WO2020083264A1 - 胍类衍生物及其用途 - Google Patents

胍类衍生物及其用途 Download PDF

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WO2020083264A1
WO2020083264A1 PCT/CN2019/112392 CN2019112392W WO2020083264A1 WO 2020083264 A1 WO2020083264 A1 WO 2020083264A1 CN 2019112392 W CN2019112392 W CN 2019112392W WO 2020083264 A1 WO2020083264 A1 WO 2020083264A1
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disease
atoms
group
diseases
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顾峥
黎健豪
刘建余
王伟华
李峥
覃浩雄
王绪礼
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a guanidine derivative as a VAP-1 (Vascular adhesion protein-1, VAP-1) inhibitor, and a preparation method and application thereof. More specifically, the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt or stereoisomers, geometric isomers thereof, and a pharmaceutical composition containing the compound, and further relates to The compound and the pharmaceutical composition described in the preparation of a medicament for preventing, treating or alleviating inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection the use of.
  • VAP-1 Vascular adhesion protein-1, VAP-1
  • the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt or stereoisomers, geometric isomers thereof, and a pharmaceutical composition containing the compound, and further relates to The compound and the pharmaceutical composition described in the preparation of
  • Amine Oxidase (Amine Oxidase, AO) is a type of protein with special biological functions, widely exists in the body, participates in the metabolism of biological amines, oxidatively cleaves amines into aldehydes and ammonia.
  • amine oxidases There are two main types of amine oxidases that are well known.
  • One is copper-containing amine oxidase (COAs) with quinone as a coenzyme; the other is flavin adenine dinucleotide (FAD).
  • COAs copper-containing amine oxidase
  • FAD flavin adenine dinucleotide
  • Coenzyme containing flavinamine oxidase Flavin-containing oxidases mainly include monoamine oxidases (MAOs) and polyamine oxidases (POs).
  • MAOs There are two subtypes of MAOs, namely monoamine oxidase A (Monoamine oxidase A, MAO-A) and monoamine oxidase B (Monoamine oxidase B, MAO-B), which are mainly present in the outer mitochondrial membrane of mammalian cells and can be selectively metabolized Oxidative deamination) primary, secondary and tertiary amines. Drugs that inhibit MAOs can be used to treat depression. There are 3 subtypes of POs. They are involved in the regulation of cell growth by oxidizing polyamines such as spermine and spermidine.
  • Copper-containing amine oxidase can be further divided into: 2,4,5-trihydroxyphenylalanine quinone (TPQ) dependent copper-containing amine oxidase family and lysine tyrosylaminoquinone (LTQ) dependent lysine Acyl oxidase family.
  • TPQ 2,4,5-trihydroxyphenylalanine quinone
  • LTQ lysine tyrosylaminoquinone
  • the copper-containing amine oxidase family dependent on 2,4,5-trihydroxyphenylalanine quinone (TPQ) includes diamine oxidase (DAO), retina-specific amine oxidase (Retina specific amine oxidase, RAO), Vascular adhesion protein-1 (Vascular adhesion protein-1, VAP-1) and serum amine oxidase (SAO).
  • DAO diamine oxidase
  • Retina specific amine oxidase RAO
  • Mammalian copper-containing amine oxidases are mainly encoded by AOC1, AOC2, AOC3 and AOC4 genes.
  • AOC1 encodes DAO
  • AOC2 encodes RAO
  • AOC3 encodes VAP-1
  • AOC4 encodes SAO.
  • DAO is mainly expressed in the kidney, placenta, intestine, and seminal vesicles, and it only acts on diamines, especially histamine, so it is also called histamine oxidase.
  • RAO was cloned from the human retina in 1997 and is retinal-specific. The overall folding of its three-dimensional structure is similar to VAP-1.
  • RAO can oxidize 2-phenethylamine, tryptamine and tyramine.
  • SAO is only highly expressed in cattle, horses, pigs and sheep, and in humans it is a protein that lacks functionality.
  • Vascular adhesion protein-1 (VAP-1) is encoded by the AOC3 gene located on human chromosome 17 and is an amine oxidase sensitive to semicarbazide.
  • VAP-1 is widely present in mammalian tissues rich in vascular content, mainly in two forms, one is soluble form, mainly in circulating blood; the other is membrane-bound form, widely distributed in organs And tissues, especially in fat cells, vascular endothelial cells and smooth muscle cells.
  • VAP-1 has dual functions. On the one hand, it is an adhesion molecule of lymphocytes, which can promote the adhesion of lymphocytes to vascular endothelium.
  • VAP-1 can also regulate the inflammatory microenvironment by regulating transcription factors, chemokines, and other adhesion molecules; VAP-1 also has the effect of enzymes, which can catalyze the primary amines to the corresponding aldehydes, ammonia and hydrogen peroxide.
  • Inflammation is the immune system's first response to infection or irritation.
  • the movement of white blood cells into the tissue circulation is important to this process.
  • An inappropriate inflammatory response can lead to local inflammation of additional healthy tissue, which can lead to diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, chronic obstructive pulmonary disease (COPD), eczema, psoriasis, etc.
  • Leukocytes need to adhere to the endothelium by binding adhesion molecules before passing through the blood vessel wall.
  • VAP-1 As an endothelial adhesion molecule, VAP-1 is abundantly expressed in vascular endothelial cells such as high-efficiency venous endothelial cells (HVE) of lymphoid organs, and also expressed in hepatic sinusoidal endothelial cells (HSEC), smooth muscle cells and adipocytes Induces cell adhesion, regulates leukocyte transport, participates in granulocyte extravasation, and its level rises during inflammation. The migration of neutrophils from the blood to the site of inflammation is achieved by binding molecules to vascular endothelial cells. Therefore, VAP-1 plays an important role in diseases related to inflammation and has been widely valued by researchers.
  • HVE high-efficiency venous endothelial cells
  • HSEC hepatic sinusoidal endothelial cells
  • smooth muscle cells smooth muscle cells
  • adipocytes Induces cell adhesion, regulates leukocyte transport, participates in granulocyte extravasation, and its level rises during inflammation.
  • VAP-1 VAP-1-related diseases: diabetes (Li, H, Y. et al., 2009, Clin. Chim. Acta 404: 149-153), obesity (Meszaros, Z .et., 1999, Metabolism 48: 113-117; Weiss, H, G.et.al., 2003, Metabolism 52: 688-692), ischemic heart failure (Boomsma, F.et.al., 1997, Cardiovasc.Res. 33: 387-391), end-stage renal disease (Kurkijarvi, R. et al., 2001, Eur, J. Immunol. 31: 2876-2884) and inflammatory liver disease (Kurkijarvi, R.
  • VAP-1 is also associated with the following diseases: melanoma and lymphoma (Martila-lchihara, F. et al., 2010, J. Immunol. 184: 3164-3173), acute and chronic arthritis (Tabi, T.
  • liver allograft rejection Martelius, T. et.al., 2004, Am. J. Pathol. 165: 1993-2001
  • non-alcoholic liver disease etc.
  • VAP-1 inhibitors will benefit humans in the treatment of various diseases, especially inflammation and / or inflammation-related diseases and diabetes and / or diabetes-related diseases.
  • the present invention provides a new class of compounds with better VAP-1 inhibitory activity.
  • Such compounds and their pharmaceutical compositions can be prepared for the prevention, treatment or alleviation of inflammatory diseases and / or inflammation-related diseases, diabetes and / or Diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection drugs, especially for the preparation, prevention, treatment or alleviation of patients with non-alcoholic fatty liver disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetes Drugs for macular edema.
  • 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 of a compound represented by formula (I) Acceptable salts or their prodrugs,
  • U 1 and U 2 are each independently CH or N;
  • R 1 , R 2 and R 3 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy or hydroxy C 1-6 alkyl;
  • R 4 and R 5 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl Oxy or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-6 cycloalkyl are each independently unsubstituted or Substitution by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 haloalkoxy;
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3-6 carbocyclic ring or a heterocycle consisting of 3-6 atoms, wherein the C 3-6 carbocyclic ring and 3-6 atoms are
  • the heterocycles are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 haloalkoxy;
  • A is a heterocyclic group composed of 5-14 atoms or a heteroaryl group composed of 5-14 atoms, wherein A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 ;
  • q 0, 1, or 2;
  • Each R a, R b, R c , R d, R e and R f are independently H, D, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl and 5-6 Heteroaryl groups consisting of three atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, -OH , NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN , -OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
  • A is the following substructure:
  • Each E is independently N or CH;
  • Each T is independently-(CH 2 ) x- ;
  • Each y is independently 0, 1, or 2;
  • Each w is independently 0, 1, or 2;
  • x is 1, 2 or 3;
  • Ring C is a C 3-6 carbocyclic ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms;
  • Each ring D is independently a C 3-6 carbocycle, a heterocycle consisting of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring consisting of 5-6 atoms;
  • A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 .
  • Ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane, 1, 3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine , Pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine or pyridazine.
  • Each ring D is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane, 1,3-dioxane Cyclopentane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine, pyrimidine, thiazole , Thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine or pyridazine.
  • A is Wherein, A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 .
  • q 0, 1, or 2;
  • Each R a, R b, R c , R d, R e and R f are independently H, D, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C 6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C 6-10 aryl and 5-6 Heteroaryl groups consisting of three atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, -OH , NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN , -OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
  • R 1 , R 2 and R 3 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , methyl, ethyl, n-propyl, Isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylamino, trifluoromethoxy or hydroxymethyl.
  • R 4 and R 5 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , methyl, ethyl, n-propyl, isopropyl , Trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, tri Fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F , Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or
  • R 4 and R 5 together with the carbon atoms to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thia Cyclobutane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine , Wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane, 1,3-dioxolane Alkanes, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, t
  • each of R a, R b, R c , R d, R e and R f are independently H, D, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl , Tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclic group, phenyl group or 5-6 atom heteroaryl group, wherein the methyl, ethyl, n-propyl , Isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclic group, phenyl group and 5-6 atom heteroaryl group are independently unsubstituted or substituted by 1 , 2, 3, or 4 substituents, the substituents are independently selected from D, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl,
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I,- CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention, optionally, further comprising a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof.
  • the invention relates to the use of the compound or pharmaceutical composition of the invention in the preparation of a medicament, wherein the medicament is used to inhibit VAP-1.
  • the invention relates to the use of the compounds or pharmaceutical compositions of the invention for inhibiting the activity of VAP-1.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to inhibit VAP-1 activity, the method comprising administering to a patient an effective therapeutic amount of the compound or pharmaceutical composition of the present invention.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate diseases related to or regulated by VAP-1 protein .
  • the invention relates to the use of the compounds or pharmaceutical compositions of the invention for the prevention, treatment or alleviation of diseases associated with or regulated by VAP-1 protein.
  • the present invention relates to a method for preventing, treating or alleviating diseases related to or regulated by VAP-1 protein using the compound or pharmaceutical composition of the present invention, the method is to administer the present invention to a patient An effective therapeutic amount of the compound or the pharmaceutical composition.
  • the disease associated with or regulated by VAP-1 protein is an inflammatory disease and / or inflammation-related disease, diabetes and / or diabetes-related disease, ischemic disease, vascular disease, Fibrosis or tissue transplant rejection.
  • the inflammatory diseases and / or inflammation-related diseases of the present invention are arthritis, systemic inflammatory syndrome, sepsis, synovitis, Crohn's disease, ulcerative colitis, inflammatory Bowel disease, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease.
  • the arthritis of the present invention is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
  • systemic inflammatory syndrome of the present invention is systemic inflammatory sepsis.
  • the inflammatory bowel disease of the present invention is allergic bowel disease.
  • the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic Fatty liver disease.
  • the respiratory disease of the present invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.
  • the eye diseases of the present invention are uveitis, ulcerative colitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis,
  • the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.
  • the neuroinflammatory disease of the present invention is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, or chronic multiple sclerosis.
  • 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 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 ischemic disease of the present invention is stroke and / or complications thereof, myocardial infarction and / or complications thereof, or destruction of tissues by inflammatory cells after stroke.
  • the fibrosis of the present invention is liver fibrosis, cystic fibrosis, renal fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.
  • the vascular disease of the present invention is atherosclerosis, chronic heart failure, or congestive heart failure.
  • the invention provides a class of guanidine derivatives with VAP-1 inhibitory activity, preparation methods and uses thereof. Those skilled in the art can learn from this article and appropriately improve the process parameters to achieve. In particular, it should be noted that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the scope of the present invention.
  • the articles “a”, “an” and “said” as used herein are intended to include “at least one” or “one or more”. Therefore, the articles used herein refer to one or more than one (ie, at least one) object articles.
  • a component refers to one or more components, that is, more than one component may be considered for use or use in the implementation of the described embodiment.
