WO2019024924A1 - 抑制ssao/vap-1的胺类化合物及其在医药上的应用 - Google Patents

抑制ssao/vap-1的胺类化合物及其在医药上的应用 Download PDF

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WO2019024924A1
WO2019024924A1 PCT/CN2018/098563 CN2018098563W WO2019024924A1 WO 2019024924 A1 WO2019024924 A1 WO 2019024924A1 CN 2018098563 W CN2018098563 W CN 2018098563W WO 2019024924 A1 WO2019024924 A1 WO 2019024924A1
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group
alkylene
atoms
heteroaryl
cycloalkyl
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French (fr)
Inventor
顾峥
黎健豪
李峥
王伟华
覃浩雄
崔云增
王绪礼
余淑娜
张英俊
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

Definitions

  • the present invention belongs to the field of medicine, and relates to an amine compound for inhibiting semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1), a method for preparing the same, and a method for preparing the same Pharmaceutical compositions and the use of the compounds and compositions thereof in medicine.
  • SSAO semicarbazide-sensitive amine oxidase
  • VAP-1 vascular adhesion protein-1
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a geometric isomer thereof, and a pharmaceutical composition containing the same, and the Use of a compound and a pharmaceutical composition for the manufacture of a medicament for inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
  • Amine Oxidase is a kind of protein with special biological functions, which is widely existed in living organisms, including higher animals and microbial cells including humans. It can metabolize a variety of endogenous or exogenous monoamine, diamine and polyamine compounds.
  • amine oxidases There are two main types of amine oxidases, one is copper-containing amine oxidase, which mainly includes Semicarbazide-Sensitive Amine Oxidase (SSAO) and Diamine oxidase (DAO).
  • SSAO Semicarbazide-Sensitive Amine Oxidase
  • DAO Diamine oxidase
  • Flavin-containg amine oxidase which mainly includes monoamine oxidase and polyamine oxidase.
  • semicarbazide-sensitive amine oxidase is a kind of amine oxidase which contains divalent copper ions and is particularly sensitive to semicarbazide with 6-hydroxydopaquinone as a coenzyme, and mainly exists in the form of dimer.
  • Diamine oxidase is also known as histamine oxidase because it acts only on diamines, especially histamine.
  • Monoamine oxidase is divided into monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which are mainly found in mitochondria of most cell types, and covalently bound flavin adenine II Nucleotides (FAD) act as cofactors.
  • Polyamine oxidase is another FAD-dependent amine oxidase that oxidizes deaminospermine and spermidine.
  • SSAO differs from MAO-A and MAO-B in its substrate, inhibitor, cofactor, subcellular localization and function, which is dependent on copper and uses substances other than FAD such as trihydroxyphenylalanine.
  • Amino oxidase Trihydroxyphenylalanine Quinone, TPQ
  • SSAO is widely present in mammalian tissues rich in vasculature, mainly in two forms, one is soluble form, mainly in circulating blood; the other is membrane-bound form, widely distributed in organs and tissues.
  • Medium especially in adipocytes, vascular endothelial cells, and smooth muscle cells.
  • SSAO is a multifunctional enzyme whose pathophysiological function is diverse due to the different tissue distribution of SSAO.
  • SSAO can promote the transfer of glucose transporter 4 (GLUT 4) from the adipocytes to the cell membrane, thereby regulating glucose transport.
  • SSAO exists in the form of vascular adhesion protein-1 (VAP-1), mediates the adhesion and exudation of leukocytes and endothelial cells, and participates in inflammatory reactions.
  • VAP-1 vascular adhesion protein-1
  • Vascular adhesion protein-1 is an endothelial adhesion molecule with dual functions. It is a lymphocyte adhesion molecule that promotes the adhesion of lymphocytes to the vascular endothelium. On the other hand, VAP-1 also has an enzyme effect. It is capable of catalyzing a primary amine to the corresponding aldehyde. VAP-1 is encoded by the AOC3 gene localized to human chromosome 17. The VAP-1 protein may be present in plasma as a solute or in the form of a membrane-bound form on the surface of endothelial cells, adipocytes, and smooth muscle cells.
  • VAP-1 antigen belongs to the semicarbazide-sensitive amine oxidase (Smith DJ, Salmi M, Bono P, et a1. JI. J ExpMed, 1998, 188(1): 17-27), structurally and SSAO is the same. Therefore, in recent years, researchers have generally equated SSAO with VAP-1 for research. Therefore, the present invention uniformly describes the protein as SSAO/VAP-1.
  • Inflammation is the first response of the immune system to infection or irritation.
  • the movement of white blood cells into the tissue circulation is important to the process. Inappropriate inflammatory reactions can lead to local inflammation in other healthy tissues, which can lead to diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, chronic obstructive pulmonary disease (COPD), eczema, psoriasis, etc. .
  • Leukocytes first adhere to the endothelium by binding adhesion molecules before they pass through the vessel wall.
  • Membrane-bound SSAO/VAP-1 is abundantly expressed in vascular endothelial cells such as lymphoid organs of highly efficient venous endothelial cells (HVE), and is also expressed in hepatic sinusoidal endothelial cells (HSEC), smooth muscle cells, and adipocytes.
  • SSAO/VAP-1 contains sialic acid, which induces cell adhesion, regulates leukocyte transport, participates in granulocyte extravasation, and increases its level during inflammation. The migration of neutrophils from the blood to the site of inflammation is achieved by binding of adhesion molecules to vascular endothelial cells.
  • insulin mainly promotes the uptake and utilization of glucose by insulin-sensitive tissues such as adipose tissue, myocardium and skeletal muscle by promoting the transfer of glucose transporter (GLUT) from the cell to the cell membrane.
  • GLUT 4 is an important GLUT subtype involved in glucose transport and is primarily stored in the cytoplasm as vesicles. Enrique-Tarancon et al.
  • the thickness of the elastic layer of the vessel wall is positively correlated with the ratio of SSAO/VAP-1 and elastin, indicating that SSAO/VAP-1 may be involved in the mechanization of elastic fibers, and the properties and quantity of elastic fibers are affecting the mechanical properties and blood vessels of the arterial wall.
  • An important factor in the differentiation of smooth muscle cells Increased SSAO/VAP-1 activity can lead to disruption of the membrane elastic fiber structure in the aorta, accompanied by decreased maturity of the elastin component and increased collagen, eventually causing aortic swelling.
  • Overexpression of SSAO/VAP-1 in smooth muscle can reduce arterial elasticity and impair its ability to regulate blood pressure.
  • the present invention provides a novel class of compounds having better SSAO/VAP-1 inhibitory activity, and such compounds and compositions thereof can be prepared for the prevention, treatment or alleviation of inflammatory diseases and/or inflammation-related diseases in patients, diabetes and/or Or a drug associated with a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, fibrosis, or a tissue transplant rejection.
  • the invention relates to a compound which is a stereoisomer, geometric isomer, tautomer, oxynitride, solvate of a compound of formula (I) or a compound of formula (I). a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the definitions as defined in the present invention.
  • X is O or S
  • Each of R 5 and R 6 is independently H, D, F, Cl, Br, I, -OR b , C 1-6 alkyl, C 3-6 cycloalkyl or a heterocyclic group consisting of 3-8 atoms.
  • said C 1-6 alkyl group, C 3-6 cycloalkyl group and heterocyclic group consisting of 3-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents,
  • the substituents are independently selected from the group consisting of D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b OC 1-4 alkylene or R d R c NC 1-4 alkylene;
  • R 5 , R 6 together with the carbon atom to which they are attached form a C 3-6 carbocyclic ring or a heterocyclic ring composed of 5-6 atoms, wherein the C 3-6 carbocyclic ring and 5-6 atoms are
  • the heterocycles are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b OC 1-4 alkylene or R d R c NC 1-4 alkylene;
  • Each of R 3 and R 4 is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene a heterocyclic group of 3-8 atoms, (heterocyclic group of 3-8 atoms)-C 1-4 alkylene group, C 6-10 aryl group, C 6-10 aryl-C 1- a 4 alkylene group, a heteroaryl group of 5-10 atoms, a heteroaryl group of 5-10 atoms, a C 1-4 alkylene group or Wherein the C 1-6 alkyl group, the C 1-6 haloalkyl group, the C 3-6 cycloalkyl group, the C 3-6 cycloalkyl-C 1-4 alkylene group, and the heterocyclic ring composed of 3-8 atoms Base, (3-8 atomic heterocyclic group)-C 1-4 alkylene group, C 6-10 aryl group, C 6-10 ary
  • R 3 , R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring of 3-8 atoms or a heteroaromatic ring of 5-8 atoms, wherein the heterocyclic ring consisting of 3-8 atoms
  • the heteroaryl rings of 5-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • Each of R a , R b , R c , R d , R e and R f is independently H, D, hydroxy, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclic group consisting of 3-8 atoms, (3 a heterocyclic group consisting of -8 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-10 atoms Or a (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3- 6 cycloalkyl, C 3-6 cycloalkyl-C 1-4
  • R c , R d together with the nitrogen atom to which they are attached form a heterocyclic ring of 3-8 atoms or a heteroaromatic ring of 5-8 atoms, wherein the heterocyclic ring consisting of 3-8 atoms
  • the heteroaryl rings of 5-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
  • X is O or S
  • X is O or S
  • each R 5 and R 6 are independently H, D, F, Cl, Br, I, -OR b , C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 a heterocyclic group consisting of an atom, wherein the C 1-4 alkyl group, the C 3-6 cycloalkyl group, and the heterocyclic group consisting of 5-6 atoms are each independently unsubstituted or 1, 2, 3 or Substituted by four substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , methyl, ethyl, n-propyl, Isopropyl or C 1-3 haloalkyl;
  • R 5 , R 6 together with the carbon atom to which they are attached form a C 3-6 carbocyclic ring or a heterocyclic ring composed of 5-6 atoms, wherein the C 3-6 carbocyclic ring and the 5-6 atomic constituent are hetero
  • the rings are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , - NR c R d , methyl, ethyl, n-propyl, isopropyl or C 1-3 haloalkyl.
  • each R 3 and R 4 are independently H, D, methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene group, heterocyclic group of 5-6 atoms, (heterocyclic group of 5-6 atoms)-C 1-2 alkylene group, phenyl group, a phenyl-C 1-2 alkylene group, a heteroaryl group of 5-6 atoms, a heteroaryl group of 5-6 atoms, a C 1-4 alkylene group or Wherein the methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5- Heterocyclic group consisting of 6 atoms, (heterocyclic group of 5-6
  • R 3 , R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring of 5-6 atoms or a heteroaromatic ring of 5-6 atoms, wherein the heterocyclic ring consisting of 5-6 atoms
  • the heteroaryl rings of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, C 1-3 haloalkyl or C 1-3 alkoxy.
  • each R a , R b , R c , R d , R e , and R f are, independently, H, D, hydroxy, trifluoromethyl, difluoromethyl, methyl, ethyl, Isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuran Base, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyridyl Azyl, imidazoly
  • R c , R d together with the nitrogen atom to which they are attached form a heterocyclic ring of 5-6 atoms or a heteroaryl ring of 5-6 atoms, wherein the heterocyclic ring consists of 5-6 atoms
  • the heteroaryl rings of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, C 1-3 haloalkyl or C 1-3 alkoxy.
  • the compounds of the invention, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide or methanesulfonate.
  • the invention in another aspect, relates to a pharmaceutical composition comprising a compound of the invention.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.
  • the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament, wherein the medicament is for inhibiting SSAO/VAP-1.
  • the present invention relates to the use of a compound of the present invention or the pharmaceutical composition for the preparation of a medicament, wherein the medicament is for preventing, treating or alleviating the association with SSAO/VAP-1 protein or by SSAO /VAP-1 regulates the disease.
  • the disease associated with or regulated by SSAO/VAP-1 protein of the invention is an inflammatory disease and/or inflammation-related disease, diabetes and/or diabetes-related disease, a psychiatric disorder , ischemic disease, vascular disease, fibrosis or tissue transplant rejection.
  • the inflammatory disease and/or inflammation-related diseases of the present invention are arthritis, systemic inflammatory syndrome, sepsis, synovitis, Crohn's disease, ulcerative colitis, inflammation Sexual enteropathy, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease.
  • the diabetes and/or diabetes related diseases of the invention are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
  • the psychiatric condition of the invention is severe depression, bipolar depression or attention deficit hyperactivity disorder.
  • the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications or destruction of tissue by inflammatory cells following stroke.
  • the fibrosis of the invention is liver fibrosis, cystic fibrosis, renal fibrosis, idiopathic pulmonary fibrosis or radioactively induced fibrosis.
  • the vascular disease of the invention is atherosclerosis, chronic heart failure or congestive heart failure.
  • the arthritis of the invention is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.
  • systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.
  • the inflammatory bowel disease of the present invention is an allergic bowel disease.
  • the liver disease of the present invention is a liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non- Alcoholic liver disease.
  • the respiratory disease of the 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, pulmonary fibroblasts, and/or inflammation caused by lymphoid formation or macular degeneration.
  • the skin disorder of the invention is contact dermatitis, skin inflammation, psoriasis or eczema.
  • the neuroinflammatory disease of the invention is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
  • the present invention provides a class of amine compounds having SSAO/VAP-1 inhibitory activity, a process for their preparation and their use in medicine. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be noted that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included within the scope of the invention.
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds may be understood that the term “optionally substituted” is used interchangeably with the term “unsubstituted or replaced by”.
  • the term “optionally”, “optional” or “optionally” means that the subsequently described event or condition may, but does not necessarily, occur, and that the description includes the occurrence of the event or condition in which the event did not occur. Or the situation. In general, unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group.
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • C 1-6 alkyl refers particularly to the disclosure independently a C 1 alkyl (methyl), C 2 alkyl (ethyl), C. 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl, and "heteroaryl consisting of 5-6 atoms” means a heteroaryl group composed of 5 atoms and a heteroaryl group composed of 6 ring atoms.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • halogen means F, Cl, Br, I.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbyl group containing from 1 to 20 carbon atoms. Unless otherwise stated, an alkyl group contains from 1 to 20 carbon atoms; in some embodiments, an alkyl group contains from 1 to 10 carbon atoms; in still other embodiments, an alkyl group contains from 1 to 8 A carbon atom; in still other embodiments, the alkyl group contains from 1 to 6 carbon atoms; in some embodiments, the alkyl group contains from 1 to 4 carbon atoms; and in some embodiments, an alkyl group Contains 1-2 carbon atoms.
  • the alkyl group having 1 to 6 carbon atoms in the present invention is referred to as a lower alkyl group.
  • 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 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(CHCH
  • alkyl and its prefix “alk”, as used herein, encompass both straight-chain and branched saturated carbon chains.
  • alkylene means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-3 carbon atoms; in some embodiments, the alkylene group contains 1-2 carbon atoms.
  • Such examples include methylene (-CH 2 -), ethylene (including -CH 2 CH 2 - or -CH(CH 3 )-), isopropylidene (including -CH(CH 3 )CH 2 - Or -C(CH 3 ) 2 -) and so on.
  • the alkylene group may be optionally substituted by one or more substituents described herein.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one of the sites of unsaturation is a carbon-carbon sp 2 double bond, wherein the alkenyl group is capable Optionally, it is replaced by one or more substituents described herein, including the positioning of "cis” and “trans”, or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in other embodiments, the alkenyl group contains 2-6 carbon atoms; in still other embodiments, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one of the sites of unsaturation is a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (including 1-propynyl (-C ⁇ CH-CH 3 ) and propargyl (-CH 2 C ⁇ CH) )), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.
  • the alkynyl group can be independently and optionally substituted with one or more substituents described herein.
  • alkoxy refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, i.e., alkyl-O-, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group contains from 1 to 20 carbon atoms; in other embodiments, the alkoxy group contains from 1 to 10 carbon atoms; in still other embodiments, the alkoxy group The group contains from 1 to 8 carbon atoms; in still other embodiments, the alkoxy group contains from 1 to 6 carbon atoms; in still other embodiments, the alkoxy group contains from 1 to 4 carbon atoms, in In still other 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- Propyloxy, -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-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH
  • 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 a lower alkylamino group having one or two C1-6 alkyl groups attached to the nitrogen atom.
  • the alkylamino group is a lower alkylamino group of C1-3 .
  • the C 1-2 alkylamino lower alkyl amino groups are examples of the alkylamino group.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-di Ethylamino and so on.
  • haloalkyl refers to an alkyl group having one or more halo substituents.
  • the haloalkyl group contains 1-10 carbon atoms, and in other embodiments, the haloalkyl group contains 1-8 carbon atoms, and in still other embodiments, the haloalkyl group contains 1 -6 carbon atoms, in still other embodiments, the haloalkyl group contains 1-4 carbon atoms, and in some embodiments, the haloalkyl group contains 1-3 carbon atoms. In some embodiments, the haloalkyl group contains 1-2 carbon atoms.
  • haloalkyl groups 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 , -CHFCHFCH 3 , -CH 2 CH 2 CHF 2 , -CH 2 CF 2 CH 3 , -CH 2 CHFCH 2 F) , trifluoropropyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • the haloalkyl group can
  • Carbocyclyl may be used alone or as a large part of “carbocyclylalkyl” or “carbocyclylalkoxy”, meaning saturated or containing one or more units of unsaturation, containing from 3 to 14 A non-aromatic carbocyclic ring system of ring carbon atoms.
  • the terms “carbocyclic”, “carbocyclic” or “carbocyclic” are used interchangeably herein.
  • the number of ring carbon atoms of the carbocyclic ring is from 3 to 12; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is from 3 to 10; in other embodiments, the carbocyclic ring The number of ring carbon atoms is from 3 to 8; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is from 3 to 6; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is five. -6; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 5-8. In other embodiments, the number of ring carbon atoms of the carbocyclic ring is from 6 to 8.
  • Carbocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes wherein the carbocyclic ring may be bonded to one or more non-aromatic carbocyclic rings or one or more aromatic rings Or a combination thereof, a fused polycyclic ring system in which the attached atomic groups or points are on the carbocyclic ring.
  • Bicyclic carbocyclyl groups include bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spiro bicyclic carbocyclyl, and "fused" bicyclic ring systems contain two rings sharing two adjacent ring atoms.
  • a bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms.
  • the spiro ring system shares one ring atom.
  • Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • carbocyclic groups further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptane Base, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • Bridged carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] fluorenyl, bicyclo [3.2.3] fluorene Base, and so on.
  • cycloalkyl refers to a monocyclic, bicyclic or tricyclic ring system having one or more attachment points attached to the remainder of the molecule, saturated, containing from 3 to 12 ring carbon atoms.
  • a cycloalkyl group is a ring system containing from 3 to 10 ring carbon atoms, such as a C 3-10 cycloalkyl group; in other embodiments, a cycloalkyl group contains from 3 to 8 ring carbon atoms.
  • Ring system such as a C 3-8 cycloalkyl group; in still other embodiments, a cycloalkyl group is a ring system having 5-8 ring carbon atoms, such as a C 5-8 cycloalkyl group; in still other embodiments In the cycloalkyl group, a ring system having 3 to 6 ring carbon atoms, such as a C 3-6 cycloalkyl group; in still other embodiments, the cycloalkyl group is a ring system having 5 to 6 ring carbon atoms.
  • C 5-6 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl group can be Independently unsubstituted or substituted with one or more substituents described herein.
  • heterocyclyl may be used alone or as a large part of “heterocyclylalkyl” or “heterocyclylalkoxy”, meaning a saturated or partially unsaturated non-aromatic containing from 3 to 12 ring atoms.
  • heterocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems.
  • Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups.
  • the terms "heterocyclyl” and “heterocycle” are used interchangeably herein.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • a heterocyclic group is a ring system of from 3 to 8 ring atoms; in other embodiments, a heterocyclic group is a ring system of from 3 to 6 ring atoms; in other embodiments, The heterocyclic group is a ring system of 5 to 7 ring atoms; in other embodiments, the heterocyclic group is a ring system of 5 to 8 ring atoms; in other embodiments, the heterocyclic group is 6- a ring system consisting of 8 ring atoms; in other embodiments, the heterocyclic group is a ring system of 5-6 ring atoms; in other embodiments, the heterocyclic group is a ring system of 4 ring atoms.
  • the heterocyclic group is a ring system of 5 ring atoms; in other embodiments, the heterocyclic group is a ring system of 6 ring atoms; in other embodiments, the heterocyclic ring
  • the base is a ring system of 7 ring atoms; in other embodiments, the heterocyclic group is a ring system of 8 ring atoms.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazole Alkyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxocyclopentane Base, dithiocyclopentyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazinyl, thiomorpholinyl and piperazinyl.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the bridged heterocyclyl group includes, but is not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. 1] ⁇ , and so on.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • m atoms typically describes the number of ring atoms in the molecule in which the number of ring atoms is m.
  • piperidinyl is a heterocyclic group consisting of 6 ring atoms
  • 1,2,3,4-tetrahydronaphthyl is a carbocyclic group consisting of 10 ring atoms.
  • aryl may be used alone or as a large part of “arylalkyl” or “arylalkoxy”, meaning 6-14 ring atoms, or 6-12 ring atoms, or 6-10. Monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems of ring atoms wherein each ring contains from 3 to 7 ring atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl may be used interchangeably with the terms "aromatic ring” or “aromatic ring”, as aryl may include phenyl, naphthyl and anthracenyl.
  • the aryl group may be independently unsubstituted or substituted with one or more substituents described herein.
  • heteroaryl may be used alone or as a large part of “heteroarylalkyl” or “heteroarylalkoxy”, meaning a monocyclic, bicyclic and tricyclic aromaticity of a 5-16 ring atom.
  • heteroaryl group can be attached to the remainder of the molecule (e.g., the host structure in the formula) by any reasonable site (which can be C in CH, or N in NH).
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • a heteroaryl is a heteroaryl group of 5 to 14 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl is a heteroaryl group comprising from 5 to 12 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, A heteroaryl group is a heteroaryl group comprising from 5 to 10 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl group comprises 1, 2, 3 or 4 heteroaryl groups of 5-8 atoms independently selected from the heteroatoms of O, S and N; in other embodiments, the heteroaryl group comprises 1, 2, 3 or 4 independent a heteroaryl group consisting of 5-7 atoms of a hetero atom selected from O, S and N; in other embodiments, the heteroaryl group comprises 1, 2, 3 or 4 independently selected from O, S and N a heteroaryl group of 5-6 atoms of a heteroatom; in other embodiments, the heteroaryl group is 5 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl group is
  • the heteroaryl group includes the following monocyclic groups, but is not limited to these monocyclic groups: 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 (2-pyridyl, 3-pyridine) , 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg 3-pyridazinyl), thiazolyl
  • furyl
  • heteroatom means O, S, N, P and Si, including the form of any oxidation state of S, N and P; the form of primary, secondary, tertiary and quaternary ammonium salts; or the nitrogen atom of a heterocyclic ring.
