WO2020063696A1 - 胺基脲敏感性胺氧化酶抑制剂制备及其应用 - Google Patents

胺基脲敏感性胺氧化酶抑制剂制备及其应用 Download PDF

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WO2020063696A1
WO2020063696A1 PCT/CN2019/107972 CN2019107972W WO2020063696A1 WO 2020063696 A1 WO2020063696 A1 WO 2020063696A1 CN 2019107972 W CN2019107972 W CN 2019107972W WO 2020063696 A1 WO2020063696 A1 WO 2020063696A1
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unsubstituted
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ring
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PCT/CN2019/107972
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WO2020063696A8 (zh
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刘胜洋
邓建稳
冯志勇
江磊
乔智
尚珂
谢小平
徐雪丽
徐圆
赵海霞
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上海轶诺药业有限公司
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Priority to EA202190752A priority Critical patent/EA202190752A1/ru
Priority to AU2019347947A priority patent/AU2019347947B2/en
Priority to US17/279,394 priority patent/US20220081426A1/en
Priority to CA3114243A priority patent/CA3114243A1/en
Priority to JP2021516921A priority patent/JP2022501393A/ja
Priority to KR1020217012064A priority patent/KR102649362B1/ko
Priority to CN201980062160.XA priority patent/CN112839940B/zh
Priority to EP19865565.6A priority patent/EP3858827A4/en
Publication of WO2020063696A1 publication Critical patent/WO2020063696A1/zh
Publication of WO2020063696A8 publication Critical patent/WO2020063696A8/zh
Priority to JP2023098412A priority patent/JP2023130361A/ja

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Definitions

  • the invention relates to the technical field of medicine, and more particularly, to an aminourea-sensitive amine oxidase inhibitor.
  • SSAO Semicarbazide-sensitive amine oxidase
  • SSAO Semicarbazide-sensitive amine oxidase
  • AOC3 vascular adhesion protein
  • Mammalian smooth muscle cells, adipocytes, and endothelial cells are rich in SSAO.
  • SSAO Vascular system, cartilage, kidney and other organs are also expressed.
  • SSAO is divided into two types: membrane-bound and soluble. Enzyme activity varies greatly between different species and different tissues of the same species.
  • SSAO can catalyze the metabolism of endogenous or food amines into aldehydes, with the production of hydrogen peroxide and ammonia.
  • the natural metabolic substrates in the body are mainly aliphatic amines and aromatic amines, of which methylamine (MA) and aminoacetone (Aminoacetone) are generally recognized as physiological substrates of SSAO, which are catalyzed to formaldehyde and pyruvaldehyde, respectively.
  • MA methylamine
  • Amoacetone aminoacetone
  • SSAO exists as vascular adhesion protein-1, which mediates the adhesion and exudation of leukocytes and endothelial cells.
  • SSAO and its metabolites are related to atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, retinopathy, chronic obstructive pulmonary disease (COPD), autoimmune diseases, multiple sclerosis, and similar Rheumatoid arthritis, pain caused by arthritis, and inflammation-related diseases such as Alzheimer's disease are closely related.
  • SSAO / VAP-1 is reported to play an important role in cancer biology.
  • SSAO / VAP-1 small molecule inhibitors reduce the number of proangiogenic factor bone marrow cells in melanoma and lymphoma.
  • SSAO dysfunction plays a role in the occurrence and development of liver diseases such as fatty liver disease. Fatty liver disease with inflammatory reactions will progress to non-alcoholic fatty liver, and a certain percentage of patients will progress to liver fibrosis, cirrhosis and even liver cancer after a period of time.
  • the purpose of the present invention is to provide a new type of SSAO inhibitor, its preparation method and use.
  • A is selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, or A is a chemical bond (or none);
  • B is selected from the group consisting of: substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic ring (including monocyclic and conjunct rings), substituted or unsubstituted 5-12 membered heteroaromatic ring (Including monocyclic and paracyclic), substituted or unsubstituted 3-12 membered heterocyclic rings (including monocyclic, paracyclic, bridged and spiro); wherein the heteroaromatic ring or heterocyclic ring also contains 1- 3 heteroatoms selected from nitrogen, oxygen and sulfur;
  • L 3 is selected from the group consisting of: substituted or unsubstituted carbocyclic rings of C3-12 (including monocyclic, paracyclic, bridged and spiro rings), substituted or unsubstituted 5-12 membered heterocyclic rings (including monocyclic, and Ring, bridged ring and spiro ring), or substituted or unsubstituted 5-6 membered heteroaryl ring;
  • the heterocyclic ring contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur;
  • R 1 and R 2 are each independently selected from the group consisting of H, F, Cl;
  • R 3 and R 4 are each independently selected from the group consisting of H, F, -OH, -CN, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted Substituted -O-C1-C8 alkyl, substituted or unsubstituted -O-C3-C8 cycloalkyl, substituted or unsubstituted -C6-C10 aryl, substituted or unsubstituted -O-C1-C4 alkane -C6-C10 aryl, substituted or unsubstituted -S-C1-C8 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring, or a 3-8 membered heterocyclic ring Ring; and when L 1 is -O-, -NH-
  • R 5 and R 6 are each independently hydrogen; or R 5 and R 6 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic ring; or each independently selected from the group -NR a R b , wherein R a and R b are each independently H, -C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, -C1-C4 alkyl-C6-C10 aryl, or R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen heterocyclic ring;
  • R 7 is selected from the group consisting of: a substituted or unsubstituted group selected from the group consisting of a C5-C6 cycloalkyl group, a 5- to 6-membered heterocyclic ring containing 1 nitrogen atom, and a 4- to 6-membered hetero ring containing 1 oxygen atom Heterocyclic, fluorinated C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkoxy, C1-C6 alkylcarbonyl, C2-C6 amide, C1-C6 alkylNH-, (C1- C6 alkyl) (C1-C6 alkyl) N-; said substitution means that the above group is replaced by a group selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkylcarbonyl, 5-12 members Heteroaromatic ring (monocyclic, fused ring, or fused ring), C6-C12 aromatic ring (mono
  • R 7 is selected from the group consisting of: H, a substituted or unsubstituted C1-C6 alkoxy group
  • L 3 is selected from the group consisting of: a substituted or unsubstituted 5-12 membered bridged ring, or a 5-12 membered oxygenated spiro Ring heterocyclic
  • R 8 and R 8 ′ are each independently selected from the group consisting of H, F, Cl, Br, —NO 2 , —OH, —CN, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C3 -C8 cycloalkyl, substituted or unsubstituted -O-C1-C8 alkyl, substituted or unsubstituted -O-C3-C8 cycloalkyl, substituted or unsubstituted -C6-C10 aryl, substituted or unsubstituted Substituted -O-C1-C4 alkyl-C6-C10 aryl, substituted or unsubstituted -S-C1-C8 alkyl, -NRaRb, -NHRc, and -SO 2- (C1-C8 alkyl), -CONRaRb; wherein Ra and Rb are each independently H, -
  • R 9 and R 10 are each independently selected from the group consisting of H, C1-C8 alkyl, -O-C1-C8 alkyl, -O-C3-C8 cycloalkyl, -C6-C10 aryl, -O- C1-C4 alkyl-C6-C10 aryl, -S-C1-C8 alkyl, -CF 3 , -S-CF 3 , -OCF 3 , -OCH 2 CF 3 , F, -OH, -CN; or R 9 and R 10 together with the carbon atom to which they are attached form a group selected from the group consisting of C3-C8 cycloalkyl, 5-12 membered heterocyclic group;
  • R 11 and R 12 are each independently selected from the group consisting of H, F, -OH, -CN, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted Substituted -O-C1-C8 alkyl, substituted or unsubstituted -O-C3-C8 cycloalkyl, substituted or unsubstituted -C6-C10 aryl, substituted or unsubstituted -O-C1-C4 alkane -C6-C10 aryl, substituted or unsubstituted -S-C1-C8 alkyl; or R 11 and R 12 together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring, or a 3-8 membered heterocyclic ring ring;
  • the 5-12 membered oxygen-containing spiro heterocyclic ring is a spiro ring selected from the group consisting of: oxygen-containing spiro [3,3] ring, oxygen-containing spiro [3,4] ring, containing Oxyspiro [3,5] ring, Oxyspiro [3,6] ring, Oxyspiro [4,5] ring.
  • L3 is a structure selected from the group consisting of a piperazine ring, And the L3 is substituted or unsubstituted.
  • the compound of formula I has a structure represented by the following formula:
  • n 0, 1, 2, 3, or 4.
  • R 7 is selected from the group consisting of substituted or unsubstituted groups selected from the group consisting of C5-C6 cycloalkyl, 5-6 membered heterocyclic ring containing 1 nitrogen atom, and 1 containing 4-6 membered heterocyclic ring, 5-12 membered heteroaromatic ring (monocyclic, fused ring, or fused ring) of oxygen atom; or R 7 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkoxy
  • L 3 is selected from the group consisting of a substituted or unsubstituted 5-12 membered bridged ring, or a 5-12 membered oxygen-containing spiro heterocyclic ring.
  • the R 7 is selected from the following group: Wherein, said p and q are each independently selected from the group: 0, 1, 2, 3 or 4, and the sum of p and q is ⁇ 1.
  • the compound is selected from the following group:
  • the compound is selected from the following group:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described in the first aspect of the present invention, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, And pharmaceutically acceptable excipients.
  • the pharmaceutical composition is used to prevent and / or treat diseases related to SSAO or modulated by SSAO / VAP-1 protein or activity; preferably, the disease is selected from the group consisting of inflammation Disease and / or inflammation related diseases, diabetes and / or diabetes related diseases, mental disorders, ischemic diseases, vascular diseases, ocular diseases, fibrosis, neuroinflammatory diseases, cancer, pain, fibrosis or tissue transplant rejection.
  • the inflammatory disease and / or inflammation-related disease is in another preferred example, the inflammation is selected from the group consisting of arthritis (including juvenile rheumatoid arthritis) and arthritis Caused pain, Crohn's disease, ulcerative colitis, inflammatory bowel disease (e.g., irritable bowel syndrome), psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease , Contact dermatitis, hepatitis, liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestion Heart failure, ischemic disease, stroke and its complications, myocardial infarction and its complications, inflammatory cell destruction after stroke, synovitis, systemic inflammatory sepsis, etc.
  • arthritis including juvenile rheumatoid arthritis
  • arthritis causesd
  • the pain is selected from the group consisting of muscle pain, bone and joint pain, neuropathic pain, tumor-induced pain, low back pain, and inflammatory pain.
  • the ocular disease is uveitis or macular degeneration.
  • the fibrosis is selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver disease (NASH), and Alcohol-induced fibrosis causes cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and complications caused by fibrosis.
  • cystic fibrosis idiopathic pulmonary fibrosis
  • liver fibrosis including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver disease (NASH), and Alcohol-induced fibrosis causes cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and complications caused by fibrosis.
  • NASH non-alcoholic fatty liver disease
  • the neuroinflammatory disease is selected from the group consisting of stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis, and the like.