  • subject refers to animals. Typically the animal is a mammal.
  • the test subjects also refer to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • 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 (eg, birds or mammals such as chickens, quails, or turkeys), especially “mammals” including non-primates (eg, cattle, pigs) , Horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (eg, monkeys, chimpanzees, and humans), and more particularly humans.
  • the subject is a non-human animal, such as a domestic animal (eg, horse, cow, pig, or sheep) or pet (eg, dog, cat, guinea pig, or rabbit).
  • "patient” refers to a human.
  • 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 whose atomic mass or mass number is different from the atomic mass or mass number 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.
  • Isotope-labeled compounds of the invention such as radioisotopes, such as 3 H and 14 C
  • incorporated into compounds of the invention can be used for drug and / or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, ie, 3 H, and carbon-14, ie, 14 C, isotopes are particularly preferred.
  • substitution with heavy isotopes, such as deuterium, ie 2 H can provide some therapeutic advantages that result from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Therefore, it may be preferable in some cases.
  • stereoisomers refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc. .
  • stereochemistry used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemicals (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry "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 invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof such as racemic mixtures, It is also included in the scope of the present invention.
  • any asymmetric atoms (for example, carbon, etc.) of the compounds of the present invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, (R, R)-, (S, S)-, (S, R)-or (R, S)-configuration forms exist.
  • each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70% in the (R)-or (S) -configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the substituent on the atom having an unsaturated double bond may exist in the form of cis- (Z)-or trans- (E)-.
  • the compounds of the present invention may be one of the possible isomers or their mixtures, such as racemates and diastereomer mixtures (this depends on the number of asymmetric carbon atoms) 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 E or Z configuration; if the compound contains disubstituted cycloalkyl, the substituent of cycloalkyl may be in cis or trans (cis- or trans-) configuration .
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography Method and / or step crystallization method.
  • racemates of any resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, such as, for example, by obtaining the diastereomeric salts obtained Separate. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents.
  • 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 ( 2nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomer (valence tautomer) includes interconversion through the recombination of some bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of 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 invention are within the scope of the invention.
  • the compound of the present invention may exist in one form or a mixture of possible isomers, rotamers, atropisomers, tautomers, Examples 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 an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (eg peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March).
  • an oxidizing agent such as hydrogen peroxide or peracid (eg peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March).
  • N-oxide 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 and m-chloro
  • solvent refers to the association of one or more solvent molecules with the compound of the invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecule being water.
  • metabolite refers to a product obtained by metabolizing a specific compound or its salt in the body.
  • the metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention. Such products may be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of the compound, including metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • salts formed from pharmaceutically acceptable non-toxic acids 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 other methods described in the literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben, pectate, persulfate, 3 -Phen
  • Salts obtained by suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -8 sulfonate and aromatic sulfonate.
  • prodrug means that a compound is converted into a compound represented by formula (I) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue.
  • the prodrug compounds of the present invention may be esters.
  • esters can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters, as these phosphate ester compounds are obtained by phosphorylation of hydroxyl groups on the parent.
  • phosphate esters as these phosphate ester compounds are obtained by phosphorylation of hydroxyl groups on the parent.
  • 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 specific substituents.
  • the compound of the present invention may be optionally substituted with one or more substituents, such as the compound of general formula (I), or like the specific examples, subclasses, and inclusions of the present invention in the examples A class of compounds.
  • substituents such as the compound of general formula (I), or like the specific examples, subclasses, and inclusions of the present invention in the examples A class of compounds.
  • optionally substituted by may be used interchangeably with the term “unsubstituted or substituted by”, ie the structure is unsubstituted or substituted by one or more substituents described in the present invention .
  • an optional substituent may be substituted at each substitutable position of the group.
  • the substituents can be substituted at the same positions or differently.
  • C 1-6 alkyl particularly 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
  • heteroaryl consisting of 5-6 atoms refers to heteroaryl consisting of 5 atoms and heteroaryl consisting of 6 atoms.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition for the variable lists “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” represents the linked group, respectively An alkylene group or an arylene group.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms; in some embodiments, the alkyl group contains 1-12 carbon atoms; in some embodiments, the alkyl group contains 1-10 carbon atoms Carbon atoms; in some embodiments, the alkyl group contains 1-9 carbon atoms; in some embodiments, the alkyl group contains 1-8 carbon atoms; in some embodiments, the alkyl group contains 1-6 carbon atoms; in some embodiments, the alkyl group contains 1-4 carbon atoms, and in some embodiments, the alkyl group contains 1-2 carbon atoms.
  • 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 refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturated site, that is, there is a carbon-carbon sp 2 double bond, wherein, the alkenyl group
  • the group may be optionally substituted with one or more substituents described in the present invention, which includes the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in one embodiment, the alkenyl group contains 2-6 carbon atoms; in one embodiment, the alkenyl group contains 2-4 Carbon atoms.
  • alkynyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturated site, that is, there is a carbon-carbon sp triple bond, wherein, the alkynyl group It may be optionally substituted with one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in some embodiments, the alkynyl group contains 2-6 carbon atoms; in some embodiments, the alkynyl group contains 2-4 Carbon atoms.
  • 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-octynyl Base, etc.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, ie -O-alkyl, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in some embodiments, the alkoxy group contains 1-4 carbon atoms; in some embodiments, the alkoxy group contains 1-3 carbon atoms.
  • 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 3 ),
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N, N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is an alkylamino group having one or two C 1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is an alkylamino group having one or two C 1-4 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is an alkylamino group having one or two C 1-3 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is an alkylamino group having one or two C 1-2 alkyl groups attached to a nitrogen atom.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, such examples include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N, N- Dimethylamino, N, N-diethylamino, etc.
  • haloalkyl mean alkyl, alkenyl or alkoxy groups are substituted by one or more halogen atoms, respectively.
  • examples include, but are not limited to, 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
  • Carbocyclic group or “carbocyclic ring” refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-14 ring atoms.
  • Carbobicyclic groups include spiro-carbon bicyclic groups, fused carbon bicyclic groups and bridged carbon bicyclic groups.
  • the number of carbon atoms is 3-12, or C 3-12 carbocycles; in other embodiments, the number of carbon atoms is 3-10, or C 3-10 carbocycles; In other embodiments, the number of carbon atoms is 3-8, or C 3-8 carbocycles; in other embodiments, the number of carbon atoms is 3-6, or C 3-6 carbocycles; In other embodiments, the number of carbon atoms is 5-6, or C 5-6 carbocycles; in other embodiments, the number of carbon atoms is 5-8, or C 5-8 carbocycles.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl Group, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.
  • cycloalkyl refers to a monovalent or polyvalent 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 In some embodiments, the cycloalkyl group contains 3 to 6 carbon atoms, that is, 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 herein.
  • aryl or "aromatic ring” are used interchangeably herein to denote monocyclic, bicyclic, and tricyclic rings containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms Carbocyclic ring system, wherein at least one ring system is aromatic, wherein each ring system contains a carbocyclic ring composed of 3-7 atoms, and one or more attachment points are 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 N, S and P in any form of oxidation state; primary, secondary, tertiary amine and quaternary ammonium salt forms; or heterocyclic nitrogen atoms Hydrogen substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
  • heterocyclic group 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 meaning of the present invention.
  • the “heterocyclic group” may be fully saturated or contain one or more unsaturations, but none of the aromatic rings.
  • heterocyclyl used interchangeably herein.
  • the heterocyclyl group is a ring system composed of 5-14 ring atoms, that is, a heterocyclic group composed of 5-14 atoms; in some embodiments, the heterocyclyl group is 3-8 A ring system consisting of 3 ring atoms, ie a heterocyclic group consisting of 3-8 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 3-6 ring atoms, ie consisting of 3-6 atoms Heterocyclic group; in some embodiments, the heterocyclic group is a ring system composed of 5-6 ring atoms, that is, a heterocyclic group composed of 5-6 atoms; in some embodiments, the heterocyclic group is A ring system composed of 4 ring atoms, that is, a heterocyclic group composed of 4 atoms; in some embodiments, a heterocyclic group is a ring system composed of 5 ring atoms, that is, a heterocyclic group composed of 3 atoms
  • the heterocyclyl group is a monocyclic ring consisting of 3-8 atoms (2-7 carbon atoms and 1-3 heteroatoms selected from N, O, P, S), or 7- 13 atoms bicyclic ring (4-12 carbon atoms and 1-3 heteroatoms selected from N, O, P, S).
  • the heterocyclic group is a monocyclic heterocyclic group consisting of 5-6 atoms.
  • the heterocyclic group is a bridged heterocyclic group consisting of 7-9 atoms.
  • the heterocyclic group is a spiro bicyclic heterocyclic group consisting of 9-13 atoms; in some embodiments, the heterocyclic group is a spiro bicyclic heterocyclic group consisting of 9-10 atoms. In some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-11 atoms.
  • the heterocyclyl group is optionally substituted with one or more substituents described in this invention.
  • the sulfur atom of the ring can optionally be oxidized to an 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: ethylene oxide, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Oxazolidinyl, thiazolidinyl, dioxanyl, dithianyl, thioxanyl, homopiperaz
  • heterocyclic groups examples include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Ketone, 3,5-dioxopiperidinyl, etc.
  • oxidized sulfur atoms in the heterocyclic group include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. Also includes the following bicyclic or tricyclic groups, but is not limited to the following groups and many more.
  • the heterocyclic group may be optionally substituted with one or more substituents described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is The system is aromatic, and at least one ring contains one or more heteroatoms, the heteroatoms having the definitions described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is The system is aromatic, and at least one ring contains one or more heteroatoms, the heteroatoms having the definitions described in the present invention.
  • heteroaryl “heteroaryl ring” or “heteroaromatic compound” are used interchangeably herein.
  • the heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, consisting of 5-14 atoms Heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, consisting of 5-10 atoms Heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, consisting of 5-6 atoms Heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, a heteroaryl group consisting of 5 atoms base.
  • the heteroaryl group is a heteroaryl group consisting of 6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, that is, a heteroaryl group consisting of 6 atoms .
  • the heteroaryl group is a monocyclic heteroaryl group composed of 5-6 atoms.
  • the heteroaryl group is a spiro bicyclic heteroaryl group consisting of 9-13 atoms.
  • the heteroaryl group is a fused bicyclic heteroaryl group composed of 7-11 atoms; in some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group composed of 8-10 atoms.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl groups include, but are not limited to, furyl (eg 2-furyl, 3-furyl), imidazolyl (eg N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl), pyrrolyl (eg N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg 3-pyridazinyl), thiazolyl (eg 2-thiazolyl, 4-thiazo
  • m atoms typically describes the number of ring-forming atoms in the molecule, and the number of ring-forming atoms in the molecule is m.
  • piperidinyl is a heterocyclic group consisting of 6 ring atoms
  • naphthyl is an aryl group consisting of 10 atoms.
  • halogen refers to F, Cl, Br or I.
  • D refers to deuteration, that is, 2 H.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • hydroxyl refers to -OH.
  • amino refers to -NH 2.
  • cyano refers to -CN.
  • Carboxy 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 functionality when other functional groups in the compound react.
  • amino protecting group refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to the functionality of the hydroxy substituent to block or protect the hydroxyl group.
  • Suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxy Benzyl and silane groups.
  • Carboxyl protecting group refers to the substituent of carboxyl group used to block or protect the functionality of carboxyl group, general carboxyl protecting group includes -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 Phosphino) ethyl, nitroethyl, etc.
  • protecting groups can refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups,
  • LG refers to an atom or functional group that is detached from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution reactions and elimination reactions.
  • a nucleophilic substitution reaction a reactant attacked by a nucleophilic reagent is called a substrate, and an atom or atomic group that breaks out with a pair of electrons from a substrate molecule is called a leaving group.
  • Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, or hydroxyl groups.
  • pharmaceutically acceptable means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients containing the formulation and / or the mammal treated with it.
  • pharmaceutically acceptable in the present invention refers to use in animals, especially humans, approved by the federal regulatory agency or national government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia.
  • carrier includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (eg, antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient Forming agents, dispersing agents, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceuticals, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.
  • pharmaceutical composition refers to a mixture of one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable Carriers, excipients, diluents, adhesives, fillers and other auxiliary materials, as well as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerosis agents 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.
  • Inflammatory disease refers to any disease with excessive inflammatory symptoms, damage to host tissue or loss of tissue function due to excessive or uncontrolled inflammatory response , Disorder or symptoms.
  • Inflammatory disease also refers to a pathological state mediated by leukocyte influx and / or neutrophil chemotaxis.
