WO2021102774A1 - 一种作为ssao/vap-1抑制剂的胺类衍生物及其用途 - Google Patents

一种作为ssao/vap-1抑制剂的胺类衍生物及其用途 Download PDF

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WO2021102774A1
WO2021102774A1 PCT/CN2019/121469 CN2019121469W WO2021102774A1 WO 2021102774 A1 WO2021102774 A1 WO 2021102774A1 CN 2019121469 W CN2019121469 W CN 2019121469W WO 2021102774 A1 WO2021102774 A1 WO 2021102774A1
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compound
present
deuterium
atoms
ring
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PCT/CN2019/121469
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English (en)
French (fr)
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顾峥
黎健豪
王伟华
覃浩雄
李峥
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广东东阳光药业有限公司
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Priority to PCT/CN2019/121469 priority Critical patent/WO2021102774A1/zh
Priority to CN201980102424.XA priority patent/CN114728925B/zh
Publication of WO2021102774A1 publication Critical patent/WO2021102774A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an amine compound as an inhibitor of semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1) and a preparation method thereof, further comprising the compound
  • SSAO semicarbazide-sensitive amine oxidase
  • VAP-1 vascular adhesion protein-1
  • Vascular adhesion protein-1 is a dimeric glycoprotein with a relative molecular mass (MW) of 170,000 to 180,000. It is a multifunctional protein that exists widely in mammals. VAP-1 has a dual function. On the one hand, it is an adhesion molecule of lymphocytes, which promotes the adhesion of lymphocytes to the vascular endothelium; on the other hand, VAP-1 also has semicarbazide-sensitive amine oxidase (SSAO). effect. VAP-1 protein can exist in plasma in the form of a solute, or it can exist on the surface of endothelial cells, adipocytes, and smooth muscle cells in a form bound to membranes.
  • SSAO semicarbazide-sensitive amine oxidase
  • SSAO/VAP-1 can describe the protein.
  • SSAO/VAP-1 can promote the transfer of glucose transport 4 (GLUT 4) from adipocytes to the cell membrane, thereby regulating glucose transport.
  • SSAO/VAP-1 can mediate the adhesion and exudation process of leukocytes and endothelial cells, and participate in the inflammatory response.
  • SSAO/VAP-1 is also related to the following diseases: melanoma and lymphoma (Martila-lchihara, F. et al., 2010, J. Immunol. 184: 3164-3173), acute and chronic arthritis (Tabi, T.et al., 2013, J. Neural Transm. 120: 963-967), pneumonia (Foot, J Set al., 2013, J. Pharmacol. Exp. Ther. 347: 365-374), diabetic macular edema ( Inoue, T. et al., 2013, Bioorg. Med. Chem. 21: 1219-1233), diabetic retinopathy (Boomsma, F.
  • SSAO/VAP-1 inhibitors will be beneficial to humans in the treatment of various diseases, especially inflammation/or inflammation-related diseases and diabetes and/or diabetes-related diseases disease.
  • the present invention provides a class of amine compounds with better inhibition of SSAO/VAP-1 activity.
  • Such compounds and their pharmaceutical compositions can be prepared for the prevention, treatment or alleviation of inflammatory diseases and/or inflammation-related diseases or diabetes in patients And/or medicines for diabetes-related diseases, especially medicines for preventing, treating or alleviating patients with non-alcoholic fatty liver disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
  • the present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds and compositions to prepare drugs for treating the above-mentioned diseases in mammals, especially humans.
  • the compound of the present invention Compared with existing similar compounds, the compound of the present invention has good pharmacological activity, and/or excellent in vivo pharmacokinetic properties or in vivo pharmacodynamic properties. At the same time, the preparation method is simple and feasible, the process method is stable, and it is suitable for industrialized production. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • a compound which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • Acceptable salts or their prodrugs
  • the ring A, R 1 , R 2 , R 3 , R z and q have the definitions described in the present invention, wherein It means that the compound represented by formula (I) can be in the "E” configuration, the "Z” configuration, or a combination of the "E” configuration and the “Z” configuration in any ratio.
  • R 2 is F, Cl, Br, or I.
  • R 3 is H, deuterium, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • ring A is an oxygen-containing heterocyclic ring composed of 5-8 atoms or an oxygen-containing heteroaromatic ring composed of 5-8 atoms, wherein the ring A is unsubstituted or is composed of 1, 2, or 3 R y is substituted; wherein said R y has the definition described in the present invention.
  • q is 0, 1, 2, or 3.
  • ring A is an oxygen-containing heterocyclic ring composed of 5-6 atoms or an oxygen-containing heteroaromatic ring composed of 5-6 atoms, wherein the ring A is unsubstituted or is 1, 2, or 3 Is substituted by R y , wherein said R y has the definition described in the present invention.
  • ring A is Wherein said ring A is unsubstituted or substituted by 1, 2 or 3 R y , wherein said R y has the definition described in the present invention.
  • R 3 is H, deuterium, C 1-4 alkyl, or C 3-6 cycloalkyl.
  • R 3 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the present invention relates to the structure of one of the following, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs ,
  • the present invention relates to the structure of one of the following, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs ,
  • the pharmaceutically acceptable salt of the present invention is hydrochloride, hydrobromide, phosphate, oxalate, maleate, tartrate, citrate, malate or formate. Sulfonate.
  • the present invention relates to a pharmaceutical composition, which comprises the compound of the present invention, and optionally, further comprises a pharmaceutically acceptable adjuvant.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used to inhibit SSAO/VAP-1; or the medicine is used to prevent, treat or reduce inflammation Diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention to inhibit the activity of SSAO/VAP-1; or to prevent, treat or alleviate inflammatory diseases and/or inflammation-related diseases or diabetes and/or Diabetes related diseases.
  • the present invention relates to a method for inhibiting the activity of SSAO/VAP-1; or a method for preventing, treating or alleviating inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases; the method is administered to a patient The effective therapeutic amount of the compound or the pharmaceutical composition of the present invention.
  • the inflammatory diseases and/or inflammation-related diseases of the present invention are liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcohol Liver disease or non-alcoholic fatty liver disease.
  • the diabetes and/or diabetes-related diseases of the present invention are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.
  • the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer .
  • the present invention provides a class of amine derivatives with better inhibition of SSAO/VAP-1 activity, and a preparation method and application thereof.
  • Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the scope of the present invention.
  • subject used in the present invention refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
  • subject and patient used in the present invention are used interchangeably.
  • the terms “subject” and “patient” refer to animals (for example, birds or mammals such as chickens, quails, or turkeys), especially “mammals” including non-primates (for example, cattle, pigs, etc.) , Horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans.
  • the subject is a non-human animal, such as a domestic animal (e.g., horse, cow, pig, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit).
  • "patient” refers to a human being.
  • the present invention also includes isotopically-labeled compounds of the present invention, which are the same as those described in the present invention except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature.
  • Exemplary isotopes that can also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.
  • the compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are all included in the scope of the present invention.
  • Isotope-labeled compounds of the present invention such as radioisotopes, such as 3 H and 14 C, incorporated into the compounds of the present invention can be used for drug and/or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred.
  • substitution with heavy isotopes, such as deuterium, or 2 H can provide some therapeutic advantages derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.
  • stereoisomers refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • stereochemistry definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry” of Organic Compounds", John Wiley&Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomeric forms. It is expected that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and their mixtures such as racemic mixtures, It is also included in the scope of the present invention.
  • any asymmetric atom (for example, carbon, etc.) of the compound of the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, (R,R)-, (S, S)-, (S,R)- or (R,S)-configuration forms exist.
  • each asymmetric atom has at least 50% enantiomeric excess in (R)- or (S)- configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the substituents on the atoms with unsaturated double bonds may exist in the form of cis-(Z)- or trans-(E)-.
  • the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in the cis or trans (cis- or trans-) configuration .
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemates of any final product or intermediate obtained can be resolved into optical enantiomers by methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compound of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers, or in the form of mixtures thereof,
  • they are substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
  • nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March).
  • N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent, such as dichloromethane, the amine compound is combined with m-chloroperbenzoic acid (MCPBA) reaction.
  • LWDeady Syn.Comm.1977, 7,509-514
  • MCPBA m-chloroperbenzoic acid
  • solvate refers to an association formed by one or more solvent molecules with the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the term "metabolite” refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage, etc. of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • prodrug represents the conversion of a compound into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as compounds of general formula (I), or as specific examples, subclasses, and the present invention includes A class of compounds.
  • substituents such as compounds of general formula (I), or as specific examples, subclasses
  • the present invention includes A class of compounds.
  • optionally substituted by can be used interchangeably with the term “unsubstituted or substituted by”, that is, the structure is unsubstituted or substituted by one or more substituents described in the present invention .
  • an optional substituent group can be substituted at each substitutable position of the group.
  • substituents selected from specific groups then the substituents can be substituted at each position with the same or different substitutions.
  • C 1-6 alkyl specifically refers to independently disclosed C 1 alkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl
  • 5-8 atom-containing oxygen-containing heterocyclic group refers to a 5-atom oxygen-containing heterocyclic group, a 6-atom oxygen-containing heterocyclic group, and a 7-atom oxygen-containing heterocyclic group Cyclic group and 8-atom oxygen-containing heterocyclic group.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon radical containing 1-20 carbon atoms.
  • the alkyl group contains 1-8 carbon atoms, that is, C 1-8 alkyl; in some embodiments, the alkyl group contains 1-6 carbon atoms, that is, C 1-6 alkane
  • the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-2 carbon atoms.
  • the alkyl group is optionally substituted with one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms, ie C 2-8 alkenyl; in some embodiments, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 alkenyl Group; In some embodiments, the alkenyl group contains 2-4 carbon atoms, ie C 2-4 alkenyl.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • alkynyl groups contain 2-8 carbon atoms, i.e. C 2-8 alkynyl;
  • alkynyl groups contain 2-6 carbon atoms, i.e. C 2- 6 alkynyl
  • an alkynyl group contains 2-4 carbon atoms, ie, C 2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 1 -Butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octyne Kee, wait.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, that is, -O-alkyl, where the alkyl group has the meaning as described in the present invention.
  • the alkoxy group contains 1-12 carbon atoms, namely C 1-12 alkoxy; in some embodiments, the alkoxy group contains 1-6 carbon atoms, namely C 1 -6 alkoxy; in some embodiments, an alkoxy group having 1 to 4 carbon atoms, i.e. C 1- 4 alkoxy; in some embodiments, alkoxy groups contain from 1 to 3 Carbon atom, namely C 1-3 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 1-
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino” in which the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is an alkylamino group with one or two Ci-6 alkyl groups attached to the nitrogen atom, that is, a Ci -6 alkylamino group.
  • the alkylamino group is an alkylamino group with one or two C 1-4 alkyl groups attached to the nitrogen atom, that is, a C 1-4 alkylamino group.
  • the alkylamino group is an alkylamino group with one or two C 1-3 alkyl groups attached to the nitrogen atom, that is, a C 1-3 alkylamino group.
  • one or two alkylamino C 1-2 alkyl groups attached to the alkylamino group on the nitrogen atom i.e., C 1-2 alkylamino.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), and N,N-dimethylamino. Amino, N,N-diethylamino, etc.
  • alkylthio refers to a group containing a C 1-10 linear or branched alkyl group attached to a divalent sulfur atom.
  • the alkylthio group is a C 1-6 alkylthio group.
  • the alkylthio group is a C 1-4 alkylthio group, such examples include, but are not limited to methylthio (-SCH 3 ).
  • the alkylthio group is optionally substituted with one or more substituents described in the present invention.
  • haloalkyl haloalkenyl or haloalkoxy
  • haloalkyl haloalkenyl or haloalkoxy
  • fluoromethyl -CH 2 F
  • difluoromethyl -CHF 2
  • trifluoromethyl -CF 3
  • fluoroethyl -CHFCH 3 , -CH 2 CH 2 F
  • difluoroethyl -CF 2 CH 3 , -CHFCH 2 F, -CH 2 CHF 2
  • perfluoroethyl fluoropropyl (-CHFCH 2 CH 3 , -CH 2 CHFCH 3 , -CH 2 CH 2 CH 2 F), difluoropropyl (-CF 2 CH 2 CH 3 , -CFHCFHCH 3 , -CH 2 CH 2 CHF 2 , -CH 2 CF 2 CH 3 , -CH 2 CHFCH 2
  • cycloalkyl refers to a monovalent or multivalent non-aromatic saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-14 ring atoms.
  • the cycloalkyl group contains 3-12 carbon atoms, that is, C 3-12 cycloalkyl; in some embodiments, the cycloalkyl group contains 3-8 carbon atoms, that is, C 3-8 cycloalkane. Group; In some embodiments, the cycloalkyl group contains 3-6 carbon atoms, that is, a C 3-6 cycloalkyl group.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in the present invention.
  • aryl or "aromatic ring” are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic rings containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms
  • the carbocyclic ring system wherein at least one ring system is aromatic, and each ring system contains a carbocyclic ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule.
  • aryl groups may include phenyl, naphthyl, and anthracenyl.
  • the aryl group may be optionally substituted with one or more substituents described in the present invention.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
  • heterocyclyl refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein at least one ring atom is selected from heteroatoms, and the heteroatoms have the characteristics of the present invention The meaning described.
  • the “heterocyclic group” can be fully saturated or contain one or more degrees of unsaturation, but it cannot have an aromatic ring.
  • the terms “heterocyclyl”, “heterocyclic” and “heterocyclic” are used interchangeably herein.