  • a form in which hydrogen is substituted for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • the structure in which the bond is bonded may be a "cis isomer", a “trans isomer” or a "mixture of a cis isomer and a trans isomer in any ratio";
  • the formula a represents a mixture of the formula a-1, the formula a-2 or both (a-1 and a-2) in any ratio:
  • Means single or double keys, when When it is a double bond, the structure in which the double bond is bonded may be a "cis isomer", a “trans isomer” or a “mixture of a cis isomer and a trans isomer in any ratio”.
  • protecting group refers to a substituent group used to block or protect a particular functionality when other functional groups in the compound react.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a "hydroxy protecting group” refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group.
  • Suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxy A benzyl group, a silane group and the like.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • &quot pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith.
  • "pharmaceutically acceptable" as used herein refers to that is approved by a federal or national government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, particularly humans.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.
  • Examples of pharmaceutically acceptable non-limiting salts include inorganic acid salts formed by reaction with amino groups, hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, nitrates, perchlorates, And organic acid salts such as methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, lemon Acid salts, succinates, malonates, besylate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate, or other methods described in the literature These salts are obtained by ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzoate, disulfate, borate, butyrate, camphorate, camphorsulfonic acid Salt, cyclopentylpropionate, digluconate, lauryl sulfate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, Heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, Oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate Salt, eleven acid salt, valerate, and the like.
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. 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 comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • carrier includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (eg antibacterial, antifungal), isotonic, salt, drug stabilizer, binder, Forming agents, dispersing agents, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, are known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). The use thereof in a therapeutic or pharmaceutical composition is encompassed except where any conventional carrier is incompatible with the active ingredient.
  • pharmaceutical composition means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable Excipients such as carriers, excipients, diluents, binders, fillers, and the like, as well as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, antihypertensive agents, anti-platelet agents, anti-atherosclerotic agents or An additional therapeutic agent such as a lipid lowering agent.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • prodrug denotes a compound which is converted in vivo to the formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie). Compound. Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • metabolite refers to a product obtained by metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • solvate refers to an association of one or more solvent molecules with a compound of the invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • nitrogen oxide means that when a compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound and m-chloroperbenzoic acid (MCPBA) are, for example, in an inert solvent such as dichloromethane. reaction.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds of the invention may exist in racemic or enantiomerically enriched form, such as in the (R)-, (S)- or (R, S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the substituent on the atom having an unsaturated double bond may exist in the cis-(Z)- or trans-(E)- form.
  • the compounds of the invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof.
  • it is a substantially pure geometric (cis or trans) isomer, a diastereomer, an optical isomer (enantiomer), a racemate or a mixture thereof.
  • the resulting mixture of any isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and/or fractionation, depending on the physicochemical differences of the components.
  • the crystallization is carried out to carry out the separation.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation.
  • the racemic product can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • the invention also includes isotopically-labeled compounds of the invention which are identical to those described herein except that the one or more atoms are replaced by an atom having an atomic mass or mass number different from the natural common atomic mass or mass number.
  • Exemplary isotopes which may also be incorporated into the compounds of the 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.
  • Isotopically labeled compounds of the invention such as radioisotopes, such as 3 H and 14 C
  • Isotope, i.e., 3 H, and carbon-14, i.e., 14 C is particularly preferred because of ease of preparation and detection.
  • substitution with heavy isotopes such as deuterium, i.e., 2 H may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some cases.
  • stereochemical definitions and conventions used in the present invention are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Definitions and conventions as documented by The Organic Compounds, John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the invention include, but are not limited to, diastereomers, enantiomers and atropisomers, and mixtures thereof such as racemic mixtures, It is also included in the scope of the invention.
  • optically active forms i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule.
  • the prefixes d and l or (+) and (–) are symbols used to specify the rotation of the plane polarized light caused by the compound, where (–) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that these stereoisomers are mirror images of one another.
  • stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as mixtures of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Spin body.
  • the compounds of the invention may exist as one of the possible isomers or as a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as as racemic and non-
  • the corresponding isomer mixture depends on the number of asymmetric carbon atoms.
  • the optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be cis or trans (cis- or trans-) structure.
  • the compounds of the invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the invention include, but are not limited to, diastereomers, enantiomers and atropisomers and geometric (or conformational) isomers. And mixtures thereof, such as racemic mixtures, are within the scope of the invention.
  • structures depicted in the present invention are also meant to include all isomers (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformation)) forms of this structure; for example, each The R and S configurations of the asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformers.
  • isomers e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformation)
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • subject refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (eg, humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
  • subject and patient refer to animals (eg, birds or mammals such as chickens, quails, or turkeys), particularly “mammals” including non-primates (eg, cows, 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, a horse, cow, pig, or sheep) or a pet (eg, a dog, cat, guinea pig, or rabbit).
  • "patient” refers to a human.
  • X Syndrome also known as the disease, disease of the metabolic syndrome, is described in detail in Johannsson et al., J. Clin. Endocrinol. Metab., 1997, 82, 727-734.
  • inflammatory disease refers to any disease in which excessive inflammatory symptoms, host tissue damage, or loss of tissue function due to excessive or uncontrolled inflammatory response. , disorder or symptom.
  • Inflammatory disease also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.
  • inflammation refers to a local protective response caused by damage or destruction of tissue that is used to destroy, dilute, or isolate (insulate) harmful substances and Damaged organization.
  • inflammation can result from infection with pathogenic organisms and viruses as well as non-infectious forms such as trauma or reperfusion after myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune responses.
  • inflammatory diseases that can be treated with the compounds disclosed herein include diseases associated with specific defense system responses as well as non-specific defense system responses.
  • Allergy refers to any symptom of allergy, tissue damage or loss of tissue function.
  • Arthritic disease as used in the present invention refers to any disease characterized by arthritic damage attributable to various etiology.
  • Dermatitis as used in the present invention refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiology.
  • transplant rejection refers to any immune response against transplanted tissue, such as an organ or cell (eg, bone marrow), characterized by loss of function, pain, swelling, leukocytosis, and thrombocytopenia in the transplant or surrounding tissue.
  • the methods of treatment of the invention include methods for treating diseases associated with inflammatory cell activation.
  • cancer and “cancerous” refer to or describe a physiological condition in a patient that is typically characterized by uncontrolled cell growth.
  • a “tumor” contains one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies.
  • squamous cell carcinoma such as squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma
  • peritoneal cancer Hepatocellular cancer
  • gastric or stomach cancer including gastrointestinal cancer
  • pancreatic cancer malignant glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma (hepatoma) ), breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer ( Hepatic carcinoma), anal cancer, penile cancer, and head and neck cancer.
  • the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • the present invention provides a class of compounds having better SSAO/VAP-1 inhibitory activity and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, psychosis Drugs for the disease, ischemic disease, vascular disease, fibrosis or tissue transplant rejection.
  • the invention also provides methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using the compounds and compositions to prepare a medicament for treating the above-described diseases in mammals, particularly humans.
  • the compounds of the present invention Compared with the existing analogous compounds, the compounds of the present invention not only have good pharmacological activity, but also have high selectivity to SSAO/VAP-1, and also have excellent in vivo metabolic kinetic properties and in vivo pharmacodynamic properties.
  • the preparation method is simple and easy, the process method is stable, and is suitable for industrial production. Therefore, the compound provided by the present invention has more excellent drug-yielding properties than the currently-prepared compound.
  • the invention relates to a compound which is a stereoisomer, geometric isomer, tautomer, oxynitride, solvate of a compound of formula (I) or a compound of formula (I). a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the definitions as defined in the present invention.
  • X is O or S
  • Each of R 5 and R 6 is independently H, D, F, Cl, Br, I, -OR b , C 1-6 alkyl, C 3-6 cycloalkyl or a heterocyclic group consisting of 3-8 atoms.
  • said C 1-6 alkyl group, C 3-6 cycloalkyl group and heterocyclic group consisting of 3-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents,
  • the substituents are independently selected from the group consisting of D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b OC 1-4 alkylene or R d R c NC 1-4 alkylene;
  • R 5 , R 6 together with the carbon atom to which they are attached form a C 3-6 carbocyclic ring or a heterocyclic ring composed of 5-6 atoms, wherein the C 3-6 carbocyclic ring and 5-6 atoms are
  • the heterocycles are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b OC 1-4 alkylene or R d R c NC 1-4 alkylene;
  • Each of R 3 and R 4 is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene a heterocyclic group of 3-8 atoms, (heterocyclic group of 3-8 atoms)-C 1-4 alkylene group, C 6-10 aryl group, C 6-10 aryl-C 1- a 4 alkylene group, a heteroaryl group of 5-10 atoms, a heteroaryl group of 5-10 atoms, a C 1-4 alkylene group or Wherein the C 1-6 alkyl group, the C 1-6 haloalkyl group, the C 3-6 cycloalkyl group, the C 3-6 cycloalkyl-C 1-4 alkylene group, and the heterocyclic ring composed of 3-8 atoms Base, (3-8 atomic heterocyclic group)-C 1-4 alkylene group, C 6-10 aryl group, C 6-10 ary
  • R 3 , R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring of 3-8 atoms or a heteroaromatic ring of 5-8 atoms, wherein the heterocyclic ring consisting of 3-8 atoms
  • the heteroaryl rings of 5-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • Each of R a , R b , R c , R d , R e and R f is independently H, D, hydroxy, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclic group consisting of 3-8 atoms, (3 a heterocyclic group consisting of -8 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-10 atoms Or a (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3- 6 cycloalkyl, C 3-6 cycloalkyl-C 1-4
  • R c , R d together with the nitrogen atom to which they are attached form a heterocyclic ring of 3-8 atoms or a heteroaromatic ring of 5-8 atoms, wherein the heterocyclic ring consisting of 3-8 atoms
  • the heteroaryl rings of 5-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
  • the compound of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ia) or a compound of formula (Ia). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 have the definitions as described in the present invention.
  • the compound of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ib) or a compound of formula (Ib). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 have the definitions as defined in the present invention.
  • the compound of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ic) or a compound of formula (Ic). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R f have the definitions as defined in the present invention.
  • the compound of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Id) or a compound of formula (Id). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 9 have the definitions as described in the present invention.
  • the compound of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ie) or a compound of formula (Ie). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 9 have the definitions as described in the present invention.
  • X is O or S
  • X is O or S
  • each R 5 and R 6 are independently H, D, F, Cl, Br, I, -OR b , C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 a heterocyclic group consisting of an atom, wherein the C 1-4 alkyl group, the C 3-6 cycloalkyl group, and the heterocyclic group consisting of 5-6 atoms are each independently unsubstituted or 1, 2, 3 or Substituted by four substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , -NR c R d , methyl, ethyl, n-propyl, Isopropyl or C 1-3 haloalkyl;
  • R 5 , R 6 together with the carbon atom to which they are attached form a C 3-6 carbocyclic ring or a heterocyclic ring composed of 5-6 atoms, wherein the C 3-6 carbocyclic ring and the 5-6 atomic constituent are hetero
  • the rings are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , -OR b , - NR c R d , methyl, ethyl, n-propyl, isopropyl or C 1-3 haloalkyl.
  • each R 3 and R 4 are independently H, D, methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene group, heterocyclic group of 5-6 atoms, (heterocyclic group of 5-6 atoms)-C 1-2 alkylene group, phenyl group, a phenyl-C 1-2 alkylene group, a heteroaryl group of 5-6 atoms, a heteroaryl group of 5-6 atoms, a C 1-4 alkylene group or Wherein the methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5- Heterocyclic group consisting of 6 atoms, (heterocyclic group of 5-6
  • R 3 , R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring of 5-6 atoms or a heteroaromatic ring of 5-6 atoms, wherein the heterocyclic ring consisting of 5-6 atoms
  • the heteroaryl rings of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, C 1-3 haloalkyl or C 1-3 alkoxy.
  • each R a , R b , R c , R d , R e , and R f are, independently, H, D, hydroxy, trifluoromethyl, difluoromethyl, methyl, ethyl, Isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuran Base, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyridyl Azyl, imidazoly
  • R c , R d together with the nitrogen atom to which they are attached form a heterocyclic ring of 5-6 atoms or a heteroaryl ring of 5-6 atoms, wherein the heterocyclic ring consists of 5-6 atoms
  • the heteroaryl rings of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, C 1-3 haloalkyl or C 1-3 alkoxy.
  • the invention relates to a structure of one of the following, or a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt thereof or Prodrug,
  • the compounds of the invention, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide or methanesulfonate.
  • the invention in another aspect, relates to a pharmaceutical composition comprising a compound of the invention.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.
  • compositions of the present invention further comprise one or more therapeutic agents.
  • the therapeutic agent is selected from the group consisting of SSAO/VAP-1 inhibitors.
  • compositions of the invention may be in the form of a liquid, solid, semi-solid, gel or spray.
  • the pharmaceutical composition of the invention wherein the therapeutic agent involved is Vapaliximab, PRX-167700, BTT-1023, ASP-8232, PXS-4728A or RTU-1096.
  • the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament, wherein the medicament is for inhibiting SSAO/VAP-1.
  • the present invention relates to the use of a compound of the present invention or the pharmaceutical composition for the preparation of a medicament, wherein the medicament is for preventing, treating or alleviating the association with SSAO/VAP-1 protein or by SSAO /VAP-1 regulates the disease.
  • the disease according to the invention that is associated with or regulated by SSAO/VAP-1 protein is an inflammatory disease and/or inflammation-related disease, a diabetes and/or diabetes-related disease, a psychiatric disorder, Ischemic disease, vascular disease, fibrosis or tissue transplant rejection.
  • the inflammatory disease and/or inflammation-related diseases of the present invention are arthritis, systemic inflammatory syndrome, sepsis, synovitis, Crohn's disease, ulcerative colitis, inflammation Sexual enteropathy, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease.
  • the diabetes and/or diabetes related diseases of the invention are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
  • the psychiatric condition of the present invention is severe depression, bipolar depression or Attention Deficit Hyperactivity Disorder.
  • the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications or destruction of tissue by inflammatory cells following stroke.
  • the fibrosis of the invention is liver fibrosis, cystic fibrosis, renal fibrosis, idiopathic pulmonary fibrosis or radioactively induced fibrosis.
  • the vascular disease of the invention is atherosclerosis, chronic heart failure or congestive heart failure.
  • the arthritis of the invention is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.
  • systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.
  • the inflammatory bowel disease of the present invention is an allergic bowel disease.
  • the liver disease of the present invention is a liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non- Alcoholic liver disease.
  • the respiratory disease of the 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, autoimmune ocular inflammation, angiogenesis and/or inflammation caused by lymphoid formation or macular degeneration.
  • the skin condition of the invention is contact dermatitis, skin inflammation, psoriasis or eczema.
  • the neuroinflammatory disease of the invention is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
  • the present invention relates to a method of inhibiting SSAO/VAP-1 activity using a compound or pharmaceutical composition of the present invention, which comprises administering to a subject in need thereof the compound or the pharmaceutical composition Effective therapeutic amount.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention for preventing or treating a disease comprising administering to a patient an effective treatment of a compound or a pharmaceutical composition of the present invention
  • the amount wherein the disease is an inflammatory disease and/or an inflammation-related disease, a diabetes and/or a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, a fibrosis, or a tissue transplant rejection.
  • the above compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at regular intervals.
  • the dosage of the compound or pharmaceutical composition required to effect a therapeutic, prophylactic or prolonged effect will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, the route and frequency of administration, and the like, and The specific situation is judged. For example, when the compound or pharmaceutical composition provided by the present invention is administered by the intravenous route, it can be administered once a week or even at a longer interval.
  • the invention relates to the use of a compound or pharmaceutical composition of the invention for inhibiting the activity of SSAO/VAP-1.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention for the prevention or treatment of a disease which alleviates or delays the development or onset of a disease which is an inflammatory disease and/or Inflammatory-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
  • a disease which is an inflammatory disease and/or Inflammatory-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith.
  • the compounds of the invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, but which may be used in the preparation and/or purification of the compounds of the invention and/or for the isolation of the compounds of the invention.
  • An intermediate of an enantiomer An intermediate of an enantiomer.
  • the pharmaceutically acceptable salts of the present invention comprise an acid addition salt and a base addition salt.
  • the pharmaceutically acceptable acid addition salt can be formed from a compound with an inorganic or organic acid, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, hydrogencarbonate Salt/carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, sulfate, citrate, ethanedisulfonate, fumarate, glucoheptane Sodalate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Acid salt, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oil Acid salt
  • Inorganic acids from which the compounds of the present invention can be derivatized include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids which can be derivatized as salts of the compounds of the invention include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, Sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed from the compounds with inorganic and organic bases.
  • Inorganic bases which can be used to derivatize the compounds of the present invention include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases which can be derivatized into salts of the compounds of the invention include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, and the like, or by The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds of the present invention, including the salts thereof may also be obtained in the form of their hydrates or include other solvents for their crystallization.
  • the compounds of the invention may be formed intrinsically or by design to form solvates having a pharmaceutically acceptable solvent, including water; thus, the invention is intended to include
  • isotopically labeled compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F , 31 P, 32 P, 36 S, 37 Cl or 125 I.
  • the compounds of the invention include compounds defined by the invention, labeled with various isotopes, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, Such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically labeled compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or primers.
  • PET positron emission tomography
  • SPECT Single photon emission computed tomography
  • 18 F-labeled compounds are particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • hydrazine in this context is considered to be a substituent of the compound of formula (I).
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, or DMSO-d 6 solvate of those.
  • compositions, formulations and administration of the compounds of the invention are provided.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie) or shown in the examples A compound of the structure, or a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, metabolite thereof, and a pharmaceutically acceptable salt or a prodrug thereof.
  • 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 is effective to detectably inhibit the activity of SSAO/VAP-1 in a biological specimen or a patient.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compound.
  • the pharmaceutically acceptable carrier should be biocompatible, for example non-toxic, non-inflammatory, non-immunogenic or have no other adverse effects or side effects once administered to the patient. Standard pharmaceutical technology can be used.
  • the pharmaceutical compositions or pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or excipient, as applied herein, including suitable for specific Target dosage form, any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. .
  • a pharmaceutically acceptable carrier including suitable for specific Target dosage form, any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.
  • Remington The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Trooy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J.
  • materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (eg, Tween 80) , phosphate, glycine, sorbic acid or potassium sorbate), a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes (eg, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts) , silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, methyl cellulose, hydroxypropyl methylcellulose, lanolin, sugar (for example) Lactose, glucose and sucrose), starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, e
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents conventional in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate.
  • the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • sterile injectable preparations such as sterile injectable aqueous or oily suspensions
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any odorless, fixed oil may be employed including synthetic monoglycerides or diglycerides.
  • fatty acids such as oleic acid, are used in the preparation of injectables.
  • the injectable preparation can be sterilized by filtration through a bacterial retention filter or by the addition of a bactericidal agent which is previously dissolved or dispersible in sterile water or other sterile injectable medium.
  • Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The rate of compound release can be controlled based on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
  • Composition for rectal or vaginal administration is especially a suppository which can be prepared by admixing a compound according to the invention and a suitable non- irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax, the excipient Or the carrier is solid at ambient temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and releases the active compound.
  • a suitable non- irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax
  • Oral solid dosage forms include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agent, for example starch, lactose, sucrose , glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerin, d) disintegrants For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution blockers, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) Wetting agents, such as cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard gel capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also be of a nature such that the active ingredient is optionally released in a delayed manner or, preferably, in a portion of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard gel capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active compounds may also be presented in microencapsulated form with one or more of the above-mentioned excipients.
  • Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical arts.
  • the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • such dosage forms may also contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage form may also contain a buffer.
  • opacifying agents may optionally contain opacifying agents and may also be of a nature such that the active ingredient is optionally released in a delayed manner or, preferably, in a portion of the intestinal tract.
  • embedding compositions include polymers and waxes.
  • Topical or transdermal administration forms of the compounds of the invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required under sterile conditions.
  • Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention.
  • the present invention contemplates the use of a dermal patch that provides the added benefit of controlling the delivery of the compound to the body.
  • This dosage form can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by implantation of a kit.
  • parenteral as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of the invention may be aqueous or oily suspensions. These suspensions can be prepared following techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any odorless, fixed oil may be employed including synthetic monoglycerides or diglycerides.
  • oils especially in the form of polyoxyethylenated, such as olive oil or castor oil
  • fatty acids such as oleic acid and its glyceride derivatives
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent, such as carboxymethylcellulose or similar dispersing agents which are conventionally employed in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersing agent such as carboxymethylcellulose or similar dispersing agents which are conventionally employed in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.
  • compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • conventional carriers include, but are not limited to, lactose and starch.
  • a lubricant such as magnesium stearate is also usually added.
  • useful diluents include lactose and dried cornstarch.
  • compositions of the invention may be administered in the form of a suppository for rectal use.
  • These pharmaceutical compositions can be prepared by mixing agents and non-irritating excipients which are solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • agents and non-irritating excipients include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • compositions of the present invention may also be administered topically, especially when the therapeutic target includes areas or organs that are readily accessible by topical application, including ocular, cutaneous or low intestinal disease. It is easy to prepare suitable topical formulations for each of these areas or organs.
  • Topical application to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or a suitable enema formulation.
  • a topical skin patch can also be used.
  • the pharmaceutical compositions may be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers suitable for topical application to the compounds of the present invention include, but are not limited to, mineral oil, petroleum jelly, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active component in suspension or in apharmaceutically acceptable carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. .
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or especially in isotonic pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride.
  • the pharmaceutical composition can be formulated as a salve, such as petrolatum.
  • the pharmaceutical composition can also be administered by nasal aerosolized spray or by inhalation.
  • This composition is prepared according to techniques well known in the pharmaceutical arts and prepared in saline using benzyl alcohol and other suitable preservatives, bioavailability absorption enhancers, fluorocarbons and/or other conventional solubilizers or dispersants. Solution.
  • the compounds used in the methods of the invention can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosages of the subject, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be one of a single daily dose or multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
  • the compounds or pharmaceutical compositions provided herein can be used to prepare a medicament for inhibiting SSAO/VAP-1.
  • the compounds or pharmaceutical compositions provided by the present invention are useful for preventing, treating or ameliorating diseases associated with or regulated by SSAO/VAP-1 proteins, which are inflammatory diseases and/or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
  • the present invention provides a method for treating, preventing or ameliorating a disease associated with or regulated by SSAO/VAP-1 protein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the above compound or Its pharmaceutical composition.
  • the disease is an inflammatory disease and/or an inflammation-related disease, a diabetes and/or a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, a fibrosis or a tissue transplant rejection.
