CN109988106B - Amine compound for inhibiting SSAO/VAP-1 and application thereof in medicine - Google Patents

Abstract

The invention relates to an amine compound serving as a semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1) inhibitor and application thereof in medicines, and further relates to a pharmaceutical composition containing the compound. The compounds or pharmaceutical compositions of the invention are useful for treating inflammation and/or inflammation-related disorders, diabetes and/or diabetes-related disorders, psychiatric conditions, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.

Description

Amine compound for inhibiting SSAO/VAP-1 and application thereof in medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to amine compounds serving as semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1) inhibitors, a preparation method thereof, a pharmaceutical composition containing the compounds, and medical applications of the compounds and the composition. More specifically, the invention relates to a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer and a geometric isomer thereof, and a pharmaceutical composition containing the compound, and further relates to application of the compound and the pharmaceutical composition in preparing medicines for preventing, treating or relieving inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplantation rejection.

Background

Amine Oxidase (AO) is a type of protein having a specific biological function, and is widely present in organisms, for example, in cells of higher animals including humans and microorganisms. It metabolizes various endogenous or exogenous mono-, di-and polyamine compounds. Two major classes of Amine oxidases are well known, one class being copper-containing Amine oxidases, including primarily Semicarbazide-Sensitive Amine Oxidase (SSAO) and Diamine Oxidase (DAO); another class is Flavin-containing amine oxidases, which include primarily Monoamine oxidases (Monoamine oxidases) and Polyamine oxidases (Polyamine oxidases). Among them, semicarbazide-sensitive amine oxidase (SSAO) is a kind of amine oxidase containing divalent copper ions and particularly sensitive to semicarbazide with 6-hydroxydopaquinone as a coenzyme, and mainly exists in a dimer form. Diamine oxidase (DAO) is expressed primarily in the kidney, placenta, intestine and seminal vesicles (Elmore et al, 2002), and is also called histamine oxidase because it acts only on diamines, especially histamine. Monoamine oxidases are classified into Monoamine oxidase A (Monoamine oxidase A, MAO-A) and Monoamine oxidase B (Monoamine oxidase B, MAO-B), which are mainly present in the mitochondriA of most cells, and use covalently bound Flavin Adenine Dinucleotide (FAD) as A cofactor. Polyamine oxidase is another FAD-dependent amine oxidase that oxidatively deaminates spermine and spermidine. SSAO, which is different from MAO-A and MAO-B in its substrate, inhibitor, cofactor, subcellular localization and function, is an amine oxidase that is copper dependent and uses other substances than FAD, such as Trihydroxyphenylalanine Quinone (TPQ), as A cofactor.

SSAO is widely present in tissues of mammalian bodies that are rich in vascular content, primarily in two forms, one soluble, primarily in circulating blood; one is the membrane-bound form, which is widely distributed in organs and tissues, especially in adipocytes, vascular endothelial cells and smooth muscle cells. SSAO is a multifunctional enzyme whose pathophysiological functions are diverse due to the different tissue distribution of SSAO. In adipocytes and smooth muscle cells, SSAO can promote intracellular transfer of Glucose transporter 4 (glut 4) from adipocytes to cell membranes, thereby regulating Glucose transport. In endothelial cells, SSAO exists in the form of vascular adhesion protein-1 (VAP-1), mediates the adhesion and exudation process of leukocytes and endothelial cells, and participates in inflammatory response.

Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule and has double functions, namely, on one hand, the vascular adhesion protein is an adhesion molecule of lymphocytes and promotes the adhesion of the lymphocytes to vascular endothelium; on the other hand, VAP-1 also has enzymatic efficacy and is capable of catalyzing primary amines to the corresponding aldehydes. VAP-1 is encoded by the AOC3 gene located on human chromosome 17. The VAP-1 protein may be present in the plasma in the form of a solute, or may be present on the surface of endothelial cells, adipocytes and smooth muscle cells in a membrane-bound form. Cloning of the VAP-1 antigen revealed that it belongs to semicarbazide-sensitive amine oxidase (Smith D.J, salmi M, bono P, et a1.JI. J. ExpMed,1998,188 (1): 17-27), which is structurally identical to SSAO. Therefore, researchers have often studied SSAO in recent years in an equivalent fashion to VAP-1. Therefore, the present invention describes the protein in SSAO/VAP-1.

Inflammation is the first response of the immune system to infection or irritation. The movement of leukocytes into the tissue circulation is important to this process. Inappropriate inflammatory responses can lead to local inflammation of otherwise healthy tissue, which can lead to diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, chronic Obstructive Pulmonary Disease (COPD), eczema, psoriasis and the like. Leukocytes adhere to the endothelium by binding adhesion molecules first before they pass through the vessel wall. Membrane-bound SSAO/VAP-1 is abundantly expressed in vascular endothelial cells such as high-potency venous endothelial cells (HVEs) of lymphoid organs, and is also expressed in Hepatic Sinus Endothelial Cells (HSEC), smooth muscle cells and adipocytes. SSAO/VAP-1 contains sialic acid, induces cell adhesion, regulates leukocyte trafficking, participates in granulocyte extravasation, and increases its levels during inflammation. Migration of neutrophils from the blood to the site of inflammation is achieved by the binding of adhesion molecules to vascular endothelial cells. The research shows that in the transgenic mice over-expressing SSAO/VAP-1 pneumonia, the SSAO/VAP-1 activity is increased, tissue protein-formaldehyde accumulation is formed, and inflammatory cells of bronchoalveolar lavage fluid are obviously increased. After inhibition of their activity with SSAO/VAP-1 selective inhibitors, neutrophil granulocytes as well as macrophage inflammatory protein 1- α and tumor necrosis factor- α were significantly reduced in broncho-pulmonary lavage fluid, suggesting that SSAO/VAP-1 mediated deamination has a significant impact on the development of pneumonia (Smith DJ, salmi M, bono P, et a1, J Exp Med,1998, 188.

In the Glucose transport system, insulin stimulates Glucose uptake and utilization in insulin-sensitive tissues such as adipose tissue, cardiac muscle and skeletal muscle mainly by promoting the transfer of Glucose transporter (GLUT) from the inside of cells to cell membranes. GLUT4 is an important GLUT subtype involved in glucose transport and is stored in the cytoplasm mainly in the form of vesicles. Enrique-Tarancon et al found in studies of the mechanism of action of SSAO/VAP-1 in promoting adipocyte glucose transport and GLUT4 transfer that SSAO/VAP-1 in rat adipocytes is expressed predominantly in a membrane-bound form with the surface of the adipocyte membrane, 18% -24% SSAO/VAP-1 was expressed in rat adipocytes, 3T3-L1 adipocytes, GLUT 4-containing vesicles in rat skeletal muscle cells (Enrique-Tarancon G, marti L, morin N, et a1.J Biol Chem,1998,273 (14): 8025-8032). Mercader et al, long-term administration of the SSAO/VAP-1 inhibitor semicarbazide to FVB/n male mice in drinking water, found that the body mass index of FVB/n mice decreased by 31% and the body mass decreased by 15%, indicating that the SSAO/VAP-1 inhibitor can inhibit fat deposition in mice, decrease body mass, and play an important role in regulating fat metabolism (Mereader J, iffiu-Soltesz, bour S, et a1, J Obes,2011, 475-786).

The thickness of the elastic layer of the vascular wall is positively correlated with the ratio of SSAO/VAP-1 and elastin, which indicates that SSAO/VAP-1 may participate in the organization of elastic fibers, and the characteristics and quantity of the elastic fibers are important factors affecting the mechanical properties of the arterial wall and the differentiation of vascular smooth muscle cells. Increased SSAO/VAP-1 activity can lead to structural disruption of the membranous elastic fibers in the aorta, with a concomitant decrease in the maturation of the elastin component and an increase in collagen, ultimately leading to aortic dilatation. Overexpression of SSAO/VAP-1 in smooth muscle decreases arterial tone, impairing its ability to regulate blood pressure. It was found that although rodents are generally less prone to develop atherosclerosis, certain mouse species, such as C57BL/6 mice, develop atherosclerotic plaques after administration of an atherogenic, high cholesterol diet. The SSAO/VAP-1 activity of the C57BL/6 mouse which is easy to generate atherosclerosis is obviously increased, and the SSAO/VAP-1 mediated deamination is probably existed in the process of atherogenesis and vascular diseases.

Taken together, the fact that SSAO/VAP-1 inhibitors have enzymatic and adhesive activity and have significant correlation between their upregulation of many inflammatory conditions makes them therapeutic targets for all of the above disease conditions and promising for pharmaceutical development.

Summary of the invention

The invention provides a novel compound with better SSAO/VAP-1 inhibition activity, and the compound and the composition thereof can be used for preparing medicaments for preventing, treating or relieving inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection of patients, in particular for preparing medicaments for preventing, treating or relieving non-alcoholic fatty liver diseases of the patients.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I), or prodrug thereof,

wherein the content of the first and second substances,

x is-N = or-CH =;

y is-N (R) ⁷ ) -or-N =;

l is-O-, -S-or-NH-;

the ring Cy is a nitrogen-containing heterocyclic ring consisting of 5 to 8 atoms or a nitrogen-containing heteroaromatic ring consisting of 5 to 8 atoms;

R ⁷ is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl or C _3-6 A cycloalkyl group;

each R ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b 、R ^b O-C _1-4 Alkylene radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _2-8 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C _6-10 Aryl, or heteroaryl of 5 to 10 atoms, wherein said C _1-6 Alkyl radical, C _2-8 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

or any R ⁵ 、R ⁶ And together with the carbon or nitrogen atom to which they are each attached, or any two R ⁶ Together with the carbon or nitrogen atom to which they are each attached, form C _3-8 Carbocyclic ring, heterocyclic ring of 3-8 atoms, C _6-10 An aromatic ring or a 5-10 atom heteroaromatic ring; wherein said C _3-8 Carbocyclic ring, heterocyclic ring of 3-8 atoms, C _6-10 The aromatic ring and the 5-10 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ¹ is H, D, F, cl, br, I, C _1-6 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C _1-6 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ² is F, cl, br, I, C _1-6 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-6 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ³ and R ⁴ Each independently is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C _6-10 Aryl, heteroaryl of 5 to 10 atoms or

Wherein said C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ³ 、R ⁴ And together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

each R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Independently H, D, hydroxy, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ^c 、R ^d Together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

n is 0, 1 or 2.

In other embodiments, ring Cy is a nitrogen-containing heterocyclic ring of 5-6 atoms or a nitrogen-containing heteroaromatic ring of 5-6 atoms.

In still other embodiments, ring Cy is

In still other embodiments, ring Cy is

In other embodiments, the invention relates to compounds of the structure shown in formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ And R ⁶ Having the definitions set out in the present invention.

In other embodiments, the invention relates to compounds of the structure shown in formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions set forth herein.

In other embodiments, the present invention relates to compounds having the structure shown in formula (IV) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions set out in the present invention.

In other embodiments, the present invention relates to compounds having the structure shown in formula (V) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

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wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ And R ⁶ Having the definitions set forth herein.

In other embodiments, the invention relates to compounds of the structure shown in formula (VI) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions set forth herein.

In other embodiments, R ⁷ Is H, D, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl or C _3-6 A cycloalkyl group.

In other embodiments, each R is ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b 、R ^b O-C _1-2 Alkylene radical, R ^d R ^c N-C _1-2 Alkylene radical, C _1-4 Haloalkyl, C _1-4 Alkyl radical, C _2-6 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C _6-10 Aryl, or heteroaryl of 5 to 6 atoms, wherein said C _1-4 Alkyl radical, C _2-6 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C _6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group;

or any R ⁵ 、R ⁶ And together with the carbon or nitrogen atom to which they are each attached, or any two R ⁶ Together with the carbon or nitrogen atom to which they are each attached, form C _3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C _6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms; wherein said C _3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C _6-10 The aromatic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3 or 4 substituentsIndependently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group.

In still other embodiments, R ⁷ Is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In yet other embodiments, each R is ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OH、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-C(＝O)OCH(CH ₃ ) ₂ 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b Trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, 1,3,each of the 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl independently is unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or difluoromethoxy;

or any R ⁵ 、R ⁶ And together with the carbon or nitrogen atom to which they are each attached, or any two R ⁶ And together with the carbon or nitrogen atom to which they are each attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl; wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, triazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or difluoromethoxy.