  • the heterocyclic group is a heterocyclic group consisting of 5-10 ring atoms including 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a heterocyclic group consisting of 5-10 atoms
  • the heterocyclic group is a heterocyclic group consisting of 5-8 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, 5 -8-atom heterocyclic group
  • the heterocyclic group is a heterocyclic group consisting of 3-6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N
  • Cyclic group is a heterocyclic group consisting of 3-6 atoms; in some embodiments, the heterocyclic group is 5-6 containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N
  • a heterocyclic group composed of ring atoms that is, a heterocyclic group composed of 5-6 atoms; in some embodiments, a
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Oxazolidinyl, thiazolidinyl, dioxanyl, dithiazyl, thiazoly
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-10 ring atoms, or 5-8 ring atoms, or 5-6 ring atoms, in which at least one ring The system is aromatic, and at least one ring contains one or more heteroatoms, and the heteroatoms have the definition described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-10 ring atoms, or 5-8 ring atoms, or 5-6 ring atoms, in which at least one ring The system is aromatic, and at least one ring contains one or more heteroatoms, and the heteroatoms have the definition described in the present invention.
  • heteroaryl “heteroaromatic ring” or “heteroaromatic compound” are used interchangeably herein.
  • the heteroaryl group is a heteroaryl group composed of 5-10 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, a heteroaryl group consisting of 5-10 atoms ⁇ heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-8 atoms ⁇ heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, a heteroaryl group consisting of 5-6 atoms ⁇ heteroaryl.
  • the heteroaryl group is 5-8 ring atoms containing 1, 2, 3, or 4 O heteroatoms and 0, 1, 2, 3, or 4 heteroatoms independently selected from S and N Heteroaryl group composed of 5-8 atoms; in some embodiments, the heteroaryl group is a heteroatom containing 1, 2, 3 or 4 O and 0, 1, 2, 3 or 4 heteroaryl groups composed of 5-6 ring atoms independently selected from heteroatoms of S and N, that is, oxygen-containing heteroaryl groups composed of 5-6 atoms.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl groups include, but are not limited to, furyl (e.g. 2-furyl, 3-furyl), imidazolyl (e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl (
  • 2-thienyl, 3-thienyl 2-thienyl, 3-thienyl
  • pyrazolyl e.g., 2-pyrazolyl, 3-pyrazolyl
  • isothiazolyl oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl), thiodiazolyl (such as 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl) , Pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic or tricyclic groups, but not limited to the following groups: benzimidazolyl, benzofuranyl, benzothienyl, indino Dolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinol
  • m typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is m.
  • piperidinyl is a heterocyclic group composed of 6 ring atoms
  • naphthyl is an aryl group composed of 10 atoms.
  • halogen refers to F, Cl, Br or I.
  • D refers to deuterium, i.e., 2 H.
  • Carboxyl means -COOH, whether used alone or in combination with other terms, such as “carboxyalkyl”.
  • protecting group refers to a substituent group used to block or protect a specific functional group when other functional groups in the compound react.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to the substituent of the hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, and p-methoxy. Benzyl and silyl, etc.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • the ring system formed by the substituent R 0 connected to the central ring by a bond means that the substituent R 0 can only be substituted at any substitutable or any reasonable position on the ring to which it is connected.
  • the formula b represents that the substituent R 0 can be substituted at any position on the C ring that may be substituted, as shown in formulas b-1 to b-3:
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
  • pharmaceutically acceptable in the present invention refers to those approved by the federal regulatory agency or national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, especially humans.
  • pharmaceutical composition means a mixture of one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable Carriers, excipients, diluents, adhesives, fillers and other excipients, as well as anti-diabetic reagents, anti-hyperglycemia reagents, anti-obesity reagents, anti-hypertensive reagents, anti-platelet reagents, anti-atherosclerotic reagents or Additional therapeutic agents such as lipid-lowering agents.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • Synchronome X is also referred to as a disorder or disease of metabolic syndrome.
  • the disorder is described in detail in Johannsson et al., J. Clin. Endocrinol. Metab., 1997, 82, 727-734.
  • Inflammatory disease refers to any disease in which excessive inflammatory symptoms, host tissue damage, or loss of tissue function caused by excessive or uncontrolled inflammatory response , Disorders or symptoms.
  • Inflammatory disease also refers to a pathological state mediated by leukocyte influx and/or neutrophil chemotaxis.
  • inflammation refers to the local protective response caused by tissue damage or destruction, and it is used to destroy, dilute or separate (isolate) harmful substances and affected areas. Damaged organization. Inflammation is significantly associated with leukocyte influx and/or neutrophil chemotaxis. Inflammation can be caused by pathogenic organisms and viral infections and non-infectious methods, such as trauma or reperfusion after myocardial infarction or stroke, immune response to foreign antigens and autoimmune response. Therefore, the inflammatory diseases that can be treated with the compounds disclosed in the present invention include diseases related to specific defense system responses and non-specific defense system responses.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the term “treating" any disease or condition in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to regulating the disease or condition physically (for example, stabilizing the perceptible symptoms) or physiologically (for example, stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • compositions, formulation and administration of the compound of the present invention are provided.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, and pharmaceutically acceptable salts or their prodrugs .
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant, and optionally, other therapeutic and/or preventive components.
  • the pharmaceutical composition includes an effective amount of at least one pharmaceutically acceptable adjuvant.
  • the amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably inhibit the activity of SSAO/VAP-1 in biological specimens or patients.
  • compositions of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of patients.
  • the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable adjuvants, which, like those used in the present invention, include any solvents, diluents, or other liquid excipients, dispersing agents Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms.
  • pharmaceutically acceptable adjuvants include any solvents, diluents, or other liquid excipients, dispersing agents Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • substances that can be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g.
  • protamine sulfate disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt
  • silica gel magnesium trisilicate
  • polyvinylpyrrolidone polyacrylate
  • wax polyethylene-polyoxypropylene-block copolymer
  • methylcellulose hydroxypropylmethylcellulose, lanolin
  • sugars Such as lactose, glucose and sucrose
  • starch such as corn starch and potato starch
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate
  • powdered tragacanth malt
  • Gel talc
  • excipients e.g. cocoa butter and suppository wax
  • oils e.g.
  • magnesium hydroxide and aluminum hydroxide examples include alginic acid, pyrogen-free water, isotonic saline, Ringer's Ringer's solution, ethanol and phosphate buffer, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and colorants, anti-sticking agents, and coating agents according to the judgment of the formulator , Sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • colorants such as sodium lauryl sulfate and magnesium stearate
  • sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
  • the compound or composition of the present invention can be administered by any suitable method, according to the severity of the disease, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) or Nasal sprays and the like administer the above-mentioned compounds and pharmaceutically acceptable compositions to humans or other animals.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cotton seed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof.
  • oral compositions may also include adjuvants such as we
  • Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • water, Ringer's solution and isotonic sodium chloride solution can be used.
  • sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice.
  • any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as octadecenoic acid
  • fatty acids such as octadecenoic acid
  • it can be filtered through a bacteria-retaining filter or added in the form of a sterile solid composition, and the sterilant that can be dissolved or dispersed in sterile water or other sterile injectable medium before use is sterilized for the injectable preparation.
  • the absorption of the compound In order to prolong the effect of the compound or composition of the present invention, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water-soluble crystals or amorphous substances, because the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form.
  • delayed absorption of the parenterally administered compound can be achieved by dissolving or suspending the compound in an oil vehicle.
  • a biodegradable polymer such as polylactide-polyglycolic acid to make an injectable storage form, depending on the compound to polymer ratio and the nature of the particular polymer used, Control the rate of compound release.
  • biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • composition for rectal or vaginal administration is particularly a suppository prepared by mixing the compound of the present invention and a suitable non-irritating adjuvant, such as cocoa butter, polyethylene glycol or suppository wax, which is at ambient temperature It is solid but liquid at body temperature and therefore melts and releases the active compound in the rectum or vaginal cavity.
  • a suitable non-irritating adjuvant such as cocoa butter, polyethylene glycol or suppository wax
  • Oral solid dosage forms include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable adjuvant, such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agent, such as starch, lactose, sucrose, glucose , Mannitol and silicic acid, b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerin, d) disintegrants, such as Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) solution blocker, such as paraffin, f) absorption accelerator, such as quaternary ammonium compound, g) wetting agent , Such as cetyl alcohol and glyceryl monostearate,
  • solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the active compound may also be in a microencapsulated form with one or more of the above-mentioned excipients.
  • the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch.
  • inert diluents such as sucrose, lactose or starch.
  • dosage forms may also contain other substances besides inert diluents, such as tableting lubricants and other tableting adjuvants, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the topical or transdermal application dosage forms of the compound of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of the present invention.
  • the present invention contemplates the use of a skin patch that has the added advantage of providing controlled delivery of the compound to the body.
  • This dosage form can be made by dissolving or dispersing the compound in an appropriate medium.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • composition of the present invention can also be administered orally, parenterally, locally, rectum, nose, oral cavity, vagina via inhalation spray, or via implanted kit.
  • parenteral as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally or intravenously.
  • the sterile injectable form of the composition of the present invention may be a water or oil suspension. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art.
  • sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice.
  • any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides.
  • natural pharmaceutically acceptable oils such as olive oil or castor oil, in particular in polyoxyethylated form, fatty acids such as octadecenoic acid and its glyceride derivatives are used in the preparation of injections.
  • oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions).
  • long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions).
  • Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.
  • the pharmaceutical composition of the present invention can be taken orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.
  • commonly used carriers include, but are not limited to, lactose and starch.
  • Lubricants such as magnesium stearate are usually added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavor enhancers or colorants can also be added.
  • the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal use.
  • These pharmaceutical compositions can be prepared by mixing reagents and non-irritating excipients.
  • Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • the pharmaceutical composition of the present invention can also be applied locally. It is easy to prepare a suitable topical formulation for each of these areas or organs.
  • Rectal suppository preparations (see above) or suitable enema preparations can be used to achieve local drip administration to the lower intestinal tract.
  • a topical skin patch can also be used.
  • the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.
  • Carriers suitable for topical instillation of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water .
  • the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or especially a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride.
  • the pharmaceutical composition can be formulated as an ointment, such as petrolatum.
  • the pharmaceutical composition can also be administered via nasal vaporized spray or inhalation.
  • This composition is prepared according to well-known techniques in the pharmaceutical field and prepared into salt water by using benzyl alcohol and other suitable preservatives, absorption promoters that improve bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants Solution.
  • the compound used in the method of the present invention can be formulated into a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for a subject, each unit containing a predetermined amount of active substance calculated to produce the expected therapeutic effect, optionally combined with a suitable pharmaceutical carrier.
  • the unit dosage form can be used as a single daily dose or one of multiple daily doses (for example, about 1-4 times or more per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used to inhibit SSAO/VAP-1, or the medicine is used to prevent, treat or relieve Inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to inhibit the activity of SSAO/VAP-1, or to prevent, treat or alleviate inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases Method;
  • the method is to administer an effective therapeutic amount of the compound or the pharmaceutical composition to an individual in need.
  • the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at certain time intervals.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention to inhibit the activity of SSAO/VAP-1, or to prevent, treat or alleviate inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.
  • the compound of the present invention can also be applied to veterinary treatment of pets, introduced species of animals and farm animals, including mammals, rodents and so on. Other examples of animals include horses, dogs, and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the "effective amount”, “effective therapeutic amount” or “effective dose” of the compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention .
  • the compound or pharmaceutically acceptable pharmaceutical composition of the present invention is effective in a relatively wide dosage range.
  • the daily dose is about 0.1mg-1000mg/person, divided into one or several doses.
  • the methods, compounds and pharmaceutical compositions according to the present invention can be of any dosage and any route of administration to be effectively used to treat or reduce the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, general condition of the patient, severity of infection, special factors, method of administration, etc.
  • the compound or pharmaceutical composition of the present invention can be administered in combination with one or more other therapeutic agents, as discussed in the present invention.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or/and 19 F-NMR).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts ( ⁇ ) are given in units of parts per million (ppm).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR are measured by Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, and the measuring solvent is deuterated chloroform (CDCl 3 ), deuterated Methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • Novasep Pump 250 High Performance Liquid Chromatograph is used for preparative purification or preparative resolution.
  • the Agilent-6120 Quadrupole LC/MS mass spectrometer is used for the determination of LC-MS.
  • the starting materials of the present invention are known and can be purchased on the market, purchased from Shanghai Accela Company, Energy Company, J&K, Tianjin Alfa Companies such as Alfa Company can alternatively adopt or synthesize according to methods known in the art.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon or steel kettle with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L or a stainless steel autoclave with a volume of about 1L.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature; if there are no special instructions in the examples, the room temperature is 20°C-40°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent systems used in the reaction are: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system , The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the eluent system of column chromatography includes: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and ethyl acetate system
  • C dichloromethane and methanol system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of ammonia and acetic acid.
  • HPLC refers to high performance liquid chromatography
  • HPLC determination uses Agilent 1260 high pressure liquid chromatograph (Eclipse Plus C18 4.6 ⁇ 150mm 3.5um chromatographic column);
  • the mobile phase gradient is shown in Table A:
  • the LC/MS/MS system used for analysis in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column incubator, Agilent G6430 three-stage with electrospray ionization source (ESI) Quadrupole mass spectrometer. Quantitative analysis is performed in MRM mode, and the parameters of MRM conversion are shown in Table B:
  • the Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ M column was used for analysis, and 5 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min.
  • the mobile phase gradient is shown in Table C:
  • Agilent 6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source.
  • a Capcell MP-C18 column was used, the specification was: 100 ⁇ 4.6mm I.D., 5 ⁇ M (Phenomenex, Torrance, California, USA).
  • the mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 ⁇ L of sample.