  • Inflammation refers to a local protective response caused by tissue damage or destruction, which is used to destroy, dilute or isolate (isolate) harmful substances and Damaged organization. Inflammation is significantly associated with leukocyte influx and / or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses and non-infectious means, such as trauma or reperfusion after myocardial infarction or stroke, immune response to foreign antigens, and autoimmune response. Therefore, inflammatory diseases that can be treated with the compounds disclosed herein include diseases related to specific defense system responses as well as non-specific defense system responses.
  • allergy refers to any symptom, tissue damage, or loss of tissue function that produces an allergy.
  • Arthritis disease as used in the present invention refers to any disease characterized by arthritic damage that can be attributed to various etiologies.
  • Dermatis as used in the present invention refers to any of a large family of skin diseases characterized by skin inflammation that can be attributed to various etiologies.
  • Transplant rejection as used in the present invention refers to any immune response against transplanted tissues, such as organs or cells (such as bone marrow), characterized by loss of function of transplantation or surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia.
  • the treatment methods of the present invention include methods for treating diseases associated with inflammatory cell activation.
  • the structural formula of the compounds described in the present invention includes one or more different atom-enriched isotopes.
  • treating any disease or disorder as used in the present invention, in some embodiments, refers to improving the disease or disorder (ie, slowing or preventing or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, “treatment” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to regulating a disease or condition physically (eg, stabilizing perceptible symptoms) or physiologically (eg, 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 disorder.
  • the present invention provides a class of compounds with good VAP-1 inhibitory activity and pharmaceutical compositions thereof.
  • the compounds and pharmaceutical compositions of the present invention can be prepared for the treatment of inflammatory diseases and / or inflammation-related diseases, diabetes and / or Or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection drugs, especially for the treatment of non-alcoholic fatty liver disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
  • the present invention also provides methods of preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions to prepare medicaments for the above-mentioned diseases in mammals, especially humans.
  • the compounds of the present invention Compared with the existing similar compounds, the compounds of the present invention have good pharmacological activity, and / or excellent in vivo metabolic kinetic properties or in vivo pharmacodynamic properties. At the same time, the preparation method is simple and easy, and the technological method is stable, which is suitable for industrial production. Therefore, the compounds provided by the present invention have more excellent drug-forming properties 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 of a compound represented by formula (I) Acceptable salts or their prodrugs,
  • A, R 1 , R 2 , R 3 , R 4 , R 5 , U 1 and U 2 have the definitions as described in the present invention.
  • U 1 and U 2 are each independently CH or N.
  • R 1 , R 2 and R 3 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1- 6 Haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy or hydroxy C 1-6 alkyl.
  • R 4 and R 5 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 haloalkoxy or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-6 cycloalkyl are each Independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH , -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 haloalkoxy;
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3-6 carbocyclic ring or a heterocycle consisting of 3-6 atoms, wherein the C 3-6 carbocyclic ring and 3-6 atoms are
  • the heterocycles are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, or C 1-6 haloalkoxy.
  • A is a heterocyclic group consisting of 5-14 atoms or a heteroaryl group consisting of 5-14 atoms, wherein A is unsubstituted or substituted by 1, 2, 3, or 4 R 6 Substitution; wherein said R 6 has the definition described in the present invention.
  • q is 0, 1, or 2.
  • each R a, R b, R c , R d, R e and R f are independently H, D, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl Group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 3-6 atom heterocyclic group, C 6-10 aryl group or 5-6 atom heteroaryl group, wherein the C 1- 6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10
  • the aryl group and the heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, -OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN , -OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
  • A is a monocyclic heterocyclic group composed of 5-6 atoms, a monocyclic heteroaryl group composed of 5-6 atoms, a bridged heterocyclic group composed of 7-9 atoms, 9-13 Spiro bicyclic heterocyclic group consisting of 9 atoms, spiro bicyclic heteroaryl consisting of 9-13 atoms, fused bicyclic heterocyclic group consisting of 7-11 atoms or fused bicyclic heteroaryl group consisting of 7-11 atoms , Wherein the A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 ; wherein the R 6 has the definition described in the present invention.
  • A is the following substructure formula:
  • Each E is independently N or CH;
  • Each T is independently-(CH 2 ) x- ;
  • Each y is independently 0, 1, or 2;
  • Each w is independently 0, 1, or 2;
  • x is 1, 2 or 3;
  • Ring C is a C 3-6 carbocyclic ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms;
  • Each ring D is independently a C 3-6 carbocycle, a heterocycle consisting of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring consisting of 5-6 atoms;
  • A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 .
  • Ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane, 1, 3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine , Pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine or pyridazine.
  • each ring D is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane , 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, Pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine or pyridazine.
  • A is wherein, the A is unsubstituted or substituted with 1, 2, 3 or 4 R 6 , wherein the R 6 has the definition described in the present invention.
  • each of R a, R b, R c , R d, R e and R f are independently H, D, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 atom heterocyclic group, C 6-10 aryl group or 5-6 atom heteroaryl group, wherein C 1- 4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C 6- 10 aryl groups and heteroaryl groups consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br , I, CN, -OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alk
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN , -OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
  • each of R a, R b, R c , R d, R e and R f are independently H, D, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl , Tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclic group, phenyl group or 5-6 atom heteroaryl group, wherein the methyl, ethyl, n-propyl , Isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclic group, phenyl group and 5-6 atom heteroaryl group are independently unsubstituted or substituted by 1 , 2, 3, or 4 substituents, the substituents are independently selected from D, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl,
  • R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and Heteroaromatic rings composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I,- CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
  • R 1 , R 2 and R 3 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-4 alkyl, C 1- 4 Haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy or hydroxy C 1-4 alkyl.
  • R 1 , R 2 and R 3 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , methyl, ethyl, n-propyl , Isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylamino, trifluoromethoxy or hydroxymethyl.
  • R 4 and R 5 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 haloalkoxy or C 3-6 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy and C 3-6 cycloalkyl are each Independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH , -SH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino or C 1-4 haloalkoxy;
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3-6 carbocyclic ring or a heterocycle consisting of 3-6 atoms, wherein the C 3-6 carbocyclic ring and 3-6 atoms are
  • the heterocycles are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, or C 1-4 haloalkoxy.
  • R 4 and R 5 are each independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , methyl, ethyl, n-propyl, isopropyl Group, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, Trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or
  • R 4 and R 5 together with the carbon atoms to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thia Cyclobutane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine , Wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene oxide, azetidine, oxetane, thietane, 1,3-dioxolane Alkanes, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, t
  • the invention relates to one of the following structures, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or their pro medicine,
  • the invention in another aspect, relates to a pharmaceutical composition comprising the compound of the invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition of the present invention further comprises one or more other therapeutic agents.
  • the other therapeutic agents described herein are selected from VAP-1 inhibitors.
  • the other therapeutic agent of the present invention is Vapaliximab, PRX-167700, BTT-1023, ASP-8232, PXS-4728A, or RTU-1096.
  • the pharmaceutical composition of the present invention may be in the form of liquid, solid, semi-solid, gel or spray.
  • the invention relates to the use of the compound or pharmaceutical composition of the invention in the preparation of a medicament, wherein the medicament is used to inhibit VAP-1.
  • the invention relates to the use of the compounds or pharmaceutical compositions of the invention for inhibiting the activity of VAP-1.
  • the present invention relates to a method for inhibiting VAP-1 activity using the compound or pharmaceutical composition of the present invention, the method is to administer an effective therapeutic amount of the compound or the pharmaceutical composition to a patient.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used for the prevention, treatment or alleviation of VAP-1 protein or by VAP-1 Regulated diseases.
  • the invention relates to the use of the compounds or pharmaceutical compositions of the invention for the prevention, treatment or alleviation of diseases associated with or regulated by VAP-1 protein.
  • the present invention relates to a method for preventing, treating or alleviating diseases related to or regulated by VAP-1 protein using the compound or pharmaceutical composition of the present invention, the method is to administer the invention An effective therapeutic amount of the compound or the pharmaceutical composition.
  • 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 diseases described herein that are related to or regulated by VAP-1 protein are inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, ischemic diseases, vascular diseases , Fibrosis or tissue transplant rejection.
  • the inflammatory diseases and / or inflammation-related diseases of the present invention are arthritis, systemic inflammatory syndrome, sepsis, synovitis, Crohn's disease, ulcerative colitis, inflammatory Bowel disease, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease.
  • the arthritis of the present invention is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
  • systemic inflammatory syndrome of the present invention is systemic inflammatory sepsis.
  • the inflammatory bowel disease of the present invention is allergic bowel disease.
  • the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic Fatty liver disease.
  • 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 respiratory disease of the present invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.
  • the eye diseases of the present invention are uveitis, ulcerative colitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis,
  • the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.
  • the neuroinflammatory disease of the present invention is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, or chronic multiple sclerosis.
  • 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 ischemic disease of the present invention is stroke and / or complications thereof, myocardial infarction and / or complications thereof, or destruction of tissues by inflammatory cells after stroke.
  • the fibrosis of the present invention is liver fibrosis, cystic fibrosis, renal fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.
  • the vascular disease of the present invention is atherosclerosis, chronic heart failure, or congestive heart failure.
  • the disease described herein is cancer.
  • the cancer of the present invention is melanoma and lymphoma.
  • the dosage of the compound or pharmaceutical composition required for the implementation of treatment, prevention or delay is usually dependent on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by the attending physician Determine the specific situation.
  • the compound or pharmaceutical composition provided by the present invention when administered by an intravenous route, it can be administered once a week or even at longer intervals.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically related to the other components that make up the formulation and the mammal used for treatment.
  • the salt of the compound of the present invention also includes an intermediate for preparing or purifying an intermediate of the compound represented by formula (I) or a salt of an enantiomer isolated from the compound represented by formula (I), but it is not necessarily pharmaceutically acceptable salt.
  • compositions, formulations and administration of compounds of the present invention are provided.
  • the present invention relates to a pharmaceutical composition, which includes the compound of the present invention or the compound of the structure shown in the examples, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceuticals Acceptable salts or their prodrugs.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof, and optionally, other therapeutic and / or prophylactic ingredients.
  • the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, excipient, adjuvant or vehicle.
  • the amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably inhibit the activity of VAP-1 in a biological specimen or a patient.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof.
  • a pharmaceutically acceptable carrier include any solvent, diluent, Or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form.
  • substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween 80 , Phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (eg protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt) , Silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, methyl cellulose, hydroxypropyl methyl cellulose, lanolin, sugars (e.g.
  • 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, Gels, talc, excipients (e.g. cocoa butter and suppository wax), oils (e.g. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), ethylene glycol (e.g.
  • propylene glycol or polyglycol Ethylene glycol
  • ester example Ethyl oleate and ethyl dodecanoate
  • agar buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, 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, coating agents, sweeteners and flavoring agents, according to the judgment of the formulator, Preservatives and antioxidants can also be present in the composition.
  • buffers such as magnesium hydroxide and aluminum hydroxide
  • alginic acid such as pyrogen-free water, isotonic saline, Ringer's solution, ethanol and Phosphate buffer and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium
  • the compound or composition of the present invention can be administered by any suitable means, and can be taken orally, rectum, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment or drops) according to the severity of the disease or Nasal sprays and the like administer the compounds described above 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.
  • liquid dosage forms 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 Ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed 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 their mixtures.
  • oral compositions can also include adjuvants, such as
  • Injectable formulations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, for example, 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, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents water, Ringer's solution, and isotonic sodium chloride solution can be used.
  • sterile fixed oils as solvents or suspending media. For this, any odorless fixed oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as octadecenoic acid
  • the injectable formulations can be sterilized by filtration through a bacteria-retaining filter or by addition in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds according to the invention with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or suppository waxes, said excipients Or the carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
  • suitable non-irritating excipients or carriers for example cocoa butter, polyethylene glycol or suppository waxes, said excipients Or the carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier 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, gel, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants, such as glycerin, d) disintegrants , Such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) Wetting agents, such as cetyl alcohol and gly
  • excipients such as lactose or milk sugar and high molecular weight polyethylene glycol
  • 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 opacifiers and may also have the properties of the composition, so that only the active ingredient is optionally 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 opacifiers and may also have the properties of the composition, so that only the active ingredient is optionally 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 compounds may also take the form of micro-seals with one or more excipients mentioned above.
  • the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch.
  • this dosage form may also contain additional substances in addition to inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifiers and may also have the properties of the composition, so that only the active ingredient is optionally 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.
  • Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Under sterile conditions, 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 skin patches that provide the additional advantage of controlling the delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flow of compounds through the skin. The rate can be controlled by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.
  • composition of the present invention can also be administered orally, parenterally, by topical, rectal, nasal, buccal, vaginal inhalation spray, or by implantation kit.
