Preparation and Application of Semicarbazide-Sensitive Amine Oxidase Inhibitors

Abstract

The present invention provides a method for preparing a semicarbazide-sensitive amine oxidase inhibitor and its application. Specifically, the present invention discloses a compound represented by Formula I, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof. It also discloses that the compound can inhibit semicarbazide-sensitive amine oxidase.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, and more specifically, to semicarbazide-sensitive amine oxidase inhibitors.

Background Art

[0002] Semicarbazide-sensitive amine oxidase (SSAO) is an amine oxidase containing a dopamine quinone group, belonging to the semicarbazide-sensitive amine oxidase family, and is also called vascular adhesion protein-1, VAP-1. In the animal body, it is mainly encoded by the AOC3 gene. The SSAO content in mammalian smooth muscle cells, adipocytes, and endothelial cells is relatively rich, and it is also expressed in various organs such as the vascular system, cartilage, and kidney. In mammals, SSAO can be divided into two types: membrane-bound and soluble. The enzyme activity varies greatly among different species and different tissues of the same species. SSAO catalyzes the metabolism of endogenous or dietary amines to aldehydes, accompanied by the production of hydrogen peroxide and ammonia.

[0003] The natural metabolic substrates in the body are mainly aliphatic amines and aromatic amines. Here, methylamine (MA) and aminoacetone are recognized as physiological substrates of SSAO, and are catalyzed to formaldehyde and pyruvaldehyde respectively. In endothelial cells, SSAO exists in the form of vascular adhesion protein-1 and mediates the process of adhesion and infiltration between leukocytes and endothelial cells.

[0004] According to a large number of studies, SSAO and its metabolites have been confirmed to be closely related to inflammation-related diseases such as atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, retinopathy, chronic obstructive pulmonary disease (COPD), autoimmune diseases, multiple sclerosis, rheumatoid arthritis, pain caused by arthritis, and Alzheimer's disease. SSAO / VAP-1 plays an important role in cancer biology, and it has been reported that small molecule inhibitors of SSAO / VAP-1 can affect the number of bone marrow cells of angiogenesis factors in melanoma and lymphoma. According to recent studies, it has been suggested that abnormal functions of SSAO play a role in the occurrence and development of liver diseases such as fatty liver. Fatty liver disease accompanied by inflammation develops into non-alcoholic fatty liver after progression, and a certain proportion of patients will further develop liver fibrosis, cirrhosis, and even liver cancer after a certain period.

[0005] Considering that the function of SSAO plays an important role in the pathological processes of various inflammation-related diseases, finding effective inhibitors has very important value and significance for controlling diseases caused by abnormal SSAO.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The object of the present invention is to provide a new SSAO inhibitor, as well as its preparation method and uses.

Means for Solving the Problems

[0007] The first aspect of the present invention provides a compound represented by formula I, or its stereoisomer or racemic compound, or its pharmaceutically acceptable salt, Formula I:

Chemical

[0008] Wherein, A is selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring and a substituted or unsubstituted 5-12 membered heteroaromatic ring, or A is a chemical bond (or none), B is selected from the group consisting of a substituted or unsubstituted C3-10 cycloalkyl group, a substituted or unsubstituted C6-C10 aromatic ring (including monocyclic and fused rings), a substituted or unsubstituted 5-12 membered heteroaromatic ring (including monocyclic and fused rings), and a substituted or unsubstituted 3-12 membered heterocycle (including monocyclic, fused rings, bridged rings and spirocyclic rings), wherein the heteroaromatic ring or heterocycle further contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur,

[0009] L 1 is selected from the group consisting of -O-, -NH-, -(C=O)-, -NH(C=O)-, -(C=O) n H-, -NHS(=O) 2 -, -S(=O) 2 NH-, or (CR 9 R 10 ) n In each of the above groups, when written from left to right, the left side of the group is connected to the A ring and the right side is connected to -CR 3 R 4 -, indicating that it is connected to L 2 is a chemical bond (or none), or is -O-, -NH-, -S-, -(C=O)-, -SO 2 -, -NH-(C=O)-NH-, -NH-S(=O) 2 -NH-, -(S=O)-, -NH-(S=O)-NH-, -NH-(C=O)-, -(C=O)-NH-, -(CH=CH) n -, -(C≡C) n -, -NH-S(=O) 2 -, -S(=O) 2 -NH-, a C3-C8 cycloalkyl group, a 5-8 membered heterocyclic group, or (CR 9 R 10 ) nis a group selected from the group consisting of, L 3 is selected from the group consisting of a substituted or unsubstituted C3-12 carbocyclic ring (including monocyclic, fused rings, bridged rings and spiro rings), a substituted or unsubstituted 5-12 membered heterocyclic ring (including monocyclic, fused rings, bridged rings and spiro rings), or a substituted or unsubstituted 5-6 membered heteroaromatic ring, and the heterocyclic ring contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur,

[0010] R 1 and R 2 are each independently selected from the group consisting of H, F and Cl, R 3 and R 4 are each independently selected from the group consisting of H, F, -OH, -CN, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted -O-C1-C8 alkyl group, a substituted or unsubstituted -O-C3-C8 cycloalkyl group, a substituted or unsubstituted -C6-C10 aryl group, a substituted or unsubstituted -O-C1-C4 alkyl-C6-C10 aryl group, and a substituted or unsubstituted -S-C1-C8 alkyl group, or R 3 and R 4 together with the carbon atom to which they are attached form a 3-8 membered carbon ring or a 3-8 membered heterocyclic ring, and L 1 is -O-, -NH-, -(C=O) n H- or -S(=O) 2 NH- and when it is, R 3 and R 4 are both not groups selected from the group consisting of -OH, a substituted or unsubstituted -O-C1-C8 alkyl group, a substituted or unsubstituted -O-C3-C8 cycloalkyl group, a substituted or unsubstituted -O-C1-C4 alkyl-C6-C10 aryl group, and a substituted or unsubstituted -S-C1-C8 alkyl group,