  • the above compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at regular intervals.
  • the compounds of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and farm animals, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats.
  • the compounds of the invention include pharmaceutically acceptable derivatives thereof.
  • an “effective amount”, “effective therapeutic amount” or “effective amount” of a compound of the invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein. .
  • the compounds of the invention or pharmaceutically acceptable pharmaceutical compositions are effective over a relatively wide dosage range. For example, a daily dose of about 0.1 mg to 1000 mg per person is divided into one or several administrations.
  • the methods, compounds and pharmaceutical compositions according to the present invention can be administered in any amount and in any route of administration to effectively treat or alleviate the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific factors, mode of administration, and the like.
  • the compounds or pharmaceutical compositions of this invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
  • the compound number of the examples, the compound number in the claims, or the compound numbers at other positions in the specification are independent of each other and do not affect each other.
  • the compound corresponding to the compound number in the test example corresponds one-to-one with the compound number in the preparation example.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • the structure of the compound was determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or/and 19 F-NMR).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • 1 H-NMR, 13 C-NMR, and 19 F-NMR were measured using a Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer.
  • the solvent was 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 is generally carried out using a Novasep pump 250 high performance liquid chromatograph.
  • the LC-MS was measured using an Agilen-6120 Quadrupole LC/MS mass spectrometer.
  • the starting materials of the present invention are known and commercially available from Shanghai Accela Company, Energy Company, J&K, Tianjin Alpha Companies such as the Alfa Company can be synthesized or synthesized according to methods known in the art.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon or steel kettle of about 1L volume;
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume or a stainless steel high pressure reactor having a volume of about 1 L;
  • the solution means an aqueous solution
  • reaction temperature is room temperature
  • room temperature is 20 ° C to 30 ° C unless otherwise specified.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the systems used for the reaction were: dichloromethane and methanol systems, dichloromethane and ethyl acetate systems, petroleum ether and ethyl acetate systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Column chromatography eluent systems include: A: petroleum ether and ethyl acetate systems, B: dichloromethane and ethyl acetate systems, C: dichloromethane and methanol systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water, acetic acid or the like.
  • HPLC refers to high performance liquid chromatography
  • HPLC HPLC was measured using an Agilent 1200 high pressure liquid chromatograph (Zorbax Eclipse Plus C18 150 x 4.6 mm column);
  • the mobile phase gradient is shown in Table A:
  • the LC/MS/MS system for analysis in the biotest test included the Agilent 1200 Series Vacuum Degassing Furnace, Binary Syringe Pump, Orifice Autosampler, Column Incubator, Electrostatic Spray Ionization (ESI) Source, Agilent G6430 Level 3 Quadrupole mass spectrometer. Quantitative analysis is performed in MRM mode. The parameters of MRM conversion are shown in Table B:
  • the Agilent 6330 Series LC/MS/MS spectrometer was equipped for analysis with a G1312A binary syringe pump, a G1367A autosampler and a G1314C UV detector; and an LC/MS/MS spectrometer with an ESI source.
  • Each analyte was subjected to the best cation model processing and MRM conversion for optimal analysis using standard solutions.
  • a Capcell MP-C18 column was used during the analysis in the format: 100 x 4.6 mm I.D., 5 [mu]M (Phenomenex, Torrance, California, USA).
  • the mobile phase was 5 mM ammonium acetate, 0.1% aqueous methanol (A): 5 mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/30, v/v); flow rate was 0.6 mL/min; column temperature was kept at room temperature; Inject 20 ⁇ L of sample.
  • CD 3 OD deuterated methanol
  • Mass% mass percentage.
  • each R 7 , R 8 , R 9 , R 10 , R 11 , R x and R f has the definitions as defined herein; W is halogen; ring Q is PG is a suitable amino protecting group.
  • a compound having a structure represented by the formula (I-A) can be produced by the general synthesis method described in Synthesis Scheme 1, and specific steps can be referred to the examples.
  • the compound (Ia) is subjected to a nucleophilic reaction with the compound (Ib) under basic conditions (such as potassium carbonate) to obtain a compound (Ic); and the compound (Ic) is deprotected with an amino group PG to obtain a formula (IA).
  • Target compound Generally, a free amino compound, that is, a target compound represented by the formula (I-A), is converted into an acid addition salt for the convenience of handling and improvement of chemical stability.
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide or methanesulfonate.
  • a compound having a structure represented by the formula (I-B) can be produced by the general synthesis method described in the synthesis scheme 2, and specific steps can be referred to the examples.
  • the compound (Id) undergoes a nucleophilic reaction with the compound (Ie) at a low temperature to obtain a compound (If); the compound (If) is reduced with a reducing agent (such as sodium borohydride) to obtain a compound (Ig); the compound (Ig) is removed.
  • a reducing agent such as sodium borohydride
  • the compound (Ig) is removed.
  • Deprotection of the amino group PG gives the target compound of the formula (IB).
  • a free amino compound that is, a target compound represented by the formula (I-B)
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide or methanesulfonate.
  • a compound having a structure represented by the formula (I-C) can be produced by the general synthesis method described in Synthetic Scheme 3, and specific steps can be referred to the examples.
  • Compound (Ih) undergoes nucleophilic reaction with compound (Ib) under basic conditions (such as potassium carbonate) to obtain compound (Ii); compound (Ii) is deprotected with amino group PG to obtain a formula (IC) Target compound.
  • a free amino compound that is, a target compound represented by the formula (I-C)
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide or methanesulfonate.
  • a compound having a structure represented by the formula (I-D) can be produced by the general synthesis method described in Synthetic Scheme 4, and specific steps can be referred to the examples.
  • Compound (Ib) is reacted with triphenylphosphine to obtain compound (Ij); compound (Ij) is reacted with compound (Ik) at a low temperature to obtain compound (Il); and compound (Il) is deprotected with amino group PG to obtain A target compound represented by the formula (ID).
  • a free amino compound that is, a target compound represented by the formula (I-D)
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide or methanesulfonate.
  • a compound having a structure represented by the general formula (IE) can be produced by the general synthetic method described in Synthesis Scheme 5, and specific steps can be referred to the examples.
  • the compound (Im) is subjected to ring formation reaction with an azide compound (such as sodium azide) to obtain a compound (In); the compound (In) is reacted with R x -I to obtain a compound (Io); and the compound (Io) is removed.
  • the amino protecting group PG gives the target compound represented by the formula (IE).
  • a free amino compound that is, a target compound represented by the formula (IE)
  • acid addition salts include, but are not limited to, hydrochloride, hydrobromide or methanesulfonate.
  • a saturated ammonium chloride solution (20 mL) and ethyl acetate (20 mL) were added dropwise and the mixture was stirred for 10 minutes.
  • the mixture was transferred to a separatory funnel, and the aqueous layer was separated.
  • the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic phases were washed sequentially with water (10mL) and saturated sodium chloride solution (10mL). Dry with sodium sulfate.
  • the residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut .
  • E Ethyl (E)-3-(2-acetamido-4-hydroxy-phenyl)-2-methyl-prop-2-enoate 1d (42 mg, 0.1685 mmol) and N-[2-(bromo) Methyl)-3-fluoro-allyl]carbamic acid tert-butyl ester 1e (73 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then potassium carbonate (67.6 mg, 0.48 mmol) ). After the addition, the reaction solution was stirred at room temperature for 16 hours. In the TLC control, the raw material points disappear and new points are generated.
  • Step 1 N-[(E)-3-Fluoro-2-[[4-(1H-imidazol-2-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 3b and N-[( Z) -3- fluoro -2 - [[4- (1H- imidazol-2-yl) phenoxy] methyl] allyl] carbamate 3c
  • Step 4 N-[(E)-3-Fluoro-2-[[4-(2H-tetrazol-2-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 5e and N- [(Z)-3-fluoro-2-[[4-(2H- Tert-butyl 4-tetrazol-2-yl)phenoxy]methyl]allyl]carbamate 5f
  • N-[2-[(4-Cyanophenoxy)methyl]-3-fluoro-allyl]carbamic acid tert-butyl ester 7b (0.84 g, 2.74 mmol) was dissolved in anhydrous N,N- Ammonium chloride (0.44 g, 8.06 mmol) and sodium azide (0.53 g, 7.97 mmol) were added to methylformamide (6 mL), and the reaction mixture was heated to 120 ° C under nitrogen atmosphere and stirred for 48 hours. The mixture was poured into water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • N-[(Z)-3-Fluoro-2-[[4-(1H-tetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 7c (350 mg, 1.0 mmol Ethyl acetate (1 mL) was added, and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 mol/L) was added, and the mixture was stirred at room temperature for 30 minutes.
  • the solvent was evaporated to dryness ⁇ mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 1 N-[(E)-3-Fluoro-2-[[4-(2-methyl-2H-tetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 9a and N-[(Z)-3-fluoro -2-[[4-(2-methyl-2H-tetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 9b
  • N-[3-Fluoro-2-(hydroxymethyl)allyl]carbamic acid tert-butyl ester 11a (2.00 g, 9.75 mmol) was dissolved in dichloromethane (20 mL). Dess-Martin oxidant (4.69 g, 10.7 mmol), the resulting mixture was gradually warmed to room temperature and stirred for 2.5 hours. The reaction mixture was filtered with celite, and then filtered and washed with methylene chloride (10 mL). The organic layer was washed with saturated aqueous sodium hydrogen sulfate (50 mL ⁇ 3), dried over anhydrous sodium sulfate and evaporated. 2] Purification gave the title compound 11b (1.49 g, yield: 75%) as a yellow liquid.
  • N-[3-Fluoro-2-formyl-allyl]carbamic acid tert-butyl ester 11b (300 mg, 1.48 mmol) was dissolved in methanol (10 mL) and cooled to -80 ° C under nitrogen. Sodium deuterated sodium borohydride (68.0 mg, 1.62 mmol) was added and allowed to react for one hour. The reaction mixture was quenched with aq.
  • EtOAc EtOAc
  • EtOAc The ammonium chloride solution (10 mL) was washed with EtOAcqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 212 mg, yield 70%), as a pale yellow liquid.
  • N-[2-[deuterated (hydroxy)methyl]-3-fluoroallyl]carbamic acid tert-butyl ester 11c (212 mg, 1.03 mmol) was dissolved in acetone (5 mL), cooled to 0 ° C, Amine (0.3 mL, 2.17 mmol) was stirred for 5 min then EtOAc (EtOAc &lt Filtration was carried out to give the crude product of the title compound 11d as a yellow solution, which was directly subjected to the next reaction.
  • Step 5 N-[(E)-2-[[4-(tert-butylcarbamoyl)phenoxy]-deuterated-methyl]-3-fluoroallyl]carbamic acid tert-butyl ester 11f and N-[(Z)-2-[[4-(tert-butylcarbamoyl)phenoxy]-deuterated-methyl]-3-fluoroallyl]carbamic acid tert-butyl ester 11g
  • N-tert-Butyl-4-hydroxy-phenyl-l-carboxamide (411 mg, 2.12 mmol) was dissolved in N,N-dimethylformamide (12 mL), and potassium carbonate (384 mg, 2. After 20 minutes, N-[2-[bromo(deutero)methyl]-3-fluoroallyl]carbamic acid tert-butyl ester 11e (681 mg, 2.54 mmol). The reaction mixture was quenched with water (20 mL), EtOAc EtOAc (EtOAc (EtOAc) The organic layer was dried (EtOAc mjjjjjjjjjjjj 113 mg, yield 14%), both as a pale yellow solid.
  • N-[(E)-2-[[4-(tert-butylcarbamoyl)phenoxy]-deutero-methyl]-3-fluoroallyl]carbamic acid tert-butyl ester 11f (217 mg, 0.569 mmol) was dissolved in ethyl acetate (3 mL), cooled to 0 ° C, and ethyl acetate (3 mL, 4 mol/L) was added dropwise, and then warmed to room temperature and stirred for 1 hour. After completion of the reaction, the mixture was filtered.
  • Step 1 N-[(E)-3-fluoro-2-[[4-(4-methylpiperazin-1-yl)sulfonylanilino]methyl]allyl]carbamic acid tert-butyl ester 13b and N-[(Z)-3-fluoro -2-[[4-(4-Methylpiperazin-1-yl)sulfonylanilinyl]methyl]allyl]carbamic acid tert-butyl ester 13c
  • Step 1 N-[3-Fluoro-2-[(E)-(4-morpholinylsulfonylphenyl)iminemethyl]allyl]carbamic acid tert-butyl ester 15b
  • N-[3-Fluoro-2-[(E)-(4-morpholinesulfonylphenyl)iminemethyl]allyl]carbamic acid tert-butyl ester 15b (0.50 g, 1.2 mmol) was dissolved in methanol (10 mL), sodium borohydride (0.35 g, 9.3 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 2.5 hr, then water was added to the reaction mixture (30 mL), and the mixture was evaporated. The sodium chloride solution (30 mL) was evaporated.
  • Step 4 4-[[(E)-2-(Aminomethyl)-3-fluoro-allyl]-methyl-amino]-N-tert-butylbenzamide hydrochloride 16 and 4-[[ (Z)-2-(Aminomethyl)-3-fluoro-Allyl]-methyl-amino]-N-tert-butylbenzamide hydrochloride 17
  • Example 16 4-[(1E,3Z)-3-(Aminomethyl)-4-fluoro-butyl-1,3-dienyl]-N-tert-butyl-benzamide hydrochloride 18, 4 -[(1E,3E)-3-(aminomethyl)-4-fluoro-butyl-1,3-dienyl]-N-tert-butyl-benzamide hydrochloride 19 and 4-[(1Z , 3Z)-3-(aminomethyl)-4-fluoro-butyl-1,3-dienyl]-N-tert-butyl-benzamide hydrochloride 20
  • Step 3 4-[(1E,3Z)-3-(Aminomethyl)-4-fluoro-butyl-1,3-dienyl]-N-tert-butyl-benzamide hydrochloride 18,4- [(1E,3E)-3-(aminomethyl)-4-fluoro -butyl-1,3-dienyl]-N-tert-butyl-benzamide hydrochloride 19 and 4-[(1Z,3Z)-3-(aminomethyl)-4-fluoro-but-1 ,3-dienyl]-N-tert-butyl-benzene Amide hydrochloride 20
  • Step 1 N-[(E)-2-[[4-(2-Cyclopropyltetrazol-5-yl)phenoxy]methyl]-3-fluoro-allyl]carbamic acid tert-butyl ester 21a and N-[(Z)-2-[[4-(2- Cyclopropyltetrazol-5-yl)phenoxy]methyl]-3-fluoro-allyl]carbamic acid tert-butyl ester 21b
  • Step 1 N-[(E)-3-Fluoro-2-[[4-(2-phenyltetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 23a and N -[(Z)-3-fluoro-2-[[4-(2- Phenyltetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 23b
  • 4-(5-Methyltetrazolyl-2-yl)phenylamine 25b (0.90 g, 5.10 mmol) was dissolved in dilute sulfuric acid (30 mL, 1.00 mol/L), and sodium nitrite (1.00 g was added dropwise at 0 ° C, A solution of 14.50 mmol) in water (2 mL) was reacted at 120 ° C for 1 hour. The reaction mixture was cooled to EtOAc.
  • Step 4 N-[(E)-3-fluoro-2-[[4-(5-methyltetrazol-2-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 25d and N-[(Z)-3-fluoro -2-[[4-(5-Methyltetrazolyl-2-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 25e
  • 3-(4-Methoxyphenyl)oxazolidin-2-one 27b (0.50 g, 2.60 mmol) was dissolved in dichloromethane (20 mL), and boron tribromide (1.0 mL, 3.40) was added dropwise at 0 °C. Methyl), kept at 0 ° C for 0.5 hours. The reaction mixture was poured into ice water (20 mL), and evaporated, evaporated, evaporated.
  • Step 3 N-[(E)-3-Fluoro-2-[[4-(2-oxooxazolidin-3-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 27d And N-[(Z)-3-fluoro -2-[[4-(2-oxooxazolidin-3-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 27e
  • Step 5 N-[(E)-3-Fluoro-2-[[4-(1-methyltetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 29f and N -[(Z)-3-fluoro-2-[[4-(1- Methyltetrazol-5-yl)phenoxy]methyl]allyl]carbamic acid tert-butyl ester 29g
  • Test Purpose The following method was used to determine the inhibitory activity of the compounds of the invention against human recombinant SSAO/VAP-1.
  • VAP-1 Human recombinant SSAO/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;
  • Red Hydrogen Peroxide Peroxidase Assay Kit was purchased from Invitrogen, Cat. No. A22188.
  • 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 to a total of 10 concentrations.
  • 25 ⁇ L of human recombinant SSAO/VAP-1 (1.6 ⁇ g/mL) was added to each well.
  • 100 nL of different concentrations of test compound were added to each well containing human recombinant SSAO/VAP-1 and incubated for 30 min at room temperature.
  • 25 ⁇ L Red Monoamine Oxidase Assay Kit 200 ⁇ M Amplex Red reagent, 1 U/mL HRP and 1 mM benzylamine hydrochloride reaction mixture was added to the corresponding wells and incubated for 60 min at room temperature in the dark.
  • test results show that the compound of the present invention has a significant inhibitory effect on human recombinant SSAO/VAP-1.
  • Test Purpose The following method was used to determine the inhibitory activity of the compounds of the present invention on rat fat homogenate SSAO/VAP-1.
  • HPES SODIUM SALT N-piperazine-N-ethanesulfonic acid sodium salt
  • EDTA Ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid
  • Sucrose was purchased from Sigma, Cat. No. V900116;
  • PMSF Phenylmethanesulfonyl fluoride, phenylmethylsulfonyl fluoride
  • ⁇ -Glycerophosphate disodium salt hydrate purchased from Sigma, Cat. No. G5422-25G;
  • Pargyline hydrochloride was purchased from Sigma, Cat. No. P8013-500MG;
  • DMSO Dimethyl Sulfoxide, dimethyl sulfoxide
  • Benzylamine hydrochloride was purchased from Sigma, Cat. No. B5136-25G;
  • Red Hydrogen Peroxide Peroxidase Assay Kit was purchased from Invitrogen, Cat. No. A22188.
  • the adipose tissue was homogenized for 3 min using a Bertin Precellys 24 multi-sample homogenizer from Bertin Technologies, and the adipose tissue homogenate was centrifuged at 20,000 g for 10 min at 4 ° C to obtain an intermediate clear supernatant. The supernatant was incubated with 0.5 mM eugenol hydrochloride dissolved in HES buffer for 30 min at 37 °C. After 30 min incubation, 25 ⁇ l of adipose tissue supernatant was added to a standard 96-well plate. Test compounds were dissolved in DMSO and diluted to 6 concentrations.
  • Table 2 Inhibitory activity of the compounds provided in the examples of the present invention on adipose tissue homogenate SSAO/VAP-1
  • test results show that the compound of the present invention has a significant inhibitory effect on the adipose tissue homogenate SSAO/VAP-1.
  • Test Purpose The following method was used to determine the inhibitory activity of the compounds of the present invention against human recombinant MAO-A and MAO-B enzymes.
  • the method utilizes human recombinant MAO-A and MAO-B enzymes to detect the inhibitory effects of the compounds on the two enzymes at different concentrations.
  • concentrations of the compounds were 1 ⁇ M and 10 ⁇ M, respectively.
  • concentrations of the compounds were 1 ⁇ M and 5 ⁇ M, respectively.
  • the purchased human recombinant MAO-A and MAO-B enzyme (Active Motif) were used as the source of this method.
  • the test compound was dissolved in 100% DMSO to a concentration of 10 mM.
  • test compound at a concentration of 10 mM was added to a 384-well plate, followed by the addition of 10 ⁇ L of human recombinant MAO-A or MAO-B enzyme to give a final concentration of 1, 10 ⁇ M (MAO-A) or 1, 5 ⁇ M (MAO, respectively).
  • -B incubate for 15 min at room temperature.
  • add 20 ⁇ L of Lufiferin detection reagent mix well and incubate for 20 min at room temperature.
  • Table 3 Inhibitory activity of the compounds provided by the examples of the present invention on human recombinant MAO-A and MAO-B enzymes
  • test results showed that the compound of the present invention had no significant inhibitory effect on human recombinant MAO-A and MAO-B enzymes, indicating that the compounds of the present invention have high selectivity to SSAO/VAP-1.
  • SD rats male, 180-220 g, 7-8 weeks old, purchased from Hunan Slack Laboratory Animal Co., Ltd.
  • test solution was prepared according to 5% DMSO + 5% Kolliphor HS15 + 90% physiological saline, and the compound was adjusted according to the dissolution of each compound to completely dissolve the compound.
  • Dosage Dosing concentration Dosing volume Intravenous I.V. male 3 1mg/kg 1mg/mL 1mL/kg Oral P.O. male 3 5mg/kg 1mg/mL 5mL/kg
  • test stock solution accurately weigh the appropriate amount of the test sample, dissolve it in DMSO, dilute to 1 mg/mL with acetonitrile, and shake it to obtain. Store at -20 ° C for use.
  • the samples were treated by liquid-liquid extraction method, chromatographic separation, quantitative analysis by multiple reaction ion monitoring (MRM) on a triple quadrupole mass spectrometer, and the results were calculated by instrumental quantitative software.
  • MRM multiple reaction ion monitoring
  • the content of the test compound in the plasma of rats after administration of different compounds was determined by LC/MS/MS method.
  • the pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.
  • Table 4 shows the pharmacokinetic data for the compounds of the invention.
  • AUC last — 0-24 hours of AUC
  • AUC INF — 0 AUC for infinite time.
  • test results show that the compound of the present invention exhibits excellent pharmacokinetic properties, good absorption, high exposure, and high oral bioavailability when administered intravenously or orally.
  • test results show that the compounds of the present invention have excellent pharmacokinetics.