  • parenteral as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial cavity, 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 water or oil suspension. These suspensions can be prepared following techniques known in the art using suitable dispersing or wetting agents and suspending agents. In addition, it is customary to use sterile fixed oils as solvents or suspending media. For this, any odorless fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, just as natural pharmaceutically acceptable oils, especially in polyoxyethylated form, such as olive oil or castor oil, fatty acids such as octadecenoic acid and its glyceride derivatives are used to prepare injections.
  • oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions.
  • long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersants commonly used in formulating 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 oral 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 pharmaceutical composition of the present invention can 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 suitable topical formulations for each of these areas or organs.
  • Rectal suppository formulations (see above) or suitable enema formulations can achieve local drip application to the lower intestine.
  • Topical skin patches can also be used.
  • the pharmaceutical composition may be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers suitable for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum oil, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active components 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 may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or in particular as a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride.
  • the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
  • the pharmaceutical composition can also be administered by nasal vaporized spray or inhalation.
  • This composition is prepared according to techniques well known in the pharmaceutical field and is prepared in saline using benzyl alcohol and other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants Solution.
  • unit dosage form refers to physically discrete units suitable as unit doses for the subject, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier.
  • the unit dosage form can be a single daily dose or one of multiple daily doses (eg, 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 medicament, wherein the medicament is used to inhibit VAP-1, or the medicament is used to prevent, treat or alleviate VAP -1 protein related or regulated by VAP-1 disease.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to inhibit VAP-1 activity, or a method of preventing, treating or alleviating diseases related to or regulated by VAP-1 protein;
  • the method is to give 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 a method of using the compound or pharmaceutical composition of the present invention for inhibiting VAP-1 activity, or preventing, treating or alleviating diseases related to or regulated by VAP-1 protein.
  • the diseases related to or regulated by VAP-1 protein in the present invention are inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection .
  • the compound of the present invention can also be applied to veterinary treatment of pets, introduced breeds of animals and farm animals, including mammals, rodents and so on. Examples of other 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 of the present invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or reduce the severity of one or more of the disorders mentioned in the present invention .
  • the compounds of the present invention or pharmaceutically acceptable pharmaceutical compositions are effective in a relatively wide range of dosages.
  • the daily dose is in the range of 0.1 mg-1000 mg / person, divided into one or several administrations.
  • the methods, compounds and pharmaceutical compositions according to the present invention can be used in any amount and route of administration to effectively treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on race, age, patient's general condition, severity of infection, special factors, mode of administration, etc.
  • the compounds or pharmaceutical compositions 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 method described in the present invention, unless otherwise specified, wherein the definition of the substituent 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, and 19 F-NMR chemical shifts ( ⁇ ) are given in units of parts per million (ppm).
  • 1 H-NMR, 13 C-NMR and 19 F-NMR were measured with Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, and the solvent was determined to be deuterated chloroform (CDCl 3 ), deuterated Methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • Preparative purification or preparative resolution generally use Novasep pump 250 high performance liquid chromatograph.
  • the starting materials of the present invention are known and can be purchased on the market, purchased from Shanghai Accela Company (Shanghai Accela Company), An Nai Company (Energy Company), Braunway Company (J & K), Tianjin Alfa Alfa Company (Alfa Company) and other companies can either adopt or synthesize according to methods known in the art.
  • Nitrogen atmosphere means that the reaction bottle 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 high-pressure reactor with a volume of about 1L.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature; unless otherwise specified in the examples, the room temperature is 20 ° C to 40 ° C.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing system used in the reaction was: 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 was determined using Agilent 1260 high-pressure liquid chromatograph (Eclipse Plus C18 4.6 ⁇ 150mm 3.5um column);
  • the gradient of the mobile phase is shown in Table A:
  • the LC / MS / MS system used for analysis in the biological test includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice autosampler, column incubator, and 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 analysis used Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ M column, and injected 5 ⁇ L of sample. Analysis conditions: The mobile phase was 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL / min. The gradient of the mobile phase is shown in Table C:
  • the Agilent 6330 series LC / MS / MS spectrometer equipped with a G1312A binary injection pump, G1367A automatic sampler and G1314C UV detector; LC / MS / MS spectrometer adopts ESI radiation source.
  • the Capcell MP-C18 column was used during the analysis, and the specifications were: 100 ⁇ 4.6mm I.D., 5 ⁇ M (Phenomenex, Torrance, California, USA).
  • the mobile phase is 5mM ammonium acetate, 0.1% aqueous methanol 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.
  • a typical synthetic procedure for preparing the disclosed compounds of the present invention is shown in the following Synthesis Scheme 1. Unless otherwise stated, A has the definition as described in the present invention, X is halogen; PG is a hydroxy protecting group.
  • the compound having the structure represented by the general formula (I-A) can be prepared by the general synthesis method described in Synthesis Scheme 1, and the specific steps can refer to the examples.
  • Compound (Ia) undergoes nucleophilic reaction with compound (Ib) under basic conditions to obtain compound (Ic); compound (Ic) undergoes nucleophilic reaction with compound (Id) under basic conditions and palladium catalyst to obtain compound (Ie) ); Compound (Ie) removes the hydroxyl protecting group to obtain Compound (If); or Compound (Ic) undergoes a nucleophilic reaction with Compound (Ig) under basic conditions and a palladium catalyst to directly obtain Compound (If); Compound ( If) first react with 1,1'-dicarbonylimidazole and then react with a suitable guanidine salt (such as guanidine carbonate) to obtain the target compound represented by the general formula (IA).
  • a suitable guanidine salt such as guanidine carbonate
  • Step 1) 4- [5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl] morpholine
  • Step 2 tert-Butyl-[[3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridyl] methoxy] -dimethyl-silane
  • Step 1) 7- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl] -3- (tri (Fluoromethyl) -6,8-dihydro-5H- [1,2,4] triazole [4,3-a] pyrazine
  • Step 2 tert-Butyl-[[3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4] triazolo [4 , 3-a] pyrazin-7-yl] pyrimidin-5-yl] -4-pyridyl] Methoxy] -dimethyl-silane
  • Step 1) 8- [5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyrimidin-2-yl] -3,8-di Azaspiro [4,5] decane-2-one
  • reaction solution was cooled to room temperature, concentrated, ethanol (5 mL) was added, stirred for 10 minutes, filtered, the filter cake was washed with ethanol (1 mL), and the filter cake was collected and dried to give the title compound (0.86 g, yield 58%) as off-white solid.
  • Step 2) 8- [5- [4- [tert-butyl (dimethyl) silyl] oxymethyl] -3-fluoro-2-pyridyl] pyrimidin-2-yl] -3,8-diazepine Heterospiro [4,5] decane-2-one
  • N, N'-carbonyldiimidazole (0.21g, 1.31mmol) was added to 8- [5- [3-fluoro-4- (hydroxymethyl) -2-pyridyl] pyrimidin-2-yl] -3, A solution of 8-diazaspiro [4,5] decane-2-one (0.18 g, 0.50 mmol) in N, N-dimethylformamide (10 mL) was reacted at room temperature for 2 hours. Guanidine carbonate (0.25 g, 2.01 mmol) was added to continue the reaction for 8 hours.
  • Step 1) 8- [5- [4-[[tert-butyl (dimethyl) silyl] oxymethyl] -3-fluoro-2-pyridyl] pyrimidin-2-yl] -3-methyl- 3,8-diazaspiro [4,5] decane-2-one
  • reaction solution was poured into ice water (10 mL) and quenched, saturated ammonium chloride solution (10 mL) was added, extracted with ethyl acetate (15 mL ⁇ 2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL), Dry over anhydrous sodium sulfate and concentrate by suction filtration.
  • Step 2) 8- [5- [3-fluoro-4- (hydroxymethyl) -2-pyridyl] pyrimidin-2-yl] -3-methyl-3,8-diazaspiro [4,5 ] Decane-2-one
  • N, N'-carbonyldiimidazole (0.10 g, 0.59 mmol) was added to 8- [5- [3-fluoro-4- (hydroxymethyl) -2-pyridyl] pyrimidin-2-yl] -3-
  • a solution of methyl-3,8-diazaspiro [4,5] decane-2-one (85mg, 0.23mmol) in N, N-dimethylformamide (6mL) was reacted at room temperature for 3 hours, and then Guanidine carbonate (0.25 g, 2.01 mmol) was added, and the reaction was continued for 12 hours.
  • Step 1) 2- (1-piperidinyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborate-2-yl) pyrimidine
  • reaction solution was cooled to room temperature, concentrated, ethanol (6 mL) was added, stirred for 10 minutes, filtered, the filter cake was washed with ethanol (2 mL), and the filter cake was collected and dried to obtain the title compound (2.00 g, yield 77%), which was off-white solid.
  • Step 2 tert-Butyl-[[3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl] -4-pyridyl] methoxy] -dimethyl-silane
  • Test purpose The following method is used to determine the inhibitory activity of the compounds of the present invention on VAP-1.
  • VAP-1 Human recombinant VAP-1 (VAP-1, human) was purchased from Sigma, Cat. No. SRP6241;
  • Red Monoamine Oxidase Assay Kit was purchased from Invitrogen, Cat. No. A12214;
  • 384-well plates were purchased from Corning, Cat. No. 6005174;
  • Benzylamine hydrochloride was purchased from Sigma, Cat. No. B5136-25G;
  • DMSO Dimethyl Sulfoxide, dimethyl sulfoxide
  • test compound was dissolved in DMSO and diluted 4-fold for a total of 10 concentrations.
  • 25 ⁇ L of human recombinant VAP-1 (1.6 ⁇ g / mL) was added to each well.
  • 100 nL of test compound with different concentrations was added to each well containing human recombinant VAP-1 and incubated at room temperature for 30 min.
  • 25 ⁇ L of 1mM benzylamine hydrochloride Red Monoamine Oxidase Assay Kit reaction mixture containing 200 ⁇ M Amplex Red reagent, 1U / mL HRP was added to the corresponding wells, and incubated at room temperature in the dark for 60min.
  • test results show that the compound of the present invention has a significant inhibitory effect on human recombinant VAP-1.
  • Test purpose The following method is used to determine the selective inhibitory activity of the compounds of the present invention on DAO.
  • Human reorganization DAO (Recombinant Human ABP-1 / DAO) was purchased from R & D, Cat. No. 8298-AO;
  • Red Hydrogen PeroxidePeroxidase Assay Kit was purchased from Invitrogen, Cat.No.A22188;
  • 1,4-Butanediamine dihydrochloride (1,4-Diaminobutane dihydrochloride) was purchased from Aladdin, Cat. No. D106194-25G;
  • test compound was dissolved in DMSO and diluted 5 times, for a total of 6 concentrations.
  • 24 ⁇ L of human recombinant DAO (1 ⁇ g / ml) was added to each well.
  • 1 ⁇ L of test compound with different concentrations was added to each well containing human recombinant DAO and incubated at 37 ° C. for 30 min.
  • 25 ⁇ L containing 1M 1,4-butanediamine dihydrochloride Red Hydrogen PeroxidePeroxidase Assay Kit (with 100 ⁇ M The reaction mixture of Red and 0.2 U / ml HRP) was added to the corresponding wells and incubated at 37 ° C in the dark for 30 min.
  • the fluorescence value (RFU) was read at 540 nm excitation and 580 nm emission using PHERAstar FSX microplate reader of BMG LABTECH.
  • Graph Pad Prism 5 software was used to draw the curve and calculate the IC 50 value.
  • test results show that the compounds of the present invention have high selectivity for VAP-1.
  • Measurement purpose The following method is used to determine the pharmacokinetics of the compound of the present invention.
  • SD rat male, 180-220g, 7-8 weeks old, purchased from Hunan Slake Experimental Animal Co., Ltd.
  • test sample stock solution Weigh an appropriate amount of test sample precisely, dissolve with DMSO, dilute to 1 mg / mL with acetonitrile, and shake to obtain. Store at -20 °C until use.
  • the liquid-liquid extraction method was used to process the samples, and the chromatographic separation was performed.
  • quantitative analysis was performed by multiple reactive ion monitoring (MRM), and the results were calculated with the instrument quantitative software.
  • the content of the compound to be tested in the plasma of rats after administration of different compounds was determined by LC / MS / MS method.
  • test results show that the compound of the present invention has good pharmacokinetic properties.