[0011] R 5 and R 6 are each independently hydrogen, or R 5 and R6 either forms, together with the nitrogen atom to which it is attached, a substituted or unsubstituted 5- to 6-membered nitrogen-containing heterocyclic ring, or each independently is selected from the group consisting of —NRaRb, where Ra and Rb are each independently H, a —C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a —C1-C4 alkyl-C6-C10 aryl group, or Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen-containing heterocyclic ring, and R 7 is selected from the group consisting of a C5-C6 cycloalkyl group, a 5- to 6-membered heterocyclic ring containing one nitrogen atom, a 4- to 6-membered heterocyclic ring containing one oxygen atom, a fluoro C1-C6 alkoxyl group, a C1-C6 alkoxy-C1-C6 alkoxyl group, a C1-C6 alkylcarbonyl group, a C2-C6 amide group, a C1-C6 alkylNH—, and a (C1-C6 alkyl)(C1-C6 alkyl)N—, which is a substituted or unsubstituted group selected from the group consisting of substituted groups, where the substitution means that the group is substituted by a group selected from the group consisting of a C1-C6 alkoxyl group, a C1-C6 alkylcarbonyl group, a 5- to 12-membered heteroaromatic ring (monocyclic, condensed ring, or fused ring), and a C6-C12 aromatic ring (monocyclic, condensed ring, and fused ring), or R 7 is selected from the group consisting of H and a substituted or unsubstituted C1-C6 alkoxyl group, and L 3 is selected from the group consisting of a substituted or unsubstituted 5- to 12-membered bridged ring or a 5- to 12-membered oxygen-containing spirocyclic heterocyclic ring,

[0012] R 8 and R 8 ’ are each independently H, F, Cl, Br, —NO 2, —OH, —CN, a substituted or unsubstituted C1-C8-alkyl group, a substituted or unsubstituted C3-C8-cycloalkyl group, a substituted or unsubstituted —O—C1-C8-alkyl group, a substituted or unsubstituted —O—C3-C8-cycloalkyl group, a substituted or unsubstituted —C6-C10-aryl group, a substituted or unsubstituted —O—C1-C4-alkyl-C6-C10-aryl group, a substituted or unsubstituted —S—C1-C8-alkyl group, —NRaRb, —NHRc, —SO 2 selected from the group consisting of —(C1-C8-alkyl) and —CONRaRb, wherein Ra and Rb are each independently H, a C1-C8-alkyl group, a C1-C4-alkyl-C6-C10-aryl group, or Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen-containing heterocycle, and Rc is selected from the group consisting of —C(=O)—(C1-C8-alkyl) and —C(=O)—(C6-C10-aryl group),

[0013] R 9 and R 10 are each independently H, a C1-C8-alkyl group, an —O—C1-C8-alkyl group, an —O—C3-C8-cycloalkyl group, a —C6-C10-aryl group, an —O—C1-C4-alkyl-C6-C10-aryl group, an —S—C1-C8-alkyl group, —CF 3 , —S—CF 3 , —OCF 3 , —OCH 2 CF 3 , F, —OH, and —CN, or R 9 and R 10 together with the carbon atom to which they are attached form a group selected from the group consisting of a C3-C8-cycloalkyl group and a 5- to 12-membered heterocyclic group, X is selected from the group consisting of —(C=O)—, —(C=O)—NH—, and —CR 11 R 12 selected from the group consisting of,

[0014] R 11 and R 12is independently selected from the group consisting of H, F, -OH, -CN, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted -O-C1-C8 alkyl group, a substituted or unsubstituted -O-C3-C8 cycloalkyl group, a substituted or unsubstituted -C6-C10 aryl group, a substituted or unsubstituted -O-C1-C4 alkyl-C6-C10 aryl group, and a substituted or unsubstituted -S-C1-C8 alkyl group, or R 11 and R 12 together with the carbon atom to which they are attached form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocyclic ring,

[0015] the condition being that the respective groups together form a chemically stable structure, Unless otherwise specified, the "substituted" means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of oxo (=O), hydroxyl group, a substituted or unsubstituted C5-C6 cycloalkyl group, a 5- to 6-membered heterocyclic ring containing one nitrogen atom, a 4- to 6-membered heterocyclic ring containing one oxygen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a fluoro C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C2-C6 amide group, a C1-C6 alkylNH-, and (C1-C6 alkyl)(C1-C6 alkyl)N-, and the "substituted" means that the group is substituted by a group selected from the group consisting of a C1-C6 alkoxy group and a C1-C6 alkylcarbonyl group.

[0016] In another preferred example, the 5- to 12-membered oxygen-containing spirocyclic heterocyclic ring is a spiro ring selected from the group consisting of an oxygen-containing spiro[3,3] ring, an oxygen-containing spiro[3,4] ring, an oxygen-containing spiro[3,5] ring, an oxygen-containing spiro[3,6] ring, and an oxygen-containing spiro[4,5] ring.

[0017] In another preferred example, L 3 is a piperazine ring, [Chemical formula] is a structure selected from the group consisting of, wherein said L 3 is substituted or unsubstituted.

[0018] In another preferred example, the compound of formula I has a structure represented by the following formula, [Chemical formula] wherein m is 0, 1, 2, 3 or 4. In another preferred example, said R 7 is selected from the group consisting of a C5-C6 cycloalkyl group, a 5-6 membered heterocyclic ring containing one nitrogen atom, a 4-6 membered heterocyclic ring containing one oxygen atom, and a 5-12 membered heteroaromatic ring (monocyclic, fused ring, or bridged ring), or R 7 is selected from the group consisting of H and a substituted or unsubstituted C1-C6 alkoxy group, and L 3 is selected from the group consisting of a substituted or unsubstituted 5-12 membered bridged ring and / or a 5-12 membered oxygen-containing spirocyclic heterocyclic ring.

[0019] In another preferred example, said R 7 is [Chemical formula] selected from the group consisting of, wherein said p and q are each independently selected from the group consisting of 0, 1, 2, 3 or 4, and the sum of said p and q is ≧1.

[0020] In another preferred example, the compound is [Chemical formula] selected from the group consisting of.

[0021] In another preferred example, the compound is Compound Number Compound Structure

Table 1

Table 2

[0022] A second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect of the present invention, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another preferred example, the pharmaceutical composition is used for preventing and / or treating a disease related to SSAO or regulated by SSAO / VAP-1 protein or activity, preferably, the disease is selected from the group consisting of inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, eye diseases, fibrosis, neuroinflammatory diseases, cancer, pain, fibrosis or tissue transplant rejection.