  • DMSO-d 6 deuterated dimethyl sulfoxide; Boc: tert-butoxycarbonyl;
  • CD 3 OD Deuterated methanol; mL,ml: mL;
  • H 2 hydrogen; min: minutes;
  • N 2 Nitrogen; MPa: MPa;
  • the compound having the structure represented by the general formula (IA) can be prepared by the general synthesis method described in the synthesis scheme 1, and the specific steps can refer to the examples.
  • compound (Ia) undergoes diazotization of the carboxyl group to obtain compound (Ib); then reacts with an organic solution of hydrogen bromide to obtain compound (Id); or compound (Id) can also be brominated by compound (Ic) The response is obtained.
  • compound (Id) is substituted with amino group to form a salt to obtain the salt of compound (If); alternatively, compound (Id) can also be subjected to azidation to obtain compound (Ie), and then azide is reduced to form a salt to obtain compound (If). ) Of salt.
  • the salt of compound (If) is protected by amino group to obtain compound (Ig); or, compound (Ig) can also be obtained by azide reduction of compound (Ie) in the presence of acid anhydride (such as Boc 2 O).
  • acid anhydride such as Boc 2 O
  • compound (Ig) undergoes Wittig reaction to obtain compound (Ih); compound (Ih) is deprotected from the amino group to obtain the target compound represented by general formula (IA).
  • the free amino compound, that is, the target compound represented by the general formula (IA) is converted into acid addition salts.
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide Acid salt and methanesulfonate.
  • Step 12 (E)-2-[1-(Aminomethyl)-2-fluoro-vinyl]-N-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine- 6-Carboxamide hydrochloride (Compound E2- 1) and (Z)-2-[1-(aminomethyl)-2-fluoro-vinyl]-N-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine- 6-formamide hydrochloride (compound E2-2)
  • N-[2-[6-(tert-butylcarbamoyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]-3-fluoro-allyl]amino 3l of tert-butyl formate (1.1 g, 2.7 mmol) was dissolved in ethyl acetate (5 mL), and ethyl acetate solution of hydrogen chloride (10 mL, 4.0 mol/L) was added, and reacted at room temperature for 30 minutes.
  • Step 2) Ethyl 6-(tert-butylcarbamoyl)-2,3-dihydro-1,4-benzodioxin-2-carboxylate
  • Methyl 2-acetylbenzofuran-5-carboxylate (3.0g, 14mmol) was dissolved in acetic acid (60mL), and pyridine perbromide hydrobromide (4.8g, 15mmol) was added in portions at 55°C, and reacted for 4 hours .
  • the reaction solution was cooled to room temperature and concentrated.
  • the resulting residue was added with saturated sodium bicarbonate solution (80 mL), stirred for 10 minutes, filtered with suction, and the yield filter cake was dried to obtain the title compound (3.90 g, yield 95%) as a yellow solid .
  • Step 7) 2-[(E)-1-[(tert-butoxycarbonylamino)methyl]-2-fluoro-vinyl]benzofuran-5-carboxylic acid methyl ester and 2-[(Z)-1- [(Tert-Butoxycarbonylamino) Methyl]-2-fluoro-vinyl]benzofuran-5-methyl carboxylate
  • reaction was quenched by adding a mixture of ice and water (10mL), extracted with ethyl acetate (20mL ⁇ 3), and the combined organic phase was washed with water (20mL) and saturated sodium chloride solution (20mL) successively, dried with anhydrous sodium sulfate, and pumped.
  • Test purpose The following method is used to determine the inhibitory activity of the compound of the present invention on rat fat homogenate SSAO/VAP-1.
  • HPES SODIUM SALT N-piperazine-N-ethanesulfonic acid sodium salt
  • EDTA Ethylenediaminetetraacetic acid
  • Sucrose was purchased from Sigma, Cat. No. V900116;
  • PMSF Phenylmethanesulfonyl fluoride
  • ⁇ -Glycerophosphate disodium salt hydrate was purchased from Sigma, Cat.No.G5422-25G;
  • Pargyline hydrochloride was purchased from Sigma, Cat. No. P8013-500MG;
  • DMSO Dimethyl Sulfoxide
  • Benzylamine hydrochloride was purchased from Sigma, Cat. No. B5136-25G;
  • 96-well plate was purchased from COSTAR, Cat. No. 3631;
  • Red Hydrogen Peroxide Peroxidase Assay Kit was purchased from Invitrogen, Cat. No. A22188.
  • test compounds of different concentrations 25 ⁇ l were added to each well containing adipose tissue supernatant, and incubated at 37° C. for 30 min. After incubation, 50 ⁇ l of the reaction mixture containing 80 ⁇ M benzylamine hydrochloride (containing 100 ⁇ M Red and 0.2U/ml HRP, Red Hydrogen Peroxide Peroxidase Assay Kit) was added to the corresponding wells and incubated at 37°C for 30 min. After 30 minutes, use the PHERAstar FSX microplate reader of BMG LABTECH to read the fluorescence value (RFU) under excitation at 540nm and emission at 580nm. Using Graph Pad Prism 5 software plotted and IC50 values calculated IC. The compound of the present invention has an IC 50 of less than 15 nM for the inhibitory activity of adipose tissue homogenate SSAO/VAP-1. The results are shown in Table 1:
  • Table 1 Inhibitory activity of the compounds provided in the examples of the present invention on SSAO/VAP-1 of adipose tissue homogenate
  • test results show that the compound of the present invention has a significant inhibitory effect on adipose tissue homogenate SSAO/VAP-1.

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Abstract

一种作为SSAO/VAP-1抑制剂的胺类衍生物及其用途，进一步涉及包含所述化合物的药物组合物。化合物或药物组合物可用于治疗炎症和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。

Description

一种作为SSAO/VAP-1抑制剂的胺类衍生物及其用途 技术领域
本发明属于药物领域，具体涉及一种作为氨基脲敏感性胺氧化酶(SSAO)和/或血管黏附蛋白-1(VAP-1)抑制剂的胺类化合物及其制备方法，进一步包含所述化合物的药物组合物及所述化合物及其药物组合物的用途。
背景技术
血管黏附蛋白-1(vascular adhesion protein-1,VAP-1)是一种相对分子质量(MW)为170,000～180,000的二聚体糖蛋白，是一种在哺乳动物体内广泛存在的多功能蛋白。VAP-1具有双重功能，一方面是淋巴细胞的黏附分子，促进淋巴细胞黏附于血管内皮；另一方面，VAP-1还具有氨基脲敏感性胺氧化酶(semicarbazide-sensitive amine oxidase,SSAO)的功效。VAP-1蛋白可以以溶质的形式存在于血浆中，也可以以与膜结合的形式存在于内皮细胞、脂肪细胞及平滑肌细胞的表面。近年来研究者通常以SSAO/VAP-1来描述该蛋白。在脂肪细胞和平滑肌细胞内，SSAO/VAP-1可以促进葡萄糖转运蛋白4(Glucose transport 4,GLUT 4)从脂肪细胞胞内转移至细胞膜，进而调节葡萄糖转运。在内皮细胞，SSAO/VAP-1可以介导白细胞与内皮细胞的黏附和渗出过程，参与炎症反应。
据报道，已经在以下疾病中观测到SSAO/VAP-1含量的升高：糖尿病(Li,H,Y.et al.,2009,Clin.Chim.Acta 404:149-153)、肥胖症(Meszaros,Z.et al.,1999,Metabolism 48:113-117；Weiss,H,G.et al.,2003,Metabolism 52:688-692)、缺血性心脏衰竭(Boomsma,F.et al.,1997,Cardiovasc.Res.33:387-391)、末期肾病(Kurkijarvi,R.et al.,2001,Eur,J.Immunol.31:2876-2884)及炎症性肝病(Kurkijarvi,R.et al.,1998,J.Immunol.161:1549-1557)。对于炎症性肝病，科学家已将SSAO/VAP-1血浆活性水平与肝纤维化相关联，并且用作非酒精性脂肪性肝病(Nonalcoholic Fatty Liver Disease,NAFLD)的患者的预测因子。
另外，SSAO/VAP-1还与以下疾病有关：黑色素瘤和淋巴瘤(Martila-lchihara，F.et al.,2010,J.Immunol.184：3164-3173)、急性和慢性关节炎(Tabi,T.et al.,2013,J.NeuralTransm.120:963-967)、肺炎(Foot,J.S.et al.,2013,J.Pharmacol.Exp.Ther.347:365-374)、糖尿病性黄斑水肿(Inoue,T.et al.,2013,Bioorg.Med.Chem.21：1219-1233)、糖尿病视网膜病(Boomsma,F.et al.,1999,Diabetologia,42:233-237and Garpenstrand H.et al.1999,Diabetic medicine,16:514-521)、肾纤维化(Wong,M.et al.,2014,Am.J.Physiol Renal Physiol 307:F908-F916)、肝同种异体移植物排斥(Martelius,T.et al.,2004,Am.J.Pathol.165:1993-2001)和非酒精性肝病，等等。
综上所述，开发选择性强、强效且耐受性良好的SSAO/VAP-1抑制剂，将有益于人类治疗各种疾病，尤其是炎症/或炎症相关疾病以及糖尿病和/或糖尿病相关疾病。
发明内容
本发明提供了一类具有较好的抑制SSAO/VAP-1活性的胺类化合物，此类化合物及其药物组合物可以制备用于预防、治疗或减轻患者炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病的药物，尤其是制备用于预防、治疗或减轻患者非酒精性脂肪性肝病、糖尿病视网膜病、糖尿病肾病、糖尿病神经病或糖尿病黄斑水肿的药物。本发明也提供了制备这些化合物的方法，包含这些化合物的药物组合物，以及使用这些化合物和组合物制备治疗哺乳动物，尤其是人类的上述疾病的药物的方法。与已有的同类化合物相比，本发明的化合物具有良好的药理活性，和/或优良的体内药代动力学性质或体内药效学性质。同时制备方法简单易行，工艺方法稳定，适合工业化生产。因此，本发明提供的化合物相对于目前已有的同类化合物而言，具有更优良的成药性。
一方面，本发明涉及一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2019121469-appb-000001
其中，所述环A、R 1、R 2、R 3、R z和q具有本发明所述的定义，其中
Figure PCTCN2019121469-appb-000002
表示式(I)所示化合物可为“E”构型、“Z”构型或“E”构型和“Z”构型以任意比例形成的组合。
在一些实施方案中，R 2为F、Cl、Br或I。
在一些实施方案中，R 3为H、氘、C 1-6烷基或C 3-6环烷基。
在一些实施方案中，环A为5-8个原子组成的含氧杂环或5-8个原子组成的含氧杂芳环，其中所述环A未被取代或被1、2或3个R y所取代；其中所述R y具有本发明所述的定义。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、R i和R j各自独立地为H、氘、C 1-6烷基或C 3-6环烷基。
在一些实施方案中，各R z独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基。
在一些实施方案中，各R y独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基。
在一些实施方案中，q为0、1、2或3。
在另一些实施方案中，环A为5-6个原子组成的含氧杂环或5-6个原子组成的含氧杂芳环，其中所述环A未被取代或被1、2或3个R y所取代，其中所述R y具有本发明所述的定义。
在又一些实施方案中，环A为
Figure PCTCN2019121469-appb-000003
Figure PCTCN2019121469-appb-000004
Figure PCTCN2019121469-appb-000005
其中所述环A未被取代或被1、2或3个R y所取代，其中所述R y具有本发明所述的定义。