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Abstract

属于药物领域，具体涉及一种作为VAP-1抑制剂的胍类衍生物及其用途，进一步涉及包含所述化合物的药物组合物。所述的化合物或药物组合物可用于治疗炎症和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。

Description

胍类衍生物及其用途
相关申请的交叉引用
本申请要求在2018年10月22日提交的中国专利申请号201811228252.4享有优先权，该专利通过引用被全部合并于此。
技术领域
本发明属于药物领域，具体涉及一种作为VAP-1(Vascular adhesion protein-1,VAP-1)抑制剂的胍类衍生物及其制备方法和用途。更具体地说，本发明涉及通式(I)所示的化合物或其在药学上可接受的盐或其立体异构体、几何异构体，以及含有该化合物的药物组合物，进一步涉及所述的化合物及药物组合物在制备用于预防、治疗或减轻炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥的药物中的用途。
背景技术
胺氧化酶(Amine Oxidase,AO)是一类有特殊生物功能的蛋白质，在生物体内广泛存在，参与生物胺的代谢，使胺氧化裂解成醛和氨。大家所熟知的主要有两类胺氧化酶，一类是以醌为辅酶的含铜胺氧化酶(copper amine oxidase,COAs)；另一类是以黄素腺嘌呤二核苷酸(FAD)为辅酶的含黄素胺氧化酶。含黄素胺氧化酶主要包括单胺氧化酶(Monoamine oxidases,MAOs)和多胺氧化酶(Polyamine oxidases,POs)。MAOs有2个亚型，分别为单胺氧化酶A(Monoamine oxidase A,MAO-A)和单胺氧化酶B(Monoamine oxidase B,MAO-B)，主要存在于哺乳动物细胞的线粒体外膜中，能选择性代谢(氧化脱氨基)伯胺、仲胺和叔胺。抑制MAOs的药物可用于治疗抑郁症。POs有3个亚型，它们通过氧化多胺如精胺和亚精胺，参与细胞的生长调节。含铜胺氧化酶可以进一步分为：2,4,5-三羟基苯丙氨酸醌(TPQ)依赖的含铜胺氧化酶家族和赖氨酸酪氨酰氨醌(LTQ)依赖的赖氨酰氧化酶家族。其中，2,4,5-三羟基苯丙氨酸醌(TPQ)依赖的含铜胺氧化酶家族包括二胺氧化酶(diamine oxidase,DAO)、视网膜特异的胺氧化酶(Retina specific amine oxidase,RAO)、血管黏附蛋白-1(Vascular adhesion protein-1,VAP-1)和血清胺氧化酶(serum amine oxidase,SAO)。
哺乳动物的含铜胺氧化酶主要由AOC1、AOC2、AOC3和AOC4基因编码。其中，AOC1编码DAO，AOC2编码RAO，AOC3编码VAP-1，AOC4编码SAO。DAO主要在肾、胎盘、肠和精囊中表达，其只对二胺，尤其是组胺起作用，故又称为组胺氧化酶。RAO于1997年从人类视网膜中克隆出来，具有视网膜特异性，其三维结构的总体折叠跟VAP-1相似。RAO可氧化2-苯乙胺、色胺和酪胺。SAO只在牛、马、猪和绵羊的体内高度表达，在人类的体内，是一段缺乏功能性的蛋白。
血管黏附蛋白-1(VAP-1)由定位于人17号染色体的AOC3基因编码，是一种对氨基脲敏感的胺氧化酶。VAP-1广泛存在于哺乳动物体内脉管含量丰富的组织中，主要以两种形式存在，一种是可溶性的形式，主要存在于循环血液中；一种是膜结合的形式，广泛分布于器官和组织中，尤其是在脂肪细胞、血管内皮细胞和平滑肌细胞中。VAP-1具有双重功能，一方面是淋巴细胞的黏附分子，可促进淋巴细胞黏附于血管内皮，还可以通过调节转录因子、趋化因子和其他粘附分子来调节炎症微环境；另一方面，VAP-1还具有酶的功效，能够催化伯胺为相应的醛、氨和过氧化氢。
炎症是免疫系统对感染或刺激的第一反应。白细胞进入组织循环的移动对该过程是重要的。不适当的炎症反应可导致另外的健康组织的局部炎症，其可导致诸如类风湿性关节炎、炎症性肠病、多发性硬化症、哮喘、慢性阻塞性肺病(COPD)、湿疹、牛皮癣等疾病。白细胞在通过血管壁之前需通过结合黏附分子黏附于内皮。VAP-1作为一种内皮黏附分子，在诸如淋巴器官的高效静脉内皮细胞(HVE)的血管内皮细胞 中大量表达，并且还在肝窦内皮细胞(HSEC)、平滑肌细胞和脂肪细胞中表达，能诱导细胞黏附，调节白细胞转运，参加粒细胞外渗，并且在炎症过程中其水平升高。中性粒细胞从血液向炎症部位迁移是通过黏附分子结合血管内皮细胞实现的。因此，VAP-1在与炎症相关的疾病中发挥着重要作用，受到了科研人员的广泛重视。
据报道，已经在以下疾病中观测到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，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。
发明摘要
本发明提供了一类具有较好的抑制VAP-1活性的新化合物，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、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥的药物，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。
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 PCTCN2019112392-appb-000001
其中，
U 1和U 2各自独立地为CH或N；
R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基或羟基C 1-6烷基；
R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 3-6环烷基，其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-6环烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
或R 4、R 5和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环，其中所述C 3-6碳环和3-6个原子组成的杂环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
A为5-14个原子组成的杂环基或5-14个原子组成的杂芳基，其中所述A未被取代或被1、2、3或4个R 6所取代；
各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1- 6卤代烷氧基、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C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
q为0、1或2；
各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-6卤代烷基、C 1-6烷基、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C 1-6卤代烷基、C 1-6烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基；
或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基。
在一些实施方案中，A为以下子结构式：
Figure PCTCN2019112392-appb-000002
其中，
各E独立地为N或CH；
各G独立地为-CH 2-、-NH-、-O-、-S-、-S(＝O)-或-S(＝O) 2-；
U为N、-C＝或CH；
各T独立地为-(CH 2) x-；
各y独立地为0、1或2；
各w独立地为0、1或2；
x为1、2或3；
环C为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
各环D独立地为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
其中，所述A未被取代或被1、2、3或4个R 6所取代。
在另一些实施方案中，环C为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪。
各环D独立地为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪。
在又一些实施方案中，A为
Figure PCTCN2019112392-appb-000003
Figure PCTCN2019112392-appb-000004
Figure PCTCN2019112392-appb-000005
其中，所述A未被取代或被1、2、3或4个R 6所取代。
在一些实施方案中，各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1- 4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、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C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4卤代烷氧基；
q为0、1或2；
各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-4卤代烷基、C 1-4烷基、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C 1-4卤代烷基、C 1-4烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基；
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基。
在又一些实施方案中，各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-NHCH 3、-N(CH 3) 2、＝O、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-C(＝O)N(CH 3) 2、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-NHC(＝O)R a、-NHS(＝O) 2R e、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基或哒嗪基，其中所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟乙基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基。
在一些实施方案中，R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、甲氨基、三氟甲氧基或羟基甲基。
在一些实施方案中，R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、三氟乙基、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基；
或R 4、R 5和与它们相连的碳原子一起，形成环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉或哌嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉和哌嗪各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基。
在又一些实施方案中，各R a、R b、R c、R d、R e和R f独立地为H、D、三氟甲基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、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，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基；
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。
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载体、赋形剂、辅剂、媒介物或它们的组合。
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VAP-1。
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VAP-1的活性。
另一方面，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VAP-1活性的方法，所述方法包括给予患者本发明所述化合物或药物组合物的有效治疗量。
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，所述药物用于预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
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预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
另一方面，本发明涉及一种使用本发明所述的化合物或药物组合物预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病的方法，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，其中，所述与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
在另一些实施方案中，本发明所述炎症疾病和/或炎症相关疾病为关节炎、全身炎性综合征、脓血症、滑膜炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、肝病、呼吸道疾病、眼睛疾病、皮肤疾病或神经炎性疾病。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明所述全身炎性综合征为全身炎性脓毒症。
在又一些实施方案中，本发明所述炎症性肠病为过敏性肠病。
在又一些实施方案中，本发明所述肝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。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明所述皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹。
在又一些实施方案中，本发明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。
在另一些实施方案中，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。
在另一些实施方案中，本发明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。
在另一些实施方案中，本发明所述纤维化为肝纤维化、囊性纤维化、肾纤维化、特发性肺纤维化或放射性诱导的纤维化。
在另一些实施方案中，本发明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。
前面所述内容只概述了本发明的某些方面，但不限于这些方面。这些方面及其他的方面的内容将在下面更加具体完整的描述。
本发明详细说明书
本发明提供了一类具有抑制VAP-1活性的胍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.14of 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、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、氧代(＝O)、-COOH、-SH、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、卤代烷基、烷氧基、烷硫基、烷氨基、卤代烷氧基、羟基烷基、烷基、烯基、炔基、环烷基、碳环基、杂环基、芳基或杂芳基，其中，所述各R a、R b、R c、R d、R f和q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，而“5-6个原子组成的杂芳基”指5个原子组成的杂芳基和6个原子组成的杂芳基。
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。除非另外详细说明，烷基基团含有1-20个碳原子；在一些实施方案中，烷基基团含有1-12个碳原子；在一些实施方案中，烷基基团含有1-10个碳原子；在一些实施方案中，烷基基团含有1-9个碳原子；在一些实施方案中，烷基基团含有1-8个碳原子；在一些实施方案中，烷基基团含有1-6个碳原子；在一些实施方案中，烷基基团含有1-4个碳原子，在一些实施方案中，烷基基团含有1-2个碳原子。
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。在一实施方案中，烯基基团包含2-8个碳原子；在一实施方案中，烯基基团包含2-6个碳原子；在一实施方案中，烯基基团包含2-4个碳原子。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；在一些实施方案中，炔基基团包含2-6个碳原子；在一些实施方案中，炔基基团包含2-4个碳原子。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。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-6个碳原子；在一些实施方案中，烷氧基基团含有1-4个碳原子；在一些实施方案中，烷氧基基团含有1-3个碳原子。
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”或“烷基氨基”包括“N-烷基氨基”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，烷氨基是一个或两个C 1-6烷基连接到氮原子上的烷氨基基团。在一些实施方案中，烷氨基是一个或两个C 1-4烷基连接到氮原子上的烷基氨基基团。在一些实施方案中，烷氨基是一个或两个C 1-3烷基连接到氮原子上的烷基氨基基团。在一些实施方案中，烷氨基是一个或两个C 1-2烷基连接到氮原子上的烷基氨基基团。合适的烷氨基基团可以是单烷基氨基或二烷基氨基，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“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“碳环基”或“碳环”表示含有3-14个环原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环碳环体系。碳双环基包括螺碳双环基、稠合碳双环基和桥碳双环基。在一些实施方案中，碳原子的数量为3-12个，即C 3-12碳环；在另一些实施方案中，碳原子的数量为3-10个，即C 3-10碳环；在另一些实施方案中，碳原子的数量为3-8个，即C 3-8碳环；在另一些实施方案中，碳原子的数量为3-6个，即C 3-6碳环；在另一些实施方案中，碳原子的数量为5-6个，即C 5-6碳环；在其它一些实施方案中，碳原子的数量为5-8个，即C 5-8碳环。碳环基基团的实例包括，但并不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基，等等。
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，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，杂环基基团为5-14个环原子组成的环体系，即5-14个原子组成的杂环基；在一些实施方案中，杂环基基团为3-8个环原子组成的环体系，即3-8个原子组成的杂环基；在一些实施方案中，杂环基基团为3-6个环原子组成的环体系，即3-6个原子组成的杂环基；在一些实施方案中，杂环基为5-6个环原子组成的环体系，即5-6个原子组成的杂环基；在一些实施方案中，杂环基基团为4个环原子组成的环体系，即4个原子组成的杂环基；在一些实施方案中，杂环基基团为5个环原子组成的环体系，即5个原子组成的杂环基；在一些实施方案中，杂环基基团为6个环原子组成的环体系，即6个原子组成的杂环基； 在一些实施方案中，杂环基基团为7个环原子组成的环体系，即7个原子组成的杂环基。在一些实施方案中，杂环基基团是3-8个原子组成的单环(2-7个碳原子和选自N，O，P，S的1-3个杂原子)，或7-13个原子组成的双环(4-12个碳原子和选自N，O，P，S的1-3个杂原子)。在一些实施方案中，杂环基是5-6个原子组成的单环杂环基。在一些实施方案中，杂环基是7-9个原子组成的桥杂环基。在一些实施方案中，杂环基是9-13个原子组成的螺双环杂环基；还在一些实施方案中，杂环基是9-10个原子组成的螺双环杂环基。在一些实施方案中，杂环基为7-11个原子组成的稠合双环杂环基。所述杂环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。
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 PCTCN2019112392-appb-000006
基，二氮杂
Figure PCTCN2019112392-appb-000007
基，硫氮杂
Figure PCTCN2019112392-appb-000008
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，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。也包括以下的双环或三环基团，但绝不限于以下基团
Figure PCTCN2019112392-appb-000009
Figure PCTCN2019112392-appb-000010
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5-14个环原子，或5-10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5-14个环原子组成的杂芳基，即5-14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5-10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5-6个环原子组成的杂芳基，即5-6个原子组成的杂芳基。在另一些实施方案中，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个环原子组成的杂芳基，即5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6个环原子组成的杂芳基，即6个原子组成的杂芳基。在一些实施方案中，杂芳基为5-6个原子组成的单环杂芳基。在一些实施方案中，杂芳基为9-13个原子组成的螺双环杂芳基。在一些实施方案中，杂芳基为7-11个原子组成的稠合双环杂芳基；还在一些实施方案中，杂芳基为8-10个原子组成的稠合双环杂芳基。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、
Figure PCTCN2019112392-appb-000011
Figure PCTCN2019112392-appb-000012
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“硝基”是指-NO 2。
术语“巯基”是指-SH。
术语“羟基”是指-OH。
术语“氨基”是指-NH 2。
术语“氰基”是指-CN。
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.
