。多聚磷酸(3.24g,39.5mmol)、上步粗品缓慢加到反应瓶中,150℃搅拌1小时。反应液冷却至室温,倒入水(30ml)中,二氯甲烷萃取,有机相浓缩。柱层析(石油醚/乙酸乙酯=50/1)得标题化合物黄色油状液滴(480mg,57%)。1H NMR(400MHz,CHLOROFORM-d)7.61(d,J=8.8Hz,1H),7.05(d,J=2.0Hz,1H),6.93(dd,J=2.0,8.8Hz,1H),3.89(s,3H),2.48(s,3H),2.27(s,3H)。
43-2:6-溴-5-甲氧基-2,3-二甲基苯并[b]噻吩
5-甲氧基-2,3-二甲基苯并[b]噻吩(480mg,2.5mmol)加到乙醚(3ml)中,0℃搅拌10分钟。液溴(400mg,2.5mmol)溶于乙醚(2ml)中,0℃下缓慢滴加至反应液。加完后,缓慢升至室温继续搅拌1小时。反应液倒入饱和碳酸氢钠水溶液(30ml),室温搅拌10分钟,乙酸乙酯萃取,有机相干燥,浓缩,HPLC制备得标题化合物与4-溴-5-甲氧基-2,3-二甲基苯并[b]噻吩棕色固体(240mg)。1H NMR(400MHz,CHLOROFORM-d)7.87(s,1H),7.00(s,1H),3.97(s,3H),2.46(s,3H),2.26(s,3H)。
43:7-乙基-4-(4-氟-3-(5-甲氧基-2,3-二甲基苯并[b]噻吩-6-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(70mg,0.19mmol),6-溴-5-甲氧基-2,3-二甲基苯并[b]噻吩(103mg,0.19mmol)为原料,得标题化合物白色固体(11mg,13%)。
1H NMR(400MHz,CHLOROFORM-d)d=9.37(s,1H),8.32-8.19(m,3H),7.69(s,1H),7.33(t,J=8.8Hz,1H),7.13(s,1H),4.57(q,J=7.3Hz,2H),3.90(s,3H),2.50(s,3H),2.32(s,3H),1.68(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=433。
实施例44
44-1:2-氯-1-甲氧基-3-(2-甲氧基乙烯基)苯
在0℃下,将叔丁醇钾(855mg,7.62mmol)加入氯化(甲氧基甲基)三苯基(2.61g,7.62mmol)的四氢呋喃(20mL)中,并将混合物搅拌1小时。然后滴加2-氯-3-甲氧基苯甲醛(1g,5.86mmol),将该溶液在0℃下搅拌1小时。加入饱和氯化铵水溶液并将混合物用乙醚(3×40mL)萃取。合并的有机相用水和盐水洗涤,然后经无水硫酸钠干燥,在真空中浓缩得到2-氯-1-甲氧基-3-(2-甲氧基乙烯基)苯(1g,产率85%),无需进一步纯化即可使用。
44-2:2-(2-氯-3-甲氧基苯基)乙醛
将6N HCl(20mL)添加到2-氯-1-甲氧基-3-(2-甲氧基乙烯基)苯(1g)的四氢呋喃溶液中(20mL),并将混合物加热回流4小时。加入水,然后用乙醚(3×40mL)萃取。合并的有机相用水和盐水洗涤。然后经无水硫酸钠干燥并真空浓缩。然后通过柱色谱纯化(石油醚:乙酸乙酯=100:1~10:1)获得无色油状的2-(2-氯-3-甲氧基苯基)乙醛(500mg,产率45%)。
44-3:2-(2-氯-3-甲氧基苯基)乙-1-醇
在0℃下,将硼氢化钠(0.61g,15mmol)添加到2-(2-氯-3-甲氧基苯基)乙醛(1g,15mmol)的甲醇溶液中。将混合物在0℃下搅拌2小时。加入饱和碳酸氢钠水溶液,混合物用乙醚萃取(3x 10mL)。合并的有机相经无水硫酸钠干燥并真空浓缩,然后通过柱色谱纯化(石油醚:乙酸乙酯=100:1~10:1)得到呈无色油状的2-(2-氯-3-甲氧基苯基)乙-1-醇(0.3g,产率29%)。1H NMR(400MHz,CDCl3)7.15(dd,1H),6.88(dd,1H),6.81(dd,1H),3.86(m,5H),3.01(t,2H),1.85(s,1H)。
44-4:4-氯-5-甲氧基-2,3-二氢苯并呋喃
在0℃氩气氛围下,将双(三氟乙酰氧基)碘]对甲苯(720mg,1.76mmol),三乙胺(40mg,0.4mmol)添加到2-(2-氯-3-甲氧基苯基)乙-1-醇(300mg,1.6mmol)的三氟乙醇(30mL)中。将混合物在50℃搅拌36小时。在50℃下,加入三乙胺(640mg,6.4mmol)后立即加入六氟乙酰丙酮铜(II)(760mg,1.6mmol)。将该混合物加热至50℃并搅拌直至碘鎓盐中间体消耗。加入饱和碳酸氢钠水溶液,混合物用乙醚萃取(3x 10mL)。合并的有机相经无水硫酸钠干燥并真空浓缩,然后通过柱色谱纯化(石油醚:乙酸乙酯=100:1~10:1)得到4-氯-5-甲氧基-2,3-二氢苯并呋喃(40mg,产率14%)白色的固体。1H NMR(400MHz,CDCl3)6.69(d,1H),6.61(d,H),4.59(t,2H),3.84(s,3H),3.24(t,2H)。
44:7-乙基-4-(4-氟-3-(5-甲氧基-2,3-二氢苯并呋喃-4-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以4-氯-5-甲氧基-2,3-二氢苯并呋喃(30mg,0.16mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(45mg,0.16mmol)为原料,得标题化合物(14mg,产率16%)。
1H NMR(400MHz,DMSO-d6)9.39(s,1H),8.43–8.10(m,3H),7.36(t,1H),6.85–6.73(m,2H),4.57(t,4H),3.74(s,3H),3.10(m,2H),1.70(m,3H)。LC-MS:m/z[M+H]+=391。
实施例45
45-A1:6-溴-5-甲氧基-1-甲基-1H-吲唑
45-A2:6-溴-5-甲氧基-2-甲基-2H-吲唑
将6-溴-5-甲氧基-1H-吲唑(200mg,0.88mmol),碳酸铯(287mg,0.88mmol),碘甲烷(125mg,0.88mmol)依次加入四氢呋喃(5ml)中。35摄氏度搅拌过夜。反应液直接薄层层析(石油醚/乙酸乙酯=5/1)得到A1化合物(76mg,36%,Rf=0.4),得到A2化合物(70mg,33%,Rf=0.3)。LC-MS:m/z[M+H]+=241。
45:7-乙基-4-(4-氟-3-(5-甲氧基-2-甲基-2H-吲唑-6-基)苯基)-7H-咪唑并4,5-c]哒嗪
实验操作同实施例1,以6-溴-5-甲氧基-2-甲基-2H-吲唑(70mg,0.29mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(107mg,0.29mmol)为原料,得到标题化合物(20mg,16%)。LC-MS:m/z[M+H]+=403。
1H NMR(400MHz,DMSO-d6)d ppm 1.51(br.s.,3H)3.72(br.s.,3H)4.12(br.s.,3H)4.47(br.s.,2H)7.14(br.s.,1H)7.35-7.63(m,2H)8.21(br.s.,1H)8.45(br.s.,2H)8.81(br.s.,1H)9.53(br.s.,1H)。
实施例46、实施例47
46-1:4-((5-溴-4-甲氧基-2-硝基亚苄基)氨基)-3,3-二氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(780mg,3.0mmol),4-氨基-3,3-二氟哌啶-1-羧酸叔丁酯(1.06g,4.5mmol)为原料,得标题化合物为黄色色油状物(950mg,产率66%)。LC-MS:m/z[M+H-56]+=422。
46-2:4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,3-二氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1的合成方法,以4-((5-溴-4-甲氧基-2-硝基亚苄基)氨基)-3,3-二氟哌啶-1-羧酸叔丁酯(950mg,2.0mmol)为原料,得标题化合物为蓝褐色固体(500mg,产率56%)。LC-MS:m/z[M+H]+=446。
46-3:5-溴-2-(3,3-二氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐
将4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,3-二氟哌啶-1-羧酸叔丁酯(500mg,1.1mmol)用甲醇(25mL)溶解后,加入盐酸1,4二氧六环溶液(4mol/L,25mL),室温反应2小时后,反应液直接浓缩得标题化合物为白色固体(420mg,产率98%)。LC-MS:m/z[M+H]+=346。
46-4:5-溴-2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑
将5-溴-2-(3,3-二氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐(420mg,1.1mmol)用二氯甲烷(20mL)
溶解后,依次加入甲醛(37%水溶液,1mL),乙酸(0.5mL),搅拌30分钟后加入三乙酰氧基硼氢化钠(467mg,2.2mmol),室温搅拌16小时。将反应液直接浓缩,经过柱层析(二氯甲烷:甲醇=10:1)纯化得标题化合物为类白色固体(396mg,产率99.5%)。LC-MS:m/z[M+H]+=360。
实施例46:rel-(S)-4-(3-(2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙
基-7H-咪唑并[4,5-c]哒嗪
实施例47:rel-(R)-4-(3-(2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙
基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑(396mg,1.1mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基-7H-咪唑并[4,5-c]哒嗪(315g,1.1mmol)为原料,得到黄色固体(570mg)。进一步手性拆分,拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:A for CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
实施例46:得到标题化合物(275mg,第一个峰)。1H NMR(400MHz,CDCl3)9.38(s,1H),8.35–8.25(m,2H),8.22(m,1H),8.07(s,1H),7.65(s,1H),7.33(t,1H),7.09(s,1H),4.81(s,1H),4.58(q,J=7.3Hz,2H),3.92–3.80(m,3H),3.40(m,2H),2.56(m,6H),1.69(t,J=7.3Hz,3H),1.32(m,1H).LC-MS:m/z[M+H]+=522。
实施例47:得到标题化合物(273mg,第二个峰)。1H NMR(400MHz,DMSO-d6)9.56(s,1H),8.85(s,1H),8.55–8.36(m,3H),7.71(s,1H),7.48(t,J=9.1Hz,1H),7.14(s,1H),5.06(m,1H),4.51(q,J=7.2Hz,2H),3.80(s,3H),3.22(m,1H),2.99(m,1H),2.64–2.53(m,1H),2.35(m,4H),2.16(m,1H),1.55(t,J=7.3Hz,3H),1.26(m,1H).LC-MS:m/z[M+H]+=522。
实施例48
48:7-乙基-4-(4-氟-3-(5-甲氧基-1-甲基-1H-吲唑-6-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以6-溴-5-甲氧基-1-甲基-1H-吲唑(70mg,0.29mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(107mg,0.29mmol)为原料,得到标题化合物(33mg,28%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(br.s.,1H),8.41-8.17(m,3H),7.93(br.s.,1H),7.45-7.32(m,2H),7.19(br.s.,1H),4.66-4.46(m,2H),4.07(s,3H),3.85(s,3H),1.68(t,J=6.8Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例49
49-A1:5-溴-6-甲氧基-1-甲基-1H-吲唑
49-A2:5-溴-6-甲氧基-2-甲基-2H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol)加到无水N,N-二甲基甲酰胺(5mL)中,在室温下加入氢化钠(43mg,1.06mmol),在室温下搅拌0.5小时后,加入碘甲烷(151mg,1.06mmol),再在室温下搅拌0.5小时。把反应液滴到饱和氯化铵水溶液(20mL)中,用乙酸乙酯萃取(20mL×3),合并有机相,并用饱和食盐水(30mL)洗涤,浓缩有机相,制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得黄色固体5-溴-6-甲氧基-1-甲基-1H-吲唑(150mg,70%),白色固体5-溴-6-甲氧基-2-甲基-2H-吲唑(60mg,28%)。
A1:5-溴-6-甲氧基-1-甲基-1H-吲唑(展开剂石油醚:乙酸乙酯=3:1,Rf=0.5),1H NMR(400MHz,CHLOROFORM-d)7.89(s,1H),7.83(s,1H),6.74(s,1H),4.03(s,3H),3.98(s,3H).LC-MS:m/z[M+H]+=241,243。
A2:5-溴-6-甲氧基-2-甲基-2H-吲唑(展开剂石油醚:乙酸乙酯=3:1,Rf=0.3),1H NMR(400MHz,CHLOROFORM-d)7.85(s,1H),7.76(s,1H),7.02(s,1H),4.16(s,26H),3.94(s,3H).LC-MS:m/z[M+H]+=241,243。
49:4-(4-氟-3-(6-甲氧基-2-甲基-2H-吲唑-5-基)苯基)-7-异丙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-甲基-2H-吲唑(52mg,0.22mmol)和4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-7-异丙基-7H-咪唑并[4,5-c]哒嗪(68.8mg,0.18mmol)为原料,得标题化合物(45mg,60%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.34-8.24(m,2H),8.19(d,J=4.9Hz,1H),7.85(s,1H),7.60(s,1H),7.32(t,J=9.0Hz,1H),7.08(s,1H),5.18(br.s.,1H),4.19(s,3H),3.86(s,3H),1.75(d,J=6.8Hz,6H)。LC-MS:m/z[M+H]+=417。
实施例50
50-1:1-溴-2,4-二氟-3-硝基苯
将1,3-二氟-2-硝基苯(5.0g,31.4mmol)用浓硫酸(10mL)和三氟乙酸(50mL)的混合液溶解后,加入N-溴代丁二酰亚胺(6.7g,37.7mmol),室温搅拌16h。将反应液倒入冰水(300mL)中,用乙酸乙酯
(150mlx3)萃取,合并有机相,再分别用2mol/L的氢氧化钠溶液(200mLx2)、饱和碳酸氢钠溶液(200mL)和饱和食盐水(200mL)洗,无水硫酸钠干燥,浓缩后后得到红色油状液体(5.0g,产率65%)。
50-2:1-溴-4-氟-2-甲氧基-3-硝基苯
将1-溴-2,4-二氟-3-硝基苯(4.5g,18.9mmol)溶入甲醇(50mL)中,滴加甲醇钠的甲醇溶液(4.0mL,5mol/L),室温搅拌2小时后倒入冰水(200mL)中,用乙酸乙酯(150mlx3)萃取,合并有机相,无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=10:1)纯化后得到白色固体(1.0g,产率21%)。1H NMR(400MHz,DMSO-d6)8.04(dd,J=9.2Hz,5.9Hz,1H),7.44(t,J=9.3Hz 1H),3.95(s,3H)。
50-3:4-溴-N-环丙基-3-甲氧基-2-硝基苯胺
将1-溴-4-氟-2-甲氧基-3-硝基苯(500mg,2.0mmol),环丙胺(1.14g,20mmol)和二甲基亚砜(5mL)加入微波管中并将此反应于微波下80℃反应2小时。将反应液倒入冰水(50mL)中,用乙酸乙酯(50mlx3)萃取,合并有机相,无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=15:1)纯化后得到黄色固体(300mg,产率85%)。LC-MS:m/z[M+H]+=287。
50-4:4-溴-N1-环丙基-3-甲氧基苯-1,2-二胺
将4-溴-N-环丙基-3-甲氧基-2-硝基苯胺(300.0mg,1.04mmol)溶于甲醇(20mL)中,并加入雷尼镍(100mg),氢气球下室温搅拌2小时后,反应完毕。过滤,滤液浓缩得到棕色固体(256mg,收率:94%)。LC-MS:m/z[M+H]+=257。
50-5:5-溴-1-环丙基-4-甲氧基-1H-苯并[d][1,2,3]三唑
将4-溴-N1-环丙基-3-甲氧基苯-1,2-二胺(256mg,1.0mmol)用乙酸(5mL)溶解加入反应瓶中,0℃下再将亚硝酸钠(173mg,2.5mmol)的水溶液(1mL)滴加到反应瓶中,室温搅拌30min后将反应液倒入水(30mL)中,用乙酸乙酯(50mLx5)萃取,浓缩,柱层析(石油醚:乙酸乙酯=2:1)纯化后得到黄色固体(150mg,产率56%)。LC-MS:m/z[M+H]+=268。
50:4-(3-(1-环丙基-4-甲氧基-1H-苯并[d][1,2,3]三唑-5-基)-4-氟苯基)-7-异丙基-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-1-环丙基-4-甲氧基-1H-苯并[d][1,2,3]三唑(58mg,0.22mmol)和4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-7-异丙基-7H-咪唑并[4,5-c]哒嗪(68.8mg,0.18mmol)为原料,得标题化合物(45mg,60%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.32(s,1H),8.29-8.20(m,2H),7.49(d,J=8.3Hz,1H),7.41-7.31(m,2H),5.32-5.15(m,1H),4.60(s,3H),3.78(d,J=3.9Hz,1H),1.77(d,J=6.4Hz,6H),1.41(br.s.,2H),1.33(d,J=5.9Hz,2H)。LC-MS:m/z[M+H]+=444。
实施例51
51-1:6-溴-3-环丙基-5-甲氧基苯并[d]噁唑-2(3H)-酮
将6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(500mg,2.05mmol),乙酸铜(102mg,0.51mmol),1,10-菲罗啉(56mg,0.15mmol),碳酸钾(566mg,4.10mmol)悬浮于甲苯(10mL)和水(2.5mL)的溶液中,并于氧气氛(1atm)下加热到70℃反应16h.将反应液倒入饱和氯化铵(100mL)淬灭后,用乙酸乙酯(50mLx3)萃取,旋干后得一粗品,HPLC制备纯化后得到标题产物(144mg,白色固体)产率21%.LCMS:m/z[M+H]+=284.1。
51:3-环丙基-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑-2(3H)-
酮
实验操作同实施例1,以6-溴-3-环丙基-5-甲氧基苯并[d]噁唑-2(3H)-酮(144.0mg,0.51mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(144.9mg,0.51mmol)为原料,得到标题产物(25.1mg,白色固体)产率11%。
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.85(s,1H),8.44(m,2H),7.48(t,1H),7.36(s,1H),7.04(s,1H),4.51(q,J=7.2Hz,2H),3.84(s,3H),3.05(m,1H),1.56(t,J=7.2Hz,3H),1.21–0.96(m,4H).LCMS:m/z[M+H]+=446.1。
实施例52
52-1:6-溴-3-乙基-5-甲氧基苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(200mg,0.82mmol)加入二甲亚砜(20mL)中,加碘乙烷(1.97mL,0.82mmol),碳酸铯(534.43mg,1.64mmol),80℃搅拌3h。反应液倒入水中,乙酸乙酯(40mLx3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=2:1)纯化得标题化合物为粉色固体(175mg,产率78%)。LC-MS:m/z[M+H]+=272。
52:3-乙基-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑-2(3H)-酮
实验操作同实施例1,以6-溴-3-乙基-5-甲氧基苯并[d]噁唑-2(3H)-酮(175mg,0.64mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(184.01mg,0.64mmol)为原料,得标题化合物(100mg,产率36%)。
1H NMR(400MHz,DMSO-d6)9.55(s,1H),8.85(s,1H),8.50–8.38(m,2H),7.48(t,J=9.3Hz,1H),7.39(s,1H),7.25(s,1H),4.51(q,J=7.3Hz,2H),3.94(q,J=7.2Hz,2H),3.83(s,3H),1.56(t,J=7.3Hz,3H),1.32(t,J=7.2Hz,3H)。LC-MS:m/z[M+H]+=434.2。
实施例53
53-1:6-溴-5-甲氧基-3-甲基苯并[d]噻唑-2(3H)-酮
将5-甲氧基-3-甲基苯并[d]噻唑-2(3H)-酮(230mg,1.2mmol),溶于5mL的醋酸中,加入3M溴化
氢醋酸溶液2mL室温搅拌30分钟后冷却至0摄氏度,加入双氧水1mL后升至室温搅拌2小时,加水,大量固体析出,用二氯甲烷萃取,干燥,浓缩,得到白色固体标题化合物(170mg,52%)。LC-MS:m/z[M+H]+=272。
53:6-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-甲基苯并[d]噻唑-2(3H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(220mg,0.6mmol),6-溴-5-甲氧基-3-甲基苯并[d]噻唑-2(3H)-酮(160mg,0.6mmol)为原料,得到白色固体标题化合物(118mg,45%)。
1H NMR(400MHz,CHLOROFORM-d)9.28-9.41(m,1H)8.23-8.31(m,2H)8.21(d,J=6.85Hz,1H)7.41(s,1H)7.35(t,J=8.80Hz,1H)6.71(s,1H)4.59(q,J=7.17Hz,2H)3.90(s,3H)3.52(s,3H)1.68-1.73(m,3H)。LC-MS:m/z[M+H]+=436。
实施例54
54-1:1-(2-氨基-5-溴-4-甲氧基苯基)-2-氯乙烷-1-酮
将4-溴-3-甲氧基苯胺(CAS:19056-40-7,100mg,0.5mmol)加入到5mL的1,2-二氯乙烷中,加入1M氯化硼(1.5ml,1.5mmol)搅拌10分钟后加入氯乙腈(112mg,1.5mmol)和氯化锌(204mg,1.5mmol),然后40℃反应过夜。冷却至室温后加入1M盐酸中和后再加热回流1小时,用二氯甲烷萃取,干燥,浓缩,得到黄色固体标题化合物(100mg,90%)。LC-MS:m/z[M+H]+=278。
54-2:5-溴-6-甲氧基-1H-吲哚
将1-(2-氨基-5-溴-4-甲氧基苯基)-2-氯乙烷-1-酮(500mg,1.8mmol)和硼氢化钠(62mg,1.6mmol)依次加入到20mL的二氧六环和2mL的水中,然后100℃反应过夜。加水,用乙酸乙酯萃取,浓缩,制备板纯化(石油醚:乙酸乙酯=5:1),得到黄色固体标题化合物(170mg,42%)。LC-MS:m/z[M+H]+=226。
54-3:5-溴-6-甲氧基二氢吲哚
5-溴-6-甲氧基-1H-吲哚(100mg,0.45mmol)加到二氯甲烷(1mL),甲醇(0.5ml)中,将氰基硼氢化钠(56mg,0.89mmol)加到反应液中,然后将乙酸(1ml)滴加入反应体系中,常温搅拌2小时。反应液中加10ml饱和氢氧化钠水溶液,PH值调至碱性。然后加乙酸乙酯萃取(3x 50ml),乙酸乙酯用水洗三次后用饱和食盐水洗一次,然后用无水硫酸钠干燥,浓缩后得到标题化合物(80mg,79%)。LC-MS:m/z[M+H]+=228。
54-4:(5-溴-6-甲氧基吲哚-1-基)(吡咯烷-1-基)甲酮
5-溴-6-甲氧基二氢吲哚(80mg,0.35mmol),吡咯烷-1-碳酰氯(93.5mg,0.7mmol),三乙胺(106mg,1.05mmol)加到二氯甲烷(4ml)中,30摄氏度搅拌过夜。反应液直接薄层析纯化(二氯甲烷/甲醇=20/1)得到标题化合物(20mg,18%)。LC-MS:m/z[M+H]+=325。
54:(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基吲哚-1-基)(吡咯烷-1-基)甲酮
实验操作同实施例1,以(5-溴-6-甲氧基吲哚-1-基)(吡咯烷-1-基)甲酮(20mg,0.062mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(23mg,0.06mmol)为原料,得到标题化合物(9mg,27%)。LC-MS:m/z[M+H]+=487。
1H NMR(400MHz,CHLOROFORM-d)1.69(br.s.,3H)1.94(br.s.,4H)3.11(t,J=8.07Hz,2H)3.52(br.s.,4H)3.82(s,3H)4.04(t,J=8.31Hz,2H)4.54-4.62(m,2H)7.13(s,2H)7.30-7.36(m,1H)8.16(d,J=6.85Hz,1H)8.21-8.30(m,2H)9.37(s,1H)。
实施例55
55:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-1-甲基喹啉-2(1H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(136mg,0.37mmol),6-溴-7-甲氧基-1-甲基喹啉-2(1H)-酮(99mg,0.37mmol)为原料,得到白色固体标题化合物(90mg,57%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.26-8.34(m,2H)8.24(dd,J=6.85,1.96Hz,1H)7.67(d,J=9.29Hz,1H)7.57(s,1H)7.36(t,J=9.05Hz,1H)6.87(s,1H)6.63(d,J=9.29Hz,1H)4.59(q,J=7.34Hz,2H)3.97(s,3H)3.79(s,3H)1.68-1.72(m,3H).LC-MS:m/z[M+H]+=430。
实施例56
56-1:5-溴-4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑
将5-溴-4-甲氧基-1H-吲唑(CAS:850363-67-6 250mg,1.1mmol)溶于10mLN,N-二甲基甲酰胺中,加入四氢-2H-吡喃-4-基甲磺酸酯(400mg,2.2mmol)和碳酸铯(1g,3.3mmol)加热至70摄氏度搅拌3小时,加水稀释,用乙酸乙酯萃取,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1),,得到白色固体标题化合物(240mg,70%)。LC-MS:m/z[M+H]+=311。
56:7-乙基-4-(4-氟-3-(4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒
嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(129mg,0.35mmol),5-溴-4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑(110mg,0.35mmol)为原料,得到白色固体标题化合物(50mg,30%)。
1H NMR(400MHz,CHLOROFORM-d)δppm 9.39(s,1H)8.19-8.32(m,4H)7.33-7.45(m,2H)7.22(d,J=8.31Hz,1H)4.63-4.73(m,1H)4.59(q,J=7.34Hz,2H)4.13-4.27(m,5H)3.66(t,J=11.49
Hz,2H)2.45(qd,J=12.23,4.40Hz,2H)2.04(d,J=12.72Hz,2H)1.70(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=473。
实施例57
57-1:N-(3-甲氧基-2-硝基苯基)四氢-2H-吡喃-4-胺
将1-氟-3-甲氧基-2-硝基苯(500mg,2.9mmol),四氢-2H-吡喃-4-胺(590mg,5.8mmol),碳酸钾(1200mg,8.8mmol)加入二甲基亚砜(20ml)中。90摄氏度搅拌过夜。反应液加乙酸乙酯(300ml),用水洗(200ml x 3),乙酸乙酯干燥后浓缩得到标题化合物(730mg,99%)。LC-MS:m/z[M+H]+=253。
57-2:N-(4-溴-3-甲氧基-2-硝基苯基)四氢-2H-吡喃-4-胺
将N-(3-甲氧基-2-硝基苯基)四氢-2H-吡喃-4-胺(730mg,2.9mmol),N-溴代丁二酰亚胺(620mg,3.48mmol)加入乙腈(20ml)中。室温搅拌过夜。反应液加乙酸乙酯(300ml),用水洗(200ml x 3),乙酸乙酯干燥后浓缩得到标题化合物(750mg,75%)。LC-MS:m/z[M+H]+=331。
57-3:4-溴-3-甲氧基-N1-(四氢-2H-吡喃-4-基)苯-1,2-二胺
将N-(4-溴-3-甲氧基-2-硝基苯基)四氢-2H-吡喃-4-胺(750mg,2.3mmol),雷尼镍(100mg,1.7mmol)加入甲醇(20ml)中。室温搅拌过夜。反应液过滤后浓缩得到标题化合物(600mg,88%)。LC-MS:m/z[M+H]+=301。
57-4:5-溴-4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-(四氢-2H-吡喃-4-基)苯-1,2-二胺(500mg,1.66mmol)加入原甲酸三乙酯(20ml)中。90摄氏度搅拌过夜。反应液直接薄层层析(二氯甲烷/甲醇=30/1)得到标题化合物(400mg,70%)。LC-MS:m/z[M+H]+=311。
57:7-乙基-4-(4-氟-3-(4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑
[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑(100mg,0.32mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(118mg,0.32mmol)为原料,得到标题化合物(35mg,22%)。
1H NMR(400MHz,CHLOROFORM-d)d ppm 1.68(t,J=7.09Hz,3H)2.13-2.28(m,4H)3.64(t,J=11.00Hz,2H)4.20(d,J=10.27Hz,2H)4.38(s,3H)4.44(d,J=11.25Hz,1H)4.57(d,J=7.34Hz,2H)7.19(d,J=7.83Hz,1H)7.25-7.40(m,2H)7.98(br.s.,1H)8.14-8.34(m,3H)9.37(s,1H)。LC-MS:
m/z[M+H]+=473。
实施例58
58-1:5-甲氧基-3-甲基苯并呋喃-2-羧酸乙酯
在氩气环境下,将1-(2-羟基-5-甲氧基苯基)乙烷-1-酮(CAS:705-15-7 1g,6mmol)溶于10mLN,N-二甲基甲酰胺中,加入溴乙酸乙酯(1.3g,7.8mmol)和碳酸钾(1.7g,4、5mmol)加热至100摄氏度搅拌过夜,加水稀释,用乙酸乙酯萃取,浓缩得到红色固体标题化合物(1g,71%)。LC-MS:m/z[M+H]+=235。
58-2:5-甲氧基-3-甲基苯并呋喃-2-羧酸
将5-甲氧基-3-甲基苯并呋喃-2-羧酸乙酯(1g,4.2mmol)溶于10mL乙醇中,加入4M氢氧化钠水溶液(10mL)室温搅拌过夜,加水稀释,用1M盐酸中和,过滤固体干燥,得到红色固体标题化合物(600mg,70%)。LC-MS:m/z[M+H]+=207。
58-3:(5-甲氧基-3-甲基苯并呋喃-2-基)(吡咯烷-1-基)甲酮
将5-甲氧基-3-甲基苯并呋喃-2-羧酸(600mg,2.9mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.2g,5.8mmol),吡咯烷(310mg,4.3mmol)和N,N-二异丙基乙胺(2mL)依次加入到10mL的二氯甲烷中,然后室温搅拌3小时。用饱和氯化铵水溶液洗涤,干燥,浓缩得到红色固体标题化合物粗品(1g,100%)。LC-MS:m/z[M+H]+=260。
58-4:(6-溴-5-甲氧基-3-甲基苯并呋喃-2-基)(吡咯烷-1-基)甲酮
将(5-甲氧基-3-甲基苯并呋喃-2-基)(吡咯烷-1-基)甲酮(300mg,1mmol)溶于10mL的乙腈中,加入N-溴代丁二酰亚胺(150mg,1mmol),加热至40摄氏度搅拌2小时。制备板纯化(石油醚:乙酸乙酯=3:1),得到白色固体标题化合物(60mg,18%)。LC-MS:m/z[M+H]+=338。
58:(6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-甲基苯并呋喃-2-基)(吡咯烷
-1-基)甲酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(77mg,0.21mmol),(6-溴-5-甲氧基-3-甲基苯并呋喃-2-基)(吡咯烷-1-基)甲酮(70mg,0.21mmol)为原料,得到白色固体标题化合物(15mg,14%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.28(s,2H)8.19-8.26(m,1H)7.47(s,1H)7.32-7.40(m,1H)7.11(s,1H)4.54-4.62(m,2H)3.87-3.95(m,5H)3.65-3.72(m,2H)2.60(s,3H)1.92-2.02(m,4H)1.66-1.73(m,3H)。LC-MS:m/z[M+H]+=500。
实施例59
59-1:6-溴-3-异丙基-5-甲氧基苯并[d]噁唑-2(3H)-酮
将6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(1.0g,4.10mmol),2-碘丙烷(17.4mL,122.95mmol),碳酸铯(2.67g,8.20mmol)溶于二甲基亚砜(20.0mL),用闷罐加热到80℃反应16h.将反应液倒入水(100mL)中,用乙酸乙酯(50mLx3)萃取,饱和食盐水洗涤后,无水硫酸钠干燥,旋干后得一粗品,HPLC纯化后得到标题产物(344mg,白色固体)产率29%。1H NMR(400MHz,DMSO-d6)7.64(s,1H),7.19(s,1H),4.52(m,1H),3.89(s,3H),1.47(d,J=6.9Hz,6H)。LCMS:m/z[M+H]+=286.1。
59:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-3-异丙基-5-甲氧基苯并[d]噁唑-2(3H)-
酮
实验操作同实施例1,以6-溴-3-异丙基-5-甲氧基苯并[d]噁唑-2(3H)-酮(244mg,0.85mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(244mg,0.85mmol),碳酸铯(277.9mg,0.85mmol)为原料,得到标题产物(144.1mg,白色固体)产率38%。