In other embodiments, R ¹ Is H, D, F,Cl, br, I, methyl, ethyl, isopropyl, n-propyl, -C (= O) OH, -C (= O) OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)R ^a 、-OC(＝O)R ^a OR-OC (= O) OR ^a Wherein the methyl, ethyl, isopropyl and n-propyl groups are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ² Is F, cl, br, I, methyl, ethyl, isopropyl, n-propyl, -C (= O) OH, -C (= O) OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)R ^a 、-OC(＝O)R ^a OR-OC (= O) OR ^a Wherein the methyl, ethyl, isopropyl and n-propyl groups are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ³ And R ⁴ Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, 5-6-membered heterocyclic radical, phenyl, 5-6-membered heteroaryl or

Wherein the methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, heterocyclyl of 5 to 6 atoms, phenyl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

or R ³ 、R ⁴ Together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein said 5-the heterocyclic ring of 6 atoms and the heteroaromatic ring of 5-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, each R is ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Independently H, D, hydroxyl, trifluoromethyl, difluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Cycloalkyl, heterocyclyl of 5 to 6 atoms, phenyl or heteroaryl of 5 to 6 atoms, wherein said methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C _3-6 The cycloalkyl, heterocyclyl of 5-6 atoms, phenyl and heteroaryl of 5-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, the pharmaceutically acceptable salt of the present invention is a hydrochloride, hydrobromide or mesylate salt.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for inhibiting SSAO/VAP-1.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for the prevention, treatment or alleviation of a disease or a disorder associated with or modulated by SSAO/VAP-1 protein.

In some embodiments, the diseases related to or modulated by SSAO/VAP-1 protein according to the present invention are inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.

In other embodiments, the inflammatory disease and/or inflammation-related disease of the present invention is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease, or neuroinflammatory disease.

In other embodiments, the diabetes and/or diabetes related disorders of the present invention are type i diabetes, type ii diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.

In other embodiments, the psychiatric disorder of the invention is major depression, bipolar depression, or attention deficit hyperactivity disorder.

In other embodiments, the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications, or tissue damage by inflammatory cells after stroke.

In other embodiments, the fibrosis of the present invention is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.

In other embodiments, the vascular disease of the present invention is atherosclerosis, chronic heart failure, or congestive heart failure.

In still other embodiments, the arthritis of the invention is osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

In still other embodiments, the systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.

In still other embodiments, the inflammatory bowel disease of the present invention is irritable bowel disease.

In other embodiments, the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease.

In still other embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated negative cirrhosis, or primary liver cancer.

In still other embodiments, the respiratory disease of the invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.

In still other embodiments, the ocular disease of the present invention is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation due to angiogenesis and/or lymphangiogenesis, or macular degeneration.

In still other embodiments, the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.

In still other embodiments, the neuroinflammatory disorder of the invention is parkinson's disease, alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.

The foregoing merely summarizes certain aspects of the invention, but is not limited to such aspects. These and other aspects are more fully described below.

Detailed description of the invention

The invention provides an amine compound with good SSAO/VAP-1 inhibition activity, a preparation method and a medical application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein, and in cases where one or more of the incorporated documents, patents, and similar materials is different from or contradictory to the present application (including but not limited to defined terms, application of terms, described techniques, and the like), the present application shall control.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, 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. All patents and publications referred to herein are incorporated by reference in their entirety. The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with CAS version of the periodic Table of the elements, and with handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry may be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, the articles are used herein to refer to articles of one or more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.

Unless otherwise indicated, the terms used in the specification and claims have the following definitions.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted 8230; \8230;" substituted ". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. Generally, an optional substituent group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)OR ^b 、-OC(＝O)R ^a 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-OR ^b 、-NR ^c R ^d 、R ^b O-alkylene, R ^d R ^c N-alkylene, alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, alkylamino, alkoxy, alkenyl, alkynyl, cycloalkyl-alkylene, carbocyclyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene, and

wherein each R is ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Have the meaning as described in the present invention.

In addition, unless otherwise expressly indicated, the description of the present invention includes the terms "\8230;" 8230 ";" and "\8230; independently of each other," \8230 ";" and "\8230"; "8230"; "and" independently of each other ";" 8230 ";" and "independently of each other" are interchangeable and are to be construed broadly, and they may mean that specific items expressed between the same symbols do not affect each other in different groups, or that specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C _1-6 Alkyl "in particular denotes independently disclosed C ₁ Alkyl (methyl), C ₂ Alkyl (ethyl), C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ Alkyl, and "heteroaryl of 5-6 atoms" refers to heteroaryl of 5 atoms and heteroaryl of 6 ring atoms.

In the various parts of this specification, linking substituents are described. When the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "halogen" refers to F, cl, br, I.

The term "alkyl" or "alkyl group" refers to a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms; in some embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in still other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 2 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are referred to herein as lower alkyl groups.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl group (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl group (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 (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like. The alkyl group may be optionally substituted with one or more substituents described herein.

The term "alkyl" and its prefix "alkane", as used herein, are intended to encompass both straight and branched saturated carbon chains.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains from 1 to 4 carbon atoms; in still other embodiments, the alkylene group contains 1 to 3 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples of this 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 the like. Wherein said alkylene may be optionally substituted with one or more substituents as described herein.

The term "alkenyl" denotes a radical containing from 2 to 12 carbonsA linear or branched monovalent hydrocarbon radical of an atom in which at least one site of unsaturation is a carbon-carbon sp ² A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in other embodiments, alkenyl groups contain 2 to 6 carbon atoms; in still other embodiments, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ 、-CH＝CHCH ₃ ) Butenyl (-CH = CHCH) ₂ CH ₃ 、-CH ₂ CH＝CHCH ₃ 、-CH ₂ CH ₂ CH＝CH ₂ 、-CH＝C(CH ₃ ) ₂ 、-CH＝C(CH ₃ ) ₂ 、-CH ₂ C(CH ₃ )＝CH ₂ ) Pentenyl (-CH) ₂ CH ₂ CH ₂ CH＝CH ₂ 、-CH ₂ CH ₂ CH＝CHCH ₃ 、-CH ₂ CH ₂ CH＝CHCH ₃ 、-CH ₂ CH＝CHCH ₂ CH ₃ 、-CH＝CHCH ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ C(CH ₃ )＝CH ₂ 、-CH ₂ CH＝C(CH ₃ ) ₂ 、-CH＝CHCH(CH ₃ ) ₂ 、-C(CH ₂ CH ₃ )＝CHCH ₃ 、-CH(CH ₂ CH ₃ )CH＝CH ₂ ) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp triple bond. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH) ₃ ) Propargyl (-CH) ₂ C.ident.CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl1-hexynyl, 1-heptynyl, 1-octynyl, and the like. The alkynyl group may be independently optionally substituted with one or more substituents described herein.

The term "alkoxy" or "alkyloxy" means that an alkyl group, which alkyl group has the meaning described herein, is attached to the rest of the molecule through an oxygen atom, i.e., alkyl-O-. In some embodiments, alkoxy groups contain 1 to 20 carbon atoms; in other embodiments, the alkoxy group contains 1 to 10 carbon atoms; in still other embodiments, alkoxy groups contain 1 to 8 carbon atoms; in still other embodiments, alkoxy groups contain 1-6 carbon atoms; in still other embodiments, alkoxy groups contain 1 to 4 carbon atoms, and in still other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (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 ₃ ) 2-pentyloxy (-OCH (CH)) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyloxy (-OCH (CH)) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxy (-OC (CH)) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butoxy (-OCH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-l-butoxy (-OCH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-l-butoxy (-OCH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) And the like, wherein the alkoxy groups may independently be unsubstituted or substituted with one or more substituentsSubstituted by the substituents described in the invention.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these examples, alkylamino is one or two C _1-6 Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C _1-3 Lower alkylamino groups. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents. In some embodiments, haloalkyl groups contain 1 to 10 carbon atoms, in other embodiments, haloalkyl groups contain 1 to 8 carbon atoms, in still other embodiments, haloalkyl groups contain 1 to 6 carbon atoms, in still other embodiments, haloalkyl groups contain 1 to 4 carbon atoms, and in still other embodiments, haloalkyl groups contain 1 to 3 carbon atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH) ₂ F) Difluoromethyl (-CHF) ₂ ) Trifluoromethyl (-CF) ₃ ) Fluoroethyl group (-CHFCH) ₃ ,-CH ₂ CH ₂ F) Difluoroethyl (-CF) ₂ CH ₃ ,-CFHCFH ₂ ,-CH ₂ CHF ₂ ) Perfluoroethyl, fluoropropyl (-CHFCH) ₂ CH ₃ ,-CH ₂ CHFCH ₃ ,-CH ₂ CH ₂ CH ₂ F) Difluoropropyl (-CF) ₂ CH ₂ CH ₃ ,-CFHCFHCH ₃ ,-CH ₂ CH ₂ CHF ₂ ,-CH ₂ CF ₂ CH ₃ ,-CH ₂ CHFCH ₂ F) Trifluoropropyl, 1-dichloroethyl, 1, 2-dichloropropyl, and the like. The haloalkyl group may be optionally substituted with one or more substituents described herein.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen substituents. In some embodiments, the haloalkoxy group contains 1 to 10 carbon atoms, in other embodiments, the haloalkoxy group contains 1 to 8 carbon atoms, in yet other embodiments, the haloalkoxy group contains 1 to 6 carbon atoms, in yet other embodiments, the haloalkoxy group contains 1 to 4 carbon atoms, and in still other embodiments, the haloalkoxy group contains 1 to 3 carbon atoms. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like. The haloalkoxy group may be optionally substituted with one or more substituents described herein.

The term "carbocyclylalkyl", alone or as part of a "carbocyclylalkyl" or "carbocyclylalkoxy" refers to a non-aromatic carbocyclic ring system containing 3 to 14 ring carbon atoms that is saturated or contains one or more units of unsaturation. The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein. In some embodiments, the number of ring carbon atoms of a carbocyclic ring is from 3 to 12; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 3 to 10; in other embodiments, the number of ring carbon atoms of a carbocyclic ring is from 3 to 8; in other embodiments, the number of ring carbon atoms of a carbocyclic ring is from 3 to 6; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 5 to 6; in other embodiments, the number of carbon ring carbon atoms in a carbocyclic ring is from 5 to 8. In other embodiments, the number of carbon ring carbon atoms in a carbocyclic ring is from 6 to 8. Such "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system comprises two rings that share 2 adjacent ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridging carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.

The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring carbon atoms that is saturated, having one or more points of attachment to the rest of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, e.g., C _3-10 A cycloalkyl group; in other embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, e.g., C _3-8 A cycloalkyl group; in still other embodiments, cycloalkyl is a ring system containing 5 to 8 ring carbon atoms, e.g., C _5-8 A cycloalkyl group; in still other embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, e.g., C _3-6 A cycloalkyl group; in still other embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms, e.g., C _5-6 A cycloalkyl group; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents as described herein.

The term "heterocyclyl" may be used alone or as a majority of "heterocyclylalkyl" or "heterocyclylalkoxy" and refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the rest of the molecule. The term "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. Unless otherwise specified, a heterocyclic group may be a carbon or nitrogen group. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 to 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 to 8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms. In some embodiments, the heterocyclic ring may be a ring system consisting of 5 to 10, 5 to 8, 5 to 6, 5, or 6 ring atoms and containing at least one degree of unsaturation. In other embodiments, the heterocycle may be a ring system consisting of 5 to 10, 5 to 8, 5 to 6, 5, or 6 ring atoms and containing 1 or 2 unsaturations, said ring system containing 1,2, or 3 heteroatoms selected from N, O, or S.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaheteroalkyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "m-atomic" where m is an integer typically describes the number of ring-forming atoms in the molecule, which is m. For example, piperidinyl is a heterocyclyl consisting of 6 ring atoms, while 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl group consisting of 10 ring atoms.