[0023] In another preferred example, the inflammatory disease and / or inflammation-related disease, in another preferred example, the inflammation is selected from the group consisting of arthritis (including juvenile rheumatoid arthritis) and pain due to arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (e.g., irritable bowel syndrome), psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye diseases, contact dermatitis, hepatitis, liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic diseases, stroke and its complications, myocardial infarction and its complications, inflammatory cell destruction after stroke, synovitis, and systemic inflammatory sepsis, etc.

[0024] In another preferred example, the pain is selected from the group consisting of myalgia, osteoarthralgia, neuropathic pain, pain due to tumors, low back pain, and inflammatory pain, etc. In another preferred example, the eye disease is uveitis or macular degeneration.

[0025] In another preferred example, the fibrosis is selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, non-alcoholic fatty liver disease including non-alcoholic steatohepatitis (NASH) and cirrhosis due to alcohol-induced fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, and complications due to fibrosis. In another preferred example, the neuroinflammatory disease is selected from the group consisting of stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis, and the like.

[0026] In another preferred example, the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, anal cancer, pancreatic cancer, prostate cancer, ovarian cancer, liver and bile duct cancer, esophageal cancer, non-Hodgkin lymphoma, bladder cancer, uterine cancer, glioma, glioblastoma, medulloblastoma and other brain tumors, kidney cancer, head and neck cancer, gastric cancer, multiple myeloma, testicular cancer, germ cell tumor, neuroendocrine tumor, cervical cancer, benign tumors of the gastrointestinal tract and breast and other organs, signet ring cell cancer, sarcoma, fibrosarcoma, hemangioma, hemangiomatosis, perivascular cell tumor, pseudoangiomatous stromal hyperplasia, myofibroblastic type, fibromatosis, inflammatory myofibroblastic type, cytoma, hemangioendothelioma, granular cell tumor, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or leiomyosarcoma, and other mesenchymal cell tumors.

[0027] In another preferred example, the diabetes and / or diabetes-related diseases are type I diabetes, type II diabetes, metabolic syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema. In another preferred example, the mental disorder is major depressive disorder, bipolar disorder or attention deficit hyperactivity disorder. In another preferred example, the ischemic disease is stroke and / or its complications, myocardial infarction and / or its complications or tissue damage by inflammatory cells after stroke.

[0028] In another preferred example, the vascular disease is atherosclerosis, chronic heart failure or congestive heart failure. In another preferred example, the arthritis is osteoarthritis, rheumatic arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis. In another preferred example, the systemic inflammatory syndrome is systemic inflammatory sepsis. In another preferred example, the inflammatory bowel disease is irritable bowel disease. In another preferred example, the liver disease is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic fatty liver disease.

[0029] In another preferred example, the respiratory disease is asthma, acute lung injury, acute respiratory distress syndrome, lung inflammation, chronic obstructive pulmonary disease, bronchitis or bronchiectasis. In another preferred example, the eye disease is uveitis, iritis, retinitis, autoimmune eye inflammation, inflammation due to angiogenesis and / or lymphocytosis or macular degeneration. In another preferred example, the skin disease is contact dermatitis, skin inflammation, psoriasis or eczema. In another preferred example, the neuroinflammatory disease is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis. In another preferred example, here, the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, idiopathic cirrhosis associated with non-alcoholic fatty liver disease, or primary liver cancer.

[0030] The third aspect of the present invention provides the use of the compound according to the first aspect of the present invention, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the second aspect of the present invention, which is used for the preparation of a drug for preventing and / or treating a disease related to SSAO or regulated by SSAO / VAP-1 protein or activity. In another preferred example, the disease related to SSAO or regulated by SSAO / VAP-1 protein or activity is selected from the group consisting of inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, eye diseases, fibrosis, neuroinflammatory diseases, cancer, fibrosis or tissue transplant rejection.

[0031] In one embodiment of the method and use of the present invention, the disease is a diabetes-induced disease selected from diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease and choroidal neovascularization. In another embodiment of the method and use of the present invention, the disease is a neuroinflammatory disease. In other embodiments of the method and use of the present invention, the disease is selected from liver fibrosis, cirrhosis, renal fibrosis, idiopathic pulmonary fibrosis and radiation-induced fibrosis. In other embodiments of the method and use of the present invention, the disease is cancer.

Advantages of the Invention

[0032] It should be understood that within the scope of the present invention, new or preferred technical solutions can be formed by combining each of the above technical features of the present invention with the technical features specifically described below (for example, in the examples). Due to space limitations, it will not be repeated here.

Brief Description of the Drawings

[0033]

Figure 1

Figure 2

BEST MODE FOR CARRYING OUT THE INVENTION

[0034] Through extensive and detailed research, the present inventors have first discovered a type of SSAO small molecule inhibitor having a novel and efficient structure, and completed the present invention based on this.

[0035] TERMS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the terms "comprising" or "including" can be open-ended, semi-closed, or closed. In other words, the said terms also include "consisting essentially of" or "consisting of". As used herein, the term "alkyl group" consists of only carbon and hydrogen atoms and is connected to the rest of the molecule by a single bond, and refers to a fully saturated straight-chain or branched-chain hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms. Examples include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group, heptyl group, 2-methylhexyl group, 3-methylhexyl group, octyl group, nonyl group, and decyl group. In the present invention, the term "C1-C6 alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms.

[0036] As used herein, the term "alkoxy group" refers to an alkyloxy group. The alkyl group is as defined above. As used herein, the term "cycloalkyl group" refers to a cyclic alkyl group consisting of only carbon and hydrogen atoms. For example, it includes, but is not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, etc. The cycloalkyl group can optionally have a fused ring, a spiro ring or a bridged ring structure. "C3-C5 cycloalkyl group" refers to a cyclic alkyl group having 3 to 5 carbon atoms, and "C5-C6 cycloalkyl group" refers to a cyclic alkyl group having 5 to 6 carbon atoms.