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Abstract

一种用于抑制氨基脲敏感性氧化酶(SSAO)和/或血管黏附蛋白-1(VAP-1)抑制剂的胺类化合物及其在医药上的应用，进一步涉及含有该胺类化合物的药物组合物。所述的化合物及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、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。

Description

抑制SSAO/VAP-1的胺类化合物及其在医药上的应用 技术领域
本发明属于医药领域，涉及一种用于抑制氨基脲敏感性胺氧化酶(SSAO)和/或血管黏附蛋白-1(VAP-1)的胺类化合物、制备他们的方法、包含所述化合物的药物组合物及所述化合物和其组合物在医药上的应用。更具体的说，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和所述的化合物及药物组合物在制备炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、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，包括人在内的高等动物和微生物细胞。它能代谢各种内源性或外源性的单胺、二胺和多胺化合物。大家所熟知的主要有两类胺氧化酶，一类是含铜的胺氧化酶，主要包括氨基脲敏感性胺氧化酶(Semicarbazide-Sensitive Amine Oxidase,SSAO)和二胺氧化酶(Diamine oxidase,DAO)；另一类是含黄素(Flavin-containg)胺氧化酶，主要包括单胺氧化酶(Monoamine oxidase)和多胺氧化酶(Polyamine oxidase)。其中，氨基脲敏感性胺氧化酶(SSAO)，是一类含有二价铜离子、以6-羟基多巴醌为辅酶对氨基脲特别敏感的胺氧化酶，主要以二聚体形式存在。二胺氧化酶(DAO)由于其只对二胺尤其是组胺起作用，故又称为组胺氧化酶。单胺氧化酶被分为单胺氧化酶A(Monoamine oxidase A,MAO-A)和单胺氧化酶B(Monoamine oxidase B,MAO-B)，主要存在于大多数细胞类型的线粒体中，并且使用共价结合的黄素腺嘌呤二核苷酸(FAD)作为辅助因子。多胺氧化酶是氧化脱氨基精胺和亚精胺的另一种FAD依赖性胺氧化酶。而SSAO在其底物、抑制剂、辅助因子、亚细胞定位和功能方面不同于MAO-A和MAO-B，它是属于依赖铜并且使用除了FAD之外的其他物质如三羟基苯丙氨酸醌(Trihydroxyphenylalanine Quinone,TPQ)作为辅助因子的胺氧化酶。
SSAO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。SSAO是一种多功能酶，其病理生理功能因SSAO的组织分布不同而具有多样性。在脂肪细胞和平滑肌细胞内，SSAO可以促进葡萄糖转运蛋白4(Glucose transport 4,GLUT 4)从脂肪细胞胞内转移至细胞膜，进而调节葡萄糖转运。在内皮细胞，SSAO以血管黏附蛋白-1(vascular adhesion protein 1,VAP-1)的形式存在，介导白细胞与内皮细胞的黏附、渗出过程，参与炎症反应。
血管黏附蛋白-1(VAP-1)是一种内皮黏附分子，具有双重功能，一方面是淋巴细胞的黏附分子，促进淋巴细胞黏附于血管内皮；另一方面，VAP-1还具有酶的功效，能够催化伯胺为相应的醛。VAP-1由定位于人17号染色体的AOC3基因编码。VAP-1蛋白可以以溶质的形式存在于血浆中，也可以以膜结合的形式存在于内皮细胞、脂肪细胞及平滑肌细胞的表面。VAP-1抗原的克隆揭示其属于氨基脲敏感性胺氧化酶(Smith D.J,Salmi M,Bono P,et a1.JI.J ExpMed,1998,188(1):17-27)，在结构上与SSAO相同。因此，近年来研究者通常将SSAO等同于VAP-1进行研究。所以，本发明统一以SSAO/VAP-1描述该蛋白。
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。白细胞首先在它们通过血管壁之前通过结合黏附分子黏附于内皮。膜结合SSAO/VAP-1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。SSAO/VAP-1含有唾液酸，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。研究发现，在过度表达SSAO/VAP-1肺炎转基因小鼠体内，发现其SSAO/VAP-1活性增加，组织蛋白-甲醛堆积物形成，支气管肺泡灌洗液炎症细胞明显增加。用SSAO/VAP-1选择抑制剂抑制其活性后，支气管肺炎灌洗液中中性粒细胞以及巨噬细胞炎性蛋白1-α 和肿瘤坏死因子-α都显著减少，说明SSAO/VAP-1介导的脱氨基作用对肺炎的发生发展有明显影响(Smith DJ,Salmi M,Bono P,et a1,J Exp Med,1998,188:17-27)。
在葡萄糖转运系统中，胰岛素主要通过促进葡萄糖转运蛋白(Glucose transport,GLUT)从细胞内转移至细胞膜，刺激脂肪组织、心肌、骨骼肌等胰岛素敏感组织对葡萄糖的摄取与利用。GLUT 4是参与葡萄糖转运的一种重要的GLUT亚型，主要以囊泡的形式储存在细胞质中。Enrique-Tarancon等在研究SSAO/VAP-1促进脂肪细胞葡萄糖转运和GLUT 4转移的作用机制中发现，大鼠脂肪细胞中的SSAO/VAP-1主要以膜结合型形式表达与脂肪细胞膜表面，18％-24％SSAO/VAP-1表达于大鼠脂肪细胞、3T3-L1脂肪细胞、大鼠骨骼肌细胞内含有GLUT 4囊泡中(Enrique-Tarancon G,Marti L,Morin N,et a1.J Biol Chem,1998,273(14):8025-8032)。Mercader等给FVB/n雄性鼠饮用水中长期使用SSAO/VAP-1抑制剂氨基脲，发现FVB/n鼠体质量指数下降了31％,体质量下降了15％，表明SSAO/VAP-1抑制剂可以抑制小鼠脂肪沉积，减轻体质量，在调节脂肪代谢中发挥重要作用(Mereader J,Iffiu-Soltesz Z,Bour S,et a1,J Obes,2011,2011:475-786)。
血管壁弹性层的厚度与SSAO/VAP-1和弹性蛋白的比率成正相关，说明SSAO/VAP-1可能参与弹性纤维的机化，而弹性纤维的特性和数量是影响动脉壁的机械性能和血管平滑肌细胞分化的重要因素。SSAO/VAP-1活性增加能导致主动脉中膜弹性纤维结构破坏，并伴随弹性蛋白成分的成熟度降低及胶原增加，最终引起主动脉膨胀。SSAO/VAP-1在平滑肌的过度表达能降低动脉弹性，损害其调节血压的能力。研究发现，尽管啮齿类动物通常不易发生动脉粥样硬化，某些小鼠品种，比如C57BL/6小鼠在给予致动脉粥样硬化的高胆固醇饮食后，仍会发生动脉粥样硬化斑块。这种容易发生动脉粥样硬化的C57BL/6小鼠其SSAO/VAP-1活性显著升高，SSAO/VAP-1介导的脱氨基作用很可能存在于动脉粥样硬化发生和血管病症过程中。
综上所述，SSAO/VAP-1抑制剂，具有酶活性、粘着活性及其在许多炎症病症增量调节之间的显著相关性这一事实使得它能够成为所有上述疾病情况的治疗靶点，具有良好的药用开发前景。
发明摘要
本发明提供了一类具有较好的SSAO/VAP-1抑制活性的新化合物，此类化合物及其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、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥的药物。
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、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000001
其中，X、
Figure PCTCN2018098563-appb-000002
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11具有如本发明所述的定义。
在一些实施方案中，
Figure PCTCN2018098563-appb-000003
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000004
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、 -NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000005
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H；
各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基；其中所述C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-6烷基、C 3-6环烷基或3-8个原子组成的杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-8个原子组成的杂环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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
R 1为H、D、F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
R 2为F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
各R 3和R 4独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)-C 1-4亚烷基或
Figure PCTCN2018098563-appb-000006
其中所述C 1-6烷基、C 1-6卤代烷基、 C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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 3、R 4与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中所述3-8个原子组成的杂环和5-8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、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；
各R a、R b、R c、R d、R e和R f独立地为H、D、羟基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中所述3-8个原子组成的杂环和5-8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、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，
Figure PCTCN2018098563-appb-000007
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000008
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000009
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是 R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
在又一些实施方案中，
Figure PCTCN2018098563-appb-000010
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000011
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000012
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
在另一些实施方案中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基；其中所述C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、-OR b、-NR cR d、C 1-4烷基或C 1-3 卤代烷基。
在又一些实施方案中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基；其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、甲基、乙基、正丙基或异丙基。
在另一些实施方案中，各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-4烷基、C 3-6环烷基或5-6个原子组成的杂环基，其中所述C 1-4烷基、C 3-6环烷基和5-6个原子组成的杂环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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基；
或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6个原子组成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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基。
在另一些实施方案中，R 1为H、D、F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基；
R 2为F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基。
在另一些实施方案中，各R 3和R 4独立地为H、D、甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)-C 1-4亚烷基或
Figure PCTCN2018098563-appb-000013
其中所述甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
或R 3、R 4与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
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、羟基、三氟甲基、二氟甲基、甲基、乙基、异丙基、正丙基、正丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、异丙基、正丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢 噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
或R c、R d与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
在另一些实施方案中，本发明所述的化合物，其中，所述药学上可接受的盐为盐酸盐、氢溴酸盐或甲磺酸盐。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物。
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。
另一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于抑制SSAO/VAP-1。
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SSAO/VAP-1蛋白有关或者由SSAO/VAP-1调节的疾病。
在一些实施方案中，其中，本发明所述与SSAO/VAP-1蛋白有关或者由SSAO/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、精神病症、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，本发明所述的炎症疾病和/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。
在另一些实施方案中，本发明所述的糖尿病和/或糖尿病相关疾病为Ⅰ型糖尿病、Ⅱ型糖尿病、X综合征、糖尿病视网膜病、糖尿病肾病、糖尿病神经病或糖尿病黄斑水肿。
在另一些实施方案中，本发明所述的精神病症为严重抑郁症、两极型抑郁症或注意力不足多动症。
在另一些实施方案中，本发明所述的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，本发明所述的纤维化为肝纤维化、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，本发明所述的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。
在又一些实施方案中，本发明所述的关节炎为骨关节炎、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，本发明所述的全身炎性综合征为全身炎性脓毒症。
在又一些实施方案中，本发明所述的炎症性肠病为过敏性肠病。
在另一些实施方案中，本发明所述的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肝病。
在又一些实施方案中，本发明所述的呼吸道疾病为哮喘、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，本发明所述的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，本发明所述的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，本发明所述的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。
本发明详细说明书
本发明提供了一类具有SSAO/VAP-1抑制活性的胺类化合物、其制备方法及其在医药上的应用。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，它们均包括在如权利要求定义的本发明范围内。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的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。
除非另有说明，本发明所用在说明书和权利要求书中的术语具有下述定义。
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。
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，如上面的通式化合物，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。应了解“任选取代的”这个术语与“未被取代或被……取代”这个术语可以交换使用。术语“任选地”，“任选的”或“任选”是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。一般而言，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只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，D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R c、-OR b、-NR cR d、-OC(＝O)R a、-OC(＝O)OR b、R bO-亚烷基、R dR cN-亚烷基、烷基、卤代烷基、烷氧基、烷氨基、烯基、炔基、环烷基、碳环基、环烷基-亚烷基、杂环基、杂环基-亚烷基、芳基、芳基-亚烷基、杂芳基、杂芳基-亚烷基和
Figure PCTCN2018098563-appb-000014
其中，各R a、R b、R c、R d、R e和R f具有如本发明所述的含义。
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个环原子组成的杂芳基。
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。
术语“卤素”是指F、Cl、Br、I。
术语“烷基”或“烷基基团”是指含1-20个碳原子的，饱和的直链或支链的一价的烃基基团。除非另外说明，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1-10个碳原子；在另外一些实施方案中，烷基基团含有1-8个碳原子；在又一些实施方案中，烷基基团含有1-6个碳原子；还在一些实施方案中，烷基基团含有1-4个碳原子；还在一些实施方案中，烷基含有1-2个碳原子。本发明中含有1-6个碳原子的烷基称为低级烷基。
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。所述烷基基团可以任选地被一个或多个本发明所述的取代基所取代。
本发明所使用的术语“烷基”和其前缀“烷”，都包含直链和支链的饱和碳链。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一些实施方案中，亚烷基基团含1-6个碳原子；在另一些实施方案中，亚烷基基团含有1-4个碳原子；在又一些实施方案中，亚烷基基团含有1-3个碳原子；还在一些实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH 2-)，亚乙基(包括-CH 2CH 2-或-CH(CH 3)-)，亚异丙基(包括-CH(CH 3)CH 2-或-C(CH 3) 2-)等等。其中，所述亚烷基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“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为碳-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“trans”的定位，或者“E”和“Z”的定位。在一些实施方案中，烯基基团包含2-8个碳原子；在另一些实施方案中，烯基基团包含2-6个碳原子；在又一些实施方案中，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)、丙烯基(-CH 2CH＝CH 2、-CH＝CHCH 3)、丁烯基(-CH＝CHCH 2CH 3、-CH 2CH＝CHCH 3、-CH 2CH 2CH＝CH 2、-CH＝C(CH 3) 2、-CH＝C(CH 3) 2、-CH 2C(CH 3)＝CH 2)、戊烯基(-CH 2CH 2CH 2CH＝CH 2、-CH 2CH 2CH＝CHCH 3、-CH 2CH 2CH＝CHCH 3、-CH 2CH＝CHCH 2CH 3、-CH＝CHCH 2CH 2CH 3、-CH 2CH 2C(CH 3)＝CH 2、-CH 2CH＝C(CH 3) 2、-CH＝CHCH(CH 3) 2、-C(CH 2CH 3)＝CHCH 3、-CH(CH 2CH 3)CH＝CH 2)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为碳-碳sp三键。在一些实施方案中，炔基基团包含2-8个碳原子；在另一些实施方案中，炔基基团包含2-6个碳原子；在又一些实施方案中，炔基基团包含2-4个碳原子。炔基的实例包括，但并不限于，乙炔基(-C≡CH)、丙炔基(包括1-丙炔基(-C≡CH-CH 3)和炔丙基(-CH 2C≡CH))、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。所述炔基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“烷氧基”或“烷基氧基”是指烷基基团通过氧原子与分子其余部分相连，即烷基-O-，其中烷基基团具有如本发明所述的含义。在一些实施方案中，烷氧基基团含有1-20个碳原子；在另一些实施方案中， 烷氧基基团含有1-10个碳原子；在又一些实施方案中，烷氧基基团含有1-8个碳原子；在又一些实施方案中，烷氧基基团含有1-6个碳原子；在又一些实施方案中，烷氧基基团含有1-4个碳原子，在又一些实施方案中，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，其中所述烷氧基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“烷氨基”或“烷基氨基”包括“N-烷氨基”和“N,N-二烷氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施方案中，烷氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施方案中，烷氨基是C 1-3的较低级的烷基氨基基团。又一些实施方案中，烷氨基是C 1-2的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷氨基或二烷氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。
术语“卤代烷基”是指具有一个或者多个卤素取代基的烷基。在一些实施方案中，卤代烷基基团含有1-10个碳原子，在另一些实施方案中，卤代烷基基团含有1-8个碳原子，在又一些实施方案中，卤代烷基基团含有1-6个碳原子，在又一些实施方案中，卤代烷基基团含有1-4个碳原子，还在一些实施方案中，卤代烷基基团含有1-3个碳原子。还在一些实施方案中，卤代烷基基团含有1-2个碳原子。卤代烷基的实例包括，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,-CHFCHFCH 3,-CH 2CH 2CHF 2,-CH 2CF 2CH 3,-CH 2CHFCH 2F)、三氟丙基、1,1-二氯乙基、1,2-二氯丙基等。所述卤代烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“碳环基”可以单独使用或作为“碳环基烷基”或“碳环基烷氧基”的一大部分，是指饱和或含有一个或多个不饱和单元、含有3-14个环碳原子的非芳香族碳环体系。术语“碳环”、“碳环基”或“碳环的”在此处可交换使用。在一些实施方案中，碳环的环碳原子的数量为3-12个；在另一些实施方案中，碳环的环碳原子的数量为3-10个；在其它一些实施方案中，碳环的环碳原子的数量为3-8个；在其它一些实施方案中，碳环的环碳原子的数量为3-6个；在其它一些实施方案中，碳环的环碳原子的数量为5-6个；在其它一些实施方案中，碳环的环碳原子的数量为5-8个。在其它一些实施方案中，碳环的环碳原子的数量为6-8个。此“碳环基”包括单环、双环或多环稠合、螺式或桥连碳环环系，还包括其中碳环可与一个或多个非芳香族碳环或一个或多个芳环或其组合稠合的多环环系，其中连接的原子团或点在碳环上。双环碳环基包括桥连双环碳环基、稠合双环碳环基和螺双环碳环基，“稠合”双环环系包含两个共用2个相邻环原子的环。桥连双环基团包括两个共用3或4个相邻环原子的环。螺环环系共用1个环原子。合适的碳环基团包括，但并不限于，环烷基，环烯基和环炔基。碳环基团的实例进一步包括，但绝不限于，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。桥连碳环基基团包括但不限于，二环[2.2.2]辛基，二环[2.2.1]庚基，二环[3.3.1]壬基，二环[3.2.3]壬基，等等。
术语“环烷基”是指有一个或多个连接点连接到分子的其余部分，饱和的，含有3-12个环碳原子的单环、双环或三环体系。在一些实施方案中，环烷基是含3-10个环碳原子的环体系，例如C 3-10环烷基；在另一些实施方案中，环烷基是含3-8个环碳原子的环体系，例如C 3-8环烷基；在又一些实施方案中，环烷基是含5-8个环碳原子的环体系，例如C 5-8环烷基；在又一些实施方案中，环烷基是含3-6个环碳原子的环体系，例如C 3-6环烷基；在又一些实施方案中，环烷基是含5-6个环碳原子的环体系，例如C 5-6环烷基；环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基，等等，且所述环烷基基团可以独 立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂环基”可以单独使用或作为“杂环基烷基”或“杂环基烷氧基”的一大部分，是指包含3-12个环原子的饱和或部分不饱和的非芳香性的单环、双环或三环体系，其中至少一个环原子选自氮，硫和氧原子，其中，所述杂环基是非芳香性的，且不包含任何芳香环。术语“杂环基”包括单环、双环或多环稠合、螺式或桥连杂环环系。双环杂环基包括桥连双环杂环基、稠合双环杂环基和螺双环杂环基。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。术语“杂环基”和“杂环”在此处可交换使用。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。在一些实施方案中，杂环基为3-8个环原子组成的环体系；在另一些实施方案中，杂环基为3-6个环原子组成的环体系；在其他一些实施方案中，杂环基为5-7个环原子组成的环体系；在其他一些实施方案中，杂环基为5-8个环原子组成的环体系；在其他一些实施方案中，杂环基为6-8个环原子组成的环体系；在其他一些实施方案中，杂环基为5-6个环原子组成的环体系；在其他一些实施方案中，杂环基为4个环原子组成的环体系；在其他一些实施方案中，杂环基为5个环原子组成的环体系；在其他一些实施方案中，杂环基为6个环原子组成的环体系；在其他一些实施方案中，杂环基为7个环原子组成的环体系；在其他一些实施方案中，杂环基为8个环原子组成的环体系。
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，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，噁唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，四氢吡喃基，二氢吡喃基，1,3-二氧环戊基，二硫环戊基，哌啶基，吗啉基，四氢嘧啶基，四氢吡喃基，四氢噻喃基，噁嗪烷基，硫代吗啉基和哌嗪基等。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、2-哌啶酮基、3-吗啉酮基、3-硫代吗啉酮基、噁唑烷-2-酮基和氧代四氢嘧啶基等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基和1,1-二氧代硫代吗啉基。桥连杂环基基团包括，但不限于，2-氧杂二环[2.2.2]辛基、1-氮杂二环[2.2.2]辛基、3-氮杂二环[3.2.1]辛基，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“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1,2,3,4-四氢萘基是10个环原子组成的碳环基基团。
术语“芳基”可以单独使用或作为“芳基烷基”或“芳基烷氧基”的一大部分，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，和三环的芳香性碳环体系，其中，每一个环包含3-7个环原子，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”或“芳香环”交换使用，如芳基可以包括苯基，萘基和蒽基。所述芳基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示含有5-16环原子的单环、双环和三环的芳香性体系，其中，至少一个环是芳香族的，且至少一个环包含一个或多个杂原子，同时，所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH 2-基团时，所述的-CH 2-基团可以任选地被-C(＝O)-替代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C，或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。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5-12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5-10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5-8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5-7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5-6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6个原子组成的杂芳基。
另外一些实施例是，杂芳基包括以下的单环基团，但并不限于这些单环基团：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(2-吡啶基，3-吡啶基，4-吡啶基)，嘧啶基(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-吡唑基和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者三环基团，但绝不限于这些基团：吲哚啉基，1,2,3,4-四氢异喹啉基，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)，吩噁噻基，二苯并咪唑基，二苯并呋喃基，二苯并噻吩基，
Figure PCTCN2018098563-appb-000015
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“杂原子”是指O、S、N、P和Si，包括S，N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)。
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“羧酸”或“羧基”是指-C(＝O)OH。
像本发明所描述的，
Figure PCTCN2018098563-appb-000016
是指双键，以该键键合的结构可为“顺式异构体”、“反式异构体”或“顺式异构体和反式异构体以任何比例形成的混合物”；例如式a代表式a-1、式a-2或两者(a-1和a-2)以任何比例形成的混合物：
Figure PCTCN2018098563-appb-000017
像本发明所描述的，
Figure PCTCN2018098563-appb-000018
是指单键或双键，当
Figure PCTCN2018098563-appb-000019
为双键时，以该双键键合的结构可为“顺式异构体”、“反式异构体”或“顺式异构体和反式异构体以任何比例形成的混合物”。