The term "aryl" may be used alone or as a majority of an "arylalkyl" or "arylalkoxy" group, and refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, in which each ring contains 3 to 7 ring atoms and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group may be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" to denote monocyclic, bicyclic, and tricyclic aromatic systems containing 5-16 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, wherein at least one ring system is aromatic, and wherein the heteroaryl has one or more attachment points to the rest of the molecule. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the host structure in the formula) via any reasonable site (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-14 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 12 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5-8 atom composed heteroaryl containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 7 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 6 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl), thiadiazolyl (1, 2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl), pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl. The heteroaryl group is optionally substituted with one or more substituents described herein.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent as described herein).

The term "nitro" means-NO ₂ 。

The term "mercapto" refers to-SH.

The term "hydroxy" refers to-OH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "carboxylic acid" or "carboxyl" refers to-C (= O) OH.

The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C = O) -.

The term "D" refers to deuteration, i.e. ² H。

As described in the present invention, the ring system formed by the substituent R being connected to the central ring by a bond represents that the substituent R may be substituted only at any substitutable or reasonable position on the ring to which it is attached. For example, formula a represents that any potentially substituted position on the a ring may be optionally substituted with n R, but any potentially substituted position on the B ring cannot be substituted with R; when ring a is a bicyclic structure, R may be substituted at any substitutable position on any one ring of ring a; for another example, formula b represents that substituent R may be substituted at any possible substituted position on the C ring, as shown in formulas b-1 to b-3:

as described herein, a ring system formed by a bond to the center of a ring represents that the bond can be attached to the rest of the molecule at any point on the ring system where it can be attached. For example, formula c represents ring E may be attached to the rest of the molecule through any possible attachment position on the ring, and when ring E is a bicyclic structure, ring E may be attached to the rest of the molecule through any possible attachment position on any of the rings; for another example, a pyrimidine ring represented by formula d may be attached to the rest of the molecule via any possible attachment position, as shown in formulae d-1 to d-3:

as described in the context of the present invention,

refers to a double bond, and the structure bonded by the bond can be 'cis isomer', 'trans isomer' or 'a mixture of cis isomer and trans isomer in any proportion'; for example, formula e represents a mixture of formula e-1, formula e-2 or both (e-1 and e-2) in any proportion:

as used herein, "any two R form a ring with the carbon atom or nitrogen atom to which they are attached" means that any two R may form a spiro ring, bridged ring or condensed ring with the carbon atom or nitrogen atom to which they are attached.

As described herein, a particular group on a ring is represented by a letter indicating that the position of the group represented by the letter is definite, as shown in formula F, the position of the group J on the ring F is fixed, i.e., the group J is directly attached to the benzene ring, and the "arc" portion of the ring F can be a bond, an atom/group or a combination of atoms/groups, the position, the saturation of the bond, the atom type, the number of atoms, etc. are indefinite.

The term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group, and typical carboxyl protecting groups include-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "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 being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, as known to those skilled in the art (e.g., remington's Pharmaceutical Sciences,18th Ed. Mack Printing company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。

The term "metabolite" refers to the product of the 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 its activity can be characterized by assays as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The term "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, describe the description of the descriptive pharmaceutical acceptable salts in detail in J.Pharmacol Sci,1997,66, 1-19. Examples of pharmaceutically acceptable, non-limiting salts include salts of inorganic acids formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, nitrate, perchlorate, and salts of organic acids such as methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, glycollate, isethionate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulforatesAcid salts, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents, such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form the N-oxides (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, N-oxides may be prepared by the method of l.w. ready (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, 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 in the (R) -or (S) -configuration. Substituents on atoms having unsaturated double bonds may be present in cis- (Z) -or trans- (E) -form, if possible.

Thus, as described herein, the compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates on the basis of the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by Asymmetric Synthesis (e.g., jacques, et al, enantiomers, racemes and solutions (Wiley Interscience, new York, 1981); principles of asymmetry Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972))。

The present invention also includes isotopically-labeled compounds of the present invention which are identical to those recited in the present invention, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into 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。

compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of this invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g. ³ H and ¹⁴ incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ h, and carbon-14, i.e ¹⁴ C, the isotope is particularly preferred. In addition, heavy isotopes are used, such as deuterium, i.e. ² H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; definitions and conventions described by and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light 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 they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. 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 substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric atropisomer, and geometric (or conformational)) forms of such structures; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the present invention are within the scope of the invention.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "geometric isomer", also known as "cis-trans isomer", is an isomer resulting from the inability of double bonds (including olefinic double bonds, C = N double bonds, and N = N double bonds) or a single bond of a ring carbon atom to rotate freely.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, 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.

The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.

The term "syndrome X", also referred to as a disorder, disease of metabolic syndrome, the condition of which is described in detail in Johannsson et al, j.clin.endocrinol.metab.,1997,82, 727-734.

As used herein, "inflammatory disease," "inflammatory disease," or "inflammatory disease" refers to any disease, disorder, or symptom of excessive inflammatory symptoms, host tissue damage, or loss of tissue function resulting from an excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation," "inflammatory" or "inflammatory" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.

As used herein, "allergy" refers to any symptom of developing an allergy, tissue damage, or loss of tissue function. As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function, pain, swelling, leukocytosis, and thrombocytopenia of the transplanted or surrounding tissue. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (such as epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma (hepatic carcinoma), anal cancer, penile carcinoma, as well as head and neck cancer.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Description of the Compounds of the invention

The invention provides a compound with better SSAO/VAP-1 activity inhibition, which is used for preparing a medicament for treating inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection, in particular for preparing a medicament for preventing, treating or relieving nonalcoholic fatty liver diseases of a patient. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of using these compounds and compositions in the manufacture of medicaments for the treatment of the above-mentioned diseases in mammals, especially in humans. Compared with the existing similar compounds, the compound of the invention not only has good pharmacological activity, but also has excellent in vivo metabolic kinetics property and in vivo pharmacodynamics property, and simultaneously, the compound of the invention has high selectivity on SSAO/VAP-1. The preparation method of the compound is simple and feasible, has stable process method, and is suitable for industrial production. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein, ring Cy, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ X, Y, L and n have the definitions as described herein.

In some embodiments of the present invention, the substrate is,

x is-N = or-CH =;

y is-N (R) ⁷ ) -or-N =;

l is-O-, -S-or-NH-;

the ring Cy is a nitrogen-containing heterocyclic ring consisting of 5 to 8 atoms or a nitrogen-containing heteroaromatic ring consisting of 5 to 8 atoms;

R ⁷ is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl or C _3-6 A cycloalkyl group;

each R ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b 、R ^b O-C _1-4 Alkylene, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _2-8 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl, or heteroaryl of 5 to 10 atoms, wherein said C _1-6 Alkyl radical, C _2-8 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

or any R ⁵ 、R ⁶ And a carbon atom attached to each of themTogether with one another or with any two R ⁶ Together with the carbon or nitrogen atom to which they are each attached, form C _3-8 Carbocyclic ring, heterocyclic ring of 3-8 atoms, C _6-10 An aromatic ring or a 5-10 atom heteroaromatic ring; wherein said C _3-8 Carbocyclic ring, heterocyclic ring of 3-8 atoms, C _6-10 The aromatic ring and the 5-10 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ¹ is H, D, F, cl, br, I, C _1-6 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-6 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ² is F, cl, br, I, C _1-6 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-6 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 A haloalkoxy group;

R ³ and R ⁴ Each independently is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C _6-10 Aryl, heteroaryl of 5 to 10 atoms or

Wherein said C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ³ 、R ⁴ And together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

each R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Independently H, D, hydroxy, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 An alkenyl group,C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C _6-10 Aryl and heteroaryl of 5 to 10 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ^c 、R ^d Together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

n is 0, 1 or 2.

In other embodiments, ring Cy is a nitrogen-containing heterocyclic ring of 5-6 atoms or a nitrogen-containing heteroaromatic ring of 5-6 atoms.

In still other embodiments, ring Cy is

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In still other embodiments, wherein ring Cy is

In some embodiments, the compound of the present invention, which is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (II), or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ And R ⁶ Having the definitions as described in the present invention.

In some embodiments, the compound of the present invention, which is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (III) or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions as described herein.

In some embodiments, the compound of the present invention, which is a compound of formula (IV) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (IV) or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions as described in the present invention.

In some embodiments, the compound of the present invention, which is a compound of formula (V) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (V), or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ And R ⁶ Having the definitions as described in the present invention.

In some embodiments, the compound of the present invention, which is a compound of formula (VI) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (VI), or prodrug thereof,

wherein, X and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Having the definitions as described in the present invention.

In other embodiments, R ⁷ Is H, D, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl or C _3-6 A cycloalkyl group.

In other embodiments, each R ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b 、R ^b O-C _1-2 Alkylene radical, R ^d R ^c N-C _1-2 Alkylene radical, C _1-4 Haloalkyl, C _1-4 Alkyl radical, C _2-6 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, a heterocyclic group consisting of 3 to 6 atoms, C _6-10 Aryl, or heteroaryl of 5 to 6 atoms, wherein said C _1-4 Alkyl radical, C _2-6 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, a heterocyclic group consisting of 3 to 6 atoms, C _6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group;

or any R ⁵ 、R ⁶ And together with the carbon or nitrogen atom to which they are each attached, or any two R ⁶ Together with the carbon or nitrogen atom to which they are each attached, form C _3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C _6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms; wherein said C _3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C _6-10 The aromatic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group.

In still other embodiments, R ⁷ Is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In still other embodiments, each R is ⁵ And R ⁶ Independently H, D, F, cl, br, I, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OH、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-C(＝O)OCH(CH ₃ ) ₂ 、-C(＝O)NR ^c R ^d 、-SR ^e 、-S(＝O) ₂ R ^e 、-S(＝O)R ^e 、-S(＝O) ₂ NR ^c R ^d 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-NR ^c R ^d 、-OR ^b Trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, vinyl, 1-propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, ethenyl, 1-propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or difluoromethoxy;

or any R ⁵ 、R ⁶ And together with the carbon or nitrogen atom to which they are each attached, or any two R ⁶ And together with the carbon atom or nitrogen atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrakis-propylHydropyridazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl; wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, triazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or difluoromethoxy. In other embodiments, wherein R ¹ Is H, D, F, cl, br, I, C _1-4 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^a 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-4 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group.

In other embodiments, wherein R ¹ Is H, D, F, cl, br, I, C _1-4 Alkyl, -C (= C)O)OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-4 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group.

In still other embodiments, R ¹ Is H, D, F, cl, br, I, methyl, ethyl, isopropyl, n-propyl, -C (= O) OH, -C (= O) OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)R ^a 、-OC(＝O)R ^a OR-OC (= O) OR ^a Wherein the methyl, ethyl, isopropyl and n-propyl groups are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ² Is F, cl, br, I, C _1-4 Alkyl, -C (= O) OR ^b 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-NR ^f C(＝O)R ^a 、-NR ^f S(＝O) ₂ R ^e 、-C(＝O)NR ^c R ^d 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O) ₂ R ^e 、-SR ^e or-S (= O) R ^e Wherein, the C is _1-4 The alkyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently being D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 A haloalkoxy group.

In other embodiments, R ² Is F, cl, br, I, methyl, ethyl, isopropyl, n-propyl, -C (= O) OH, -C (= O) OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)R ^a 、-OC(＝O)R ^a OR-OC (= O) OR ^a Wherein the methyl, ethyl, isopropyl and n-propyl groups are each independently unsubstituted or substituted with 1,2,3 or 4 substituents which are independently D, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ³ And R ⁴ Each independently of the other is H, D, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C _6-10 Aryl, 5-6 atom-containing heteroaryl or

Wherein said C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C _6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group;

or R ³ 、R ⁴ And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In other embodiments, R ³ And R ⁴ Each independently is H, D, AAlkyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, 5-6-membered heterocyclic radical, phenyl, 5-6-membered heteroaryl or

Wherein the methyl, ethyl, n-propyl, isopropyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, heterocyclyl of 5-6 atoms, phenyl and heteroaryl of 5-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

or R ³ 、R ⁴ And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, each R is ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Independently H, D, hydroxyl, trifluoromethyl, difluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Cycloalkyl, heterocyclyl of 5 to 6 atoms, phenyl or heteroaryl of 5 to 6 atoms, wherein said methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C _3-6 Cycloalkyl, heterocyclyl of 5-6 atoms, phenyl and heteroaryl of 5-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In still other embodiments, the invention relates to the structure of one of the following, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

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in still other embodiments, the pharmaceutically acceptable salt of the present invention is a hydrochloride, hydrobromide or mesylate salt.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.