[0037] In the present invention, as part of a group or another group, the term "5- to 12-membered heterocyclic group" or "5- to 12-membered heterocycle" refers to a stable 5- to 12-membered non-aromatic cyclic group composed of carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or higher ring ring system, and can include a fused ring system, a bridged ring system or a spiro ring system. The nitrogen, carbon or sulfur atoms of the heterocyclic group can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclic group can be partially or completely saturated. The heterocyclic group can be connected to the rest of the molecule by a single bond through a carbon atom or a heteroatom. In a heterocyclic group containing a fused ring, one or more rings can be an aryl group or a heteroaryl group defined below, provided that the bonding point to the rest of the molecule is a non-aromatic ring atom. Examples of heterocyclic groups include tetrahydropyrrolyl group, morpholinyl group, piperazinyl group, piperidinyl group, thiomorpholinyl group, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl1) heptan-2-yl), azetidinyl group, Pyranyl group, tetrahydropyranyl group, thiopyranyl group, tetrahydrofuranyl, oxazinyl group, dioxopentyl group, tetrahydroisoquinolinyl group, decahydroisoquinolinyl group, imidazolinyl group, imidazolidinyl group, Quinazinyl group, thiazolidinyl group, isothiazolidinyl group, isoxazolidinyl group, indolinyl group, octahydroindolyl group, octahydroisoindolyl group, pyrrolidinyl group, pyrazolidinyl group, Phthalimide group, etc., but not limited thereto.

[0038] As used herein, the term "5- to 6-membered heterocyclic ring containing one nitrogen atom" refers to a 5- or 6-membered heterocyclic ring containing only one nitrogen atom in the ring. As used herein, the term "4- to 6-membered heterocyclic ring containing one oxygen atom" refers to a 4-, 5- or 6-membered heterocyclic ring containing only one oxygen atom in the ring.

[0039] As used herein, the term "5- to 6-membered aromatic ring" refers to a 5- or 6-membered aromatic ring. As used herein, the term "5- or 6-membered heteroaromatic ring" refers to a 5- or 6-membered aromatic ring having 1 to 3 heteroatoms selected from nitrogen, sulfur, and oxygen. As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

[0040] The compounds of the present invention The compounds of the present invention are compounds represented by formula I, or stereoisomers or racemic compounds thereof, or pharmaceutically acceptable salts thereof. The compounds of the present invention can contain one or more chiral carbon atoms and thus can form enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemic compounds and optically pure forms thereof. In the preparation of the compounds of the present invention, racemic compounds, diastereomers, or enantiomers can be selected as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as crystallization or chiral chromatography. Conventional techniques for preparing / separating individual isomers involve chiral synthesis from a suitable optically pure precursor or separation of a racemic compound (or a racemic compound of a salt or derivative) using chiral high-performance liquid chromatography or the like. See, for example, Gerald Gubitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004, A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010, Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816, and Heller, Acc. Chem. Res. 1990, 23, 128.

[0041] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, and phosphate. Organic acid salts include formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprate, undecanoate Acenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartame amino acid salt, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc., but are not limited to these. These salts can be prepared by methods known in the art.

[0042] "Pharmaceutically acceptable basic addition salts" refers to salts formed from inorganic bases or organic bases that can retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexane amine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by donation known in the art.

[0043] Preparation method The following reaction scheme exemplarily shows a method for preparing a compound represented by formula I, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof, wherein each group is as described above. In the following reaction scheme, it should be understood that combinations of substituents and / or variables in the general formula are only permitted when such combinations result in stable compounds. It should also be understood that other general formulas can be prepared by those skilled in the art of organic chemistry by the methods disclosed herein (applying appropriately substituted starting materials and using methods known to those skilled in the art and changing synthetic parameters as necessary) or by known methods. Those skilled in the art should understand that in any of the described methods, functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl groups, amino groups, sulfhydryl groups, and carboxylic acids. Appropriate hydroxyl protecting groups include trialkylsilyl groups or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, or trimethylsilyl group), tetrahydropyranyl group, benzyl group, etc. Appropriate protecting groups for amino groups, amidino groups, and guanidino groups include tert-butoxycarbonyl group, benzyloxycarbonyl group, etc. Appropriate protecting groups for sulfhydryl groups include -C(O)-R'' (where R'' is an alkyl group, aryl group, or aralkyl group), p-methoxybenzyl group, trityl group, etc. Appropriate protecting groups for carboxy groups include alkyl groups, aryl groups, or aralkyl esters. Protecting groups can be introduced and removed as described herein according to standard techniques known to those skilled in the art. The use of protecting groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley. A protecting group can also be a polymer resin.

[0044] Applications The compounds of the present invention have excellent SSAO inhibitory activity and can be used in pharmaceutical compositions using the compounds of the present invention as an active ingredient for preventing and / or treating diseases associated with SSAO or regulated by the SSAO / VAP-1 protein, for example, atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, chronic obstructive pulmonary disease (COPD), autoimmune diseases, multiple sclerosis, rheumatoid arthritis, pain due to arthritis, Alzheimer's disease, eye diseases, liver diseases (such as fatty liver, hepatitis, liver fibrosis, cirrhosis, liver cancer, etc.).

[0045] In the present invention, the term "pharmaceutical composition" refers to a formulation that delivers a compound of the present invention and a biologically active compound to a mammal (e.g., human) in a medium generally acceptable in the art. The medium includes a pharmaceutically acceptable vector. The purpose of the pharmaceutical composition is to facilitate administration to a living body and promote the absorption of the active ingredient, and thus the biological activity.

[0046] In the present invention, the term "pharmaceutically acceptable" refers to a substance (e.g., a vector or a diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing harmful biological reactions or interacting with the components contained in the composition in an undesirable manner.

[0047] In the present invention, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, vector, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent approved by the relevant government agency as acceptable for human or veterinary use. In the present invention, the terms "preventive", "prevention" and "prevention of" include suggesting the possibility of a disease or deterioration in a patient.

[0048] In the present invention, the term "treatment" and other similar synonyms (i) preventing the occurrence of a disease or disorder in a mammal, particularly when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder, (ii) inhibiting a disease or disorder, i.e., inhibiting its onset, (iii) alleviating a disease or disorder, i.e., treating the condition of the disease or disorder, or (iv) includes the meaning of alleviating symptoms caused by the disease or disorder and the like. In the present invention, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to the amount of at least one agent or compound sufficient to alleviate one or more symptoms of a disease or disorder to be treated after administration. As a result, reduction and / or alleviation of signs, symptoms or causes, or a desired change in a biological system may occur. For example, the "effective amount" used in treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease alleviating effect. Techniques such as dose escalation studies can be used to measure the effective amount suitable for any case.