1H NMR(400MHz,DMSO-d6)9.55(s,1H),8.86(s,1H),8.45(m,2H),7.50(m,1H),7.39(s,1H),7.22(s,1H),4.53(m,3H),3.84(s,3H),1.55(m,9H).LCMS:m/z[M+H]+=448。
实施例60
60-1:5-溴-1-(乙基磺酰基)-6-甲氧基二氢吲哚
将5-溴-6-甲氧基二氢吲哚(70mg,0.31mmol),((氯甲基)磺酰基)乙烷(79mg,0.62mmol),三乙胺(0.5ml),加入二氯甲烷(3ml)中。室温搅拌3小时。反应液直接薄层层析(石油醚/乙酸乙酯=3/1)得到标题化合物(40mg,40.1%)。LC-MS:m/z[M+H]+=320。
60:7-乙基-4-(3-(1-(乙基磺酰基)-6-甲氧基吲哚-5-基)-4-氟苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-1-(乙基磺酰基)-6-甲氧基二氢吲哚(40mg,0.125mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(46mg,0.125mmol)为原料,得到标题化合物(20mg,33%)。
1H NMR(400MHz,CHLOROFORM-d)1.45(t,J=7.58Hz,3H)1.69(t,J=7.34Hz,3H)3.10-3.24(m,4H)3.83(s,3H)4.12(t,J=8.56Hz,2H)4.58(q,J=7.17Hz,2H)7.16(d,J=15.16Hz,2H)7.33(t,J=9.05Hz,1H)8.15(d,J=6.36Hz,1H)8.22-8.33(m,2H)9.36(s,1H).LC-MS:m/z[M+H]+=482。
实施例61
61-1:6-溴-7-甲氧基异喹啉
将甲醇钠(1g,18mmol)溶于10mL甲醇中,加入6-溴-7-氟异喹啉(CAS:1258833-80-5 1g,4.2mmol),加热回流2小时。加水稀释,用乙酸乙酯萃取,干燥浓缩,得到白色固体标题化合物(800mg,80%)。LC-MS:m/z[M+H]+=238。
61-2:6-溴-7-甲氧基异喹啉2-氧化物
将6-溴-7-甲氧基异喹啉(800mg,3.9mmol)溶于10mL二氯甲烷中,加入间氯过氧苯甲酸(1.3g,8mmol),室温搅拌过夜。浓缩反应液,制备板纯化(二氯甲烷:甲醇=40:1)得到白色固体标题化合物(700mg,80%)。LC-MS:m/z[M+H]+=254。
61-3:6-溴-7-甲氧基异喹啉-1(2H)-酮
将6-溴-7-甲氧基异喹啉2-氧化物(700mg,2.7mmol)溶于10mL醋酸酐中,加热回流2小时,冷却后加水20mL,再加热回流2小时。用乙酸乙酯萃取,无水硫酸钠干燥,浓缩,制备板纯化(二氯甲烷:甲醇=20:1)得到红棕色固体标题化合物(400mg,55%)。LC-MS:m/z[M+H]+=254。
61-4:6-溴-2-乙基-7-甲氧基异喹啉-1(2H)-酮
将6-溴-7-甲氧基异喹啉-1(2H)-酮(100mg,0.39mmol)溶于5mL甲醇中,加入碳酸钾(170mg,1.2mmol)和碘乙烷0.2mL,室温搅拌3小时,加水20mL,用乙酸乙酯萃取,无水硫酸钠干燥,浓缩,制备板纯化(二氯甲烷:甲醇=20:1)得到黄色固体标题化合物(60mg,55%)。LC-MS:m/z[M+H]+=282。
61:2-乙基-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基异喹啉-1(2H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(78mg,0.21mmol),6-溴-2-乙基-7-甲氧基异喹啉-1(2H)-酮(60mg,0.21mmol)为原料,得到白色固体标题化合物(50mg,54%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.20-8.38(m,3H)7.98(s,1H)7.55(s,1H)7.36(t,J=9.05Hz,1H)7.03(d,J=7.34Hz,1H)6.53(d,J=7.34Hz,1H)4.58(q,J=7.17Hz,2H)4.11(q,J=7.34Hz,2H)3.95(s,3H)1.69(t,J=7.34Hz,3H)1.41(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=444。
实施例62
62-1:叔丁基(3S,4R)-4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(300mg,1.15mmol),叔丁基(3S,4R)-4-氨基-3-氟哌啶-1-羧酸叔丁酯(500mg,2.29mmol)为原料,得淡黄色油状液体标题化合物(250mg,51%)。LC-MS:m/z[M+H]+=428,430。
62-2:5-溴-2-((3S,4R)-3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以叔丁基(3S,4R)-4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯(250mg,0.58mmol)为原料,得黄色固体标题化合物(203mg,粗产物)。LC-MS:m/z[M+H]+=328,330。
62-3:5-溴-2–((3S,4R)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-2-((3S,4R)-3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐(203mg,0.58mmol)为原料,得黄色油状液体标题化合物(150mg,76%)。LC-MS:m/z[M+H]+=342,344。
62:7-乙基-4-(4-氟-3-(2-((3S,4R)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)苯基)-7H-咪唑
并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2–((3S,4R)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑(150mg,0.439mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(162mg,0.439mmol)为原料,得棕色固体标题化合物(18mg,8%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H),8.27(s,2H),8.22(d,J=5.4Hz,1H),8.07(s,1H),7.65(s,1H),7.33(t,J=8.8Hz,1H),7.07(s,1H),5.37-5.02(m,1H),4.69-4.52(m,3H),3.87(s,3H),3.35(br.s.,1H),3.16(br.s.,1H),2.71-2.57(m,1H),2.49-2.27(m,5H),2.22(br.s.,1H),1.69(s,3H)。LC-MS:m/z[M+H]+=504。
实施例63
63-1:叔丁基(3S,4S)-4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(300mg,1.15
mmol),叔丁基(3S,4S)-4-氨基-3-氟哌啶-1-羧酸叔丁酯(500mg,2.29mmol)为原料,得淡黄色油状液体标题化合物(280mg,57%)。LC-MS:m/z[M+H]+=428,430。
63-2:5-溴-2-((3S,4S)-3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以叔丁基(3S,4S)-4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯(280mg,0.65mmol)为原料,得黄色固体标题化合物(227mg,粗产物)。LC-MS:m/z[M+H]+=328,330。
63-3:5-溴-2-((3S,4S)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-2-((3S,4S)-3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐(227mg,0.65mmol)为原料,得白色固体标题化合物(180mg,81%)。LC-MS:m/z[M+H]+=342,344。
63:7-乙基-4-(4-氟-3-(2-((3S,4S)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)苯基)-7H-咪唑
并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-((3S,4S)-3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑(170mg,0.497mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(183mg,0.497mmol)为原料,得灰白色固体标题化合物(89mg,36%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H),8.27(s,2H),8.21(d,J=6.8Hz,1H),7.99(s,1H),7.63(s,1H),7.33(t,J=9.0Hz,1H),7.13(s,1H),5.32-4.97(m,1H),4.57(q,J=7.0Hz,2H),4.35(d,J=11.7Hz,1H),3.87(s,3H),3.40-3.29(m,1H),2.99(d,J=10.8Hz,1H),2.57-2.35(m,3H),2.30-2.16(m,3H),1.68(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=504。
实施例64
64-1:叔丁基(3S,4R)-3-(5-溴-6-甲氧基-2H-吲唑-2-基)-4-氟吡咯烷-1-甲酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(500mg,1.92mmol),叔丁基(3S,4R)-3-氨基-4-氟吡咯烷-1-羧酸叔丁酯(783mg,3.84mmol)为原料,得淡黄色油状液体标题化合物(760mg,95%)。LC-MS:m/z[M+H]+=414,416。
64-2:5-溴-2-((3S,4R)-4-氟吡咯烷-3-基)-6-甲氧基-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以叔丁基(3S,4R)-3-(5-溴-6-甲氧基-2H-吲唑-2-基)-4-氟吡咯烷-1-甲酸叔丁酯(760mg,1.84mmol)为原料得黄色固体标题化合物(720mg,粗产物)。LC-MS:m/z[M+H]+=314,316。
64-3:5-溴-2–((3S,4R)-4-氟-1-甲基吡咯烷-3-基)-6-甲氧基-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-2-((3S,4R)-4-氟吡咯烷-3-基)-6-甲氧基-2H-吲唑盐酸盐(720mg,2.06mmol)为原料,得黄色油状液体标题化合物(150mg,22%)。LC-MS:m/z[M+H]+=414,416。
64:7-乙基-4-(4-氟-3-(2-((3S,4R)-4-氟-1-甲基吡咯烷-3-基)-6-甲氧基-2H-吲唑-5-基)苯基)-7H-咪
唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2–((3S,4R)-4-氟-1-甲基吡咯烷-3-基)-6-甲氧基-2H-吲唑(150mg,0.46mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(169mg,0.46mmol)为原料,得棕色固体标题化合物(60mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.30-8.24(m,2H),8.23-8.18(m,1H),8.12(s,1H),7.62(s,1H),7.32(t,J=8.8Hz,1H),7.08(s,1H),5.42-5.19(m,2H),4.56(q,J=7.3Hz,2H),3.86(s,3H),3.37-3.30(m,1H),3.27-3.12(m,2H),3.11-2.96(m,1H),2.52(s,3H),1.67(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=490。
实施例65
65-1:2-(氮杂环丁烷-1-基)-5-甲氧基苯并[d]噁唑
将5-甲氧基苯并[d]噁唑(400mg,2.7mmol)溶于10mL乙腈中,加入氮杂环丁烷(300mg,5.3mmol),NIS(30mg,0.13mmol),醋酸0.5mL和30%双氧水(0.6mL)室温搅拌过夜,加水稀释,用二氯甲烷萃取,浓缩,制备板纯化(石油醚:乙酸乙酯=2:1)得到棕色固体标题化合物(70mg,4%)。LC-MS:m/z[M+H]+=205。
65-2:2-(氮杂环丁烷-1-基)-6-溴-5-甲氧基苯并[d]噁唑
将2-(氮杂环丁烷-1-基)-5-甲氧基苯并[d]噁唑(70mg,0.34mmol)溶于10mL乙腈中,加入N-溴代丁二酰亚胺(30mg,0.17mmol),加热至40摄氏度搅拌过夜,制备板纯化(二氯甲烷:甲醇=20:1),得到棕色固体标题化合物(55mg,57%)。LC-MS:m/z[M+H]+=283。
65:2-(氮杂环丁烷-1-基)-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁
唑
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(72mg,0.19mmol),2-(氮杂环丁烷-1-基)-6-溴-5-甲氧基苯并[d]噁唑(55mg,0.19mmol)为原料,得到白色固体标题化合物(40mg,48%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.23-8.32(m,2H)8.21(dd,J=7.09,2.20Hz,1H)7.33(t,J=9.05Hz,1H)7.26(s,1H)7.06(s,1H)4.58(q,J=7.34Hz,2H)4.32(t,J=7.58Hz,4H)3.83(s,3H)2.53(quin,J=7.58Hz,2H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=445。
实施例66
66-1:5-溴-2-(3,3-二氟环丁基)-6-甲氧基-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(200mg,0.77mmol),3,3-二氟环丁烷-1-胺(165mg,1.54mmol)为原料,得淡黄色油状液体标题化合物(150mg,62%)。LC-MS:m/z[M+H]+=317,319。
66:4-(3-(2-(3,3-二氟环丁基)-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-(3,3-二氟环丁基)-6-甲氧基-2H-吲唑(150mg,0.475mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(175mg,0.475mmol)为原料,得白色固体标题化合物(120mg,53%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.38(s,1H),8.27(br.s.,2H),8.20(d,J=6.8Hz,1H),7.95(s,1H),7.60(s,1H),7.33(t,J=8.8Hz,1H),7.13(s,1H),4.95(d,J=5.9Hz,1H),4.58(q,J=7.3Hz,2H),3.87(s,3H),3.52-3.37(m,2H),3.23(d,J=8.3Hz,2H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=479。
实施例67
67-1:5-溴-6-甲氧基-2-(1-甲基-1H-吡唑-5-基)-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(200mg,0.77mmol),1-甲基-1H-吡唑-5-胺(224mg,2.31mmol)为原料,得白色固体标题化合物(50mg,21%)。LC-MS:m/z[M+H]+=307,309。
67:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基-1H-吡唑-5-基)-2H-吲唑-5-基)苯基)-7H-咪唑[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-甲基-1H-吡唑-5-基)-2H-吲唑(50mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(59mg,0.16mmol)为原料,得黄色固体标题化合物(12mg,16%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.39(s,1H),8.33-8.26(m,2H),8.25-8.21(m,1H),8.14(s,1H),7.69(s,1H),7.57(d,J=2.0Hz,1H),7.35(t,J=8.8Hz,1H),7.12(s,1H),6.43(d,J=2.0Hz,1H),4.58(q,J=7.3Hz,2H),3.99(s,3H),3.90(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z
[M+H]+=469。
实施例68
68-1:8-溴-N-甲基喹啉-3-甲酰胺
将8-溴喹啉-3-羧酸(80mg,0.32mmol),甲氨醇盐酸盐(65mg,0.96mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(360mg,0.96mmol),三乙胺(97mg,0.96mmol)加入二氯甲烷(5ml)中。40摄氏度搅拌过夜。反应液直接薄层层析(二氯甲烷/甲醇=20/1)得到标题化合物(20mg,24%)。LC-MS:m/z[M+H]+=265。
68:8-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-N-甲基喹啉-3-甲酰胺
实验操作同实施例1,以8-溴-N-甲基喹啉-3-甲酰胺(20mg,0.076mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(28mg,0.076mmol)为原料,得到标题化合物(10mg,31%)。
1H NMR(400MHz,CHLOROFORM-d)d ppm 1.69-1.78(m,3H)3.10(br.s.,3H)4.57(d,J=6.85Hz,2H)6.52(br.s.,1H)7.43(br.s.,1H)7.71(br.s.,1H)7.85-8.06(m,2H)8.20-8.45(m,3H)8.70(br.s.,1H)9.23(br.s.,1H)9.40(br.s.,1H)。LC-MS:m/z[M+H]+=427。
实施例69
69-1:3-甲氧基-N-甲基-2-硝基苯胺
实验操作同实施例57中,57-1的合成方法,以1-氟-3-甲氧基-2-硝基苯(800mg,4.7mmol),甲胺盐酸盐(635mg,9.4mmol)为原料,得标题化合物(700mg,收率53%)红色油状液体。LC-MS:m/z[M+H]+=183。
69-2:4-溴-3-甲氧基-N-甲基-2-硝基苯胺
实验操作同实施例57中,57-2的合成方法,以3-甲氧基-N-甲基-2-硝基苯胺(700mg,3.8mmol)为原料,得标题化合物(914mg,收率91%)黄色油状液体。LC-MS:m/z[M+H]+=261。
69-3:4-溴-3-甲氧基-N1-甲基苯-1,2-二胺
实验操作同实施例57中,57-3的合成方法,以4-溴-3-甲氧基-N-甲基-2-硝基苯胺(914mg,3.5mmol)为原料,得到标题化合物(0.116g,收率55%)黄色固体。LC-MS:m/z[M+H]+=231。
69-4:5-溴-4-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(696mg,3.0mmol)用乙酸(7mL)溶解,再在0℃下将亚硝酸钠(414mg,6.0mmol)水溶液(5mL)滴加入体系中,0℃搅拌30分钟后,反应完毕。将反应液浓缩,柱层析(石油醚:乙酸乙酯=1:1)纯化得标题化合物(365mg,收率50%)黄色固体。LC-MS:m/z[M+H]+=242。
69:4-(4-氟-3-(4-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)苯基)-7-异丙基-7H-咪唑并[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-4-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑(242mg,1.0mmol),(2-氟-5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)苯基)硼酸(314mg,1.1mmol)为原料,得标题化合物(157mg,产率38%)。
1H NMR(400MHz,CDCl3)9.41(s,1H),8.38(s,1H),8.34–8.22(m,2H),7.48(d,1H),7.38(t,1H),7.18(d,1H),5.32–5.07(m,1H),4.61(s,3H),4.31(s,3H),1.77(d,J=6.7Hz,6H)。LC-MS:m/z[M+H]+=418。
实施例70
70:4-(3-(1-环丙基-4-甲氧基-1H-苯并[d][1,2,3]三唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-1-环丙基-4-甲氧基-1H-苯并[d][1,2,3]三唑(100mg,0.37mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(126mg,0.45mmol)为原料,得到标题化合物(83mg,白色固体)产率41%。
1H NMR(400MHz,CDCl3)9.41(s,1H),8.38–8.21(m,3H),7.48(d,1H),7.38(t,1H),7.33(d,1H),4.65–4.49(m,5H),3.84–3.72(m,1H),1.70(t,J=7.3Hz,3H),1.46–1.38(m,2H),1.37–1.30(m,2H)。LC-MS:m/z[M+H]+=430。
实施例71
71-1:2-溴-3-(二甲氧基甲基)苯酚
2-溴-3-羟基苯甲醛(4g,20mmol),原甲酸三甲酯(4.1g,40mmol)加到甲醇(10ml)中,浓盐酸(0.02ml)滴入,60℃反应过夜。反应液蒸干得粗品标题化合物(5338mg)。
71-2:2,4-二溴-3-羟基苯甲醛
2-溴-3-(二甲氧基甲基)苯酚(5338mg,20mmol)加到氯仿(10ml)中,0℃搅拌10分钟。液溴(1.8g,12mmol)溶于氯仿(10ml)中,0℃下缓慢滴加至反应液,滴加完后0℃反应1小时。反应液加入饱和碳酸氢钠水溶液(50ml)淬灭,二氯甲烷萃取,浓缩。所得中间体溶于二氯甲烷(20ml)中,三氟醋酸(2ml)加入,25℃搅拌30分钟。反应液浓缩,柱色谱(石油醚/乙酸乙酯=6/1)得标题化合物黄色固体(570mg,10%)。LC-MS:m/z[M+H]+=279,281,283。
71-3:2,4-二溴-3-甲氧基苯甲醛
2,4-二溴-3-羟基苯甲醛(570mg,2.036mmol),碳酸钾(2484mg,18mmol),碘甲烷(1406mg,9.9mmol)加到乙腈(5ml)中,50℃反应过夜。反应液倒入水(50ml),乙酸乙酯萃取,浓缩,得粗品标题化合物黄色固体(688mg)。LC-MS:m/z[M+H]+=293,295,297。
71-4:N'-(2,4-二溴-3-甲氧基亚苄基)-4-甲基苯磺酰肼
2,4-二溴-3-甲氧基苯甲醛(688mg,2.340mmol),对甲苯磺酰肼(1637mg,8.8mmol)加到乙醇(5ml)中,80℃反应过夜。反应液浓缩,柱色谱(二氯甲烷/甲醇=30/1)得标题化合物黄色固体(717mg,66%)。LC-MS:m/z[M+H]+=461,463,465。
71-5:6-溴-7-甲氧基-1-甲苯磺酰基-1H-吲唑
N'-(2,4-二溴-3-甲氧基亚苄基)-4-甲基苯磺酰肼(717mg,1.552mmol),氧化亚铜(343mg,2.4mmol)加到异丙醇(10ml)中,100℃反应过夜。反应液抽滤,浓缩,柱色谱(二氯甲烷/甲醇=30/1)得标题化合物棕色油状液体(327mg,55%)。LC-MS:m/z[M+H]+=381,383。
71-6:6-溴-7-甲氧基-1H-吲唑
6-溴-7-甲氧基-1-甲苯磺酰基-1H-吲唑(327mg,0.858mmol)加到甲醇(6ml)中,镁屑(42mg,1.716mmol)加入,氩气保护下,0℃反应3小时。反应液抽滤,浓缩,制备薄层色谱(石油醚/二氯甲烷/甲醇=10/30/1)得标题化合物黄色固体(141mg,72%)。LC-MS:m/z[M+H]+=227,229。
71-A1:6-溴-7-甲氧基-1-甲基-1H-吲唑
71-A2:6-溴-7-甲氧基-2-甲基-2H-吲唑
6-溴-7-甲氧基-1H-吲唑(135mg,0.595mmol),碘甲烷(85mg,0.595mmol),碳酸铯(395mg,1.190mmol)加到N,N-二甲基甲酰胺(2ml)中,25℃反应15分钟。反应液抽滤,制备薄层色谱(石油醚/乙酸乙酯=3/1)得化合物白色固体(A1,49mg,34.17%,Rf=0.6)和(A2,51mg,34.23%,Rf=0.4)。LC-MS:m/z[M+H]+=241,243。
71:7-乙基-4-(4-氟-3-(7-甲氧基-2-甲基-2H-吲唑-6-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(61mg,0.166mmol),6-溴-7-甲氧基-2-甲基-吲唑(40mg,0.166mmol)为原料,得标题化合物淡黄色固体(25mg,37%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.32-8.25(m,3H),7.95(s,1H),7.42-7.34(m,2H),7.07(d,J=8.8Hz,1H),4.58(q,J=7.3Hz,2H),4.27(s,3H),4.24(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例72
72:7-乙基-4-(4-氟-3-(7-甲氧基-1-甲基-1H-吲唑-6-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(61mg,0.166mmol),6-溴-7-甲氧基-1-甲基-吲唑(40mg,0.166mmol)为原料,得标题化合物淡黄色固体(14mg,21%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(br.s.,1H),8.39-8.32(m,2H),8.29(s,1H),8.00(s,1H),7.53(d,J=8.3Hz,1H),7.41(t,J=8.8Hz,1H),7.14(d,J=7.8Hz,1H),4.58(q,J=7.3Hz,2H),4.33(s,3H),3.60(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例73
73-1:5-甲氧基苯并[d]噁唑
将2-氨基-4-甲氧基苯酚(CAS:20734-76-3 1g,7.2mmol)溶于10mL甲苯中,加入3A分子筛(1g),原甲酸三乙酯(1.5g,10mmol)加热至100摄氏度搅拌过夜,加饱和氯化铵水溶液稀释,用乙酸乙酯萃取,浓缩,柱层析纯化(石油醚:乙酸乙酯=30:1)得到黄色固体标题化合物(900mg,83%)。LC-MS:m/z[M+H]+=150。
73-2:5-甲氧基-2-吗啉代苯并[d]噁唑
将5-甲氧基苯并[d]噁唑(40mg,2.7mmol)溶于10mL乙腈中,加入吗啉(464mg,5.3mmol),N-碘代丁二酰亚胺(30mg,0.13mmol),醋酸0.5mL和30%双氧水(0.6mL)室温搅拌过夜,加水稀释,用二氯甲烷萃取,浓缩,制备板纯化(石油醚:乙酸乙酯=5:1)得到白色固体标题化合物(120mg,20%)。LC-MS:m/z[M+H]+=235。
73-3:6-溴-5-甲氧基-2-吗啉苯并[d]噁唑
将5-甲氧基-2-吗啉代苯并[d]噁唑(120mg,0.5mmol)溶于10mL乙腈中,加入N-溴代丁二酰亚胺(108mg,0.6mmol),室温搅拌30分钟,制备板纯化(二氯甲烷),得到白色固体标题化合物(200mg,100%)。LC-MS:m/z[M+H]+=313。
73:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-2-吗啉代苯并[d]噁唑
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.27mmol),6-溴-5-甲氧基-2-吗啉苯并[d]噁唑(100mg,0.27mmol)为原料,得到棕色固体标题化合物(42mg,33%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(br.s.,1H)8.24-8.34(m,2H)8.11-8.22(m,1H)7.34(t,J=9.05Hz,1H)7.25(s,1H)7.06(s,1H)4.58(q,J=7.34Hz,2H)3.78-3.89(m,7H)3.67-3.75(m,4H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=475。
实施例74
74-1:4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,3-二氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(275mg,1.06mmol),4-氨基-3,3-二氟哌啶-1-羧酸叔丁酯(250mg,1.06mmol)为原料,得淡黄色油状液体标题化合物(330mg,70%)。LC-MS:m/z[M+H]+=446,448。
74-2:5-溴-2-(3,3-二氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,3-二氟哌啶-1-羧酸叔丁酯(330mg,0.74mmol)为原料,得黄色固体标题化合物(190mg,67%)。LC-MS:m/z[M+H]+=346,348。
74-3:5-溴-2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-2-(3,3-二氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐(190mg,0.50mmol)为原料,得无色油状液体标题化合物(160mg,90%)。LC-MS:m/z[M+H]+=360,362。
74:4-(3-(2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙基7H咪唑并
[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-(3,3-二氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑(150mg,0.42mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(155mg,0.42mmol)为原料,得灰白色固体标题化合物(37mg,17%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.28(s,2H),8.22(d,J=6.4Hz,1H),8.08(s,
1H),7.65(s,1H),7.33(t,J=8.8Hz,1H),7.10(s,1H),4.84-4.71(m,1H),4.58(q,J=7.3Hz,2H),3.87(s,3H),3.29(br.s.,1H),3.13(d,J=11.7Hz,1H),2.60-2.52(m,1H),2.46(s,3H),2.40-2.30(m,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=522。
实施例75
75-1:2-(二氟甲基)-5-甲氧基苯并[d]噁唑
2-氨基-4-甲氧基苯酚(500mg,3.59mmol),三乙胺(725mg,7.18mmol),三苯基膦(941mg,3.59mmol)和二氟乙酸(344.7mg,3.59mmol)加到四氯化碳(8mL)闷罐100℃搅拌过夜。将反应液过滤,母液上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(110mg,15%)。
75-2:4-溴-2-(二氟甲基)-5-甲氧基苯并[d]噁唑
2-(二氟甲基)-5-甲氧基苯并[d]噁唑(100mg,0.5mmol)和N-溴代丁二酰亚胺(90mg,0.5mmol)加到醋酸中(4mL)90℃搅拌两小时。将反应浓缩,加适量甲醇爬制备板分离纯化(石油醚/乙酸乙酯=6/1)得标题化合物(68mg,49%)。1H NMR(400MHz,CDCl3)7.55(d,J=8.8Hz,1H),7.13(d,J=9.3Hz,1H),6.91-6.69(m,1H),3.99(s,3H)。
75:2-(二氟甲基)-4-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑
实验操作同实施例1,以4-溴-2-(二氟甲基)-5-甲氧基苯并[d]噁唑(60mg,0.215mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(67mg,0.17mmol)为原料,得标题化合物(40mg,54%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.39(br.s.,1H),8.32-8.20(m,3H),7.72-7.62(m,1H),7.45-7.37(m,1H),7.24(d,J=9.8Hz,1H),6.90-6.62(m,1H),4.63-4.56(m,1H),3.90(s,3H),1.71-1.68(m,3H)。LC-MS:m/z[M+H]+=440。
实施例76
76-1:4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(300mg,1.15mmol),4-氨基-3-氟哌啶-1-羧酸叔丁酯(377mg,1.73mmol)为原料,得淡黄色油状液体标题化合物(400mg,81%)。LC-MS:m/z[M+H]+=428,430。
76-2:5-溴-2-(3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3-氟哌啶-1-羧酸叔丁酯(400mg,0.93mmol)为原料,得黄色固体标题化合物(290mg,86%)。LC-MS:m/z[M+H]+
=328,330。
76-3:5-溴-2-(3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-2-(3-氟哌啶-4-基)-6-甲氧基-2H-吲唑盐酸盐(290mg,0.80mmol)为原料,得无色油状液体标题化合物(100mg,37%)。LC-MS:m/z[M+H]+=342,346。
76:7-乙基-4-(4-氟-3-(2-(3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)苯基)-7H-咪唑[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-2-(3-氟-1-甲基哌啶-4-基)-6-甲氧基-2H-吲唑(100mg,0.29mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(95mg,0.29mmol)为原料,得黄色固体标题化合物(68mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.26(br.s.,2H),8.22(d,J=6.4Hz,1H),7.99(s,1H),7.63(s,1H),7.32(t,J=9.0Hz,1H),7.13(s,1H),5.18-4.98(m,1H),4.57(q,J=6.8Hz,2H),4.35(d,J=9.3Hz,1H),3.87(s,3H),3.40-3.30(m,1H),2.98(d,J=10.3Hz,1H),2.56-2.38(m,4H),2.30-2.16(m,3H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=504。