In some embodiments, the pharmaceutical composition of the invention further comprises one or more additional therapeutic agents.

In other embodiments, the therapeutic agent is selected from an SSAO/VAP-1 inhibitor.

In other embodiments, the pharmaceutical compositions of the present invention may be in liquid, solid, semi-solid, gel, or spray form.

In still other embodiments, the pharmaceutical composition of the invention, wherein the therapeutic agent involved is Vapaliximab, PRX-167700, BTT-1023, ASP-8232, PXS-4728A, or RTU-1096.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for inhibiting SSAO/VAP-1.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for the prevention, treatment or alleviation of diseases associated with or modulated by SSAO/VAP-1 protein.

In some embodiments, the diseases related to or modulated by SSAO/VAP-1 protein according to the present invention are inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.

In other embodiments, the inflammatory disease and/or inflammation-related disorder of the invention is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease, or neuroinflammatory disease.

In other embodiments, the diabetes and/or diabetes related disorders of the present invention are type i diabetes, type ii diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.

In other embodiments, the psychiatric Disorder of the invention is major depression, bipolar depression, or Attention Deficit Hyperactivity Disorder (Attention Deficit Hyperactivity Disorder).

In other embodiments, the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications, or tissue damage by inflammatory cells after stroke.

In other embodiments, the fibrosis of the present invention is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.

In other embodiments, the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament, wherein the vascular disease is atherosclerosis, chronic heart failure, or congestive heart failure.

In still other embodiments, the arthritis of the invention is osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

In still other embodiments, the systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.

In still other embodiments, the inflammatory bowel disease of the present invention is irritable bowel disease.

In still other embodiments, the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease.

In some embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated negative cirrhosis, or primary liver cancer.

In still other embodiments, the respiratory disease of the invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.

In still other embodiments, the ocular disease of the present invention is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation due to angiogenesis and/or lymphangiogenesis, or macular degeneration.

In still other embodiments, the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.

In still other embodiments, the neuroinflammatory disorder of the invention is parkinson's disease, alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.

In some embodiments, the disease of the invention is cancer.

In another aspect, the invention relates to a method of inhibiting SSAO/VAP-1 activity using a compound or pharmaceutical composition described herein by administering to a subject in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition.

In another aspect, the present invention relates to a method for preventing or treating an inflammatory disease and/or an inflammation-related disease, diabetes and/or a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection using the compound or the pharmaceutical composition of the present invention, the method comprising administering to a patient a therapeutically effective amount of the compound or the pharmaceutical composition of the present invention. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.

The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay of action or the like will generally depend on the particular compound, patient, particular disease or condition being administered and its severity, route and frequency of administration, etc., and will be decided by the attending physician as the case may be. For example, when a compound or pharmaceutical composition provided by the present invention is administered by intravenous route, administration may be performed once per week or at even longer intervals.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for inhibiting the activity of SSAO/VAP-1.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for the prevention or treatment of, alleviating the symptoms of, or delaying the progression or onset of an inflammatory disease and/or an inflammation-related disease, diabetes and/or a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "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 being treated therewith.

The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of enantiomers of the compounds of the present invention.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, polyhemilactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived 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, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., na, ca, mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In e.g. "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "handbook of pharmaceutical salts: properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002), may find a list of additional suitable Salts.

Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form, either inherently or by design, solvates with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the unlabelled forms of these compounds as well as the isotopically labeled forms. Isotopically-labelled compounds have the structure depicted by the general formula given in this invention, except that one or more atoms are selected to haveAtomic substitution by atomic mass or mass number. Exemplary isotopes that can be incorporated into 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。

In another aspect, the compounds of the invention include compounds defined herein which are labelled with various isotopes, for example where a radioactive isotope is present, such as ³ H， ¹⁴ C and ¹⁸ those compounds of F, or in which a non-radioactive isotope is present, e.g. ² H and ¹³ C. the isotope labeled compound can be used for metabolic research (use) ¹⁴ C) Reaction kinetics study (using, for example ² H or ³ H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including measurement of the tissue distribution of drugs or substrates, or in radiation therapy of patients. ¹⁸ F-labelled compounds are particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by using suitable isotopically-labelled reagents in place of the original non-labelled reagents described in the examples and preparations of this invention.

In addition, heavier isotopes are particularly preferred for deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in this context is to be taken as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has at least 3500 for each designated deuterium atom (52.5% of each designated deuterium atomDeuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-d ₆ Or DMSO-d ₆ Those solvates of (a).

Compositions, formulations and administration of the compounds of the invention

The invention relates to a pharmaceutical composition, which comprises the compound disclosed by the invention or a compound with a structure shown in an embodiment, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite and a pharmaceutically acceptable salt thereof 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. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle. The amount of compound in the pharmaceutical composition of the present invention is effective to detectably inhibit SSAO/VAP-1 activity in a biological sample or patient.

Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.

The pharmaceutical composition or pharmaceutically acceptable composition according to the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form, as used herein. The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York disclose various carriers for use in formulating pharmaceutically acceptable compositions and well known methods for their preparation. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.

Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methyl cellulose, hydroxypropyl methyl cellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifying agents, gelling agents, and the like, as judged by the formulator, coating agents, sweetening and flavoring agents, preservatives and antioxidants can also be present in the compositions.

The compounds or compositions of the present invention may be administered by any suitable means, and the compounds and pharmaceutically acceptable compositions described above may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), orally as an oral or nasal spray, and the like, depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example 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, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used for the preparation of injections.

For example, injectable formulations can be sterilized by filtration through a bacterial-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also be of a composition such that the active ingredient is released only, optionally 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 gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.

The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, 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 art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a dermal patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may 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.

The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated forms. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used 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.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers which are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions may be prepared by mixing the agent with a non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Local instillation to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical skin patches may also be used.

For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or solutions in particular isotonic, pH adjusted, sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in 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.

Use of the Compounds and compositions of the invention

The compounds or pharmaceutical compositions provided by the present invention are useful for the preparation of medicaments for inhibiting SSAO/VAP-1 activity.

The compounds or pharmaceutical compositions provided herein are useful for preventing, treating or ameliorating a disease associated with or modulated by SSAO/VAP-1 protein, wherein the disease is an inflammatory disease and/or an inflammation-related disease, diabetes and/or a diabetes-related disease, a psychiatric disorder, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection.

The compounds or pharmaceutical compositions provided by the present invention are useful for the preparation of medicaments for the prevention, treatment or alleviation of diseases associated with or modulated by SSAO/VAP-1 protein, wherein said diseases are inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, psychiatric disorders, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.

The present invention provides a method for treating, preventing or ameliorating diseases associated with or modulated by SSAO/VAP-1 protein, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described above or a pharmaceutical composition thereof. The disease is an inflammatory disease and/or an inflammation-related disease, diabetes and/or a diabetes-related disease, a psychiatric condition, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection. Also, the above-described compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The mode of administration may be simultaneous, sequential or at time intervals.

In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

An "effective amount", "therapeutically effective amount" or "effective dose" of a compound or pharmaceutically acceptable pharmaceutical composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis and detection methods

To describe the invention, examples are set forth below. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

In the present specification, the compound numbers of the examples, the compound numbers of the claims or the compound numbers at other positions in the specification are independent of each other and do not affect each other. Wherein, the compound corresponding to the compound number in the activity test example is the compound of the same compound number in the preparation example.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known drugs other than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The structure of the compound is determined by nuclear magnetic resonance ¹ H-NMR、 ¹³ C-NMR or/and ¹⁹ F-NMR). ¹ H-NMR、 ¹³ C-NMR、 ¹⁹ F-NMR chemical shifts (. Delta.) are given in parts per million (ppm). ¹ H-NMR、 ¹³ C-NMR、 ¹⁹ F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometerThe solvent for determination is deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD or MeOH-d ₄ ) Or deuterated dimethyl sulfoxide (DMSO-d) ₆ ). TMS (0 ppm) or chloroform (7.25 ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broadeded, broad), dd (doublet of doublets), dt (doublets ), td (triplets of doublets, triplets), br (broadedended singlets, broad singlet). Coupling constant J, in Hertz (Hz).

Preparative purification or preparative resolution generally uses a Novasep pump 250 high performance liquid chromatograph.

The LC-MS was determined using an Agilen-6120Quadrupole LC/MS mass spectrometer.

The column chromatography generally uses 300-400 mesh silica gel as a carrier in Qingdao ocean chemical industry.

The starting materials of the present invention are known and commercially available, are available from Shanghai Accela Company, annage Company, bailingwei Company (J & K), tianjin Afaha Angsa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.

In the examples, the reaction was carried out in a nitrogen atmosphere unless otherwise specified;

the nitrogen atmosphere refers to the condition that a reaction bottle is connected with a nitrogen balloon or a steel kettle with the volume of about 1L;

the hydrogen atmosphere refers to that a reaction bottle is connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L;

in the examples, unless otherwise specified, the solution means an aqueous solution;

in the examples, the reaction temperature is room temperature unless otherwise specified;

in the examples, the room temperature is 20 ℃ to 30 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.

HPLC refers to high performance liquid chromatography;

HPLC was performed using an Agilent 1200 high pressure liquid chromatograph (Zorbax Eclipse Plus C18X 4.6mm column);

HPLC test conditions: operating time: column temperature 15min-20 min: 35 ℃ PDA:210nm,254nm

Mobile phase: phase A: ph2.5 monopotassium phosphate phase B: flow rate of acetonitrile: 1.0ml/min

Mobile phase gradients are shown in table a:

TABLE A

Time	Gradient of mobile phase A	Gradient of mobile phase B
			0min	90％	10％
15min	30％	70％

The analytical LC/MS/MS system in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice plate automatic sampler, column thermostat, agilent G6430 three-stage quadrupole mass spectrometer with Electric Spray Ionization (ESI) source. Quantitative analysis was performed in MRM mode, with the parameters of the MRM transformation as shown in table B:

TABLE B

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Analysis 5. Mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. Mu.M column. The analysis conditions are as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4mL/min. Mobile phase gradients are shown in table C:

watch C

Time	Gradient of mobile phase B
		0.5min	5％
1.0min	95％
		2.2min	95％
2.3min	5％
		5.0min	Terminate

Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5. Mu.M (Phenomenex, torrance, california, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.

The following acronyms are used throughout the invention:

DMSO-d ₆ deuterated dimethyl sulfoxide; CDCl ₃ Deuterated chloroform; CD (compact disc) ₃ OD is deuterated methanol;

ac is acetyl; b, bn: a benzyl group; et is ethyl;

me is methyl; ms is methylsulfonyl; boc is tert-butyloxycarbonyl;

PMB is p-methoxybenzyl; % wt,% mass: the weight percentage is as follows; mL, mL is mL;

mol/L is mol per liter; mol: mol; mmol is millimole;

g, g is; h is hours; h ₂ : hydrogen gas;

min is min; n is a radical of hydrogen ₂ Nitrogen gas; NH (NH) ₃ Ammonia gas;

MPa is the ratio of MPa.

General synthetic methods

A typical synthetic procedure for the preparation of the disclosed compounds is shown in scheme 1 below. Unless otherwise stated, each ring Cy, R ⁵ 、R ⁶ X, Y and n have the definitions as described herein, PG is an amino protecting group and LG is a leaving group.

Synthesis scheme 1:

the compounds having the structure shown in general formula (I-A) can be prepared by general synthetic methods described in scheme 1, and specific procedures can be referred to examples. Enabling the compound (I-a) to have nucleophilic reaction with the compound (I-b) under an alkaline condition (such as potassium carbonate) to obtain a compound (I-c); the compound (I-c) removes the amino protecting group PG to obtain the target compound represented by the general formula (I-A). In some embodiments, the subject compounds of formula (I-A) form acid addition salts with acids to improve chemical stability. Examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide and mesylate salts.