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“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美 国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“药学上可接受的盐”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：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括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、偏磷酸盐、硫酸盐、硝酸盐、高氯酸盐，和有机酸盐如甲磺酸盐、乙磺酸盐、乙酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐，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、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、月桂酸盐、月桂基硫酸盐、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、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“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。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)或式(Ie)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：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。
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“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“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,pages)。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。
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)-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。
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。
可以根据组分的物理化学差异将所得的任何异构体混合物分离成纯或基本纯的几何或光学异构体、非对映异构体、外消旋体，例如通过色谱法和/或分步结晶来进行分离。
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压液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备(如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)；and 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))。
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都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。
本发明使用的立体化学定义和惯例大体上按照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所记载的定义和惯例。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。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。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。
依据原料和方法的选择，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的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对应异构体混合物，这取决于不对称碳原子的数量。旋光性的(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。如果此化 合物含有一个双键，取代基可能为E或Z构型；如果此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。
本发明化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(或构象)异构体及它们的混合物，如外消旋混合物，均在本发明的范围之内。
除非另外指出，本发明描述的结构还表示包括此结构的所有异构体(如，对映体、非对映体阻转异构体(atropisomer)和几何(或构象))形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此，本发明化合物的单个立体化学异构体以及对映体混合物、非对映体混合物和几何异构体(或构象异构体)混合物均在本发明的范围之内。
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。
术语“几何异构体”也称“顺反异构体”，因双键(包括烯烃的双键、C＝N双键和N＝N双键)或环碳原子的单健不能自由旋转而引起的异构体。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象也是指灵长类动物(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“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。
术语“癌症”和“癌的”是指或描述患者中通常以失控的细胞生长为特征的生理学病症。“肿瘤”包含一种或多种癌细胞。癌症的实例包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤、肉瘤和白血病，或恶性淋巴增殖性疾病(lymphoid malignancies)。此类癌症的更具体的实例包括鳞状细胞癌(如上皮鳞状细胞癌)、肺 癌(包括小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状癌)、腹膜癌、肝细胞癌(hepatocellular cancer)、胃癌(gastric or stomach cancer)(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌(kidney or renal cancer)、前列腺癌、外阴癌、甲状腺癌、肝脏癌(hepatic carcinoma)、肛门癌、阴茎癌以及头颈癌。
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SSAO/VAP-1抑制活性的化合物及其药学上可接受的盐，用于制备治疗炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥的药物。本发明也提供了制备这些化合物的方法、包含这些化合物的药物组合物，以及使用这些化合物和组合物制备治疗哺乳动物，尤其是人类的上述疾病的药物的方法。与已有的同类化合物相比，本发明的化合物不仅具有良好的药理活性，对SSAO/VAP-1的选择性高，还具有优良的体内代谢动力学性质和体内药效学性质。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、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000020
其中，X、
Figure PCTCN2018098563-appb-000021
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11具有如本发明所述的定义。
在一些实施方案中，
Figure PCTCN2018098563-appb-000022
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000023
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个 原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000024
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H；
各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基；其中所述C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-6烷基、C 3-6环烷基或3-8个原子组成的杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-8个原子组成的杂环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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
R 1为H、D、F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
R 2为F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
各R 3和R 4独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)-C 1-4亚烷基或
Figure PCTCN2018098563-appb-000025
其中所述C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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 3、R 4与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中 所述3-8个原子组成的杂环和5-8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、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；
各R a、R b、R c、R d、R e和R f独立地为H、D、羟基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中所述3-8个原子组成的杂环和5-8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、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，本发明所述的化合物，其为式(Ia)所示化合物或式(Ia)所示化合物的立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000026
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 9具有如本发明所述的定义。
在一些实施方案中，本发明所述的化合物，其为式(Ib)所示化合物或式(Ib)所示化合物的立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000027
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 9和R 10具有如本发明所述的定义。
在一些实施方案中，本发明所述的化合物，其为式(Ic)所示化合物或式(Ic)所示化合物的立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000028
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 9和R f具有如本发明所述的定义。
在一些实施方案中，本发明所述的化合物，其为式(Id)所示化合物或式(Id)所示化合物的立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000029
其中，R 1、R 2、R 3、R 4、R 5和R 9具有如本发明所述的定义。
在一些实施方案中，本发明所述的化合物，其为式(Ie)所示化合物或式(Ie)所示化合物的立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000030
其中，R 1、R 2、R 3、R 4、R 5和R 9具有如本发明所述的定义。
在另一些实施方案中，
Figure PCTCN2018098563-appb-000031
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000032
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000033
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
在又一些实施方案中，
Figure PCTCN2018098563-appb-000034
为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉 基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000035
为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
或
Figure PCTCN2018098563-appb-000036
为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
在另一些实施方案中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基；其中所述C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、-OR b、-NR cR d、C 1-4烷基或C 1-3卤代烷基。
在又一些实施方案中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、 硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基；其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、甲基、乙基、正丙基或异丙基。
在另一些实施方案中，各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-4烷基、C 3-6环烷基或5-6个原子组成的杂环基，其中所述C 1-4烷基、C 3-6环烷基和5-6个原子组成的杂环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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基；
或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6个原子组成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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基。
在另一些实施方案中，R 1为H、D、F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基。
在另一些实施方案中，R 2为F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基。
在另一些实施方案中，各R 3和R 4独立地为H、D、甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)-C 1-4亚烷基或
Figure PCTCN2018098563-appb-000037
其中所述甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
或R 3、R 4与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
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、羟基、三氟甲基、二氟甲基、甲基、乙基、异丙基、正丙基、正丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、异丙基、正丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
或R c、R d与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
另一方面，本发明涉及以下其中之一的结构，或其立体异构体、几何异构体、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的前药，
Figure PCTCN2018098563-appb-000038
Figure PCTCN2018098563-appb-000039
在另一些实施方案中，本发明所述的化合物，其中，所述药学上可接受的盐为盐酸盐、氢溴酸盐或甲磺酸盐。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物。
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治疗剂。
在另一些实施方案中，所述治疗剂选自SSAO/VAP-1抑制剂。
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。
在又一些实施方案中，本发明所述的药物组合物，其中所涉及的治疗剂为Vapaliximab、PRX-167700、BTT-1023、ASP-8232、PXS-4728A或RTU-1096。
另一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中， 所述药物用于抑制SSAO/VAP-1。
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SSAO/VAP-1蛋白有关或者由SSAO/VAP-1调节的疾病。
在一些实施方案中，本发明所述的与SSAO/VAP-1蛋白有关或者由SSAO/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、精神病症、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，本发明所述的炎症疾病和/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。
在另一些实施方案中，本发明所述的糖尿病和/或糖尿病相关疾病为Ⅰ型糖尿病、Ⅱ型糖尿病、X综合征、糖尿病视网膜病、糖尿病肾病、糖尿病神经病或糖尿病黄斑水肿。
在另一些实施方案中，本发明所述的精神病症为严重抑郁症、两极型抑郁症或注意力不足多动症(Attention Deficit Hyperactivity Disorder)。
在另一些实施方案中，本发明所述的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，本发明所述的纤维化为肝纤维化、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，本发明所述的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。
在又一些实施方案中，本发明所述的关节炎为骨关节炎、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，本发明所述的全身炎性综合征为全身炎性脓毒症。
在又一些实施方案中，本发明所述的炎症性肠病为过敏性肠病。
在又一些实施方案中，本发明所述的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肝病。
在另一些实施方案中，本发明所述的呼吸道疾病为哮喘、急性肺损伤、急性呼吸窘迫综合征、肺部炎症、慢性阻塞性肺疾病、支气管炎或支气管扩张。
在另一些实施方案中，本发明所述的眼睛疾病为眼色素层炎、虹膜炎、视网膜炎、自身免疫性眼炎症、血管生成和/或淋巴生成引起的炎症或黄斑变性。
在另一些实施方案中，本发明所述的皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹。
在另一些实施方案中，本发明所述的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。
在一些实施方案中，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，所述疾病是癌症。
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SSAO/VAP-1活性的方法，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。
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用于预防或治疗下列疾病的方法，所述的方法包含给予患者本发明所述的化合物或药物组合物的有效治疗量，其中所述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、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。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。
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。
另一方面，本发明涉及将本发明所述的化合物或药物组合物用于抑制SSAO/VAP-1的活性。
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或治疗下列疾病，减轻下列疾病 症状或者延缓下列疾病的发展或发作，其中所述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、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。
在一些实施方案中，所述盐是指药学上可接受的盐。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。
本发明的化合物还包括这样的化合物的其他盐，该其他盐不一定是药学上可接受的盐，但是可以用于制备和/或提纯本发明的化合物和/或用于分离本发明的化合物的对映体的中间体。
本发明药学上可接受的盐包含酸加成盐和碱加成盐。
药学上可接受的酸加成盐可由化合物与无机酸或有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、硫酸盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以将本发明化合物衍生成盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以将本发明化合物衍生成盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
药学上可接受的碱加成盐可由化合物与无机碱和有机碱形成。
可以将本发明化合物衍生成盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以将本发明化合物衍生成盐的有机碱包括伯胺、仲胺和叔胺、取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明药学上可接受的盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。而且，本发明化合物、包括其盐也可以以其水合物形式获得，或者包括其他用于其结晶的溶剂。本发明化合物可以固有地或通过设计形成具有可药用溶剂(包括水)的溶剂化物；因此，本发明意在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被标记的形式以及同位素标记的形式。同位素标记的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。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， 11C， 13C， 14C， 15N， 18F， 31P， 32P， 36S， 37Cl或 125I。
另一方面，本发明所述化合物包括用各种同位素标记的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素标记的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F标记的化合物对PET或SPECT研究而言是特别理想的。同位素标记的式(I)化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素 标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，这一上下文中的氘被看做式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、或DMSO-d 6的那些溶剂化物。
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，其包括式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)或式(Ie)所示的化合物或实施例中所示结构的化合物，或其立体异构体、几何异构体、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SSAO/VAP-1的活性。
药学上可接受的载体可能含有不会过度抑制化合物的生物活性的惰性成分。药学上可接受的载体应生物相容，例如无毒、非炎性、非免疫原性或一旦施用给患者无其它不良反应或副作用。可采用标准制药技术。
像本发明所描述的，本发明所述的药物组合物或药学上可接受的组合物进一步包含药学上可接受的载体、辅剂或赋形剂，像本发明所应用的，包括适合于特有的目标剂型的，任何溶剂、稀释剂、液体赋形剂、分散剂、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。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公开了配制药学上可接受的组合物中使用的各种载体及其公知制备方法。除了与本发明的化合物不相容的常规载体媒介，例如会产生不良生物效应或与药学上可接受的组合物中的任何其他组分发生有害的相互作用，其他任何常规的载体媒介及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。
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、U.S.P.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。然后，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。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。也可使用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。
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。可用包衣和壳，例如肠溶衣、控释包衣和制药领域中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。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。在为胶囊、片剂和丸剂的情况下，剂型也可包含缓冲剂。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。无菌可注射制剂也可能是于无毒的可经肠胃外接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液，例如于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，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，所述赋形剂在室温下为固体，但在直肠温度下为液体，因此将在直肠内融化以释放药物。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
本发明提供的化合物或药物组合物可用于制备用于抑制SSAO/VAP-1的药物。
本发明提供的化合物或药物组合物可用于预防、治疗或减轻与SSAO/VAP-1蛋白有关或者由SSAO/VAP-1调节的疾病，所述疾病是炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。
本发明提供一种用于治疗、预防或减轻与SSAO/VAP-1蛋白有关或者由SSAO/VAP-1调节的疾病的方法，所述方法包括给予有治疗需要的患者治疗有效量的上述化合物或其药物组合物。所述疾病是炎症疾病 和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。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。
在本说明书中，实施例的化合物编号、权利要求书中的化合物编号或说明书中的其他位置的化合物编号是相互独立，互不影响的。其中，测试实施例中的化合物编号所对应的化合物与制备实施例中的化合物编号一一对应。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的药物除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
化合物的结构是通过核磁共振( 1H-NMR、 13C-NMR或/和 19F-NMR)来确定的。 1H-NMR、 13C-NMR、 19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。 1H-NMR、 13C-NMR、 19F-NMR的测定是用Bruker Ultrashield-400核磁共振谱仪和Bruker Avance III HD 600核磁共振谱仪，测定溶剂为氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD或MeOH-d 4)或者氘代二甲基亚砜(DMSO-d 6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet,单峰)，d(doublet,双峰)，t(triplet,三重峰)，m(multiplet,多重峰)，br(broadened,宽峰)，dd(doublet of doublets,双二重峰)，dt(doublet of triplets,双三重峰)，td(triplet of doublets,三双重峰)，brs(broadened singlet,宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
制备纯化或制备拆分一般使用Novasep pump 250高效液相色谱仪。
LC-MS的测定用Agilen-6120 Quadrupole LC/MS质谱仪。
柱层析一般使用青岛海洋化工300目～400目硅胶为载体。
本发明的起始原料是已知的，并且可以在市场上购买到得，购买自上海韶远公司(Shanghai Accela Company)、安耐吉公司(Energy Company)、百灵威公司(J&K)、天津阿法埃莎公司(Alfa Company)等公司，或者可以采用或者按照本领域已知的方法来合成。
实施例中无特殊说明，反应均在氮气氛围下进行；
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℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：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1200高压液相色谱仪(Zorbax Eclipse Plus C18 150x4.6mm色谱柱)；
HPLC测试条件：运行时间：15min-20min柱温：35℃PDA：210nm,254nm
流动相：A相：pH2.5磷酸二氢钾 B相：乙腈 流速：1.0ml/min
流动相梯度如表A所示：
表A
时间 流动相A的梯度 流动相B的梯度
0min 90％ 10％
15min 30％ 70％
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(ESI)源的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
多反应检测扫描 490.2→383.1
碎裂电压 230V
毛细管电压 55V
干燥器温度 350℃
雾化器 0.28MPa
干燥器流速 10L/min
分析使用Agilent XDB-C18，2.1×30mm，3.5μM柱，注入5μL样品。分析条件：流动相为0.1％的甲酸水溶液(A)和0.1％的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表C所示：
表C
时间 流动相B的梯度
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min 终止
此外，用于分析的还有Agilent 6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和G1314C UV检测器；LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱，规格为：100×4.6mm I.D.,5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵，0.1％甲醇水溶液(A)：5mM醋酸铵，0.1％甲醇乙腈溶液(B)(70/30,v/v)；流速为0.6mL/min；柱温保持在室温；注入20μL样品。
下面简写词的使用贯穿本发明：
DMSO-d 6:氘代二甲基亚砜；
CDCl 3:氘代氯仿；
CD 3OD:氘代甲醇；
-Ms:methanesulfonyl,甲磺酰基；
D: 2H，氘代；
MPa:兆帕；
-Boc:t-Butyloxy carbonyl,即叔丁氧羰基；
mass％:质量百分数。
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1-5所示。除非另外说明，各R 7、R 8、R 9、R 10、R 11、R x和R f具有如本发明所述的定义；W为卤素；环Q为
Figure PCTCN2018098563-appb-000040
PG为合适的氨基保护基团。
合成方案1：