在另一些实施方案中，R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、R i和R j各自独立地为H、氘、C 1-4烷基或C 3-6环烷基。
在另一些实施方案中，R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、甲氧基、乙氧基、甲氨基、甲硫基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3、三氟甲氧基、乙烯基、烯丙基、丙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、R i和R j各自独立地为H、氘、甲基、 乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或环己基。
在另一些实施方案中，R 3为H、氘、C 1-4烷基或C 3-6环烷基。
在又一些实施方案中，R 3为H、氘、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基或环己基。
在另一些实施方案中，各R z独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基。
在又一些实施方案中，各R z独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3或三氟甲氧基。
在另一些实施方案中，各R y独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基。
在又一些实施方案中，各R y独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3或三氟甲氧基。
在一些实施方案中，本发明涉及以下其中之一的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2019121469-appb-000006
在一些实施方案中，本发明涉及以下其中之一的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2019121469-appb-000007
Figure PCTCN2019121469-appb-000008
在一些实施方案中，本发明所述药学上可接受的盐为盐酸盐、氢溴酸盐、磷酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、苹果酸盐或甲磺酸盐。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物，任选地，进一步包含药学上可接受的辅剂。
另一方面，本发明涉及本发明所述的化合物或药物组合物在制备药物中的用途，其中，所述药物用于抑制SSAO/VAP-1；或所述药物用于预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。
另一方面，本发明涉及将本发明所述的化合物或药物组合物用于抑制SSAO/VAP-1的活性；或用于预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。
另一方面，本发明涉及一种抑制SSAO/VAP-1活性的方法；或预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病的方法；所述方法是给予患者本发明所述化合物或所述药物组合物的有效治疗量。
在一些实施方案中，本发明所述炎症疾病和/或炎症相关疾病为肝自身免疫性疾病、自身免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎、自身免疫性胆管炎、酒精性肝病或非酒精性脂肪性肝病。
在一些实施方案中，本发明所述糖尿病和/或糖尿病相关疾病为Ⅰ型糖尿病、Ⅱ型糖尿病、X综合征、糖尿病视网膜病、糖尿病肾病、糖尿病神经病或糖尿病黄斑水肿。
在又一些实施方案中，本发明所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、非酒精性脂肪性肝病相关隐源型肝硬化或原发性肝癌。
本发明详细说明书
本发明提供了一类具有较好抑制SSAO/VAP-1活性的胺类衍生物及其制备方法和用途。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的范围中。
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“受试对象”是指动物。典型的所述动物是哺乳动物。受试对象也指灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在另外其他实施方案中，所述受试对象是人。
本发明所使用的术语“受治疗者”和“患者”可交换地使用。术语“受治疗者”和“患者”指动物(例如，鸡、鹌鹑或火鸡等鸟类或哺乳动物)，特别是包括非灵长类动物在内的“哺乳动物”(例如，牛、猪、马、羊、兔、豚鼠、大鼠、猫、狗和小鼠)和灵长类动物(例如，猴子、黑猩猩和人类)，更特别的是人类。在一个实施方案中，受治疗者为非人类动物，例如家畜(例如，马、牛、猪或羊)或宠物(例如，狗、猫、豚鼠或兔)。在另一些实施方案中，“患者”是指人类。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
本发明还包括同位素标记的本发明化合物，其除以下事实外与本发明所述的那些化合物相同：一个或多个原子被原子质量或质量数不同于天然常见原子质量或质量数的原子代替。还可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 13C， 14C， 15N， 16O， 17O， 31P， 32P， 36S， 18F和 37Cl。
包含前述同位素和/或其他原子的其他同位素的本发明化合物以及所述化合物的药学上可接受的盐均包括在本发明范围内。同位素标记的本发明化合物，例如放射性同位素，如 3H和 14C掺入到本发明化合物中可用于药物和/或底物组织分布分析。由于易于制备以及检测，氚代的，即， 3H，以及碳-14，即 14C，同位素特别优选。此外，用重的同位素，如氘，即 2H取代，可提供一些源自更大的代谢稳定性的治疗上的优势，例如增加的体内半衰期或减少的剂量需求。因此，在一些情形下可能是优选的。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。本发明化合物可含有不对称中心或手性中心，因此以不同的立体异构形式存在。所预期的是，本发明化合物的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)及它们的混合物如外消旋混合物，也包含在本发明范围之内。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀d和l或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。
本发明化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-、(R,R)-、(S,S)-、(S,R)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。如果可能的话，具有不饱和双键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消 旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
因此，如本发明所描述的那样，本发明的化合物可以以可能的异构体、旋转异构体、阻转异构体、互变异构体中的一种形式或其混合物的形式存在，例如为基本纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物形式。
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂，例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯 甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如通式(I)化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代。
除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、氧代(＝O)、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、卤代烷基、烷氧基、烷硫基、烷氨基、卤代烷氧基、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中，所述各R a、R b、R c、R d、R e、R f、R g、R h、R i和R j具有如本发明所述定义。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的C 1烷基(甲基)、C 2烷基(乙基)、C 3烷基、C 4烷基、C 5烷基和C 6烷基；术语“5-8个原子组成的含氧杂环基”指5个原子组成的含氧杂环基、6个原子组成的含氧杂环基、7个原子组成的含氧杂环基和8个原子组成的含氧杂环基。
在本发明书的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应当理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含1-20个碳原子的饱和直链或支链的一价碳氢化合物原 子团。在一些实施方案中，烷基基团含有1-8个碳原子，即C 1-8烷基；在一些实施方案中，烷基基团含有1-6个碳原子，即C 1-6烷基；在一些实施方案中，烷基基团含有1-4个碳原子，即C 1-4烷基；在一些实施方案中，烷基基团含有1-2个碳原子。所述烷基基团任选地被一个或多个本发明所描述的取代基所取代。
烷基基团的实例包含，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，异丁基(i-Bu，-CH 2CH(CH 3) 2)，仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一些实施方案中，烯基基团包含2-8个碳原子，即C 2-8烯基；在一些实施方案中，烯基基团包含2-6个碳原子，即C 2-6烯基；在一些实施方案中，烯基基团包含2-4个碳原子，即C 2-4烯基。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、丙烯基(-CH＝CH-CH 3)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子，即C 2-8炔基；在一些实施方案中，炔基基团包含2-6个碳原子，即C 2- 6炔基；在一些实施方案中，炔基基团包含2-4个碳原子，即C 2-4炔基。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、1-己炔基、1-庚炔基、1-辛炔基，等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，即-O-烷基，其中烷基基团具有如本发明所述的含义。在一些实施方案中，烷氧基基团含有1-12个碳原子，即C 1-12烷氧基；在一些实施方案中，烷氧基基团含有1-6个碳原子，即C 1-6烷氧基；在一些实施方案中，烷氧基基团含有1-4个碳原子，即C 1- 4烷氧基；在一些实施方案中，烷氧基基团含有1-3个碳原子，即C 1-3烷氧基。
烷氧基基团的实例包含，但并不限于，甲氧基(MeO,-OCH 3)，乙氧基(EtO,-OCH 2CH 3)，1-丙氧基(n-PrO,n-丙氧基,-OCH 2CH 2CH 3)，2-丙氧基(i-PrO,i-丙氧基,-OCH(CH 3) 2)，1-丁氧基(n-BuO,n-丁氧基,-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO,i-丁氧基,-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO,s-丁氧基,-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO,t-丁氧基,-OC(CH 3) 3)，1-戊氧基(n-戊氧基,-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。
术语“烷氨基”包括“N-烷氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。在一些实施方案中，烷氨基为一个或两个C 1-6烷基连接到氮原子上的烷氨基基团，即C 1-6烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-4烷基连接到氮原子上的烷氨基基团，即C 1-4烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-3烷基连接到氮原子上的烷氨基基团，即C 1-3烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-2烷基连接到氮原子上的烷氨基基团，即C 1-2烷氨基。合适的烷氨基基团可以是单烷氨基或二烷氨基，这样的实例包括，但并不限于，甲氨基(N-甲氨基)，乙氨基(N-乙氨基)，N,N-二甲氨基，N,N-二乙氨基，等等。
术语“烷硫基”是指含有C 1-10的直链或支链的烷基连接到二价硫原子上的基团，在一些实施方案中，烷硫基为C 1-6烷硫基；在一些实施方案中，烷硫基为C 1-4烷硫基，这样的实施例包括，但并不限于甲硫基(-SCH 3)。所述烷硫基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“卤代烷基”，“卤代烯基”或“卤代烷氧基”分别表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代。这样的实例包含，但并不限于，氟甲基(-CH 2F)、二氟甲基(-CHF 2)、三氟甲基(-CF 3)、氟乙基(-CHFCH 3,-CH 2CH 2F)、二氟乙基(-CF 2CH 3,-CHFCH 2F,-CH 2CHF 2)、全氟乙基、氟丙基(-CHFCH 2CH 3,-CH 2CHFCH 3,-CH 2CH 2CH 2F)、二氟丙基(-CF 2CH 2CH 3,-CFHCFHCH 3,-CH 2CH 2CHF 2,-CH 2CF 2CH 3,-CH 2CHFCH 2F)、三氟乙基(-CH 2CF 3,-CHFCHF 2,-CF 2CH 2F)、三氟丙基、1,1-二氯乙基、1,2-二氯丙基、三氟甲氧基(-OCF 3)、二氟甲氧基(-OCHF 2)、2,2,2-三氟乙氧基(-OCH 2CF 3)等。
术语“环烷基”表示含有3-14个环原子的，单价或多价的非芳香性的饱和单环、双环或三环碳环体系。在一些实施方案中，环烷基包含3-12个碳原子，即C 3-12环烷基；在一些实施方案中，环烷基包含3-8个碳原子，即C 3-8环烷基；在一些实施方案中，环烷基包含3-6个碳原子，即C 3-6环烷基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基”或“芳环”在此处可交换使用，表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的碳环，且有一个或多个附着点与分子的其余部分相连。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂原子”是指O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3，4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R为本发明所描述的取代基)。
术语“杂环基”是指包含3-14个环原子的，单价或多价的单环、双环或者三环体系，其中至少有一个环原子选自杂原子，所述杂原子具有如本发明所述的含义。“杂环基”可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。术语“杂环基”、“杂环的”和“杂环”在此处可交换使用。在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂环基，即5-10个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂环基，即5-8个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的3-6个环原子组成的杂环基，即3-6个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂环基，即5-6个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个O的杂原子和0，1，2，3或4个独立选自S和N的杂原子的5-8个环原子组成的杂环基，即5-8个原子组成的含氧杂环基；在一些实施方案中，杂环基为包含1，2，3或4个O的杂原子和0，1，2，3或4个独立选自S和N的杂原子的5-6个环原子组成的杂环基，即5-6个原子组成的含氧杂环基。
除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，噁唑烷基，噻唑烷基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019121469-appb-000009
基，二氮杂
Figure PCTCN2019121469-appb-000010
基，硫氮杂
Figure PCTCN2019121469-appb-000011
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，
Figure PCTCN2019121469-appb-000012
Figure PCTCN2019121469-appb-000013
Figure PCTCN2019121469-appb-000014