实施例77
77-1:4-(5-溴-6-甲氧基-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(300mg,1.15mmol),4-氨基哌啶-1-羧酸叔丁酯(345mg,1.73mmol)为原料,得淡黄色油状液体标题化合物(300mg,64%)。LC-MS:m/z[M+H]+=410,412。
77-2:5-溴-6-甲氧基-2-(哌啶-4-基)-2H-吲唑盐酸盐
实验操作同实施例46中,46-3的合成方法,以4-(5-溴-6-甲氧基-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(300mg,0.73mmol)为原料,得白色固体标题化合物(251mg,100%)。LC-MS:m/z[M+H]+=310,312。
77-3:5-溴-6-甲氧基-2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑
实验操作同实施例46中,46-4的合成方法,以5-溴-6-甲氧基-2-(哌啶-4-基)-2H-吲唑盐酸盐(280
mg,0.81mmol),氧杂环丁烷-3-酮(62mg,1.62mmol)为原料,得黄色固体标题化合物(170mg,58%)。LC-MS:m/z[M+H]+=366,368。
77:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑
并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑(70mg,0.19mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(70mg,0.19mmol)为原料,得白色固体标题化合物(28mg,28%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.31-8.24(m,2H),8.20(d,J=5.4Hz,1H),7.93(s,1H),7.62(s,1H),7.32(t,J=8.8Hz,1H),7.10(s,1H),4.67(td,J=6.4,18.1Hz,4H),4.56(q,J=7.3Hz,2H),4.46-4.37(m,1H),3.86(s,3H),3.56(quin,J=6.4Hz,1H),2.93(d,J=11.2Hz,2H),2.36-2.28(m,2H),2.28-2.16(m,2H),2.13-2.04(m,2H),1.68(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=528。
实施例78
78-1:5-溴-6-甲氧基-2-(1-甲基-1H-咪唑-2-基)-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(200mg,0.77mmol),1-甲基-1H-咪唑-2-胺(112mg,3.45mmol)为原料,得淡黄色油状液体标题化合物(50mg,54%)。LC-MS:m/z[M+H]+=307,309。
78:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基-1H-咪唑-2-基)-2H-吲唑-5-基)苯基)-7H-咪唑[4,5-c]哒
嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-甲基-1H-咪唑-2-基)-2H-吲唑(50mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(59mg,0.16mmol)为原料,得黄色固体标题化合物(6mg,8%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.58(s,1H),8.30-8.24(m,3H),7.70(s,1H),7.34(t,J=8.8Hz,1H),7.09(s,1H),7.03(s,1H),6.94(s,1H),4.58(q,J=7.3Hz,2H),4.00(s,3H),3.90(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=469。
实施例79
79-1:4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,5-二甲基异噁唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(300mg,1.15mmol),3,5-二甲基异噁唑-4-胺(386mg,3.45mmol)为原料,得淡黄色油状液体标题化合物(200mg,54%)。LC-MS:m/z[M+H]+=322,324。
79:4-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2-基)-3,5-二甲基异
噁唑
实验操作同实施例1,以4-(5-溴-6-甲氧基-2H-吲唑-2-基)-3,5-二甲基异噁唑(200mg,0.62mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(228mg,0.62mmol)为原料,得白色固体标题化合物(28mg,9%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.33-8.26(m,2H),8.22(d,J=6.4Hz,1H),8.00(s,1H),7.68(s,1H),7.34(t,J=8.8Hz,1H),7.12(s,1H),4.57(q,J=7.3Hz,2H),3.89(s,3H),2.51(s,3H),2.34(s,3H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=484。
实施例80
80-1:5-溴-2-(二氟甲基)-4-甲氧基-1-甲基-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(200mg,0.87mmol),邻苯三酚(20mg,0.159mmol)和2,2-二氟乙-1-胺(211mg,2.61mmol)依次加到甲醇(5mL)中,在80℃下搅拌16小时。反应液浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得棕色固体标题化合物(30mg,49%)。LC-MS:m/z[M+H]+=291,293。
80:4-(3-(2-(二氟甲基)-4-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-
c]哒嗪
实验操作同实施例1,以5-溴-2-(二氟甲基)-4-甲氧基-1-甲基-1H-苯并[d]咪唑(30mg,0.1mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(37mg,0.1mmol)为原料,得黄色固体标题化合物(2mg,4%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(br.s.,1H),8.28(s,2H),8.23(d,J=6.8Hz,1H),7.42-7.35(m,2H),7.18(d,J=8.3Hz,1H),7.08-6.80(m,1H),4.58(q,J=7.3Hz,2H),4.37(s,3H),3.99(s,3H),1.71-1.67(m,3H)。LC-MS:m/z[M+H]+=453。
实施例81
81:7-乙基-4-(4-氟-3-(4-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(90mg,0.24mmol),5-溴-4-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑(60mg,0.24mmol)为原料,得到棕色固体标题化合物(48mg,48%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.34-8.19(m,3H),7.49(d,J=8.3Hz,1H),7.37(t,J=9.0Hz,1H),7.17(d,J=8.8Hz,1H),4.64-4.52(m,5H),4.34-4.28(m,3H),1.70-1.66(m,3H)。LC-MS:m/z[M+H]+=404。
实施例82
82-1:5-溴-2-甲基-2H-吲唑-6-醇
将5-溴-6-甲氧基-2-甲基-2H-吲唑(500mg,2mmol)溶于10mL二氯甲烷中,加入1M三溴化硼二氯甲烷溶液(5mL)然后室温搅拌过夜,浓缩,制备板纯化(二氯甲烷:甲醇=20:1)得到黄色固体标题化合物(800mg,100%)。LC-MS:m/z[M+H]+=227。
82-2:5-溴-6-(二氟甲氧基)-2-甲基-2H-吲唑
将5-溴-2-甲基-2H-吲唑-6-醇(500mg,2mmol)溶于10mL乙腈中,加入氢氧化钾水溶液(200mg溶于5mL),冷却至0度,加入二氟氯乙酸钠(600mg,4mmol),搅拌1小时,分液,浓缩,制备板纯化(石油醚:乙酸乙酯=1:1)得到黄色固体标题化合物(160mg,29%)。LC-MS:m/z[M+H]+=277。
82:4-(3-(6-(二氟甲氧基)-2-甲基-2H-吲唑-5-基)-4-氟苯基)-7-乙基7H咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(90mg,0.24mmol),5-溴-6-(二氟甲氧基)-2-甲基-2H-吲唑(66mg,0.24mmol)为原料,得到棕色固体标题化合物(47mg,49%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.36-8.20(m,3H),7.96(s,1H),7.74(s,1H),7.50(s,1H),7.36(t,J=9.0Hz,1H),6.75-6.31(m,1H),4.58(q,J=7.3Hz,2H),4.25(s,3H),1.69(s,3H)。LC-MS:m/z[M+H]+=439。
实施例83、实施例84
83-A1:2-(5-溴-6-甲氧基-2H-吲唑-2-基)-1-(吡咯烷-1-基)乙基-1-酮
83-A2:2-(5-溴-6-甲氧基-1H-吲唑-1-基)-1-(吡咯烷-1-基)乙基-1-酮
将5-溴-6-(甲氧基)-1H-苯并[d]咪唑(CAS:1008361-65-6 300mg,1.3mmol)溶于10mL乙腈中,加入碳酸铯(1g,2.6mmol)和2-氯-1-(吡咯烷-1-基)乙基-1-酮(200mg,1.3mmol),80摄氏度下,搅拌1小时,过滤固体,加水稀释,固体析出,制备板纯化(二氯甲烷:甲醇=10:1)得到白色固体标题化合物A1(70mg,16%,Rf=0.3)和白色固体标题化合物A2(270mg,60%,Rf=0.4)。LC-MS:m/z[M+H]+=338。
83:2-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2-基)-1-(吡咯烷-1-
基)乙基-1-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.22mmol),2-(5-溴-6-甲氧基-2H-吲唑-2-基)-1-(吡咯烷-1-基)乙基-1-酮(70mg,0.22mmol)为原料,得到棕色固体标题化合物(70mg,64%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.25-8.30(m,2H)8.23(dd,J=6.85,2.45Hz,1H)8.07(s,1H)7.63(s,1H)7.32(t,J=9.05Hz,1H)7.07(s,1H)5.16(s,2H)4.51-4.61(m,2H)3.85(s,3H)3.54(dt,J=14.06,6.91Hz,4H)1.97-2.05(m,2H)1.86-1.93(m,2H)1.68(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=500。
84:2-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-1H-吲唑-1-基)-1-(吡咯烷-1-
基)乙基-1-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.22mmol),2-(5-溴-6-甲氧基-1H-吲唑-1-基)-1-(吡咯烷-1-基)乙基-1-酮(70mg,0.22mmol)为原料,得到棕色固体标题化合物(46mg,42%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H)8.19-8.29(m,3H)7.98(s,1H)7.68(s,1H)7.34(t,J=9.05Hz,1H)6.99(s,1H)5.17(s,2H)4.54-4.63(m,2H)3.90(s,3H)3.53(q,J=6.85Hz,4H)1.99(quin,J=6.73Hz,2H)1.84-1.92(m,2H)1.69(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=500。
实施例85、实施例86
85-A1:3-((5-溴-6-甲氧基-2H-吲唑-2-基)甲基)-5-甲基异噁唑
85-A2:3-((5-溴-6-甲氧基-1H-吲唑-1-基)甲基)-5-甲基异噁唑
将5-溴-6-(甲氧基)-1H-苯并[d]咪唑(CAS:1008361-65-6 300mg,1.3mmol)溶于10mL乙腈中,加入碳酸铯(845mg,2.6mmol)和3-(氯甲基)-5-甲基异噁唑(180mg,1.3mmol)加热至80摄氏度搅拌2小时,
过滤固体,制备板纯化(石油醚:乙酸乙酯=10:1)得到黄色固体标题化合物A1(110mg,26%,Rf=0.3)和黄色固体标题化合物A2(260mg,61%,Rf=0.5)。LC-MS:m/z[M+H]+=322。
85:3-((5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2-基)甲基)-5-甲
基异噁唑
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.22mmol),3-((5-溴-6-甲氧基-2H-吲唑-2-基)甲基)-5-甲基异噁唑(70mg,0.22mmol)为原料,得到白色固体标题化合物(29mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H)8.27(br.s.,2H)8.20(d,J=5.38Hz,1H)7.96(s,1H)7.61(s,1H)7.33(t,J=8.80Hz,1H)7.10(s,1H)5.98(s,1H)5.60(s,2H)4.58(q,J=6.85Hz,2H)3.87(s,3H)2.39(s,3H)1.69(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=484。
86:3-((5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-1H-吲唑-1-基)甲基)-5-甲
基异噁唑
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.22mmol),3-((5-溴-6-甲氧基-1H-吲唑-1-基)甲基)-5-甲基异噁唑(70mg,0.22mmol)为原料,得到棕色固体标题化合物(38mg,35%)。
1H NMR(400MHz,CHLOROFORM-d)9.28-9.43(m,1H)8.24-8.31(m,2H)8.21(d,J=6.85Hz,1H)7.98(s,1H)7.68(s,1H)7.33(t,J=9.05Hz,1H)6.92(s,1H)5.87(s,1H)5.61(s,2H)4.58(q,J=7.34Hz,2H)3.87(s,3H)2.37(s,3H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=484。
实施例87
87:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-甲基苯并[d]噁唑-2(3H)酮
实验操作同实施例1,以6-溴-5-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮(500.0mg,1.94mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(554mg,1.94mmol)为原料,得到标题产物(310mg,白色固体)产率38%。
1H NMR(400MHz,DMSO-d6)9.55(s,1H),8.86(s,1H),8.45(dd,2H),7.48(t,1H),7.38(s,1H),7.21(s,1H),4.51(q,2H),3.82(s,3H),3.42(s,3H),1.56(t,3H)。LC-MS:m/z[M+H]+=420。
实施例88
88-1:5-溴-2-环丙基-4-甲氧基-1-甲基-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(200mg,0.87mmol),邻苯三酚(20mg,0.159mmol)和环丙甲胺(93mg,1.31mmol)依次加到甲醇(5mL)中,在60℃下搅拌16小时。反应液浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得棕色油状液体标题化合物(120mg,49%)。LC-MS:m/z
[M+H]+=281,283。
88:4-(3-(2-环丙基-4-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-2-环丙基-4-甲氧基-1-甲基-1H-苯并[d]咪唑(120mg,0.43mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(158mg,0.43mmol)为原料,得白色固体标题化合物(17mg,9%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.30-8.24(m,2H),8.21(dd,J=2.0,6.8Hz,1H),7.34(t,J=8.8Hz,1H),7.21(d,J=8.3Hz,1H),7.04(d,J=8.3Hz,1H),4.57(q,J=7.0Hz,2H),4.29(s,3H),3.85(s,3H),2.05-1.97(m,1H),1.68(t,J=7.3Hz,3H),1.25(br.s.,2H),1.14-1.07(m,2H)。LC-MS:m/z[M+H]+=443。
实施例89
89-1:8-溴喹啉-5-碳酰肼
8-溴喹啉-5-羧酸甲酯(500mg,1.88)和水合肼(280mg,5.6mmol)加到无水乙醇(10mL)中50℃搅拌过夜。将反应液直接上制备板分离纯化(二氯甲烷/甲醇=15/1)得标题化合物(260mg,52%)。
89-2:8-溴-N'-(环丙烷羰基)喹啉-5-碳酰肼
8-溴喹啉-5-碳酰肼(230mg,0.86mmol),N,N-二异丙基乙胺(223mg,1.73mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(162mg,1.73mmol)和环丙甲酸(150mg,1.73nnol)加到二氯甲烷(6mL)室温搅拌过夜。将反应液直接上制备板分离纯化(二氯甲烷/醇=20/)得到标题化合物(150mg,52%)。
89-3:2-(8-溴喹啉-5-基)-5-环丙基-1,3,4-噁二唑
8-溴-N'-(环丙烷羰基)喹啉-5-碳酰肼(150mg,0.45mmol),N,N-二异丙基乙胺(174mg,1.35mmol)和对甲苯磺酰氯(256mg,1.35mmol)加到二氯甲烷(6ml)室温搅拌过夜。将反应液直接上制备板分离纯化(石油醚乙酸乙酯=11)得到标题化合物(20mg,14.1%)。
89:2-环丙基-5-(8-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)喹啉-5-基)-1,3,4--噁二唑
实验操作同实施例1,以2-(8-溴喹啉-5-基)-5-环丙基-1,3,4-噁二唑(23mg.0.06mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(23mg,0.06mmol)为原料,得到标题化合物(13mg,45%)。
1H NMR(400MHz,CHLOROFORM-d)9.77(d,J=8.8Hz,1H),9.42(s,1H),9.00(br.s.,1H),8.40(d,J=6.4Hz,2H),8.30-8.22(m,2H),7.92(d,J=7.8Hz,1H),7.60(br.s.,1H),7.45(s,1H),4.58(d,J=6.8Hz,2H),2.33(br.s.,1H),1.71-1.67(m,3H),1.32-1.30(m,4H)。
实施例90
90-1:5-甲氧基苯并[d]噁唑-2-羧酸甲酯
将2-氨基-4-甲氧基苯酚(1.0g,7.19mmol)和2,2,2-三甲氧基乙酸甲酯(11.8g,72mmol)在微波反应器中加热到110℃反应3h。反应液浓缩,柱层析分离(石油醚/乙酸乙酯=10:1-5:1),得到红棕色标题化合物固体(0.46g,产率31%)。LC-MS:m/z[M+H]+=208。
90-2:6-溴-5-甲氧基苯并[d]噁唑-2-羧酸甲酯
将5-甲氧基苯并[d]噁唑-2-羧酸甲酯(0.4g,1.93mmol)和N-溴代丁二酰亚胺(0.376g,2.1mmol)依次加入到乙腈(20mL)中。然后,在50℃条件下反应4小时。浓缩纯化得到标题化合物粗品(0.4g,产率72%)。LC-MS:m/z[M+H]+=286。
90-3:6-溴-5-甲氧基苯并[d]噁唑-2-羧酸
将6-溴-5-甲氧基苯并[d]噁唑-2-羧酸甲酯(0.4g,1.4mmol)和氢氧化锂(0.117g,2.8mmol)依次加入到四氢呋喃:水=10:1(5mL)中。然后,在室温条件下反应4小时。用1N盐酸调pH至3-4,乙酸乙酯萃取3次,有机相浓缩纯化得到标题化合物(300mg,产率79%)。LC-MS:m/z[M+H]+=272。
90-4:(6-溴-5-甲氧基苯并[d]噁唑-2-基)(吡咯烷-1-基)甲酮
将原料6-溴-5-甲氧基苯并[d]噁唑-2-羧酸(300mg,1.1mmol),四氢吡咯(90mg,1.2mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(630mg,1.6mmol),N,N-二异丙基乙胺(280mg,2.2mmol),加入到N,N-二甲基甲酰胺(10mL)中。氮气条件下,常温反应过夜。向反应液中加水淬灭反应,浓缩,柱层析分离(二氯甲烷/甲醇=30:1-10:1),得到棕色标题化合物固体(200mg,产率56%)。LC-MS:m/z[M+H]+=325。
90:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑-2-基)(吡咯烷-1-基)
甲酮
实验操作同实施例1,以(6-溴-5-甲氧基苯并[d]噁唑-2-基)(吡咯烷-1-基)甲酮(100mg,0.3mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(124mg,0.33mmol)为原料,得到类白色标题化合物固体(80mg,产率54%)。
1H NMR(400MHz,CDCl3):δ9.38(s,1H),8.28(t,3H),7.65(s,1H),7.42–7.32(m,2H),4.58(q,2H),4.15(t,2H),3.89(s,3H),3.77(t,2H),2.03(m,4H),1.69(t,3H)。
实施例91
91-1:5-溴-1-甲基-1H-吲唑-6-醇
将5-溴-6-甲氧基-1-甲基-1H-吲唑(500mg,2mmol)溶于10mL二氯甲烷中,加入1M三溴化硼二氯甲烷溶液(5mL)然后室温搅拌2小时,浓缩,制备板纯化(石油醚:乙酸乙酯=1:1)得到黄色液体
标题化合物(300mg,65%)。LC-MS:m/z[M+H]+=227。
91-2:5-溴-6-(二氟甲氧基)-1-甲基-1H-吲唑
将5-溴-1-甲基-1H-吲唑-6-醇(300mg,1mmol)溶于10mLN,N-二甲基甲酰胺中,加入碳酸铯(700mg,1mmol)和二氟氯乙酸钠(230mg,1.5mmol)加热至100摄氏度搅拌2小时,加水稀释,用乙酸乙酯萃取,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到白色固体标题化合物(150mg,50%)。LC-MS:m/z[M+H]+=277。
91:4-(3-(6-(二氟甲氧基)-1-甲基-1H-吲唑-5-基)-4-氟苯基)-7-乙基7H咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.22mmol),5-溴-6-(二氟甲氧基)-1-甲基-1H-吲唑(75mg,0.22mmol)为原料,得到棕色固体标题化合物(25mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)9.41(s,1H)8.30(s,3H)8.04(s,1H)7.82(s,1H)7.34-7.42(m,1H)7.27(s,1H)6.32-6.78(m,1H)4.59(d,J=7.34Hz,2H)4.12(s,3H)1.70(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=439。
实施例92
92-1:8-溴-4-(甲基氨基)-N-丙基肉啉-3-甲酰胺
将4-氨基-8-溴-N-丙基肉啉-3-甲酰胺(400mg,1.3mmol),碳酸铯(1300mg,3.9mmol),碘甲烷(553mg,3.9mmol)加入四氢呋喃(10ml)中。40摄氏度搅拌72小时。反应液直接薄层析纯化(二氯甲烷/甲醇=30/1)得到标题化合物(200mg,48%)。LC-MS:m/z[M+H]+=323。
92:8-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-4-(甲氨基)-N-丙基肉啉-3-甲酰胺
实验操作同实施例1,以8-溴-4-(甲基氨基)-N-丙基肉啉-3-甲酰胺(53mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.13mmol)为原料,得到标题化合物(26mg,40%)。
1H NMR(400MHz,CHLOROFORM-d)0.97(t,J=6.36Hz,3H)1.63(br.s.,5H)3.40(d,J=5.38Hz,2H)3.55(d,J=4.40Hz,3H)4.57(d,J=6.85Hz,2H)7.41(t,J=8.56Hz,1H)7.64(br.s.,1H)7.84(d,J=5.87Hz,1H)8.26(br.s.,1H)8.34(br.s.,2H)8.48(d,J=7.83Hz,1H)8.60(br.s.,1H)9.39(br.s.,1H)10.54(br.s.,1H)。LC-MS:m/z[M+H]+=485。
实施例93
93-1:N-(2,4-二溴-5-甲氧基苯基)四氢-2H-吡喃-4-甲酰胺
将2,4-二溴-5-甲氧基苯胺(500mg,1.8mmol),四氢-2H-吡喃-4-羧酸甲酯(308mg,2.1mmol),叔丁
醇钾(400mg,3.6mmol)加入四氢呋喃(20ml)中。室温在空气中搅拌5小时。反应液直接加乙酸乙酯(200ml),用水(100ml)洗三次,然后乙酸乙酯用无水硫酸钠干燥后浓缩得到标题化合物(600mg,85.8%)。LC-MS:m/z[M+H]+=394。
93-2:6-溴-5-甲氧基-2-(四氢-2H-吡喃-4-基)苯并[d]噁唑
将N-(2,4-二溴-5-甲氧基苯基)四氢-2H-吡喃-4-甲酰胺(300mg,0.76mmol),碳酸钾(316mg,2.3mmol),铜粉(147mg,2.3mmol),三氧化二铝(233mg,2.3mmol)加入N,N-二甲基甲酰胺(10ml)中。110摄氏度搅拌4小时。反应液直接柱层层析得到标题化合物(170mg,71.7%)。LC-MS:m/z[M+H]+=312。
93:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-2-(四氢-2H-吡喃-4-基)苯并[d]
噁唑
实验操作同实施例1,以6-溴-5-甲氧基-2-(四氢-2H-吡喃-4-基)苯并[d]噁唑(50mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.13mmol)为原料,得到标题化合物(12mg,19%)。
1H NMR(400MHz,CHLOROFORM-d)1.66-1.70(m,3H)2.03-2.16(m,4H)3.23(br.s.,1H)3.59(t,J=10.76Hz,2H)3.85(s,3H)4.08(d,J=11.25Hz,2H)4.57(q,J=7.34Hz,2H)7.28-7.40(m,2H)7.49(s,1H)8.22(d,J=6.85Hz,1H)8.27(br.s.,2H)9.38(br.s.,1H)。LC-MS:m/z[M+H]+=474。实施例94、实施例95
94-A1:3-(5-溴-6-甲氧基-1H-吲唑-1-基)氮杂环丁烷-1-羧酸叔丁酯
94-A2:3-(5-溴-6-甲氧基-2H-吲唑-2-基)氮杂环丁烷-1-羧酸叔丁酯
将5-溴-6-甲氧基-1H-吲唑(2g,8.81mmol)加到无水N,N-二甲基甲酰胺(20mL)中,在室温下加入氢化钠(705mg,17.62mmol),在室温下搅拌0.5小时后,加入3-碘代氮杂环丁烷-1-羧酸叔丁酯(4.19g,17.62mmol),再在室温下搅拌16小时。往反应液中加入十水硫酸钠(500mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得3-(5-溴-6-甲氧基-2H-吲唑-2-基)氮杂环丁烷-1-羧酸
叔丁酯(340mg,10%,Rf=0.3)、3-(5-溴-6-甲氧基-1H-吲唑-1-基)氮杂环丁烷-1-羧酸叔丁酯(900mg,27%,Rf=0.5)。LC-MS:m/z[M+H]+=382,384。
94-2:1-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-1H-吲唑盐酸盐
将3-(5-溴-6-甲氧基-1H-吲唑-1-基)氮杂环丁烷-1-羧酸叔丁酯(900mg,2.36mmol)加到二氯甲烷(5mL)中,再加入盐酸乙酸乙酯溶液(2mL,6M),在室温下搅拌10分钟。把析出的固体过滤出得白色固体标题化合物(663mg,100%)。LC-MS:m/z[M+H]+=282,284。
94-3:5-溴-6-甲氧基-1-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-1H-吲唑
将1-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-1H-吲唑盐酸盐(80mg,0.25mmol),2,2,2-三氟乙基三氟甲磺酸酯(116mg,0.50mmol)和三乙胺(126mg,1.25mmol)依次加到二氯甲烷(2mL)中,在室温下搅拌2小时。反应液浓缩,制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得白色固体标题化合物(60mg,66%)。LC-MS:m/z[M+H]+=364,366。
94:7-乙基-4-(4-氟-3-(6-甲氧基-1-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-3a,7α二氢-1H-吲唑-5-
基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-1H-吲唑(60mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(59mg,0.16mmol)为原料,得黄色固体标题化合物(35mg,42%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.26(s,2H),8.20(d,J=6.8Hz,1H),7.99(s,1H),7.67(s,1H),7.33(t,J=9.0Hz,1H),7.08(s,1H),5.39-5.30(m,1H),4.57(q,J=7.2Hz,2H),4.14-4.06(m,2H),3.99(t,J=7.1Hz,2H),3.90(s,3H),3.24(q,J=9.1Hz,2H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=526。
95-2:2-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-2H-吲唑盐酸盐
操作方法同94-2,以3-(5-溴-6-甲氧基-2H-吲唑-2-基)氮杂环丁烷-1-羧酸叔丁酯(900mg,2.36mmol)为原料,得白色固体标题化合物(660mg,100%)。LC-MS:m/z[M+H]+=282,284。
95-3:5-溴-6-甲氧基-2-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-2H-吲唑
操作方法同94-2,以2-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-2H-吲唑盐酸盐(80mg,0.25mmol)为原料,得淡黄色油状液体标题化合物(50mg,55%)。LC-MS:m/z[M+H]+=364,366。
95:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-2H-吲唑-5-基)苯基)-7H-
咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-(2,2,2-三氟乙基)氮杂环丁烷-3-基)-2H-吲唑(50mg,0.14mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(52mg,0.14mmol)为原料,得黄色固体标题化合物(35mg,48%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.26(s,2H),8.20(d,J=6.4Hz,1H),8.01(s,1H),7.60(s,1H),7.32(t,J=8.6Hz,1H),7.11(s,1H),5.24(t,J=6.4Hz,1H),4.61-4.53(m,2H),4.13-4.06(m,2H),3.96(t,J=6.6Hz,2H),3.87(s,3H),3.23(q,J=9.1Hz,2H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=526。
实施例96
96-1:4-((5-溴-6-甲氧基-2H-吲唑-2-基)甲基)四氢-2H-吡喃-4-醇
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(150mg,0.58mmol),4-(氨基甲基)四氢-2H-吡喃-4-醇(152mg,1.16mmol)为原料,得淡黄色油状液体标题化合物(50mg,25%)。LC-MS:m/z[M+H]+=341,343。
96:4-((5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2-基)甲基)四氢
-2H-吡喃-4-醇
实验操作同实施例1,以4-((5-溴-6-甲氧基-2H-吲唑-2-基)甲基)四氢-2H-吡喃-4-醇(50mg,0.15mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(55mg,0.15mmol)为原料,得黄色固体标题化合物(8mg,11%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.28(s,2H),8.20(d,J=6.8Hz,1H),7.90(s,1H),7.63(s,1H),7.36-7.30(m,1H),7.08(s,1H),4.57(q,J=7.3Hz,2H),4.34(s,2H),3.87(s,3H),3.83-3.73(m,4H),2.23-2.11(m,4H),1.70-1.67(m,3H)。LC-MS:m/z[M+H]+=503。
实施例97
97-1:1-(3-(5-溴-6-甲氧基-1H-吲唑-1-基)氮杂环丁烷-1-基)乙-1-酮