Synthesis scheme 2:

compounds having the structure shown in general formula (I-B) can be prepared by general synthetic methods described in scheme 2, with reference to the examples for specific procedures. Hydrogenating the compound (I-d) and sodium cyanoborohydride to obtain a compound (I-e); and (e) removing the amino protecting group PG from the compound (I-e) to obtain the target compound shown as the general formula (I-B). In some embodiments, the target compounds of formula (I-B) form acid addition salts with acids to increase chemical stability. Examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide and mesylate salts.

Examples

Preparation examples

Example 1 (E) -3-fluoro-2- (6-quinolinyloxymethyl) prop-2-en-1-amine hydrochloride 1

Step 1N- [ (E) -3-fluoro-2- (6-quinolinyloxymethyl) allyl]Amino-methylTert-butyl ester 1c and N- [ (Z) -3- Fluoro-2- (6-quinolinyloxymethyl) allyl]Carbamic acid tert-butyl ester 1d

N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (0.50g, 1.9mmol) was dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (0.39g, 2.8mmol) and 6-hydroxyquinoline (0.31g, 2.1mmol) were added to react at room temperature for 24 hours. Quenched with water (5 mL), extracted with ethyl acetate (20 mL), the organic phase washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/2] to give the title compound 1c (0.28 g, yield 44%), 1d (0.13 g, yield 31%) as a white solid.

MS(ESI,pos.ion)m/z:333.1[M+H] ⁺ 。

Step 2 (E) -3-fluoro-2- (6-quinolinyloxymethyl) -prop-2-en-1-amine hydrochloride 1

N- [ (E) -3-fluoro-2- (6-quinolinyloxymethyl) allyl ] carbamic acid tert-butyl ester 1c (0.28g, 0.84mmol) was dissolved in ethyl acetate (0.5 mL), a solution of hydrogen chloride in ethyl acetate (3 mL,4 mol/L) was added, reaction was carried out at room temperature for 20 minutes, a white solid precipitated, and suction filtration was carried out to give the title compound 1 (0.16 g, yield 82%, HPLC purity: 91.17%) as a white solid.

MS(ESI,pos.ion)m/z:233.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.10(d,J＝4.6Hz,1H),9.00(d,J＝8.3Hz,1H),8.54(s,3H),8.39(d,J＝9.1Hz,1H),8.00(dd,J＝8.1,5.1Hz,1H),7.85(m,2H),7.44(d,J＝81.6Hz,1H),4.90(d,J＝2.0Hz,2H),3.64(d,J＝4.5Hz,2H)。

Example 2 (Z) -3-fluoro-2- (6-quinolinyloxymethyl) prop-2-en-1-ylamine hydrochloride 2

The procedure described in example 1, step 2 was followed using N- [ (Z) -3-fluoro-2- (6-quinolinyloxymethyl) allyl ] carbamic acid tert-butyl ester 1d (0.13g, 0.39mmol) instead of compound 1c to give the title compound 2 (81 mg, yield 89%, HPLC purity: 83.98%) as a white solid.

MS(ESI,pos.ion)m/z:233.1[M-Cl] ⁺ ；

¹ HNMR(400MHz,DMSO-d ₆ )δ(ppm)9.09(d,J＝4.5Hz,1H),8.94(d,J＝8.4Hz,1H),8.47(s,3H),8.36(d,J＝9.0Hz,1H),7.98(dd,J＝8.2,5.1Hz,1H),7.83(d,J＝8.4Hz,2H),7.32(d,J＝82.0Hz,1H),4.98(s,2H),3.60(s,2H)。

EXAMPLE 3 (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolyl ] oxymethyl ] prop-2-en-1-amine hydrochloride 3 and (Z) -3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolyl ] oxymethyl ] prop-2-en-1-amine hydrochloride 4

Step 1 2- (4-fluorophenyl) -6-methoxy-quinoline 3b

After 2-chloro-6-methoxy-quinoline (2.00g, 10.3mmol), (4-fluorophenyl) boronic acid (1.88g, 13.4 mmol) and sodium carbonate (5.47g, 51.6 mmol) were mixed with stirring, a mixed solvent of 1, 4-dioxane (80 mL) and water (20 mL) was added, and the resulting mixture was stirred at room temperature for 10 minutes, tetrakis (triphenylphosphine) palladium (612mg, 0.529mmol) was added, followed by heating to 100 ℃ and refluxing for 16 hours. The reaction solution was cooled to room temperature, and filtered through celite, the filter cake was washed with ethyl acetate (100 mL), the filtrate was washed with a saturated ammonium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated through suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/20] to give the title compound 3b (1.88 g, yield 69%) as a yellow solid.

MS(ESI,pos.ion)m/z:254.2[M+H] ⁺ 。

Step 2- (4-fluorophenyl) quinolin-6-ol 3c

2- (4-fluorophenyl) -6-methoxy-quinoline 3b (1.8g, 7.1mmol) is dissolved in dichloromethane (50 mL), the resulting mixture is cooled to-30 ℃ under the protection of nitrogen, boron tribromide (2.8mL, 30mmol) is added dropwise, and the reaction is stirred at room temperature for 3 hours. The reaction solution was poured into ice water (20 mL), concentrated to remove the organic solvent, filtered under suction, washed with water (20 mL. Times.3), and the resulting solid was slurried with ethyl acetate (30 mL), filtered under suction, washed with ethyl acetate (20 mL), and concentrated to give the title compound 3c (1.36 g, yield 80%) as a yellow solid.

MS(ESI,pos.ion)m/z:240.0[M+H] ⁺ 。

Step 3N- [ 3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolinyl ]]Oxymethyl radical]Allyl radical]Carbamic acid tert-butyl group Ester 3d

2- (4-fluorophenyl) quinolin-6-ol 3c (1.00g, 4.18mmol) was dissolved in N, N-dimethylformamide (20 mL), and potassium carbonate (788mg, 5.64mmol) and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (0.448g, 1.67mmol) were added and the mixture was stirred at room temperature for 20 hours. Quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases washed with saturated ammonium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/5] to give the title compound 3d (1.15 g, yield 65%) as a dark yellow solid.

MS(ESI,pos.ion)m/z:427.0[M+H] ⁺ 。

Step 4 (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolinyl]Oxymethyl radical]Propan-2-en-1-amine hydrochloride 3 and (Z) -3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolinyl]Oxymethyl radical]Prop-2-en-1-amine hydrochloride 4

Tert-butyl N- [ 3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolinyl ] oxymethyl ] allyl ] carbamate 3d (1.15g, 2.70mmol) was dissolved in ethyl acetate (12 mL), the temperature was reduced to 0 ℃, an ethyl acetate solution of hydrogen chloride (5mL, 4 mol/L) was added dropwise, the resulting mixture was warmed to room temperature and stirred for reaction for 16 hours, suction filtration was conducted, washing was conducted with ethyl acetate (20 mL), and the residue was treated with preparative resolution and an ethyl acetate solution of hydrogen chloride to give the title compounds 3 (0.17 g, yield 17%, HPLC purity: 94.22%) and 4 (43 mg, yield 4.4%, HPLC purity: 94.78%) each as a white solid.

Compound 3:

MS(ESI,pos.ion)m/z:327.0[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.62(d,J＝8.0Hz,1H),8.48(s,3H),8.32(s,2H),8.24(dd,J＝18.2,8.6Hz,2H),7.62(d,J＝8.7Hz,2H),7.44(t,J＝8.2Hz,2H),7.53-7.29(m,1H),4.85(s,2H),3.66(s,2H)。

compound 4:

MS(ESI,pos.ion)m/z:327.0[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.54(d,J＝8.5Hz,1H),8.39(s,3H),8.32(d,J＝5.7Hz,2H),8.19(d,J＝8.2Hz,2H),7.61(s,2H),7.36(dd,J＝54.6,45.7Hz,3H),4.93(s,2H),3.61(s,2H)。

example 4 (E) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] prop-2-en-1-ylamine hydrochloride 5

Step 1 6-methoxy-2-phenyl-quinoline 5a

Phenylboronic acid (7.2g, 58mmol) and 2-chloro-6-methoxy-quinoline (8.0g, 41mmol) were dissolved in anhydrous N, N-dimethylformamide (100 mL), anhydrous potassium phosphate (22.9g, 108mmol) was added under nitrogen, the resulting mixture was stirred for 30 minutes, tetrakis (triphenylphosphine) palladium (2.88g, 2.48mmol) was added, and the reaction was stirred while warming to 140 ℃ for 24 hours. Cooled to room temperature, filtered with suction, water (150 mL) was added to the filtrate, extracted with ethyl acetate (200 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, concentrated with suction, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =15/1] to give the title compound 5a (3.6 g, yield 37%) as a white solid.

MS(ESI,pos.ion)m/z:236.1[M+H] ⁺ 。

Step 2-phenylquinolin-6-ol 5b

6-methoxy-2-phenyl-quinoline 5a (1.44g, 6.12mmol) was dissolved in dichloromethane (14 mL), cooled to 0 deg.C, boron tribromide (1.75mL, 18.3mmol) was added dropwise, and the reaction was stirred at room temperature for 4 hours. The reaction was quenched by pouring into ice water (20 mL), adjusted pH =7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 5b (1.35 g, yield 99%) as a yellow solid.

MS(ESI,pos.ion)m/z:222.3[M+H] ⁺ 。

Step 3N- [ 3-fluoro-2- [ (2-phenyl-6-quinolyl) oxymethyl group]Allyl radical]Carbamic acid tert-butyl ester 5c

2-phenylquinolin-6-ol 5b (400mg, 1.81mmol) was dissolved in N, N-dimethylformamide (10 mL), and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (581mg, 2.17mmol) and potassium carbonate (504mg, 3.61mmol) were added to stir the mixture at room temperature for 18 hours. Water (10 mL) was added, extraction was performed with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated with suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =6/1] to give the title compound 5c (574 mg, yield 78%) as a white solid.

MS(ESI,pos.ion)m/z:409.3[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.38-8.29(m,1H),8.17(dd,J＝53.1,8.0Hz,2H),8.03-7.93(m,2H),7.58-7.38(m,5H),7.28-7.00(m,2H),4.78-4.54(m,2H),3.74(d,J＝59.5Hz,2H),1.33(t,J＝6.6Hz,9H)。

Step 4N- [ (E) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl]Allyl radical]Amino group Tert-butyl formate 5d and N- [ (Z) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl]Allyl radical]Amino group (iv) Carboxylic acid tert-butyl ester 5e

Tert-butyl N- [ 3-fluoro-2- [ (2-phenyl-6-quinolyl) oxymethyl ] allyl ] carbamate 5c (662mg, 1.62mmol) was dissolved in a mixed solvent of acetic acid (5 mL) and tetrahydrofuran (5 mL), and sodium cyanoborohydride (415mg, 6.47mmol) was added thereto, followed by stirring at room temperature for 18 hours. pH =7 was adjusted with saturated sodium bicarbonate solution, ethyl acetate (10 mL) was added to the resulting mixture, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1] to give the title compounds 5d (190 mg, yield 28%) and 5e (82 mg, yield 12%) as yellow oils.

MS(ESI,pos.ion)m/z:413.4[M+H] ⁺ 。

Step 5 (E) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl]Propan-2-en-1-amine salts Acid salt 5

Tert-butyl N- [ (E) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] allyl ] carbamate 5d (190mg, 0.46mmol) was dissolved in ethyl acetate (2 mL), a solution of hydrogen chloride in ethyl acetate (4 mL,4 mol/L) was added, and the resulting mixture was stirred at room temperature for reaction for 30 minutes. Concentration gave the title compound 5 (160 mg, yield 99%, HPLC purity: 94.89%) as a yellow solid.