等等。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-哌啶酮基，3,5-二氧代哌啶基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-10个环原子，或5-8个环原子，或5-6个环原子的单价或多价的的单环、双环或三环体系，其中至少一个环体系是芳香族的，且至少一个环包含一个或多个杂原子，所述杂原子具有本发明所述的定义。术语“杂芳基”、“杂芳环”或“杂芳族化合物”在此可交换使用。当杂芳基基团存在-CH 2-基团时，所述-CH 2-基团可任选的被-C(＝O)-替代。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂芳基，即5-10个原子组成的杂芳基。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂芳基，即5-8个原子组成的杂芳基。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂芳基，即5-6个原子组成的杂芳基。在一些实施方案中，杂芳基为包含1，2，3或4个O的杂原子和0，1，2，3或4个独立选自S和N的杂原子的5-8个环原子组成的杂芳基，即5-8个原子组成的含氧杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个O的杂原子和0，1，2，3或4个独立选自S和N的杂原子的5-6个环原子组成的杂芳基，即5-6个原子组成的含氧杂芳基。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。
杂芳基基团的实例包括，但并不限于，呋喃基(如2-呋喃基，3-呋喃基)，咪唑基(如N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基)，异噁唑基(如3-异噁唑基，4-异噁唑基，5-异噁唑基)，噁唑基(如2-噁唑基，4-噁唑基，5-噁唑基)，吡咯基(如N-吡咯基，2-吡咯基，3-吡咯基)，吡啶基(如2-吡啶基，3-吡啶基，4-吡啶基)，嘧啶基(如2-嘧啶基，4-嘧啶基，5-嘧啶基)，哒嗪基(如3-哒嗪基)，噻唑基(如2-噻唑基，4-噻唑基，5-噻唑基)，四唑基(如5H-四唑基，2H-四唑基)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，噻吩基(如2-噻吩基，3-噻吩基)，吡唑基(如，2-吡唑基，3-吡唑基)，异噻唑基，噁二唑基(如1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基)，硫代二唑基(如1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基)，吡嗪基，1,3,5-三嗪基；也包括以下的双环或三环基团，但绝不限于以下基团：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、吲哚啉基、1,2,3,4-四氢异喹啉基、等等。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“m个原子组成的”，其中m是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是m。例如，哌啶基是6个环原子组成的杂环基，而萘基是10个原子组成的芳基基团。
术语“卤素”是指F，Cl，Br或I。
术语“D”是指氘代，即 2H。
术语“羧基”，表示-COOH，无论是单独使用还是和其他术语连用，如“羧烷基”。
术语“羰基”，表示-(C＝O)-，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”。
术语“保护基团”或“PG”是指当化合物中其他官能团发生反应的时候，用来阻断或保护特定的功能性的取代基团。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性， 合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括，但不限于，乙酰基、苯甲酰基、苄基、对甲氧基苄基和硅烷基等。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
像本发明所描述的，取代基R 0由一个键连接到中心的环上形成的环体系代表取代基R 0只可以在与其相连的环上任何可取代或任何合理的位置进行取代。例如，式b代表取代基R 0可以在C环上任何可能被取代的位置取代，如式b-1至b-3所示：
Figure PCTCN2019121469-appb-000015
术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、赋形剂、稀释剂、粘合剂、填充剂等辅料，以及抗糖尿病试剂、抗高血糖试剂、抗肥胖症试剂、抗高血压试剂、抗血小板试剂、抗动脉粥样硬化试剂或者降脂试剂等附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
术语“X综合症”，也称作代谢综合症的病症、疾病，其疾患详述于Johannsson et al.,J.Clin.Endocrinol.Metab.,1997,82,727-734中。
本发明所使用的“炎症疾病”、“炎性疾病”或“炎症性疾病”是指由于过度或失控的炎性响应所导致的过度的炎性症状、宿主组织损害或组织功能丧失的任何疾病，紊乱或症状。“炎症疾病”还指受白细胞流入和/或嗜中性粒细胞趋化性介导的病理学状态。
本发明所使用的“炎症”、“炎性”或“炎症性”是指由组织受损或破坏引起的局部保护性响应，它用于破坏、稀释或隔开(隔绝)有害的物质和受损的组织。炎症与白细胞流入和/或嗜中性粒细胞趋化性有显著的联系。炎症可以产生于病原性生物体和病毒的感染以及非传染性方式，如心肌梗塞或中风后的创伤或再灌注，对外来抗原的免疫应答和自身免疫应答。因此，可以用本发明公开化合物治疗的炎性疾病包括：与特异性防御系统反应以及非特异性防御系统反应相关的疾病。
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明的化合物的组合物、制剂和给药
本发明涉及一种药物组合物，其包括本发明所述化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物及药学上可接受的盐或它们的前药。所述药物组合物进一步包含至少一种药学上可接受的辅剂，以及任选地、其它的治疗和/或预防成分。在一些实施方案，所述药物组合物包含有效量的至少一种药学上可接受的辅剂。本发明的药物组合物中化合物的量能有效地可探测地抑制生物标本或患者体内的 SSAO/VAP-1的活性。
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的辅剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅剂可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅剂与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可用作药学上可接受的辅剂的物质的一些实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质(例如吐温80、磷酸盐、甘氨酸、山梨酸或山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠或锌盐)、硅胶、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧化丙烯-嵌段共聚物、甲基纤维素、羟丙基甲基纤维素、羊毛脂、糖类(例如乳糖、葡萄糖和蔗糖)、淀粉(例如玉米淀粉和马铃薯淀粉)、纤维素及其衍生物(例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素)、粉状黄蓍胶、麦芽、凝胶、滑石、赋形剂(例如可可油和栓剂蜡)、油(例如花生油、棉花子油、红花油、芝麻油、橄榄油、玉米油和大豆油)、乙二醇(例如丙二醇或聚乙二醇)、酯(例如油酸乙酯和十二酸乙酯)、琼脂、缓冲剂(例如氢氧化镁和氢氧化铝)、褐藻酸、无热原水、等渗盐水、林格氏溶液(Ringer'ssolution)、乙醇和磷酸盐缓冲液以及其它无毒相容性滑润剂(例如硫酸月桂酯钠和硬脂酸镁)以及根据配制人的判断着色剂、防粘剂、涂层剂、甜味剂和增香剂、防腐剂和抗氧化剂也可存在于组合物中。
本发明的化合物或组合物可以通过任何合适方式给药，可根据疾病的严重程度经口、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如同通过粉剂、药膏或滴剂)或喷鼻剂等向人或其它动物施用以上所述化合物和药学上可接受的组合物。
供口服的液体剂型包括但不限于药学上可接受的乳剂、微型乳剂、溶液、悬浮剂、糖浆和酏剂。除活性化合物外，液体剂型可能含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉花子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨聚糖的脂肪酸酯及其混合物。除惰性稀释剂外，口服组合物也可包括佐剂，例如湿润剂、乳化和悬浮剂、甜味剂、调味剂和增香剂。
可根据已知技术使用适合的分散或湿润剂和悬浮剂配制可注射制剂，例如无菌可注射水或油悬浮剂。无菌可注射制剂也可能是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮剂或乳剂，例如1,3-丁二醇中的溶液。在可接受的媒介物和溶剂中，可采用的是水、林格氏溶液和等渗氯化钠溶液。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，脂肪酸，例如十八烯酸，用于制备注射剂。例如，可通过细菌保留过滤器过滤或通过加入呈无菌固体组合物形式，使用之前可溶于或分散于无菌水或其它无菌可注射介质中的杀菌剂为可注射制剂灭菌。
为延长本发明所述化合物或组合物的作用，常常希望减缓化合物由皮下或肌肉注射的吸收。这可通过使用水溶性差的晶体或无定形物质的液体悬浮液实现，因为化合物的吸收速率取决于其溶解速率，而溶解速率又取决于晶体大小和晶形。或者，通过将化合物溶解或悬浮于油媒介物中实现延迟吸收经肠胃外施用 的化合物。或者，通过在生物可降解的聚合物例如聚交酯-聚羟基乙酸中形成化合物的微胶囊矩阵制成可注射的储存形式，根据化合物与聚合物之比和采用的特殊聚合物的性质，可控制化合物释放速率。其它生物可降解的聚合物的实例包括聚原酸酯和聚酸酐。也可通过将化合物截留在与身体组织相容的脂质体或微型乳剂中制备可注射的储存制剂。
经直肠或阴道施用的组合物特别是可通过混合本发明所述化合物和适合的非刺激性辅剂，例如可可油、聚乙二醇或栓剂蜡制备的栓剂，所述辅剂在环境温度下为固体但在体温下为液体并因此在直肠或阴道腔内融化并释放活性化合物。
口服固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒。在这种固体剂型中，活性化合物混有至少一种惰性的药学上可接受的辅剂，例如柠檬酸钠或磷酸二钙和/或a)填料或膨胀剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸，b)粘合剂，例如羧基甲基纤维素、藻酸盐、凝胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶，c)保湿剂，例如甘油，d)崩解剂，例如琼脂--琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠，e)溶液阻滞剂，例如石蜡，f)吸收加速剂，例如季铵化合物，g)湿润剂，例如鲸蜡醇和单硬脂酸甘油酯，h)吸收剂，例如高岭土和膨润土，和i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、硫酸月桂酯钠及其混合物。在为胶囊、片剂和丸剂的情况下，剂型也可包含缓冲剂。
也可使用如乳糖或奶糖以及高分子聚乙二醇等辅剂将相似类型的固体组合物用作软和硬凝胶胶囊中的填料。可用包衣和壳，例如肠溶衣和制药领域众所周知的其它包衣制备片剂、糖锭、胶囊、丸剂和颗粒的固体剂型。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。
活性化合物也可呈现具有一种或多种上述赋形剂的微密封形式。在这种固体剂型中，活性化合物可能混有至少一种惰性稀释剂，例如蔗糖、乳糖或淀粉。一般地，这种剂型也可能包含除惰性稀释剂外的另外的物质，例如压片润滑剂和其它压片辅剂，例如硬脂酸镁和微晶纤维素。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。
本发明所述化合物的局部或经皮施用剂型包括药膏、软膏、乳膏、洗剂、凝胶、粉剂、溶液、喷剂、吸入剂或贴片。在无菌条件下，活性化合物与药学上可接受的载体和任何需要的防腐剂或可能需要的缓冲剂。眼科制剂、耳滴剂和眼药水也被考虑到本发明的范围之内。另外，本发明考虑到具有提供控制化合物向身体递送的附加优点的皮肤贴片的用途。可通过将化合物溶解或分散于恰当介质中制成这种剂型。吸收促进剂也可用于提高化合物通过皮肤的流量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中控制速率。
也可经口、肠胃外，通过吸入喷剂经局部、直肠、鼻、口腔、阴道或通过植入药盒施用本发明所述的组合物。如本发明使用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉、关节内、滑膜腔内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。特别地，经口、腹膜内或静脉内施用组合物。
本发明所述组合物的无菌可注射形式可为水或油悬浮液。这些悬浮液可跟进本领域已知的技术使用适合的分散或湿润剂和悬浮剂制备。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，正如尤其呈聚氧乙烯化形式的天然药学上可接受的油，例如橄榄油或蓖麻油，脂肪酸例如十八烯酸及其甘油酯衍生物用于制备注射剂。这些油溶液或悬浮液也可能含有长链醇稀释剂或分散剂，例如羧甲基纤维素或在配制药学上可接受的剂型(包括乳剂和悬浮液)中常用的类似分散剂。其它常用表面活性剂，例如Tweens、Spans和在生产药学上可接受的固体、液体或其它剂型中常用的其它乳化剂或生物利用率增强剂也可用于配制的目的。
可以任何口服可接受的剂型，包括但不限于胶囊、片剂、水悬浮液或溶液，口服本发明所述药物组合物。在为供口服片剂的情况下，常用载体包括但不限于乳糖和淀粉。通常还加入润滑剂，例如硬脂酸镁。为了以胶囊形式口服，有用的稀释剂包括乳糖和干玉米淀粉。当口服需要水悬浮液时，活性成分与乳化剂 和悬浮剂结合。若需要，还可加入某些甜味剂、增味剂或着色剂。
或者，可以供直肠使用的栓剂形式施用本发明所述的药物组合物。可通过混合试剂和非刺激性赋形剂制备这些药物组合物。这种物质包括但不限于可可油、蜂蜡和聚乙二醇。
尤其是当治疗目标包括局部滴施易于接近的区域或器官，包括眼部、皮肤或低位肠道疾病时，还可局部施用本发明所述的药物组合物。易于为这些区域或器官的每一个制备适合的局部制剂。
以直肠栓剂制剂(见上文)或适合的灌肠剂制剂可实现对低位肠道的局部滴施。也可使用局部皮肤贴片。
对于局部滴施而言，可将药物组合物配制为含有悬浮或溶于一种或多种载体中的活性组分的适合药膏。适于局部滴施本发明的化合物的载体包括但不限于矿物油、凡士林油、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者，可将药物组合物配制为含有悬浮或溶于一种或多种药学上可接受的载体中的活性组分的适合洗剂或乳膏。适合的载体包括但不限于矿物油、山梨醇酐单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二醇、苯甲醇和水。
为了眼科使用，可用或不用防腐剂例如苯扎氯铵，将药物组合物配制为在等渗pH调节无菌盐水中的微粉化悬浮液，或特别是等渗pH调节无菌盐水中的溶液。或者，为了眼科使用，可将药物组合物配制为药膏，例如凡士林。
也可通过鼻用气化喷雾剂或吸入施用药物组合物。根据制药领域中众所周知的技术制备这种组合物并且采用苯甲醇和其它适合的防腐剂、提高生物利用率的吸收促进剂、碳氟化合物和/或其它常规增溶剂或分散剂制备成盐水中的溶液。
可将用于本发明的方法的化合物配制成单位剂型。术语“单位剂型”指适合作为受治疗者的单位剂量的物理分立单位，每单位含有经计算产生预期疗效的预定量的活性物质，任选地与适合的药物载体结合。单位剂型可作单次日剂量或多次日剂量(例如，每日约1-4次或更多次)的其中一次。当使用多次日剂量时，对于每次剂量的单位剂型可相同或不同。
本发明化合物及组合物的用途
本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于抑制SSAO/VAP-1，或所述药物用于预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。
本发明涉及一种使用本发明所述的化合物或药物组合物来抑制SSAO/VAP-1活性的方法，或预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病的方法；所述方法是给予有需要的个体所述化合物或所述药物组合物的有效治疗量。并且，本发明提供的上述化合物或其药物组合物可以与其它疗法或治疗剂共同施用。施用方式可以为同时、顺序或以一定时间间隔进行。
本发明涉及将本发明所述的化合物或药物组合物用于抑制SSAO/VAP-1活性，或预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。
本发明的化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
本发明的化合物或药学上可接受的药物组合物的“有效量”、“有效治疗量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。本发明的化合物或药学上可接受的药物组合物在相当宽的剂量范围内是有效的。例如，每天服用的剂量约在0.1mg-1000mg/人范围内，分为一次或数次给药。根据本发明的方法、化合物和药物组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度，特殊的因素，给药方式等。本发明的化合物或药物组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。
一般合成和检测方法
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的药物除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