Figure PCTCN2018098563-appb-000041
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(如碳酸钾)，与化合物(I-b)发生亲核反应，得到化合物(I-c)；化合物(I-c)脱去氨基保护基PG，得到通式(I-A)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-A)所示的目标化合物转化为酸加合盐。酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐或甲磺酸盐。
合成方案2:
Figure PCTCN2018098563-appb-000042
具有如通式(I-B)所示结构的化合物可以通过合成方案2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-d)在低温下与化合物(I-e)发生亲核反应，得到化合物(I-f)；化合物(I-f)与还原剂(如硼氢化钠)发生还原反应，得到化合物(I-g)；化合物(I-g)脱去氨基保护基PG，得到通式(I-B)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-B)所示的目标化合物转化为酸加合盐。酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐或甲磺酸盐。
合成方案3:
Figure PCTCN2018098563-appb-000043
具有如通式(I-C)所示结构的化合物可以通过合成方案3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-h)在碱性条件下(如碳酸钾)，与化合物(I-b)发生亲核反应，得到化合物(I-i)；化合物(I-i)脱去氨基保护基PG，得到通式(I-C)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-C)所示的目标化合物转化为酸加合盐。酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐或甲磺酸盐。
合成方案4:
Figure PCTCN2018098563-appb-000044
具有如通式(I-D)所示结构的化合物可以通过合成方案4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-b)与三苯基膦反应，得到化合物(I-j)；化合物(I-j)在低温下与化合物(I-k)发 生反应，得到化合物(I-l)；化合物(I-l)脱去氨基保护基PG，得到通式(I-D)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-D)所示的目标化合物转化为酸加合盐。酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐或甲磺酸盐。
合成方案5:
Figure PCTCN2018098563-appb-000045
具有如通式(I-E)所示结构的化合物可以通过合成方案5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-m)与叠氮化合物(如叠氮化钠)进行成环反应，得到化合物(I-n)；化合物(I-n)与R x-I发生反应，得到化合物(I-o)；化合物(I-o)脱去氨基保护基PG，得到通式(I-E)所示的目标化合物。通常，为方便处理和提高化学稳定性而将游离氨基化合物，即通式(I-E)所示的目标化合物转化为酸加合盐。酸加合盐的实例包括但不限于盐酸盐、氢溴酸盐或甲磺酸盐。
实施例
制备实施例
实施例1(E)-3-[2-乙酰胺基-4-[(E)-2-(氨基甲基)-3-氟烯丙基氧基]苯基]-2-甲基-丙-2-烯酸乙酯盐酸盐1
Figure PCTCN2018098563-appb-000046
步骤1(E)-3-(4-甲氧基-2-硝基-苯基)-2-甲基-丙-2-烯酸乙酯1b
氮气保护，-40℃下，向氢化钠(0.43g,11mmol,60mass％)的四氢呋喃(20mL)悬浮液中加入乙氧甲酰亚乙基三苯基膦(2.20g,5.77mmol)。加毕，搅拌5分钟后，再滴加入4-甲氧基-2-硝基-苯甲醛1a(1.05g,5.62mmol)的四氢呋喃(10mL)溶液。滴毕，继续在-40℃下搅拌反应1小时。然后升温至0℃反应3小时(反应液由淡黄色悬浮液变成棕色液体)。再向反应液中滴加入饱和氯化铵溶液(20mL)和乙酸乙酯(20mL)，搅拌10分钟。将混合液转移至分液漏斗中，分出下层水相，水相用乙酸乙酯(20mL×2)萃取，合并的有机相依次用水(10mL)和饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥。抽滤，脱除溶剂，残留物用硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物1b(1.35g,产率91％)，为黄色固体。
MS(ESI,poi.ion)m/z:288.4[M+Na] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.20(d,J＝9.2Hz,1H),7.92(s,1H),6.94(dd,J＝9.2,2.7Hz,1H),6.76(d,J＝2.6Hz,1H),4.29(d,J＝7.1Hz,2H),3.90(s,3H),1.90(d,J＝1.3Hz,3H),1.35(t,J＝7.1Hz,3H)。
步骤2(E)-3-(2-乙酰胺基-4-甲氧基-苯基)-2-甲基-丙-2-烯酸乙酯1c
将(E)-3-(4-甲氧基-2-硝基-苯基)-2-甲基-丙-2-烯酸乙酯1b(0.11g,0.41mmol)用乙酸(5mL)溶解，所得混合物升温至50℃，加入铁粉(0.11g,2.0mmol)。加毕，反应液在80℃下搅拌反应(加热过程中反应液由淡黄色变成棕色)。反应24小时后，TLC中控原料点消失。停止加热，减压脱除溶剂，残留物用乙酸乙酯(20mL)稀释，有机相依次用饱和碳酸氢钠水溶液(10mL)、水(10mL)和饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥。抽滤，脱除溶剂，残留物用硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物1c(70mg,产率89％)，为棕色固体。
MS(ESI,poi.ion)m/z:300.1[M+Na] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.71(d,J＝8.9Hz,1H),7.53(s,1H),7.31(s,1H),6.82(dd,J＝8.9,2.8Hz,1H),6.70(d,J＝2.7Hz,1H),4.22(q,J＝7.1Hz,2H),3.75(s,3H),2.10(s,3H),1.91(s,3H),1.31(t,J＝7.1Hz,3H)。
步骤3(E)-3-(2-乙酰胺基-4-羟基-苯基)-2-甲基-丙-2-烯酸乙酯1d
将(E)-3-(2-乙酰胺基-4-甲氧基-苯基)-2-甲基-丙-2-烯酸乙酯1c(70mg,0.37mmol)用二氯甲烷(5mL)溶解，再将反应液降温至0℃，然后加入三溴化硼(0.10mL,1.1mmol)。滴毕，继续在0℃搅拌反应。反应3小时后，TLC中控原料点消失，向反应液中加入水(10mL)搅拌10分钟。将混合液转移至分液漏斗中，分出下层有机相，水相用二氯甲烷(10mL×3)萃取，合并的有机相依次用水(10mL)和饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥。抽滤，脱除溶剂，得到标题化合物1d(42mg,产率65％)，为棕色固体。
MS(ESI,poi.ion)m/z:264.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.94(s,1H),7.48(s,1H),7.43(s,1H),7.37(d,J＝8.4Hz,1H),6.67(d,J＝8.1Hz,1H),4.22(q,J＝7.1Hz,2H),2.12(s,3H),1.88(s,3H),1.31(t,J＝7.1Hz,4H)。
步骤4(E)-3-[2-乙酰胺基-4-[(E)-2-[(叔丁氧羰基氨基)甲基]-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯1f和 (E)-3-[2-乙酰胺基-4-[(Z)-2-[(叔丁氧羰基氨基)甲基]-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯1g
将(E)-3-(2-乙酰胺基-4-羟基-苯基)-2-甲基-丙-2-烯酸乙酯1d(42mg,0.1685mmol)和N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(73mg,0.27mmol)溶于N,N-二甲基甲酰胺(3mL)中，再加入碳酸钾(67.6mg,0.48mmol)。加毕，反应液在室温下搅拌反应16小时。TLC中控，原料点消失，有新点生成。向反应液中加入乙酸乙酯(30mL)和水(20mL)搅拌10分钟，分出下层水相，水相用乙酸乙酯萃取(15mL×3)，合并的有机相依次用水(10mL)和饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥。抽滤，脱除溶剂，残留物用硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物1f(42mg,产率55％)和1g(23mg,产率30％)，均为无色粘稠液体。
MS(ESI,poi.ion)m/z:473.6[M+Na] +；
化合物1f：
1H NMR(400MHz,CDCl 3)δ(ppm)7.84(d,J＝8.9Hz,1H),7.53(s,1H),7.01(s,1H),6.88(dd,J＝8.9,2.6Hz,1H),6.74(d,J＝2.2Hz,1H),6.71(d,J＝80Hz,1H),4.81(s,1H),4.41(d,J＝2.6Hz,2H),4.27(q,J＝7.1Hz, 2H),3.97(d,J＝4.4Hz,2H),2.15(s,3H),1.93(s,3H),1.40(s,9H),1.34(t,J＝7.1Hz,3H)；
19F NMR(376MHz,CDCl 3)δ(ppm)-128.68；
化合物1g：
1H NMR(400MHz,CDCl 3)δ(ppm)7.87(d,J＝8.9Hz,1H),7.54(s,1H),6.92(dd,J＝9.0,2.8Hz,1H),6.88(s,1H),6.77(d,J＝2.5Hz,1H),6.71(d,J＝82Hz,1H),4.77(s,1H),4.68(s,2H),4.29(q,J＝7.1Hz,2H),3.75(s,2H),2.16(s,3H),1.95(s,3H),1.41(s,9H),1.36(t,J＝7.1Hz,3H)。
步骤5(E)-3-[2-乙酰胺基-4-[(E)-2-(氨基甲基)-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯盐酸盐1
将(E)-3-[2-乙酰胺基-4-[(E)-2-[(叔丁氧羰基氨基)甲基]-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯1f(0.29g,0.65mmol)溶于氯化氢的乙酸乙酯溶液(5mL,4mol/L)。在室温下搅拌反应0.5小时。减压脱除溶剂，真空干燥得到标题化合物1(0.25g,产率99％,HPLC纯度:94.2％)，为淡黄色固体。
MS(ESI,poi.ion)m/z:351.1[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.60(s,1H),7.37(d,J＝8.8Hz,1H),7.24(d,J＝81.3Hz,1H),7.04(dd,J＝8.8,2.7Hz,1H),6.98(d,J＝2.7Hz,1H),4.65(d,J＝2.9Hz,2H),4.28(q,2H),3.84(s,2H),2.12(s,3H),1.97(s,3H),1.35(t,3H)；
19F NMR(376MHz,CD 3OD)δ(ppm)-123.35。
实施例2(E)-3-[2-乙酰胺基-5-[(Z)-2-(氨基甲基)-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯盐酸盐2
Figure PCTCN2018098563-appb-000047
以(E)-3-[2-乙酰胺基-4-[(Z)-2-[(叔丁氧羰基氨基)甲基]-3-氟烯丙基氧]苯基]-2-甲基-丙-2-烯酸乙酯1g(18mg,0.039mmol)代替化合物1f根据实施例根据实施例1步骤5阐述的方法，得到标题化合物2(15mg,99％,HPLC纯度:94.2％)，为淡黄色固体。
MS(ESI,poi.ion)m/z:351.1[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.60(s,1H),7.37(d,J＝8.6Hz,1H),7.25-7.02(m,2H),6.99(s,1H),4.87(m,2H),4.27(q,J＝7.1Hz,2H),3.71(s,2H),2.12(s,3H),1.97(s,3H),1.35(t,J＝7.1Hz,3H)；
19F NMR(376MHz,CD 3OD)δ(ppm)-121.52。
实施例3(E)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐3
Figure PCTCN2018098563-appb-000048
Figure PCTCN2018098563-appb-000049
步骤1  N-[(E)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯3b和N-[(Z)-3-氟-2-[[4-(1H-咪 唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯3c
将4-(1H-咪唑-2-基)苯酚3a(111mg,0.66mmol)溶于N,N-二甲基酰胺(4mL)中，加入碳酸钾(106mg,0.76mmol)，室温下搅拌反应20分钟后加入N-[2-(溴甲基)-3-氟烯丙基]氨基甲酸叔丁酯1e(170mg,0.63mmol)，室温下搅拌反应20小时。向反应液中加水(10mL)淬灭，用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化铵溶液(10mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/1]纯化，得到标题化合物3b(42mg,产率19％)和3c(56mg,产率26％)，均为红色油状物。
MS(ESI,pos.ion)m/z:348.1[M+H] +。
步骤2(E)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐3
将N-[(E)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯3b(42mg,0.12mmol)溶于乙酸乙酯(2mL)中，氮气保护下降温至0℃，逐滴加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，所得混合物升温至室温反应8小时。反应液减压浓缩，经制备拆分和氯化氢的乙酸乙酯溶液处理得到标题化合物3(27mg,产率79％,HPLC纯度:97.18％)，为黄色油状物。
MS(ESI,pos.ion)m/z:248.1[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.94(d,J＝8.3Hz,2H),7.60(s,2H),7.31(d,J＝8.4Hz,2H),7.29(d,J＝80.9Hz,1H).4.77(s,2H),3.86(s,2H)。
实施例4(Z)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐4
Figure PCTCN2018098563-appb-000050
以N-[(Z)-3-氟-2-[[4-(1H-咪唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯3c(56mg,0.16mmol)代替化合物3b根据实施例3步骤2阐述的方法，得到标题化合物4(41mg,产率80％,HPLC纯度:89.14％)，为黄色油状物。
MS(ESI,pos.ion)m/z:248.1[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.94(d,J＝8.8Hz,2H),7.61(s,2H),7.32(d,J＝8.8Hz,2H),7.17(d,J＝80.5Hz,1H),4.81-4.77(m,2H),3.75(d,J＝2.3Hz,2H)。
实施例5(E)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐5
Figure PCTCN2018098563-appb-000051
步骤1 2-(4-硝基苯基)-2H-四氮唑5b
将对氟硝基苯5a(1.0g,7.1mmol)和四氮唑(0.60g,8.6mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(1.5g,11mmol)，所得混合物加热到80℃反应24小时。向反应液中加入水(20mL)，有黄色固体析出，冷却至室温搅拌30分钟，抽滤得到的固体用乙酸乙酯/石油醚(v/v＝1/2,30mL)的混合溶剂重结晶，得到标题化合物5b(0.83g,产率61％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:192.2[M+H] +。
步骤2 4-(2H-四氮唑-2-基)苯胺5c
将2-(4-硝基苯基)-2H-四氮唑5b(0.20g,1.0mmol)溶于乙酸乙酯(1mL)和乙醇(1mL)的混合溶剂中，加入10％钯炭(0.2g)，所得混合物在氢气氛围(3MPa)中反应5小时。反应结束后，过滤，滤液浓缩得到标题化合物5c(0.17g,100％)，为黄色固体。
MS(ESI,pos.ion)m/z:162.3[M+H] +。
步骤3 4-(2H-四氮唑-2-基)苯酚5d
往4-(2H-四氮唑-2-基)苯胺5c(0.17g,1.1mmol)和水(6mL)的悬浊液中滴加硫酸(6.6mL,1mol/L)，然后0℃下滴加亚硝酸钠(0.11g,1.6mmol)的水溶液(6mL)，搅拌10分钟后加入水(3mL)和滴加硫酸(6.6mL,1mol/L)，随后加热到120℃反应1小时。冷却至室温，用乙酸乙酯(30mL×3)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝2/3]纯化，得到标题化合物5d(0.042g,产率25％)，为黄色固体。
MS(ESI,pos.ion)m/z:163.2[M+H] +。
步骤4 N-[(E)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯5e和N-[(Z)-3-氟-2-[[4-(2H- 四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯5f
将N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(15mg,0.18mmol)溶于N,N-二甲基甲酰胺(1mL)中，然后加入碳酸钾(22mg,0.16mmol)和4-(2H-四氮唑-2-基)苯酚5d(26mg,0.16mmol)，所得混合物室温反应24小时。向反应液中加水(5mL)淬灭，用乙酸乙酯(10mL)萃取，有机相用饱和氯化钠溶液(5mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/2]纯化，得到 标题化合物5e(19mg,产率34％)和5f(11mg,产率20％)，均为黄色固体。
MS(ESI,pos.ion)m/z:350.3[M+H] +。
步骤5(E)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐5
将N-[(E)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯5e(0.25g,0.72mmol)溶于乙酸乙酯(1mL)中，加入氯化氢的乙酸乙酯溶液(5mL,4mol/L)反应15分钟，减压浓缩，得到的固体经制备纯化和氯化氢的乙酸乙酯溶液处理，得到标题化合物5(0.19g,产率99％,HPLC纯度:97.91％)，为黄色固体。
MS(ESI,pos.ion)m/z:250.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)10.02(s,1H),8.32(s,3H),7.85(d,J＝8.9Hz,2H),7.50-7.21(m,3H),4.74(s,2H),3.63(s,2H)。
实施例6(Z)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐6
Figure PCTCN2018098563-appb-000052
以N-[(E)-3-氟-2-[[4-(2H-四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯5f(0.14g,0.40mmol)代替化合物5e根据实施例5步骤5阐述的方法，得到标题化合物6(24mg,产率22％,HPLC纯度:80.78％)，为黄色固体。
MS(ESI,pos.ion)m/z:250.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)10.03(s,1H),8.42(s,3H),7.85(d,J＝8.6Hz,2H),7.27(d,J＝8.6Hz,1H),7.14(dd,J＝106.1,8.7Hz,1H),4.86(s,2H),3.55(s,2H)。
实施例7(E)-3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐7和(Z)-3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐8
Figure PCTCN2018098563-appb-000053
步骤1 N-[2-[(4-氰基苯氧基)甲基]-3-氟-烯丙基]氨基甲酸叔丁酯7b
将4-羟基苯甲腈7a(0.5g,4.07mmol)溶于N,N-二甲基甲酰胺(10mL)中，向其中加入N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(1.24g,4.62mmol)和碳酸钾(0.88g,6.29mmol)，室温下搅拌3小时。 向反应液中加入水(20mL)，用乙酸乙酯(20mL×2)萃取，合并的有相机用饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤旋干，残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝15/1]纯化，得到标题化合物7b(0.84g,产率67％)，为白色固体。
MS(ESI,pos.ion)m/z:329.1[M+Na] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.77(d,J＝8.7Hz,2H),7.23-6.94(m,4H),4.53(d,J＝2.9Hz,2H),3.76(d,J＝4.1Hz,2H),1.33(s,9H)。
步骤2 N-[3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯7c
将N-[2-[(4-氰基苯氧基)甲基]-3-氟-烯丙基]氨基甲酸叔丁酯7b(0.84g,2.74mmol)溶于无水N,N-二甲基甲酰胺(6mL)中，加入氯化铵(0.44g,8.06mmol)和叠氮化钠(0.53g,7.97mmol)，反应液在氮气保护下升温至120℃搅拌反应48小时。降至室温，向反应液中加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤旋干，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7c(0.94g,产率98％)，为白色固体。
MS(ESI,pos.ion)m/z:372.2[M+Na] +。
步骤3(E)-3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐7和(Z)-3-氟-2-[[4-(1H-四唑-5-基)苯氧 基]甲基]丙-2-烯-1-胺盐酸盐8
将N-[(Z)-3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯7c(350mg,1.0mmol)溶于乙酸乙酯(1mL)，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温下搅拌反应30分钟。旋干溶剂，残余物经制备纯化和氯化氢的乙酸乙酯溶液处理，得到标题化合物7(143mg,产率50％,HPLC纯度:98.90％)和8(52mg,产率18％,HPLC纯度:98.80％)，均为白色固体。
化合物7：
MS(ESI,pos.ion)m/z:250.2[M-Cl] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)8.41(s,3H),8.09(d,J＝8.7Hz,2H),7.29(dd,J＝77.4,45.3Hz,3H),4.76(d,J＝2.5Hz,2H),3.61(d,J＝5.1Hz,2H)；
化合物8：
MS(ESI,pos.ion)m/z:250.2[M-Cl] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)8.38(s,3H),8.08(d,J＝8.6Hz,2H),7.46-7.13(m,4H),4.86(s,2H),3.55(s,2H)。
实施例8(E)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐9
Figure PCTCN2018098563-appb-000054
步骤1 N-[(E)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯9a和N-[(Z)-3-氟 -2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯9b
将N-[3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯7c(1.0g,2.86mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入氢氧化钾(0.4g,7.15mmol)和碘甲烷(0.27mL,4.3mmol)，反应液在室温下搅拌反应4小时。加入水(30mL)，所得混合物用乙酸乙酯(30mL×3)萃取，合并的有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝7/1]纯化，得到标题化合物9a(0.41g,产率39％)，为白色固体和标题化合物9b(0.21g,产率20％)，为无色油状物。
化合物9a：
MS(ESI,pos.ion)m/z:386.2[M+Na] +；
化合物9b：
MS(ESI,pos.ion)m/z:386.1[M+Na] +。
步骤2(E)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐9
将N-[(E)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯9a(0.15g,0.41mmol)溶于乙酸乙酯(2mL)中，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温下搅拌反应30分钟。旋干溶剂，得到标题化合物9(0.12g,产率99％,HPLC纯度:97.2％)，为白色固体。
MS(ESI,pos.ion)m/z:264.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.31(s,3H),8.01(d,J＝8.6Hz,2H),7.35(d,J＝82.0Hz,1H),7.18(d,J＝8.6Hz,2H),4.72(d,J＝2.6Hz,2H),4.37(d,J＝25.3Hz,3H),3.62(s,2H)。
实施例9(Z)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐10
Figure PCTCN2018098563-appb-000055
以N-[(Z)-3-氟-2-[[4-(2-甲基-2H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯9b(43mg,0.12mmol)代替化合物9a根据实施例8步骤2阐述的方法，得到标题化合物10(36mg,产率99％,HPLC纯度:98.1％)，为白色固体。
MS(ESI,pos.ion)m/z:264.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.37(s,3H),8.01(d,J＝8.8Hz,2H),7.43-7.09(m,3H),4.83(d,J＝1.6Hz,2H),4.40(s,3H),3.55(s,2H)。
实施例10 4-[(E)-2-(胺甲基)-1-氘代-3-氟烯丙氧基]-N-叔丁基-苯甲酰胺盐酸盐11
Figure PCTCN2018098563-appb-000056
Figure PCTCN2018098563-appb-000057
步骤1 N-[3-氟-2-甲酰基-烯丙基]氨基甲酸叔丁酯11b
将N-[3-氟-2-(羟甲基)烯丙基]氨甲酸叔丁酯11a(2.00g,9.75mmol)溶于二氯甲烷(20mL)中，氮气保护降温至0℃，加入戴斯-马丁氧化剂(4.69g,10.7mmol)，所得混合物逐渐升温至室温搅拌2.5小时。反应液用硅藻土抽滤，滤饼用二氯甲烷(10mL)洗涤，有机相中加入饱和碳酸氢钠溶液(20mL)和硫代硫酸钠溶液(10mL,1mol/L)，搅拌10分钟，分液，有机相用饱和碳酸氢钠溶液(50mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/2]纯化，得到标题化合物11b(1.49g,产率75％)，为黄色液体物。
步骤2 N-[2-[氘代(羟基)甲基]-3-氟烯丙基]氨基甲酸叔丁酯11c
将N-[3-氟-2-甲酰基-烯丙基]氨基甲酸叔丁酯11b(300mg,1.48mmol)溶于甲醇(10mL)中，在氮气保护下降温至-80℃，此温度下加入氘代硼氢化钠(68.0mg,1.62mmol)，反应一个小时。向反应液中加入饱和氯化铵溶液(5mL)淬灭，减压旋蒸，所得混合物用乙酸乙酯(10mL×2)萃取，合并的有机相依次用饱和氯化钠溶液(10mL)和饱和氯化铵溶液(10mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/1]纯化，得到标题化合物11c(212mg,产率70％)，为浅黄色液体物。
步骤3[2-[(叔丁氧基羰基氨基)甲基]-1-氘代-3-氟烯丙基]甲磺酸酯11d
将N-[2-[氘代(羟基)甲基]-3-氟烯丙基]氨基甲酸叔丁酯11c(212mg,1.03mmol)溶于丙酮(5mL)，降温至0℃，加入三乙胺(0.3mL,2.17mmol)，搅拌5分钟，加入甲磺酰氯(0.15mL,1.94mmol)，反应1.5小时。抽滤，得到标题化合物11d的粗产物，为黄色溶液，直接进行下一步反应。
步骤4 N-[2-[溴代(氘代)甲基]-3-氟烯丙基]氨基甲酸叔丁酯11e
往上一步的黄色溶液中加入溴化锂(448mg,5.15mmol)，反应2小时。加入水(50mL)淬灭，乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化铵溶液(10mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/1]纯化，得标题化合物11e(130mg,产率50％)，为黄色油状物。
步骤5 N-[(E)-2-[[4-(叔丁基氨基甲酰)苯氧基]-氘代-甲基]-3-氟烯丙基]氨基甲酸叔丁酯11f和 N-[(Z)-2-[[4-(叔丁基氨基甲酰)苯氧基]-氘代-甲基]-3-氟烯丙基]氨基甲酸叔丁酯11g
将N-叔丁基-4-羟基-苯基-1-甲酰胺(411mg,2.12mmol)溶于N,N-二甲基甲酰胺(12mL)，加入碳酸钾(384mg,2.75mmol)，搅拌20分钟后加入N-[2-[溴代(氘代)甲基]-3-氟烯丙基]氨基甲酸叔丁酯11e(681mg,2.54mmol)，反应16小时。向反应液中加水(20mL)淬灭，乙酸乙酯(20mL×2)萃取，合并的有机相依次用饱和氯化铵溶液(20mL)和饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/6]和制备拆分，得到标题化合物11f(217mg,产率27％)和11g (113mg,产率14％)，均为淡黄色固体。
步骤6 4-[(E)-2-(胺甲基)-1-氘代-3-氟烯丙氧基]-N-叔丁基-苯甲酰胺盐酸盐11
将N-[(E)-2-[[4-(叔丁基氨基甲酰)苯氧基]-氘代-甲基]-3-氟烯丙基]氨基甲酸叔丁酯11f(217mg,0.569mmol)溶于乙酸乙酯(3mL)中，降温至0℃，滴加氯化氢的乙酸乙酯溶液(3mL,4mol/L)，然后升温至室温搅拌1小时。反应结束后，抽滤，用乙酸乙酯(20mL)洗涤滤渣，滤渣经制备分离得到标题化合物11(121mg,产率67％,HPLC纯度:89.40％)，为黄色固体。
MS(ESI,pos.ion)m/z:282.1[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.77(d,J＝8.8Hz,2H),7.10(dd,J＝44.8,36.0Hz,1H),7.07(d,J＝8.8Hz,2H),4.93(s,1H),3.71(s,2H),1.46(s,9H)。
实施例11(Z)-3-氟-2-[[4-(2-甲基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐12
Figure PCTCN2018098563-appb-000058
以N-[(Z)-2-[[4-(叔丁基氨基甲酰)苯氧基]-氘代-甲基]-3-氟烯丙基]氨基甲酸叔丁酯11g(113mg,0.296mmol)代替化合物11f根据实施例10步骤6阐述的方法，得到标题化合物12(41mg,产率39％,HPLC纯度:93.80％)，为黄色固体。
MS(ESI,pos.ion)m/z:282.3[M-Cl] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.77(d,J＝8.8Hz,2H),7.10(dd,J＝44.8,36.0Hz,1H),7.07(d,J＝8.8Hz,2H),4.93(s,1H),3.71(s,2H),1.46(s,9H)。
实施例12(2E)-2-(氟亚甲基)-N'-[4-(4-甲基哌嗪-1-基)磺酰基苯基]丙烷-1,3-二胺盐酸盐13
Figure PCTCN2018098563-appb-000059
步骤1 N-[(E)-3-氟-2-[[4-(4-甲基哌嗪-1-基)磺酰基苯胺基]甲基]烯丙基]氨基甲酸叔丁酯13b和N-[(Z)-3-氟 -2-[[4-(4-甲基哌嗪-1-基)磺酰基苯胺基]甲基]烯丙基]氨基甲酸叔丁酯13c
将4-(4-甲基哌嗪-1-基)磺酰基苯胺13a(0.5g,1.96mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(0.63g,2.35mmol)，100℃微波反应3小时。降至室温，旋干溶剂，经制备纯化，得到标题化合物13b(125mg,产率14％)，为黄色固体，和13c(45mg,产率5.2％)， 为黄色油状物。