MS(ESI,pos.ion)m/z:313.3[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.47(s,3H),7.65(d,J＝6.6Hz,2H),7.52-6.89(m,8H),4.68(s,2H),4.57(d,J＝10.0Hz,1H),3.57(d,J＝3.8Hz,2H),2.95(dd,J＝58.3,11.7Hz,2H),2.25(d,J＝45.3Hz,2H)。

Example 5 (Z) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] prop-2-en-1-amine hydrochloride 6

The procedure described in example 4, step 5 was followed using tert-butyl N- [ (Z) -3-fluoro-2- [ (2-phenyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] allyl ] carbamate 5e (82mg, 0.20mmol) instead of compound 5d to give the title compound 6 (60 mg, yield 87%, HPLC purity: 90.56%) as an off-white solid.

MS(ESI,pos.ion)m/z:313.3[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.36(s,3H),7.62(d,J＝6.7Hz,3H),7.37(ddd,J＝82.5,36.3,29.0Hz,4H),7.02(d,J＝79.4Hz,3H),4.75(s,2H),4.55(d,J＝10.2Hz,1H),3.51(s,2H),2.92(dd,J＝61.2,11.9Hz,2H),2.22(d,J＝32.2Hz,2H)。

Example 6 (E) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) prop-2-en-1-ylamine hydrochloride 7

Step 1-chloro-7-methoxy-1, 2,3, 4-tetrahydroacridine 7b

2-amino-5-methoxy-benzoic acid (5.0g, 30mmol) is added into cyclohexanone (4.8g, 49mmol), the temperature is reduced to 0 ℃ under the protection of nitrogen, phosphorus oxychloride (28 mL) is added dropwise, and the reaction solution is refluxed for 2.5 hours. The reaction was quenched by pouring into ice water (100 mL), adjusted to neutral with saturated potassium carbonate solution, extracted with dichloromethane/methanol (v/v =1/9,200ml × 3), and the combined organic phases were washed with saturated ammonium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 7b (5.35 g, yield 78%) as a yellow solid.

MS(ESI,pos.ion)m/z:248.2[M+H] ⁺ 。

Step 2-methoxy-1, 2,3, 4-tetrahydroacridine 7c

9-chloro-7-methoxy-1, 2,3, 4-tetrahydroacridine 7b (0.75g, 3.0 mmol) was dissolved in methanol (50 mL), 10% palladium on carbon (322 mg) was added to replace hydrogen, and the mixture was hydrogenated (0.1 MPa) for 15 hours. The residue was filtered off with suction, washed with methanol (20 mL) and concentrated to give the title compound 7c (0.65 g, 100% yield) as a yellow solid.

Step 3, 6,7, 8-Tetrahydroacridin-2-ol 7d

7-methoxy-1, 2,3, 4-tetrahydroacridine 7c (610mg, 2.86mmol) is dissolved in dichloromethane (20 mL), the obtained mixture is cooled to-30 ℃ under the protection of nitrogen, boron tribromide (1.5mL, 169mol) is slowly added, and the reaction liquid is heated to room temperature and stirred for reaction for 16 hours. The reaction was quenched into ice water (10 mL), filtered with suction, and the filter residue was dissolved in methanol (5 mL), followed by dropwise addition of ethyl acetate (15 mL) and stirring for 4 hours, whereupon a large amount of solid precipitated. The solid was collected by suction filtration and dried to give the title compound 7d (0.50 g, 88% yield) as a white solid.

MS(ESI,pos.ion)m/z:200.1[M+H] ⁺ 。

Step 4N- [ (E) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) allyl]Carbamic acid tert-butyl ester Ester 7e and N- [ (Z) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) allyl]Carbamic acid tert-butyl ester 7f

5,6,7,8-tetrahydroacridin-2-ol 7d (0.55g, 2.7mmol) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (0.52g, 3.7mmol) and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (0.52g, 1.9mmol) were added sequentially, and the reaction solution was allowed to react at room temperature for 22 hours. The reaction was quenched by the addition of water (20 mL), extracted with ethyl acetate (20 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/4] to give the title compound 7e (0.18 g, yield 25%) and 7f (60 mg, yield 8.2%) as white solids.

Step 5 (E) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) prop-2-en-1-ylamine hydrochloride 7

Tert-butyl N- [ (E) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) allyl ] carbamate 7E (0.18g, 0.466 mmol) was dissolved in ethyl acetate (15 mL), the temperature was reduced to 0 ℃, a solution of hydrogen chloride in ethyl acetate (5 mL,4.0 mol/L) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 20 minutes. Suction filtration and washing of the filter cake with ethyl acetate (10 mL. Times.2) gave the title compound 7 (0.12 g, yield 80%, HPLC purity: 98.6%) as a white solid.

MS(ESI,pos.ion)m/z:287.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.67(s,1H),8.38(s,3H),8.28(d,J＝9.3Hz,1H),7.72(d,J＝9.1Hz,1H),7.66(s,1H),7.54-7.31(d,J＝84Hz,1H),4.83(d,J＝2.7Hz,2H),3.66(d,J＝4.6Hz,2H),3.29(t,J＝6.1Hz,2H),3.04(t,J＝6.1Hz,2H),1.98-1.92(m,2H),1.91-1.84(m,2H)。

Example 7 (Z) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) prop-2-en-1-ylamine hydrochloride 8

By N- [ (Z) -3-fluoro-2- (5, 6,7, 8-tetrahydroacridin-2-yloxymethyl) allyl]Tert-butyl carbamate 7f (60mg, 0.16mmol) instead of compound 7e the method described in example 6, step 5 was followed to give the title compound 8 (35 mg, yield 70%, HPLC purity: 91.3%) as a white solid. MS (ESI, pos.ion) m/z:287.1[ M-Cl ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.62(s,1H),8.23(d,J＝24.9Hz,4H),7.75-7.63(m,2H),7.40-7.17(d,J＝84Hz,1H),4.92(s,2H),3.61(s,2H),3.27(s,2H),3.04(t,J＝6.1Hz,2H),1.98-1.93(m,2H),1.88(d,J＝5.5Hz,2H)。

Example 8 (E) -2- (acridin-2-yloxymethyl) -3-fluoro-prop-2-en-1-ylamine hydrochloride 9

Step 1-Bromobenzoic acid 9b

Methyl o-bromobenzoate (4.00g, 18.6 mmol) was dissolved in a mixed solution of ethanol (45 mL) and water (15 mL), cooled to 10 deg.C, added sodium hydroxide (2.25g, 56.3 mmol), stirred for 5 minutes, and then stirred at room temperature for 1 hour. Concentration removed ethanol, adjusted the reaction solution to pH less than 1 with hydrochloric acid (2.0 mol/L), extracted with ethyl acetate (50 mL. Times.2), the combined organic phases washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 9b (3.74 g, 100% yield) as a white solid.

Step 2- (4-Methoxyaniline) benzoic acid 9c

2-Bromobenzoic acid 9b (3.74g, 18.6 mmol) was dissolved in ethylene glycol monomethyl ether (15 mL), 4-methoxyaniline (2.75g, 22.3mmol), cuprous oxide (92mg, 0.64mmol), copper (65mg, 1.0mmol) and potassium carbonate (2.86g, 20.7 mmol) were added in this order, and the resulting mixture was heated to 140 ℃ for reflux reaction for 3 hours. The reaction solution was cooled, quenched with water (40 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed successively with saturated ammonium chloride solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/4] to obtain the title compound 9c (2.2 g, yield 49%) as a yellow solid.

Step 3 2-methoxy-10H-acridin-9-one 9d

2- (4-Methoxyaniline) benzoic acid 9c (1.27g, 5.22mmol) was dissolved in polyphosphoric acid (15 mL), the resulting mixture was warmed to 100 deg.C, stirred for 4 hours, quenched while hot by pouring into ice water (50 mL), then cooled to 0 deg.C, adjusted to a weakly basic pH with saturated sodium bicarbonate solution, filtered, and the filter cake was washed with water (20 mL) and ethanol (20 mL) to give the title compound 9d (1.10 g, 94% yield) as a yellow-green solid.

Step 4-methoxy-9, 10-dihydroacridine 9e

2-methoxy-10H-acridin-9-one 9d (950mg, 4.22mmol) was dissolved in tetrahydrofuran (25 mL), the temperature was lowered to 0 ℃ under the protection of reaction liquid nitrogen, a borane-tetrahydrofuran solution (10.0mL, 10mmol, 1.0mol/L) was slowly added, and the reaction was refluxed at 66 ℃ for 2 hours. The temperature was reduced to 0 ℃, saturated sodium chloride solution (10 mL) was slowly added to quench, the pH was adjusted to neutral with aqueous sodium hydroxide solution (1.0 mol/L), the aqueous phase was separated and extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated ammonium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/4] to give the title compound 9e (384 mg, yield 43%) as a white solid.

Step 5-Methoxyacridine 9f

2-methoxy-9, 10-dihydroacridine 9e (384mg, 0.09mmol), cuprous iodide (34.5mg, 0.18mmol), diisopropyl azodicarboxylate (36mg, 0.18mmol) and 4-methoxypyridine (41mg, 0.38mmol) were mixed in a reaction flask, oxygen was replaced, acetonitrile (6 mL) was added, and the reaction was stirred at room temperature for 17 hours. After quenching with water (20 mL), the reaction solution was filtered through celite, the residue was washed with ethyl acetate (100 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (30 mL), the combined organic layers were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/4] to give the title compound 9f (283 mg, yield 75%) as a yellow solid.

Step 6 acridin-2-ol 9g

2-methoxyacridine 9f (400mg, 1.91mmol) is dissolved in dichloromethane (20 mL), the resulting mixture is cooled to-20 ℃ under nitrogen protection, boron tribromide (0.90mL, 9.3mmol) is then added, and the reaction mixture is then allowed to warm to room temperature and stirred for reaction for 3 hours. The reaction was quenched by pouring into ice water (20 mL), filtered with suction, the aqueous phase was extracted with methanol/dichloromethane (v/v =1/9, 60ml), the organic phase was dried over anhydrous sodium sulfate, concentrated with suction, and the residue was combined with the filter cake and dried to give the title compound 9g (250 mg, 67% yield) as a yellow solid.

Step 7N- [ (E) -2- (acridin-2-yloxymethyl) -3-fluoro-allyl]Carbamic acid tert-butyl ester 9h and N- [ (Z) -2- (acridin-2-yloxymethyl) -3-fluoro-allyl]Carbamic acid tert-butyl ester 9i

9g (250mg, 1.28mmol) of acridin-2-ol was dissolved in N, N-dimethylformamide (20 mL), potassium carbonate (360mg, 2.6 mmol) and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (420mg, 1.6 mmol) were sequentially added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (40 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sulfuric acid, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/4] to give the title compounds 9h (180 mg, yield 36%) and 9i (80 mg, yield 16%) as yellow solids.

MS(ESI,pos.ion)m/z:383.1[M+H] ⁺ 。

Step 8 (E) -2- (acridin-2-yloxymethyl) -3-fluoro-prop-2-en-1-amine hydrochloride 9

N- [ (E) -tert-butyl 2- (acridin-2-yloxymethyl) -3-fluoro-allyl ] carbamate (180mg, 0.47mmol) was dissolved in ethyl acetate (5 mL) and the resulting mixture was cooled to 0 ℃ under nitrogen, a solution of hydrogen chloride in ethyl acetate (5mL, 4 mol/L) was added slowly and the reaction was stirred at room temperature for 1 hour. Suction filtration gave the title compound 9 (124 mg, yield 83%, HPLC purity: 99.5%) as a yellow solid.

MS(ESI,pos.ion)m/z:283.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.46(s,1H),8.38-8.27(m,6H),8.06(s,1H),7.87(d,J＝8.2Hz,1H),7.83-7.76(m,2H),7.47(d,J＝81.7Hz,1H),4.88(d,J＝2.7Hz,2H),3.70(d,J＝5.2Hz,2H)。

Example 9 (Z) -2- (acridin-2-yloxymethyl) -3-fluoro-prop-2-en-1-amine hydrochloride 10

The procedure described in example 8, step 8 was repeated except for using tert-butyl N- [ (Z) -2- (acridin-2-yloxymethyl) -3-fluoro-allyl ] carbamate 9i (80mg, 0.21mmol) instead of the compound 9h to give the title compound 10 (51 mg, yield 77%, HPLC purity: 98.6%) as a yellow solid.