[0049] In the present invention, terms such as "administering", "applying", "dosing", etc. refer to methods by which a compound or composition can be delivered to a desired site for a biological effect. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used with the compounds and methods described herein, for example, those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed., Pergamon, and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0050] In the present invention, terms such as "drug combination", "drug co-administration", "co-administered", "administration of another treatment", "administration of another therapeutic agent", etc. refer to drug therapies obtained by mixing or combining a plurality of active substances, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient in the form of a single entity or a single dosage form of at least one compound and at least one synergist described herein. The term "non-fixed combination" refers to the simultaneous administration, combination or sequential administration to a patient in the form of separate entities of at least one compound and at least one synergist described herein. These are also applicable to cocktail therapies such as the administration of three or more active ingredients. The relative inhibitory potency of a compound can be determined by the amount required to inhibit the amine oxidase activity of SSAO / VAP-1 in various ways, for example, using recombinant human proteins or using recombinant non-human enzymes in tests such as in vitro tests, tests of cells expressing normal rodent enzymes, tests of cells transfected with human proteins, in vivo tests in rodents and other mammals, etc.

[0051] The present invention further discloses a method for inhibiting SSAO / VAP-1 in a patient suffering from an inflammatory disease and a method for treating an inflammatory disease using the compounds described in Formula I and Formula II. Human inflammatory diseases include arthritis and pain due to arthritis, Crohn's disease, irritable bowel syndrome, psoriasis, asthma, chronic obstructive pulmonary disease, bronchiectasis, scleroderma, inflammation due to diabetes, and inflammatory cell destruction after stroke. Accordingly, in one aspect, the present invention relates to a method for inhibiting amine oxidase in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of Formula I or Formula II to provide a positive therapeutic response. In another aspect, the present invention relates to a method for treating a disease associated with amine oxidase, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or Formula II.

[0052] In another aspect, the present invention relates to a method for treating a disease regulated by SSAO / VAP-1, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or Formula II. The method is also applicable when the disease is inflammation. As used herein, "inflammation" includes various indications including arthritis (including juvenile rheumatoid arthritis), Crohn's disease, ulcerative colitis, inflammatory bowel disease (e.g., irritable bowel syndrome), psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye diseases, contact dermatitis, hepatitis, liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic diseases, stroke and its complications, myocardial infarction and its complications, inflammatory cell destruction after stroke, synovitis, systemic inflammatory sepsis, etc.

[0053] The method is also applicable when the disease is type I diabetes and its complications, type II diabetes and its complications, etc. The method is also applicable when the disease is macular degeneration and / or other eye diseases. The method is also applicable when the disease is fibrosis. As used herein, "fibrosis" includes cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) and cirrhosis due to alcohol-induced fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, and other diseases such as those in which excessive fibrosis contributes to the pathology of the disease.

[0054] The method is also applied to the treatment of neuroinflammatory diseases. As used herein, "neuritis diseases" include various indications including stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, and chronic multiple sclerosis. The method is also applicable to pain-related diseases selected from the group consisting of, but not limited to, myalgia, osteoarthralgia, neuropathic pain, pain due to tumors, low back pain, and inflammatory pain.

[0055] The method is also applicable to the treatment of cancer. In one embodiment, the cancer is selected from lung cancer, breast cancer, colorectal cancer, anal cancer, pancreatic cancer, prostate cancer, ovarian cancer, liver and bile duct cancer, esophageal cancer, non-Hodgkin lymphoma, bladder cancer, uterine cancer, glioma, glioblastoma, medulloblastoma and other brain tumors, kidney cancer, head and neck cancer, gastric cancer, multiple myeloma, testicular cancer, germ cell tumor, neuroendocrine tumor, cervical cancer, benign tumors of the gastrointestinal tract and breast and other organs, signet ring cell cancer, sarcoma, fibrosarcoma, hemangioma, hemangiomatosis, perivascular cell tumor, pseudoangiomatous stromal hyperplasia, myofibroblastic type, fibromatosis, inflammatory myofibroblastic type, cytoma, hemangioendothelioma, granular cell tumor, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or leiomyosarcoma, etc., including mesenchymal cell tumors.

[0056] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to explain the present invention and do not limit the scope of the present invention. In the following embodiments, experimental methods without specific conditions are usually carried out according to conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated as weight percentages and weight parts. The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

[0057] The synthesis method of the intermediate is as follows. Example A: tert-butyl (E)-(2-(bromomethyl)-3-fluoroallyl)carbamate

Chemical formula

Chemical formula

[0058] Example A2:

Chem.

[0059] Example A4:

Chem.

[0060] Example A5: tert-butyl (E)-(3-fluoro-2-(hydroxymethyl)allyl)carbamate [Chemical formula] At 0 °C, tetrabutylammonium fluoride tetrahydrate (170.0 g, 538.9 mmol) is added to a solution of Example A4 (173.0 g, 538.9 mmol, E:Z = 10:1) in tetrahydrofuran (400 mL). After addition, the reaction solution is warmed to room temperature and reacted for 1 hour with stirring. The reaction is monitored by LCMS. When no starting material remains in the reaction solution, water (1000 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (400 mL × 2). The organic phases are combined, washed with 0.1 N aqueous hydrochloric acid solution (200 mL × 2), washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product is purified by distillation under reduced pressure (collecting the fraction at 100 - 120 °C) to obtain the title compound A5 (pale yellow oil, 104.0 g, 94.2%, E:Z = 10:1). 1 H NMR (400 MHz, CDCl₃) δ 6.59 (d, J = 83.7 Hz, 1H), 5.01 (br s, 1H), 3.95 (s, 2H), 3.91 (dd, J = 6.5, 1.6 Hz, 2H), 3.81 (br s, 1H), 1.43 (s, 9H).

[0061] Example A: tert-butyl (E)-(2-(bromomethyl)-3-fluoroallyl)carbamate

Chemical Structure

[0062] Example 1: (E)-2-(((2-(3,5-dimethyl-4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)-3-fluoroprop-2-en-1-amine

Chem.

Chem.

[0063] Example 1-2: 5-(benzyloxy)-2-(3,5-dimethylpiperazin-1-yl)pyrimidine

Chem.