  • the cancer is selected from the group consisting of: lung cancer: breast cancer: colorectal cancer: anal cancer: glandular cancer: prostate cancer: ovarian cancer: liver and bile duct cancer: esophageal cancer: non-Hodgkin Lymphoma: Bladder cancer: Uterine cancer: Glioma, Glioblastoma, Myeloblastoma, and other brain tumors: Kidney cancer: Head and neck cancer: Gastric cancer: Multiple myeloma: Testicular cancer: Germ cell tumor: Neuroendocrine Tumors: cervical cancer: benign tumors of the gastrointestinal tract, breast and other organs: signet ring cell carcinoma: mesenchymal cell tumors including sarcoma, fibrosarcoma, hemangioma, hemangiomatosis, hemangiopericytoma, pseudohemangioma Hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastom
  • the diabetes and / or diabetes-related disease is type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.
  • the mental disorder is major depression, bipolar depression, or ADHD.
  • the ischemic disease is a stroke and / or its complications, a myocardial infarction and / or its complications or the destruction of tissues by inflammatory cells after a stroke.
  • the vascular disease is atherosclerosis, chronic heart failure or congestive heart failure.
  • the arthritis is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.
  • systemic inflammatory syndrome is systemic inflammatory sepsis.
  • the inflammatory bowel disease is allergic bowel disease.
  • the liver disease is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic disease Fatty liver disease.
  • the respiratory disease is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis or bronchiectasis.
  • the eye disease is inflammation caused by uveitis, ulcerative colitis, retinitis, autoimmune eye inflammation, angiogenesis and / or lymphogenesis or macular degeneration.
  • the skin disease is contact dermatitis, skin inflammation, psoriasis, or eczema.
  • the neuroinflammatory disease is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
  • the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related causative cirrhosis, or primary liver cancer .
  • a compound according to the first aspect of the present invention or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, or a medicament according to the second aspect of the present invention.
  • the diseases related to SSAO or regulated by SSAO / VAP-1 protein or activity are selected from the group consisting of inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, Ischemic disease, vascular disease, ocular disease, fibrosis, neuroinflammatory disease, cancer, fibrosis or tissue transplant rejection.
  • the disease is a diabetes-induced disease selected from diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease, and choroidal neovascularization.
  • the disease is a neuroinflammatory disease.
  • the disease is selected from the group consisting of liver fibrosis, cirrhosis, renal fibrosis, idiopathic pulmonary fibrosis, and radiation-induced fibrosis.
  • the disease is cancer.
  • FIG. 1 shows the results of a study on the efficacy of the SSAO compound in a ocular inflammation-related disease model in Biological Test Example 6 of the present invention
  • Figure 2 shows the effect of the compounds of the present invention on the expression of inflammatory signaling pathway genes in the retina in a rat model of inflammatory disease induced by LPS.
  • the terms "containing” or “including (comprising)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain radical consisting of only carbon and hydrogen atoms and connected to the rest of the molecule by a single bond; having, for example, 1 to 12 ( Preferably 1 to 8, more preferably 1 to 6) carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary Butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl Wait.
  • C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
  • alkoxy refers to an alkyloxy group.
  • the alkyl group is as defined above.
  • cycloalkyl refers to a cyclic alkyl group consisting only of carbon and hydrogen atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group may optionally have a fused ring, a spiro ring, or a bridged ring structure.
  • C3-C5 cycloalkyl means a cyclic alkyl group having 3-5 carbon atoms;
  • C5-C6 cycloalkyl means a cyclic alkyl group having 5-6 carbon atoms.
  • the term "5-12 membered heterocyclic group” or “5-12 membered heterocyclic group” means a group consisting of a carbon atom and 1 to 3 selected from nitrogen, oxygen It is a stable 5-membered to 12-membered non-aromatic cyclic group composed of a hetero atom of sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic ring system, which may include a fused ring system, a bridged ring system, or a spiro ring system;
  • a nitrogen, carbon or sulfur atom may be optionally oxidized;
  • a nitrogen atom may be optionally quaternized;
  • a heterocyclic group may be partially or fully saturated.
  • Heterocyclyl can be attached to the rest of the molecule via a carbon atom or a heteroatom and via a single bond.
  • one or more rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • heterocyclyls include, but are not limited to, tetrahydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3.5] nonane-7- Base, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] heptane-2-yl, azetidinyl , Pyranyl, tetrahydropyranyl, thianyl, tetrahydrofuranyl, oxazinyl, dioxolyl, tetrahydroisoquinolinyl, decahydroisoquino
  • the term "5- to 6-membered heterocyclic ring containing 1 nitrogen atom” refers to a 5- or 6-membered heterocyclic ring containing only one nitrogen atom in the ring.
  • 4- to 6-membered heterocyclic ring containing 1 oxygen atom refers to a 4-, 5-, or 6-membered heterocyclic ring containing only one oxygen atom in the ring.
  • 5- to 6-membered aromatic ring refers to a 5- or 6-membered aromatic ring.
  • 5- to 6-membered heteroaromatic ring refers to a 5- or 6-membered aromatic ring having 1-3 heteroatoms selected from nitrogen, sulfur, and oxygen.
  • halo refers to fluoro, chloro, bromo or iodo.
  • the compound of the present invention is a compound represented by Formula I or a stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus can give enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared as racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .
  • organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesul
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base capable of maintaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
  • reaction scheme exemplarily illustrates a method for preparing a compound represented by Formula I or a stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein each group is as described above. It should be understood that in the following reaction schemes, combinations of substituents and / or variables in the general formula are only permissible if such combinations result in stable compounds. It should also be understood that other general formulae can be prepared by those skilled in the art of organic chemistry by the methods disclosed herein (by applying appropriately substituted starting materials and using methods well known to those skilled in the art to modify synthesis parameters as needed) or known methods.
  • the intermediate compound functional group may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl and the like.
  • Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C (O) -R "(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M.Wuts, Protective Groups in Synthesis, (1999), 4th Ed., Wiley.
  • the protective group may also be a polymer resin.
  • the compound of the present invention has excellent SSAO inhibitory activity and can be used in a pharmaceutical composition using the compound of the present invention as an active ingredient for the prevention and / or treatment of diseases related to SSAO or regulated by SSAO / VAP-1 protein, such as arteries Atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, chronic obstructive pulmonary disease (COPD), autoimmune disease, multiple sclerosis, rheumatoid arthritis, pain caused by arthritis, Alzheimer's Symptomatic disease, eye disease, liver disease (such as fatty liver, hepatitis, liver fibrosis, cirrhosis, liver cancer).
  • diseases related to SSAO or regulated by SSAO / VAP-1 protein such as arteries Atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, chronic obstructive pulmonary disease (COPD), autoimmune disease, multiple sclerosis, rheumatoid arthritis, pain caused by arthritis, Alzheimer's Symptomatic disease, eye disease,
  • the term "pharmaceutical composition” refers to a formulation of a compound of the invention and a medium commonly accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without Adverse biological reactions or interact with any components contained in the composition in an adverse manner.
  • the term "pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, approved by the relevant government authority as acceptable for human or livestock use, Sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonicity agents, solvents or emulsifiers.
  • prevention include reducing the likelihood that a patient will develop or worsen a disease or condition.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for use in therapy is an amount of a composition comprising a compound disclosed herein that is required to provide a significant clinically alleviating effect on a condition.
  • An effective amount suitable for any individual case can be determined using techniques such as a dose escalation test.
  • the terms "taking,” “administering,” “administering,” and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. The ones discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drugs obtained by mixing or combining more than one active ingredient Treatment, which includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
  • the relative inhibitory potency of a compound can be determined by the amount required to inhibit the amine oxidase activity of SSAO / VAP-1 in a variety of ways, such as using recombinant human proteins in in vitro assays or using recombinant non-human enzymes, expressing normal rodents In cell tests of enzymes, in cell tests that have been transfected with human proteins, in vivo tests in rodents and other mammalian species, etc.
  • the invention also discloses a method for inhibiting SSAO / VAP-1 in a patient suffering from an inflammatory disease and a method for treating an inflammatory disease using a compound described by Formulae I and II.
  • Human inflammatory diseases include pain caused by arthritis and arthritis, Crohn's disease, irritable bowel syndrome, pruritus, asthma, chronic obstructive pulmonary disease, bronchiectasis, joint sclerosis, inflammation caused by diabetes, and post-stroke inflammation Sexual cell destruction.
  • the invention relates to a method of inhibiting an amine oxidase in an individual in need thereof, said method comprising administering to said individual an effective amount of a compound of formula I or formula II to produce a positive therapeutic response.
  • the invention in another aspect, relates to a method of treating a disease associated with amine oxidase, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or formula II.
  • the invention in another aspect, relates to a method of treating a disease modulated by SSAO / VAP-1, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or Formula II.
  • inflammation includes a variety of indications, including arthritis (including juvenile rheumatoid arthritis), Crohn's disease, ulcerative colitis, inflammatory bowel disease (e.g., irritable bowel syndrome ), Psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease, contact dermatitis, hepatitis, liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, Sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and its complications, myocardial infarction and its complications, post-stroke inflammatory Cell destruction, synovitis, systemic inflammatory sepsis, etc.
  • arthritis including juvenile rheumatoid arthritis
  • Crohn's disease Crohn's disease, ulcerative colitis
  • inflammatory bowel disease e.g
  • the above method is also applicable in which the diseases are type I diabetes and its complications, type II diabetes and its complications, and the like.
  • the above method is also applicable in which the disease is macular degeneration and / or other eye diseases.
  • fibrosis includes such diseases as cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH), and alcohol-induced Fibrosis causes cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and other diseases in which excessive fibrosis contributes to disease pathology.
  • non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH)
  • alcohol-induced Fibrosis causes cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and other diseases in which excessive fibrosis contributes to disease pathology.
  • neuroinflammatory diseases includes a variety of indications, including stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis, and the like.
  • the above method is also applicable to pain-related diseases selected from, but not limited to, the following groups: muscle pain, bone and joint pain, neuropathic pain, tumor-induced pain, low back pain, inflammatory pain, and the like.
  • the cancer is selected from lung cancer: breast cancer: colorectal cancer: anal cancer: membrane adenocarcinoma: prostate cancer: ovarian cancer: liver and bile duct cancer: esophageal cancer: non-Hodgkin's lymphoma: bladder cancer : Uterine Cancer: Glioma, Glioblastoma, Myeloblastoma, and Other Brain Tumors: Kidney Cancer: Head and Neck Cancer: Gastric Cancer: Multiple Myeloma: Testicular Cancer: Germ Cell Tumor: Neuroendocrine Tumor: Cervical Cancer : Benign tumors of the gastrointestinal tract, breast and other organs: signet ring cell carcinoma: mesenchymal cell tumors including sarcoma, fibrosarcoma, hemangioma, hemangiomatosis, hemangiopericytoma, pseudohemangioma interstitial hyperplasia, my
  • Example A tert-butyl (E)-(2- (bromomethyl) -3-fluoroallyl) carbamate
  • Triethylamine (545.1 g, 5344.0 mmol) was slowly added dropwise at -78 degrees Celsius (moisture required to be controlled). After the dropping was completed, the reaction solution was warmed to room temperature and stirred for 1 hour. The reaction was monitored by TLC. When no raw materials remain in the reaction liquid, water (1000 ml) is added to the reaction liquid, and the organic layer is separated. The aqueous layer is extracted with dichloromethane (200 ml * 2).
  • the reaction solution was warmed to 0 ° C and stirred at 0 ° C for 2 hours.