MS(ESI,pos.ion)m/z:283.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.66(s,1H),8.52-8.35(m,6H),8.20-8.10(m,1H),7.99(d,J＝9.1Hz,1H),7.91-7.83(m,2H),7.34(d,J＝82.0Hz,1H),5.02(s,2H),3.63(s,2H)。

Example 10 (E) -3-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxymethyl) prop-2-en-1-amine hydrochloride 11 and (Z) -3-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxymethyl) prop-2-en-1-amine hydrochloride 12

Step 1N- [ 3-fluoro-2- (1H-pyrrolo [2,3-b ]]Pyridin-5-yloxymethyl) allyl]Carbamic acid tert-butyl ester Esters 11b

N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (0.50g, 1.9mmol) was dissolved in N, N-dimethylformamide (8 mL), and potassium carbonate (0.39g, 2.8mmol) and 1H-pyrrolo [2,3-b ] pyridin-5-ol 11a (0.28g, 2.1mmol) were added to react the resulting mixture at room temperature for 22 hours. The reaction was quenched with water (5 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by column chromatography [ ethyl acetate/petroleum ether (v/v) =1/1] to give the title compound 11b (0.60 g, yield 100%) as a yellow solid.

MS(ESI,pos.ion)m/z:322.1[M+H] ⁺ 。

Step 2 (E) -3-fluoro-2- (1H-pyrrolo [2, 3-b)]Pyridin-5-yloxymethyl) prop-2-en-1-ylamine hydrochloride 11 And (Z) -3-fluoro-2- (1H-pyrrolo [2, 3-b)]Pyridin-5-yloxymethyl) prop-2-en-1-amine hydrochloride 12

Tert-butyl N- [ 3-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxymethyl) allyl ] carbamate 11b (0.55g, 1.7 mmol) was dissolved in ethyl acetate (0.5 mL), a solution of hydrogen chloride in ethyl acetate (2mL, 4 mol/L) was added, and the resulting mixture was reacted at room temperature for 15 minutes. Concentration and the resulting solid was subjected to preparative purification and treatment with a solution of hydrogen chloride in ethyl acetate to give the title compounds 11 (0.11 g, yield 25%, HPLC purity: 97.03%) and 12 (51 mg, yield 12%, HPLC purity: 94.64%) as off-white solids.

Compound 11:

MS(ESI,pos.ion)m/z:222.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)12.06(s,1H),8.47(s,3H),8.18(s,1H),7.96(s,1H),7.56(s,1H),7.31(d,J＝82.1Hz,1H),6.52(s,1H),4.77(s,2H),3.62(d,J＝4.9Hz,2H)。

compound 12:

MS(ESI,pos.ion)m/z:222.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)12.04(s,1H),8.39(s,3H),8.17(d,J＝2.0Hz,1H),7.96(d,J＝1.9Hz,1H),7.55(s,1H),7.23(d,J＝82.2Hz,1H),6.52(s,1H),4.86(s,2H),3.56(s,2H)。

example 11- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy ] -1, 2-dimethyl-indole-3-carboxylic acid ethyl ester hydrochloride 13 and 5- [ (Z) -2- (aminomethyl) -3-fluoro-allyloxy ] -1, 2-dimethyl-indole-3-carboxylic acid ethyl ester hydrochloride 14

Step 1- [ (E) -2- [ (tert-Butoxycarbonylamino) methyl]-3-fluoro-allyloxy-oxygen]-1, 2-dimethyl-indole- 3-Carboxylic acid ethyl ester 13b

N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (0.50g, 1.9mmol) was dissolved in N, N-dimethylformamide (8 mL), and cesium carbonate (0.91g, 2.8mmol) and ethyl 5-hydroxy-1, 2-dimethyl-1H-indole-3-carboxylate (0.48g, 2.1mmol) were added and reacted at 40 ℃ for 4.5 hours. The reaction solution was quenched by addition of water (5 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/1] to give the title compound 13b (0.74 g, yield 94%) as a yellow solid.

Step 2- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy-2]-1, 2-dimethyl-indole-3-carboxylic acid ethyl ester hydrochloride Salts 13 and 5- [ (Z) -2- (aminomethyl) -3-fluoro-allyloxy-3]-1, 2-dimethyl-indole-3-carboxylic acid ethyl ester hydrochloride 14

Ethyl 5- [ (E) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -1, 2-dimethyl-indole-3-carboxylate 13b (0.74g, 1.8 mmol) was dissolved in ethyl acetate (0.5 mL), a solution of hydrogen chloride in ethyl acetate (5mL, 4 mol/L) was added, and the resulting mixture was reacted at room temperature for 30 minutes. Concentration and workup of the resulting solid with preparative purification and a solution of hydrogen chloride in ethyl acetate afforded the title compounds 13 (0.26 g, yield 41%, HPLC purity: 97.18%) and 14 (54 mg, yield 8.6%, HPLC purity: 98.95%) as off-white solids.

Compound 13:

MS(ESI,pos.ion)m/z:321.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.49(s,3H),7.55(d,J＝2.2Hz,1H),7.44(d,J＝8.9Hz,1H),7.31(d,J＝82.5Hz,1H),6.92(dd,J＝8.8,2.4Hz,1H),4.67(d,J＝2.9Hz,2H),4.29(q,J＝7.1Hz,2H),3.69(s,3H),3.61(d,J＝4.5Hz,2H),2.69(s,3H),1.36(t,J＝7.1Hz,3H)。

compound 14:

MS(ESI,pos.ion)m/z:321.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.49(s,3H),7.55(d,J＝2.2Hz,1H),7.44(d,J＝8.9Hz,1H),7.31(d,J＝82.5Hz,1H),6.92(dd,J＝8.8,2.4Hz,1H),4.67(d,J＝2.9Hz,2H),4.29(q,J＝7.1Hz,2H),3.69(s,3H),3.61(d,J＝4.5Hz,2H),2.69(s,3H),1.36(t,J＝7.1Hz,3H)。

example 12 (E) -3-fluoro-2- (1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-7-yloxymethyl) prop-2-en-1-amine dihydrochloride 15

Step 1-methoxy-3, 4-dihydro-1H-pyrrolo [3,4-b ]]Indole-2-carboxylic acid tert-butyl ester 15b

1-t-butoxycarbonyl-3-pyrrolidone (10.6 g,57.2 mmol) and (4-methoxyphenyl) hydrazine hydrochloride (10g, 57.3 mmol) were dissolved in methanol (100 mL), and the resulting mixture was refluxed for 18 hours. Suction filtered and washed with methanol (40 mL) to give the title compound 15b (7.89 g, 48% yield) as a white solid.

MS(ESI,pos.ion)m/z:311.1[M+Na] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.91(d,J＝20.7Hz,1H),7.26(dd,J＝8.8,6.1Hz,1H),7.07-6.86(m,1H),6.70(d,J＝8.8Hz,1H),4.61-4.35(m,4H),3.74(d,J＝3.8Hz,3H),1.48(s,9H)。

Step 2,3, 4-Tetrahydropyrrolo [3,4-b ]]Indol-7-ol 15c

Tert-butyl 7-methoxy-3, 4-dihydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 15b (7.68g, 26.6 mmol) was dissolved in methylene chloride (100 mL), boron tribromide (7.65mL, 79.9 mmol) was added dropwise at 0 ℃ and the resulting mixture was allowed to warm to room temperature and stirred for reaction for 3 hours. The reaction mixture was quenched by pouring into ice water (40 mL), separated, and the aqueous phase was adjusted to pH7 with aqueous sodium hydroxide (2 mol/L) and directly subjected to the next reaction.

Step 3-hydroxy-3, 4-dihydro-1H-pyrrolo [3,4-b ]]Indole-2-carboxylic acid tert-butyl ester 15d

To an aqueous solution (40 mL) of 1,2,3, 4-tetrahydropyrrolo [3,4-b ] indol-7-ol 15c (4.64g, 26.6 mmol) were added tetrahydrofuran (40 mL), sodium hydroxide (3.36g, 79.8 mmol) and di-tert-butyl dicarbonate (6.46g, 29.3 mmol), and the resulting mixture was stirred at room temperature for reaction for 18 hours. Ethyl acetate (200 mL × 2) was added for extraction, the combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1] to give the title compound 15d (1.94 g, yield 27%) as a white solid.

MS(ESI,pos.ion)m/z:297.1[M+Na] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.75(d,J＝22.8Hz,1H),8.69(s,1H),7.15(dd,J＝8.6,5.3Hz,1H),6.71(d,J＝2.9Hz,1H),6.57(dd,J＝8.7,2.1Hz,1H),4.55-4.37(m,4H),1.47(d,J＝1.6Hz,9H)。

Step 4 (E) -2- [ (tert-butoxycarbonylamino) methyl group]-3-fluoro-allyloxy]-3, 4-dihydro-1H-pyrrolo [3,4-b]Indole-2-carboxylic acid tert-butyl ester 15e and (Z) -2- [ (tert-butoxycarbonylamino) methyl]-3-fluoro-allyloxy]-3, 4-dihydro-1H-pyrrolo [3,4-b ]]Indole-2-carboxylic acid tert-butyl ester 15f

Tert-butyl 7-hydroxy-3, 4-dihydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 15d (686mg, 2.5 mmol) and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (684mg, 2.5 mmol) were dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (534mg, 3.8mmol) was added, and the resulting mixture was stirred at room temperature for 24 hours. Water (15 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by preparative chromatography to give the title compounds 15e (554 mg, yield 48%) and 15f (86 mg, yield 7.5%) as white solids.

MS(ESI,pos.ion)m/z:484.1[M+Na] ⁺ 。

Step 5 (E) -3-fluoro-2- (1, 2,3, 4-tetrahydropyrrolo [3, 4-b)]Indol-7-yloxymethyl) prop-2-en-1- Amine hydrochloride 15

Tert-butyl (E) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -3, 4-dihydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 15E (583mg, 1.3mmol) was dissolved in ethyl acetate (2 mL), a solution of hydrogen chloride in ethyl acetate (2mL, 4 mol/L) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Concentration gave the title compound 15 (120 mg, yield 32%, HPLC purity: 92.7%) as a yellow solid.

MS(ESI,pos.ion)m/z:262.1[M-2Cl-H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.22(s,1H),10.35(s,2H),8.28(s,3H),7.31(dd,J＝45.6,36.7Hz,2H),7.08(d,J＝2.1Hz,1H),6.84(dd,J＝8.9,2.3Hz,1H),4.61(d,J＝3.2Hz,2H),4.45(s,2H),4.40(s,2H),3.61(d,J＝4.6Hz,2H)。

Example 13 (Z) -3-fluoro-2- (1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-7-yloxymethyl) prop-2-en-1-amine dihydrochloride 16

The procedure described in example 12, step 5 was followed using (Z) -tert-butyl 2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -3, 4-dihydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 15f (95mg, 0.21mmol) instead of compound 15e to give the title compound 16 (60 mg, yield 98%, HPLC purity: 87.80%) as a brown solid.

MS(ESI,pos.ion)m/z:262.2[M-2Cl-H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.26(s,1H),10.52(s,2H),8.35(s,3H),7.38-7.28(m,2H),7.09(s,1H),6.85(d,J＝8.4Hz,1H),4.73(s,2H),4.44(s,2H),4.39(s,2H),3.53(s,2H)。

Example 14 (E) -2- (1, 2, 3a,4,8 b-hexahydropyrrolo [3,4-b ] indol-7-yloxymethyl) -3-fluoro-prop-2-en-1-ylamine hydrochloride 17

Step 1 7-hydroxy-1, 3a,4, 8b-tetrahydro-1H-pyrrolo [3,4-b ]]Indole-2-carboxylic acid tert-butyl ester 17a

Tert-butyl 7-hydroxy-3, 4-dihydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 15d (0.94g, 3.4 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and acetic acid (8 mL), sodium cyanoborohydride (0.88g, 14mmol) was added, and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was adjusted to pH7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 17a (0.95 g, yield 100%) as a yellow solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.49(s,1H),6.53(d,J＝1.9Hz,1H),6.40(dd,J＝8.2,2.3Hz,1H),6.33(d,J＝8.2Hz,1H),5.27(s,1H),4.28(s,1H),3.71(s,1H),3.60(t,J＝9.5Hz,1H),3.45(dd,J＝11.0,6.3Hz,1H),3.30(d,J＝9.8Hz,1H),3.21(d,J＝10.4Hz,1H),1.36(s,9H)。

Step 2-hydroxy-1, 3a,8 b-tetrahydropyrrolo [3,4-b ]]Indole-2, 4-dicarboxylic acid tert-butyl ester 17b

Tert-butyl 7-hydroxy-1, 3a,4, 8b-tetrahydro-1H-pyrrolo [3,4-b ] indole-2-carboxylate 17a (0.94g, 3.4 mmol) was dissolved in tetrahydrofuran (15 mL), a solution of sodium hydroxide (0.43g, 10.2 mmol) in water (4 mL) and di-tert-butyl dicarbonate (0.82g, 3.7 mmol) were added, and the resulting mixture was stirred at room temperature for reaction for 2 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =4/1] to give the title compound 17b (0.50 g, yield 39%) as a white solid.