化合物13b：
MS(ESI,pos.ion)m/z:443.3[M+H] +；
化合物13c：
MS(ESI,pos.ion)m/z:443.3[M+H] +。
步骤2(2E)-2-(氟亚甲基)-N'-[4-(4-甲基哌嗪-1-基)磺酰基苯基]丙烷-1,3-二胺盐酸盐13
往N-[(E)-3-氟-2-[[4-(4-甲基哌嗪-1-基)磺酰基苯胺基]甲基]烯丙基]氨基甲酸叔丁酯13b(39mg,0.088mmol)，加入乙酸乙酯(1mL)和氯化氢的乙酸乙酯溶液(1mL,4mol/L)，室温下搅拌30分钟。旋干溶剂，得标题化合物13(33mg,产率98％,HPLC纯度:98.9％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:343.2[M-Cl] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)8.46(s,3H),7.45(d,J＝8.8Hz,2H),7.43-7.24(m,1H),7.16(d,J＝83.2Hz,1H),6.81(d,J＝8.8Hz,2H),3.90(s,2H),3.67-3.65(m,2H),3.51(d,J＝5.2Hz,2H),3.41(d,J＝11.9Hz,2H),3.11(dd,J＝21.3,9.6Hz,2H),2.71(d,J＝3.9Hz,3H),2.64(t,J＝11.5Hz,2H)。
实施例13(2Z)-2-(氟亚甲基)-N'-[4-(4-甲基哌嗪-1-基)磺酰基苯基]丙烷-1,3-二胺盐酸盐14
Figure PCTCN2018098563-appb-000060
以N-[(Z)-3-氟-2-[[4-(4-甲基哌嗪-1-基)磺酰基苯胺基]甲基]烯丙基]氨基甲酸叔丁酯13c(14mg,0.03mmol)代替化合物13b根据实施例12步骤2阐述的方法，得到标题化合物14(11mg,产率92％,HPLC纯度:95.6％)，为淡黄色油状物。
MS(ESI,pos.ion)m/z:343.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.45(s,3H),7.47(d,J＝8.8Hz,2H),7.21(s,1H),7.19(d,J＝83.0Hz,1H),6.72(d,J＝8.8Hz,2H),4.37(q,J＝7.0Hz,2H),4.00(d,J＝5.2Hz,2H),3.17(s,4H),2.67(s,3H),2.33(s,4H)。
实施例14(E)-2-氟甲烯基-N'-(4-吗啉磺酰苯基)-1,3-丙二胺二盐酸盐15
Figure PCTCN2018098563-appb-000061
Figure PCTCN2018098563-appb-000062
步骤1 N-[3-氟-2-[(E)-(4-吗啉磺酰苯基)亚胺甲基]烯丙基]氨基甲酸叔丁酯15b
将4-吗啉磺酰苯胺15a(0.60g,2.5mmol)溶于四氢呋喃(15mL)中，向其中加入N-[3-氟-2-(甲酰基)丙烯基]氨基甲酸叔丁酯11b(0.50g,2.5mmol)和乙酸(0.05mL)。将反应液在室温下搅拌反应，15小时后，反应液由淡黄色变成黄色，TLC中控原料点消失。减压浓缩得标题化合物15b(1.07g,产率99％)，为黄色固体。
步骤2 N-[(E)-3-氟-2-[(4-吗啉磺酰苯胺基)甲基]烯丙基]氨基甲酸叔丁酯15c
将N-[3-氟-2-[(E)-(4-吗啉磺酰苯基)亚胺甲基]烯丙基]氨基甲酸叔丁酯15b(0.50g,1.2mmol)溶于甲醇(10mL)中，0℃下加入硼氢化钠(0.35g,9.3mmol)，室温搅拌2.5小时，向反应液中加水(30mL)淬灭反应，用乙酸乙酯(60mL)萃取，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，制备纯化得到标题化合物15c(0.17g,产率34％)，为黄色油状物。
MS(ESI,pos.ion)m/z:430.3[M+H] +。
步骤3(E)-2-氟甲烯基-N'-(4-吗啉磺酰苯基)-1,3-丙二胺二盐酸盐15
将N-[(E)-3-氟-2-[(4-吗啉磺酰苯胺基)甲基]烯丙基]氨基甲酸叔丁酯15c(0.13g,0.30mmol)溶于乙酸乙酯(1mL)，加入氯化氢的乙酸乙酯溶液(3mL,4mol/L)反应15分钟，TLC监测原料反应完全，减压浓缩，用甲醇/乙酸乙酯(v/v＝1/9，2mL)重结晶得到标题化合物15(30mg,产率27％,HPLC纯度:92.49％)，为白色固体。
MS(ESI,pos.ion)m/z:330.1[M+H] +，
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.07(s,3H),7.46(m,3H),7.31(s,1H),7.19(s,1H),6.75(d,J＝8.8Hz,2H),3.61(s,4H),3.15(s,2H),2.87(d,J＝5.4Hz,2H),2.77(s,4H)。
实施例15 4-[[(E)-2-(胺甲基)-3-氟-烯丙基]-甲基-氨基]-N-叔丁基苯甲酰胺盐酸盐16和4-[[(Z)-2-(胺甲基)-3-氟-烯丙基]-甲基-氨基]-N-叔丁基苯甲酰胺盐酸盐17
Figure PCTCN2018098563-appb-000063
Figure PCTCN2018098563-appb-000064
步骤1 4-(甲基胺)苯甲酸16b
将氢氧化钠(3.0g,71.3mmol)溶于水(15mL)中，加入4-氨基苯甲酸乙酯16a(1.0g,6.0mmol)搅拌10分钟，加入40％甲醛(17.0g,226mmol)，继续搅拌30分钟，加入20％氢氧化钠水溶液(15mL)，升温至90℃，分三批加入锌粉(15.0g,229mmol)，保温搅拌反应16小时。抽滤，收集滤液，用浓盐酸调节滤液的pH＝3，有白色固体析出，抽滤，水洗滤饼，收集滤饼，滤饼经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/2]纯化，得到标题化合物16b(0.51g,产率56％)，为类白色固体。
1H NMR(400MHz,DMSO-d 6)δ(ppm)11.97(s,1H),7.68(d,J＝8.7Hz,2H),6.53(d,J＝8.8Hz,2H),6.44(d,J＝4.9Hz,1H),2.72(d,J＝5.0Hz,3H)。
步骤2 N-叔丁基-4-(甲基胺)苯甲胺16c
将叔丁胺(0.6mL,5.5mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.8g,4.7mmol)加入到4-(甲基胺)苯甲酸16b(0.64g,4.2mmol)的二氯甲烷(15mL)溶液中，0℃下滴加二异丙基乙二胺(0.84mL,5.1mmol)，滴加完毕后移至室温搅拌反应16小时。加水(30mL)淬灭，用二氯甲烷(30mL)萃取，有机相依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/4]纯化，得到标题化合物16c(0.43g,产率49％)，为浅黄色油状物。
MS(ESI,pos.ion)m/z:207.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.61(d,J＝8.7Hz,2H),7.23(s,1H),6.49(d,J＝8.7Hz,2H),6.09(d,J＝4.9Hz,1H),2.71(d,3H),1.35(s,9H)。
步骤3 N-[[2-[[4-(叔丁基氨甲酰基)-N-甲基-苯胺]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯16d
将碳酸钾(0.35g,2.5mmol)和N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(0.50g,1.9mmol)加入N-叔丁基-4-(甲基胺)苯甲胺16c(0.43g,2.1mmol)的N,N-二甲基甲酰胺(4mL)溶液中，40℃搅拌反应12小时，向反应液中加水(20mL)淬灭，用乙酸乙酯(30mL×2)萃取，合并的有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经柱层析[乙酸乙酯/石油醚(v/v)＝1/4]纯化，得到标题化合物16d(0.35g,产率43％)，为浅黄色油状物。
MS(ESI,pos.ion)m/z:394.3[M+H] +。
步骤4 4-[[(E)-2-(胺甲基)-3-氟-烯丙基]-甲基-氨基]-N-叔丁基苯甲酰胺盐酸盐16和4-[[(Z)-2-(胺甲基)-3-氟- 烯丙基]-甲基-氨基]-N-叔丁基苯甲酰胺盐酸盐17
将N-[[2-[[4-(叔丁基氨甲酰基)-N-甲基-苯胺]甲基]-3-氟-烯丙基]氨基甲酸叔丁酯16d(0.35g,0.89mmol)加入到氯化氢的乙酸乙酯溶液(5mL,4mol/L)，室温反应1小时，减压浓缩除去溶剂，残余物制备分离，再经氯化氢的乙酸乙酯溶液处理，得到标题化合物16(0.13g,产率44％,HPLC纯度:89.90％)，为浅黄色固体和17(0.06g,产率20％,HPLC纯度:99.49％)，类白色固体。
化合物16：
MS(ESI,pos.ion)m/z:294.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.48(s,3H),7.69(d,J＝8.8Hz,2H),7.38(s,1H),6.81(d,J＝8.7Hz,2H),6.80(d,J＝83.0Hz,1H),4.16(d,J＝2.9Hz,2H),3.41(d,J＝4.7Hz,2H),2.95(s,3H),1.36(s,9H)；
化合物17：
MS(ESI,pos.ion)m/z:294.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.32(s,3H),7.70(d,J＝8.9Hz,2H),7.37(s,1H),7.14(d,J＝83.1Hz,1H),6.77(d,J＝8.9Hz,2H),4.22(s,2H),3.27(s,2H),2.95(s,3H),1.36(s,9H)。
实施例16 4-[(1E,3Z)-3-(氨甲基)-4-氟-丁-1,3-二烯基]-N-叔丁基-苯甲酰胺盐酸盐18、4-[(1E,3E)-3-(氨甲基)-4-氟-丁-1,3-二烯基]-N-叔丁基-苯甲酰胺盐酸盐19和4-[(1Z,3Z)-3-(氨甲基)-4-氟-丁-1,3-二烯基]-N-叔丁基-苯甲酰胺盐酸盐20
Figure PCTCN2018098563-appb-000065
步骤1[2-[(叔丁氧羰基胺)甲基]-3-氟-烯丙基]-三苯基-溴化膦18a
将N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(1.0g,3.7mmol)和三苯基膦(1.0g,3.8mmol)溶于乙腈(10mL)，85℃反应25小时。冷却至室温，减压除去溶剂得黄色油状物，用二氯甲烷/乙酸乙酯(v/v＝1/9,10mL)重结晶，得到标题化合物18a(1.6g,产率81％)，为白色固体。
步骤2 N-[4-[4-(叔丁基氨甲酰基)苯基]-2-(氟亚甲基)丁-3-烯基]氨基甲酸叔丁酯18b
将[2-[(叔丁氧羰基胺)甲基]-3-氟-烯丙基]-三苯基-溴化膦18a(1.0g,1.9mmol)溶于四氢呋喃(15mL)，氮气保护，-20℃下滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(1.4mL,2.8mmol,2mol/L)，反应20分钟后，缓慢滴加N-叔丁基-甲酰基-苯胺(0.39g,1.9mmol)的四氢呋喃溶液(0.5mL)，随后自然升至室温反应24小时。加水(5mL)淬灭反应，用乙酸乙酯(20mL)萃取，有机相用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，抽滤浓缩，残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/5]纯化，得到标题化合物18b(0.46g,产率65％)，为黄色固体。
步骤3 4-[(1E,3Z)-3-(氨甲基)-4-氟-丁-1,3-二烯基]-N-叔丁基-苯甲酰胺盐酸盐18、4-[(1E,3E)-3-(氨甲基)-4-氟 -丁-1,3-二烯基]-N-叔丁基-苯甲酰胺盐酸盐19和4-[(1Z,3Z)-3-(氨甲基)-4-氟-丁-1,3-二烯基]-N-叔丁基-苯甲 酰胺盐酸盐20
将N-[4-[4-(叔丁基氨甲酰基)苯基]-2-(氟亚甲基)丁-3-烯基]氨基甲酸酯叔丁18c(0.46g,1.2mmol)溶于乙酸乙酯(0.5mL)，加入氯化氢的乙酸乙酯溶液(5mL)，反应30分钟。减压浓缩，得到的固体经制备拆分和氯化氢的乙酸乙酯溶液处理得标题化合物18(51mg,产率14％,HPLC纯度:97.64％)，为黄色固体；标题化合物19(25mg,产率6.6％,HPLC纯度:86.06％)，为棕色固体；和标题化合物20(40mg,产率11％,HPLC纯度:96.73％)，为棕色固体。
化合物18：
MS(ESI,pos.ion)m/z:277.3[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.40(s,3H),7.90-7.72(m,3H),7.46(d,J＝8.0Hz,2H),6.85(d,J＝83.3Hz,1H),6.71(d,J＝12.1Hz,1H),6.10(dd,J＝11.6,5.7Hz,1H),3.55(s,2H),1.37(s,9H)；
化合物19：
MS(ESI,pos.ion)m/z:277.1[M-Cl] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)8.31(s,3H),7.78(d,J＝6.8Hz,2H),7.46(d,J＝7.7Hz,1H),7.37-7.18(m,2H),6.96-6.69(m,2H),6.10(dd,J＝11.6,5.2Hz,1H),3.56(s,2H),1.38(s,9H)；
化合物20：
MS(ESI,pos.ion)m/z:277.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.32(s,3H),7.75(d,J＝8.2Hz,2H),7.50-7.39(m,2H),7.22(d,J＝50.8Hz,1H),7.02(d,J＝81.3Hz,1H),6.76(d,J＝12.2Hz,1H),6.03(d,J＝11.8Hz,1H),3.50(s,2H),1.37(s,9H)。
实施例17(E)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-丙-2-烯-1-胺盐酸盐21
Figure PCTCN2018098563-appb-000066
步骤1 N-[(E)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯21a和N-[(Z)-2-[[4-(2- 环丙基四唑-5-基)苯氧基]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯21b
将醋酸铜(0.48g,2.6mmol)，2,2'-联吡啶(0.42g,2.6mmol)溶于1,2-二氯乙烷(20mL)，升温至70℃，搅拌10分钟，加入N-[3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁基酯7c(0.70g,2.0mmol)、环丙硼酸(0.43g,5.0mmol)和碳酸钠(0.59g,5.5mmol)，继续反应4小时。反应液降至室温，加入饱和氯化铵溶液(100mL)淬灭，用乙酸乙酯(60mL×3)萃取，合并的有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物21a(70mg,产率9.0％)和21b(81mg,产率10％)，均为黄色油状物。
MS(ESI,pos.ion)m/z:390.3[M+H] +。
步骤2(E)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-丙-2-烯-1-胺盐酸盐21
将N-[(E)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯21a(70mg,0.18mmol)溶于乙酸乙酯(1mL)，加入氯化氢的乙酸乙酯溶液(1mL,4mol/L)，室温下搅拌反应30分钟。旋干溶剂，得到标题化合物c(56mg,产率95％,HPLC纯度:96.92％)，为类白色固体。
MS(ESI,pos.ion)m/z:290.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.37(s,3H),8.00(d,J＝8.2Hz,2H),7.38(d,J＝53.2Hz,1H),7.18(d,J＝8.2Hz,2H),4.73(s,2H),4.43(s,1H),3.62(s,2H),1.37(d,J＝14.2Hz,2H),1.18(t,J＝7.0Hz,2H)。
实施例18(Z)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-丙-2-烯-1-胺盐酸盐22
Figure PCTCN2018098563-appb-000067
以N-[(Z)-2-[[4-(2-环丙基四唑-5-基)苯氧基]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯21b(81mg,0.21mmol)代替化合物21a根据实施例17步骤2阐述的方法，得到标题化合物22(67mg,产率99％,HPLC纯度:94.20％)，为类白色固体。
MS(ESI,pos.ion)m/z:290.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.36(s,3H),7.99(d,J＝8.3Hz,2H),7.48-7.30(m,1H),7.20-7.13(m,2H),4.83(s,2H),4.43(s,1H),3.55(s,2H),1.37(d,J＝14.7Hz,2H),1.17(t,J＝7.0Hz,2H)。
实施例19(E)-3-氟-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐23
Figure PCTCN2018098563-appb-000068
步骤1 N-[(E)-3-氟-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯23a和N-[(Z)-3-氟-2-[[4-(2- 苯基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯23b
将醋酸铜(421mg,2.27mmol)和2,2'-联吡啶(362mg,2.27mmol)溶于1.2-二氯乙烷(10mL)，升温至70℃搅拌10分钟，加入N-[3-氟-2-[[4-(1H-四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯7c(530mg,1.52mmol)、苯硼酸(369mg,3.03mmol)和碳酸钠(323mg,3.03mmol)，继续搅拌反应5小时。反应液冷却至室温，加入饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝9/1]纯化和制备拆分，得到标题化合物23a(100mg,产率16％)和23b(51mg,产率8.0％)，均为白色固体。
MS(ESI,pos.ion)m/z:448.3[M+Na] +。
步骤2(E)-3-氟-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐23
将N-[(E)-3-氟-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯23a(100mg,0.24mmol)溶于乙酸乙酯(4mL)，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温下搅拌反应30分钟。旋干溶剂，得到标题化合物23(85mg,产率99％,HPLC纯度:99.90％)，为白色固体。
MS(ESI,pos.ion)m/z:326.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.42(s,3H),8.15(dd,J＝7.9,6.4Hz,4H),7.70(t,J＝7.6Hz,2H),7.27(dd,J＝21.7,18.6Hz,4H),4.77(d,J＝2.9Hz,2H),3.63(s,2H)。
实施例20(Z)-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]-3-氟-丙-2-烯-1-胺盐酸盐24
Figure PCTCN2018098563-appb-000069
以N-[(Z)-2-[[4-(2-苯基四唑-5-基)苯氧基]甲基]-3-氟-烯丙基]氨基甲酸叔丁基酯23b(51mg,0.12mmol)代替化合物23a根据实施例19步骤2阐述的方法，得到标题化合物24(34mg,产率78％,HPLC纯度:96.01％)，为白色固体。
MS(ESI,pos.ion)m/z:326.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.37(s,3H),8.15(t,J＝7.6Hz,4H),7.70(t,J＝7.7Hz,2H),7.21(dd,J＝28.4,8.5Hz,4H),4.87(s,2H),3.56(s,2H)。
实施例21(E)-3-氟-2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]丙基-2-烯-1-胺盐酸盐25
Figure PCTCN2018098563-appb-000070
步骤1 5-甲基-2-(4-硝基苯)四氮唑25a
将1-氟-4-硝基苯5a(2.00g,14.20mmol)和5-甲基-1H-四氮唑(1.20g,13.80mmol)溶于N,N-二甲基甲酰胺(15mL)，加入碳酸钾(3.00g,21.50mmol)，80℃搅拌反应18小时。加入水(20mL)，用乙酸乙酯(30mL)萃取，合并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)＝1/1]纯化，得到标题化合物25a(1.10g,产率38％)，为黄色固体。MS(ESI,pos.ion)m/z:206.1[M+H] +。
步骤2 4-(5-甲基四氮唑-2-基)苯胺25b
将5-甲基-2-(4-硝基苯)四氮唑25a(1.20g,5.36mmol)溶于乙酸乙酯(20mL)和甲醇(20mL)的混合溶剂，加入10％钯炭(1.00g)，置换氢气，氢化反应(4MPa)1.5小时。过滤，滤液旋干，得到标题化合物25b(0.90g,产率88％)，为白色固体。
MS(ESI,pos.ion)m/z:176.3[M+H] +。
步骤3 4-(5-甲基四氮唑-2-基)苯酚25c
将4-(5-甲基四氮唑-2-基)苯胺25b(0.90g,5.10mmol)溶于稀硫酸(30mL,1.00mol/L)，0℃下滴加亚硝酸钠(1.00g,14.50mmol)的水(2mL)溶液，120℃反应1小时。反应液冷却至室温，过滤，得到标题化合物25c(0.75g,产率83％)，为黄色固体。
MS(ESI,pos.ion)m/z:177.2[M+H] +。
步骤4 N-[(E)-3-氟-2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯25d和N-[(Z)-3-氟 -2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯25e
将4-(5-甲基四氮唑-2-基)苯酚25c(0.20g,1.10mmol)和N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(0.30g,1.10mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸铯(0.30g,2.10mmol)，反应液在室温下搅拌反应13小时。加入水(10mL)淬灭反应，用乙酸乙酯(20mL)萃取，有机相用饱和氯化钠溶液(20mL×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25d(47mg,产率11％)和25e(229mg,产率56％)，均为无色油状物。
MS(ESI,pos.ion)m/z:364.3[M+H] +。
步骤5(E)-3-氟-2-[[4-(2-甲基四氮唑-5-基)苯氧基]甲基]丙基-2-烯-1-胺盐酸盐25
将N-[(E)-3-氟-2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯25d(47mg,0.13mmol)溶于乙酸乙酯(2mL)，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温下搅拌反应1小时。旋干溶剂，得到标题化合物25(35mg,产率90％,HPLC纯度:94.23％)，为无色油状物。
MS(ESI,pos.ion)m/z:264.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.38(d,J＝2.6Hz,1H),8.33(d,J＝38.9Hz,4H),8.04(dd,J＝9.0,2.6Hz,1H),7.70(d,J＝9.1Hz,1H),7.39(d,J＝84.0Hz,1H),4.96(d,J＝2.4Hz,2H),3.63(s,2H),2.55(s,3H)。
实施例22(Z)-3-氟-2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]丙基-2-烯-1-胺盐酸盐26
Figure PCTCN2018098563-appb-000071
以N-[(Z)-3-氟-2-[[4-(5-甲基四氮唑-2-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯25e(0.04g,0.12mmol)代替化合物25d根据实施例21步骤5阐述的方法，得到标题化合物26(86mg,产率70％,HPLC纯度:90.64％)，为白色固体。
MS(ESI,pos.ion)m/z:264.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.38(d,J＝2.6Hz,1H),8.27(s,4H),8.05(dd,J＝9.0,2.6Hz,1H),7.73(d,J＝9.1Hz,1H),7.20(d,J＝84.0Hz,1H),5.06(s,2H),3.57(s,2H),2.55(s,3H)。
实施例23 3-[4-[(E)-2-(氨甲基)-3-氟-烯丙氧基]苯基]噁唑烷-2-酮盐酸盐27
Figure PCTCN2018098563-appb-000072
Figure PCTCN2018098563-appb-000073
步骤1 3-(4-甲氧基苯基)噁唑烷-2-酮27b
将1-碘-4-甲氧基苯27a(2.34g,10.00mmol)和2-噁唑烷酮(1.00g,11.30mmol)溶于四氢呋喃(20mL)，加入氟化铯(2.50g,11.30mmol)、碘化亚铜(0.10g,0.53mmol)和N,N'-二甲基乙二胺(0.09g，1.00mmol)，60℃反应44小时。反应液冷却，加入水(20mL)淬灭，用乙酸乙酯(50mL)萃取，有机相用饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物27b(0.75g,产率39％)，为白色固体。
MS(ESI,pos.ion)m/z:194.1[M+H] +。
步骤2 3-(4-羟基苯基)噁唑烷-2-酮27c
将3-(4-甲氧基苯基)噁唑烷-2-酮27b(0.50g,2.60mmol)溶于二氯甲烷(20mL)，0℃下滴加三溴化硼(1.0mL,3.40mmol)，保持在0℃下反应0.5小时。将反应液倒入冰水(20mL)中淬灭，待冰融化后，抽滤，收集滤饼干燥，得到标题化合物27c(0.14g,产率30％)，为白色固体。
步骤3 N-[(E)-3-氟-2-[[4-(2-氧代噁唑烷-3-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁基酯27d和N-[(Z)-3-氟 -2-[[4-(2-氧代噁唑烷-3-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁基酯27e
将3-(4-羟基苯基)噁唑烷-2-酮27c(0.14g,0.78mmol)溶于N,N-二甲基甲酰胺(10mL)，加入N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(0.21g,0.78mmol)和碳酸铯(0.50g,1.53mmol)，室温下搅拌反应2小时。加入水(10mL)淬灭反应，用乙酸乙酯(30mL)萃取，有机相用饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物27d(50mg,产率17％)和27e(13mg,产率4.5％)，均为无色油状物。
MS(ESI,pos.ion)m/z:389.2[M+Na] +。
步骤4 3-[4-[(E)-2-(氨甲基)-3-氟-烯丙氧基]苯基]噁唑烷-2-酮盐酸盐27
将N-[(E)-3-氟-2-[(1-氧代-2-(4-氟苯基)-3,4-二氢异喹啉-6-基)氧甲基]烯丙基]氨基甲酸叔丁酯27d(50mg,0.14mmol)溶于乙酸乙酯(2mL)，加入氯化氢的乙酸乙酯溶液(2mL,4mol/L)，室温下反应1小时。旋干溶剂，得到标题化合物27(40mg,产率97％,HPLC:93.21％)，为无色油状物。
MS(ESI,pos.ion)m/z:267.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.16(s,3H),7.49(d,J＝8.0Hz,2H),7.30(d,J＝80.0Hz,1H),7.04(d,J＝8.0Hz,2H),4.62(s,2H),4.42(t,J＝8.0Hz,2H),4.03(t,J＝8.0Hz,2H),3.60(s,2H)。
实施例24 3-[4-[(Z)-2-(氨甲基)-3-氟-烯丙氧基]苯基]噁唑烷-2-酮盐酸盐28
Figure PCTCN2018098563-appb-000074
以N-[(Z)-3-氟-2-[[4-(2-氧代噁唑烷-3-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁基酯27e(13mg,0.04mmol)代替化合物27d根据实施例23步骤4阐述的方法，得到标题化合物28(10mg,产率93％,HPLC:83.51％)，为无色油状物。
MS(ESI,pos.ion)m/z:267.2[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.19(s,3H),7.49(d,J＝8.0Hz,2H),7.21(d,J＝80.0Hz,1H),7.04(d,J＝8.0Hz,2H),4.73(s,2H),4.42(t,J＝8.0Hz,2H),4.02(t,J＝8.0Hz,2H),3.52(s,2H)。
实施例25(E)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐29
Figure PCTCN2018098563-appb-000075
步骤1 4-(1H-四唑-5-基)苯酚29b
将4-羟基苯甲腈29a(2.0g,16.6mmol)溶于无水N,N-二甲基甲酰胺(30mL)，加入氯化铵(2.69g,49.8mmol)和叠氮化钠(3.34g,49.8mmol)，氮气保护下升至120℃搅拌反应48小时。冷却至室温，加入水(25mL)，用乙酸乙酯(100mL×5)萃取，合并的有机相用饱和氯化钠溶液(50mL)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]纯化，得到标题化合物29b(1.08g,产率40％)，为白色固体。
MS(ESI,pos.ion)m/z:163.2[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.95(s,2H),7.87(d,J＝8.6Hz,2H),6.96(d,J＝8.6Hz,2H)。
步骤2 4-(2-叔丁基四唑-5-基)苯酚29c
将4-(1H-四唑-5-基)苯酚29b(980mg,6.04mmol)和叔丁醇(1.1mL,12mmol)溶于高氯酸(10mL)和浓硫酸(7mL)混合溶液，室温搅拌反应18小时。将反应液倒入冰水(50mL)中淬灭，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和碳酸氢钠溶液调节pH至中性，然后用饱和氯化钠水溶液(20mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物29c(457mg,产率35％)，为白色固体。
MS(ESI,pos.ion)m/z:219.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)9.96(s,1H),7.88(d,J＝8.6Hz,2H),6.91(d,J＝8.6Hz,2H),1.72(s,9H)。
步骤3 4-(3-叔丁基-1-甲基-四唑-1-盐-5-基)苯酚高氯酸盐29d
将4-(2-叔丁基四唑-5-基)苯酚29c(426mg,1.95mmol)溶于硫酸二甲酯(2mL,163mmol)，50℃搅拌反应24小时。向反应液中加入水(2mL)和高氯酸(2mL)，室温搅拌反应1小时。旋干溶剂，得到标题化合物29d(650mg,产率99％)，为黄色油状物。
MS(ESI,pos.ion)m/z:233.2[M-ClO 4] +。
步骤4 4-(1-甲基四唑-5-基)苯酚29e
将4-(3-叔丁基-1-甲基-四唑-1-盐-5-基)苯酚高氯酸盐29d(649mg,1.95mmol)溶于浓盐酸(6mL)，升温至100℃搅拌反应18小时。反应液冷却至室温，加入水(40mL)淬灭，用乙酸乙酯(30mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL×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)＝5/1]纯化，得到标题化合物29e(330mg,产率96％)，为白色固体。
MS(ESI,pos.ion)m/z:177.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)10.19(s,1H),7.70(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),4.14(s,3H)。
步骤5 N-[(E)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯29f和N-[(Z)-3-氟-2-[[4-(1- 甲基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯29g
将4-(1-甲基四唑-5-基)苯酚29e(318mg,1.81mmol)和N-[2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯1e(532mg,1.98mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸铯(1.18g,3.59mmol)，室温搅拌反应24小时。向反应液中加入水(10mL)，用乙酸乙酯(20mL×2)萃取，合并的有机相用饱和氯化钠溶液(8mL×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29f(181mg,产率28％)和29g(344mg,产率53％)，均为白色固体。