  • the reaction was monitored by LCMS.
  • water 1000 ml was added to the reaction liquid, followed by extraction with ethyl acetate (500 ml x 3).
  • the organic phases were combined, washed with saturated brine (200 ml x 2), and then The anhydrous sodium sulfate was dried and spin-dried to obtain a crude product.
  • 1 kg of silica gel was added to the crude product, eluted with petroleum ether, and spin-dried to obtain a concentrate.
  • Example A5 tert-butyl (E)-(3-fluoro-2- (hydroxymethyl) allyl) carbamate
  • Example A tert-butyl (E)-(2- (bromomethyl) -3-fluoroallyl) carbamate
  • Example A5 A solution of Example A5 (104.0 g, 507.3 mmol) and triphenylphosphine (199.4 g, 761.0 mmol) in anhydrous 1,2-dichloromethane (580 ml) was slowly added at zero degrees Celsius. CBr 4 (251.9 g, 761.0 mmol) in dry 1,2-dichloromethane (100 ml). After the dropping was completed, the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction was monitored by LCMS. When no raw material remained in the reaction solution, the reaction solution was spin-dried to obtain a crude product.
  • Example 1-1 t - butyl 4- (5- (benzyloxy) pyrimidin-2-yl) -2,6-dimethyl-piperazine-1-carboxylate
  • Example 1-5 tert-butyl (E)-(2-(((2- (3,5-dimethyl-4- (oxetan-3-yl) piperazin-1-yl) pyrimidine -5-yl) oxy Substituted) methyl) -3-fluoroallyl) carbamate
  • Example 1-4 To Example 1-4 (22 mg, 0.08 mmol), tert-butyl (E)-(2- (bromomethyl) -3-fluoroallyl) carbamate (26 mg, 0.1 mmol) To a solution of N, N-dimethylformamide (2 ml) was added potassium carbonate (17 mg, 0.12 mmol), and the mixture was heated to 50 ° C and stirred for 1 hour. The reaction solution was directly separated and purified using a reversed-phase C-18 column (acetonitrile / formic acid aqueous solution) to obtain the title compound 1-5 (15 mg, 40%) as a colorless oil.
  • MS (ESI): m / z 452.2 [M + H] + /
  • Example 4-1 tert-Butyl (E)-(2-(((2-chloropyrimidin-5-yl) oxo) methyl) -3-fluoroallyl) carbamate
  • Example 4-2 tert-Butyl (E)-(3-fluoro-2-((((2- (4- (oxetan-3-yl) piperazin-1-yl) pyrimidin-5-yl Oxo) (Methyl) allyl) carbamate
  • Example 4-1 To a solution of Example 4-1 (9600 mg, 30.2 mmol) in N-methylpyrrolidone (80 ml) was added 1- (oxetane-3-yl) piperazine (10750 mg, 75.7 mmol) and N , N-diisopropylethylamine (7813 mg, 60.5 mmol), heated at 120 ° C. overnight under sealed conditions. After the reaction was completed, water (500 ml) was added, and ethyl acetate (100 ml) was used for extraction three times. The organic phases were combined, washed three times with water (80 ml), once with saturated brine (80 ml), dried over anhydrous sodium sulfate, and concentrated.
  • 1- (oxetane-3-yl) piperazine 10750 mg, 75.7 mmol
  • N , N-diisopropylethylamine 7813 mg, 60.5 mmol
  • This test method is used to evaluate the in vitro inhibitory activity of the compounds of the present invention on SSAO / VAP-1 of different species.
  • a recombinant human SSAO protein or a mouse SSAO protein or a rat SSAO protein (provided by Eli Lilly) is used.
  • the enzyme activity detection kit MAO-Glo Assays kit (V1402) was purchased from Promega.
  • An enzyme reaction buffer (50 mM HEPES, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1.4 mM MgCl 2 , 0.001% Tween-20, pH 7.4) was prepared.
  • the test compound is dissolved in DMSO, and a 3-fold concentration dilution is performed.
  • the final concentration of the test compound in a 10 ⁇ l reaction system is 1 ⁇ M to 0.05 nM.
  • the content of DMSO in the detection reaction was 1%.
  • the test compound DMSO solution was diluted in the enzyme reaction buffer at a volume ratio of 1:25, 2.5 ⁇ l was added to each well in the detection plate, and two replicates were used at each concentration. 5 ⁇ l of SSAO protein diluted in enzyme reaction buffer was added to each well, and the final concentration was 10 nM to 80 nM in 10 ⁇ l reaction system. Incubate at room temperature for 10 minutes.
  • Inhibition rate (Signal positive -Signal test ) / (Signal positive -Signal negative ) ⁇ 100%
  • Signal positive is a positive control without test compounds
  • Signal negative is a negative control without test compounds and SSAO
  • Signal test is the detection value of each concentration of different compounds. 4-parameter curve fitting calculates IC50 data. For compounds with inhibition rates less than 50% within the compound test range, the IC50 value is reported as higher than the highest test concentration.
  • the compounds of the examples of the present invention can effectively inhibit the SSAO / VAP-1 enzyme activity of different species, and the results are shown in Table 1.
  • Recombinant human MAO-A, MAO-B proteins were purchased from Sigma (M7316, M7441). Other reagents are the same as in Biological Test Example 1.
  • the final concentration of the test compound in a 10 ⁇ l reaction system is 100 ⁇ M to 5 nM.
  • the final concentrations of MAO-A and MAO-B proteins in the 10 ⁇ l reaction system were 70 nM and 300 nM, respectively.
  • Other reaction conditions are the same as in Biological Test Example 1.
  • the data analysis and IC50 calculation method are the same as those in Biological Test Example 1. For compounds with inhibition rates less than 50% within the compound test range, the IC50 value is reported as higher than the highest test concentration. The results are shown in Table 1.
  • Recombinant human AOC1 / DAO protein was purchased from R & D systems (Cat: 8298-AO). Amplex UltraRed was purchased from Thermo scientific (Cat: A36006). HRP (Cat: P8250), Putrescine (Cat: V900377) were purchased from Sigma.
  • An enzyme reaction buffer 50 mM HEPES, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1.4 mM MgCl 2 , 0.001% Tween-20, pH 7.4) was prepared. The test compound is dissolved in DMSO, and a 3-fold concentration dilution is performed.
  • the final concentration of the test compound in a 10 ⁇ l reaction system is 100 ⁇ M to 5 nM.
  • the content of DMSO in the detection reaction was 1%.
  • 10 ⁇ l was added to each well in the detection plate.
  • a 4 ⁇ substrate mixture (containing 400 ⁇ M Putrescine, 4 U / ml HRP, 4 ⁇ M Amplex UltraRed) was prepared with an enzyme reaction buffer, and 10 ⁇ l was added to each well.
  • 20 ⁇ l of AOC1 protein diluted in enzyme reaction buffer was added to each well, and the final concentration was 0.4 nM in 40 ⁇ l reaction system. Synergy Neo 2 plate detection.
  • the instrument is set to a temperature of 30 ° C, an excitation wavelength of 530nm, and a transmission wavelength of 590nm. The detection is performed every minute for 30 minutes. Enzyme activity was calculated as the value increasing from 10 minutes to 30 minutes per well. The value is converted into a suppression rate by the following formula
  • Inhibition rate (Signal positive -Signal test ) / (Signal positive -Signal negative ) ⁇ 100%
  • Signal positive is a positive control without test compounds
  • Signal negative is a negative control without test compounds and AOC1
  • Signal test is the detection value of each concentration of different compounds. 4-parameter curve fitting calculates IC50 data. For compounds with inhibition rates less than 50% within the compound test range, the IC50 value is reported as higher than the highest test concentration.
  • Recombinant human AOC2 protein (supplied by Eli Lilly and Company). Other reagents are the same as in Biological Test Example 1.
  • the test compound When AOC2 is detected, the test compound has a final concentration of 100 ⁇ M to 5 nM in a 10 ⁇ l reaction system.
  • the final concentration of AOC2 protein in 10 ⁇ l reaction system was 10 nM.
  • Other reaction conditions are the same as in Biological Test Example 1.
  • the data analysis and IC50 calculation method are the same as those in Biological Test Example 1. For compounds with inhibition rates less than 50% within the compound test range, the IC50 value is reported as higher than the highest test concentration.
  • the activity of SSAO in animal tissues was measured using the MAO-Glo kit (Promega, V1402). After the test compound is administered to the animal, the SSAO enzyme activity is calculated by measuring the activity of the monoamine oxidase in the insensitive portions of the animal tissue homogenate to the MAO inhibitors Clogyline and Pargyline.
  • the compounds of the present invention were orally administered to rats at different concentrations for different purposes, and the same volume of vehicle was orally administered to control animals. Animal plasma, brain, retina, small intestine, lung, liver, and kidney tissues were collected 24 hours after administration (small intestine, lung, liver, and pre-renal animals were collected by PBS systemic perfusion) and stored in -80 ° C refrigerator until analysis When removed.
  • tissue sections were homogenized in a tissue homogenate lysate (20mM HEPES, pH7.4, 150mM NaCl, 1mM EDTA, 1mM EGTA, 1% Triton X-100, and Roche Complete Protease Inhibitor Tablet).
  • the homogenized tissue fluid was centrifuged at 12,000 rpm for 30 minutes at 4 ° C to remove tissue debris. 5ul of the supernatant was mixed with 2ul of Clogyline (10 ⁇ M) and Pargyline (10 ⁇ M) at room temperature for 10 minutes, and then added to the MAO-Glo detection kit to detect substrate 2ul, and reacted at room temperature for 60 minutes. Add detection reagents according to the kit instructions and stop the reaction.
  • Biotek Neo2 analyzer reads fluorescein data. Monoamine oxidase activity that is insensitive to MAO inhibitors in tissues represents SSAO activity. SSAO activity of the control animals was calculated as the percentage of activity of the control animals to calculate the compound inhibition rate.
  • test results show that the compound of the present invention can effectively inhibit SSAO activity in different tissues of animals after administration.
  • the results are shown in Tables 2 and 3.
  • mice Twenty-two rats (7-8 weeks, 220-250g) were divided into 3 groups, a control group (6 animals), a model group (8 animals), and a drug administration group (8 animals).
  • a control group (6 animals)
  • a model group (8 animals)
  • a drug administration group 8 animals.
  • ocular inflammation was induced by a single footpad injection of 8ug / 100ul lipopolysaccharide (Sigma-Aldrich-L2880).
  • the rats were divided into groups according to the weight of rats, and compound Example 4 (6 mg / kg, 10 ml / kg) or vehicle (10 ml / kg) was orally administered.
  • Anterior aqueous humor was collected 24 hours after induction, the eyeball was removed to isolate the retina, and ocular inflammation was quantitatively evaluated by measuring the concentration of protein in the aqueous humor and the number of cells, and QPCR was used to verify the expression of genes related to retinal inflammation in the eye.
  • Example 4 can significantly reduce the symptoms of ocular inflammation-related diseases. As shown in FIG. 1, in an LPS-induced rat inflammatory disease model, Example 4 can significantly reduce symptoms related to eye inflammation.
  • Figure 1A Changes in protein concentration (ug / ml) in aqueous humor;
  • Figure 1B Changes in cell number (* 10 ⁇ 4 / ml) in aqueous humor.