术语“离去基团”或“LG”是指在化学反应中从一较大分子中脱离的原子或官能基，是亲核取代反应与消除反应中应用的术语。在亲核取代反应中，被亲核试剂进攻的反应物称为底物，而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。常见的离去基团例如但不限于，卤素原子、酯基、磺酸酯基、硝基、叠氮基或羟基等。
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“载体”包括任何溶剂，分散介质，包衣衣料，表面活性剂，抗氧化剂，防腐剂(例如抗细菌剂、抗真菌剂)，等渗剂，盐，药物稳定剂，粘合剂，赋形剂，分散剂，润滑剂，甜味剂，调味剂，着色剂，或其组合物，这些载体都是所属技术领域技术人员的已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。除了任意常规载体与活性成分不相容的情况外，涵盖其在治疗或药物组合物中的用途。
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。
本发明所使用的“过敏”是指产生过敏的任意症状、组织损害或组织功能丧失。如本发明所使用的“关节炎疾病”是指以可归因于各种病因学的关节炎性损伤为特征的任意疾病。如本发明所使用的“皮炎”是指以可归因于各种病因学的皮肤炎症为特征的皮肤疾病的大家族中的任意一种。如本发明所使用的“移植排斥” 是指以移植或周围组织的功能丧失、疼痛、肿胀、白细胞增多和血小板减少为特征的对抗移植组织，如器官或细胞(如骨髓)的任意免疫反应。本发明的治疗方法包括用于治疗与炎性细胞活化相关的疾病的方法。
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。
本发明化合物的描述
本发明提供了一类具有较好的抑制VAP-1活性的化合物及其药物组合物，本发明所述化合物及其药物组合物可制备用于治疗炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥的药物，尤其是治疗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。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/或优良的体内代谢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。
具体地说：
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 PCTCN2019112392-appb-000013
其中，A、R 1、R 2、R 3、R 4、R 5、U 1和U 2具有如本发明所述的定义。
在一些实施方案中，U 1和U 2各自独立地为CH或N。
在一些实施方案中，R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基或羟基C 1-6烷基。
在一些实施方案中，R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 3-6环烷基，其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-6环烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
或R 4、R 5和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环，其中所述C 3-6碳环和3-6个原子组成的杂环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基。
在一些实施方案中，A为5-14个原子组成的杂环基或5-14个原子组成的杂芳基，其中所述A未被取代或被1、2、3或4个R 6所取代；其中所述R 6具有本发明所述的定义。
在一些实施方案中，各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1- 6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、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C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；其中所述R a、R b、R c、R d、R e、R f和q具有本发明所述的定义。
在一些实施方案中，q为0、1或2。
在一些实施方案中，各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-6卤代烷基、C 1-6烷基、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C 1- 6卤代烷基、C 1-6烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基；
或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基。
在另一些实施方案中，A为5-6个原子组成的单环杂环基、5-6个原子组成的单环杂芳基、7-9个原子组成的桥杂环基、9-13个原子组成的螺双环杂环基、9-13个原子组成的螺双环杂芳基、7-11个原子组成的稠合双环杂环基或7-11个原子组成的稠合双环杂芳基，其中所述A未被取代或被1、2、3或4个R 6所取代；其中所述R 6具有本发明所述的定义。
在另一些实施方案中，A为以下子结构式：
Figure PCTCN2019112392-appb-000014
其中，
各E独立地为N或CH；
各G独立地为-CH 2-、-NH-、-O-、-S-、-S(＝O)-或-S(＝O) 2-；
U为N、-C＝或CH；
各T独立地为-(CH 2) x-；
各y独立地为0、1或2；
各w独立地为0、1或2；
x为1、2或3；
环C为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
各环D独立地为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
其中，所述A未被取代或被1、2、3或4个R 6所取代。
在又一些实施方案中，环C为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪。
在又一些实施方案中，各环D独立地为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪。
在又一些实施方案中，A为
Figure PCTCN2019112392-appb-000015
Figure PCTCN2019112392-appb-000016
Figure PCTCN2019112392-appb-000017
其中，所述A未被取代或被1、2、3或4个R 6所取代，其中所述R 6具有本发明所述的定义。
在另一些实施方案中，各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1- 4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、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C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4卤代烷氧基；其中所述R a、R b、R c、R d、R e、R f和q具有本发明所述的定义。
在另一些实施方案中，各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-4卤代烷基、C 1-4烷基、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C 1- 4卤代烷基、C 1-4烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基；
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基。
在又一些实施方案中，各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-NHCH 3、-N(CH 3) 2、＝O、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-C(＝O)N(CH 3) 2、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-NHC(＝O)R a、-NHS(＝O) 2R e、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基或哒嗪基，其中所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟乙基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基，其中所述R e和R a具有本发明所述的定义。
在又一些实施方案中，各R a、R b、R c、R d、R e和R f独立地为H、D、三氟甲基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、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，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基；
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。
在一些实施方案中，R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氧基或羟基C 1-4烷基。
在又一些实施方案中，R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、甲氨基、三氟甲氧基或羟基甲基。
在一些实施方案中，R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基或C 3-6环烷基，其中所述C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基和C 3-6环烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4卤代烷氧基；
或R 4、R 5和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环，其中所述C 3-6碳环和3-6个原子组成的杂环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4卤代烷氧基。
在又一些实施方案中，R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、三氟乙基、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基；
或R 4、R 5和与它们相连的碳原子一起，形成环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉或哌嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉和哌嗪各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基。
还在一些实施方案中，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 PCTCN2019112392-appb-000018
Figure PCTCN2019112392-appb-000019
Figure PCTCN2019112392-appb-000020
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。
在一些实施方案中，本发明所述的药物组合物，其进一步包含药学上可接受的载体、赋形剂、辅剂、媒介物或它们的组合。
在一些实施方案中，本发明所述的药物组合物，其进一步包含一种或多种其他治疗剂。
在另一些实施方案中，本发明所述其他治疗剂选自VAP-1抑制剂。
在另一些实施方案中，本发明所述其他治疗剂为Vapaliximab、PRX-167700、BTT-1023、ASP-8232、PXS-4728A或RTU-1096。
在另一些实施方案中，本发明所述的药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。
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VAP-1。
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VAP-1的活性。
另一方面，本发明涉及一种使用本发明所述的化合物或药物组合物抑制VAP-1活性的方法，所述方法是给予患者所述化合物或所述药物组合物的有效治疗量。
另一方面，本发明涉及本发明所述的化合物或所述的药物组合物在制备药物中的用途，其中，所述药物用于预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
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预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
另一方面，本发明涉及一种使用本发明所述的化合物或药物组合物预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病的方法，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。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。
在一些实施方案中，本发明所述的与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
在另一些实施方案中，本发明所述炎症疾病和/或炎症相关疾病为关节炎、全身炎性综合征、脓血症、滑膜炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、肝病、呼吸道疾病、眼睛疾病、皮肤疾病或神经炎性疾病。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明所述全身炎性综合征为全身炎性脓毒症。
在又一些实施方案中，本发明所述炎症性肠病为过敏性肠病。
在又一些实施方案中，本发明所述肝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。
还在一些实施方案中，本发明所述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。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明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。
在又一些实施方案中，本发明所述皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹。
在又一些实施方案中，本发明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。
在另一些实施方案中，本发明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。
在另一些实施方案中，本发明所述纤维化为肝纤维化、囊性纤维化、肾纤维化、特发性肺纤维化或放射性诱导的纤维化。
在另一些实施方案中，本发明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。
在一些实施方案中，本发明所述疾病是癌症。
在另一些实施方案中，本发明所述癌症为黑色素瘤和淋巴瘤。
实施治疗、预防或延缓等作用所需的化合物或药物组合物的剂量通常取决于施用的具体化合物、患者、具体疾病或病症及其严重程度、给药途径和频率等，并且需要由主治医师根据具体情况判定。例如，在通过经静脉途径施用本发明提供的化合物或药物组合物时，可以每周一次甚至以更长时间间隔进行施用。
除非其他方面表明，本发明的化合物所有的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐和药学上可接受的前药都属于本发明的范围。
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。
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实施例中所示结构的化合物，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载体、赋形剂、辅剂、媒介物或它们的组合，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载体、赋形剂、辅剂或媒介物。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载体，辅剂，媒介物或它们的组合，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，表明不同的载体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。除了任何常规的载体媒介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载体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赋形剂或载体，例如可可油、聚乙二醇或栓剂蜡制备的栓剂，所述赋形剂或载体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赋形剂或载体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赋形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助剂，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VAP-1，或所述药物用于预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
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VAP-1活性的方法，或预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病的方法；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VAP-1活性的方法，或预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病。
本发明所述与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
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-6120Quadrupole 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：
Figure PCTCN2019112392-appb-000021
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，A具有如本发明所述的定义，X为卤素；PG为羟基保护基。
合成方案1：
Figure PCTCN2019112392-appb-000022
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。化合物(I-a)在碱性条件下与化合物(I-b)发生亲核反应，得到化合物(I-c)；化合物(I-c)在碱性条件及钯催化剂作用下与化合物(I-d)发生亲核反应，得到化合物(I-e)；化合物(I-e)脱除羟基保护基，得到化合物(I-f)；或化合物(I-c)在碱性条件及钯催化剂作用下与化合物(I-g)发生亲核反应，直接得到化合物(I-f)；化合物(I-f)先与1,1’-二羰基咪唑反应后，再与合适的胍盐(如碳酸胍)反应，得到通式(I-A)所示的目标化合物。
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
在以下制备实施例中，发明人以本发明的部分化合物为例，详细描述了本发明化合物的制备过程。
实施例1[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲基N-脒基氨基甲酸酯(化合物1)
Figure PCTCN2019112392-appb-000023
步骤1)4-[5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶-2-基]吗啉
Figure PCTCN2019112392-appb-000024
将2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(2.00g,8.93mmol)溶于四氢呋喃(50mL)，加入吗啉(0.80mL,9.20mmol)和N,N-二异丙基乙胺(2.00g，12.00mmol)，80℃回流反应24小时。反应液冷却至室温，有固体析出，过滤，收集滤饼，得到标题化合物(2.00g,产率77％)，为白色固体。
MS(ESI,pos.ion)m/z:292.2[M+H] +。
步骤2)叔丁基-[[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲氧基]-二甲基-硅烷
Figure PCTCN2019112392-appb-000025