将1-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-1H-吲唑盐酸盐(100mg,0.31mmol),乙酸酐(63mg,0.62mmol)和三乙胺(116mg,1.15mmol)依次加到二氯甲烷(5mL)中,在室温下搅拌2小时。把反应液滴入饱和氯化铵水溶液(10mL)中,将分层的有机相经制备薄层色谱(乙酸乙酯)分离得淡黄色油状液体标题化合物(100mg,100%)。LC-MS:m/z[M+H]+=324,326。
97:1-(3-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-3a,7a-二氢-1H-吲唑-1-
基)氮杂环丁烷-1-基)乙-1-酮
实验操作同实施例1,以1-(3-(5-溴-6-甲氧基-1H-吲唑-1-基)氮杂环丁烷-1-基)乙-1-酮(60mg,0.19mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(70mg,0.19mmol)为原料,得黄色固体标题化合物(30mg,33%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.28(s,2H),8.20(d,J=6.8Hz,1H),8.04(s,1H),7.70(s,1H),7.33(t,J=8.8Hz,1H),6.84(s,1H),5.42(d,J=6.4Hz,1H),4.86-4.79(m,1H),4.66(t,J=8.3Hz,1H),4.60-4.54(m,4H),3.89(s,3H),1.99(s,3H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=486。
实施例98
98-1:1-(3-(5-溴-6-甲氧基-2H-吲唑-2-基)氮杂环丁烷-1-基)乙-1-酮
将2-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-2H-吲唑盐酸盐(100mg,0.31mmol),乙酸酐(63mg,0.62mmol)和三乙胺(116mg,1.15mmol)依次加到二氯甲烷(5mL)中,在室温下搅拌2小时。把反应液滴入饱和氯化铵水溶液(10mL)中,将分层的有机相经制备薄层色谱(乙酸乙酯)分离得淡黄色油状液体标题化合物(50mg,50%)。LC-MS:m/z[M+H]+=324,326。
98:1-(3-(5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2H-吲唑-2-基)氮杂环丁
烷-1-基)乙-1-酮
实验操作同实施例1,以1-(3-(5-溴-6-甲氧基-2H-吲唑-2-基)氮杂环丁烷-1-基)乙-1-酮(50mg,0.15mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(55mg,0.15mmol)为原料,得黄色固体标题化合物(20mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.26(s,2H),8.19(d,J=6.4Hz,1H),7.98(s,1H),7.59(s,1H),7.31(t,J=9.0Hz,1H),7.11(s,1H),5.36-5.27(m,1H),4.80-4.73(m,1H),4.65(t,J=8.3Hz,1H),4.59-4.52(m,4H),3.86(s,3H),1.96(s,3H),1.66(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=486。
实施例99
99:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(1-甲基哌啶-4-基)-2H-吲唑(200mg,0.62mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(228mg,0.62mmol)为原料,得白色固体标题化合物(160mg,53%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.27(br.s.,2H),8.20(d,J=5.9Hz,1H),7.95(s,1H),7.62(s,1H),7.33(t,J=8.8Hz,1H),7.10(s,1H),4.63-4.53(m,2H),4.47(br.s.,1H),3.87(s,3H),3.17(br.s.,2H),2.52-2.26(m,9H),1.69(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=486。
实施例100
100-1:5-溴-6-甲氧基-2-(4-甲基四氢-2H-吡喃-4-基)-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(150mg,0.58mmol),四氢-4-甲基-2H-吡喃-4-胺(132mg,1.16mmol)为原料,得淡黄色油状液体标题化合物(80mg,43%)。LC-MS:m/z[M+H]+=325,327。
100:7-乙基-4-(4-氟-3-(6-甲氧基-2-(4-甲基四氢-2H-吡喃-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑
[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(4-甲基四氢-2H-吡喃-4-基)-2H-吲唑(80mg,0.25mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(92mg,0.25mmol)为原料,得黄色固体标题化合物(25mg,21%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.31-8.24(m,2H),8.20(dd,J=2.0,6.8Hz,1H),8.01(s,1H),7.62(s,1H),7.32(t,J=9.0Hz,1H),7.14(s,1H),4.56(q,J=7.3Hz,2H),3.90-3.79(m,5H),3.74-3.66(m,2H),2.65–2.56(m,2H),2.17-2.08(m,2H),1.71-1.61(m,6H)。LC-MS:m/z[M+H]+=487。
实施例101、实施例102
101-A1:5-溴-6-甲氧基-2-苯基-2H-吲唑
101-A2:5-溴-6-甲氧基-1-苯基-1H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol)溶在N,N-二甲基甲酰胺(4mL)中,依次加入碘苯(359mg,1.76mmol)、碘化铜(17mg,0.088mmol)、N,N-二甲基乙二胺(8mg,0.088mmol)和磷酸钾(560mg,2.64mmol),在室温下搅拌16小时。反应液经制备薄层色谱(石油醚/乙酸乙酯=5/1)分离得5-溴-6-甲氧基-2-苯基-2H-吲唑(20mg,8%,Rf=0.3)、5-溴-6-甲氧基-1-苯基-1H-吲唑(120mg,45%,Rf=0.5)。LC-MS:m/z[M+H]+=303,305。
实施例101:7-乙基-4-(4-氟-3-(6-甲氧基-2-苯基-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-苯基-2H-吲唑(20mg,0.07mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(37mg,0.07mmol)为原料,得黄色固体标题化合物(8mg,25%)。
1H NMR(400MHz,CHLOROFORM-d)9.43(s,1H),8.39(s,1H),8.34-8.23(m,3H),7.91(S,1H),7.89(S,1H),7.69(s,1H),7.56-7.51(m,2H),7.42-7.34(m,2H),7.17(s,1H),4.62–4.55(m,2H),3.90(s,3H),1.70(d,J=6.4Hz,3H)。LC-MS:m/z[M+H]+=465。
实施例102:7-乙基-4-(4-氟-3-(6-甲氧基-1-苯基-3a,7a-二氢-1H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-苯基-1H-吲唑(60mg,0.20mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(74mg,0.20mmol)为原料,得黄色固体标题化合物(35mg,38%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H),8.32-8.23(m,3H),8.16(s,1H),7.79-7.74(m,3H),7.59(t,J=7.8Hz,2H),7.44-7.32(m,2H),7.20(s,1H),4.62–4.55(m,2H),3.88(s,3H),1.72-1.66(m,3H)。LC-MS:m/z[M+H]+=465。
实施例103
103-1:5-溴-4-甲氧基-1,2-二甲基-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(200mg,0.87mmol)加入原乙酸三乙酯(5ml)中。90摄氏度搅拌过夜。反应液直接薄层层析(二氯甲烷/甲醇=40/1)得到标题化合物(200mg,90%)。LC-MS:m/z[M+H]+=255。
103:7-乙基-4-(4-氟-3-(4-甲氧基-1,2-二甲基-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-甲氧基-1,2-二甲基-1H-苯并[d]咪唑(42mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.13mmol)为原料,得到标题化合物(25mg,44%)。
1H NMR(400MHz,CHLOROFORM-d)1.63-1.72(m,3H)2.63(br.s.,3H)3.73(br.s.,3H)4.29(br.s.,3H)4.56(d,J=7.34Hz,2H)7.05(d,J=7.83Hz,1H)7.22(br.s.,1H)7.34(t,J=8.07Hz,1H)8.16-8.32(m,3H)9.37(br.s.,1H)。LC-MS:m/z[M+H]+=417。
实施例104
104-1:N-(3-甲氧基-2-硝基苯基)四氢呋喃-3-胺
实验操作同实施例57中,57-1的合成方法,以1-氟-3-甲氧基-2-硝基苯(500mg,2.9mmol),四氢呋喃-3-胺(508mg,5.8mmol)为原料,得到标题化合物(700mg,100%)。LC-MS:m/z[M+H]+=239。
104-2:N-(4-溴-3-甲氧基-2-硝基苯基)四氢呋喃-3-胺
实验操作同实施例57中,57-2的合成方法,以N-(3-甲氧基-2-硝基苯基)四氢呋喃-3-胺(700mg,2.94mmol)为原料,得到标题化合物(1000mg,100%)。LC-MS:m/z[M+H]+=317。
104-3:4-溴-3-甲氧基-N1-(四氢呋喃-3-基)苯-1,2-二胺
实验操作同实施例57中,57-3的合成方法,以N-(4-溴-3-甲氧基-2-硝基苯基)四氢呋喃-3-胺(1000mg,3.2mmol)为原料,得到标题化合物(700mg,77%)。LC-MS:m/z[M+H]+=287。
104-4:5-溴-4-甲氧基-1-(四氢呋喃-3-基)-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-(四氢呋喃-3-基)苯-1,2-二胺(200mg,1.75mmol)加入原甲酸三乙酯(10ml)中。90摄氏度搅拌过夜。反应液直接薄层层析(二氯甲烷/甲醇=30/1)得到标题化合物(140mg,68%)。LC-MS:m/z[M+H]+=297。
104:7-乙基-4-(4-氟-3-(4-甲氧基-1-(四氢呋喃-3-基)-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-4-甲氧基-1-(四氢呋喃-3-基)-1H-苯并[d]咪唑(85mg,0.16mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.13mmol)为原料,得到标题化合物(14mg,23%)。
1H NMR(400MHz,CHLOROFORM-d)1.68(br.s.,3H)2.32(br.s.,1H)2.60(dd,J=13.69,6.36Hz,1H)3.95-4.04(m,1H)4.11(dd,J=10.03,6.11Hz,1H)4.21-4.28(m,2H)4.37(br.s.,3H)4.55-4.60(m,2H)5.07(br.s.,1H)7.22(br.s.,1H)7.29-7.39(m,2H)8.01(br.s.,1H)8.22(d,J=5.87Hz,1H)8.26(s,2H)9.37(s,1H)。LC-MS:m/z[M+H]+=459。
实施例105
105-1:四氢-2H-吡喃-4-基4-甲基苯磺酸盐
将四氢吡喃-4-醇(CAS:2081-44-9 500mg,5mmol)溶于10mL二氯甲烷中,加入对甲苯磺酰氯(1g,5.3mmol)和N,N-二异丙基乙胺(2ml),然后室温搅拌2小时。用饱和氯化铵水溶液洗涤反应液,浓缩反应液,制备板纯化(石油醚:乙酸乙酯=20:1),得到白色固体标题化合物(400mg,30%)。LC-MS:m/z[M+H]+=257。
105-2:5-溴-6-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑
将5-溴-6-(甲氧基)-1H-苯并[d]咪唑(CAS:1008361-65-6 354mg,1.5mmol)溶于10mL乙腈中,加入碳酸铯(1g,3mmol)和四氢-2H-吡喃-4-基4-甲基苯磺酸盐(400mg,1.5mmol)然后加热至60摄氏度搅拌3小时,过滤固体,浓缩,制备板纯化(石油醚:乙酸乙酯=5:1)得到白色固体标题化合物(300mg,62%)。LC-MS:m/z[M+H]+=311。
105:7-乙基-4-(4-氟-3-(6-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.16mmol),5-溴-6-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吲唑(50mg,0.16mmol)为原
料,得到白色固体标题化合物(36mg,48%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H)8.28(s,2H)8.23(d,J=6.36Hz,1H)7.98(s,1H)7.70(s,1H)7.35(t,J=9.05Hz,1H)6.89(s,1H)4.54-4.68(m,3H)4.22(d,J=11.74Hz,2H)3.93(s,3H)3.68(t,J=11.74Hz,2H)2.40-2.54(m,2H)2.04(d,J=11.74Hz,2H)1.68-1.71(m,3H)。LC-MS:m/z[M+H]+=473。
实施例106
106:4-氨基-8-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-N-丙基肉啉-3-甲酰胺
将4-氨基-8-碘代-N-丙基辛诺林-3-甲酰胺(40mg,0.11mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(40mg,0.11mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(9mg,0.011mmol),碳酸铯(108mg,0.33mmol)和水(0.4mL)加到1,4-二氧六环(4mL)中,置换氮气,在100℃下搅拌2小时。反应液过滤后浓缩,制备薄层色谱(二氯甲烷/甲醇=20/1)分离得棕色固体标题化合物(30mg,58%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.52(br.s.,1H),8.42-8.30(m,2H),8.26(s,1H),7.99(d,J=7.8Hz,1H),7.86(d,J=6.8Hz,1H),7.72(t,J=7.6Hz,1H),7.62-7.53(m,1H),7.48-7.36(m,2H),4.56(q,J=7.3Hz,2H),3.43(q,J=6.4Hz,2H),1.69-1.59(m,5H),0.97(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=471。
实施例107
107-1:5-溴-6-甲氧基-1-(四氢呋喃-3-基)-1H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol),溶在N,N-二甲基甲酰胺(4mL)中,在室温下加入氢化钠(70mg,1.76mmol),在室温下搅拌0.5小时后,加入3-碘四氢呋喃(349mg,1.76mmol),再在室温下搅拌16小时。往反应液中加入十水硫酸钠(100mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得淡黄色固体标题化合物(90mg,35%)。LC-MS:m/z[M+H]+=297,299。
107:7-乙基-4-(4-氟-3-(6-甲氧基-1-(四氢呋喃-3-基)-3a,7a-二氢-1H-吲唑-5-基)苯基)-7H-咪唑
[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-(四氢呋喃-3-基)-1H-吲唑(55mg,0.19mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(70mg,0.19mmol)为原料,得黄色固体标题化合物(40mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.38(br.s.,1H),8.35-8.14(m,3H),7.96(s,1H),7.68(s,1H),7.33(t,J=8.8Hz,1H),6.97(s,1H),5.29(br.s.,1H),4.57(q,J=7.0Hz,2H),4.34-4.17(m,3H),4.06-3.99(m,1H),3.90(s,3H),2.53(d,J=6.8Hz,2H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=461。
实施例108
108-1:5-溴-6-甲氧基-1-(氧杂环丁烷-3-基)-1H-吲唑
将5-溴-6-甲氧基-1H-吲唑(1000mg,4.40mmol),溶在N,N-二甲基甲酰胺(8mL)中,在室温下加入氢化钠(176mg,4.40mmol),在室温下搅拌0.5小时后,加入3-碘氧杂环丁烷(1619mg,8.80mmol),再在室温下搅拌16小时。往反应液中加入十水硫酸钠(500mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得淡黄色固体标题化合物(310mg,25%)。LC-MS:m/z[M+H]+=283,285。
108:7-乙基-4-(4-氟-3-(6-甲氧基-1-(氧杂环丁烷-3-基)-3a,7a-二氢-1H-吲哚唑-5-基)苯基)-7H-咪
唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-(氧杂环丁烷-3-基)-1H-吲唑(50mg,0.18mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(66mg,0.18mmol)为原料,得黄色固体标题化合物(40mg,50%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(br.s.,1H),8.27(s,2H),8.21(d,J=6.8Hz,1H),8.04(s,1H),7.70(s,1H),7.34(t,J=9.0Hz,1H),7.00(s,1H),5.79(quin,J=6.8Hz,1H),5.34(t,J=6.4Hz,2H),5.18(t,J=7.1Hz,2H),4.57(q,J=7.3Hz,2H),3.91(s,3H),1.68(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=447。
实施例109
109-1:5-溴-4-甲氧基-1-甲基-2-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(200mg,0.87mmol),四氢吡喃-4-甲醛(100mg,0.87mmol)加入四氢呋喃(10ml),乙酸(0.5ml)中。氩气保护下65摄氏度搅拌过夜。反应液直接薄层层析得到标题化合物(100mg,36%)。LC-MS:m/z[M+H]+=325。
109:7-乙基-4-(4-氟-3-(4-甲氧基-1-甲基-2-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-5-基)苯基)-7H-
咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-甲氧基-1-甲基-2-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑(85mg,0.26mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.13mmol)为原料,得到标题化合物(24mg,36.3%)。
1H NMR(400MHz,CHLOROFORM-d)1.70(br.s.,3H)1.92(d,J=11.74Hz,2H)2.21(br.s.,2H)3.15(br.s.,1H)3.62(t,J=10.03Hz,2H)3.78(br.s.,3H)4.15(d,J=10.76Hz,2H)4.37(s,3H)4.57(d,J=6.85Hz,2H)7.05(d,J=6.85Hz,1H)7.20-7.23(m,1H)7.31-7.38(m,1H)8.19-8.29(m,3H)9.37(br.s.,1H)。LC-MS:m/z[M+H]+=487。
实施例110、实施例111
110-A1:5-溴-1-(二氟甲基)-6-甲氧基-1H-吲唑
110-A2:5-溴-2-(二氟甲基)-6-甲氧基-2H-吲唑
将5-溴-6-(甲氧基)-1H-苯并[d]咪唑(CAS:1008361-65-6 440mg,1.9mmol)溶于10mLN,N-二甲基甲酰胺中,加入碳酸铯(2g,5.8mmol),氟化钾(1g,5.8mmol)和二氟氯乙酸钠(589mg,3.8mmol)加热至100摄氏度搅拌过夜,过滤固体,制备板纯化(石油醚:乙酸乙酯=3:1)得到极性小白色固体标题化合物A1(80mg,15%,展开剂石油醚:乙酸乙酯=3:1,Rf=0.7)和极性大黄色固体标题化合物A2(200mg,38%,展开剂石油醚:乙酸乙酯=3:1,Rf=0.5)。LC-MS:m/z[M+H]+=277。
110:4-(3-(1-(二氟甲基)-6-甲氧基-1H-吲唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.16mmol),5-溴-1-(二氟甲基)-6-甲氧基-1H-吲唑(50mg,0.16mmol)为原料,得到白色固体标题化合物(36mg,51%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H)8.28(s,2H)8.23(d,J=6.85Hz,1H)8.04(s,1H)7.72(s,1H)7.33-7.65(m,2H)7.27(s,1H)4.58(q,J=7.34Hz,2H)3.93(s,3H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=439。
111:4-(3-(2-(二氟甲基)-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.16mmol),5-溴-2-(二氟甲基)-6-甲氧基-2H-吲唑(50mg,0.16mmol)为原料,得到黄色固体标题化合物(32mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H)8.30(d,J=5.87Hz,3H)8.23(d,J=6.85Hz,1H)7.67(s,1H)7.28-7.61(m,2H)7.06(s,1H)4.59(q,J=7.17Hz,2H)3.89(s,3H)1.70(s,3H)。LC-MS:m/z[M+H]+=439。
实施例112
112-1:2,5-二溴-4-甲氧基苯甲醛
将2-溴-4-甲氧基苯甲醛(5000mg,23.26mmol)和三溴化吡啶(14886mg,46.52mmol)加到甲醇(50mL),在35℃下搅拌16小时。把反应液滴入饱和氯化铵水溶液(100mL)中,过滤得白色固体标题化合物(6000mg,88%)。LC-MS:m/z[M+H]+=293,295。
112-2:(Z)-1,4-二溴-2-(2-溴乙烯基)-5-甲氧基苯
将(溴甲基)三苯基溴化膦(8000mg,18.35mmol)溶解在四氢呋喃中(50mL),在-78℃下将溶解在四氢呋喃(20mL)中的叔丁醇钾(3394mg,30.30mmol)滴加进反应液中,在-78℃下搅拌2小时后,再加入2,5-二溴-4-甲氧基苯甲醛(4000mg,15.15mmol),再在室温下搅拌16小时。反应液浓缩后,经柱层析(石油醚)分离得白色固体标题化合物(1500mg,27%)。LC-MS:m/z[M+H]+=369,371。
112-3:6-溴-7-甲氧基肉桂碱-1,2-二羧酸二乙酯
将(Z)-1,4-二溴-2-(2-溴乙烯基)-5-甲氧基苯(1500mg,4.05mmol),肼-1,2-二羧酸二乙酯(1426mg,8.10mmol),碳酸钾(1397mg,10.13mmol),碘化亚铜(77mg,0.405mmol)和N,N-二甲基乙二胺(179mg,2.03mmol)加到1,4-二氧六(10mL)中,置换氮气,在90℃下搅拌16小时。反应液中加入水(40mL),用乙酸乙酯萃取(30mL×3),有机相经柱层析(石油醚/乙酸乙酯=10/1)分离得黄色油状液体标题化合物(950mg,61%)。LC-MS:m/z[M+H]+=385,387。
112-4:6-溴-7-甲氧基肉啉
将6-溴-7-甲氧基肉桂碱-1,2-二羧酸二乙酯(950mg,2.47mmol)和氢氧化钠(99mg,2.47mmol)加到乙醇(20mL)中,在室温下搅拌16小时。把乙醇浓缩干后,经制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得黄色固体标题化合物(300mg,51%)。LC-MS:m/z[M+H]+=239,241。
112:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基肉啉
实验操作同实施例1,以6-溴-7-甲氧基肉啉(200mg,0.84mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(309mg,0.84mmol)为原料,得白色固体标题化合物(135mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),9.27(d,J=5.4Hz,1H),8.39-8.26(m,3H),7.92(s,1H),7.88-7.80(m,2H),7.45-7.36(m,1H),4.59(q,J=7.0Hz,2H),4.05(s,3H),1.69(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=401。
实施例113
113-1:5-溴-6-甲氧基-2-(四氢-2H-吡喃-4-基)-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(500mg,1.92mmol),四氢-2H-吡喃-4-胺(388mg,3.84mmol)为原料,得淡黄色油状液体标题化合物(500mg,84%)。LC-MS:m/z[M+H]+=311,313。
113:7-乙基-4-(4-氟-3-(6-甲氧基-2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]
哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(四氢-2H-吡喃-4-基)-2H-吲唑(200mg,0.64mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(236mg,0.64mmol)为原料,得黄色固体标题化合物(140mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.25(s,2H),8.19(d,J=6.8Hz,1H),7.92(s,1H),7.61(s,1H),7.31(t,J=9.0Hz,1H),7.10(s,1H),4.56(td,J=7.5,14.8Hz,3H),4.15(d,J=11.2Hz,2H),3.85(s,3H),3.64-3.54(m,2H),2.23(br.s.,4H),1.66(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=473。
实施例114
114-1:5-溴-2-环丙基-6-甲氧基-2H-吲唑
实验操作同实施例40中,40-1和40-2的合成方法,以5-溴-4-甲氧基-2-硝基苯甲醛(100mg,0.38mmol),环丙胺(43mg,0.76mmol)为原料,得淡黄色油状液体标题化合物(70mg,69%)。LC-MS:m/z[M+H]+=267,269。
114:4-(3-(2-环丙基-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-环丙基-6-甲氧基-2H-吲唑(70mg,0.26mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(96mg,0.26mmol)为原料,得黄色固体标题化合物(15mg,13%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.35(br.s.,1H),8.24(br.s.,2H),8.17(d,J=5.9Hz,1H),7.93(s,1H),7.56(s,1H),7.30(t,J=8.8Hz,1H),7.05(br.s.,1H),4.55(d,J=7.3Hz,2H),3.89(br.s.,1H),3.83(s,3H),1.66(t,J=7.1Hz,3H),1.31(br.s.,2H),1.14(d,J=6.4Hz,2H)。LC-MS:m/z[M+H]+=429。
实施例115
115-1:N-(3-甲氧基-2-硝基苯基)氧杂环丁烷-3-胺
实验操作同实施例57中,57-1的合成方法,以1-氟-3-甲氧基-2-硝基苯(500mg,2.9mmol)为原料,得到黄色油状标题化合物(400mg,62%).LC-MS:m/z[M+H]+=225。
115-2:N-(4-溴-3-甲氧基-2-硝基苯基)氧杂环丁烷-3-胺
实验操作同实施例57中,57-2的合成方法,以N-(3-甲氧基-2-硝基苯基)氧杂环丁烷-3-胺(400mg,1.79mmol)为原料,得到黄色油状标题化合物(400mg,74%)。LC-MS:m/z[M+H]+=303。
115-3:4-溴-3-甲氧基-N1-(氧杂环丁-3-基)苯-1,2-二胺
实验操作同实施例57中,57-3的合成方法,以N-(4-溴-3-甲氧基-2-硝基苯基)氧杂环丁烷-3-胺(400mg,1.32mmol)为原料,得到红色油状标题化合物(300mg,84%)。LC-MS:m/z[M+H]+=273。
115-4:5-溴-4-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑
实验操作同实施例57中,57-4的合成方法,以4-溴-3-甲氧基-N1-(氧杂环丁-3-基)苯-1,2-二胺(300mg,1.1mmol)为原料,得到红色油状标题化合物(140mg,45%)。LC-MS:m/z[M+H]+=283。
115:7-乙基-4-(4-氟-3-(4-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑[4,5-c]
哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.136mmol),5-溴-4-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑(60mg,0.21mmol)为原料,得到标题化合物(13mg,22%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(br.s.,1H)8.19-8.32(m,3H)8.03(br.s.,1H)7.45(d,J=7.83Hz,1H)7.31-7.39(m,2H)5.56(br.s.,1H)5.14-5.27(m,4H)4.56(d,J=7.34Hz,2H)4.36(br.s.,3H)1.66-1.69(m,3H)。LC-MS:m/z[M+H]+=445。
实施例116
116-1:N-(2,4-二溴-5-甲氧基苯基)-2-甲氧基乙酰胺
2,4-二溴-5-甲氧基苯胺(200mg,0.71mmol),三乙胺(36mg,0.35mmol)和2-甲氧基乙酰氯(154mg,1.42mmol)加到二氯甲烷(4mL)中,室温搅拌一小时。将反应液浓缩,直接上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(300mg,80%)。LC-MS:m/z[M+H]+=354。
116-2:6-溴-5-甲氧基-2-(甲氧基甲基)苯并[d]噁唑
N-(2,4-二溴-5-甲氧基苯基)-2-甲氧基乙酰胺(300mg,0.85mmol),碳酸钾(293mg,2.12mmol),碘化亚铜(16mg,0.09mmol)和N,N-二甲基乙二胺(37.4mg,0.43mmol)加到甲苯(6mL)中,110℃下搅拌16小时。将反应液浓缩,直接上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(60mg,26%)。LC-MS:m/z[M+H]+=272,274。
116:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-2-(甲氧基甲基)苯并噁唑
实验操作同实施例1,以6-溴-5-甲氧基-2-(甲氧基甲基)苯并噁唑(60mg,0.22mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(68mg,0.17mmol)为原料,得标题化合物(10mg,11%)。
1H NMR(400MHz,CDCl3)δ9.38(br.s.,1H),8.32-8.20(m,3H),7.54(s,1H),7.38-7.34(m,1H),7.32(s,1H),4.72(s,2H),4.57(q,J=7.0Hz,2H),3.92-3.83(m,3H),3.54(s,3H),1.72-1.67(m,3H)。LC-MS:m/z[M+H]+=434。
实施例117
117-1:5-溴-6-甲氧基-2-(1-甲基氮杂环丁烷-3-基)-2H-吲唑
将2-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-2H-吲唑(150mg,0.5mmol)溶于20mL的甲醇中,加入37%甲醛水溶液(1mL)和氰基硼氢化钠(620mg,10mmol),然后室温搅拌过夜。浓缩,加入二氯甲烷溶解,过滤不溶物,浓缩,制备板纯化(二氯甲烷:甲醇=10:1),得到白色固体标题化合物(100mg,64%)。LC-MS:m/z[M+H]+=296。
117:7-乙基-4-(4-氟-3-(6-甲氧基-2-(1-甲基氮杂环丁烷-3-基)-2H-吲哚-5-基)苯基)-7H-咪唑[4,5-c]
哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.16mmol),5-溴-6-甲氧基-2-(1-甲基氮杂环丁烷-3-基)-2H-吲唑(50mg,0.16mmol)为原料,得到黄色固体标题化合物(20mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H),8.27(s,2H),8.21(d,J=6.4Hz,1H),8.03(s,1H),7.62(s,1H),7.34(t,J=9.0Hz,1H),7.12(s,1H),5.28(d,J=17.1Hz,1H),4.58(q,J=7.2Hz,2H),4.17(br.s.,2H),3.88(br.s.,5H),2.67(br.s.,3H),1.71-1.68(m,3H)。LC-MS:m/z[M+H]+=458。
实施例118
118-1:5-溴-6-甲氧基-1-(1-甲基氮杂环丁烷-3-基)-1H-吲唑