MS(ESI,pos.ion)m/z:386.1[M+Na] +。
步骤6(E)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐29
将N-[(E)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯29f(181mg,0.50mmol)，溶于甲醇(1mL)，加入氯化氢的甲醇溶液(4mL,5mol/L)，室温搅拌反应30分钟。旋干溶剂，得到标题化合物29(149mg,产率99％,HPLC纯度:95.70％)，为类白色固体。
MS(ESI,pos.ion)m/z:264.1[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.39(s,3H),7.84(s,2H),7.36(d,J＝90.7Hz,3H),4.77(s,2H),4.16(s,3H),3.64(s,2H)。
实施例26(Z)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]丙-2-烯-1-胺盐酸盐30
Figure PCTCN2018098563-appb-000076
以N-[(Z)-3-氟-2-[[4-(1-甲基四唑-5-基)苯氧基]甲基]烯丙基]氨基甲酸叔丁酯29g(198mg,0.55mmol)代替化合物29f根据实施例25步骤6阐述的方法，得到标题化合物30(163mg,产率99％,HPLC纯度:92.67％)，为类白色固体。
MS(ESI,pos.ion)m/z:264.0[M-Cl] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.48(s,3H),7.84(d,J＝8.3Hz,2H),7.26(dd,J＝45.3,36.9Hz,3H),4.89(s,2H),4.16(s,4H),3.58(s,2H)。
测试实施例
一、人重组SSAO/VAP-1抑制活性测定
测试目的：下面的方法是用来测定本发明化合物对人重组SSAO/VAP-1的抑制活性。
试验材料：
人重组SSAO/VAP-1(VAP-1，human)购于Sigma，Cat.No.SRP6241；
Figure PCTCN2018098563-appb-000077
Red Monoamine Oxidase Assay Kit购于Invitrogen，Cat.No.A12214；
384孔板购于Corning，Cat.No.6005174；
Figure PCTCN2018098563-appb-000078
Red Hydrogen PeroxidePeroxidase Assay Kit购于Invitrogen，Cat.No.A22188。
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SSAO/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SSAO/VAP-1的各个孔中，室温孵育30min。30min孵育后，将25μL
Figure PCTCN2018098563-appb-000079
Red Monoamine Oxidase Assay Kit(含200μM Amplex Red reagent,1U/mL HRP和1mM苄胺盐酸盐的反应混合物)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SSAO/VAP-1的抑制活性
实施例中化合物编号 SSAO/VAP-1(人重组蛋白)IC 50/nM
3 1.69
4 1.07
5 2.63
6 1.04
9 0.31
10 0.56
12 1.91
21 0.20
22 0.22
27 0.69
28 0.44
29 2.29
30 0.91
试验结果显示：本发明化合物对人重组SSAO/VAP-1具有明显的抑制作用。
二、大鼠脂肪组织匀浆SSAO/VAP-1抑制活性测定
测试目的：下面的方法是用来测定本发明化合物对大鼠脂肪匀浆SSAO/VAP-1的抑制活性。
试验材料：
N-哌嗪-N-乙磺酸钠盐(HEPES SODIUM SALT)购于AMRESCO，Cat.No.0485-500G；
EDTA(Ethylenediaminetetraacetic acid，乙二胺四乙酸)购于Sigma，Cat.No.EDS-100G；
蔗糖(Sucrose)购于Sigma，Cat.No.V900116；
PMSF(Phenylmethanesulfonyl fluoride，苯甲基磺酰氟)购于Beyotime，Cat.No.ST506；
β-甘油磷酸二钠盐水合物(β-Glycerophosphate disodium salt hydrate)购于Sigma，Cat.No.G5422-25G；
优降宁盐酸盐(Pargyline hydrochloride)购于Sigma，Cat.No.P8013-500MG；
DMSO(Dimethyl Sulfoxide，二甲基亚砜)购于Sigma，Cat.No.D2650-100ML；
苄胺盐酸盐(Benzylamine hydrochloride)购于Sigma，Cat.No.B5136-25G；
96孔板购于COSTAR，Cat.No.3631；
Figure PCTCN2018098563-appb-000080
Red Hydrogen PeroxidePeroxidase Assay Kit购于Invitrogen，Cat.No.A22188。
试验方法：
手术切除来自Sprague Dawley大鼠的腹部脂肪，其为富含SSAO/VAP-1的组织。对于每克大鼠腹部脂肪组织，加入5ml HES缓冲液(20mM N-哌嗪-N-乙磺酸钠盐,1mM EDTA,250mM蔗糖，1×PMSF and 100mM β-甘油磷酸二钠盐水合物,pH 7.4)进行匀浆。使用Bertin Technologies的Bertin Precellys 24多功能样品均质器将脂肪组织均质化3min，在4℃，20000g的条件下将脂肪组织匀浆液离心10min，取中间透明上清液。将上清液与溶于HES缓冲液的0.5mM优降宁盐酸盐在37℃下孵育30min。在30min孵育后，将25μl脂肪组织上清液加入至标准96孔板中。将试验化合物溶于DMSO中并稀释6个浓度。将25μL不同浓度的试验 化合物加入至含有脂肪组织上清液的各个孔中，在37℃下孵育30min。孵育后，将50μL含80μM苄胺盐酸盐的反应混合物(含100μM
Figure PCTCN2018098563-appb-000081
Red and 0.2U/ml HRP,
Figure PCTCN2018098563-appb-000082
Red Hydrogen PeroxidePeroxidase Assay Kit)加入至相应孔中，在37℃下孵育30min。30min后，使用BMG LABTECH的PHERAstar FSX酶标仪在激发540nm和发射580nm下读取荧光值(RFU)。使用Graph Pad Prism 5软件绘制曲线并计算出IC 50值。其结果如表2所示：
表2：本发明实施例提供的化合物对脂肪组织匀浆SSAO/VAP-1的抑制活性
实施例中化合物编号 SSAO/VAP-1(脂肪组织匀浆)IC 50/nM
2 10.47
9 8.365
11 10.74
12 10.70
27 10.98
28 6.550
试验结果显示：本发明化合物对脂肪组织匀浆SSAO/VAP-1具有明显的抑制作用。
三、人重组MAO-A和MAO-B酶抑制活性测定
测试目的：下面的方法是用来测定本发明化合物对人重组MAO-A和MAO-B酶的抑制活性。
试验材料：
人重组MAO-A，购于Active Motif，Cat.No.31502；
人重组MAO-B，购于Active Motif，Cat.No.31503；
Clorgyline，购于Sigma，Cat.No.M3778；
R(-)-deprenyl，购于Abam，Cat.No.ab120604；
384-well plate，购于Perkin Elmer，Cat.No.6007299；
试验方法：
本方法利用人重组MAO-A和MAO-B酶，检测化合物在不同浓度下对这2种酶的抑制作用。在对MAO-A酶的抑制实验中，化合物的浓度分别为1μM和10μM。在对MAO-B酶的抑制实验中，化合物的浓度分别为1μM和5μM。购买的人重组MAO-A和MAO-B酶(Active Motif)用于此方法的来源。将试验化合物溶于100％DMSO中，使其使用浓度为10mM。将浓度为10mM的受试化合物加入至384孔板中，随后加入10μL人重组MAO-A或MAO-B酶，使化合物的终浓度分别为1、10μM(MAO-A)或1、5μM(MAO-B)，室温孵育15min。加入10μL Clorgyline(Sigma，MAO-A酶底物)或R(-)-deprenyl(Abcam，MAO-B酶底物)，室温孵育60min。最后加入20μL Lufiferin检测试剂，充分混匀后室温孵育20min。20min后使用plate-reading luminometer检测并读取发光信号。在Excel软件中计算抑制率，使用公式为：Inh％＝(Max-Signal)/(Max-Min)*100。使用Graphpad Prism 5软件计算IC 50值，使用公式为：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*Hill Slope)，Y是％inhibition，X是化合物浓度。其结果如表3所示：
表3：本发明实施例提供的化合物对人重组MAO-A和MAO-B酶的抑制活性
实施例中化合物编号 人重组MAO-A IC 50/μM 人重组MAO-B IC 50/μM
4 >10 >5.0
5 >10 >5.0
6 10 1.0
9 10 1.0
10 10 1.0
11 >10 >5.0
12 >10 5.0
试验结果显示：本发明化合物对人重组MAO-A和MAO-B酶无明显的抑制作用，说明本发明化合物对 SSAO/VAP-1的选择性高。
四、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 PCTCN2018098563-appb-000083
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。
表4显示了本发明化合物的药代动力学数据。
表4：本发明实施例提供的化合物的药代动力学数据
Figure PCTCN2018098563-appb-000084
备注：
AUC last—0-24小时的AUC；
AUC INF—0-无穷时间的AUC。
试验结果表明，静脉注射给药或口服给药时，本发明化合物表现出优良的药代动力学性质，吸收良好，暴露量比较高，口服生物利用度高。
试验结果表明，本发明化合物具有优良的药代动力学。
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 (15)

  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、几何异构体、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的前药，
    Figure PCTCN2018098563-appb-100001
    其中，
    Figure PCTCN2018098563-appb-100002
    为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100003
    为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100004
    为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6卤代烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，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 3-12环烷基、C 3-12环烷基-C 1-4亚烷基、3-12个原子组成 的杂环基、(3-12个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H；
    各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基；其中所述C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
    各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-6烷基、C 3-6环烷基或3-8个原子组成的杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-8个原子组成的杂环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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
    或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6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、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
    R 1为H、D、F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
    R 2为F、Cl、Br、I、C 1-6烷基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a、-OC(＝O)OR b、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-C(＝O)NR cR d、-S(＝O) 2NR cR d、-S(＝O) 2R e、-SR e或-S(＝O)R e，其中，所述C 1-6烷基未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、C 1-6烷基、C 1-6卤代烷基、R bO-C 1-4亚烷基或R dR cN-C 1-4亚烷基；
    各R 3和R 4独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子 组成的杂芳基、(5-10个原子组成的杂芳基)-C 1-4亚烷基或
    Figure PCTCN2018098563-appb-100005
    其中所述C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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 3、R 4与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中所述3-8个原子组成的杂环和5-8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、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；
    各R a、R b、R c、R d、R e和R f独立地为H、D、羟基、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)-C 1-4亚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、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与和它们相连的氮原子一起，形成3-8个原子组成的杂环或5-8个原子组成的杂芳环，其中所述3-8个原子组成的杂环和5-8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、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，
    Figure PCTCN2018098563-appb-100006
    为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100007
    为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、 -NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100008
    为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-4亚烷基、R dR cN-C 1-4亚烷基、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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，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、C 3-6环烷基-C 1-4亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
  3. 根据权利要求1或2所述的化合物，其中，
    Figure PCTCN2018098563-appb-100009
    为单键，X为O或S，各R 7、R 8、R 9、R 10和R 11独立地为H、D、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-SR e、-S(＝O) 2R e、-S(＝O)R e、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、噁唑烷基、噁唑烷-2-酮基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100010
    为单键，X为S(＝O)、S(＝O) 2或NR f，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑 烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是至少一个R 7、R 8、R 9、R 10和R 11不为H；
    或
    Figure PCTCN2018098563-appb-100011
    为双键，X为N或CH，各R 7、R 8、R 9、R 10和R 11独立地为H、D、F、Cl、Br、I、CN、NO 2、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-NR cR d、-OR b、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、三氟甲基、二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述二氟甲基、氟甲基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个R x所取代，条件是R 6不存在，且至少一个R 7、R 8、R 9、R 10和R 11不为H。
  4. 根据权利要求1-3任意一项所述的化合物，其中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基；其中所述C 1-4烷基、C 1-3卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、-OR b、-NR cR d、C 1-4烷基或C 1-3卤代烷基。
  5. 根据权利要求1-4任意一项所述的化合物，其中，各R x独立地为D、F、Cl、Br、I、CN、NO 2、 ＝O、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、-SR e、-S(＝O) 2R e、-S(＝O)R e、-S(＝O) 2NR cR d、-NR fC(＝O)R a、-NR fS(＝O) 2R e、-OR b、-NR cR d、R bO-C 1-2亚烷基、R dR cN-C 1-2亚烷基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基；其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、甲基、乙基、正丙基或异丙基。
  6. 根据权利要求1-5任意一项所述的化合物，其中，各R 5和R 6独立地为H、D、F、Cl、Br、I、-OR b、C 1-4烷基、C 3-6环烷基或5-6个原子组成的杂环基，其中所述C 1-4烷基、C 3-6环烷基和5-6个原子组成的杂环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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基；
    或R 5、R 6与和它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环，其中所述C 3-6碳环和5-6个原子组成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、-OR b、-NR cR d、甲基、乙基、正丙基、异丙基或C 1-3卤代烷基。
  7. 根据权利要求1-6任意一项所述的化合物，其中，R 1为H、D、F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基；
    R 2为F、Cl、Br、I、甲基、乙基、异丙基、正丙基、-C(＝O)OR b、-C(＝O)R a、-OC(＝O)R a或-OC(＝O)OR b，其中，所述甲基、乙基、异丙基和正丙基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地为D、F、Cl、Br、I、CN、NO 2、-OR b、-NR cR d、甲基、乙基、正丙基或异丙基。
  8. 根据权利要求1-7任意一项所述的化合物，其中，各R 3和R 4独立地为H、D、甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)-C 1-4亚烷基或
    Figure PCTCN2018098563-appb-100012
    其中所述甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、C 3-6环烷基、C 3-6环烷基-C 1-2 亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、苯基、苯基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
    或R 3、R 4与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
  9. 根据权利要求1-8任意一项所述的化合物，其中，各R a、R b、R c、R d、R e和R f独立地为H、D、羟基、三氟甲基、二氟甲基、甲基、乙基、异丙基、正丙基、正丁基、叔丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、异丙基、正丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基；
    或R c、R d与和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、CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、C 1-3卤代烷基或C 1-3烷氧基。
  10. 一种化合物，其具有以下其中之一的结构：
    Figure PCTCN2018098563-appb-100013
    Figure PCTCN2018098563-appb-100014
    Figure PCTCN2018098563-appb-100015
    Figure PCTCN2018098563-appb-100016
    或其立体异构体、几何异构体、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的前药。
  11. 根据权利要求1-10任意一项所述的化合物，其中所述药学上可接受的盐为盐酸盐、氢溴酸盐或甲磺酸盐。
  12. 一种药物组合物，其包含权利要求1-11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。
  13. 权利要求1-11任意一项所述的化合物或权利要求12所述的药物组合物在制备药物中的用途，其中，所述药物用于抑制SSAO/VAP-1；或用于预防、治疗或减轻与SSAO/VAP-1蛋白有关或者由SSAO/VAP-1调节的疾病；其中，所述与SSAO/VAP-1蛋白有关或者由SSAO/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、精神病症、缺血性疾病、血管疾病、纤维化或组织移植排斥。
  14. 根据权利要求13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；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；所述精神病症为严重抑郁症、两极型抑郁症或注意力不足多动症；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。
  15. 根据权利要求14所述的用途，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；所述全身炎性综合征为全身炎性脓毒症；所述炎症性肠病为过敏性肠病；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肝病；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；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；所述皮肤疾病为接触性皮炎、皮肤炎症、牛皮癣或湿疹；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。
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810041A (zh) * 2017-11-21 2019-05-28 南京药捷安康生物科技有限公司 卤代烯丙基胺类ssao/vap-1抑制剂及其应用
WO2020006177A1 (en) * 2018-06-29 2020-01-02 Blade Therapeutics, Inc. Vascular adhesion protein-1 (vap-1) modulators and therapeutic uses thereof
WO2020125776A1 (zh) * 2018-12-20 2020-06-25 山东丹红制药有限公司 式(iv)化合物的工艺路线、晶型及其制备方法
WO2021083209A1 (en) * 2019-10-29 2021-05-06 Eccogene (Shanghai) Co., Ltd. Ssao inhibitors and use thereof
WO2021258159A1 (en) * 2020-06-26 2021-12-30 Pharmaxis Ltd. Haloallylamine dual amine oxidase inhibitors
US12213970B2 (en) 2018-10-29 2025-02-04 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof
US12258317B2 (en) 2019-05-20 2025-03-25 Sunshine Lake Pharma Co., Ltd. Isoquinolinone compound for inhibiting ssao/vap-1, and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018287777B2 (en) * 2017-06-20 2020-05-21 Shandong Danhong Pharmaceutical Co., Ltd. SSAO inhibitor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1921841A (zh) * 2004-02-25 2007-02-28 拉卓拉药物公司 用于治疗疾病的胺和酰胺类化合物
US20070293548A1 (en) * 2006-03-31 2007-12-20 Wang Eric Y Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and VAP-1 mediated adhesion useful for treatment and prevention of diseases
CN101917845A (zh) * 2007-11-21 2010-12-15 法马克西斯制药公司 Ssao/vap-1的卤代烯丙胺抑制剂及其用途
CN104520268A (zh) * 2012-05-02 2015-04-15 法马克西斯制药公司 Ssao的取代的3-卤代烯丙基胺抑制剂及其用途
CN108341752A (zh) * 2017-01-21 2018-07-31 广东东阳光药业有限公司 抑制ssao/vap-1的胺类化合物及其在医药上的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1921841A (zh) * 2004-02-25 2007-02-28 拉卓拉药物公司 用于治疗疾病的胺和酰胺类化合物
US20070293548A1 (en) * 2006-03-31 2007-12-20 Wang Eric Y Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and VAP-1 mediated adhesion useful for treatment and prevention of diseases
CN101917845A (zh) * 2007-11-21 2010-12-15 法马克西斯制药公司 Ssao/vap-1的卤代烯丙胺抑制剂及其用途
CN104520268A (zh) * 2012-05-02 2015-04-15 法马克西斯制药公司 Ssao的取代的3-卤代烯丙基胺抑制剂及其用途
CN108341752A (zh) * 2017-01-21 2018-07-31 广东东阳光药业有限公司 抑制ssao/vap-1的胺类化合物及其在医药上的应用

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810041B (zh) * 2017-11-21 2023-08-15 药捷安康(南京)科技股份有限公司 卤代烯丙基胺类ssao/vap-1抑制剂及其应用
CN109810041A (zh) * 2017-11-21 2019-05-28 南京药捷安康生物科技有限公司 卤代烯丙基胺类ssao/vap-1抑制剂及其应用
WO2020006177A1 (en) * 2018-06-29 2020-01-02 Blade Therapeutics, Inc. Vascular adhesion protein-1 (vap-1) modulators and therapeutic uses thereof
US12213970B2 (en) 2018-10-29 2025-02-04 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof
WO2020125776A1 (zh) * 2018-12-20 2020-06-25 山东丹红制药有限公司 式(iv)化合物的工艺路线、晶型及其制备方法
US12077513B2 (en) 2018-12-20 2024-09-03 Shandong Danhong Pharmaceutical Co., Ltd. Process route of compound of formula (IV), crystal form and preparation method therefor
US12258317B2 (en) 2019-05-20 2025-03-25 Sunshine Lake Pharma Co., Ltd. Isoquinolinone compound for inhibiting ssao/vap-1, and use thereof
CN114901649A (zh) * 2019-10-29 2022-08-12 上海诚益生物科技有限公司 Ssao抑制剂及其用途
JP2022554330A (ja) * 2019-10-29 2022-12-28 エコジーン （シャンハイ） カンパニー リミテッド Ｓｓａｏ阻害剤およびその使用
EP4051669A4 (en) * 2019-10-29 2023-12-13 Eccogene (Shanghai) Co., Ltd. SSAO INHIBITORS AND USE THEREOF
US11964942B2 (en) 2019-10-29 2024-04-23 Eccogene (Shanghai) Co., Ltd. SSAO inhibitors and use thereof
CN114901649B (zh) * 2019-10-29 2024-07-23 诚益生物(美国)公司 Ssao抑制剂及其用途
US11472769B2 (en) 2019-10-29 2022-10-18 Eccogene (Shanghai) Co., Ltd. SSAO inhibitors and use thereof
WO2021083209A1 (en) * 2019-10-29 2021-05-06 Eccogene (Shanghai) Co., Ltd. Ssao inhibitors and use thereof
JP7703272B2 (ja) 2019-10-29 2025-07-07 エコジーン インコーポレイテッド Ｓｓａｏ阻害剤およびその使用
AU2020377093B2 (en) * 2019-10-29 2026-02-26 Eccogene Inc. SSAO inhibitors and use thereof
JP2023531468A (ja) * 2020-06-26 2023-07-24 ファーマクシス リミテッド ハロアリルアミン系二重アミンオキシダーゼ阻害剤
WO2021258159A1 (en) * 2020-06-26 2021-12-30 Pharmaxis Ltd. Haloallylamine dual amine oxidase inhibitors
JP7665122B2 (ja) 2020-06-26 2025-04-21 シンタラ リミテッド ハロアリルアミン系二重アミンオキシダーゼ阻害剤
US12428370B2 (en) 2020-06-26 2025-09-30 Syntara Limited Haloallylamine dual amine oxidase inhibitors

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