将4-[5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶-2-基]吗啉(1.85g,6.35mmol)溶于四氢呋喃(40mL)，加入叔丁基-[(2-氯-3-氟-4-吡啶基)甲氧基]-二甲基-硅烷(1.50g,5.44mmol)、四(三苯基膦)钯(0.30g,0.26mmol)和饱和碳酸钠溶液(30mL)，90℃反应25小时。反应液冷却，分出有机相，用无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物(1.80g,产率82％)，为无色油状物。
MS(ESI,pos.ion)m/z:405.3[M+H] +。
步骤3)[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲醇
Figure PCTCN2019112392-appb-000026
将叔丁基-[[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲氧基]-二甲基-硅烷(1.80g,4.45mmol)溶于四氢呋喃(30mL)，0℃下缓慢滴加四丁基氟化铵的四氢呋喃溶液(8mL,1mol/L)，反应0.5小时。加入水(30mL)淬灭反应，用乙酸乙酯(30mL)萃取，有相机用饱和氯化钠溶液(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(0.60g,产率46％)，为白色固体。
MS(ESI,pos.ion)m/z:291.1[M+H] +。
步骤4)[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲基N-脒基氨基甲酸酯
Figure PCTCN2019112392-appb-000027
将[3-氟-2-(2-吗啉基嘧啶-5-基)-4-吡啶基]甲醇(0.45g,1.56mmol)溶于N,N-二甲基甲酰胺(20mL)，加入1,1’-二羰基咪唑(0.60g,3.60mmol)，室温反应0.5小时，加入碳酸胍(0.70g,3.80mmol)，继续反应3小时。加入水(20mL)淬灭反应，用乙酸乙酯(30mL)萃取，有相机用饱和氯化钠溶液(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[二氯甲烷/甲醇(v/v)＝20/1]纯化，得到标题化合物(0.23g,产率40％,HPLC纯度:99.13％)，为白色固体。
MS(ESI,pos.ion)m/z:376.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.02(s,1H),8.91(s,2H),8.47(d,J＝4.7Hz,1H),7.64(s,1H),7.33(t,J＝4.9Hz,1H),7.02(s,2H),5.13(s,2H),3.89-3.74(m,4H),3.75-3.60(m,4H)。
实施例2[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯(化合物2)
Figure PCTCN2019112392-appb-000028
步骤1)7-[5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶-2-基]-3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑 并[4,3-a]吡嗪
Figure PCTCN2019112392-appb-000029
将3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐(1.05g,4.6mmol)溶于乙醇(10mL)，加入三乙胺(1.5mL,7.7mmol)，反应5分钟后，加入2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(1.0g,4.2mmol)，加热至80℃反应4小时。反应液冷却至室温，有固体析出，过滤，用少量无水乙醇洗涤滤饼，收集滤饼干燥，得到标题化合物(1.0g,产率61％)，为白色固体。
MS(ESI,pos.ion)m/z:397.1[M+H] +。
步骤2)叔丁基-[[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑并[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基] 甲氧基]-二甲基-硅烷
Figure PCTCN2019112392-appb-000030
将7-[5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶-2-基]-3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑并[4,3-a]吡嗪(1.0g,2.5mmol)和叔丁基-[(2-氯-3-氟-4-吡啶基)甲氧基]-二甲基-硅烷(0.65g,2.4mmol)溶于乙二醇二甲醚(20mL)，加入碳酸钠溶液(7mL,7mmol,1mol/L)，置换氮气保护，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.18g,0.24mmol)，90℃反应12小时。反应液冷却过滤，滤液分出水相，有机相浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物(0.95g,产率79％)，为类白色固体。
MS(ESI,pos.ion)m/z:510.3[M+H] +。
步骤3)[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑并[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基]甲醇
Figure PCTCN2019112392-appb-000031
将叔丁基-[[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑并[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基]甲氧基]-二甲基-硅烷(1.0g,2.0mmol)溶于四氢呋喃(4mL)，0℃下滴加四丁基氟化铵的四氢呋喃溶液(4mL,4mmol,1mol/L)，室温反应1.5小时。加水(10mL)淬灭反应，用乙酸乙酯(20mL)萃取，有机相用饱和氯化钠水溶液(8mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物用乙醇/乙酸乙酯/石油醚(v/v/v＝1/1/3,15mL)重结晶，得到标题化合物(0.56g,产率72％)，为白色固体。
步骤4)[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基]甲基N-脒 基氨基甲酸酯
Figure PCTCN2019112392-appb-000032
将[3-氟-2-[2-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三氮唑并[4,3-a]吡嗪-7-基]嘧啶-5-基]-4-吡啶基]甲醇(0.10g,0.25mmol)，溶于N,N-二甲基甲酰胺(6mL)，加入N,N'-羰基二咪唑(0.11g,0.66mmol)，氮气保护下室温反应2小时，加入碳酸胍(0.12g,0.99mmol)，继续反应8小时。将反应液直接柱层析[二氯甲烷/甲醇(v/v)＝10/1]纯化，得到标题化合物(86mg,产率71％,HPLC纯度:98.73％)，为白色固体。
MS(ESI,pos.ion)m/z:418.3[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)9.00(s,2H),8.51(s,1H),7.37(s,1H),5.26(s,2H),5.14(s,2H),4.34(d,J＝31.2Hz,4H)。
实施例3[3-氟-2-[2-(2-氧代-3,8-二氮杂螺[4,5]癸烷-8-基)嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯(化合物3)
Figure PCTCN2019112392-appb-000033
步骤1)8-[5-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮
Figure PCTCN2019112392-appb-000034
将二异丙基乙胺(2.1mL,13mmol)，2,8-二氮杂螺[4,5]癸烷-3-酮(0.77g,5.0mmol)加入到2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(1.0g,4.2mmol)的无水乙醇(30mL)溶液中，80℃反应15小时。反应液冷却至室温，浓缩，加入乙醇(5mL)，搅拌10分钟，过滤，用乙醇(1mL)洗涤滤饼，收集滤饼干燥，得到标题化合物(0.86g,产率58％)，为类白色固体。
1H NMR(600MHz,DMSO-d 6)δ(ppm)8.47(s,2H),7.56(s,1H),3.94(dt,J＝10.9,5.0Hz,2H),3.72-3.63(m,2H),3.09(s,2H),2.13(s,2H),1.62-1.49(m,4H),1.27(s,12H)。
步骤2)8-[5-[4-[叔丁基(二甲基)硅基]氧甲基]-3-氟-2-吡啶基]嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮
Figure PCTCN2019112392-appb-000035
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.11g,0.15mmol)，碳酸钠水溶液(4.4mL,0.76mmol,1mol/L)，8-[5-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-3-酮(0.58g,1.59mmol)加入到[(2-氯-3-氟-4-吡啶基)甲氧基]-叔丁基二甲基硅烷(0.40g,1.45mmol)的乙二醇二甲醚(13mL)溶液中，，90℃反应23小时。将反应液浓缩，残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝9/1]纯化，得到标题化合物(0.43g,产率63％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:472.3[M+1] +。
步骤3)8-[5-[3-氟-4-(羟甲基)-2-吡啶基]嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮
Figure PCTCN2019112392-appb-000036
0℃下，将四丁基氟化铵(1.1mL,1mol/L四氢呋喃溶液)滴加入8-[5-[4-[叔丁基(二甲基)硅]氧甲基]-3-氟-2-吡啶基]嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮(0.43g,0.91mmol)的四氢呋喃(5mL)溶液中，室温反应3小时。将反应液浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝9/1]纯化，得到标题化合物(0.18g,产率55％)，为浅黄色固体。
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.87(s,2H),8.47(d,J＝4.6Hz,1H),7.57(s,1H),7.46(t,J＝4.9Hz,1H),5.60(t,J＝5.6Hz,1H),4.67(d,J＝5.4Hz,2H),4.07-3.92(m,2H),3.81-3.65(m,2H),3.11(s,2H),2.15(s,2H),1.60(t,J＝5.1Hz,4H)。
步骤4)[3-氟-2-(2-氧代-3,8-二氮杂螺[4,5]癸烷-8-基)嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯
Figure PCTCN2019112392-appb-000037
将N,N'-羰基二咪唑(0.21g,1.31mmol)加入到8-[5-[3-氟-4-(羟甲基)-2-吡啶基]嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮(0.18g,0.50mmol)的N,N-二甲基甲酰胺(10mL)溶液中，室温反应2小时。加入碳酸胍(0.25g,2.01mmol)继续反应8小时。将反应液浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝10/1]纯化，得到标题化合物(0.11g,产率49％,HPLC纯度:98.35％)，为白色固体。
MS(ESI,pos.ion)m/z:443.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.88(s,2H),8.46(d,J＝4.8Hz,1H),7.57(s,1H),7.32(t,J＝4.8Hz,1H),5.13(s,2H),4.03-3.94(m,2H),3.78-3.68(m,2H),3.29(s,1H),3.12(s,1H),2.15(s,2H),1.60(t,J＝5.5Hz, 4H)。
实施例4[3-氟-2-[2-(2-氧代-3,8-二氮杂螺[4,5]癸烷-8-基)嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯(化合物4)
Figure PCTCN2019112392-appb-000038
步骤1)8-[5-[4-[[叔丁基(二甲基)硅基]氧甲基]-3-氟-2-吡啶基]嘧啶-2-基]-3-甲基-3,8-二氮杂螺[4,5]癸烷-2-酮
Figure PCTCN2019112392-appb-000039
0℃下，将氢化钠(30mg,0.75mmol)加入到8-[5-[4-[[叔丁基(二甲基)硅基]氧甲基]-3-氟-2-吡啶基]嘧啶-2-基]-3,8-二氮杂螺[4,5]癸烷-2-酮(0.23g,0.49mmol)的N,N-二甲基甲酰胺(6mL)溶液中，室温反应30分钟，加入碘甲烷(89mg,0.58mmol)，继续反应4小时。将反应液倒入冰水(10mL)中淬灭，加入饱和氯化铵溶液(10mL)，用乙酸乙酯(15mL×2)萃取，合并的有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝20/1]纯化，得到标题化合物(0.19g,产率80％)，为黄色固体。
MS(ESI,pos.ion)m/z:486.15[M+1] +。
步骤2)8-[5-[3-氟-4-(羟甲基)-2-吡啶基]嘧啶-2-基]-3-甲基-3,8-二氮杂螺[4,5]癸烷-2-酮
Figure PCTCN2019112392-appb-000040
0℃下，将四丁基氟化铵(0.5mL,1mol/L四氢呋喃溶液)滴加入8-[5-[4-[[叔丁基(二甲基)硅基]氧甲基]-3-氟-2-吡啶基]嘧啶-2-基]-3-甲基-3,8-二氮杂螺[4,5]癸烷-2-酮(0.20g,0.41mmol)的四氢呋喃(5mL)溶液中，室温反应1小时。加入水(15mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并的有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝25/1]纯化，得到标题化合物(0.10g,产率65％)，为白色固体。
步骤3)[3-氟-2-[2-(3-甲基-2-氧代-3,8-二氮杂螺[4,5]癸烷-8-基)嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯
Figure PCTCN2019112392-appb-000041
将N,N'-羰基二咪唑(0.10g,0.59mmol)加入到8-[5-[3-氟-4-(羟甲基)-2-吡啶基]嘧啶-2-基]-3-甲基-3,8-二氮杂螺[4,5]癸烷-2-酮(85mg,0.23mmol)的N,N-二甲基甲酰胺(6mL)溶液中，室温反应3小时，随后加入碳酸胍(0.25g,2.01mmol)，继续反应12小时。将反应液浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝10/1]纯化，得到标题化合物(48mg,产率46％,HPLC纯度:98.98％)，为白色固体。
MS(ESI,pos.ion)m/z:457.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.88(s,2H),8.47(d,J＝4.8Hz,1H),7.32(t,J＝4.8Hz,1H),5.13(s,2H),4.03-3.92(m,2H),3.82-3.71(m,2H),3.23(s,2H),2.73(s,3H),2.25(s,2H),1.60(t,J＝5.2Hz,4H)。
实施例5[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲基N-脒基氨基甲酸酯(化合物5)
Figure PCTCN2019112392-appb-000042
步骤1)2-(1-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼酸酯-2-基)嘧啶
Figure PCTCN2019112392-appb-000043
将2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(3.00g,12.5mmol)溶于无水乙醇(30mL)，加入哌啶(1.50mL,15.0mmol)和N,N-二异丙基乙胺(4.20mL，25.0mmol)，80℃回流反应14小时。反应液冷却至室温，浓缩，加入乙醇(6mL)，搅拌10分钟，过滤，用乙醇(2mL)洗涤滤饼，收集滤饼干燥，得到标题化合物(2.00g,产率77％)，为类白色固体。
MS(ESI,pos.ion)m/z:290.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.45(s,2H),3.82-3.74(m,4H),1.64(d,J＝4.8Hz,2H),1.50(s,4H),1.27(s,12H)。
步骤2)叔丁基-[[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲氧基]-二甲基-硅烷
Figure PCTCN2019112392-appb-000044
将2-(1-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼酸酯-2-基)嘧啶(0.50g,1.81mmol)溶于乙二醇二甲醚(15mL)，加入叔丁基-[(2-氯-3-氟-4-吡啶基)甲氧基]-二甲基-硅烷(580ng,1.99mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.14g,0.18mmol)和碳酸钠水溶液(5.4mL,1mol/L)，90℃反应23小时。反应液冷却至室温，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(0.47g,产率64％)，为无色油状物。
MS(ESI,pos.ion)m/z:403.3[M+H] +。
步骤3)[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲醇
Figure PCTCN2019112392-appb-000045
将叔丁基-[[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲氧基]-二甲基-硅烷(0.47g,1.16mmol)溶于四氢呋喃(5mL)，0℃下滴加四丁基氟化铵的四氢呋喃溶液(1.4mL,1mol/L)，室温反应3.5小时。将反应液浓缩，所得残留物经硅胶柱层析[二氯甲烷/甲醇(v/v)＝19/1]纯化，得到标题化合物(0.33g,产率99％)，为白色固体。
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.86(s,2H),8.46(d,J＝4.6Hz,1H),7.45(t,J＝5.0Hz,1H),5.60(t,J＝5.7Hz,1H),4.67(d,J＝5.7Hz,2H),3.90-3.72(m,4H),1.71-1.62(m,2H),1.59-1.47(m,4H)。
步骤4)[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲基N-脲基氨基甲酸酯
Figure PCTCN2019112392-appb-000046
将[3-氟-2-[2-(1-哌啶基)嘧啶-5-基]-4-吡啶基]甲醇(0.40g,1.39mmol)溶于N,N-二甲基甲酰胺(10mL)，加入1,1’-二羰基咪唑(0.58g,3.61mmol)，室温反应3小时，随后加入碳酸胍(0.70g,3.80mmol)，室温反应12小时。加入水(20mL)淬灭反应，用乙酸乙酯(30mL×3)萃取，合并的有相机用饱和氯化钠溶液(60mL)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/甲醇(v/v)＝12/1]纯化，得到标题化合物(0.23g,产率44％,HPLC纯度:99.20％)，为白色固体。
MS(ESI,pos.ion)m/z:374.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.87(s,2H),8.46(d,J＝4.7Hz,1H),7.31(t,J＝4.9Hz,1H),5.14(s,2H),3.91-3.76(m,4H),1.66(d,J＝4.6Hz,2H),1.56(d,J＝4.1Hz,4H)。
活性试验实施例
一、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VAP-1的抑制活性。
试验材料：
人重组VAP-1(VAP-1，human)购于Sigma，Cat.No.SRP6241；
Figure PCTCN2019112392-appb-000047
Red Monoamine Oxidase Assay Kit购于Invitrogen，Cat.No.A12214；
384孔板购于Corning，Cat.No.6005174；