将1-(氮杂环丁烷-3-基)-5-溴-6-甲氧基-1H-吲唑(150mg,0.5mmol)溶于20mL的甲醇中,加入37%甲醛水溶液(1mL)和氰基硼氢化钠(620mg,10mmol),然后室温搅拌过夜。浓缩,加入二氯甲烷溶解,过滤不溶物,浓缩,制备板纯化(二氯甲烷:甲醇=10:1),得到白色固体标题化合物(100mg,64%)。LC-MS:m/z[M+H]+=296。
118:7-乙基-4-(4-氟-3-(6-甲氧基-1-(1-甲基氮杂环丁烷-3-基)-1H-吲唑-5-基)苯基)-7H-咪唑[4,5-c]
哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.16mmol),5-溴-6-甲氧基-1-(1-甲基氮杂环丁烷-3-基)-1H-吲唑(50mg,0.16mmol)为原料,得到黄色固体标题化合物(20mg,27%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H)8.28(s,2H)8.20(d,J=5.87Hz,1H)8.05(s,1H)7.68(s,1H)7.34(t,J=8.80Hz,1H)6.93(s,1H)5.50(br.s.,1H)4.58(q,J=7.34Hz,2H)4.51(t,J=7.58Hz,2H)4.13(t,J=7.83Hz,2H)3.92(s,3H)2.85(s,3H)1.69(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=458。
实施例119
119-1:N-乙基-3-甲氧基-2-硝基苯胺
实验操作同实施例57中,57-1的合成方法,以1-氟-3-甲氧基-2-硝基苯(500mg,2.9mmol)为原料,得到黄色油状标题化合物(450mg,79%).LC-MS:m/z[M+H]+=197。
119-2:4-溴-N-乙基-3-甲氧基-2-硝基苯胺
实验操作同实施例57中,57-2的合成方法,以N-乙基-3-甲氧基-2-硝基苯胺(400mg,2.04mmol)为原料,得到黄色油状标题化合物(350mg,62.6%)。LC-MS:m/z[M+H]+=275。
119-3:4-溴-N1-乙基-3-甲氧基苯-1,2-二胺
实验操作同实施例57中,57-3的合成方法,以4-溴-N-乙基-3-甲氧基-2-硝基苯胺(350mg,1.28mmol)为原料,得到黄色标题化合物(300mg,96%)。LC-MS:m/z[M+H]+=245。
119-4:5-溴-1-乙基-4-甲氧基-1H-苯并[d]咪唑
实验操作同实施例57中,57-4的合成方法,以4-溴-N1-乙基-3-甲氧基苯-1,2-二胺(300mg,1.2mmol)为原料,得到黄色固体标题化合物(200mg,66%)。LC-MS:m/z[M+H]+=255。
119:7-乙基-4-(3-(1-乙基-4-甲氧基-1H-苯并[d]咪唑-5-基)-4-氟苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑
并[4,5-c]哒嗪(50mg,0.136mmol),5-溴-1-乙基-4-甲氧基-1H-苯并[d]咪唑(69mg,0.27mmol)为原料,得到标题化合物(48mg,85%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H)8.26(s,2H)8.22(d,J=5.87Hz,1H),7.93(br.s.,1H)7.28-7.39(m,2H)7.16(d,J=8.31Hz,1H)4.57(q,J=7.01Hz,2H)4.37(br.s.,3H)4.26(q,J=7.01Hz,2H)1.68(t,J=7.34Hz,3H)1.58(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=417。
实施例120
120-1:5-溴-6-甲氧基-2-(2-甲氧基乙基)-2H-吲唑
5-溴-6-甲氧基-1H-吲唑(200mg,0.9mmol),钠氢(108mg,4.5mmol)和1-溴-2-甲氧基乙烷(187mg,1.4mmol)加到无水N,N-二甲基甲酰胺(8mL)中,室温搅拌16小时。将反应液浓缩,加水稀释,用乙酸乙酯萃取,有机相浓缩上制备板分离纯化(乙酸乙酯)得标题化合物(80mg,31.3%)。LC-MS:m/z[M+H]+=285,287。
120:7-乙基-4-(4-氟-3-(6-甲氧基-2-(2-甲氧基乙基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(2-甲氧基乙基)-2H-吲唑(80mg,0.28mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(87mg,0.28mmol)为原料,得标题化合物(60mg,61%)。
1H NMR(400MHz,CDCl3)δ9.37(s,1H),8.30-8.24(m,2H),8.23-8.18(m,1H),7.97(s,1H),7.61(s,1H),7.32(t,J=9.0Hz,1H),7.09(s,1H),4.59-4.52(m,4H),3.90-3.86(m,2H),3.85(s,3H),3.34(s,3H),1.71-1.66(m,3H)。LC-MS:m/z[M+H]+=447。
实施例121
121-1:6-溴-7-甲氧基异喹啉
将6-溴-7-氟异喹啉(CAS:1258833-80-5,130mg,0.5mmol),4M甲醇钠的甲醇溶液(2mL)依次溶于10mL的甲醇中,然后加热回流2小时。加水,用1M盐酸中和。用二氯甲烷萃取,干燥,浓缩,得
到白色固体标题化合物(800mg,76%)。LC-MS:m/z[M+H]+=238。
121-2:6-溴-7-甲氧基异喹啉2-氧化物
将6-溴-7-甲氧基异喹啉(700mg,3.4mmol)溶于10mL的二氯甲烷中,加入间氯过氧苯甲酸(1.1g,6.8mmol),室温搅拌过夜。浓缩,制备板纯化(二氯甲烷:甲醇=20:1),得到白色固体标题化合物(600mg,80%)。LC-MS:m/z[M+H]+=254。
121-3:6-溴-7-甲氧基异喹啉-1(2H)-酮
将6-溴-7-甲氧基异喹啉2-氧化物(600mg,2.3mmol)溶于乙酸酐(50mL)中,然后加热回流2小时。降温至100℃,加入水50mL,加热回流过夜。用乙酸乙酯萃取,浓缩,制备板纯化(二氯甲烷:甲醇=20:1)。得到黄色固体标题化合物(200mg,33%)。LC-MS:m/z[M+H]+=254。
121-4:6-溴-7-甲氧基-2-甲基异喹啉-1(2H)-酮
将6-溴-7-甲氧基异喹啉-1(2H)-酮(200mg,0.78mmol),碳酸钾(500mg,1.6mmol),碘甲烷(0.5mL)依次溶于10mL的甲醇中,然后室温搅拌过夜。浓缩,制备板纯化(二氯甲烷:甲醇=20:1)。得到白色固体标题化合物(110mg,52%)。LC-MS:m/z[M+H]+=268。
121:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-2-甲基异喹啉-1(2H)-酮
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(70mg,0.2mmol),6-溴-7-甲氧基-2-甲基异喹啉-1(2H)-酮(60mg,0.2mmol)为原料,得到白色固体标题化合物(48mg,58%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.22-8.37(m,3H)7.97(s,1H)7.55(s,1H)7.37(t,J=9.05Hz,1H)7.03(d,J=6.85Hz,1H)6.51(d,J=7.34Hz,1H)4.59(q,J=7.34Hz,2H)3.96(s,3H)3.66(s,3H)1.70(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=430。
实施例122
122-1:5-溴-6-甲氧基-2-(四氢呋喃-3-基)-2H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol)加到无水N,N-二甲基甲酰胺(4mL)中,在室温下加入氢化钠(35mg,0.88mmol),在室温下搅拌0.5小时后,加入3-碘四氢呋喃(523mg,2.64mmol),再在室温下搅拌16小时。往反应液中加入十水硫酸钠(100mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(40mg,15%)。LC-MS:m/z[M+H]+=297,299。
122:7-乙基-4-(4-氟-3-(6-甲氧基-2-(四氢呋喃-3-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(四氢呋喃-3-基)-2H-吲唑(40mg,0.14mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(52mg,0.14mmol)为原料,得黄色固体标题化合物(27mg,42%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.31-8.24(m,2H),8.22-8.17(m,1H),7.98(s,1H),7.60(s,1H),7.32(t,J=9.0Hz,1H),7.10(s,1H),5.23(br.s.,1H),4.56(q,J=7.3Hz,2H),4.26-4.13(m,3H),4.03-3.96(m,1H),3.85(s,3H),2.64-2.53(m,1H),2.51-2.42(m,1H),1.67(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=459。
实施例123
123:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基异喹啉
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.14mmol),6-溴-7-甲氧基异喹啉(30mg,0.16mmol)为原料,得到白色固体标题化合物(19mg,35%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.40(s,1H)9.25(s,1H)8.48(d,J=5.38Hz,1H)8.25-8.37(m,3H)7.85(s,1H)7.65(d,J=5.38Hz,1H)7.33-7.44(m,2H)4.59(q,J=7.01Hz,2H)3.98(s,3H)1.70(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=400。
实施例124
124-1:5'-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2'-氟-4-羟基-6-甲氧基-[1,1'-联苯]-3-甲醛
实验操作同实施例1,以5-溴-2羟基-4-甲氧基苯甲醛(70mg,0.299mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.272mmol)为原料,得标题化合物(66mg,62%)。LC-MS:m/z[M+H]+=393。
124-2:5'-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2'-氟-4-羟基-6-甲氧基-[1,1'-联苯]-3-甲醛甲醛肟5'-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2'-氟-4-羟基-6-甲氧基-[1,1'-联苯]-3-甲醛(66mg,0.168mmol),盐酸羟胺(35mg,0.505mmol),碳酸钠(53mg,0.505mmol)加到乙醇(2ml),水(0.2ml)中,室温搅拌过夜,反应液抽滤,浓缩,粗品(48mg)直接投下一步。
124:5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基苯并[d]异噁唑
5'-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2'-氟-4-羟基-6-甲氧基-[1,1'-联苯]-3-甲醛甲醛肟(48mg,0.118mmol),三苯基磷(31mg,0.120mmol)加到乙腈(1ml)中,室温搅拌5分钟后,偶氮二甲酸二异丙酯(24mg,0.12mmol)溶于乙腈(0.5ml)中,Ar保护下滴加至反应液,滴加完后室温搅拌过夜,反应液抽滤,浓缩,制备薄层色谱(石油醚/乙酸乙酯=1/3)得标题化合物(1mg,2%)。
1H NMR(400MHz,CHLOROFORM-d)d=9.20(s,1H),8.31(s,1H),8.12-7.99(m,2H),7.38(s,1H),7.26-7.23(m,2H),6.50(s,1H),4.48(d,J=7.8Hz,2H),3.73(s,3H),1.59(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=390。
实施例125
125-1:7-溴-4-(氧杂环丁-3-基氧基)苯并呋喃
7-溴-4-氟苯并呋喃(200mg,0.9mmol),氧杂环丁烷-3-醇(133mg,1.8mmol),碳酸铯(472mg,1.45mmol)加到N,N-二甲基甲酰胺(1ml)中,80℃反应6小时,反应液抽滤,浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)得标题化合物(188mg,77%)。LC-MS:m/z[M+H]+=269,271。
125:7-乙基-4-(4-氟-3-(4-(氧杂环丁-3-基氧基)苯并呋喃-7-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-溴-4-(氧杂环丁-3-基氧基)苯并呋喃(46mg,0.163mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(60mg,0.163mmol)为原料,得标题化合物(33mg,47%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H),8.45(d,J=6.8Hz,1H),8.32-8.25(m,2H),7.62(s,1H),7.44-7.35(m,2H),6.98(s,1H),6.35(d,J=7.8Hz,1H),5.41(t,J=5.4Hz,1H),5.07(t,J=6.6Hz,2H),4.89(t,J=5.9Hz,2H),4.58(q,J=7.3Hz,2H),1.71-1.67(m,3H).LC-MS:m/z[M+H]+=431。
实施例126
126-1:5-溴-4-甲氧基-1-甲基-1H-苯并[d]咪唑
将4-溴-3-甲氧基-N1-甲基苯-1,2-二胺(200mg,0.87mmol)加到原甲酸三乙酯(5mL)中,在80℃下搅拌1小时。把反应液浓缩,制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得淡黄色油状液体标题化合物(100mg,47%)。LC-MS:m/z[M+H]+=241,243.
126:7-乙基-4-(4-氟-3-(4-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例106,以5-溴-4-甲氧基-1-甲基-1H-苯并[d]咪唑(50mg,0.21mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(77mg,0.21mmol)为原料,得白色固体标题化合物(26mg,30%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.34-8.19(m,3H),7.89(br.s.,1H),7.40-7.29(m,2H),7.14(d,J=7.8Hz,1H),4.57(q,J=6.8Hz,2H),4.39(s,3H),3.87(s,3H),1.68(t,J=7.1Hz,3H).LC-MS:m/z[M+H]+=403。
实施例127
127-1:6-甲氧基-2,3-二氢苯并呋喃
6甲氧基苯并呋喃(500mg,3.38mmol),钯碳(20mg)加到乙醇(5ml)中,H2保护下室温反应4小时。反应液抽滤,浓缩,收得粗品(321mg)直接投下一步。LC-MS:m/z[M+H]+=151。
127-2:5-溴-6-甲氧基-2,3-二氢苯并呋喃
6-甲氧基-2,3-二氢苯并呋喃(200mg,1.333mmol)加到乙酸(1ml)中,液溴(229mg,1.466mmol)溶于乙酸(1ml)中,缓慢滴加至反应液。滴加完后,室温反应30分钟.反应液倒入饱和碳酸钠溶液(20ml)中,二氯甲烷萃取,无水硫酸钠干燥,浓缩,制备薄层色谱(石油醚/乙酸乙酯=10/1)得标题化合物(126mg,41%)。LC-MS:m/z[M+H]+=228,230。
127:7-乙基-4-(4-氟-3-(6-甲氧基-2,3-二氢苯并呋喃-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2,3-二氢苯并呋喃(20mg,0.088mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(32mg,0.088mmol)为原料,得标题化合物(6mg,18%)。
1H NMR(400MHz,CHLOROFORM-d)9.39-9.33(m,1H),8.28-8.20(m,2H),8.14(dd,J=2.2,7.1Hz,1H),7.33-7.28(m,1H),7.16(s,1H),6.53(s,1H),4.64(t,J=8.6Hz,2H),4.59-4.55(m,2H),3.78(s,3H),3.21(t,J=8.6Hz,2H),1.70-1.67(m,3H)。LC-MS:m/z[M+H]+=391。
实施例128
128-1:5-溴-2-异丙基-6-甲氧基-2H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol)加到无水N,N-二甲基甲酰胺(5mL)中,在室温下加入氢化钠(35mg,0.88mmol),在室温下搅拌0.5小时后,加入2-碘丙烷(300mg,1.76mmol),再在室温下搅拌1小时。往反应液中加入十水硫酸钠(100mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(50mg,19%)。LC-MS:m/z[M+H]+=269,271。
128:7-乙基-4-(4-氟-3-(2-异丙基-6-甲氧基-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-异丙基-6-甲氧基-2H-吲唑(50mg,0.19mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(68mg,0.19mmol)为原料,得棕色固体标题化合物(13mg,15%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.30-8.24(m,2H),8.19(dd,J=2.0,6.8Hz,1H),7.91(s,1H),7.60(s,1H),7.31(t,J=8.8Hz,1H),7.13(s,1H),4.75(td,J=6.5,13.5Hz,1H),
4.55(q,J=7.3Hz,2H),3.85(s,3H),1.71-1.62(m,9H)。LC-MS:m/z[M+H]+=431。
实施例129
129-1:5-溴-6-甲氧基-2-(氧杂环丁烷-3-基)-2H-吲唑
将5-溴-6-甲氧基-1H-吲唑(100mg,0.44mmol)加到无水N,N-二甲基甲酰胺(4mL)中,在室温下加入氢化钠(18mg,0.44mmol),在室温下搅拌0.5小时后,加入3-碘氧杂环丁烷(162mg,0.88mmol),再在室温下搅拌1小时。往反应液中加入十水硫酸钠(100mg),过滤后浓缩,制备薄层色谱(二氯甲烷/甲醇=20/1)分离得淡黄色油状液体粗品标题化合物(100mg,粗品)。LC-MS:m/z[M+H]+=283,285。
129:7-乙基-4-(4-氟-3-(6-甲氧基-2-(氧杂环丁-3-基)-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-(氧杂环丁烷-3-基)-2H-吲唑(100mg,粗品),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(129mg,0.35mmol)为原料,得固体标题化合物(6mg,两步收率3%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.31-8.26(m,2H),8.20(d,J=6.8Hz,1H),8.05(s,1H),7.62(s,1H),7.33(t,J=8.6Hz,1H),7.14(s,1H),5.73-5.65(m,1H),5.25-5.20(m,2H),5.18-5.14(m,2H),4.57(q,J=7.3Hz,2H),3.87(s,3H),1.68(s,3H)。LC-MS:m/z[M+H]+=445。
实施例130
130-1:5-溴-2-乙基-6-甲氧基-2H-吲唑
将5-溴-6-甲氧基-1H-吲唑(100mg,0.44mmol)加到无水N,N-二甲基甲酰胺(4mL)中,在室温下加入氢化钠(18mg,0.44mmol),在室温下搅拌0.5小时后,加入碘乙烷(137mg,0.88mmol),再在室温下搅拌1小时。往反应液中加入十水硫酸钠(100mg),过滤后浓缩,制备薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(50mg,45%)。LC-MS:m/z[M+H]+=255,257。
130:7-乙基-4-(3-(2-乙基-6-甲氧基-2H-吲唑-5-基)-4-氟苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-乙基-6-甲氧基-2H-吲唑(50mg,0.20mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(74mg,0.20mmol)为原料,得棕色固体标题化合物(2mg,2%)。
1H NMR(400MHz,CHLOROFORM-d)9.34(s,1H),8.28-8.21(m,1H),8.18(dd,J=2.0,6.8Hz,
1H),7.86(s,1H),7.58(s,1H),7.29(t,J=9.0Hz,1H),7.08(s,1H),4.52(q,J=7.3Hz,2H),4.41(q,J=7.3Hz,2H),3.83(s,3H),1.69-1.55(m,6H)。LC-MS:m/z[M+H]+=417。
实施例131
131-1:1-溴-5-氟-2-甲氧基-4-硝基苯
2-溴-4-氟-5-硝基苯酚(1g,4.2mmol),碘甲烷(5.9g,42mmol)和碳酸铯(6.8g,21mmol)加到乙腈中(10ml),100℃下搅拌两小时。将反应液浓缩,用乙酸乙酯和水萃取,有机相浓缩上制备板分离纯化(石油醚/乙酸乙酯=5/1))得标题化合物(1g,95%)。LC-MS:m/z[M+H]+=250,252。
131-2:5-溴-4-甲氧基-N-甲基-2-硝基苯胺
1-溴-5-氟-2-甲氧基-4-硝基苯(1g,4mmol)和甲胺盐酸盐(1.35g,20mmol)加到乙腈中(10ml)90℃搅拌两小时。将反应液浓缩,用乙酸乙酯和水萃取,有机相浓缩上制备板分离纯化(石油醚/乙酸乙酯=5/1)得标题化合物(1g,96%)。LC-MS:m/z[M+H]+=261,263。
131-3:5-溴-4-甲氧基-N1-甲基苯-1,2-二胺
5-溴-4-甲氧基-N-甲基-2-硝基苯胺(1g,3.83mmol)和雷尼镍(250mg)加到甲醇中(20ml),氢气条件下,室温搅拌半小时。将反应液过滤浓缩,得粗品标题化合物(850mg,96%)。LC-MS:m/z[M+H]+=231,233。
131-4:6-溴-5-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑
5-溴-4-甲氧基-N1-甲基苯-1,2-二胺(900mg,3.9mmol),溴化氢(3ml)和亚硝酸钠(538mg,7.8mmol)依次加到水中(10ml),室温搅拌5小时。将反应液用乙酸乙酯和水萃取,有机相浓缩上制备板分离纯化(二氯甲烷/甲醇=20/1)得标题化合物(500mg,53%)。LC-MS:m/z[M+H]+=242,244。
131:7-乙基-4-(4-氟-3-(5-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑-6-基)苯基)-7H-咪唑[4,5-c]哒嗪
实验操作同实施例1,以6-溴-5-甲氧基-1-甲基-1H-苯并[d][1,2,3]三唑(22.4mg,0.09mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(30mg,0.01mmol)为原料,得标题化合物(18mg,50%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.35-8.23(m,3H),7.52(d,J=4.4Hz,2H),7.38(t,J=9.0Hz,1H),4.59(q,J=7.0Hz,2H),4.31(s,3H),3.92(s,3H),1.70(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=404。
实施例132
132-1:5-溴-2,2-二氟-6-碘苯并[d][1,3]二噁茂
5-溴-2,2-二氟苯并[d][1,3]二噁茂(1g,4.22mmol),碘(2.14g,8.44mmol),三氟醋酸银(560mg,2.53mmol)加到二氯甲烷(20ml)中,40℃反应48小时。反应液倒入饱和硫代硫酸钠(30ml)溶液,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱色谱(石油醚)得粗品(80%纯度)。
132-2:4-(3-(6-溴-2,2-二氟苯并[d][1,3]二噁茂-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2,2-二氟-6-碘苯并[d][1,3]二噁茂粗品(50mg,0.168mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(50mg,0.168mmol)为原料,得标题化合物(27mg,34%)。LC-MS:m/z[M+H]+=477,479。
132:4-(3-(2,2-二氟-6-甲氧基苯并[d][1,3]二噁茂-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪
4-(3-(6-溴-2,2-二氟苯并[d][1,3]二噁茂-5-基)-4-氟苯基)-7-乙基-7H-咪唑并[4,5-c]哒嗪(20mg,0.042mmol),氯化钯(1-苯基烯丙基)二聚物(2mg,0.002mmol),二-叔-丁基(2,4,6-三异丙基-3,6-二甲氧基-[1,1-二联苯]-2-基)膦(3mg,0.004mmol),碳酸铯(28mg,0.084mmol),甲醇(4mg,0.126mmol)加到甲苯(1ml)中,氩气保护下室温搅拌过夜。反应液抽滤,浓缩,制备薄层色谱(二氯甲烷/甲醇=10/1)得标题化合物(12mg,67%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.29-8.22(m,2H),8.19(d,J=6.8Hz,1H),7.33(t,J=9.0Hz,1H),7.09(s,1H),6.83(s,1H),4.65-4.48(m,2H),3.80(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=429。
实施例133
133-1:N-(2,4-二溴-5-甲氧基苯基)乙酰胺
2,4-二溴-5-甲氧基苯胺(300mg,1.075mmol),乙酸酐(132mg,1.290mmol),三乙胺(132mg,1.290mmol)加到二氯甲烷(2ml)中,室温搅拌过夜。反应液倒入饱和氯化铵溶液中,二氯甲烷萃取,无水硫酸钠干燥,浓缩,粗品(317mg)直接投下一步。LC-MS:m/z[M+H]+=322,324,326。
133-2:6-溴-5-甲氧基-2-甲基苯并[d]噁唑
N-(2,4-二溴-5-甲氧基苯基)乙酰胺(300mg,0.934mmol),碘化亚铜(18mg,0.094mmol),N,N-二甲基乙二胺(16mg,0.187mmol),碳酸钾(258mg,1.872mmol)加到甲苯(2ml)中,氩气保护下,110℃
反应过夜。反应液抽滤,浓缩,制备薄层色谱(石油醚/乙酸乙酯=1/1)得标题化合物(70mg,29%)。LC-MS:m/z[M+H]+=242,244。
133:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-2-甲基苯并[d]噁唑
6-溴-5-甲氧基-2-甲基苯并[d]噁唑(62mg,0.257mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(95mg,0.257mmol),四(三苯基膦)钯(30mg,0.026),碳酸铯(166mg,0.514mmol)加到1,4-二氧六环(2ml)中,氩气保护下,100℃反应1小时。反应液抽滤,浓缩,制备薄层色谱(二氯甲烷/甲醇=30/1)得标题化合物(50mg,48%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.27(s,2H),8.23(d,J=6.8Hz,1H),7.47(s,1H),7.35(t,J=9.0Hz,1H),7.26(s,1H),4.58(q,J=7.3Hz,2H),3.86(s,3H),2.66(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=404。
实施例134、实施例135
134-1:5-溴-6-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-(氧杂环丁-3-基)-1H-
苯并[d]咪唑混合物
将5-溴-6-甲氧基-1H-苯并[d]咪唑(100mg,0.44mmol)加到无水N,N-二甲基甲酰胺(5mL)中,在室温下加入氢化钠(35mg,0.88mmol),在室温下搅拌0.5小时后,加入3-碘氧杂环丁烷(162mg,0.88mmol),再在80℃下搅拌16小时。把反应液滴到饱和氯化铵水溶液(20mL)中,用乙酸乙酯萃取(20mL×3),合并有机相,并用饱和食盐水(30mL)洗涤,浓缩有机相,制备薄层色谱(二氯甲烷/甲醇=20/1)分离得5-溴-6-甲氧基-1-(氧杂-3-基)-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑的混合物(80mg,64%)。LC-MS:m/z[M+H]+=283,285。
134:7-乙基-4-(4-氟-3-(6-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑[4,5-c]
哒嗪
135:7-乙基-4-(4-氟-3-(5-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑-6-基)苯基)-7H-咪唑[4,5-c]
哒嗪
实验操作同实施例106,以5-溴-6-甲氧基-1-(氧杂-3-基)-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-(氧杂环丁-3-基)-1H-苯并[d]咪唑的混合物(80mg,0.28mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.28mmol)为原料,得30mg固体,进一步SFC分得(第一个峰,实施例134,12mg,9%)和(第二个峰,实施例135,6mg,4%)。拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:A for CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
实施例134:1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.33-8.21(m,3H),8.00(s,1H),7.83(s,1H),7.38-7.33(m,2H),5.58-5.52(m,1H),5.33-5.25(m,2H),5.23-5.18(m,2H),4.58(q,J=7.3Hz,2H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=445。
实施例135:1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.34-8.21(m,3H),8.08(s,1H),7.70(s,1H),7.45(s,1H),7.36(t,J=9.0Hz,1H),5.59-5.50(m,1H),5.25-5.13(m,4H),4.58(d,J=7.3Hz,2H),3.89(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=445。
实施例136、实施例137
136-1:5-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-甲基-1H-苯并[d]咪唑混合物
将5-溴-6-甲氧基-1H-苯并[d]咪唑(250mg,1.10mmol)加到无水N,N-二甲基甲酰胺(5mL)中,在室温下加入氢化钠(67mg,1.65mmol),在室温下搅拌0.5小时后,加入碘甲烷(391mg,2.75mmol),再在室温下搅拌1小时。把反应液滴到饱和氯化铵水溶液(20mL)中,用乙酸乙酯萃取(20mL×3),合并有机相,并用饱和食盐水(30mL)洗涤,浓缩有机相,制备薄层色谱(二氯甲烷/甲醇=30/1)分离得5-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-甲基-1H-苯并[d]咪唑的混合物(130mg,49%)。LC-MS:m/z[M+H]+=241,243。
136:7-乙基-4-(4-氟-3-(5-甲氧基-1-甲基-1H-苯并[d]咪唑-6-基)苯基)-7H-咪唑并[4,5-c]哒嗪
137:7-乙基-4-(4-氟-3-(6-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑和6-溴-5-甲氧基-1-甲基-1H-苯并[d]咪唑的混合物(120mg,0.50mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(184mg,0.50mmol)为原料,得80mg固体,进一步SFC分得(第一个峰,实施例136,黄色固体,18mg,8%)和(第二个峰,实施例137,白色固体,36mg,17%)。拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:Afor CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
136:1H NMR(400MHz,CHLOROFORM-d)9.55(s,1H),8.84(s,1H),8.50-8.41(m,2H),8.18(s,1H),7.59(s,1H),7.52-7.45(m,1H),7.36(s,1H),4.50(q,J=7.3Hz,2H),3.83(s,3H),3.79(s,3H),1.54(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=403。
137:1H NMR(400MHz,CHLOROFORM-d)9.55(s,1H),8.84(s,1H),8.51-8.46(m,1H),8.45-8.39(m,1H),8.17(s,1H),7.60(s,1H),7.51-7.44(m,1H),7.32(s,1H),4.50(d,J=7.3Hz,2H),3.88(s,3H),3.84(s,3H),1.54(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例138
138-1:5-溴-1-(乙基磺酰基)-6-甲氧基-1H-吲唑
将5-溴-6-甲氧基-1H-吲唑(200mg,0.88mmol)加到无水N,N-二甲基甲酰胺(5mL)中,在室温下加入氢化钠(53mg,1.32mmol),在室温下搅拌0.5小时后,加入乙基磺酰氯(170mg,1.32mmol),再在室温下搅拌1小时。把反应液滴到饱和氯化铵水溶液(20mL)中,用乙酸乙酯萃取(20mL×3),合并有机相,并用饱和食盐水(30mL)洗涤,浓缩有机相,制备薄层色谱(石油醚/乙酸乙酯=5/1)分离得黄色
固体标题化合物(210mg,78%)。LC-MS:m/z[M+H]+=319,321.
