WO2019024924A1 - Composé amine pour inhiber ssao/vap-1 et son utilisation en médecine - Google Patents

Composé amine pour inhiber ssao/vap-1 et son utilisation en médecine Download PDF

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Publication number
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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Chinese (zh)
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

La présente invention concerne un composé amine pour inhiber l'amine oxydase sensible au semicarbazide (SSAO) et/ou des inhibiteurs de la protéine 1 d'adhésion vasculaire (VAP-1) et son utilisation en médecine, l'invention concerne en outre une composition pharmaceutique comprenant le composé amine. Ledit composé et ladite composition pharmaceutique peuvent être utilisés pour traiter une inflammation et/ou des maladies associées à une inflammation, le diabète et/ou des maladies associées au diabète, des troubles psychiatriques, des maladies ischémiques, des maladies vasculaires, la fibrose ou le rejet de greffe de tissu.
PCT/CN2018/098563 2017-08-04 2018-08-03 Composé amine pour inhiber ssao/vap-1 et son utilisation en médecine Ceased WO2019024924A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880047112.9A CN110914234B (zh) 2017-08-04 2018-08-03 抑制ssao/vap-1的胺类化合物及其在医药上的应用

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WO2021258159A1 (fr) * 2020-06-26 2021-12-30 Pharmaxis Ltd. Inhibiteurs d'amine oxydase double à base d'haloallylamine
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