  • RNA extraction kit (RNeasy Mini Kit, Qiagen-74104), and then reverse transcribe the RNA into cDNA (High Capacity cDNA Reverse Transcription Kits, ABI-4374966).
  • the 10-fold dilution of the obtained cDNA was used as a QPCR reaction template.
  • Power SYBR Green Kit (ABI-A25918), QPCR reactions were performed on a CFX384 Real-Time QPCR instrument, and CFX Maestro software was used to ⁇ Ct method for gene expression of each gene. Quantitative analysis of expression changes.
  • UBC was used as a reference gene.
  • ALOX5AP, SOCS3 and TLR7 genes increased significantly.
  • the expression levels of ALOX5AP, SOCS3, and TLR7 genes were significantly reduced, as shown in Figure 2.
  • the expressions of ALOX5AP, SOCS3 and TLR7 genes are all regulated by the NFkB signaling pathway, and the NFkB signaling pathway is a very important molecular signaling pathway in inflammatory diseases.
  • Example 4 in an LPS-induced rat inflammatory disease model can significantly reduce the expression levels of inflammation-related genes in the retina

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Abstract

提供了一种胺基脲敏感性胺氧化酶抑制剂制备及其应用。具体地，公开了一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐。还公开了上述化合物可抑制胺基脲敏感性胺氧化酶。

Description

胺基脲敏感性胺氧化酶抑制剂制备及其应用 技术领域
本发明涉及医药技术领域，更具体而言，涉及一种胺基脲敏感性胺氧化酶抑制剂。
背景技术
胺基脲敏感性胺氧化酶(semicarbazide-sensitive amine oxidase,SSAO)是一类含多巴胺醌基的胺氧化酶，属于氨基脲敏感性胺氧化酶家族的一员，也被称为血管粘附蛋白-1，VAP-1(vascular adhesion protein 1)。在动物体内主要由AOC3基因编码。哺乳动物的平滑肌细胞、脂肪细胞、内皮细胞SSAO含量较丰富，血管系统、软骨、肾脏等多种脏器也有表达。在哺乳动物中，SSAO分为两种类型即膜结合型和可溶型。不同物种、同一物种的不同组织间酶的活性差异很大。SSAO能将内源性或食物中的胺类催化代谢为醛类，并伴随产生过氧化氢和氨。在体内的天然代谢底物主要是脂肪族胺和芳香胺，其中甲胺(Methylamine,MA)和氨基丙酮(Aminoacetone)被公认为SSAO的生理底物，分别被催化为甲醛和丙酮醛。在内皮细胞，SSAO以血管粘附蛋白-1的形式存在，介导白细胞与内皮细胞的黏附、渗出过程。
大量研究证实，SSAO及其代谢产物与动脉粥样硬化、糖尿病及其并发症、肥胖、中风，慢性肾病，视网膜病变，慢性阻塞性肺病(COPD)，自身免疫性疾病，多发性硬化症，类风湿性关节炎，关节炎引起的疼痛，阿尔茨海默病等炎症相关性疾病密切相关。据报道SSAO/VAP-1在癌症生物学中发挥重要作用，SSAO/VAP-1小分子抑制剂减少黑色素瘤和淋巴瘤中促血管新生因子骨髓细胞的数量。近年来也有研究提示，SSAO功能异常在肝病如脂肪性肝病等疾病发生发展过程中发挥作用。脂肪性肝病合并炎症反应并进展后会发展为非酒精性脂肪肝，并有一定比例病人在一段时间后进一步进展为肝纤维化、肝硬化甚至肝癌。
鉴于SSAO功能在各类与炎症相关疾病的病理过程中有重要作用，寻找对其高效的抑制剂对于控制SSAO异常所致的疾病具有非常重要的价值和意义。
发明内容
本发明的目的在于提供一类新的SSAO抑制剂及其制备方法和用途。
本发明第一方面，提供了一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐：
Figure PCTCN2019107972-appb-000001
其中，
A选自下组：取代或未取代的C6-C10芳环、取代或未取代的5-12元杂芳环，或A为化学键(或无)；
B选自下组：取代或未取代的C3-10的环烷基、取代或未取代的C6-C10芳环(包括单环和并环)、取代或未取代的5-12元杂芳环(包括单环和并环)、取代或未取代的3-12元杂环(包括单环、并环、桥环和螺环)；其中，所述的杂芳环或杂环还含有1-3个选自氮、氧和硫的杂原子；
L 1选自下组：-O-、-NH-、-(C＝O)-、-NH(C＝O)-、-(C＝O)NH-、-NHS(＝O) 2-、-S(＝O) 2NH-，或者(CR 9R 10) n；上述各基团中，当从左至右书写时，表示基团左侧连接A环，右侧连接-CR 3R 4-；
L 2为化学键(或无)，或选自下组的基团：-O-、-NH-、-S-、-(C＝O)-、-SO 2-、-NH-(C＝O)-NH-、-NH-S(＝O) 2-NH-、-(S＝O)-、-NH-(S＝O)-NH-、-NH-(C＝O)-、-(C＝O)-NH-、-(CH＝CH) n-、-(C≡C) n-、-NH-S(＝O) 2-、-S(＝O) 2-NH-、C3-C8环烷基、5-8元杂环基，或者(CR 9R 10) n；
L 3选自下组：取代或未取代的C3-12的碳环(包括单环、并环、桥环和螺环)、取代或未取代的5-12元杂环(包括单环、并环、桥环和螺环)，或取代或未取代的5-6元杂芳环；所述杂环含有1-3个选自氮、氧和硫的杂原子；
R 1、R 2各自独立地选自下组：H、F、Cl；
R 3、R 4各自独立地选自下组：H、F、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；或R 3、R 4与其相连的碳原子共同构成3-8元的碳环，或3-8元的杂环；且当L 1为-O-、-NH-、-(C＝O)NH-或-S(＝O) 2NH-时，R 3和R 4均不为选自下组的基团：-OH、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；
R 5、R 6各自独立地为氢；或R 5、R 6与其相连的氮原子共同形成为取代或未取代的5-6元含氮杂环；或各自独立地选自下组-NR aR b，其中，R a和R b各自独立地为H、-C1-C8烷基、取代或未取代的C3-C8环烷基、-C1-C4烷基-C6-C10芳基，或R a和R b与其相连的氮原子共同形成5-6元氮杂环；
R 7选自下组：取代或未取代的选自下组的基团：C5-C6环烷基、含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、氟代C1-C6烷氧基、C1-C6烷氧基-C1-C6烷氧基、C1-C6烷基羰基、C2-C6酰胺基、C1-C6烷基NH-、(C1-C6烷基)(C1-C6烷基)N-；所述取代表示上述基团被选自下组的基团所取代：C1-C6烷氧基、C1-C6烷基羰基，5-12元的杂芳环(单环、并环，或稠环)，C6-C12的芳香环(单环，并环，稠环)；
或R 7选自下组：H、取代或未取代的C1-C6烷氧基，且L 3选自下组：取代或未取代的5-12元桥环，或5-12元含氧螺环杂环；
R 8和R 8'各自独立地选自下组：H、F、Cl、Br、-NO 2、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基、-NRaRb、-NHRc，和-SO 2-(C1-C8烷基)、-CONRaRb；其中，Ra和Rb各自独立地为H、-C1-C8烷基,-C1-C4烷基-C6-C10芳基，或Ra和Rb与其相连的氮原子共同形成5-6元氮杂环；R c选自下组：-C(＝O)-(C1-C8烷基)、-C(＝O)-(C6-C10芳基)；
R 9、R 10各自独立地选自下组：H、C1-C8烷基、-O-C1-C8烷基、-O-C3-C8环烷基、-C6-C10芳基、-O-C1-C4烷基-C6-C10芳基、-S-C1-C8烷基、-CF 3、-S-CF 3、-OCF 3、 -OCH 2CF 3、F、-OH、-CN；或R 9和R 10与其相连的碳原子共同构成选自下组的基团：C3-C8环烷基、5-12元杂环基；
X选自下组：-(C＝O)-、-(C＝O)-NH-、-CR 11R 12；
R 11、R 12各自独立地选自下组：H、F、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；或R 11、R 12与其相连的碳原子共同构成3-8元的碳环，或3-8元的杂环；
条件是上述各基团共同形成化学上稳定的结构；
除非特别说明，上述的“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：氧代(＝O)、羟基、取代或未取代的C5-C6环烷基、取代或未取代的含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、C1-C6烷基、C1-C6烷氧基、氟代C1-C6烷氧基、C1-C6烷氧基-C1-C6烷氧基、C1-C6烷基羰基、C2-C6酰胺基、C1-C6烷基NH-、(C1-C6烷基)(C1-C6烷基)N-；所述取代表示上述基团被选自下组的基团所取代：C1-C6烷氧基、C1-C6烷基羰基。
在另一优选例中，所述的5-12元含氧螺环杂环为选自下组的螺环：含氧螺[3,3]环、含氧螺[3,4]环、含氧螺[3,5]环、含氧螺[3,6]环、含氧螺[4,5]环。
在另一优选例中，L3为选自下组的结构：哌嗪环、
Figure PCTCN2019107972-appb-000002
Figure PCTCN2019107972-appb-000003
且所述的L3为取代或未取代的。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
Figure PCTCN2019107972-appb-000004
其中，m为0、1、2、3或4。
在另一优选例中，所述的R 7选自取代或未取代的选自下组的基团：C5-C6环烷基、含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、5-12元的杂芳环(单环、并环，或稠环)；或R 7选自下组：H、取代或未取代的C1-C6烷氧基，且L 3选自下组：取代或未取代的5-12元桥环，或5-12元含氧螺环杂环。
在另一优选例中，所述的R 7选自下组：
Figure PCTCN2019107972-appb-000005
其中，所 述的p和q各自独立地选自下组：0、1、2、3或4，且所述的p与q之和≥1。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2019107972-appb-000006