138:7-乙基-4-(3-(1-(乙基磺酰基)-6-甲氧基-1H-吲唑-5-基)-4-氟苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-1-(乙基磺酰基)-6-甲氧基-1H-吲唑(35mg,0.11mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(40mg,0.11mmol)为原料,得黄色固体标题化合物(25mg,47%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.28(s,2H),8.25-8.19(m,2H),7.71(s,1H),7.63(s,1H),7.35(t,J=9.0Hz,1H),4.58(q,J=7.2Hz,2H),3.92(s,3H),3.52(q,J=7.3Hz,2H),1.68(t,J=7.3Hz,3H),1.30(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=481。
实施例139
139:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基喹啉
实验操作同实施例1,以6-溴-7-甲氧基喹啉(26mg,0.11mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(40mg,0.11mmol)为原料,得黄色固体标题化合物(17mg,38%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.86(d,J=2.4Hz,1H),8.33-8.23(m,3H),8.11(d,J=7.8Hz,1H),7.79(s,1H),7.55(s,1H),7.39-7.27(m,2H),4.55(q,J=7.0Hz,2H),3.96(s,3H),1.66(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=400。
实施例140
140:7-乙基-4-(3-(4-(乙基磺酰基)萘-1-基)-4-氟苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以溴-4-(乙基磺酰基)萘(25mg,0.084mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(31mg,0.084mmol)为原料,得标题化合物(12mg,29.1%)。
1H NMR(400MHz,CHLOROFORM-d)9.39(s,1H),8.86(d,J=8.3Hz,1H),8.41(d,J=7.8Hz,2H),8.31(d,J=4.9Hz,1H),8.26(s,1H),7.87(d,J=8.3Hz,1H),7.78-7.65(m,2H),7.63-7.57(m,1H),7.47(t,J=9.0Hz,1H),4.58(q,J=7.7Hz,2H),3.39(q,J=7.3Hz,2H),1.68(t,J=7.3Hz,3H),1.33(t,J=7.6Hz,3H)。LC-MS:m/z[M+H]+=491。
实施例141
141:7-乙基-4-(4-氟-3-(6-甲氧基-2-甲基-2H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-2-甲基-2H-吲唑(50mg,0.21mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(77mg,0.21mmol)为原料,得黄色固体标题化合物(14mg,16%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.37(br.s.,1H),8.26(br.s.,2H),8.21(d,J=5.9Hz,1H),7.84(br.s.,1H),7.59(br.s.,1H),7.32(t,J=8.6Hz,1H),7.08(br.s.,1H),4.55(d,J=7.3Hz,2H),4.17(br.s.,3H),3.86(br.s.,3H),1.67(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例142
142:7-乙基-4-(4-氟-3-(6-甲氧基-1-甲基-1H-吲唑-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-6-甲氧基-1-甲基-1H-吲唑(50mg,0.21mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(77mg,0.21mmol)为原料,得黄色固体标题化合物(35mg,41%)。
1H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.27(s,2H),8.22(d,J=5.9Hz,1H),7.93(s,1H),7.68(s,1H),7.34(t,J=8.8Hz,1H),6.83(s,1H),4.57(q,J=7.3Hz,2H),4.08(s,3H),3.92(s,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=403。
实施例143
143-1:2-(3-溴-4-甲氧基苯乙基)甲酰胺
2-(3-溴-4-甲氧基苯基)乙-1-胺(1g,4.3mmol)加到甲酰胺中(10ml)120℃搅拌16小时。反应液浓缩后用二氯甲烷和水萃取,制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(900mg,81.8%)。LC-MS:m/z[M+H]+=258,260。
143-2:6-溴-7-甲氧基-3,4-二氢异喹啉-2(1H)-甲醛
2-(3-溴-4-甲氧基苯乙基)甲酰胺(900mg,3.48mmol),多聚甲醛(300mg)和三氟醋酸(1ml)加到甲苯中(6ml),60℃搅拌16小时。反应液浓缩后用二氯甲烷和水萃取,制备板分离纯化(二氯甲烷/甲醇=12/1)得标题化合物(460mg,49%)。LC-MS:m/z[M+H]+=258,260。
143-3:6-溴-7-甲氧基-1,2,3,4-四氢异喹啉
6-溴-7-甲氧基-3,4-二氢异喹啉-2(1H)-甲醛(200mg,0.74mmol)和氢氧化钠(148mg,3.7mmol)加到乙醇中(4ml),80℃搅拌16小时。反应液浓缩后爬制备板分离纯化(二氯甲烷/甲醇=12/1)得标题化合物(120mg,67%)。LC-MS:m/z[M+H]+=242,244。
143-4:6-溴-7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉
6-溴-7-甲氧基-1,2,3,4-四氢异喹啉(100mg,0.4mmol),氰基硼氢化钠(75mg,1.2mmol)和多聚甲醛(125mg,4mmol)加到甲醇中(4ml)室温搅拌0.5小时。反应液用甲醇淬灭浓缩后爬制备板分离纯化(二氯甲烷/甲醇=12/1)得标题化合物(80mg,78.4%)。LC-MS:m/z[M+H]+=256,258。
143-5:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉
实验操作同实施例1,以6-溴-7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉(120mg,0.47mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(146mg,0.4mmol)为原料,得标题化合物(30mg,15%)。LC-MS:m/z[M+H]+=418。
143:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-2-甲基-3,4-二氢异喹啉-1(2H)
酮
6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉(30mg,0.07mmol),碘(137mg,0.54mmol),和碳酸氢钠(42mg,0.7mmol)加到四氢呋喃/水(2.5/1mL),室温搅拌16小时。用硫代硫酸钠水溶液将反应体系淬灭,用乙酸乙酯和水萃取,有机相浓缩上制备板分离纯化(二氯甲烷/甲醇=20/1)得标题化合物(30mg,99%)。
1H NMR(400MHz,CDCl3)δ9.36(s,1H),8.31-8.22(m,2H),8.18(d,J=5.4Hz,1H),7.74(s,1H),7.33(t,J=9.0Hz,1H),7.17(s,1H),4.57(q,J=7.3Hz,2H),3.87(s,3H),3.60(t,J=6.6Hz,2H),3.19(s,3H),3.00(t,J=6.6Hz,2H),1.68(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=432。
实施例144
144-1:5-溴-6-甲氧基-1-甲基-1H-吲哚
将5-溴-6-甲氧基-1H-吲哚(CAS:177360-11-1,200mg,0.89mmol),钠氢(53mg,1.3mmol)和碘甲烷(150mg,1.1mmol)依次加入到10mL的四氢呋喃中,然后室温搅拌1小时,加水淬灭,浓缩,制备板纯化(石油醚:乙酸乙酯=10:1),得到黄色固体标题化合物(170mg,80%)。LC-MS:m/z[M+H]+=240。
144:7-乙基-4-(4-氟-3-(6-甲氧基-1-甲基-1H-吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(200mg,0.54mmol),5-溴-6-甲氧基-1-甲基-1H-吲哚(130mg,0.54mmol)为原料,得到黄色固体标题化合物(150mg,68%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.27(s,2H)8.14-8.24(m,1H)7.59(s,1H)7.33(s,1H)7.01(br.s.,1H)6.89(s,1H)6.48(br.s.,1H)4.58(d,J=7.34Hz,2H)3.90(s,3H)3.82(s,3H)1.70(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=402。
实施例145
145-1:N-(3-溴-4-甲氧基苯乙基)-4-甲基苯磺酰胺
2-(3-溴-4-甲氧基苯基)乙-1-胺(2g,8.69mmol),三乙胺(3.64g,26.07mmol)和4-甲基苯磺酰氯(1.65g,8.69mmol)加到二氯甲烷(20mL)室温搅拌16小时。反应液倒入水中,用乙酸乙酯萃取,有机相浓缩,得标题化合物(2g,60%)。LC-MS:m/z[M+H]+=384。
145-2:6-溴-7-甲氧基-2-甲苯磺酰基1,2,3,4-四氢异喹啉
N-(3-溴-4-甲氧基苯乙基)-4-甲基苯磺酰胺(1g,2.6mmol),85%磷酸(5mL)和二甲氧基甲烷(5ml)加到甲苯(10mL),氩气保护,60℃下搅拌16小时。反应液浓缩后用乙酸乙酯和水萃取,制备板分离纯化(二氯甲烷/甲醇=20/1)得标题化合物(450mg,58%)。LC-MS:m/z[M+H]+=396,398。
145:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-2-甲苯磺酰基-1,2,3,4-四氢异
喹啉
实验操作同实施例1,以6-溴-7-甲氧基-2-甲苯磺酰基1,2,3,4-四氢异喹啉(100mg,0.25mmol)和7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(97mg,0.25mmol)为原料,得标题化合物(30mg)。
1H NMR(400MHz,CDCl3)δ9.33(s,1H),8.25(br.s.,2H),8.11(d,J=4.9Hz,1H),7.74(d,J=7.3Hz,2H),7.36-7.28(m,3H),7.06(s,1H),6.66(s,1H),4.56(q,J=7.3Hz,2H),4.30(br.s.,2H),3.76(s,3H),3.38(br.s.,2H),2.90(br.s.,2H),2.43(s,3H),1.32(br.s.,3H)。LC-MS:m/z[M+H]+=558。
实施例146、实施例147
146-1:7-乙基-4-(4-氟-3-(6-甲氧基-1H-吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(81mg,0.2mmol),5-溴-6-甲氧基-1H-吲哚(50mg,0.2mmol)为原料,得到黄色固体标题化合物(20mg,23%)。LC-MS:m/z[M+H]+=388。
146:7-乙基-4-(4-氟-3-(6-甲氧基-3-(甲基磺酰基)-1H-吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
147:7-乙基-4-(4-氟-3-(6-甲氧基-1-(甲基磺酰基)-1H-吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
将7-乙基-4-(4-氟-3-(6-甲氧基-1H-吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪(20mg,0.05mmol),MsCl(12mg,0.1mmol),四丁基硫酸氢铵(20mg,0.01mmol)依次加入到2mL的甲苯和2mL的50%氢氧化钾水溶液中,然后室温搅拌30分钟。加水,用二氯甲烷萃取,干燥,浓缩,柱层析纯化(二氯甲烷:甲醇=30:1),得到标题化合物实施例200(7mg,29%)和实施例199(2mg,8%)。
146:1H NMR(400MHz,DMSO-d6)δ11.98-12.16(m,1H)9.40-9.61(m,1H)8.73-8.87(m,1H)8.35-8.55(m,2H)7.85-8.05(m,1H)7.61-7.76(m,1H)7.39-7.52(m,1H)7.10-7.25(m,1H)4.37-4.60(m,2H)3.78(br.s.,3H)3.16(br.s.,3H)1.52(br.s.,3H)。LC-MS:m/z[M+H]+=466。
147:1H NMR(400MHz,DMSO-d6)δ9.56(br.s.,1H)8.85(br.s.,1H)8.48(d,J=9.29Hz,2H)7.66(br.s.,1H)7.41-7.57(m,3H)6.82(br.s.,1H)4.51(d,J=5.87Hz,2H)3.85(br.s.,3H)3.50(br.s.,3H)1.55(br.s.,3H)。LC-MS:m/z[M+H]+=466。
实施例148
148-1:5-溴-2-(甲基磺酰基)异吲哚啉
将5-溴异二氢吲哚(120mg,0.61mmol),甲基磺酰氯(177mg,1.22mmol),三乙胺(185mg,1.83mmol)加到二氯甲烷(5mL)中,在室温下搅拌1小时。将反应液滴入饱和氯化铵水溶液(20mL)中,用二氯甲烷萃取(20mL×3),合并有机相,并用饱和食盐水(20mL)洗涤,把有机相浓缩后,制备薄层色谱(二氯甲烷/甲醇=30/1)分离得白色固体标题化合物(40mg,24%)。LC-MS:m/z[M+H]+=235,237。
148:7-乙基-4-(4-氟-3-(2-(甲基磺酰基)异吲哚-5-基)苯基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-2-(甲基磺酰基)异吲哚啉(40mg,0.14mmol),7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(52mg,0.14mmol)为原料,得棕色固体标题化合物(28mg,46%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.37(br.s.,1H),8.39-8.24(m,2H),8.20(br.s.,1H),7.58(d,J=7.3Hz,1H),7.52(br.s.,1H),7.43-7.31(m,2H),4.78(br.s.,4H),4.58(d,J=6.8Hz,2H),2.91(br.s.,3H),1.69(t,J=7.1Hz,3H)。LC-MS:m/z[M+H]+=438。
实施例149
149:5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-1,3-二氢苯并[c]噻吩2,2-二氧化物
实验操作同实施例1,以(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(138mg,0.48mmol)和5-溴-1,3-二氢苯并[c]噻吩2,2-二氧化物(89mg,0.36mmol)为原料,得棕色固体标题化合物(74mg,50%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.37(s,1H),8.34(d,J=5.4Hz,1H),8.29(s,1H),8.20(br.s.,1H),7.63(d,J=7.8Hz,1H),7.58(br.s.,1H),7.49-7.33(m,2H),4.58(d,J=6.8Hz,2H),4.45(d,J=7.8Hz,4H),1.69(br.s.,3H)。LC-MS:m/z[M+H]+=409。
实施例150
150-1:6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪
将2-氨基-4-甲氧基苯酚(1000mg,7.19mmol),1,2-二溴乙烷(1350mg,7.19mmol),碳酸钾(2980mg,21.57mmol)依次加到N,N-二甲基甲酰胺(10mL)中,在100℃下搅拌16小时。往反应液加入水(60mL),并用乙酸乙酯萃取(40mL×3),有机相用饱和食盐水(50mL)洗涤后,再用硫酸钠干燥,浓缩后经制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得标题化合物(300mg,25%)。LC-MS:m/z[M+H]+=166。
150-2:7-溴-6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪
将6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪(200mg,1.21mmol)和N-溴代丁二酰亚胺(215mg,1.21mmol)依次加到乙腈(5mL)中,在60℃下搅拌3小时。反应液经制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得红色固体标题化合物(80mg,27%)。LC-MS:m/z[M+H]+=244,246。
150-3:1-(7-溴-6-甲氧基-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)乙-1-酮
将7-溴-6-甲氧基-3,4-二氢-2H-苯并[b][1,4]噁嗪(100mg,0.41mmol),乙酸酐(42mg,0.41mmol)和三乙胺(83mg,0.82mmol)依次加到二氯甲烷(5mL)中,在室温下搅拌2小时。反应液经制备薄层色谱(石油醚/乙酸乙酯=1/1)分离得标题化合物(50mg,43%)。LC-MS:m/z[M+H]+=286,288。
150:1-(7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2,3-二氢-4H-苯并[b][1,4]
噁嗪-4-基)乙-1-酮
实验操作同实施例1,以1-(7-溴-6-甲氧基-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)乙-1-酮(40mg,0.14mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(40mg,0.14mmol)为原料,得标题化合物(44mg,70%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.37(s,1H),8.27(s,2H),8.18(d,J=6.4Hz,1H),7.33(t,J=9.3Hz,1H),7.27(s,1H),6.96(s,1H),4.58(q,J=7.2Hz,2H),4.30(br.s.,2H),3.97(br.s.,2H),3.78(s,3H),2.41(br.s.,3H),1.69(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=448。
实施例151
151-1:4-(4-氯-2-氟-5-甲氧基苯基)哒嗪-3-醇
在25℃下,将(4-氯-2-氟-5-甲氧基苯基)硼酸(500mg,2.45mmol)加入含4-氯哒嗪-3-醇(350mg,2.68mmol),碳酸铯(1.6g,4.9mmol),[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(162mg,0.25mmol)的1,4-二氧六环(18mL),水(2mL)混合溶剂中,置换氮气后,将混合物于100℃微波反应3小时。HPLC制备纯化,冻干得到4-(4-氯-2-氟-5-甲氧基苯基)哒嗪-3-醇(150mg,24%)类白色固体。LC-MS:m/z[M+H]+=255。
151-2:7-氯-6-甲氧基苯并呋喃[2,3-c]哒嗪
将4-(4-氯-2-氟-5-甲氧基苯基)哒嗪-3-醇(150mg,0.59mmol,)溶解于氮甲基吡咯烷酮(4mL),添加碳酸钾(409mg,2.95mmol),置换氮气后,将混合物微波加热150℃反应1.5小时。HPLC制备纯化获得7-氯-6-甲氧基苯并呋喃[2,3-c]哒嗪(80mg,57%)类白色固体。LC-MS:m/z[M+H]+=236。
151:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基苯并呋喃[2,3-c]哒嗪
实验操作同实施例1,以7-氯-6-甲氧基苯并呋喃[2,3-c]哒嗪(50mg,0.21mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(61mg,0.21mmol)为原料,得标题化合物(40mg,43%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.60(s,1H),9.38(d,J=5.0Hz,1H),8.87(s,1H),8.56(t,J=5.6Hz,3H),8.17(s,1H),8.00(s,1H),7.57(t,J=9.3Hz,1H),4.52(q,J=7.2Hz,2H),3.93(s,3H),1.56(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=443。
实施例152
152-1:5-甲氧基苯并[d]噁唑-2-硫醇
将2-氨基-4-甲氧基苯酚(CAS:20734-76-3 1g,7.2mmol)溶于10mL乙醇中,加入乙基黄原酸钾(1.7g,10.8mmol),加热回流2小时,浓缩反应液,加入水溶解固体,加入1M盐酸酸化,固体析出。干燥,得到灰色固体标题化合物(800mg,61%)。LC-MS:m/z[M+H]+=182。
152-2:2-氯-5-甲氧基苯并[d]噁唑
将5-甲氧基苯并[d]噁唑-2-硫醇(800mg,4.4mmol)溶于10mL氯化亚砜中,加入一滴N,N-二甲基甲酰胺加热至80摄氏度搅拌1小时,浓缩反应液,制备板纯化(石油醚:乙酸乙酯=3:1)得到白色固体标题化合物(600mg,75%)。LC-MS:m/z[M+H]+=184。
152-3:2-(4,5-二氢-1H-吡唑-1-基)-5-甲氧基苯并[d]噁唑
将2-氯-5-甲氧基苯并[d]噁唑(200mg,1.1mmol),Pd2dba3(98mg,0.1mmol),4,5-二氢-1H-吡唑(150mg,2.2mmol),1,3-双[2,6-二(丙-2-基)苯基]咪唑-1-鎓氯化物(98mg,0.1mmol)和碳酸铯(1g,3.3mmol)溶于10mL二氧六环中加热至90摄氏度搅拌2小时,浓缩反应液,制备板纯化(石油醚:乙酸乙酯=1:1)得到白色固体标题化合物(100mg,42%)。LC-MS:m/z[M+H]+=218。
152-4:6-溴-2-(4,5-二氢-1H-吡唑-1-基)-5-甲氧基苯并[d]噁唑
将2-(4,5-二氢-1H-吡唑-1-基)-5-甲氧基苯并[d]噁唑(100mg,0.46mmol)溶于10mL乙腈中,加入N-溴代丁二酰亚胺(82mg,0.46mmol)室温搅拌1小时,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到白色固体标题化合物(100mg,73%)。LC-MS:m/z[M+H]+=296。
152:2-(4,5-二氢-1H-吡唑-1-基)-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯
并[d]噁唑
实验操作同实施例7,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.28mmol),6-溴-2-(4,5-二氢-1H-吡唑-1-基)-5-甲氧基苯并[d]噁唑(83mg,0.28mmol)为原料,得到白色固体标题化合物(29mg,23%)。
1H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.17-8.31(m,3H)7.39(s,1H)7.34(t,J=8.56Hz,1H)7.13(d,J=14.67Hz,2H)4.53-4.63(m,2H)4.10(t,J=10.27Hz,2H)3.85(s,3H)3.12(t,J=10.03Hz,2H)1.70(t,J=7.34Hz,3H)。LC-MS:m/z[M+H]+=458。
实施例153
153-1:5-溴-4-甲基-1氢-吲唑
将4-溴-2,3-二甲基苯胺(2.0g,10mmol)加入氯仿(30mL)中,降温0℃滴加乙酸酐(2.04g,20mmol),5分钟后加醋酸钾(1.03g,10.5mmol)与18冠醚6(5mL),5分钟后滴加亚硝酸叔丁酯(2.6mL)0℃反应10分钟。将混合物放入70℃搅拌16小时。LCMS检测反应完全,加入二氯甲烷与碳酸氢钠溶液分出有机相,干燥浓缩。粗品加入10mL甲醇与10mL盐酸在50℃搅拌2小时。倒入水中,乙酸乙酯萃取旋干,正相硅胶柱(石油醚:乙酸乙酯=100:1~1:1)纯化得5-溴-4-甲基-1氢-吲唑(2.5g,100%)类白色固体。LC-MS:m/z[M+H]+=211。
153-2:5-溴-1,4-二甲基-1氢-吲唑
将5-溴-4-甲基-1H-吲唑(1.5g,7.1mmol)分散于N,N-二甲基甲酰胺(15mL),分批加入NaH(298mg,7.1mmol),搅拌20分钟后滴加碘甲烷(2.9g,21mmol)搅拌1小时。倒入水中,乙酸乙酯萃取二次,旋干浓缩,正相纯化(石油醚:乙酸乙酯=100:1~1:10)得黄色油状的5-溴-1,4-二甲基-1氢-
吲唑(0.9g,56%,极性相对较小);另一产物,153-2B:5-溴-2,4-二甲基-2氢-吲唑(0.2g,13%,极性相对较大)。LC-MS:m/z[M+H]+=225。
153-3:5-溴-4-(溴甲基)-1-甲基-1氢-吲唑
在25℃下,将5-溴-1,4-二甲基-1H-吲唑(0.3g,1.33mmol)添加到含N-溴代丁二酰亚胺(260mg,1.46mmol),过氧化二苯甲酰(240mg,1mmol)的混合溶剂四氯化碳(10mL),二氯甲烷(4mL)中。将混合物在90℃下搅拌16小时。加入硅胶直接拌样,然后通过色谱柱纯化(石油醚:乙酸乙酯=100:1~10:2)得到5-溴-4-(溴甲基)-1-甲基-1H-吲唑(0.3g,75%)。LC-MS:m/z[M+H]+=304。
153-4:5-溴-4-(甲氧基甲基)-1-甲基-1H-吲唑
在25℃下,将5-溴-4-(溴甲基)-1-甲基-1H-吲唑(300mg,1.0mmol)分散于甲醇(8mL),5M甲醇钠溶液(0.2mL,1.0mmol)稀释到甲醇2mL后滴加倒反应液中。将混合物在25℃搅拌16小时。LCMS检测,加入数滴水后直接硅胶粉拌样,然后通过柱色谱纯化(石油醚:乙酸乙酯=100:1~5:1)得到5-溴-4-(甲氧基甲基)-1-甲基-1氢-吲唑(200mg,78%)黄色固体。LC-MS:m/z[M+H]+=257。
153:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-1-甲基-1H-吲唑-5-基)苯基)-7氢-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-1-甲基-1H-吲唑(200mg,0.78mmol),(5-(7-乙基-7氢-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(223mg,0.78mmol)为原料,得标题化合物(95mg,30%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.56(s,1H),8.86(s,1H),8.52(dq,J=3.8,2.3Hz,2H),8.23(d,J=0.8Hz,1H),7.72(d,J=8.6Hz,1H),7.57(t,J=9.1Hz,1H),7.39(d,J=8.6Hz,1H),4.64(s,2H),4.51(q,J=7.2Hz,2H),4.11(s,3H),3.18(s,3H),1.55(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=417。
实施例154
154-1:6-溴-3-(3-羟基-2,2-二甲基丙基)-5-甲氧基苯并[d]噁唑-2(3H)-酮
将6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(2g,40mmol),溶于NMP(80.0mL)中,并加入碳酸钾(7g,40mmol),微波100℃条件下反应1小时。用饱和碳酸氢钠水溶液(100mL)淬灭后,用二氯甲烷(100mLx3)萃取,旋干后得到粗品,柱层析(石油醚:乙酸乙酯=10:1~2:1)纯化后,得到标题化合物(100mg,8%)类白色固体。LC-MS:m/z[M+1]+:331。
154-2:6-溴-5-甲氧基-3-(3-甲氧基-2,2-二甲基丙基)苯并[d]噁唑-2(3H)-酮
将6-溴-3-(3-羟基-2,2-二甲基丙基)-5-甲氧基苯并[d]噁唑-2(3H)-酮(26mg,0.078mmol),碘甲烷(22mg,0.156mmol),氢化钠(6.4mg,0.156mmol)溶于四氢呋喃(2.0mL)的溶液中,室温反应5小时。