Chemical Structure

[0064] Example 1-4: 2-(3,5-dimethyl-4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-ol

Chemical Structure

[0065] Example 1-5: tert-butyl (E)-(2-(((2-(3,5-dimethyl-4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)-3-fluoroallyl)carbamate

Chemical Structure

[0066] Example 1: (E)-2-(((2-(3,5-dimethyl-4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)-3-fluoroprop-2-en-1-amine

Chemical formula

[0067] The following compounds can be obtained by using a method similar to Example 1 and replacing the corresponding raw materials.

Table 3

[0068] Example 4: (E)-3-fluoro-2-(((2-(4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)prop-2-en-1-amine [Chemical formula] Example 4-1: tert-butyl (E)-(2-(((2-chloropyrimidin-5-yl)oxo)methyl)-3-fluoroallyl)carbamate [Chemical formula] To a solution of 2-chloropyrimidine-5-phenol (5725 mg, 44.0 mmol) and K2CO3 (7600 mg, 55.0 mmol) in N,N-dimethylacetamide (80 mL) was added Compound A (9800 mg, 36.7 mmol), and the mixture was reacted for 3 hours while heating to 50 °C. After completion of the reaction, the reaction solution was cooled to room temperature, slowly added dropwise to water (800 mL), and the solid was slowly precipitated and stirred at room temperature for 2 hours until the solid became uniform. The solid was filtered, washed with water, dried, then 200 mL of a solvent (petroleum ether:ethyl acetate = 10:1) was added and slurried for 6 hours. The solid was filtered and dried to obtain the title compound 4-1 (9600 mg, 82.5%) as an off-white solid. MS (ESI): m / z = 262.0 [M−55] + .

[0069] Example 4-2: tert-butyl (E)-(3-fluoro-2-(((2-(4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)allyl)carbamate [Chemical formula] To a solution of Example 4-1 (9600 mg, 30.2 mmol) in N-methylpyrrolidone (80 mL) were added 1-(oxobutan-3-yl)piperazine (10750 mg, 75.7 mmol) and N,N-diisopropylethylamine (7813 mg, 60.5 mmol), and the mixture was reacted overnight while heating to 120 °C under sealed tube conditions. After completion of the reaction, water (500 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic phases were combined, washed 3 times with water (80 mL), washed once with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, then 80 mL of a solvent (petroleum ether:ethyl acetate = 10:1) was added and slurried for 6 hours. The solid was filtered and dried to obtain the title compound 4-2 (10200 mg, 79.6%) as an off-white solid. MS (ESI): m / z = 424.2 [M+H]+ .

[0070] Example 4: (E)-3-Fluoro-2-(((2-(4-(oxobutan-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxo)methyl)prop-2-en-1-amine

Chem.

[0071] The following compounds can be obtained by using a method similar to that of Examples 1 and 4 and replacing the corresponding raw materials.

Table 4

Table 5

[0072] Biological Test Example 1: Method for Detecting Compounds that Inhibit SSAO / VAP-1 Enzyme Activity In Vitro This detection method is used to evaluate the in vitro inhibitory activity of the compounds of the present invention against different species of SSAO / VAP-1. In this method, recombinant human SSAO protein or mouse SSAO protein or rat SSAO protein (provided by Eli Lilly and Company) is used. The enzyme activity detection kit MAO-Glo assay kit (V1402) was purchased from Promega Corporation. Prepare an enzyme reaction buffer (50 mM HEPES, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1.4 mM MgCl 2 , 0.001% Tween-20, pH 7.4). Dissolve the test compound in DMSO and dilute it with a 3-fold concentration gradient. When detecting SSAO, the final concentration of the test compound in a 10 μl reaction system is 1 μM to 0.05 nM. The content of DMSO in the detection reaction is 1%. After diluting the DMSO solution of the test compound with the enzyme reaction buffer at a volume ratio of 1:25, add 2.5 μl to each well of the detection plate, and add two duplicate wells for each concentration. Add SSAO protein diluted with 5 μl of the enzyme reaction buffer to each well, and the final concentration in a 10 μl reaction system is 10 nM to 80 nM. Incubate at room temperature for 10 minutes. Add 2.5 μl of the reaction substrate diluted with 5 μl of the enzyme reaction buffer to each well, and the final concentration in a 10 μl reaction system is 10 μM. After reacting at room temperature for 120 minutes, add 10 μl of the detection reagent to each well. Incubate at room temperature for 20 minutes, and read and detect with a Synergy Neo 2 plate. The numerical value is converted to an inhibition rate according to the following formula.

[0073] Inhibition rate = (Signal positive - Signal test ) / (Signal positive - Signal negative ) × 100% Signal positive is the positive control without the detection compound, Signal negative is the negative control without the detection compound and SSAO, Signal testThese are the detected values of the concentrations of various compounds. A four-parameter curve is fitted to calculate the IC 50 data. For compounds with an inhibition rate of less than 50% within the test range of the compound, the IC 50 value is reported to be higher than the highest test concentration. Detection shows that the compounds of the examples of the present invention can effectively inhibit the enzyme activities of different species of SSAO / VAP-1, and the results are shown in Table 1.

[0074] Biological Test Example 2: Detection of Compounds that Inhibit MAO-A and MAO-B Enzyme Activities Recombinant human MAO-A and MAO-B proteins were purchased from Sigma (M7316, M7441). Other reagents are the same as in Biological Test Example 1. When detecting MAO-A and MAO-B, the final concentration of the test compound in a 10 μl reaction system is 100 μM to 5 nM. The final concentrations of MAO-A and MAO-B proteins in a 10 μl reaction system are 70 nM and 300 nM, respectively. Other reaction conditions are the same as in Biological Test Example 1. Data analysis and IC 50 The calculation method is the same as in Biological Test Example 1. For compounds with an inhibition rate of less than 50% within the test range of the compound, the IC 50 value is reported to be higher than the highest test concentration. The results are shown in Table 1.