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2019107972-appb-000007
Figure PCTCN2019107972-appb-000008
本发明的第二方面，提供了一种药物组合物，其包含治疗有效量的本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
在另一优选例中，所述的药物组合物用于预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白或活性调节的疾病；优选地，所述的疾病选自下组：炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、眼部疾病、纤维化、神经炎性疾病，癌症、疼痛、纤维化或组织移植排斥。
在另一优选例中，所述的炎症疾病和/或炎症相关疾病为在另一优选例中，所述的炎症选自下组：关节炎(包括幼年型类风湿性关节炎)及关节炎引起的疼痛、克罗恩病、溃疡性结肠炎、炎性肠病(例如，肠易激综合征)、牛皮癖、哮喘、肺炎、慢性阻塞性肺病 (COPD)、支气管扩张、皮肤炎症、眼病、接触性皮炎、肝炎、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、酒精肝病、动脉粥样硬化、慢性心力衰竭、充血性心力衰竭、缺血性疾病、中风及其并发症、心肌梗死及其并发症、中风后炎性细胞破坏、滑膜炎、全身炎性败血症等。
在另一优选例中，所述的疼痛选自下组：肌肉疼痛、骨关节疼痛、神经病理性疼痛、肿瘤引起的疼痛、腰背痛、炎性疼痛等。
在另一优选例中，所述的眼部疾病为葡萄膜炎或黄斑变性。
在另一优选例中，所述的纤维化选自下组：囊性纤维化、特发性肺纤维化、肝纤维化、包括非酒精性脂肪肝疾病诸如非酒精性脂肪肝(NASH)和酒精诱导的纤维化导致肝硬化、肾纤维化、硬皮病、放射性诱导的纤维化、及纤维化导致的并发症。
在另一优选例中，所述的神经炎性疾病选自下组：中风、帕金森氏病、阿尔茨海默氏病、血管性痴呆、多发性硬化症、慢性多发性硬化症等。
在另一优选例中，所述的癌症选自下组：肺癌：乳腺癌：结直肠癌：肛门癌：膜腺癌：前列腺癌：卵巢癌：肝和胆管癌：食管癌：非霍奇金淋巴瘤：膀胱癌：子宫癌：胶质瘤、胶质母细胞瘤、髓母细胞瘤和其他脑肿瘤：肾癌：头颈癌：胃癌：多发性骨髓瘤：睾丸癌：生殖细胞瘤：神经内分泌瘤：子宫颈癌：胃肠道、乳腺和其他器官的良性肿瘤：印戒细胞癌：间叶细胞肿瘤包括肉瘤、纤维肉瘤、血管瘤、血管瘤病、血管外皮细胞瘤、假血管瘤性间质增生、肌纤维母细胞瘤、纤维瘤病、炎性肌纤维母细胞瘤、脂肪瘤、血管脂肪瘤、颗粒细胞瘤、纤维神经瘤、神经鞘瘤、血管肉瘤、脂肪肉瘤、横纹肌肉瘤、骨肉瘤、平滑肌瘤或平滑肌肉瘤。
在另一优选例中，所述的糖尿病和/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。
在另一优选例中，所述精神病症为严重抑郁症、两极型抑郁症或注意力不足多动症。
在另一优选例中，所述缺血性疾病为中风和/或其并发症、心肌梗死和/或其并发症或中风后炎症细胞对组织的破坏。
在另一优选例中，所述血管疾病为动脉粥样硬化、慢性心力衰竭或充血性心力衰竭。
在另一优选例中，所述关节炎为骨关节炎、风湿性关节炎、类风湿性关节炎或青少年类风湿性关节炎。
在另一优选例中，所述全身炎性综合征为全身炎性脓毒症。
在另一优选例中，所述炎症性肠病为过敏性肠病。
在另一优选例中，所述肝病为肝自身免疫性疾病、自身免疫性肝炎、原发性胆计性肝硬变、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。
在另一优选例中，所述呼吸道疾病为哮喘、急性肺损伤、急性呼吸窘迫综合征、肺部炎症、慢性阻塞性肺疾病、支气管炎或支气管扩张。
在另一优选例中，所述眼睛疾病为眼色素层炎、虹膜炎、视网膜炎、自身免疫性眼炎症、血管生成和/或淋巴生成引起的炎症或黄斑变性。
在另一优选例中，所述皮肤疾病为接触性皮炎、皮肤炎症、牛皮癖或湿疹。
在另一优选例中，所述神经炎性疾病为帕金森病、阿尔茨海默病、血管性痴呆、多发性硬化或慢性多发性硬化。
在另一优选例中，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因源型肝硬化，或原发性肝癌。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐或本发明第二方面所述的药物组合物的用途，其用于制备预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白或活性调节的疾病的药物。
在另一优选例中，所述与SSAO有关或由SSAO/VAP-1蛋白或活性调节的疾病选自下组：炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、眼部疾病、纤维化、神经炎性疾病，癌症、纤维化或组织移植排斥。
在本发明的方法和用途的一个实施方案中，疾病为选自糖尿病肾病、肾小球硬化症、糖尿病视网膜病变、非酒精性脂肪肝疾病和脉络膜新生血管的糖尿病诱导的疾病。
在本发明的方法和用途的另一个实施方案中，疾病为神经炎性疾病。在本发明的方法和用途的其他实施方案中，所述疾病选自肝纤维化、肝硬化、肾纤维化、特发性肺纤维化和放射性诱导的纤维化。在本发明的方法和用途的其他实施方案中，疾病为癌症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明生物测试例6中SSAO化合物在眼部炎症相关疾病模型中的药效研究结果；
图2显示了本发明化合物在LPS诱导的大鼠炎症疾病模型中对于视网膜中炎症信号通路基因表达的效果。
具体实施方式
本发明人通过广泛而深入的研究，首次发现了一类结构新颖且高效的SSAO小分子抑制剂。在此基础上完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成且通过单键与分子的其余部分连接；具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“C1-C6烷基”指含有1至6个碳原子的烷基。
如本文所用，术语“烷氧基”是指烷基氧基。所述烷基如上定义。
如本文所用，术语“环烷基”是指环状烷基，仅由碳原子和氢原子组成。例如包括但 不限于环丙基、环丁基、环戊基、环己基等，所述的环烷基可以任选地具有稠环、螺环或桥环结构。“C3-C5环烷基”是指具有3-5个碳原子的环状烷基；“C5-C6环烷基”是指具有5-6个碳原子的环状烷基。
在本申请中，作为基团或是其它基团的一部分，术语“5-12元杂环基”或“5-12元杂环”意指由碳原子以及1至3个选自氮、氧和硫的杂原子组成的稳定的5元-12元的非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。杂环基的实例包括但不限于：四氢吡咯基、吗啉基、哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
如本文所用，术语“含1个氮原子的5-6元杂环”是指环中仅仅含有一个氮原子的5元或6元杂环。
如本文所用，术语“含1个氧原子的4-6元杂环”是指环中仅仅含有一个氧原子的4元、5元或6元杂环。
如本文所用，术语“5-6元芳环”是指5元或6元的芳香性环。
如本文所用，术语“5-6元杂芳环”是指具有1-3个选自氮、硫和氧的杂原子的5元或6元的芳香性环。
如本文所用，术语“卤代”是指氟代、氯代、溴代或碘代。
本发明化合物
本发明的化合物为式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐。
本发明的化合物可能含有一个或多个手性碳原子，因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成 盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
制备方法
下列反应方案示例性的说明了制备式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐的方法，其中各基团均如在上所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
应用
本发明的化合物具有优异的SSAO抑制活性，可用于以本发明的化合物为活性成分的药物组合物，用于预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白调节的疾病， 例如动脉粥样硬化、糖尿病及其并发症、肥胖、中风、慢性肾病、慢性阻塞性肺病(COPD)、自身免疫性疾病、多发性硬化症、类风湿性关节炎、关节炎引起的疼痛、阿尔茨海默病、眼病、肝病(如脂肪肝、肝炎、肝纤维化、肝硬化、肝癌)。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
可通过以多种方式抑制SSAO/VAP-1的胺氧化酶活性所需的量测定化合物的相对抑制效能，例如，在体外检验中使用重组人蛋白或使用重组非人酶、在表达正常啮齿动物 酶的细胞检验中、在已经使用人蛋白转染的细胞检验中、在啮齿动物和其他哺乳动种类的体内试验中等。
本发明还公开了使用由式I和II描述的化合物抑制患有炎性疾病的患者中的SSAO/VAP-1的方法和治疗炎性疾病的方法。人炎性疾病包括关节炎及关节炎引起的疼痛、克罗恩病、肠易激综合征、牛皮痒、哮喘、慢性阻塞性肺病、支气管扩张、关节硬化、由糖尿病产生的炎症和中风后炎性细胞破坏。
因此，在一个方面中，本发明涉及抑制有此需要的个体中的胺氧化酶的方法，所述方法包括给予所述个体有效量的式I或式II的化合物以产生正性治疗反应。
在另一方面中，本发明涉及治疗与胺氧化酶相关的疾病的方法，所述方法包括给予有此需要的个体治疗有效量的式I或式II的化合物。
在另一方面中，本发明涉及治疗由SSAO/VAP-1调节的疾病的方法，所述方法包括给予有此需要的个体治疗有效量的式I或式II的化合物。
上述方法适用其中疾病为炎症。如本文使用的，“炎症”包括多种适应症，包括关节炎(包括幼年型类风湿性关节炎)、克罗恩病、溃疡性结肠炎、炎性肠病(例如，肠易激综合征)、牛皮癖、哮喘、肺炎、慢性阻塞性肺病(COPD)、支气管扩张、皮肤炎症、眼病、接触性皮炎、肝炎、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、酒精肝病、动脉粥样硬化、慢性心力衰竭、充血性心力衰竭、缺血性疾病、中风及其并发症、心肌梗死及其并发症、中风后炎性细胞破坏、滑膜炎、全身炎性败血症等。
上述方法也适用其中所述疾病为类型I糖尿病及其并发症、类型II糖尿病及其并发症等。
上述方法也适用其中所述疾病为黄斑变性和/或其他眼病。
上述方法也适用其中所述疾病为纤维化。如此处使用的，“纤维化”包括这类疾病如囊性纤维化、特发性肺纤维化、肝纤维化、包括非酒精性脂肪肝疾病诸如非酒精性脂肪肝(NASH)和醇诱导的纤维化导致肝硬化、肾纤维化、硬皮病、放射性诱导的纤维化和其中过多的纤维化促成疾病病理学的其他疾病。
上述方法也适用于神经炎性疾病的治疗。如本文使用的，“神经炎疾病”包括多种适应症，包括中风、帕金森氏病、阿尔茨海默氏病、血管性痴呆、多发性硬化症、慢性多发性硬化症等。
上述方法也适用于疼痛相关疾病选自但不限于下组：肌肉疼痛、骨关节疼痛、神经病理性疼痛、肿瘤引起的疼痛、腰背痛、炎性疼痛等。
上述方法也适用于癌症的治疗。在一个实施方案中，所述癌症选自肺癌：乳腺癌：结直肠癌：肛门癌：膜腺癌：前列腺癌：卵巢癌：肝和胆管癌：食管癌：非霍奇金淋巴瘤：膀胱癌：子宫癌：胶质瘤、胶质母细胞瘤、髓母细胞瘤和其他脑肿瘤：肾癌：头颈癌：胃癌：多发性骨髓瘤：睾丸癌：生殖细胞瘤：神经内分泌瘤：子宫颈癌：胃肠道、乳腺和其他器官的良性肿瘤：印戒细胞癌：间叶细胞肿瘤包括肉瘤、纤维肉瘤、血管瘤、血管瘤病、血管外皮细胞瘤、假血管瘤性间质增生、肌纤维母细胞瘤、纤维瘤病、炎性肌纤维母细胞瘤、脂肪瘤、血管脂肪瘤、颗粒细胞瘤、纤维神经瘤、神经哺瘤、血管肉瘤、脂肪肉瘤、横纹肌肉瘤、骨肉瘤、平滑肌瘤或平滑肌肉瘤。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