化合物的结构是通过核磁共振( 1H-NMR、 13C-NMR或/和 19F-NMR)来确定的。 1H-NMR、 13C-NMR、 19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。 1H-NMR、 13C-NMR、 19F-NMR的测定是用Bruker Ultrashield-400核磁共振谱仪和Bruker Avance III HD 600核磁共振谱仪，测定溶剂为氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD或MeOH-d 4)或者氘代二甲基亚砜(DMSO-d 6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet,单峰)，d(doublet,双峰)，t(triplet,三重峰)，m(multiplet,多重峰)，br(broadened,宽峰)，dd(doublet of doublets,双二重峰)，dt(doublet of triplets,双三重峰)，td(triplet of doublets,三双重峰)，brs(broadened singlet,宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
制备纯化或制备拆分一般使用Novasep pump 250高效液相色谱仪。
LC-MS的测定用Agilen-6120 Quadrupole LC/MS质谱仪。
柱层析一般使用青岛海洋化工300目～400目硅胶为载体。
本发明的起始原料是已知的，并且可以在市场上购买到得，购买自上海韶远公司(Shanghai Accela Company)、安耐吉公司(Energy Company)、百灵威公司(J&K)、天津阿法埃莎公司(Alfa Company)等公司，或者可以采用或者按照本领域已知的方法来合成。
氮气氛围是指反应瓶连接一个约1L容积的氮气气球或钢釜。
氢气氛围是指反应瓶连接一个约1L容积的氢气气球或者是一个约1L容积的不锈钢高压反应釜。
实施例中若无特殊说明，溶液是指水溶液。
实施例中若无特殊说明，反应温度为室温；实施例中若无特殊说明，室温为20℃～40℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：二氯甲烷和甲醇体系，二氯甲烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。
柱层析的洗脱剂的体系包括：A：石油醚和乙酸乙酯体系，B：二氯甲烷和乙酸乙酯体系，C：二氯甲烷和甲醇体系。溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。
HPLC是指高效液相色谱；
HPLC的测定使用安捷伦1260高压液相色谱仪(Eclipse Plus C18 4.6×150mm 3.5um色谱柱)；
HPLC测试条件：柱温：30℃ PDA：210nm，254nm
流动相：A相：0.1％磷酸钾 B相：乙腈 流速：1.0mL/min
流动相梯度如表A所示：
表A
时间(min) 流动相A的梯度 流动相B的梯度
0 90％ 10％
5-8 70％ 30％
12-18 80％ 20％
18.1-22 90％ 10％
生物测试试验中的分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离源(ESI)的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表B所示：
表B
全扫描 50→1400
碎裂电压 230V
毛细管电压 55V
干燥器温度 350℃
雾化器 0.28MPa
干燥器流速 10L/min
分析使用Agilent XDB-C18，2.1×30mm，3.5μM柱，注入5μL样品。分析条件：流动相为0.1％的甲酸水溶液(A)和0.1％的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表C所示：
表C
时间 流动相B的梯度
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min 终止
此外，用于分析的还有Agilent 6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和G1314C UV检测器；LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱，规格为：100×4.6mm I.D.,5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵，0.1％甲醇水溶液(A)：5mM醋酸铵，0.1％甲醇乙腈溶液(B)(70/30,v/v)；流速为0.6mL/min；柱温保持在室温；注入20μL样品。
下面简写词的使用贯穿本发明：
DMSO-d 6：             氘代二甲基亚砜；        Boc：                  叔丁氧羰基；
CDCl 3：               氘代氯仿；              ％wt,mass％：          重量百分比；
CD 3OD：               氘代甲醇；              mL,ml：                毫升；
μL,μl：             微升；                  mol/L：                摩尔/每升；
mol：                 摩尔；                  mmol：                 毫摩尔；
g：                   克；                    h：                    小时；
H 2：                  氢气；                  min：                  分钟；
N 2：                   氮气；                  MPa：                  兆帕；
atm：                  标准大气压。
一般合成方法
制备本发明公开化合物的典型合成步骤如下面的合成方案1所示。除非另外说明，环A和R 1具有本发明所述的定义，PG为氨基保护基。
合成方案1：
Figure PCTCN2019121469-appb-000016
具有如通式(I-A)所示结构的化合物可以通过合成方案1描述的一般合成方法制备得到，具体步骤可参考实施例。首先，化合物(I-a)先进行羧基重氮化，得到化合物(I-b)；再与溴化氢的有机溶液反应得到化合物(I-d)；或者，化合物(I-d)也可以由化合物(I-c)进行溴代反应得到。然后，化合物(I-d)进行氨基取代成盐，得到化合物(I-f)的盐；或者，化合物(I-d)也可以先进行叠氮化得到化合物(I-e)，再进行叠氮还原成盐得到化合物(I-f)的盐。接着，化合物(I-f)的盐进行氨基保护，得到化合物(I-g)；或者，化合物(I-g)也可以由化合物(I-e)在酸酐(如Boc 2O)存在下进行叠氮还原得到。最后，化合物(I-g)进行Wittig反应得到化合物(I-h)；化合物(I-h)脱去氨基保护，得到通式(I-A)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-A)所示的目标化合物转化为酸加合盐，酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐和甲磺酸盐。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
制备实施例
实施例1 (E)-3-氟-2-(6-氟色满-2-基)丙-2-烯-1-氨基盐酸盐(化合物E1-1)和(Z)-3-氟-2-(6-氟色满-2-基)丙-2-烯-1-氨基盐酸盐(化合物E1-2)
Figure PCTCN2019121469-appb-000017
步骤1)2-重氮-1-(6-氟色满-2-基)乙酮
将6-氟色满-2-羧酸(17.5g,89.2mmol)溶于四氢呋喃(500mL)，0℃下加入三乙胺(27mL,162mmol)，滴加氯甲酸异丁酯(16.5mL,125mmol)，40℃剧烈搅拌反应20小时，反应液冷却至室温，加入乙腈(500mL)，0℃下滴加三甲基硅烷化重氮甲烷的正已烷溶液(89mL,180mmol,2.0mol/L)，自然升至室温反应16小时。将反应液减压浓缩，所得残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/10]纯化，得到标题化合物1b(19.6g,产率99％)，为黄色油状物。
步骤2)2-溴-1-(6-氟色满-2-基)乙酮
将2-重氮-1-(6-氟色满-2-基)乙酮(19.6g,89.0mmol)溶于乙酸乙酯(100mL)，0℃下缓慢滴加溴化氢的乙酸溶液(18mL,33mass％)。向反应液中加入石油醚(100mL)，升至室温，依次用饱和氯化钠溶液(50mL×2)和饱和碳酸氢钠溶液(50mL)洗涤，有机相用无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/30]纯化，得到标题化合物(23.5g,产率97％)，为白色固体。
步骤3)2-叠氮基-1-(6-氟色满-2-基)乙酮
将2-溴-1-(6-氟色满-2-基)乙酮(23.5g,86.0mmol)溶于丙酮(100mL)，加入叠氮化钠(5.6g,86mmol)，室温反应2小时。加水(100mL)淬灭反应，用乙酸乙酯(300mL)萃取，有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物(18.4g,产率91％)，为白色固体。
步骤4)2-氨基-1-(6-氟色满-2-基)乙酮盐酸盐
将2-叠氮基-1-(6-氟色满-2-基)乙酮(18.4g,78.2mmol)溶于甲醇(100mL)和氯化氢的乙酸乙酯溶液(50mL,3.0mol/L)，加入10％钯碳(1.8g)，置换氢气(3MPa)，氢化反应6小时。将反应液过滤，收集滤液浓缩，往残留物中加入氯化氢的乙酸乙酯溶液(30mL,4.0mol/L)，有白色固体析出，过滤，收集滤饼，得到标题化合物(5.6g,产率29％)。
步骤5)N-[2-(6-氟色满-2-基)-2-氧代-乙基]氨基甲酸叔丁酯
将2-氨基-1-(6-氟色满-2-基)乙酮盐酸盐(1.0g,4.1mmol)加入到二碳酸二叔丁酯(5.0mL,22mmol)，40℃反应24小时。向反应液中加入水(10mL)，用乙酸乙酯(30mL)萃取，有机相用饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/10]纯化，得到标题化合物(1.3g,产率100％)，为无色油状物。
步骤6)N-[3-氟-2-(6-氟色满-2-基)烯丙基]氨基甲酸叔丁酯
将氟甲基(三苯基)膦四氟硼酸盐(2.6g,6.8mmol)溶于四氢呋喃(10mL,123mmol)，-20℃下加入双(三甲基硅基)氨基钠的四氢呋喃溶液(4.5mL,9.0mmol,2mol/L)，搅拌12分钟后，缓慢滴加N-[2-(6-氟色满-2-基)-2-氧代-乙基]氨基甲酸叔丁酯(1.4g,4.5mmol)的四氢呋喃溶液(3mL)，缓慢升至室温，反应3.5小时。0℃下加水(5mL)淬灭反应，用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/10]纯化，得到标题化合物(0.60g,产率41％)，为黄色固体。
步骤7)(E)-3-氟-2-(6-氟色满-2-基)丙-2-烯-1-氨基盐酸盐(化合物E1-1)和(Z)-3-氟-2-(6-氟色满-2-基)丙-2- 烯-1-氨基盐酸盐(化合物E1-2)
将N-[3-氟-2-(6-氟色满-2-基)烯丙基]氨基甲酸叔丁酯(0.60g,1.8mmol)溶于乙酸乙酯(0.5mL)，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温反应2小时。将反应液浓缩，得到的固体经制备纯化和氯化氢的乙酸乙酯溶液处理，得到标题化合物E1-1(0.23g,产率47％)和标题化合物E1-2(0.12g,产率25％)，均为黄色固体。
化合物E1-1：MS(ESI,pos.ion)m/z:226.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.17(s,3H),7.24(d,J＝82.0Hz,1H),7.00-6.89(m,2H),6.84(dd,J＝8.8,5.0Hz,1H),4.66(d,J＝10.6Hz,1H),2.96-2.83(m,1H),2.83-2.70(m,1H),2.05(d,J＝7.9Hz,1H),1.95-1.81(m,1H)。
化合物E1-2：MS(ESI,pos.ion)m/z:226.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.07(s,3H),7.12(d,J＝81.2Hz,1H),6.99-6.85(m,3H),4.99(d,J＝10.8Hz,1H),3.00-2.85(m,1H),2.76(dd,J＝16.9,3.7Hz,1H),2.07-1.88(m,2H),1.42-1.09(m,2H)。
实施例2 (E)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酰胺盐酸盐(E2-1)和(Z)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酰胺盐酸盐(E2-2)
Figure PCTCN2019121469-appb-000018
步骤1)2,3-二溴丙酸乙酯
将丙烯酸乙酯(15g,150mmol)溶于四氯化碳(100mL)，0℃下滴加溴素(9.3mL,180mmol)的四氯化碳溶液(15mL)，搅拌5分钟后升至60℃反应2小时。将反应液浓缩，得到标题化合物(38.9g，产率100％)，为黄色液体。
步骤2)2-乙氧羰基-3,4-二氢-2H-1,4-苯并噁嗪-6-甲酸
将2,3-二溴丙酸乙酯(38.9g,150mmol)和3-氨基-4-羟基-苯甲酸(19g,124mmol)溶于N,N-二甲基甲酰胺(200mL)，加入碳酸钾(51.9g,372mmol)，45℃反应18小时。加入水(200mL)淬灭反应，用4N盐酸调节pH＝3，用乙酸乙酯(100mL×3)萃取，合并的有机相用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物(13.0g,产率42％)，为棕色固体。
MS(ESI,pos.ion)m/z:252.1[M+1] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.31-7.14(m,2H),6.82(d,1H),5.04(s,1H),4.13(dd,2H),3.44(d,3H),1.17(t,3H)。
步骤3)6-(叔丁基氨基甲酰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-甲酸乙酯
将2-乙氧羰基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酸(13g,52mmol)溶于二氯甲烷(100mL)，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(22.7g,57mmol)，0℃下滴加叔丁胺(10.9mL,103mmol)和滴加三乙胺(8.7mL,62mmol)，升至室温反应4小时。加入水(50mL)淬灭反应，用二氯甲烷(100mL×2)萃取，合并的有机相用饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物(13.1g,产率82.6％)，为黄色固体。MS(ESI,pos.ion)m/z:307.3[M+1] +。
步骤4)4-苄基-6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并噁嗪-2-甲酸乙酯
将6-(叔丁基氨基甲酰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-甲酸乙酯(13.1g,42.8mmol)溶于N,N-二甲基甲酰胺，依次加入碳酸钾(17.9g,128mmol)、溴化苄(15.6mL,129mmol)和四丁基碘化铵(161mg,0.427mmol)，100℃反应24小时。加入水(200mL)淬灭反应，用乙酸乙酯(100mL×3)萃取，合并的有机相用饱和氯化钠溶液(70mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝6/1]纯化，得到标题化合物(16.8g,产率99％)，为白色固体。
MS(ESI,pos.ion)m/z:397.3[M+1] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.41(s,1H),7.39-7.23(m,6H),7.16(dd,J＝10.4,2.0Hz,2H),6.84(d,J＝8.1Hz,1H),5.12(t,J＝3.2Hz,1H),4.60(d,J＝15.7Hz,1H),4.37(dd,J＝15.5,9.5Hz,1H),4.05(dd,J＝12.8,5.5Hz,1H),3.46(ddd,J＝29.2,12.3,3.3Hz,2H),1.33(s,9H),1.14(t,J＝7.1Hz,3H)。
步骤5)4-苄基-6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并噁嗪-2-甲酸
将4-苄基-6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并噁嗪-2-甲酸乙酯(16.8g,42.4mmol)溶于四氢呋喃(150mL)，加入氢氧化锂(3.11g,127mmol)的水溶液(30mL)，室温反应3小时。向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取，有机相用水(50mL×2)洗涤，收集水相，用1N的盐酸调节pH＝2，有白色固体析出，过滤，收集滤饼干燥，得到标题化合物(7.47g,产率48％)，为白色固体。
MS(ESI,pos.ion)m/z:369.2[M+1] +。
步骤6)4-苄基-N-叔丁基-2-(2-重氮乙酰基)-2,3-二氢-1,4-苯并噁嗪-6-甲酰胺
将4-苄基-6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并噁嗪-2-甲酸(7.47g,20.3mmol)溶于四氢呋喃(70mL)，0℃下滴加氯甲酸异丁酯(3.95mL,30.5mmol)和二异丙基乙胺(9.21mL,52.7mmol)，0℃反应4小时，加入乙腈(20mL)，滴加三甲基硅烷化重氮甲烷(20mL,40mmol)，室温反应16小时。将反应液浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物(4.97g,产率62％)，为白色固体。