[0075] Biological Test Example 3: Detection Method for Compounds that Inhibit AOC1 Enzyme Activity Recombinant human AOC1 / DAO protein was purchased from R&D systems (catalog: 8298-AO). Amplex UltraRed was purchased from Thermo scientific (catalog: A36006). HRP (catalog: P8250), putrescine (catalog: V900377) were purchased from Sigma. Prepare the enzyme reaction buffer (50 mM HEPES, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1.4 mM MgCl 2, 0.001% Tween-20, pH 7.4). The test compound is dissolved in DMSO and diluted with a three-fold concentration gradient. When detecting AOC1, the final concentration of the test compound in a 10 μl reaction system is 100 μM to 5 nM. The content of DMSO in the detection reaction is 1%. After diluting the DMSO solution of the test compound with the enzyme reaction buffer at a volume ratio of 1:25, 10 μl is added to each well of the detection plate. Prepare a 4× substrate mixture with the enzyme reaction buffer (containing 400 μM putrescine, 4 U / ml HRP, and 4 μM Amplex UltraRed), and add 10 μl to each well. Add 20 μl of AOC1 protein diluted with the enzyme reaction buffer to each well, and the final concentration in a 40 μl reaction system is 0.4 nM. Read and detect the Synergy Neo 2 plate, and the instrument is set at a temperature of 30 °C, an excitation wavelength of 530 nM, an emission wavelength of 590 nM, detect once per minute, and continuously detect for 30 minutes. Calculate the enzyme activity with the increased values from the 10th minute to the 30th minute for each well. The numerical value is converted to the inhibition rate with the following formula for the detection value.

[0076] Inhibition rate = (Signal positive − Signal test ) / (Signal positive − Signal negative ) × 100% Signal positive is the positive control without the detection compound, Signal negative is the negative control without the detection compound and AOC1, and Signal test is the detection value for each concentration of various compounds. Fit a four-parameter curve to calculate the IC 50 data. For compounds with an inhibition rate less than 50% within the test range of the compound, the IC 50 value is reported to be higher than the highest test concentration. The results are shown in Table 1.

[0077] Biological Test Example 4: Method for Detecting Compounds that Inhibit AOC2 Enzyme Activity Recombinant human AOC2 protein (provided by Eli Lilly and Company) is used. Other reagents are the same as in Biological Test Example 1. When detecting AOC2, the final concentration of the test compound in a 10 μl reaction system is 100 μM to 5 nM. The final concentration of AOC2 protein in a 10 μl reaction system is 10 nM. Other reaction conditions are the same as in Biological Test Example 1. Data analysis and IC 50 The calculation method is the same as in Biological Test Example 1. For compounds with an inhibition rate of less than 50% within the test range of the compound, the IC 50 values are reported to be higher than the highest test concentration. The results are shown in Table 1.

[0078] Table 1. In vitro inhibitory activity IC of the compounds of the present invention against SSAO and other amine oxidases of different species 50 (nM)

Table 6

Table 7

[0079]

Table 8

[0080] Biological Test Example 5: Detection of Compounds that Inhibit SSAO / VAP-1 Enzyme Activity in Mouse / Rat Models The MAO-Glo kit (Promega, V1402) is used to measure the activity of SSAO in animal tissues. After administering the test compound to the animals, the SSAO enzyme activity is calculated by measuring the activity of monoamine oxidase in an animal tissue homogenate that is not sensitive to the MAO inhibitors Clogyline and Pargyline. At different target administration concentrations, the compounds of the present invention are orally administered to rats, and the same volume of vehicle is orally administered to the animals in the control group. Tissues of the animals' plasma, brain, retina, small intestine, lung, liver, and kidney are collected respectively 24 hours after administration (before collecting the small intestine, lung, liver, and kidney, the animals are perfused systemically with PBS), and stored in a -80 °C refrigerator until removed for analysis. Each tissue portion is homogenized with a tissue homogenate lysate (20 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, and 1x Roche Complete protease inhibitor tablet). The homogenized tissue fluid is centrifuged at 12,000 rpm at 4 °C for 30 minutes to remove tissue debris.

[0081] A mixture of 5 μl of the supernatant and 2 μl of Clogyline (10 μM) and Pargyline (10 μM) is co-incubated at room temperature for 10 minutes, then 2 μl of the substrate is added to the MAO-Glo detection kit and reacted at room temperature for 60 minutes. According to the kit instructions, the detection reagent is added to stop the reaction. Biotek NeO 2 Read the fluorescein data with a Biotek Neo Analyzer. The monoamine oxidase activity in tissues not sensitive to the MAO inhibitor represents the activity of SSAO. The inhibition rate of the compound is calculated by comparing the SSAO activity of the administered animals with the percentage of the activity of the animals in the control group.

[0082] The detection results show that the compounds of the present invention can effectively inhibit the activity of SSAO in different tissues in the animal body after administration. The results are shown in Tables 2 and 3.

[0083] Table 2. Percentage of remaining SSAO activity 24 hours after single administration of the compound (SSAO activity (%)) [Table 9] The data in the table are presented as mean ± SEM, with N = 3.

[0084] Table 3. Percentage of remaining SSAO activity 24 hours after single administration of the compound of Example 4 (SSAO activity (%)) [Table 10] The data in the table are presented as mean ± SEM, with N = 3.

[0085] Biological Test Example 6: Pharmacodynamic study of SSAO compounds in an eye inflammation-related disease model Twenty-two rats (7 - 8 weeks old, 220 - 250 g) are divided into three groups: a control group (6 rats), a model group (8 rats), and an administration group (8 rats). For the model group and the administration group, a single footpad injection of 8 μg / 100 μl lipopolysaccharide (Sigma - Aldrich - L 2 880) is used to induce eye inflammation. One hour before induction, the rats are grouped according to body weight, and the compound of Example 4 (6 mg / kg, 10 ml / kg) or vehicle (10 ml / kg) is orally administered respectively. Twenty-four hours after induction, aqueous humor is collected, the eyeballs are enucleated and the retinas are separated, and the protein concentration and cell count in the aqueous humor are detected to quantitatively evaluate eye inflammation, and the quantitative polymerase chain reaction (QPCR) method is used to verify the changes in the expression of inflammation-related genes in the retina of the eye.

[0086] Method for measuring the cell amount and protein concentration in aqueous humor: After diluting and mixing 10 μl of aqueous humor with 40 μl of PBS, 25 μl is mixed with 75 μl of PBS and centrifuged at 300 g for 5 minutes at 4°C. According to the method described in the Protein Detection Kit (BCA Protein Assay Kit, Pierce - 23227), 55 μl of the supernatant is carefully aspirated to measure the protein concentration. After resuspending the remaining sample, 40 μl of the cell suspension is taken. 100 μl of 1% FBS / PBS is added, and after removing cell debris with a NovoCyte 3130 flow cytometer, the remaining viable cells are analyzed and counted.