中间体的合成方法如下：
实施例A：叔-丁基(E)-(2-(溴甲基)-3-氟烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000009
实施例A1：
Figure PCTCN2019107972-appb-000010
在0-10℃下向搅拌的3-氨基丙烷-1，2-二醇(400克,4395.6毫摩尔)和三乙胺(665.9克,6593.4毫摩尔)的甲醇溶液(4升)中加入二碳酸二叔丁酯(1040.1克,4835.2毫摩尔)。反应液在25℃下搅拌2h。将反应液减压浓缩至无甲醇剩余。将浓缩物溶解于二氯甲烷(5升)中，加入咪唑(448.6克，6593.4毫摩尔)。在0-10℃下，缓慢滴入TBDMSCl(791.2克,5274.7毫摩尔)的二氯甲烷(1升)溶液。滴完后室温搅拌2h。加入1％柠檬酸溶液(2升)。分出有机相。用饱和食盐水洗两次，无水硫酸钠干燥，旋干得到无色油状物。该油状物用正庚烷(5升)溶清，用5％食盐水洗至无咪唑及三乙胺残留，无水硫酸钠干燥，旋干得到无色油状物粗品(1206.6克,91％)。
实施例A2：
Figure PCTCN2019107972-appb-000011
-78摄氏度下，氮气氛围下向草酰氯(203.4克，1603.2毫摩尔)的无水二氯甲烷(3000毫升)溶液中缓慢滴入无水DMSO(158.4克，2030.8毫摩尔)(注意：有大量CO和CO 2放出，温度不能超过-60摄氏度)。滴完后，反应液在-78摄氏度下搅拌反应30分钟。-78摄氏度下，向反应液中缓慢滴入化合物1-4(326.0克，1068.8毫摩尔)的无水二氯甲烷(500毫升)溶液。滴完后，反应液在-78摄氏度下搅拌反应1小时。在-78摄氏度下缓慢滴入三乙胺(545.1克，5344.0毫摩尔)(水分需控制)。滴完后，将反应液升至室温，搅拌反应1小时，TLC监控反应。反应液无原料残余时，向反应液中加入水(1000毫升)，分出有机层，水层用二氯甲烷(200毫升*2)萃取，合并有 机层，无水硫酸钠干燥、旋干得到粗品，粗品用3升正庚烷溶清，用3％食盐水洗至无三乙胺残留，经蒸馏纯化得到标题化合物A2(无色油状物，225.0克，70.1％)。
实施例A4:
Figure PCTCN2019107972-appb-000012
-68摄氏度下，向化合物A3(438.0克，1148.6毫摩尔)的无水四氢呋喃(1000毫升)溶液中缓慢滴入双(三甲基硅基)氨基钠(2M,1673.0毫升,3346.0毫摩尔)的四氢呋喃溶液。滴完后，反应液在-68摄氏度下搅拌反应1小时。在-68摄氏度下，向反应液中缓慢滴入化合物1-5(290.0克，956.0毫摩尔)的四氢呋喃(400毫升)溶液。滴完后，反应液在-68摄氏度下搅拌反应8小时。将反应液升温至0摄氏度，并在0摄氏度下搅拌2小时。反应用LCMS监控。当反应液无原料残余时，向反应液中加入水(1000毫升)，随后用乙酸乙酯(500毫升×3)萃取，合并有机相，用饱和食盐水(200毫升×2)洗涤，随后用无水硫酸钠干燥、旋干得到粗品。向粗品中加入1千克硅胶，用石油醚洗脱，旋干得到浓缩物，浓缩物经过减压蒸馏(收集100-110摄氏度馏分)得到A4(淡黄色油状物，173.0克，46.2％，E/Z＝10:1)。MS(ESI):m/z＝264.15[M-56+H] +。
实施例A5:叔-丁基(E)-(3-氟-2-(羟甲基)烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000013
在零摄氏度下，向实施例A4(173.0克，538.9毫摩尔，E:Z＝10:1)的四氢呋喃(400毫升)溶液中加入TBAF四水合物(170.0克，538.9毫摩尔)。加完后，反应液升至室温，搅拌反应1小时。反应用LCMS监控。当反应液无原料残余时，向反应液中加入水(1000毫升)并用乙酸乙酯(400毫升×2)萃取，合并有机相，用0.1N盐酸水溶液(200毫升×2)洗，饱和食盐水洗(100毫升×2)洗涤，无水硫酸钠干燥、旋干得到粗品。粗品经减压蒸馏纯化(收集100-120摄氏度馏分)得到标题化合物A5(淡黄色油状物，104.0克，94.2％，E:Z＝10:1)。 1H NMR(400MHz,CDCl 3)δ6.59(d,J＝83.7Hz,1H),5.01(br s,1H),3.95(s,2H),3.91(dd,J＝6.5,1.6Hz,2H),3.81(br s,1H),1.43(s,9H).
实施例A：叔-丁基(E)-(2-(溴甲基)-3-氟烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000014
在零摄氏度下，向实施例A5(104.0克，507.3毫摩尔)和三苯基膦(199.4克，761.0毫摩尔)的无水1,2-二氯甲烷(580毫升)的溶液中缓慢滴入CBr 4(251.9克，761.0毫摩尔)的无水1,2-二氯甲烷(100毫升)溶液。滴完后，将反应液升至室温并搅拌反应30分钟。反应用LCMS监控。当反应液无原料残余时，将反应液旋干得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物A(白色固体104.0克，E:Z＝10:1)。用石油醚(500毫升)重结晶两次后得到白色固体(85.5克，63.2％， E:Z＝50:1)。 1H NMR(400MHz,CDCl 3)δ6.77(d,J＝81.2Hz,1H),4.76(brs,1H),4.00(d,J＝4.6Hz,2H),3.95(dd,J＝3.4,0.6Hz,2H),1.45(s,9H).
实施例1:(E)-2-(((2-(3,5-二甲基-4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧代)甲基)-3- 氟丙-2-烯-1-胺
Figure PCTCN2019107972-appb-000015
实 施例1-1:叔-丁基4-(5-(苄氧基)嘧啶-2-基)-2,6-二甲基哌嗪-1-羧酸酯
Figure PCTCN2019107972-appb-000016
向化合物CAS:138274-14-3(220毫克,1.0毫摩尔)，叔-丁基3,5-二甲基哌嗪-1-羧酸酯(291毫克,1.5毫摩尔)，叔丁醇钠(174毫克,2.0毫摩尔)的甲苯(3毫升)溶液中加入三(二苯亚甲基丙酮)二钯(0)(45毫克,0.05毫摩尔)和2-二环己基磷-2,4,6-三异丙基联苯(47毫克,0.1毫摩尔)，氮气保护105℃加热密封反应1小时。冷却后，将反应液浓缩。残余物用硅胶柱分离纯化(二氯甲烷：甲醇＝20:1)，得标题化合物1-1(141毫克,39％)，为黄色油状物。MS(ESI):m/z＝399.2[M+H] +.
实施例1-2:5-(苄氧基)-2-(3,5-二甲基哌嗪-1-基)嘧啶
Figure PCTCN2019107972-appb-000017
向化合物1-1(141毫克,0.35毫摩尔)的二氯甲烷(2毫升)溶液中加入三氟乙酸(0.5毫升)，室温下搅拌16小时。反应液浓缩，pH用饱和碳酸氢钠溶液调节至9，乙酸乙酯萃取(20毫升×2)，干燥，浓缩得标题化合物1-2(105毫克,99％)，为黄色油状物。MS(ESI):m/z＝299.1[M+H] +.
实施例1-3:5-(苄氧基)-2-(3,5-二甲基-4-(噁丁环-3-基)哌嗪-1-基)嘧啶
Figure PCTCN2019107972-appb-000018
向化合物1-2(104毫克,0.35毫摩尔)，3-氧杂环丁酮(126毫克,1.75毫摩尔)的甲醇(5毫升)溶液中加入氯化锌四氢呋喃溶液(1M,0.52毫升，0.52毫摩尔)，氰基硼氢化钠(66毫克，1.05毫摩尔)。加热搅拌反应48小时。反应液冷却后，浓缩。残余物用硅胶柱分离纯化(石油醚：乙酸乙酯＝13：87)，得标题化合物1-3(44毫克,35％)，为黄色固体。MS(ESI):m/z＝355.2[M+H] +.
实施例1-4:2-(3,5-二甲基-4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-酚
Figure PCTCN2019107972-appb-000019
向实施例1-3(44毫克,0.12毫摩尔)的甲醇(5毫升)溶液置于单口瓶中，加入钯炭(20毫克)。用氢气球置换气体三次，反应液室温搅拌1小时。滤去钯炭，母液浓缩得标题化合物1-4(22毫克,67％)，为黄色油状物。MS(ESI):m/z＝265.1[M+H] +.
实施例1-5：叔-丁基(E)-(2-(((2-(3,5-二甲基-4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧 代)甲基)-3-氟烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000020
向实施例1-4(22毫克,0.08毫摩尔)，叔丁基(E)-(2-(溴甲基)-3-氟烯丙基)氨基甲酸酯(26毫克,0.1毫摩尔)的N,N-二甲基甲酰胺(2毫升)溶液中加入碳酸钾(17毫克,0.12毫摩尔)，加热至50℃，搅拌反应1小时。反应液直接用反相C-18柱分离纯化(乙腈/甲酸水溶液)，得标题化合物1-5(15毫克,40％)，为无色油状物。MS(ESI):m/z＝452.2[M+H] +/
实施例1：(E)-2-(((2-(3,5-二甲基-4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧代)甲基)-3- 氟丙-2-烯-1-胺
Figure PCTCN2019107972-appb-000021
向实施例1-5(15毫克,0.033毫摩尔)的二氯甲烷(2毫升)溶液中加入三氟乙酸(0.5毫升)，室温下搅拌30分钟。反应液浓缩，pH用氨水调节至7-8。反应液直接用 反相C-18柱分离纯化(乙腈/碳酸氢铵水溶液)，得标题化合物3(5.5毫克,47％)，为白色固体。MS(ESI):m/z＝352.6[M+H] +.
1H NMR(400MHz,CD 3OD):δ8.15(s,2H),8.20(d,J＝83.6Hz,1H),4.73(t,J＝6.4Hz,2H),4.54-4.53(m,2H),4.12-4.14(m,1H),3.76-3.72(m,2H),3.57-3.52(m,2H),3.48(d,J＝2.4Hz,2H),2.81-2.73(m,2H),1.04(d,J＝6.4Hz,6H).
以下化合物采用与实施例1类似的方法，替换相应原料获得。
Figure PCTCN2019107972-appb-000022
实施例4:(E)-3-氟-2-(((2-(4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧代)甲基)丙-2-烯-1-胺
Figure PCTCN2019107972-appb-000023
实施例4-1:叔-丁基(E)-(2-(((2-氯嘧啶-5-基)氧代)甲基)-3-氟烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000024
向2-氯嘧啶-5-酚(5725毫克,44.0毫摩尔)，K 2CO 3(7600毫克,55.0毫摩尔)的N,N-二甲基乙酰胺(80毫升)溶液中加入化合物A(9800毫克,36.7毫摩尔)，50℃加热反应3小时。反应结束后，反应液冷却至室温，缓慢滴加至水(800毫升)中，固体慢慢析出，室温搅2小时至固体均匀。过滤固体，水洗，干燥后，加入200毫升溶剂(石油醚：乙酸乙酯＝10:1)打浆6小时，固体过滤，干燥后得标题化合物4-1(9600毫克,82.5％)，为类白色固体。MS(ESI):m/z＝262.0[M-55] +.