MS(ESI,pos.ion)m/z:393.3[M+1] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.42-7.31(m,2H),7.28(d,J＝4.8Hz,4H),7.20(s,1H),7.01(d,J＝8.2Hz,1H),6.90(d,J＝8.2Hz,1H),5.74(d,J＝22.7Hz,2H),4.55-4.43(m,2H),3.59-3.46(m,2H),1.42(s,9H)。
步骤7)4-苄基-2-(2-溴乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并噁嗪-6-甲酰胺
将4-苄基-N-叔丁基-2-(2-重氮乙酰基)-2,3-二氢-1,4-苯并噁嗪-6-甲酰胺(4.97g,12.7mmol)溶于乙酸乙酯(150mL)，-45℃下滴加氢溴酸乙酸溶液(2.52mL,13.9mmol,33％)，继续反应1小时。向反应液中加入甲基叔丁基醚(10mL)，升至室温后加入饱和碳酸氢钠溶液调节pH＝7，分液，有机相用饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝10/1]纯化，得到标题化合物(2.8g,50％)，为黄色固体。
MS(ESI,pos.ion)m/z:446.1[M+1] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.45-7.38(m,1H),7.35(t,J＝7.3Hz,2H),7.27(t,J＝8.1Hz,3H),7.21-7.12(m,2H),6.88(dd,J＝8.4,3.2Hz,1H),5.19(t,J＝3.7Hz,1H),4.64-4.44(m,4H),3.61(dd,J＝12.6,4.4Hz,1H),3.50(dd,J＝12.7,3.2Hz,1H),1.32(s,9H)。
步骤8)2-(2-叠氮乙酰基)-4-苄基-N-叔丁基-2,3-二氢-1,4-苯并噁嗪-6-甲酰胺
将4-苄基-2-(2-溴乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并恶嗪-6-甲酰胺(4.27g,9.59mmol)溶于丙酮(60mL)，加入叠氮化钠(693mg,10.5mmol)，室温反应3小时。加入水(10mL)淬灭反应，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠溶液(40mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物(3.91g,产率100％)，为淡黄色固体。
步骤9)2-(2-氨基乙酰基)-N-叔丁基-3,4-二氢-2H-1,4-苯并噁嗪-6-甲酰胺盐酸盐
将2-(2-叠氮乙酰基)-4-苄基-N-叔丁基-2,3-二氢-1,4-苯并噁嗪-6-甲酰胺(3.7g,9.1mmol)溶于甲醇(20mL)，加入氯化氢的乙酸乙酯溶液(10mL,4.0mol/L)和10％钯碳(0.40g)，置换氢气(3MPa)，氢化反应12小时。将反应液过滤，收集滤液浓缩，往残留物中加入氯化氢的乙酸乙酯溶液(8mL,4.0mol/L)，浓缩，得到标题化合物(3.0g,产率100％)，为白色固体。
步骤10)N-[2-[6-(叔丁基氨基甲酰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-基]-2-氧代-乙基]氨基甲酸叔丁酯
将2-(2-氨基乙酰基)-N-叔丁基-3,4-二氢-1,4-苯并噁嗪-6-甲酰胺盐酸盐(3.5g,11mmol)加入到四氢呋喃(20mL)中，加入二碳酸二叔丁酯(10mL,43mmol)和碳酸钾(3.7g,27mmol)，室温反应12小时。加入水(50mL)淬灭反应，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物(1.55g,产率37％)，为黄色固体。
MS(ESI,pos.ion)m/z:414.2[M+Na] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.43(s,1H),7.07-6.97(m,3H),6.84-6.76(m,1H),5.96(s,1H),4.92(d,J＝3.5Hz,1H),4.07(dd,J＝18.9,5.6Hz,1H),3.86(dd,J＝18.9,5.9Hz,1H),3.43(dd,J＝17.3,7.7Hz,2H),1.37(s,9H),1.34(s,9H)。
步骤11)N-[2-[6-(叔丁基氨基甲酰)-3,4-二氢-2H-1,4-苯并噁嗪-2-基]-3-氟-烯丙基]氨基甲酸叔丁酯
将氟甲基(三苯基)膦四氟硼酸盐(2.7g,7.1mmol)溶于无水四氢呋喃(40mL)，-20℃下滴加双(三甲基硅基)氨基钠(5.4mL,11mmol)，搅拌30分钟后滴加N-[2-[6-(叔丁基氨基甲酰)-3,4-二氢-1,4-苯并噁嗪-2-基]-2-氧代-乙基]氨基甲酸叔丁酯(1.4g,3.6mmol)的四氢呋喃溶液(1mL)，缓慢升至室温，反应12小时。加入冰水(10mL)淬灭反应，用乙酸乙酯(40mL×2)萃取，合并的有机相用饱和氯化钠溶液(30mL×2) 洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝3/1]，得到标题化合物(1.0g,产率69％)，为黄色固体。
MS(ESI,pos.ion)m/z:408.3[M+H] +。
步骤12)(E)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并噁嗪-6-甲酰胺盐酸盐(化合物E2- 1)和(Z)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酰胺盐酸盐(化合物E2-2)
将N-[2-[6-(叔丁基氨基甲酰)-3,4-二氢-2H-1,4-苯并噁嗪-2-基]-3-氟-烯丙基]氨基甲酸叔丁酯3l(1.1g,2.7mmol)溶于乙酸乙酯(5mL)，加入氯化氢的乙酸乙酯溶液(10mL,4.0mol/L)，室温反应30分钟。将反应液浓缩，得到的固体经制备纯化和氯化氢的乙酸乙酯溶液处理，得标题化合物E2-1(0.49g,产率53％,HPLC纯度:93.1％)和标题化合物E2-2(0.12g,产率13％,HPLC纯度:95.1％)，均为棕色固体。
化合物E2-1：MS(ESI,pos.ion)m/z:308.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)(s,3H),7.45(s,1H),7.37-7.10(m,2H),7.05(dd,J＝8.3,2.0Hz,1H),6.76(d,J＝8.3Hz,1H),5.15(d,J＝138.1Hz,1H),4.76(d,J＝7.9Hz,1H),3.60(s,2H),3.48(dd,J＝12.3,2.3Hz,1H),3.22(dd,J＝12.2,8.2Hz,1H),1.34(s,9H)。
化合物E2-2：MS(ESI,pos.ion)m/z:308.3[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.22(s,3H),7.44(s,1H),7.17(dd,J＝41.4,39.5Hz,2H),7.06(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝8.3Hz,1H),4.97(dd,J＝7.2,4.1Hz,2H),3.54(s,2H),3.40-3.25(m,2H),1.35(s,9H)。
实施例3 (E)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酰胺盐酸盐(化合物E3)
Figure PCTCN2019121469-appb-000019
步骤1)2-乙氧羰基-2,3-二氢-1,4-苯并二噁英-6-甲酸
将2,3-二溴丙酸乙酯(10.3g,40mmol)和碳酸钾(22.6g,164mmol)加入到3,4-二羟基-苯甲酸(5.0g,32mmol)的N,N-二甲基甲酰胺(50mL)溶液中，45℃反应24小时。0℃后，用4N盐酸调节pH＝3，用乙酸乙酯(100mL×2)萃取，合并有机相依次用水(100mL)和饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物(8.2g,产率100％)，为黄色油状物。
MS(ESI,pos.ion)m/z:253.2[M+H] +。
步骤2)6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并二噁英-2-甲酸乙酯
将2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(13.6g,36mmol)和叔丁胺(4.1mL,39mmol)分别加入到2-乙氧羰基-2,3-二氢-1,4-苯并二噁英-6-甲酸(8.0g,32mmol)的二氯甲烷(100mL)溶液中，0℃下滴加二异丙基乙二胺(7mL,42mmol)，室温反应11小时。加入水(100mL)淬灭反应，用二氯甲烷(50mL)萃取，有机相用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物(9.7g,产率99.5％)，为白色固体。
MS(ESI,pos.ion)m/z:308.1[M+H] +。
步骤3)6-(叔丁基氨基甲酰)-2,3-二氢-1,4-苯并二噁英-2-甲酸
将氢氧化锂(2.6g,62mmol)加入到6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并二噁英-2-甲酸乙酯(9.7g,32mmol)的四氢呋喃/水混合溶液(v/v＝4/1,50mL)中，室温反应4小时。0℃下用盐酸(4mol/L)调节反应液pH＝2，用乙酸乙酯(100mL×2)萃取，合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经乙酸乙酯(30mL)打浆，得到标题化合物(6.3g,产率71％)，为白色固体。
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.58(d,J＝8.7Hz,1H),7.37(dd,J＝28.7,20.1Hz,2H),6.92(dd,J＝33.2,8.4Hz,1H),5.17-5.03(m,1H),4.48(d,J＝10.2Hz,1H),4.33-4.24(m,1H),1.35(d,J＝3.9Hz,9H)。
步骤4)N-叔丁基-2-(2-重氮乙酰基)-2,3-二氢-1,4-苯并二噁英-6-甲酰胺
0℃，氮气保护条件下，将三乙胺(13mL,92mmol)加入到6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并二噁英-2-甲酸(18g,64mmol)的无水四氢呋喃(2L)溶液中，滴加氯甲酸异丁酯(11mL,83mmol)，反应2小时，加入乙腈(2L)，滴加三甲基硅烷化重氮甲烷(60mL,120mmol,2mol/L)，室温反应20小时。将反应液浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝3/1]纯化，得到标题化合物(12.2g,产率62％)，为白色固体。
MS(ESI,pos.ion)m/z:304.3[M+1] +。
步骤5)2-(2-溴乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并二噁英-6-甲酰胺
在-45℃下，将氢溴酸乙酸溶液(8mL,44mmol,33％)滴加入N-叔丁基-2-(2-重氮乙酰基)-2,3-二氢-1,4-苯并二噁英-6-甲酰胺(12.2g,40mmol)的乙酸乙酯(200mL)溶液中，反应1小时。0℃，滴加饱和碳酸氢钠调节pH＝7，分液，有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝6/1]，得到标题化合物(13.5g,产率94％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:256.0[M+H] +。
步骤6)2-(2-叠氮乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并二噁英-6-甲酰胺
将叠氮化钠(2.5g,38mmol)加入2-(2-溴乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并二噁英-6-甲酰胺(13.5g,38mmol)的丙酮(100mL)溶液中，室温反应4.5小时。加入水(80mL)淬灭反应，用乙酸乙酯(80mL×2)萃取，合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物(6.5g,产率54％)，为浅黄色油状物。
步骤7)N-[2-[6-(叔丁基氨基甲酰基)-2,3-二氢-1,4-苯并二噁英-2-基]-2-氧代-乙基]氨基甲酸叔丁酯
将10％钯碳(0.60g)和二碳酸二叔丁酯(8.2g,38mmol)分别加入到2-(2-叠氮乙酰基)-N-叔丁基-2,3-二氢-1,4-苯并二噁英-6-甲酰胺(6.0g,19mmol)的乙酸乙酯溶液(150mL,4mol/L)中，置换氢气(3MPa)，氢化反应9小时。将反应液过滤，用乙酸乙酯(50mL)洗涤滤饼，收集滤液，浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物(4.2g,产率57％)，为白色固体。
MS(ESI,pos.ion)m/z:393.1[M+H] +。
步骤8)N-[2-[6-(叔丁基氨基甲酰基)-3,4-二氢-1,4苯并二噁英-2-基]-3-氟-烯丙基]氨基甲酸叔丁酯
-20℃，氮气保护下，将双(三甲基硅基)氨基钠(8.4mL,17mmol，2mol/L)滴加入氟甲基(三苯基)膦四氟硼酸盐(4.82g,13mmol)的无水四氢呋喃(40mL)悬浊溶液中，反应20分钟后滴加N-[2-[6-(叔丁基氨基甲酰基)-3,4-二氢-1,4-苯并恶嗪-2-基]-2-氧代-乙基]氨基甲酸叔丁酯(3.3g,8.4mmol)的四氢呋喃溶液(15mL)，室温反应18小时。0℃下加入水(30mL)淬灭反应，用乙酸乙酯(60mL×2)萃取，合并的有机相用饱和氯化钠溶液(80mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物(0.61g,产率18％)，为浅黄色粘稠物。
MS(ESI,pos.ion)m/z:409.3[M+H] +。
步骤9)(E)-2-[1-(氨甲基)-2-氟-乙烯基]-N-叔丁基-3,4-二氢-2H-1,4-苯并恶嗪-6-甲酰胺盐酸盐(化合物E3)
将氯化氢的乙酸乙酯溶液(10mL，4mol/L)加入N-3-氟-2-[[6-(4-氟苯基)-3-吡啶]甲氧基]烯丙基]氨基甲酸叔丁酯(0.60g,1.5mmol)的乙酸乙酯溶液(20mL)，室温反应1小时。将反应液浓缩，所得残留物经制备纯化和氯化氢的乙酸乙酯溶液处理，得到标题化合物E3(0.20g,产率39％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:309.4[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.36(s,3H),7.60(d,J＝2.8Hz,1H),7.47-7.16(m,3H),6.95(dd,J＝13.1,8.4Hz,1H),4.97(s,1H),4.49(dd,J＝11.6,2.1Hz,1H),4.15(ddd,J＝14.0,11.7,8.1Hz,1H),3.63(d,J＝4.2Hz,2H),1.36(s,9H)。
实施例4 2-[(E)-1-(氨甲基)-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯盐酸盐(化合物E4)
Figure PCTCN2019121469-appb-000020
步骤1)3-甲酰基-4-羟基苯甲酸
将4-羟基苯甲酸(15.3g,111mmol)溶于三氟乙酸(40mL)，滴加入六亚甲基四胺(15.8g,112mmol)的三氟乙酸(45mL)溶液，90℃反应4.5小时。反应液冷至室温，加入盐酸(4mol/L,300mL)搅拌3小时，过滤，滤饼用水(60mL×3)洗涤，收集滤饼干燥，得到标题化合物(15.4g,产率84％)，为白色固体。
MS(ESI,poi.ion)m/z:167.2[M+H] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)11.57(s,1H),10.30(s,1H),8.23(d,J＝2.1Hz,1H),8.04(dd,J＝8.7,2.1Hz,1H),7.11(d,J＝8.7Hz,1H)。
步骤2)3-甲酰基-4-羟基苯甲酸甲酯
将3-甲酰基-4-羟基苯甲酸(15.4g,92.9mmol)溶于甲醇(200mL)，加入浓硫酸(10mL)，60℃反应6小时。将反应液浓缩，所得残留物加入水(50mL)，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和碳酸氢钠溶液(30mL)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物(12.5g,产率75％)，为白色固体。
MS(ESI,neg.ion)m/z:179.1[M-H] -；
1H NMR(400MHz,CDCl 3)δ(ppm)11.31(br,1H),9.95(s,1H),8.32(d,J＝1.9Hz,1H),8.19(dd,J＝8.8,1.9Hz,1H),7.03(d,J＝8.8Hz,1H),3.93(s,3H)。
步骤3)2-乙酰基苯并呋喃-5-甲酸甲酯
将3-甲酰基-4-羟基苯甲酸甲酯(12.5g,69.4mmol)溶于乙腈(200mL)，加入氯代丙酮(7.8mL,98mmol)和碳酸钾(9.7g,70mmol)，80℃反应3小时。反应液冷却至室温，抽滤，滤饼用二氯甲烷(60mL×3)淋洗，收集滤液浓缩，所得残留物用乙醇(100mL)重结晶，得到标题化合物(7.0g,产率46％)，为白色固体。
MS(ESI,poi.ion)m/z:260.20[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.11(s,1H),7.85(d,J＝8.7Hz,1H),7.59(d,J＝8.7Hz,1H),7.52(s,1H),2.62(s,3H),1.49(s,9H).