[0087] Compared with the control group, the total protein concentration in the aqueous humor of the model group was significantly higher (mean ± SEM: 9730.04 ± 1232.30 μg / ml vs. 3147.42 ± 404.79 μg / ml), and the cell number was significantly increased (mean ± SEM: 48.28 ± 21.46 cells * 10^4 / ml vs. 2.69 ± 0.45 cells * 10^4 / ml), indicating the successful induction of an eye inflammatory disease model.

[0088] Compared with the model group, the protein concentration in the administration group was decreased (mean ± SEM: 7275.44 ± 622.66 vs. 9730.04 ± 1232.30 μg / ml), and the cell number was significantly decreased (mean ± SEM: 5.07 ± 0.80 cells * 10^4 / ml vs. 48.28 ± 21.46 cells * 10^4 / ml), indicating that Example 4 of the compound can significantly reduce the symptoms of eye inflammation-related diseases. As shown in Figure 1, Example 4 can significantly alleviate the eye inflammation-related symptoms in a rat LPS-induced inflammatory disease model. Figure 1A shows the change in protein concentration (μg / ml) in the aqueous humor, and Figure 1B shows the change in cell number (*10^4 / ml) in the aqueous humor.

[0089] Measurement of the expression level of inflammation-related genes in the retina of the eye:

[0090] 1) Primers were synthesized, and the information is as follows.

Table 11

[0091] Compared with the control group, the gene expression levels of ALOX5AP, SOCS3, and TLR7 in the model group are significantly increased. As shown in Figure 2, compared with the model group, the gene expression levels of ALOX5AP, SOCS3, and TLR7 in the administration group are significantly decreased. After analysis, the gene expressions of ALOX5AP, SOCS3, and TLR7 are all regulated by the NFkB signaling pathway, and the NFkB signaling pathway is a very important molecular signaling pathway in inflammatory diseases.

[0092] Example 4 in Figure 2 can significantly reduce the expression levels of A. ALOX5AP, B. SOCS3, and C. TLR7, which are inflammation-related genes in the retina in a rat LPS-induced inflammatory disease model.

[0093] All documents mentioned in the present invention are cited as references in this application as if each document was individually cited as a reference. Furthermore, after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and it should be understood that these equivalent forms are also within the scope defined by the appended claims of this application.

Claims

1. A compound represented by formula I, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof, wherein Formula I: [Chemical Formula 1] wherein A is absent; B is pyridine or pyrimidine; L １ is “—O—” and L ２ is none, R １ is F, and R ２ is H, or, R １ is H, R ２ is F, R ３ and R ４ is H, R ５ and R ６ are each independently hydrogen, R ７ is a 4- to 6-membered heterocyclic ring containing one oxygen atom, and L ３ is a substituted or unsubstituted 6- to 10-membered heterocyclic ring, said heterocyclic ring containing two nitrogen heteroatoms, or R ７ is a C1-C6 alkoxy group, and L ３ is an unsubstituted 6- to 10-membered bridged heterocyclic ring, and the heterocyclic ring contains 1 to 2 nitrogen heteroatoms R ８ is selected from the group consisting of H, -CN, X is -CR １１ R １２ and is R １１ and R １２ are each independently H, the condition is that each of the above groups together forms a chemically stable structure; unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a C1-C6 alkyl group, and the compound, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof.

2. L ３ is a piperazine ring, and R ７ is a 4- to 6-membered heterocyclic ring containing one oxygen atom The compound according to claim 1, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of formula I has a structure represented by the following formula: 【Chemical 2】 wherein m is 0, 1, 2, or 3; R ９ is a C1-C6 alkyl group, characterized in that The compound according to claim 1, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof.

4. The aforementioned R ７ is 【Chemical 3】 wherein p and q are each independently selected from the group consisting of 0, 1, and 2, and the sum of p and q is ≧1 and ≦4, and is characterized in that The compound according to claim 1, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof.

5. The compound is 【Table 1-1】 【Table 1-2】 selected from the group consisting of The compound according to any one of claims 1 to 4.

6. The compound is 【Table 2】 characterized in that said compound.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and characterized in that the pharmaceutical composition.

8. The pharmaceutical composition is used for preventing and / or treating a disease associated with SSAO or regulated by SSAO / VAP-1 protein, The pharmaceutical composition according to claim 7.

9. The disease is selected from the group consisting of inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, eye diseases, fibrosis, neuroinflammatory diseases, pain-related diseases, cancer, or tissue transplant rejection, and is characterized in that The pharmaceutical composition according to claim 8.

10. The inflammatory disease and / or inflammation-related disease is characterized by being selected from the group consisting of arthritis and pain due to arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye diseases, contact dermatitis, hepatitis, liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver diseases, atherosclerosis, chronic heart failure, congestive heart failure, ischemic diseases, stroke and its complications, myocardial infarction and its complications, inflammatory cell destruction after stroke, synovitis, and systemic inflammatory sepsis. The pharmaceutical composition according to claim 9.

11. The diabetes and / or diabetes-related disease is characterized by being type 1 diabetes, type 2 diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema. The pharmaceutical composition according to claim 9.

12. The eye disease is characterized by being uveitis or macular degeneration. The pharmaceutical composition according to claim 9.

13. The fibrosis is characterized by being selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, non-alcoholic fatty liver disease including non-alcoholic steatohepatitis (NASH) and cirrhosis due to alcohol-induced fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, and complications due to fibrosis. The pharmaceutical composition according to claim 9.

14. A compound according to any one of claims 1 to 6, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof, characterized by being used in the manufacture of a medicament for the treatment and / or prophylactic treatment of a disease related to SSAO or regulated by the SSAO / VAP-1 protein. The compound, or a stereoisomer or racemic compound thereof, or a pharmaceutically acceptable salt thereof.

15. The disease related to SSAO or regulated by the SSAO / VAP-1 protein is characterized by being selected from the group consisting of inflammatory diseases and / or inflammation-related diseases, diabetes and / or diabetes-related diseases, mental disorders, pain-related diseases, ischemic diseases, vascular diseases, eye diseases, fibrosis, neuroinflammatory diseases, cancer, fibrosis or tissue transplant rejection. The compound according to claim 14.

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