实施例4-2:叔-丁基(E)-(3-氟-2-(((2-(4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧代) 甲基)烯丙基)氨基甲酸酯
Figure PCTCN2019107972-appb-000025
向实施例4-1(9600毫克,30.2毫摩尔)的N-甲基吡咯烷酮(80毫升)溶液中加入1-(噁丁环-3-基)哌嗪(10750毫克,75.7毫摩尔)和N,N-二异丙基乙胺(7813毫克,60.5毫摩尔)，封管条件下120℃加热反应过夜。反应结束后，加入水(500毫升)，乙酸乙酯(100毫升)萃取三次，合并有机相，水(80毫升)洗三次，饱和食盐水(80毫升)洗一次，无水硫酸钠干燥，浓缩后加入溶剂80毫升(石油醚：乙酸乙酯＝10:1)打浆6小时，固体过滤，干燥后得标题化合物4-2(10200毫克,79.6％)，为类白色固体。MS(ESI):m/z＝424.2[M+H] +.
实施例4:(E)-3-氟-2-(((2-(4-(噁丁环-3-基)哌嗪-1-基)嘧啶-5-基)氧代)甲基)丙-2-烯 -1-胺
Figure PCTCN2019107972-appb-000026
0℃条件下，向实施例4-2(8460毫克,20毫摩尔)的二氯甲烷(60毫升)溶液中加入三氟乙酸(30毫升)，0℃下反应,3小时。反应结束后，浓缩后加入水(10毫升)，滴加氨水调节至pH＝9，反相柱纯化(流动相:乙腈/碳酸氢铵水溶液)后得到标题化合物(6000毫克,92.8％)，为类白色固体。MS(ESI):m/z＝324.0[M+H] +. 1HNMR(400MHz,CD 3OD)δ8.15(s,2H),6.94(s,0.5H),6.73(s,0.5H),4.69(t,J＝6.7Hz,2H),4.62(t,J＝6.2Hz,2H),4.52(dd,J＝3.6,0.8Hz,2H),3.73(t,J＝3.9Hz,4H),3.53–3.45(m,1H),3.43(d,J＝2.4Hz,2H),2.38(t,J＝3.9Hz,4H).
以下化合物采用与实施例1、4类似的方法，替换相应原料获得。
Figure PCTCN2019107972-appb-000027
Figure PCTCN2019107972-appb-000028
生物测试例1化合物体外抑制SSAO/VAP-1酶活性检测方法
本检测方法用来评估本发明中的化合物对于不同种属的SSAO/VAP-1的体外抑制活性。本方法中使用重组人SSAO蛋白或小鼠SSAO蛋白或大鼠SSAO蛋白(由礼来公司提供)。酶活性检测试剂盒MAO-Glo Assays kit(V1402)购自Promega公司。配制酶反应缓冲液(50mM HEPES、120mM NaCl、5mM KCl、2mM CaCl 2、1.4mM MgCl 2、0.001％Tween-20，pH7.4)。将测试化合物溶于DMSO，并进行3倍浓度梯度稀释，检测SSAO时测试化合物在10μl反应体系中终浓度为1μM至0.05nM。DMSO在检测反应中的含量为1％。测试化合物DMSO溶液以1:25体积比稀释于酶反应缓冲液后，检测板中每孔加入2.5μl，每个浓度两个复孔。每孔加入5μl酶反应缓冲液稀释的SSAO蛋白，在10μl反应体系中终浓度为10nM～80nM。室温孵育10分钟。每孔加入2.5μl酶反应缓冲液稀释的反应底物，在10μl反应体系中终浓度为10μM。室温反应120分钟后每孔加入10μl检测试剂。室温孵育20分钟，Synergy Neo 2读板检测。数值通过下列公式将读数转化成抑制率
抑制率＝(Signal positive-Signal test)/(Signal positive–Signal negative)×100％
Signal positive为不含检测化合物的阳性对照，Signal negative为不含检测化合物和SSAO的阴性对照，Signal test为不同化合物各浓度的检测值。4参数曲线拟合计算IC50数据。对于在化 合物测试范围内抑制率均小于50％的化合物，IC50数值报告为高于最高测试浓度。
经检测，本发明实施例化合物可有效抑制不同种属SSAO/VAP-1酶活性，结果在表1中示出。
生物测试例2化合物抑制MAO-A、MAO-B酶活性检测
重组人MAO-A、MAO-B蛋白购自Sigma(M7316、M7441)。其它试剂同生物测试例1。检测MAO-A、MAO-B时测试化合物在10μl反应体系中终浓度为100μM至5nM。MAO-A、MAO-B蛋白在10μl反应体系中终浓度分别为70nM和300nM。其它反应条件同生物测试例1。数据分析及IC50计算方法同生物测试例1。对于在化合物测试范围内抑制率均小于50％的化合物，IC50数值报告为高于最高测试浓度。结果在表1中示出。
生物测试例3化合物抑制AOC1酶活性检测方法
重组人AOC1/DAO蛋白购自R&D systems(Cat：8298-AO)。Amplex UltraRed购自Thermo scientific(Cat：A36006)。HRP(Cat：P8250)、Putrescine(Cat：V900377)购自Sigma。配制酶反应缓冲液(50mM HEPES、120mM NaCl、5mM KCl、2mM CaCl 2、1.4mM MgCl 2、0.001％Tween-20，pH7.4)。将测试化合物溶于DMSO，并进行3倍浓度梯度稀释，检测AOC1时测试化合物在10μl反应体系中终浓度为100μM至5nM。DMSO在检测反应中的含量为1％。测试化合物DMSO溶液以1:25体积比稀释于酶反应缓冲液后，检测板中每孔加入10μl。以酶反应缓冲液配制4×底物混合物(含400μM Putrescine、4U/ml HRP、4μM Amplex UltraRed)，每孔加入10μl。每孔加入20μl酶反应缓冲液稀释的AOC1蛋白，在40μl反应体系中终浓度为0.4nM。Synergy Neo 2读板检测，仪器设置为温度30℃，激发波长530nm，发送波长590nm，每分钟检测一次，连续检测30分钟。以每孔第10分钟到第30分钟增长的数值计算酶活力。数值通过下列公式将读数转化成抑制率
抑制率＝(Signal positive-Signal test)/(Signal positive–Signal negative)×100％
Signal positive为不含检测化合物的阳性对照，Signal negative为不含检测化合物和AOC1的阴性对照，Signal test为不同化合物各浓度的检测值。4参数曲线拟合计算IC50数据。对于在化合物测试范围内抑制率均小于50％的化合物，IC50数值报告为高于最高测试浓度。
结果在表1中示出。
生物测试例4化合物抑制AOC2酶活性检测方法
重组人AOC2蛋白(由礼来公司提供)。其它试剂同生物测试例1。检测AOC2时测试化合物在10μl反应体系中终浓度为100μM至5nM。AOC2蛋白在10μl反应体系中终浓度为10nM。其它反应条件同生物测试例1。数据分析及IC50计算方法同生物测试例1。对于在化合物测试范围内抑制率均小于50％的化合物，IC50数值报告为高于最高测试浓度。
结果在表1中示出。
表1发明化合物对不同种属SSAO及其他胺氧化酶的体外抑制活性IC50(nM)
实施例 人SSAO AOC1 AOC2 MAO-A MAO-B 大鼠SSAO 小鼠SSAO
1 A E F I K NA NA
2 A D G H K L L
3 A D G H K NA NA
4 A E G I K L L
5 B E F I K NA NA
6 B E F I K NA NA
7 C E G I J NA NA
8 A E G H J NA NA
9 A D F I K NA NA
10 B E G I K NA NA
11 C NA NA H K NA NA
12 A E G H K L L
Figure PCTCN2019107972-appb-000029
上述结果显示，本发明的化合物对于AOC3有非常好的抑制活性，且对于AOC3亚型具有相当好的选择性。
生物测试例5化合物在小鼠/大鼠模型中抑制SSAO/VAP-1酶活性的检测
SSAO在动物组织中的活性测定使用MAO-Glo试剂盒(Promega,V1402)。给予动物待测化合物后，通过测定动物组织匀浆中对于MAO抑制剂Clogyline和Pargyline不敏感部分的单胺氧化酶的活力来计算SSAO酶活性。在不同目的给药浓度下，口服给予大鼠本发明中化合物，口服给予对照组动物相同体积的媒介。在给药后24小时分别收集动物血浆、脑、视网膜、小肠、肺、肝及肾组织(收集小肠、肺、肝及肾前动物先用PBS全身灌注)并保存 在-80℃冰箱，直到分析时取出。在组织匀浆裂解液(20mM HEPES,pH 7.4,150mM NaCl,1mM EDTA,1mM EGTA,1％Triton X-100及lx Roche Complete protease inhibitor tablet)中均质化各组织部分。均质化的组织液12000rpm，4℃离心30分钟，去除组织碎片。5ul上清与2ul Clogyline(10μΜ)和Pargyline(10μΜ)混合物在室温下共孵育10分钟后加入MAO-Glo检测试剂盒中检测底物2ul，室温下反应60分钟。按照试剂盒说明书加入检测试剂并终止反应。Biotek Neo2分析仪读取荧光素数据。以组织中对MAO抑制剂不敏感的单胺氧化酶活力代表SSAO活力。给药动物SSAO活性对照对照组动物的活性百分比来计算化合物抑制率。
检测结果表明本发明化合物在给药后可有效抑制动物体内不同组织中SSAO活性。结果在表2、表3中示出。
表2化合物单次给药后24小时剩余SSAO活性百分比(SSAO activity％)
Figure PCTCN2019107972-appb-000030
表中数据显示为平均值±SEM，N＝3。
表3实施例4化合物单次给药后24小时剩余SSAO活性百分比(SSAO activity％)
Figure PCTCN2019107972-appb-000031
表中数据显示为平均值±SEM，N＝3。
生物测试例6 SSAO化合物在眼部炎症相关疾病模型中的药效学研究
将22只大鼠(7-8周，220-250g)分为3组，对照组(6只)、造模组(8只)和给药组(8只)。对于造模组和给药组，通过8ug/100ul脂多糖(Sigma-Aldrich-L2880)的单一足垫注射诱导眼部炎症。在诱导之前1h根据大鼠体重进行分组，分别口服给予化合物实施例4(6mg/kg,10ml/kg)或媒介(10ml/kg)。在诱导之后24h收集眼前房水，摘除眼球分离视网膜，通过检测房水中蛋白质的浓度和细胞数量定量评价眼部炎症，运用QPCR的方法验证眼 视网膜炎症相关基因的表达变化情况。
眼房水中细胞量和蛋白浓度的测定方法：
取10ul房水加40ul PBS稀释混匀后，取其中25ul加75ul PBS混合，300g，4度条件下离心5min。小心吸取55ul上清按照蛋白检测试剂盒(BCA Protein Assay Kit，Pierce-23227)所述方法测定蛋白浓度；剩余样本重悬后，取40ul细胞悬液加100ul 1％FBS/PBS用NovoCyte3130流式细胞仪去除细胞碎片后对剩余活细胞进行分析计数。
造模组和对照组相比，房水中总蛋白浓度明显增高(平均值±SEM：9730.04±1232.30ug/ml VS 3147.42±404.79ug/ml)，细胞数量明显增多(平均值±SEM：48.28±21.46细胞*10^4/ml VS 2.69±0.45细胞*10^4/ml)，提示眼部炎症性疾病模型诱导成功。
给药组和造模组相比，蛋白浓度降低(平均值±SEM：7275.44±622.66 VS 9730.04±1232.30ug/ml)，细胞数量明显减少(平均值±SEM：5.07±0.80细胞*10^4/ml VS 48.28±21.46细胞*10^4/ml)，提示化合物实施例4可以明显减轻眼部炎症相关疾病症状。如图1所示，在LPS诱导的大鼠炎症疾病模型中实施例4可明显减轻眼部炎症相关症状。图1A.房水中蛋白浓度(ug/ml)的变化；图1B.房水中细胞数(*10^4/ml)的变化。
眼视网膜中炎症相关基因的表达水平测定：
1)合成引物，信息如下：
Primer名称 序列(5'to3')
Rat-Alox5ap-F CCTTCGCTGGGCTGATGTAT
Rat-Alox5ap-R ATAGGATGATCCGCTTGCCG
Rat-Socs3-F CCCCGCTTTGACTGTGTACT