步骤4)2-(2-溴乙酰基)苯并呋喃-5-甲酸甲酯
将2-乙酰基苯并呋喃-5-甲酸甲酯(3.0g,14mmol)溶于乙酸(60mL)，55℃下分批加入过溴化氢溴化吡啶(4.8g,15mmol)，反应4小时。反应液冷却至室温，浓缩，所得残留物加入饱和碳酸氢钠溶液(80mL)，搅拌10分钟，抽滤，收率滤饼干燥，得到标题化合物(3.90g,产率95％)，为黄色固体。
1H NMR(400MHz,CDCl 3)δ(ppm)8.49(s,1H),8.22(d,J＝8.8Hz,1H),7.72(s,1H),7.64(d,J＝8.6Hz,1H),4.45(s,2H),3.96(s,3H)。
步骤5)2-(2-氨基乙酰基)苯并呋喃-5-甲酸甲酯盐酸盐
将2-(2-溴乙酰基)苯并呋喃-5-甲酸甲酯(1.4g,4.8mmol)溶于氯仿(30mL)，加入六亚甲基四胺(0.74g,5.2mmol)，室温反应4小时。将反应液过滤，收集滤饼，得到的淡黄色固体溶于乙醇(10mL)，加入浓盐酸(5mL)，0℃下搅拌30分钟，过滤，滤饼用乙醇(2mL×2)淋洗，收集滤饼干燥，得到标题化合物(0.44g,产率34％)，为白色固体。
MS(ESI,poi.ion)m/z:234.1[M-Cl] +；
1H NMR(600MHz,D 2O)δ(ppm)8.21(s,1H),7.96(d,J＝8.4Hz,1H),7.81(s,1H),7.50(d,J＝8.8Hz,1H),4.59(s,2H),3.85(s,3H)。
步骤6)2-[2-(叔丁氧羰基氨基)乙酰基]苯并呋喃-5-甲酸甲酯
将2-(2-氨基乙酰基)苯并呋喃-5-甲酸甲酯盐酸盐(0.22g,0.82mmol)溶于甲醇(5mL)和水(5mL)，依次加入二碳酸二叔丁酯(0.30mL,1.3mmol)和碳酸氢钠(0.17g,2.0mmol)室温反应24小时。向反应 液中加入水(20mL)，用乙酸乙酯(30mL)萃取，有机相依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝3/1]纯化，得到标题化合物(0.12g,产率44％)，为无色液体。
MS(ESI,poi.ion)m/z:356.3[M+Na] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.35(s,1H),8.10(d,J＝8.7Hz,1H),7.58(s,1H),7.51(d,J＝8.7Hz,1H),5.51(s,1H),4.58(d,J＝4.1Hz,2H),3.88(s,3H),1.41(s,9H)。
步骤7)2-[(E)-1-[(叔丁氧羰基氨基)甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯和2-[(Z)-1-[(叔丁氧羰基氨基) 甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯
将氟甲基(三苯基)膦四氟硼酸盐(0.88g,2.3mmol)加入到四氢呋喃(10mL)中，置换氮气保护，-78℃下滴加双(三甲基硅基)氨基钠(1.6mL,3.2mmol,2mol/L)，反应10分钟后滴加2-[2-(叔丁氧羰基氨基)乙酰基]苯并呋喃-5-甲酸甲酯(0.50g,1.5mmol)的四氢呋喃(5mL)溶液，随后自然恢复室温反应18小时。加入冰水混合液(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并的有机相依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝8/1]纯化，得到标题化合物2-[(E)-1-[(叔丁氧羰基氨基)甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯(0.13g,产率25％)和标题化合物2-[(Z)-1-[(叔丁氧羰基氨基)甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯(50mg,产率9.7％)，均为白色固体。
步骤8)2-[(E)-1-(氨甲基)-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯盐酸盐(化合物E4)
将2-[(E)-1-[(叔丁氧羰基氨基)甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯(0.13g,0.37mmol)用氯化氢乙酸乙酯溶液(5mL,4.0mol/L)溶解，室温反应1小时。将反应液浓缩，得到标题化合物E4(0.11g,产率100％)，为白色固体。
MS(ESI,poi.ion)m/z:250.1[M-Cl] +；
1H NMR(400MHz,MeOD)δ(ppm)8.34(d,J＝1.5Hz,1H),8.05(dd,J＝8.7,1.7Hz,1H),7.84(d,J＝80.1Hz,1H),7.60(d,J＝8.7Hz,1H),7.19(s,1H),4.14(d,J＝2.1Hz,2H),3.95(s,3H)。
实施例5 2-[(Z)-1-(氨甲基)-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯盐酸盐(化合物E5)
Figure PCTCN2019121469-appb-000021
将2-[(Z)-1-[(叔丁氧羰基氨基)甲基]-2-氟-乙烯基]苯并呋喃-5-甲酸甲酯(50mg,0.14mmol)用氯化氢乙酸乙酯溶液(5mL,4.0mol/L)溶解，室温反应1小时。将反应液浓缩，得到标题化合物E5(40mg,产率98％)，为淡黄色固体。
MS(ESI,poi.ion)m/z:250.1[M-Cl] +；
1H NMR(400MHz,MeOD)δ(ppm)8.39(d,J＝1.5Hz,1H),8.07(dd,J＝8.7,1.7Hz,1H),7.66(d,J＝8.7Hz,1H),7.38(d,J＝80Hz,1H),7.31(s,1H),4.06(d,J＝2.5Hz,2H),3.95(s,3H)。
活性试验实施例
一、大鼠脂肪组织匀浆SSAO/VAP-1抑制活性测定
测试目的：下面的方法是用来测定本发明化合物对大鼠脂肪匀浆SSAO/VAP-1的抑制活性。
试验材料：
N-哌嗪-N-乙磺酸钠盐(HEPES SODIUM SALT)购于AMRESCO，Cat.No.0485-500G；
EDTA(Ethylenediaminetetraacetic acid，乙二胺四乙酸)购于Sigma，Cat.No.EDS-100G；
蔗糖(Sucrose)购于Sigma，Cat.No.V900116；
PMSF(Phenylmethanesulfonyl fluoride，苯甲基磺酰氟)购于Beyotime，Cat.No.ST506；
β-甘油磷酸二钠盐水合物(β-Glycerophosphate disodium salt hydrate)购于Sigma，Cat.No.G5422-25G；
优降宁盐酸盐(Pargyline hydrochloride)购于Sigma，Cat.No.P8013-500MG；
DMSO(Dimethyl Sulfoxide，二甲基亚砜)购于Sigma，Cat.No.D2650-100ML；
苄胺盐酸盐(Benzylamine hydrochloride)购于Sigma，Cat.No.B5136-25G；
96孔板购于COSTAR，Cat.No.3631；
Figure PCTCN2019121469-appb-000022
Red Hydrogen PeroxidePeroxidase Assay Kit购于Invitrogen，Cat.No.A22188。
试验方法：
手术切除来自Sprague Dawley大鼠的腹部脂肪，其为富含SSAO/VAP-1的组织。对于每克大鼠腹部脂肪组织，加入5ml HES缓冲液(20mM N-哌嗪-N-乙磺酸钠盐,1mM EDTA,250mM蔗糖，1×PMSF and100mMβ-甘油磷酸二钠盐水合物,pH 7.4)进行匀浆。使用Bertin Technologies的Bertin Precellys 24多功能样品均质器将脂肪组织均质化3min，在4℃，20000g的条件下将脂肪组织匀浆液离心10min，取中间透明上清液。将上清液与溶于HES缓冲液的0.5mM优降宁盐酸盐在37℃下孵育30min。在30min孵育后，将25μl脂肪组织上清液加入至标准96孔板中。将试验化合物溶于DMSO中并稀释6个浓度。将25μl不同浓度的试验化合物加入至含有脂肪组织上清液的各个孔中，在37℃下孵育30min。孵育后，将50μl含80μM苄胺盐酸盐的反应混合物(含100μM
Figure PCTCN2019121469-appb-000023
Red and 0.2U/ml HRP,
Figure PCTCN2019121469-appb-000024
Red Hydrogen PeroxidePeroxidase Assay Kit)加入至相应孔中，在37℃下孵育30min。30min后，使用BMG LABTECH的PHERAstar FSX酶标仪在激发540nm和发射580nm下读取荧光值(RFU)。使用Graph Pad Prism 5软件绘制曲线并计算出IC 50值。本发明化合物对脂肪组织匀浆SSAO/VAP-1的抑制活性的IC 50小于15nM。其结果表1所示：
表1：本发明实施例提供的化合物对脂肪组织匀浆SSAO/VAP-1的抑制活性
Figure PCTCN2019121469-appb-000025
试验结果显示：本发明化合物对脂肪组织匀浆SSAO/VAP-1具有明显的抑制作用。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (13)

  1. 一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
    Figure PCTCN2019121469-appb-100001
    其中，
    R 2为F、Cl、Br或I；
    R 3为H、氘、C 1-6烷基或C 3-6环烷基；
    环A为5-8个原子组成的含氧杂环或5-8个原子组成的含氧杂芳环，其中所述环A未被取代或被1、2或3个R y所取代；
    R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6烷硫基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、R i和R j各自独立地为H、氘、C 1-6烷基或C 3-6环烷基；
    各R z独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1- 6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基；
    各R y独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基；
    q为0、1、2或3。
  2. 根据权利要求1所述的化合物，其中，所述环A为5-6个原子组成的含氧杂环或5-6个原子组成的含氧杂芳环，其中所述环A未被取代或被1、2或3个R y所取代。
  3. 根据权利要求1或2所述的化合物，其中，所述环A为
    Figure PCTCN2019121469-appb-100002
    Figure PCTCN2019121469-appb-100003
    Figure PCTCN2019121469-appb-100004
    其中所述环A未被取代或被1、2或3个R y所取代。
  4. 根据权利要求1-3任意一项所述的化合物，其中所述R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、C 1- 4烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4烷硫基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、R i和R j各自独立地为H、氘、C 1-4烷基或C 3-6环烷基。
  5. 根据权利要求1-4任意一项所述的化合物，其中所述R 1为H、氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-SH、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O)R e、-S(＝O) 2R f、-S(＝O)NR gR h、-S(＝O) 2NR iR j、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、甲氧基、乙氧基、甲氨基、甲硫基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3、三氟甲氧基、乙烯基、烯丙基、丙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述R a、R b、R c、R d、R e、R f、R g、R h、 R i和R j各自独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或环己基。
  6. 根据权利要1-5任意一项所述的化合物，其中所述R 3为H、氘、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基或环己基；
    各R z独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3或三氟甲氧基；
    各R y独立地为氘、F、Cl、Br、I、CN、NO 2、OH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CH 2F、-CHF 2、-CH 2CF 3或三氟甲氧基。
  7. 根据权利要求1-6任意一项所述的化合物，其具有以下其中之一的结构：
    Figure PCTCN2019121469-appb-100005
    Figure PCTCN2019121469-appb-100006
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
  8. 根据权利要求1-7任意一项所述的化合物，其具有以下其中之一的结构：
    Figure PCTCN2019121469-appb-100007
    Figure PCTCN2019121469-appb-100008
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
  9. 根据权利要求1-8任意一项所述的化合物，其中所述药学上可接受的盐为盐酸盐、氢溴酸盐、磷酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、苹果酸盐或甲磺酸盐。
  10. 一种药物组合物，其包含权利要求1-9任意一项所述的化合物，任选地，进一步包含药学上可接受 的辅剂。
  11. 权利要求1-9任意一项所述的化合物或权利要求10所述的药物组合物在制备药物中的用途，其中，所述药物用于抑制SSAO/VAP-1；或所述药物用于预防、治疗或减轻炎症疾病和/或炎症相关疾病或糖尿病和/或糖尿病相关疾病。
  12. 根据权利要求11所述的用途，其中所述炎症疾病和/或炎症相关疾病为肝自身免疫性疾病、自身免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎、自身免疫性胆管炎、酒精性肝病或非酒精性脂肪性肝病；
    所述糖尿病和/或糖尿病相关疾病为Ⅰ型糖尿病、Ⅱ型糖尿病、X综合征、糖尿病视网膜病、糖尿病肾病、糖尿病神经病或糖尿病黄斑水肿。
  13. 根据权利要求12所述的用途，其中所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、非酒精性脂肪性肝病相关隐源型肝硬化或原发性肝癌。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863763A (zh) * 2003-08-08 2006-11-15 拉卓拉药物公司 用于治疗疾病的氨基脲敏感性胺氧化酶(ssao)和vap－1介导的粘着的抑制剂
CN1921841A (zh) * 2004-02-25 2007-02-28 拉卓拉药物公司 用于治疗疾病的胺和酰胺类化合物
US20090203764A1 (en) * 2006-03-31 2009-08-13 Eric Yanjun Wang Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases
CN104520268A (zh) * 2012-05-02 2015-04-15 法马克西斯制药公司 Ssao的取代的3-卤代烯丙基胺抑制剂及其用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863763A (zh) * 2003-08-08 2006-11-15 拉卓拉药物公司 用于治疗疾病的氨基脲敏感性胺氧化酶(ssao)和vap－1介导的粘着的抑制剂
CN1921841A (zh) * 2004-02-25 2007-02-28 拉卓拉药物公司 用于治疗疾病的胺和酰胺类化合物
US20090203764A1 (en) * 2006-03-31 2009-08-13 Eric Yanjun Wang Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases
CN104520268A (zh) * 2012-05-02 2015-04-15 法马克西斯制药公司 Ssao的取代的3-卤代烯丙基胺抑制剂及其用途

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