加水淬灭,再用乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩得到标题化合物(20mg,38%)类白色固体。LC-MS:m/z[M+1]+=345。
154:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-3-(3-甲氧基-2,2-二甲基丙基)
苯并[d]噁唑-2(3H)-酮
实验操作同实施例1,以6-溴-5-甲氧基-3-(3-甲氧基-2,2-二甲基丙基)苯并[d]噁唑-2(3H)-酮(10.0mg,0.028mmol),(5-(7-异丙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(8mg,0.028mmol)为原料,得到标题产物(10mg,45%)类白色固体。
1H NMR(400MHz,CDCl3)9.45(s,1H),8.34(d,J=58.9Hz,3H),7.36(s,1H),7.21(s,1H),6.97(s,1H),4.60(s,2H),3.86(s,3H),3.76(s,2H),3.42(s,3H),3.15(s,2H),1.72(s,3H),1.08(s,6H)。LC-MS:m/z[M+1]+:507。
实施例155
155-1:6-溴-3-氟-2-硝基苯酚
将3-氟-2-硝基苯酚(2000mg,12.73mmol)加到乙酸(10mL)中,把液溴(2023mg,12.73mmol)用乙酸(10mL)稀释过后,在冰浴下滴入反应液中,反应于室温下搅拌2小时。将反应液倒入水(100mL)中,并用乙酸乙酯萃取(50mL×3),有机相用饱和食盐水(50mL)洗涤后,再用硫酸钠干燥,浓缩后经制备薄层色谱(石油醚/乙酸乙酯=20/1)分离得标题化合物(1400mg,47%)。1H NMR(400MHz,CHLOROFORM-d)δ=7.77(dd,J=5.4,8.8Hz,1H),6.76(t,J=9.8Hz,1H)。
155-2:1-溴-4-氟-2-甲氧基-3-硝基苯
将6-溴-3-氟-2-硝基苯酚(1400mg,5.93mmol),碘甲烷(1700mg,11.86mmol)和碳酸钾(2460mg,14.79mmol)依次加到乙腈(10mL)中,在80℃下搅拌2小时。反应液过滤,将滤液浓缩干得标题化合物粗产品直接投下一步(1600mg,粗品)。
155-3:4-溴-3-甲氧基-2-硝基苯酚
将1-溴-4-氟-2-甲氧基-3-硝基苯(1400mg,5.60mmol)加到二甲基亚砜(10mL),把氢氧化钠(448mg,11.20mmol)溶解在水(5mL)中加到反应液中,在80℃下搅拌2小时。将反应液倒入水(100mL)中,并用乙酸乙酯萃取(50mL×3),有机相用饱和食盐水(50mL)洗涤后,再用硫酸钠干燥,浓缩后得标题化合物粗产品直接投下一步(900mg,粗品)。
155-4:2-氨基-4-溴-3-甲氧基苯酚
将4-溴-3-甲氧基-2-硝基苯酚(900mg,3.63mmol)和雷尼镍(426mg,7.26mmol)加到甲醇(10mL)中,置换氢气,在氢气保护下于室温搅拌2小时。反应液过滤,将滤液浓缩干经薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(700mg,88%)。LC-MS:m/z[M+H]+=218,220。
155-5:5-溴-4-甲氧基苯并[d]噁唑-2(3H)-酮
将2-氨基-4-溴-3-甲氧基苯酚(300mg,1.38mmol)和三光气(819mg,2.76mmol)加到四氢呋喃(5mL)中,在室温下搅拌2小时。反应液经薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(280mg,83%)。LC-MS:m/z[M+H]+=244,246。
155-6:5-溴-4-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮
将5-溴-4-甲氧基苯并[d]噁唑-2(3H)-酮(280mg,1.15mmol),碘甲烷(329mg,2.30mmol)和碳酸铯(1124mg,3.45mmol)依次加到乙腈(5mL)中,在80℃下搅拌1小时。反应液过滤,将滤液浓缩干得标题化合物粗产品直接投下一步(210mg,粗品)。LC-MS:m/z[M+H]+=258,260。
155:5-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-4-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮
实验操作同实施例1,以5-溴-4-甲氧基-3-甲基苯并[d]噁唑-2(3H)-酮(200mg,0.77mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(220mg,0.77mmol)为原料,得标题化合物(109mg,34%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.38(s,1H),8.36-8.26(m,3H),7.39(t,J=8.8Hz,1H),7.16-7.11(m,1H),7.10-7.06(m,1H),4.58(q,J=7.2Hz,2H),3.64(s,3H),3.53(s,3H),1.69(t,J=7.3Hz,3H).LC-MS:m/z[M+H]+=420。
实施例156
156-1:6-溴-5-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将2-氨基-4-溴-3-甲氧基苯酚(300mg,1.38mmol),氯乙酰氯(236mg,2.07mmol)和碳酸钾(572mg,4.14mmol)加到乙腈(8mL)中,在80℃下搅拌16小时。反应液经薄层色谱(石油醚/乙酸乙酯=3/1)分离得标题化合物(200mg,56%)。LC-MS:m/z[M+H]+=258,260。
156-2:6-溴-5-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将6-溴-5-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(190mg,0.74mmol),碘甲烷(212mg,1.48mmol)和碳酸铯(723mg,2.22mmol)依次加到乙腈(5mL)中,在80℃下搅拌1小时。反应液过滤,将滤液浓缩干得标题化合物粗产品直接投下一步(160mg,粗品)。LC-MS:m/z[M+H]+=272,274。
156:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例1,以6-溴-5-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(150mg,0.55mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(157mg,0.55mmol)为原料,得标题化合物(46mg,19%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.38(s,1H),8.28(s,2H),8.24(d,J=6.4Hz,1H),7.37(t,J=9.0Hz,1H),7.09(d,J=7.8Hz,1H),6.92(d,J=8.3Hz,1H),4.63-4.53(m,4H),3.53(s,3H),3.48(s,3H),1.68(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=434。
实施例157
157-1:(2-硝基-3-((四氢呋喃-3-基)氨基)苯基)甲醇
(3-氟-2-硝基苯基)甲醇(500mg,2.92mmol)和四氢呋喃-3-胺(508mg,5.84mmol)加到无水乙醇中(10ml)100℃闷罐搅拌过夜。将反应液直接上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(600mg,86%)。LC-MS:m/z[M+H]+=239,241。
157-2:(6-溴-2-硝基-3-((四氢呋喃-3-基)氨基)苯基)甲醇
实验操作同实施例2中,2-3的合成方法,以(2-硝基-3-((四氢呋喃-3-基)氨基)苯基)甲醇(560mg,2.35mmol)为原料,得标题化合物(320mg,43%)。LC-MS:m/z[M+H]+=317,319。
157-3:(2-氨基-6-溴-3-((四氢呋喃-3-基)氨基)苯基)甲醇
实验操作同实施例2中,2-4的合成方法,以(6-溴-2-硝基-3-((四氢呋喃-3-基)氨基)苯基)甲醇(300mg,1.05mmol)为原料,得标题化合物(210mg,70%)。LC-MS:m/z[M+H]+=287,289。
157-4:(5-溴-1-(四氢呋喃-3-基)-1H-苯并[d][1,2,3]三唑-4-基)甲醇
实验操作同实施例3中,3-4的合成方法,以(2-氨基-6-溴-3-((四氢呋喃-3-基)氨基)苯基)甲醇(200mg,0.7mol)为原料,得到标题化合物(180mg,86%)。LC-MS:m/z[M+H]+=298,300。
157-5:5-溴-4-(甲氧基甲基)-1-(四氢呋喃-3-基)-1H-苯并[d][1,2,3]三唑
实验操作同实施例2中,2-6的合成方法,以(5-溴-1-(四氢呋喃-3-基)-1H-苯并[d][1,2,3]三唑-4-基)甲醇(180mg,0.6mmol)为原料,得到标题化合物(135mg,73%)。
157:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-1-(四氢呋喃-3-基)-1H-苯并[d][1,2,3]三唑-5-基)苯
基)-7H-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-1-(四氢呋喃-3-基)-1H-苯并[d][1,2,3]三唑(65mg,0.21mmol)和(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(60mg,0.21mmol)为原料,得标题化合物(65mg,60%)。
1H NMR(400MHz,CHLOROFORM-d)9.40(s,1H),8.42(d,J=4.9Hz,1H),8.34(d,J=6.8Hz,1H),8.27(s,1H),7.74(d,J=8.3Hz,1H),7.55(d,J=8.8Hz,1H),7.40(t,J=9.0Hz,1H),5.67(br.s.,1H),4.94(br.s.,2H),4.58(q,J=7.0Hz,2H),4.40-4.31(m,2H),4.28-4.21(m,1H),4.08-3.99(m,1H),3.39(s,3H),2.82-2.50(m,2H),1.72-1.68(m,3H)。LC-MS:m/z[M+H]+=474。
实施例158
158-1:5-溴-4-(溴甲基)-2-甲基-2H-吲唑
将5-溴-2,4-二甲基-2氢-吲唑(200mg,0.89mmol),溶解于CCl4(20.0mL)中,加入二氯甲烷(6mL),加入过氧化二苯甲酰(430mg,1.78mmol),再加入N-溴代丁二酰亚胺(178mg,1mmol),在90℃反应16小时。反应液拌样后过硅胶正相柱(乙酸乙酯:石油醚=1:5)纯化,旋干得到5-溴-4-(溴甲基)-2-甲基-2氢-吲唑(240mg,81%)黄色固体。LC-MS:m/z[M+H]+=226。
158-2:5-溴-4-(甲氧基甲基)-2-甲基-2H-吲唑
将5-溴-4-(溴甲基)-2-甲基-2氢-吲唑(240mg,1.061mmol)加入到甲醇钠(144mg,2.122mmol)和甲醇(15mL)中,室温搅拌16小时,反应完全后将体系倒入水中,乙酸乙酯(3×100ml)萃取,无水硫酸钠干燥后点板(乙酸乙酯:石油醚=1:5),柱层析(乙酸乙酯:石油醚=1:5),得标题化合物(200mg,76%)黄色固体。LC-MS:m/z[M+1]+=257。
158:7-乙基-4-(4-氟-3-(4-(甲氧基甲基)-2-甲基-2氢-吲唑-5-基)苯基)-7氢-咪唑并[4,5-c]哒嗪
实验操作同实施例1,以5-溴-4-(甲氧基甲基)-2-甲基-2氢-吲唑(200mg,0.78mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(223.9mg,0.78mmol)为原料,得标题化合物(114mg,57%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.56(s,1H),8.86(s,1H),8.54–8.44(m,3H),7.65(d,J=8.8Hz,1H),7.56(t,J=9.3Hz,1H),7.21(d,J=8.8Hz,1H),4.57(s,2H),4.51(q,J=7.3Hz,2H),4.22(s,3H),3.19(s,3H),1.55(t,J=7.3Hz,3H)。LC-MS:m/z[M+1]+=418。
实施6159
159-1:6-溴-3-(2,2-二氟乙基)-5-甲氧基苯并[d]噁唑-2(3H)-酮
6-溴-5-甲氧基苯并[d]噁唑-2(3H)-酮(100mg,0.41mmol),碳酸铯(400mg,1.2mmol)和2,2-二氟乙基三氟甲磺酸酯(105mg,0.49mmol)加到乙腈(6mL),60℃搅拌过夜。将反应液直接上制备板分离纯化(石油醚/乙酸乙酯=3/1)得标题化合物(60mg,48%)。LC-MS:m/z[M+H]+=308,310。
159:3-(2,2-二氟乙基)-6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-5-甲氧基苯并[d]噁唑
-2(3H)-酮
实验操作同实施例1,以6-溴-3-(2,2-二氟乙基)-5-甲氧基苯并[d]噁唑-2(3H)-酮(50mg,0.17mmol)和(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(52mg,0.17mmol)为原料,得标题化合物(25mg,31%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.31-8.18(m,3H),7.34(t,J=9.0Hz,1H),7.28-7.26(m,1H),6.76(s,1H),6.30-5.97(m,1H),4.58(q,J=7.3Hz,2H),4.23(dt,J=3.7,13.8Hz,2H),3.85(s,3H),1.72-1.68(m,3H)。LC-MS:m/z[M+H]+=470。
实施例160
160-1:7-溴-8-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将6-氨基-3-溴-2-甲氧基苯酚(100mg,0.46mmol)溶于10mL乙腈,加入氯乙酰氯(273mg,0.92mmol)和碳酸钾(127mg,0.92mmol),80摄氏度下,搅拌2小时,浓缩,得到白色固体标题化合物(100mg,84%)。LC-MS:m/z[M+H]+=258。
160-2:7-溴-8-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
将7-溴-8-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(100mg,0.39mmol)溶于10mL乙腈中,加入碘甲烷(110mg,0.78mmol)和碳酸铯(380mg,1.2mmol),室温搅拌过夜,过滤固体,浓缩,制备板纯化(石油醚:乙酸乙酯=3:1)得到黄色固体标题化合物(80mg,75%)。LC-MS:m/z[M+H]+=272。
160:7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-8-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪
-3(4H)-酮
实验操作同实施例7,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(100mg,0.35mmol),7-溴-8-甲氧基-4-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(90mg,0.35mmol)为原料,得到黄色固体标题化合物(45mg,30%)。
1H NMR(400MHz,CHLOROFORM-d)δppm 9.38(s,1H)8.20-8.33(m,3H)7.34(t,J=9.05Hz,1H)7.08(d,J=8.80Hz,1H)6.85(d,J=8.80Hz,1H)4.55-4.77(m,4H)3.97(s,3H)2.88(s,3H)1.68-1.73(m,3H).LC-MS:m/z[M+H]+=434。
实施例161
161-1:(E)-N-(4-溴-3-甲氧基苯基)-2-(羟基亚氨基)乙酰胺
将三氯乙醛(4.4g,30mmol)和硫酸钠(35g,247mmol)溶于盐酸(50mL,2M)和75mL水的混合溶液中,加入盐酸羟胺(5.2g,74mmol)的25mL水溶液,加热至60摄氏度搅拌30分钟,加入4-溴-3-甲氧基苯胺(CAS:19056-40-7 5g,25mmol)的2M盐酸溶液50mL,加热至90摄氏度搅拌2小时,冷却反应液,过滤固体,干燥,得到棕色固体标题化合物(5g,74%)。LC-MS:m/z[M+H]+=273。
161-2:5-溴-6-甲氧基二氢吲哚-2,3-二酮
将50mL浓硫酸加热至60摄氏度,加入(E)-N-(4-溴-3-甲氧基苯基)-2-(羟基亚氨基)乙酰胺(5g,
18mmol)升温至90摄氏度,搅拌2小时,冷却,倒入冰水中,过滤固体得到红色固体标题化合物(4g,85%)。LC-MS:m/z[M+H]+=256。
161-3:5-溴-1-甲基-6-甲氧基二氢吲哚-2,3-二酮
将5-溴-6-甲氧基二氢吲哚-2,3-二酮(400mg,1.56mmol)溶于10mL乙腈中,加入碘乙烷(490mg,3.14mmol)和碳酸铯(1.5g,4.6mmol),加热至50摄氏度搅拌2小时,过滤固体,浓缩,得到黄色固体标题化合物(400mg,90%)。LC-MS:m/z[M+H]+=270。
161-4:5-溴-1-甲基-6-甲氧基吲哚-2-酮
将5-溴-1-甲基-6-甲氧基二氢吲哚-2,3-二酮(400mg,1.4mmol)溶于10mL水合肼中,加热至130摄氏度搅拌3小时,加水,用二氯甲烷萃取,浓缩,得到黄色固体标题化合物(230mg,60%)。LC-MS:m/z[M+H]+=256。
161:5-(5-(7-乙基7H咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-1-甲基二氢-2-酮
实验操作同实施例7,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(80mg,0.28mmol),5-溴-1-甲基-6-甲氧基吲哚-2-酮(72mg,0.28mmol)为原料,得到白色固体标题化合物(8mg,7%)。
1H NMR(400MHz,CHLOROFORM-d)9.37(s,1H)8.22-8.33(m,2H)8.17(d,J=6.85Hz,1H)7.30-7.37(m,1H)7.24(s,1H)6.55(s,1H)4.59(q,J=7.34Hz,2H)3.89(s,3H)3.55(s,2H)3.29(s,3H)1.69(t,J=7.34Hz,3H).LC-MS:m/z[M+H]+=418。
实施例162、实施例163
162-1:6-甲氧基-2-(甲氧基甲基)-2H苯并[b][1,4]噁嗪-3(4H)-酮
在氮气保护下将2-氨基-4-甲氧基苯酚(1.9g,13.8mmol)和2-溴-3-甲氧基丙酸乙酯(3g,15.2mmol)溶解在20mL N,N-二甲基甲酰胺中,再加入碳酸铯(9g,27.6mmol),95℃反应16小时。反应结束后加入50ml水中,乙酸乙酯萃取(50mLx3),水反洗(30ml x3),旋干有机相,柱层析(石油醚/乙酸乙酯=5/1),得到6-甲氧基-2-(甲氧基甲基)-2氢苯并[b][1,4]噁嗪-3(4氢)-酮(200mg,7%)白色固体。LC-MS:m/z[M+H]+=224。
162-2:7-溴-6-甲氧基-2-(甲氧基甲基)-2H苯并[b][1,4]噁嗪-3(4H)-酮
在氮气保护下,6-甲氧基-2-(甲氧基甲基)-2氢苯并[b][1,4]噁嗪-3(4氢)-酮(200mg,0.09mmol)溶解在1.5ml N,N-二甲基甲酰胺中,将溶液降温至0℃,在此温度下,缓慢加入N-溴代丁二酰亚胺
(19mg,0.11mmol)。室温反应2小时,加入20ml冰水中,乙酸乙酯萃取(20ml×3),有机相旋干,得到标题化合物(195mg,71.8%)淡黄色固体。LC-MS:m/z[M+H]+=302。
162-3:7-溴-6-甲氧基-2-(甲氧基甲基)-4-甲基-2氢-苯并[b][1,4]噁嗪-3(4H)-酮
在氮气保护下将在氮气保护下将7-溴-6-甲氧基-2-(甲氧基甲基)-2氢苯并[b][1,4]噁嗪-3(4氢)-酮(175mg,0.58mmol)和加入碳酸钾(166mg,1.2mmol)溶解于甲醇中,最后加入碘甲烷(170mg,1.2mmol),40℃,2小时。反应结束后加入20ml水中,乙酸乙酯萃取(20mL×3),旋干有机相,得到标题化合物(85mg,47%)白色固体。LC-MS:m/z[M+H]+=317。
162:rel-(S)-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2-(甲氧基甲基)-4-甲基
-2氢-苯并[b][1,4]噁嗪-3(4H)-酮
163:rel-(R)-7-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-2-(甲氧基甲基)-4-甲
基-2氢-苯并[b][1,4]噁嗪-3(4H)-酮
实验操作同实施例1,以7-溴-6-甲氧基-2-(甲氧基甲基)-4-甲基-2氢-苯并[b][1,4]噁嗪-3(4H)-酮(75mg,0.24mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(69mg,0.24mmol)为原料,得两标题化合物的混合物(40mg,40%)白色固体。再经过手性拆分,得到实施例162(第一个峰)和实施例163(第二个峰)。拆分方法:Instrument:MG Ⅱ preparative SFC(SFC-1);Column:ChiralPak AD,250×30mm I.D.,10μm;Mobile phase:Afor CO2 and B for Isopropanol;Gradient:B 55%;Flow rate:80mL/min;Back pressure:100bar;Column temperature:38℃;Wavelength:220nm。
实施例162:(15mg)白色固体。1HNMR(400MHz,CDCl3)δ9.38(s,1H),8.30(s,1H),8.29–8.24(m,1H),8.21(dd,J=6.9,2.3Hz,1H),7.33(t,J=9.0Hz,1H),7.12(s,1H),6.61(s,1H),4.75(dd,J=5.4,3.4Hz,1H),4.58(q,J=7.3Hz,2H),3.99–3.90(m,2H),3.83(s,3H),3.46(s,3H),3.44(s,3H),1.70(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=478。
实施例163:(16mg)白色固体。1HNMR(400MHz,CDCl3)9.38(s,1H),8.30(s,1H),8.29–8.24(m,1H),8.21(dd,J=6.9,2.3Hz,1H),7.33(t,J=9.0Hz,1H),7.12(s,1H),6.61(s,1H),4.75(dd,J=5.4,3.4Hz,1H),4.58(q,J=7.3Hz,2H),3.99–3.90(m,2H),3.83(s,3H),3.46(s,3H),3.44(s,3H),1.70(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=478。
实施例164
164-1:6-溴-7-甲氧基喹唑啉
在25℃下,将2-氨基-5-溴-4-甲氧基苯甲醛(80mg,0.35mmol)与醋酸甲酰亚胺(305mg,3.5mmol)和N,N-二异丙基乙胺(677mg,5.25mmol)溶解于NMP(3mL)中,并将混合物于微波条件下125℃反应2小时。将该反应液倒入水中乙酸乙酯萃取,旋干后反向HPLC纯化,冻干得灰色固体6-溴-7-甲氧基喹唑啉(80mg,95%)。LC-MS:m/z[M+H]+=240。
164:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基喹唑啉
实验操作同实施例1,以6-溴-7-甲氧基喹唑啉(70mg,0.29mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(83.7mg,0.29mmol)为原料,得标题化合物(34mg,29%)类白色固体。
1H NMR(400MHz,DMSO-d6)9.60(s,1H),9.52(d,J=5.7Hz,1H),9.28(s,1H),8.87(s,1H),8.64–8.55(m,2H),8.22(s,1H),7.63–7.53(m,2H),4.52(q,J=7.3Hz,2H),4.00(s,3H),1.56(t,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=401。
实施例165
165-1:5-氯-4-甲氧基-N-甲基-2-硝基苯胺
将1-氯-5-氟-2-甲氧基-4-硝基苯(1800mg,8.76mmol)加到甲胺醇溶液(10mL)中,反应于80℃下搅拌5分钟。将反应液浓缩干得粗产物(2000mg)直接投下一步。LC-MS:m/z[M+H]+=217,219。
165-2:5-氯-4-甲氧基-N1-甲基苯-1,2-二胺
将5-氯-4-甲氧基-N-甲基-2-硝基苯胺(2000mg,9.23mmol)和雷尼镍(2709mg,46.15mmol)加到甲醇(10mL)中,置换氢气,在氢气保护下于室温搅拌2小时。反应液过滤,将滤液浓缩干得粗产物(1500mg)直接投下一步。LC-MS:m/z[M+H]+=187。
165-3:6-氯-5-甲氧基-1-甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮
将5-氯-4-甲氧基-N1-甲基苯-1,2-二胺(1500mg,8.04mmol)和三光气(2386mg,8.04mmol)加到四氢呋喃(20mL)中,在室温下搅拌2小时。将反应液用饱和碳酸氢钠水溶液调至碱性,过滤,将滤饼浓缩干得粗产物(1500mg)直接投下一步。LC-MS:m/z[M+H]+=213。
165-4:5-氯-6-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮
将6-氯-5-甲氧基-1-甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮(500mg,2.35mmol),碘甲烷(672mg,4.70mmol)和碳酸铯(2297mg,7.05mmol)依次加到乙腈(10mL)中,在80℃下搅拌1小时。反应液过滤,将滤液浓缩干经薄层色谱(二氯甲烷/甲醇=30/1)分离得标题化合物(230mg,43%)。LC-MS:m/z[M+H]+=227。
165:5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并
[d]咪唑-2-酮
实验操作同实施例4,以5-氯-6-甲氧基-1,3-二甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮(200mg,0.88mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(252mg,0.88mmol)为原料,得标题化合物(90mg,24%)。
1H NMR(400MHz,CHLOROFORM-d)δ=9.38(s,1H),8.30-8.23(m,2H),8.20(d,J=6.8Hz,1H),7.34(t,J=9.0Hz,1H),6.97(s,1H),6.70(s,1H),4.58(q,J=7.3Hz,2H),3.86(s,3H),3.47(s,3H),3.42(s,3H),1.67(br.s.,3H)。LC-MS:m/z[M+H]+=433。
实施例166
166-1:N-(4-溴-3-甲氧基苯基)丙酰胺
将乙腈(1.8g)、4-溴-甲氧基苯胺(2.25g,11mmol)和水(9.0g)加入反应器并将混合物加热至约60℃。缓慢加入丙酸酐(2.17g)。反应混合物在60℃下搅拌1小时。当反应完成时,加入水使固体沉淀。在20℃收集结晶化合物,用水洗涤并最后在真空干燥得到N-(4-溴-3-甲氧基苯基)丙酰胺(2.6g,92%)白色固体。LC-MS:m/z[M+H]+=258.0。
166-2:6-溴-2-氯-7-甲氧基-3-甲基喹啉
将N-(4-溴-3-甲氧基-苯基)丙酰胺(2.6g,10mmol),二甲基甲酰胺(1.02g)和甲苯(0.97g)加入注射器中。将形成的溶液缓慢加入另一个含有三氯氧化磷(5.31g,34.7mmol)和甲苯(1.13g)的反应器中,同时保持温度在20至30℃之间。然后将反应混合物在约30℃下再搅拌1小时。再将混合物加热至约80℃的反应温度并搅拌约1小时。之后,将混合物冷却至室温。将反应液倒入冰水(50mL)中,乙酸乙酯(60mL×3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=6:1)纯化得6-溴-2-氯-7-甲氧基-3-甲基喹啉(2.3g,收率53%)白色固体。LC-MS:m/z[M+H]+=286.0。
166-3:6-溴-3-(溴甲基)-2-氯-7-甲氧基喹啉
将6-溴-2-氯-7-甲氧基-3-甲基喹啉(2.3g,8.04mmol),N-溴代丁二酰亚胺(1.43g,8.04mmol),过氧苯甲酰(389mg,1.2mmol),四氯化碳(50mL)加入反应瓶中,在90℃反应16小时。反应液直接旋干,正相柱层析纯化(石油醚:乙酸乙酯=19:1)得到3-(4-氯-3-(甲氧基甲基)苯基)-6-(甲氧基甲基)哒嗪(1.5g,51.0%)黑色油状液体。LC-MS:m/z[M+H]+=366.0。
166-4:6-溴-2,7-二甲氧基-3-(甲氧基甲基)喹啉