Rat-Socs3-R AAAGGAAGGTTCCGTCGGTG
Rat-UBC-F ACACCAAGAAGGTCAAACAGG
Rat-UBC-R AGACACCTCCCCATCAAACC
Rat-TLR7-F AGCTCTGTTCTCCTCCACCA
Rat-TLR7-R ACCATCGAAACCCAAGGACTC
2)根据RNA抽提试剂盒(RNeasy Mini Kit，Qiagen-74104)操作说明提取视网膜RNA，然后将RNA反转录成cDNA(High Capacity cDNA Reverse Transcription Kits，ABI-4374966)。获得的cDNA10倍稀释后作为QPCR反应模板，按照Power SYBR Green kit(ABI-A25918)使用要求，在CFX384 Real-Time QPCR仪上进行QPCR反应，使用CFX Maestro软件采用ΔΔCt方法对各基因表达情况进行基因表达变化定量分析，以UBC作为内参基因。
造模组和对照组相比，ALOX5AP,SOCS3和TLR7基因表达水平明显上升。而给药组和造模组相比，ALOX5AP、SOCS3和TLR7基因表达水平明显下降，如图2所示。经分析，ALOX5AP,SOCS3和TLR7基因表达均受NFkB信号通路调节，而NFkB信号通路是炎症性疾病中非常重要的分子信号通路。
图2在LPS诱导的大鼠炎症疾病模型中实施例4可明显降低视网膜中炎症相关基因表达水平A.ALOX5AP；B.SOCS3；C.TLR7。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐：
    Figure PCTCN2019107972-appb-100001
    其中，
    A选自下组：取代或未取代的C6-C10芳环、取代或未取代的5-12元杂芳环，或A为化学键(或无)；
    B选自下组：取代或未取代的C3-10的环烷基、取代或未取代的C6-C10芳环(包括单环和并环)、取代或未取代的5-12元杂芳环(包括单环和并环)、取代或未取代的3-12元杂环(包括单环、并环、桥环和螺环)；其中，所述的杂芳环或杂环还含有1-3个选自氮、氧和硫的杂原子；
    L 1选自下组：-O-、-NH-、-(C＝O)-、-NH(C＝O)-、-(C＝O)NH-、-NHS(＝O) 2-、-S(＝O) 2NH-，或者(CR 9R 10) n；上述各基团中，当从左至右书写时，表示基团左侧连接A环，右侧连接-CR 3R 4-；
    L 2为化学键(或无)，或选自下组的基团：-O-、-NH-、-S-、-(C＝O)-、-SO 2-、-NH-(C＝O)-NH-、-NH-S(＝O) 2-NH-、-(S＝O)-、-NH-(S＝O)-NH-、-NH-(C＝O)-、-(C＝O)-NH-、-(CH＝CH) n-、-(C≡C) n-、-NH-S(＝O) 2-、-S(＝O) 2-NH-、C3-C8环烷基、5-8元杂环基，或者(CR 9R 10) n；
    L 3选自下组：取代或未取代的C3-12的碳环(包括单环、并环、桥环和螺环)、取代或未取代的5-12元杂环(包括单环、并环、桥环和螺环)，或取代或未取代的5-6元杂芳环；所述杂环含有1-3个选自氮、氧和硫的杂原子；
    R 1、R 2各自独立地选自下组：H、F、Cl；
    R 3、R 4各自独立地选自下组：H、F、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；或R 3、R 4与其相连的碳原子共同构成3-8元的碳环，或3-8元的杂环；且当L 1为-O-、-NH-、-(C＝O)NH-或-S(＝O) 2NH-时，R 3和R 4均不为选自下组的基团：-OH、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；
    R 5、R 6各自独立地为氢；或R 5、R 6与其相连的氮原子共同形成为取代或未取代的5-6元含氮杂环；或各自独立地选自下组-NR aR b，其中，R a和R b各自独立地为H、-C1-C8烷基、取代或未取代的C3-C8环烷基、-C1-C4烷基-C6-C10芳基，或R a和R b与其相连的氮原子共同形成5-6元氮杂环；
    R 7选自下组：取代或未取代的选自下组的基团：C5-C6环烷基、含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、氟代C1-C6烷氧基、C1-C6烷氧基-C1-C6烷氧 基、C1-C6烷基羰基、C2-C6酰胺基、C1-C6烷基NH-、(C1-C6烷基)(C1-C6烷基)N-；所述取代表示上述基团被选自下组的基团所取代：C1-C6烷氧基、C1-C6烷基羰基，5-12元的杂芳环(单环、并环，或稠环)，C6-C12的芳香环(单环，并环，稠环)；
    或R 7选自下组：H、取代或未取代的C1-C6烷氧基，且L 3选自下组：取代或未取代的5-12元桥环，或5-12元含氧螺环杂环；
    R 8和R 8'各自独立地选自下组：H、F、Cl、Br、-NO 2、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基、-NR aR b、-NHR c，和-SO 2-(C1-C8烷基)、-CONRaRb；其中，Ra和Rb各自独立地为H、-C1-C8烷基,-C1-C4烷基-C6-C10芳基，或Ra和Rb与其相连的氮原子共同形成5-6元氮杂环；R c选自下组：-C(＝O)-(C1-C8烷基)、-C(＝O)-(C6-C10芳基)；
    R 9、R 10各自独立地选自下组：H、C1-C8烷基、-O-C1-C8烷基、-O-C3-C8环烷基、-C6-C10芳基、-O-C1-C4烷基-C6-C10芳基、-S-C1-C8烷基、-CF 3、-S-CF 3、-OCF 3、-OCH 2CF 3、F、-OH、-CN；或R 9和R 10与其相连的碳原子共同构成选自下组的基团：C3-C8环烷基、5-12元杂环基；
    X选自下组：-(C＝O)-、-(C＝O)-NH-、-CR 11R 12；
    R 11、R 12各自独立地选自下组：H、F、-OH、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基；或R 11、R 12与其相连的碳原子共同构成3-8元的碳环，或3-8元的杂环；
    条件是上述各基团共同形成化学上稳定的结构；
    除非特别说明，上述的“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：氧代(＝O)、羟基、取代或未取代的C5-C6环烷基、取代或未取代的含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、C1-C6烷基、C1-C6烷氧基、氟代C1-C6烷氧基、C1-C6烷氧基-C1-C6烷氧基、C1-C6烷基羰基、C2-C6酰胺基、C1-C6烷基NH-、(C1-C6烷基)(C1-C6烷基)N-；所述取代表示上述基团被选自下组的基团所取代：C1-C6烷氧基、C1-C6烷基羰基。
  2. 如权利要求1所述的化合物，或其立体异构体或外消旋体，或其药学上可接受的盐，其中，L3为选自下组的结构：哌嗪环、
    Figure PCTCN2019107972-appb-100002
    Figure PCTCN2019107972-appb-100003
    且所述的L3为取代或未取代的。
  3. 如权利要求2所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，所述的式I化合物具有如下式所示的结构：
    Figure PCTCN2019107972-appb-100004
    其中，m为0、1、2、3或4。
  4. 如权利要求1所述的化合物，或其立体异构体或外消旋体，或其药学上可接受的盐，其特征在于，所述的R 7选自取代或未取代的选自下组的基团：C5-C6环烷基、含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、5-12元的杂芳环(单环、并环，或稠环)；或R 7选自下组：H、取代或未取代的C1-C6烷氧基，且L 3选自下组：取代或未取代的5-12元桥环，或5-12元含氧螺环杂环。
  5. 如权利要求4所述的化合物，或其立体异构体或外消旋体，或其药学上可接受的盐，其特征在于，所述的R 7选自下组：
    Figure PCTCN2019107972-appb-100005
    其中，所述的p和q各自独立地选自下组：0、1、2、3或4，且所述的p与q之和≥1。
  6. 如权利要求1-5任一所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2019107972-appb-100006
    Figure PCTCN2019107972-appb-100007
  7. 一种药物组合物，其包含治疗有效量的权利要求1-6任一所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
  8. 如权利要求7所述的药物组合物，其特征在于，所述的药物组合物用于预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白调节的疾病；优选地，所述的疾病选自下组：炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、 血管疾病、眼部疾病、纤维化、神经炎性疾病，疼痛相关疾病、癌症或组织移植排斥。
  9. 如权利要求8所述的药物组合物，其特征在于，所述的炎症疾病和/或炎症相关疾病选自下组：关节炎(包括幼年型类风湿性关节炎)及关节炎引起的疼痛、克罗恩病、溃疡性结肠炎、炎性肠病(例如，肠易激综合征)、牛皮癖、哮喘、肺炎、慢性阻塞性肺病(COPD)、支气管扩张、皮肤炎症、眼病、接触性皮炎、肝炎、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、酒精肝病、动脉粥样硬化、慢性心力衰竭、充血性心力衰竭、缺血性疾病、中风及其并发症、心肌梗死及其并发症、中风后炎性细胞破坏、滑膜炎、全身炎性败血症等。
  10. 如权利要求8所述的药物组合物，其特征在于，所述的炎症疾病和/或炎症相关疾病为在另一优选例中，所述的炎症选自下组：关节炎(包括幼年型类风湿性关节炎)及关节炎引起的疼痛、克罗恩病、溃疡性结肠炎、炎性肠病(例如，肠易激综合征)、牛皮癖、哮喘、肺炎、慢性阻塞性肺病(COPD)、支气管扩张、皮肤炎症、眼病、接触性皮炎、肝炎、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、酒精肝病、动脉粥样硬化、慢性心力衰竭、充血性心力衰竭、缺血性疾病、中风及其并发症、心肌梗死及其并发症、中风后炎性细胞破坏、滑膜炎、全身炎性败血症等。
  11. 如权利要求8所述的药物组合物，其特征在于，所述的糖尿病和/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。
  12. 如权利要求8所述的药物组合物，其特征在于，所述的眼部疾病为葡萄膜炎或黄斑变性。
  13. 如权利要求8所述的药物组合物，其特征在于，所述的纤维化选自下组：囊性纤维化、特发性肺纤维化、肝纤维化、包括非酒精性脂肪肝疾病诸如非酒精性脂肪肝(NASH)和酒精诱导的纤维化导致肝硬化、肾纤维化、硬皮病、放射性诱导的纤维化、及纤维化导致的并发症。
  14. 权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐或权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白调节的疾病的药物。
  15. 如权利要求14所述的用途，其特征在于，所述与SSAO有关或由SSAO/VAP-1蛋白调节的疾病选自下组：炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、疼痛相关疾病、缺血性疾病、血管疾病、眼部疾病、纤维化、神经炎性疾病，癌症、纤维化或组织移植排斥。
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