苄胺盐酸盐(Benzylamine hydrochloride)购于Sigma，Cat.No.B5136-25G；
DMSO(Dimethyl Sulfoxide,二甲基亚砜)购于Sigma，Cat.No.D2650-100ML；
试验方法：
将试验化合物溶于DMSO中并进行4倍稀释，共稀释10个浓度。在384孔板中，将25μL人重组VAP-1(1.6μg/mL)加入至各个孔中。将100nL不同浓度的试验化合物加入至含人重组VAP-1的各个孔中，室温孵育30min。30min孵育后，将25μL含1mM苄胺盐酸盐的
Figure PCTCN2019112392-appb-000048
Red Monoamine Oxidase Assay Kit(含200μM Amplex Red reagent,1U/mL HRP的反应混合物)加入至相应孔中，室温避光孵育60min。60min后，使用PerkinElmer的Envision在激发530-560nm和发射590nm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。其结果如表1所示：
表1：本发明实施例提供的化合物对人重组VAP-1的抑制活性
实施例编号 VAP-1(IC 50/nM)
实施例1 1.5
实施例3 1.18
试验结果显示：本发明化合物对人重组VAP-1具有明显的抑制作用。
二、DAO选择性抑制测定
测试目的：下面的方法是用来测定本发明化合物对DAO选择性抑制活性。
试验材料：
人重组DAO(Recombinant Human ABP-1/DAO)购于R&D，Cat.No.8298-AO；
Figure PCTCN2019112392-appb-000049
Red Hydrogen PeroxidePeroxidase Assay Kit购于Invitrogen，Cat.No.A22188；
1,4-丁二胺双盐酸盐(1,4-Diaminobutane dihydrochloride)购于Aladdin，Cat.No.D106194-25G；
试验方法：
将试验化合物溶于DMSO中并进行5倍稀释，共稀释6个浓度。在384孔板中，将24μL人重组DAO(1μg/ml)加入至各个孔中。将1μL不同浓度的试验化合物加入至含人重组DAO的各个孔中，37℃孵育30min。30min孵育后，将25μL含1M 1,4-丁二胺双盐酸盐的
Figure PCTCN2019112392-appb-000050
Red Hydrogen PeroxidePeroxidase Assay Kit(含100μM
Figure PCTCN2019112392-appb-000051
Red和0.2U/ml HRP的反应混合物)加入至相应孔中，37℃避光孵育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。
试验结果表明，本发明化合物对VAP-1的选择性高。
三、本发明化合物的药代动力学测定
测量目的:下面的方法是用来测定本发明化合物的药代动力学。
试验材料：
所用实验试剂及供试品：Propranolol(普萘洛尔(内标))、甲醇、乙酸铵、K 2EDTA(乙二胺四乙酸钾)、甲酸、乙腈、MTBE(甲基叔丁基醚)、KolliphorHS15(聚乙二醇12羟基硬脂酸酯)、DMSO(二甲亚砜)均为市售可得；
SD大鼠：雄性，180-220g，7-8周龄，购自湖南斯莱克实验动物有限公司。
试验方法：
1、供试品配制
按5％DMSO+5％KolliphorHS15+90％生理盐水配置供试品溶液，具体根据每个化合物的溶解情况进行调整，使化合物能完全溶解。
2、动物实验设计
Figure PCTCN2019112392-appb-000052
3、动物给药剂量表
组别 性别 动物数量 给药剂量 给药浓度 给药体积
静脉注射I.V. 雄性 3 1mg/kg 1mg/mL 1mL/kg
口服P.O. 雄性 3 5mg/kg 1mg/mL 5mL/kg
4、溶液配制
(1)供试品储备液的配置：精密称取适量供试品，用DMSO溶解，用乙腈稀释至1mg/mL，摇匀即得。置于-20℃条件下保存待用。
(2)内标物溶液配制：精密吸取一定量1mg/mL Propranolol储备液，用水稀释至100ng/mL。
5、样品分析
采用液液萃取法处理样品，进行色谱分离，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM) 方式进行定量分析，用仪器定量软件对结果进行浓度计算。
6、血浆样品预处理
精密吸取30μL的血浆样品，加入250μL内标，涡旋混合均匀。用1mL的MTBE提取一次，13000rpm，4℃下离心2min，吸取上清液800μL，于96孔氮吹仪中挥干，残留物用150μL甲醇/水＝50/50复溶，涡旋混合，进样，进样量为8μL。
7、标准样品的制备
准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为3、5、10、30、100、300、1000、3000、5000和10000ng/mL的血浆样品，均按“血浆样品预处理”操作，每一浓度进行双样本分析，建立标准曲线。
8、分析方法
使用LC/MS/MS法测定不同化合物给药后大鼠血浆中的待测化合物含量。
9、数据处理
采用WinNonlin 6.1软件，非房室模型法计算药动学参数。
试验结果显示：本发明化合物具有良好的药代动力学性质。
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 (20)

  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 PCTCN2019112392-appb-100001
    其中，
    U 1和U 2各自独立地为CH或N；
    R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基或羟基C 1-6烷基；
    R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 3-6环烷基，其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-6环烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
    或R 4、R 5和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环，其中所述C 3-6碳环和3-6个原子组成的杂环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
    A为5-14个原子组成的杂环基或5-14个原子组成的杂芳基，其中所述A未被取代或被1、2、3或4个R 6所取代；
    各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1- 6卤代烷氧基、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C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基或C 1-6卤代烷氧基；
    q为0、1或2；
    各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-6卤代烷基、C 1-6烷基、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C 1-6卤代烷基、C 1-6烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基；
    或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基。
  2. 根据权利要求1所述的化合物，其中，所述A为以下子结构式：
    Figure PCTCN2019112392-appb-100002
    其中，
    各E独立地为N或CH；
    各G独立地为-CH 2-、-NH-、-O-、-S-、-S(＝O)-或-S(＝O) 2-；
    U为N、-C＝或CH；
    各T独立地为-(CH 2) x-；
    各y独立地为0、1或2；
    各w独立地为0、1或2；
    x为1、2或3；
    环C为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
    各环D独立地为C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环；
    其中，所述A未被取代或被1、2、3或4个R 6所取代。
  3. 根据权利要求2所述的化合物，其中，所述环C为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪；
    各环D独立地为环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉、哌嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、三唑、四唑、噁唑、异噁唑、噁二唑、吡嗪或哒嗪。
  4. 根据权利要求1-3任意一项所述的化合物，其中，所述A为
    Figure PCTCN2019112392-appb-100003
    Figure PCTCN2019112392-appb-100004
    Figure PCTCN2019112392-appb-100005
    Figure PCTCN2019112392-appb-100006
    其中，所述A未被取代或被1、2、3或4个R 6所取代。
  5. 根据权利要求1-4任意一项所述的化合物，其中，所述各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、-NR cR d、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-S(＝O) qR e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、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C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4卤代烷氧基；
    q为0、1或2；
    各R a、R b、R c、R d、R e和R f独立地为H、D、C 1-4卤代烷基、C 1-4烷基、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C 1-4卤代烷基、C 1-4烷基、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芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基；
    或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、-OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基。
  6. 根据权利要1-5任意一项所述的化合物，其中，所述各R 6独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-NHCH 3、-N(CH 3) 2、＝O、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-C(＝O)N(CH 3) 2、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-NHC(＝O)R a、-NHS(＝O) 2R e、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩 基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基或哒嗪基，其中所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟乙基、环丙基、环丁基、环戊基、四氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基。
  7. 根据权利要求1-6任意一项所述的化合物，其中，所述R 1、R 2和R 3各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、甲氨基、三氟甲氧基或羟基甲基。
  8. 根据权利要求1-7任意一项所述的化合物，其中，所述R 4和R 5各自独立地为H、D、F、Cl、Br、I、CN、NO 2、OH、NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、环丙基、环丁基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、三氟乙基、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基；
    或R 4、R 5和与它们相连的碳原子一起，形成环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉或哌嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、环氧乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、1,3-二氧环戊烷、四氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、吡咯烷、哌啶、吗啉、硫代吗啉和哌嗪各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、CN、NO 2、OH、NH 2、-COOH、-SH、甲基、乙基、三氟甲基、甲氧基或乙氧基。
  9. 根据权利要求1-8任意一项所述的化合物，其中，所述各R a、R b、R c、R d、R e和R f独立地为H、D、三氟甲基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、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，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基；
    或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自D、F、Cl、Br、I、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。
  10. 根据权利要求1-9任意一项所述的化合物，其具有以下其中之一的结构：
    Figure PCTCN2019112392-appb-100007
    Figure PCTCN2019112392-appb-100008
    Figure PCTCN2019112392-appb-100009
    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。
  11. 一种药物组合物，其包含权利要求1-10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载体、赋形剂、辅剂、媒介物或它们的组合。
  12. 权利要求1-10任意一项所述的化合物或权利要求11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VAP-1；或所述药物用于预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病，其中所述与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
  13. 根据权利要求12所述的用途，其中，所述炎症疾病和/或炎症相关疾病为关节炎、全身炎性综合征、脓血症、滑膜炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、肝病、呼吸道疾病、眼睛疾病、皮肤疾病或神经炎性疾病；其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；全身炎性综合征为全身炎性脓毒症；炎症性肠病为过敏性肠病；肝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；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；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；皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹；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；
    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；
    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；
    所述纤维化为肝纤维化、囊性纤维化、肾纤维化、特发性肺纤维化或放射性诱导的纤维化；
    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。
  14. 根据权利要求13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。
  15. 权利要求1-10任意一项所述的化合物或权利要求11所述的药物组合物用于抑制VAP-1；或用于预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病，其中所述与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
  16. 根据权利要求15所述的化合物或药物组合物，其中，所述炎症疾病和/或炎症相关疾病为关节炎、全身炎性综合征、脓血症、滑膜炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、肝病、呼吸道疾病、眼睛疾病、皮肤疾病或神经炎性疾病；其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；全身炎性综合征为全身炎性脓毒症；炎症性肠病为过敏性肠病；肝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；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；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；皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹；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；
    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；
    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；
    所述纤维化为肝纤维化、囊性纤维化、肾纤维化、特发性肺纤维化或放射性诱导的纤维化；
    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。
  17. 根据权利要求16所述的化合物或药物组合物，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。
  18. 一种抑制VAP-1；或预防、治疗或减轻与VAP-1蛋白有关或者由VAP-1调节的疾病的方法，包括给予患者有效治疗量的权利要求1-10任意一项所述的化合物或权利要求11所述的药物组合物，其中所述与VAP-1蛋白有关或者由VAP-1调节的疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、缺血性疾病、血管疾病、纤维化或组织移植排斥。
  19. 根据权利要求18所述的方法，其中，所述炎症疾病和/或炎症相关疾病为关节炎、全身炎性综合征、脓血症、滑膜炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、肝病、呼吸道疾病、眼睛疾病、皮肤疾病或神经炎性疾病；其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；全身炎性综合征为全身炎性脓毒症；炎症性肠病为过敏性肠病；肝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；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；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；皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹；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；
    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；
    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；
    所述纤维化为肝纤维化、囊性纤维化、肾纤维化、特发性肺纤维化或放射性诱导的纤维化；
    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。
  20. 根据权利要求19所述的方法，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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