将3-(4-氯-3-(甲氧基甲基)苯基)-6-(甲氧基甲基)哒嗪(300mg,0.82mmol)用四氢呋喃(20mL)溶解后,加入甲醇钠的甲醇溶液(1.6mL,80mmol)室温下搅拌16小时。当反应完成时,直接浓缩得到6-溴-2,7-二甲氧基-3-(甲氧基甲基)喹啉(250mg,97.8%)白色固体。LC-MS:m/z[M+H]+=312.0。
166-5:6-溴-7-甲氧基-3-(甲氧基甲基)喹啉-2(1氢)-酮
将6-溴-2,7-二甲氧基-3-(甲氧基甲基)喹啉(250mg,0.8mmol)和盐酸的1,4-二氧六环溶液(20mL,4Mol/L)加入反应瓶中,在125℃下回流2小时后反应完毕浓缩,得6-溴-7-甲氧基-3-(甲氧基甲基)喹啉-2(1氢)-酮(200mg,83.8%)白色固体。LC-MS:m/z[M+H]+=298.0。
166-6:6-溴-7-甲氧基-3-(甲氧基甲基)-1-甲基喹啉-2(1H)-酮
将6-溴-7-甲氧基-3-(甲氧基甲基)喹啉-2(1H)-酮(200mg,0.67mmol)加入四氢呋喃(10ml)中,0℃下加入NaH(40mg,1.0mmol)并搅拌30分钟后,加入碘甲烷(284mg,2.0mmol),加完室温搅拌2h。反应液倒入冰水(20mL)中,乙酸乙酯(60mL×3)萃取,浓缩,柱层析(石油醚:乙酸乙酯=7:1)纯化得6-溴-7-甲氧基-3-(甲氧基甲基)-1-甲基喹啉-2(1氢)-酮(160mg,收率76%)白色固体。LC-MS:m/z[M+H]+=312.0。
166:6-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-7-甲氧基-3-(甲氧基甲基)-1-甲基喹啉
-2(1H)–酮
实验操作同实施例1,以6-溴-7-甲氧基-3-(甲氧基甲基)-1-甲基喹啉-2(1H)-酮(63mg,0.2mmol),(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)硼酸(58mg,0.2mmol)为原料,得标题化合物(65mg,68%)类白色固体。
1H NMR(400MHz,CDCl3)9.44(s,1H),8.40(s,1H),8.31(dd,J=11.0,5.3Hz,2H),7.77(s,1H),7.59(s,1H),7.38(t,J=8.9Hz,1H),6.87(s,1H),4.60(d,J=7.3Hz,2H),4.51(s,2H),3.96(s,3H),3.80(s,3H),3.53(s,3H),1.70(d,J=7.3Hz,3H)。LC-MS:m/z[M+H]+=474.0。
实施例167
167-1:5-溴-1-乙基-6-甲氧基二氢吲哚-2,3-二酮
将5-溴-6-甲氧基二氢吲哚-2,3-二酮(400mg,1.56mmol)溶于10mL乙腈中,加入碘乙烷(490mg,3.14mmol)和碳酸铯(1.5g,4.6mmol),加热至50摄氏度搅拌2小时,过滤固体,浓缩,得到黄色固体标题化合物(400mg,90%)。LC-MS:m/z[M+H]+=284。
167-2:5-溴-1-乙基-6-甲氧基吲哚-2-酮
将5-溴-1-乙基-6-甲氧基二氢吲哚-2,3-二酮(400mg,1.4mmol)溶于10mL水合肼中,加热至130摄氏度搅拌3小时,冷却,加水稀释,用二氯甲烷萃取,浓缩,得到黄色固体标题化合物(230mg,60%)。LC-MS:m/z[M+H]+=270。
167:1-乙基-5-(5-(7-乙基-7H-咪唑并[4,5-c]哒嗪-4-基)-2-氟苯基)-6-甲氧基吲哚-2-酮
实验操作同实施例7,以7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(240mg,0.84mmol),5-溴-1-乙基-6-甲氧基吲哚-2-酮(230mg,0.84mmol)为原料,得到白色固体标题化合物(57mg,16%)。
1H NMR(400MHz,CHLOROFORM-d)9.36(s,1H)8.21-8.34(m,2H)8.18(d,J=6.85Hz,1H)7.33(t,J=9.05Hz,1H)7.24(s,1H)6.56(s,1H)4.58(q,J=7.34Hz,2H)3.74-3.92(m,5H)3.53(s,2H)1.69(t,J=7.34Hz,3H)1.33(t,J=7.09Hz,3H)。LC-MS:m/z[M+H]+=432。
实施例168
168-1:3-甲氧基苯并[b]噻吩
3-溴苯并[b]噻吩(500mg,2.35mmol),甲醇钠(1267mg,23.5mmol),氧化铜(93mg,1.18mmol),碘
化亚铜(22mg,0.12mmol),碘化钾(19mg,0.12mmol)加到N,N-二甲基甲酰胺(5ml),甲醇(5ml)中,密封管中120℃反应过夜。反应液加入水(30ml),乙酸乙酯萃取,有机相合并,饱和氯化钠水溶液洗,无水硫酸钠干燥,浓缩,柱色谱(纯石油醚)得标题化合物无色油状液体(308mg,80%)。LC-MS:m/z[M+H]+=165。
168-2:2-溴-3-甲氧基苯并[b]噻吩
3-甲氧基苯并[b]噻吩(308mg,1.88mmol),N-溴代丁二酰亚胺(368mg,2.07mmol)加到二氯甲烷(5ml)中,25℃搅拌30分钟。反应液抽滤,浓缩,制备薄层色谱(纯石油醚)得标题化合物粉色油状液体(311mg,68%)。1H NMR(400MHz,CHLOROFORM-d)d=7.72(d,J=7.3Hz,1H),7.66(d,J=7.8Hz,1H),7.39-7.31(m,2H),4.05(s,3H)。
168:7-乙基-4-(4-氟-3-(3-甲氧基苯并[b]噻吩-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪
7-乙基-4-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-7H-咪唑并[4,5-c]哒嗪(59mg,0.16mmol),2-溴-3-甲氧基苯并[b]噻吩(97mg,0.4mmol),碳酸铯(104mg,0.32mmol),四(三苯基膦)钯(9mg,0.008mmol)加到1,4-二氧六环(2ml)和水(0.2ml)中,氩气保护下,100℃反应4小时。反应液抽滤,浓缩,制备薄层色谱(石油醚/二氯甲烷/甲醇=20/30/1)得标题化合物淡黄色固体(6mg,9%)。
1H NMR(400MHz,CHLOROFORM-d)9.43(br.s.,1H),8.68(d,J=5.4Hz,1H),8.31(br.s.,2H),7.90-7.76(m,2H),7.41(br.s.,3H),4.60(d,J=7.3Hz,2H),3.93(br.s.,3H),1.70(t,J=6.4Hz,3H)。LC-MS:m/z[M+H]+=405。
实验例
细胞系构建和传代培养
α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的。在该实施例中,本发明通过脂质体转染法(Felgner,P.L.,et al.Proceedings of the National Academy of Sciences,1987,84:7413-7417)构建并分别筛选出稳定表达人源α1-GABAA受体(α1-GABAAR)和α2-GABAA受体(α2-GABAAR)的HEK293细胞。α1-GABAAR-HEK293细胞模型同时表达α1亚基(蛋白序列见GenBank登录号:NM_000806.5)、β3亚基(蛋白序列见GenBank登录号:NM_000814.5)和γ2亚基(蛋白序列见GenBank登录号:NM_000816.3)。α2-GABAAR-HEK293细胞模型同时表达α2亚基(蛋白序列见GenBank登录号:NM_000807.4)、β3亚基(蛋白序列见GenBank登录号:NM_000814.5)和γ2亚基(蛋白序列见GenBank登录号:NM_000816.3)。
将以上细胞系进行传代培养。扩增α2-GABAAR-HEK293细胞用于化合物对GABAA受体的苯二氮卓位点(BZD)亲和力测试。α1-GABAAR-HEK293细胞和α2-GABAAR-HEK293细胞在传代过程中部分悬浮细胞铺在用Poly-D-Lysine(多聚赖氨酸)预处理的玻片上用于电生理测试(方法参照专利CN 107344936A第0586段)。
本发明化合物对α2-GABAA受体的亲和活性
通过竞争3H-flunitrazepam(同位素3H标记的氟硝西泮)与稳定表达人源α2-GABAAR-HEK293细胞的膜蛋白BZD位点结合来测定化合物对α2-GABAA受体的亲和力。
膜制备:细胞悬浮于50mM Tris-HCl缓冲液(pH=7.4)中,在冰上经匀浆机匀浆20秒10次,4℃,1000g离心10min。取上清,重复以上步骤。将上清在4℃(33800g;Thermo(赛默飞),rotor(转子):A27-8x50)离心60min,取沉淀重悬于Tris缓冲液(50mM Tris-HCl,10mM MgCl2,0.5mM EDTA,10%glycerol)中。测定蛋白质含量(基于铜离子还原法的BCA(二辛可宁酸)蛋白定量测试法,BCA试剂盒购自Pierce(安诺伦生物)),制备1mL等分物,-80℃保存。
放射性配体竞争结合试验:本试验在在200μL体系中(96孔板)进行,其中有装有100μL细胞膜。3H-flunitrazepam的浓度为1nM,待测化合物的浓度在1x 10-5-10-6M范围内。以flumazenil(氟马泽尼)为对照。低信号对照孔(Low control,LC)加入1μL 2mM flumazenil(终浓度10μM),高信号对照孔(High control,HC)加入1μL二甲基亚砜。最终靶点膜蛋白的浓度为5μg/孔。所有待测化合物样品储存液均为10mM二甲基亚砜溶液。样品工作浓度为将所有样品用二甲基亚砜稀释至0.2mM,然后进行4倍连续梯度稀释,共8个浓度梯度。用封板膜将96孔板密封,然后置于室温摇床孵育1小时。同时用浸板缓冲液(0.3%PEI(聚乙烯亚胺,
购自:sigmaaldrich(西格玛奥德里奇),型号:P314),4℃保存)浸泡GF/C过滤板,至少0.5小时。结合孵育完毕用细胞收集器收集到GF/C过滤板上,用洗板缓冲液(50mM Tris-HCl,pH 7.4,4℃保存)洗4次。50℃烘箱干燥1小时后把干燥好的GF/C过滤板底部封膜,用液体闪烁计数法检测滤膜残留放射性,每孔加入50μL闪烁液,并密封,使用Microbeta2(微孔板计数器,购自:PerkinElmer(珀金埃尔默仪器),型号:CNLL0153)读数。计算待测样品对3H-flunitrazepam与GABAA受体膜蛋白结合的抑制活性,通过量效曲线拟合(GraphPad Prism 5软件)计算各待测样品的IC50,并通过IC50计算样品的Ki,从而评估化合物与α2-GABAA受体BZD位点的结合能力。
通过上述测定化合物与表达人源α2-GABAAR-HEK293细胞膜蛋白BZD位点结合亲和力的方法获得的代表性检测结果如表3所示。
本发明化合物对不同亚型GABAA受体的功能活性
通过电生理的方法检测待测药物对α1-GABAA受体和α2-GABAA受体的正向调控活性。具体方法如下所示:
化合物浓度设定:化合物筛选使用的化合物终浓度均为100nM。对于表达α1-GABAA受体的细胞系,GABA浓度为0.05~0.07μM(约EC2~4);对于表达α2-GABAA受体的细胞系,GABA浓度为0.10~0.11μM(约EC7~8)。电生理试验采用全细胞膜片钳技术,该方法可参照文献(Nickolls,S.A.,et al.British Journal of Pharmacology,2018,175:708–725)报道的方法。电生理用细胞外液(ECS)成分如下:150mM NaCl,5mM KCl,2.5mM CaCl2,1mM MgCl2,10mM HEPES和10mM glucose(pH7.4);电生理用电极内液(ICS)配方如下:140mM CsCl,11mM EGTA,10mM HEPES,2mM CaCl2,1mM MgCl2,4mM MgATP,2mM TEA(pH 7.3)。将GABA(γ-氨基丁酸)粉末用纯水配制成母液,在稀释于ECS中;化合物先用二甲基亚砜配制成为4mM的母液,再逐步稀释相应浓度的GABA-ECS中。溶液均在电生理测试前新鲜配制。
电生理信号采集使用EPC 10放大器及PatchMaster软件(HEKA)或Axon700B放大器及Clampex软件(AXON)。记录电极使用硼硅酸盐(borosilicate)玻璃拉制,电极电阻为4~6MΩ。胞外给药采用ALA-VC-8PGTM系统。选取单个独立生长的细胞,玻璃电极与细胞形成良好封接后破膜,形成全细胞模式。将细胞膜电位被钳制在-60mV,Gap-free模式下记录。试验时,先在胞外施加约20秒的细胞外液。待基线(Iprebaseline)稳定后,将胞外液切换至GABA-ECS。此时,可以检测到GABA引起的电流(Igaba)。大约10~20秒,待电流稳定后,将胞外液切换至化合物和GABA-ECS的混合溶液,直到此时可以检测到化合物和GABA共同引起的电流(Itreatment)。最后,将溶液切换至细胞外液,记录20~40秒终止试验。只有基线平稳、对照电流大小(Igaba-Iprebaseline)绝对值大于40pA且10~20秒内电流相对平稳的细胞才会用于化合物测试。
α1-GABAAR和α2-GABAAR的正向别构调节活性的实验结果分析采用PatchMaster v2x90.1或PatchMaster v2x90.3软件(EPC 10放大器)和Clampex10.6软件(Axon700B放大器)。各阶段的电流值按相应条件下稳定后电流的平均值计算。我们将对照电流定义为Igaba-Iprebaseline,化合物处理后电流定义为Itreatment-Iprebaseline。化合物的别构调节活性以百分比表示,按以下公式计算:功能活性=[(Itreatment-Igaba)/(Igaba-Iprebaseline)]×100%。如果数值为负,则表示测试化合物对GABA受体的调节作用为反向别构调节。如果数值为正,则表示测试化合物对GABA受体的调节作用为正向别构调节。为了方便比较,以阳性化合物WO2014091368A1实施例4(CVL-865)作为参照物,进行归一化,即正向别构调节活性=[化合物的功能活性/阳性化合物的功能活性]×100%。化合物对α1-GABAA受体和α2-GABAA受体的正向别构调节活性测试结果如表3所示。
体外微核试验
1、遗传毒性研究指导原则
本实验设计基于实验目的,遵循下列实验设计指导原则:
(1)2016年修订的OECD化学品测试准则487,体外哺乳动物细胞微核试验;
(2)2011年11月生效的ICH S2(R1):人用药物遗传毒性试验和结果分析指导原则。
2、材料和方法
实验系统和选择理由:本实验使用中国仓鼠卵巢细胞(CHO-WBL细胞)作为实验系统,该细胞系核型含有21条染色体,生长周期为12到13小时。CHO-WBL细胞最初来源于美国三藩市加利福利亚大学的S.Wolff博士,后在纽约哥伦比亚大学A.Bloom博士的实验室克隆,后被马里兰州Litton Bionetics实验室S.Galloway博士再次克隆。细胞储备液储存在液氮中。每一批次的细胞储备液都鉴定了细胞核型,并经检测证明未被支原体污染。细胞克隆后传代数将不会超过15次。之所以选择中国仓鼠卵巢细胞,是因为在OECD化学品测试指导原则487中推荐使用该细胞系,并被证明对许多种致染色体断裂剂/非整倍体诱变剂敏感(Marilyn J.et al.,2006)。
培养基和细胞生长条件:中国仓鼠卵巢细胞培养在McCoy’s 5A全培养基中(McCoy’s 5A全培养基补充加入10vt%胎牛血清、2mM GlutaMAXTM培养基、100units/mL青霉素和100μg/mL链霉素),在标准环境中生长(温度37℃、CO2浓度为5%的高湿度培养箱)。给药前一天,将处于指数生长期的CHO-WBL细胞按照8×103个细胞/400μL McCoy’s 5A全培养基/孔接种到八孔细胞培养玻片上。
代谢活化系统:体外代谢活化系统(Maron and Ames,1983)包含β-萘黄酮和苯巴比妥诱导的大鼠肝脏微粒体匀浆(简称S9)和一个NADPH生成系统(即NADP二钠加异柠檬酸三钠)。S9从齐氏生物科技有限公司购买,使用前保存在-75℃冰箱里。S9匀浆的制备方法:将β-萘黄酮和苯巴比妥单次腹腔注射雄性Sprague Dawley大鼠,取材制备。
S9代谢活化系统的制备:先将NADP二钠盐和异柠檬酸三钠盐溶解在不含血清培养基中,制成核心溶液,并用0.22μm的滤头过滤除菌。临用前,将S9匀浆融化,将S9代谢活化系统的各组分按照如下表2所示比例混匀。
表2 S9代谢活化系统组分及配比
剂量探索实验:在剂量探索实验中,每个给药处理系列中设立8个给药浓度。受试物每个浓度设1孔细胞。在ICH指导原则S2(R1)中,当不受限于受试物在溶剂/培养基中的溶解度或受试物的细胞毒性时,推荐的最高浓度为1mM或0.5mg/mL,取较低者。然而,若受限于溶解度,测试的最高浓度为在显微镜下培养基中可见少量沉淀的最低浓度。为了确保能够达到在培养基中的溶解度上限,可以测试多达4个含有可见沉淀的浓度。
给药处理:S9代谢活化3小时给药系列中,将每孔中培养基吸掉,参照ICH S2(R1)指导原则,添加含有合适浓度受试物/对照品的不含血清McCoy’s 5A/S9混合物培养基。
非代谢活化3小时给药系列中,将每孔中培养基吸掉,添加含有合适浓度受试物/对照品的McCoy’s 5A全培养基。
将细胞放在标准条件下孵育3小时,3小时后,将各孔中旧培养基吸掉,用McCoy’s 5A全培养基洗2次。每孔加入含有细胞松弛素B(培养基中终浓度为约3μg/mL)的McCoy’s 5A全培养基,接着培养21小时直至收获。
对于非代谢活化24小时给药系列,处理方式与非代谢活化3小时给药系列类似,不同之处在于细胞将与受试物/对照品在含有细胞松弛素B(培养基中终浓度为约3μg/mL)的全培养基中培养24小时(±30分钟)。
玻片制备:收获时,倒掉八孔玻片中的培养基,用吸水纸吸干,每孔中加入75mM KCl低渗液,然后将细胞连续更换两次固定液(无水甲醇:冰醋酸,3:1v/v)固定5分钟,风干。避光条件下,用吖啶橙染色并风干。
计数细胞毒性:通过低倍镜检查呈现出来的染色情况,评估每张玻片的所有孔的可被分析的可能性(足够数量的细胞)。在荧光显微镜下,每孔分析至少500个细胞,分别计数含有的单核、双核和
多核细胞的数目,以计算胞质分裂阻断增殖指数(CBPI)。
用CBPI评估受试物的细胞毒性。CBPI的计算公式如下:
%细胞毒性=100-100{(CBPIT-1)/(CBPIC-1)};
其中,T=受试物处理培养组,C=溶媒对照培养组。
当CBPI为1时,等于100%的细胞毒性。
微核主实验:微核主实验将CHO-WBL细胞暴露于受试物的3-8个浓度下,同时设立与溶剂组相同处理的阳性对照组(环磷酰胺一水合物)和溶媒对照组(二甲基亚砜),每个剂量组均设2孔细胞。在非活化测试系统中,给药时间为3和24小时,在S9活化测试系统中,受试物暴露时间为3小时。受试物测试的上限取决于它在培养基中的溶解度,但总的来说不会超过最大浓度1mM或0.5mg/mL,取较低者。选择微核频率分析的最高剂量时,该受试物剂量组与相应溶媒对照组相比细胞毒性应不超过50%太多。若最高浓度不受限于细胞毒性,为了达到培养基中溶解度上限,可以测试多个含有可见沉淀的剂量,且最高剂量组的培养基中可见少量可识别的沉淀。
选择微核分析的剂量:CHO-WBL细胞微核分析剂量的选择将取决于受试物的细胞毒性。选择用于评估的最高剂量将诱导不超过50%太多的细胞毒性。至少再分析两个更低的剂量组(在中等细胞毒性到非细胞毒性范围内,如适用)。若受试物没有细胞毒性,则选择在给药末期在显微镜下可以观察到沉淀的剂量,或者最大待测浓度(1mM或0.5mg/mL,取较低者)为用于微核分析的最高浓度。
计数微核频率:所有选择作微核分析的玻片均用随机生成的盲码标注,以减少读片的主观性,盲码由不参与读片的人员制作。盲码标记的片子标签中包含以下信息:实验编号、处理系列和随机数字。
每一剂量组分析2000个双核细胞(每孔1000个),以计数含有微核的双核细胞频率。
双核细胞应符合下列标准才可计数:
a.具有完整的细胞膜;b.两个子核大小相等。
微核的判断标准如下:
a.微核具有与主核类似的荧光强度。b.微核应游离于细胞质中。c.微核边缘光滑,直径小于等于主核直径的三分之一。
玻片在签署实验报告前废弃。
数据
数据报告:给药组的细胞毒性根据与对应的溶媒对照相比的细胞毒性来判定并作呈列。微核主实验中每一孔和每一剂量组的微核频率也作呈列。
统计分析:使用Fisher’s确切概率法比较给药组与相应溶媒对照组含有微核的双核细胞发生频率差异的显著性。作多重比较时,P值经过Bonferroni校正。多组数据比较时,用Cochran-Armitage检验来检测剂量效应关系。
当P≤0.05时,可认为差异具有显著性。
实验有效性标准:一个可接受的遗传毒性测试必须满足以下标准:溶媒/阴性对照微核细胞的频率必须与历史阴性对照数据具有可比性。应该至少有三个可被分析的浓度。阳性对照微核细胞的比例应该和平行溶媒/阴性对照组相比有统计学上的显著的升高(p≤0.05)。
实验结果的评判标准:在该实验有效前提下,根据指导原则ICH S2(R1),试验结果判定,需结合不同给药处理条件下(加S9给药3小时,不加S9给药3小时,不加S9给药24小时),不同受试物浓度下,微核率的结果,参照试验结果的评判标准,综合分析判定受试物的体外微核结果为阴性,阳性或可疑阳性,结果以阴性表示为佳。具体标准评估实验结果如下:
阳性:若受试物同时满足以下标准,可认为该受试物为阳性:在一个或多个剂量组中观察到微核细胞频率与平行溶媒对照组相比显著性增加。微核频率的增加具有剂量效应关系。在一个或多个剂量组中观察到微核细胞频率超出实验室阴性历史数据范围。
阴性:若以上三点均不符合,可认为该受试物为阴性。
可疑阳性:若一个受试物仅部分满足以上三点,应科学地判断。浓度相关效应的迹象被认为是有用的,但在评价阳性结果时并不是必要的。将考虑生物相关性,例如浓度范围内和浓度之间的反应一致性,以及(如适用)实验之间的反应一致性,或仅在高或极强细胞毒性浓度下发生的效应。
本发明各化合物对α2-GABAA受体的亲和活性以及对α1、α2-GABAA受体的正向别构调节活性结果见下表3,体外微核测试的结果如表4所示。
需要注意的是,由于本发明所述化合物的优势在于受体较高的选择性而不仅仅在于药物的绝对活性,同时考虑到在不同的检测体系下,化合物的功能活性绝对值会有一定差异,不具有可比性,因此,为了方便比较,本发明实验在同一检测系统下同步检测对照和涉及的化合物,并以阳性化合物WO2014091368A1实施例4(CVL-865)作为参照物,进行归一化处理,即正向别构调节活性=[化合物的功能活性/阳性化合物的功能活性]×100%,具体结果见下表3。
表3化合物对α2-GABAA受体的亲和活性以及对α1、α2-GABAA受体的正向别构调节活性
本发明实施例化合物对比参考化合物CVL-865,选择性更好,在保持适当的α2-GABAA受体亲和力和电生理活性的情况下,使α1-GABAA受体电生理活性小于CVL-865,这样在维持体内药效的同时,有更小的副作用。
表4体外微核测试的结果
由体外微核结果可见,本发明化合物具有更好的遗传毒安全性,有更好的成药性。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (18)
- 一种式(1)所示咪唑并哒嗪取代苯环类化合物及其衍生物、立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物:
其中,所述R1为取代或者未取代的苯环与杂环形成的稠合基;所述R2选自H、卤素、OH、C1-C6烷氧基或CN;所述R3选自H、取代或者未取代的直链或者支链C1-C6烷基或取代或者未取代的C3-C6环烷基。 - 根据权利要求1所述的化合物,其特征在于,形成所述R1所示稠合基的杂环为含有1-3个选自N、O或S的环杂原子的5-7元饱和或不饱和的单环或双环基团。
- 根据权利要求1或2所述的化合物,其特征在于,所述R1具有如下式(M)所示的结构:
其中,m为1、2或3,n为1或2,表示连接位点;所述A环是指含有选自N、O或S中至少一种杂原子的5-7元饱和或部分不饱和的单环或双环。 - 根据权利要求3所述的化合物,其特征在于,当所述R1具有如式(M)所示结构时,所述R1具有如下(a)-(e)所示的结构:
- 根据权利要求3或4所述的化合物,其特征在于,当所述R1具有如式(M)所示结构时,所述A环可选自如下结构:
或者 - 根据权利要求3-5任一项所述的化合物,其特征在于,所述R4选自氢、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基、;上述基团可选择的未被取代或者彼此独立的被1-4个分别选自卤素、羟基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或者卤代C1-C3烷氧基中的至少一种所取代。
- 根据权利要求6所述的化合物,其特征在于,所述R4选自氢、C1-C3烷基或C1-C3烷氧基;上述基团可选择的未被取代或者彼此独立的被C1-C3烷氧基或卤素取代。
- 根据权利要求3-7任一项所述的化合物,其特征在于,所述R5选自氢、卤素、羟基、氧代、C1-C6烷基酰基、C1-C6烷基酰胺基、C1-C6烷氧基亚胺基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C6-C10的芳基、含有1-3个杂原子的5-7元的杂芳基或者含有1-3个杂原子的C3-C7的非芳族杂环;上述基团可选择的未被取代或者彼此独立的被1-4个分别选自卤素、羟基、氧代、C1-C4酰基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基或者磺酰基中的至少一种所取代。
- 根据权利要求8所述的化合物,其特征在于,所述R5选自氢、卤素、氧代、C1-C3烷基酰基、C1-C3烷基酰胺基、C1-C3烷氧基亚胺基、C1-C3烷基、C3-C4环烷基、C1-C3烷氧基、C6-C8芳基、含有1-2个杂原子的5-6元的杂芳基或者含有1-2个杂原子的C4-C6的非芳族杂环;上述基团可选择的未被取代或者彼此独立的被1-2个分别选自卤素、羟基、氧代、C1-C3酰基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基或者磺酰基中的至少一种所取代。
- 根据权利要求8或9所述的化合物,其特征在于,所述R5选自:H、氧代、甲基、乙基、异丙基、乙酰基、甲基甲氧基、乙基甲氧基、环丙基、甲基环丙基、乙基环丙基、甲基环丁基、甲基胺基、苯基、 或者
- 根据权利要求3-10任一项所述的化合物,其特征在于,所述R1选自如下结构中的任意一种:
并且,所述R4选自H、C1-C3烷氧基、或者取代或未取代的甲氧基C1-C3烷基;优选为H、甲基甲氧基、乙基甲氧基、甲氧基或者二氟代甲氧基;所述R5选自H、甲基、乙基、乙酰基、乙基甲氧基、甲基甲氧基、甲基环丙基、苯基、 或者 - 根据权利要求1-11任一项所述的化合物,其特征在于:所述R2选自H或F,优选为F;所述R3选自H或直链或者支链C1-C6烷基,优选乙基或异丙基。
- 根据权利要求1-3任一项所述的化合物,其特征在于,所述化合物选自以下化合物中的任意一种:
- 一种药物组合物,其特征在于,其包含如权利要求1-13中任一项所述的咪唑并哒嗪取代苯环类化合物或其衍生物、立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物中的至少一种,并可选择的添加药学上可接受的载体和/或辅助剂。
- 如权利要求1-13中任一项所述的咪唑并哒嗪取代苯环类化合物或其衍生物、立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物,或权利要求14所述的药物组合物用于制备治疗或预防与GABAA受体有关的疾病的药物中的用途。
- 根据权利要求15所述的用途,其特征在于,所述与GABAA受体有关的疾病选自如下至少一种:疼痛、阿尔茨海默氏病、多梗塞性痴呆、癫痫、瘙痒或中风。
- 根据权利要求16所述的用途,其特征在于,所述的疼痛包括神经病理性疼痛、炎性疼痛和癌性痛。
- 根据权利要求16或17所述的用途,其特征在于,所述的疼痛选自:头痛,面部痛、颈痛、肩痛、背痛、胸痛、腹痛、背部痛、腰痛、下肢痛、肌肉与骨骼疼痛、血管疼痛、痛风、关节炎疼痛、内脏疼痛、感染性疾病导致的疼痛、多骨疼痛、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛,损伤或手术引起的慢性疼痛、伤害感受性疼痛、糖尿病性疼痛、三叉神经痛、腰部或子宫颈神经根病痛、舌咽神经痛、自主神经反射性疼痛、反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染或退行性骨关节病有关的疼痛。
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WO2002038568A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
CN104837843A (zh) * | 2012-12-14 | 2015-08-12 | 辉瑞有限公司 | 作为gabaa受体调节剂的咪唑并哒嗪衍生物 |
WO2015189744A1 (en) * | 2014-06-12 | 2015-12-17 | Pfizer Limited | Imidazopyridazine derivatives as modulators of the gabaa receptor activity. |
CN112979655A (zh) * | 2019-12-16 | 2021-06-18 | 上海赛默罗生物科技有限公司 | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 |
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WO2002038568A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
CN104837843A (zh) * | 2012-12-14 | 2015-08-12 | 辉瑞有限公司 | 作为gabaa受体调节剂的咪唑并哒嗪衍生物 |
WO2015189744A1 (en) * | 2014-06-12 | 2015-12-17 | Pfizer Limited | Imidazopyridazine derivatives as modulators of the gabaa receptor activity. |
CN112979655A (zh) * | 2019-12-16 | 2021-06-18 | 上海赛默罗生物科技有限公司 | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 |
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