MS(ESI,pos.ion)m/z:399.2[M+Na] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)6.91(d,J＝1.8Hz,1H),6.72(dd,J＝8.4,2.3Hz,1H),6.43(d,J＝8.4Hz,1H),5.88(s,1H),4.39(dd,J＝8.3,6.1Hz,1H),3.80(dd,J＝8.0,3.4Hz,1H),3.61(t,J＝9.7Hz,1H),3.52-3.41(m,1H),3.27(d,J＝8.4Hz,2H),1.47(s,9H),1.36(s,9H)。

Step 3- [ (E) -2- [ (tert-butoxycarbonylamino) methyl group]-3-fluoro-allyloxy]-1,3a, 8 b-tetrahydro Pyrrolo [3,4-b]Indole 2, 4-dicarboxylic acid di-tert-butyl ester 17c and 7- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl]-3- Fluoro-allyloxy]-1,3,3a, 8b-tetrahydropyrrolo [3,4-b]Indole 2, 4-dicarboxylic acid di-tert-butyl ester 17d

Reacting 7-hydroxy-1, 3a,8 b-tetrahydropyrrolo [3,4-b ]]Indole-2, 4-dicarboxylic acid tert-butyl ester 17b (310mg, 0.82mmol) and N- [2- (bromomethyl) -3-fluoro-allyl]Tert-butyl carbamate 1b (242mg, 0.90mmol) was dissolved in acetonitrile (6 mL), potassium carbonate (229mg, 1.64mmol) was added, and the resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with a saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was subjected to silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =6/1 =]Purification gave the title compounds 17c (372 mg, 80% yield) and 17d (71 mg, 15% yield) as yellow solids. MS (ESI, pos.ion) m/z:564.4[ 2], [ M + H ]] ⁺ 。

Step 4 (E) -2- (1, 2, 3a,4,8 b-hexahydropyrrolo [3,4-b ]]Indol-7-yloxymethyl) -3-fluoro-propanone 2-en-1-amine hydrochloride 17

Di-tert-butyl 7- [ (E) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -1,3a, 8b-tetrahydropyrrolo [3,4-b ] indole 2, 4-dicarboxylate 17c (372mg, 0.66mmol) was dissolved in ethyl acetate (2 mL), a solution of hydrogen chloride in ethyl acetate (2mL, 4 mol/L) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Concentration gave the title compound 17 (190 mg, yield 96%, HPLC purity: 89.6%) as a yellow solid.

MS(ESI,pos.ion)m/z:264.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.88(s,1H),9.15(s,1H),8.47(s,3H),7.15(d,J＝82.9Hz,1H),6.64(d,J＝8.6Hz,2H),6.53(dd,J＝8.4,2.3Hz,1H),4.28-4.21(m,1H),4.04-3.97(m,2H),3.53(t,J＝12.8Hz,4H),3.34(d,J＝8.4Hz,1H),3.27-3.19(m,1H),3.13-3.05(m,1H)。

Example 15 (Z) -2- (1, 2, 3a,4,8 b-hexahydropyrrolo [3,4-b ] indol-7-yloxymethyl) -3-fluoro-prop-2-en-1-ylamine hydrochloride 18

The procedure described in example 14, step 4 was repeated except for using 7- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -1,3a, 8b-tetrahydropyrrolo [3,4-b ] indole 2, 4-dicarboxylic acid di-tert-butyl ester 17d (71mg, 0.13mmol) in place of compound 17c to give the title compound 18 (35 mg, yield 93%, HPLC purity: 87.7%) as a yellow solid.

MS(ESI,pos.ion)m/z:264.2[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.76(s,1H),9.12(s,1H),8.41(s,3H),7.28(d,J＝5.1Hz,1H),6.61(dd,J＝13.8,5.2Hz,2H),6.53(dd,J＝8.4,2.3Hz,1H),4.22(dd,J＝8.3,4.8Hz,1H),4.00(dd,J＝9.1,5.2Hz,1H),3.95-3.84(m,2H),3.45(d,J＝20.6Hz,4H),3.21(d,J＝5.1Hz,1H),3.11(s,1H)。

Example 16 (E) -3-fluoro-2- (2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-8-oxymethyl) prop-2-en-1-amine hydrochloride 19

Step 1-methoxy-1.3.4.5-tetrahydropyrido [4,3-b ]]Indole-2-carboxylic acid tert-butyl ester19b

N-tert-Butoxycarbonyl-4-piperidone (5g, 25.1mmol) and (4-methoxyphenyl) hydrazine hydrochloride (4.3g, 25mmol) were dissolved in methanol (100 mL) and the reaction was stirred at 70 ℃ for 18 hours. Cooled to room temperature and filtered with suction to give the title compound 19b (5.7 g, 75% yield) as a white solid. MS (ESI, pos.ion) m/z 303.1[ m + H ]] ⁺ 。

Step 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-8-ol 19c

Tert-butyl 8-methoxy-1.3.4.5-tetrahydropyrido [4,3-b ] indole-2-carboxylate 19b (5.7g, 19mmol) was dissolved in dichloromethane (100 mL), boron tribromide (5.4 mL, 56mmol) was added dropwise at 0 deg.C, and after stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice water (50 mL), the aqueous phase was separated, the pH was adjusted to 7 with aqueous sodium hydroxide (2 mol/L), and the reaction mixture was directly fed to the next step.

MS(ESI,pos.ion)m/z:189.4[M+H] ⁺ 。

Step 3-hydroxy-1, 3,4, 5-tetrahydropyrido [4,3-b ]]Indole-2-carboxylic acid tert-butyl ester 19d

To an aqueous solution (50 mL) of 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-8-ol 19c (3.5g, 19mmol) were added tetrahydrofuran (30 mL), sodium hydroxide (2.3g, 55mmol) and di-tert-butyl dicarbonate (4.5g, 20mmol), and the resulting mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the solvent, and the precipitated solid was cooled to 5 ℃ and stirred for 1 hour, filtered, and dried to give the title compound 19d (3.86 g, yield 72%) as an off-white solid.

MS(ESI,pos.ion)m/z:289.4[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.55(s,1H),8.59(s,1H),7.07(d,J＝8.6Hz,1H),6.66(s,1H),6.54(dd,J＝8.6,2.2Hz,1H),4.43(s,2H),3.68(t,J＝5.6Hz,2H),2.72(t,J＝5.2Hz,2H),1.44(s,9H)。

Step 4- [ (E) -2- [ (tert-butoxycarbonylamino) methyl group]-3-fluoro-allyloxy]-1,3,4, 5-tetrahydropyridine Pyrido [4,3-b ]]Indole-2-carboxylic acid tert-butyl ester 19e and 8- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl]-3-fluoro-allyl Oxy radical]-1,3,4, 5-tetrahydropyrido [4,3-b ]]Indole-2-carboxylic acid tert-butyl ester 19f

Tert-butyl 8-hydroxy-1, 3,4, 5-tetrahydropyrido [4,3-b ] indole-2-carboxylate 19d (0.7 g, 2.43mmol) and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (0.65g, 2.43mmol) were dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (0.51g, 3.65mmol) was added and the reaction was stirred at room temperature for 24 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL. Times.2), and the combined organic phases were washed with saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and preparative-purified to give the title compounds 19e (402 mg, yield 36%) and 19f (97 mg, yield 8.6%) as yellow solids.

MS(ESI,pos.ion)m/z:498.1[M+Na] ⁺ 。

Step 5 (E) -3-fluoro-2- (2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indole-8-oxymethyl) prop-2-ene- 1-amine hydrochloride 19

Tert-butyl 8- [ (E) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -1,3,4, 5-tetrahydropyrido [4,3-b ] indole-2-carboxylate 19E (402mg, 0.85mmol) was dissolved in ethyl acetate (2 mL), a solution of hydrogen chloride in ethyl acetate (4 mL,4 mol/L) was added, and the resulting mixture was stirred at room temperature for 30 minutes for reaction and concentrated to give the title compound 19 (255 mg, 96% yield, HPLC purity: 84.8%) as a brown solid.

MS(ESI,pos.ion)m/z:276.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.06(s,1H),9.51(s,1H),8.31(s,3H),7.26(dd,J＝45.5,36.8Hz,2H),7.09(d,J＝2.0Hz,1H),6.80(dd,J＝8.7,2.3Hz,1H),4.62(d,J＝3.0Hz,2H),4.24(s,2H),3.60(d,J＝4.8Hz,2H),3.44(d,J＝6.9Hz,2H),3.01(s,2H)。

Example 17 (Z) -3-fluoro-2- (2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-8-oxymethyl) prop-2-en-1-amine hydrochloride 20

The procedure described in example 16, step 5 was followed using tert-butyl 8- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -1,3,4, 5-tetrahydropyrido [4,3-b ] indole-2-carboxylate 19f (97mg, 0.20 mmol) instead of compound 19e to give the title compound 20 (60 mg, yield 94%, HPLC purity: 82.2%) as a brown solid.

MS(ESI,pos.ion)m/z:276.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.07(s,1H),9.53(s,1H),8.30(s,3H),7.32-7.23(m,2H),7.09(s,1H),6.81(dd,J＝8.7,2.2Hz,1H),4.73(s,2H),4.23(s,2H),3.53(s,2H),3.44(d,J＝4.6Hz,2H),3.01(s,2H)。

Example 18 (E) -3-fluoro-2- (pyridin [1,2-a ] benzimidazol-8-yloxymethyl) prop-2-en-1-amine hydrochloride 21

Step 1 N- (4-methoxyphenyl) pyridin-2-amine 21b

To 4-methoxyaniline (924mg, 7.5 mmol), palladium acetate (115mg, 0.50mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (311mg, 0.48mmol) and potassium tert-butoxide (1.12g, 9.5 mmol), a solution of 2-bromopyridine (790mg, 5.0 mmol) in toluene (10 mL) was added under a nitrogen atmosphere, followed by sealing, and the resulting mixture was stirred at 110 ℃ for 14 hours. The reaction solution was quenched by addition of saturated sodium chloride solution (25 mL), extracted with ethyl acetate (25 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1] to give the title compound 21b (936 mg, yield 94%) as an orange-red solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.74(s,1H),8.07(d,J＝4.7Hz,1H),7.57-7.28(m,3H),6.96-6.77(m,2H),6.77-6.59(m,2H),3.71(d,J＝1.2Hz,3H)。

Step 2 8-methoxypyridine [1,2-a ]]Benzimidazole 21c

N- (4-methoxyphenyl) pyridin-2-amine 21b (200mg, 1.0 mmol) was dissolved in hexafluoroisopropanol (5 mL), iodobenzene (11. Mu.L, 0.10 mmol) and m-chloroperoxybenzoic acid (250mg, 1.1 mmol) were added, and the reaction was stirred at 25 ℃ for 2 hours. To the reaction solution was added a saturated sodium chloride solution (25 mL), extracted with ethyl acetate (25 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =3/1] to give the title compound 21c (128 mg, yield 65%) as a red liquid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.99(d,J＝6.9Hz,1H),7.90(d,J＝2.4Hz,1H),7.70(d,J＝8.9Hz,1H),7.60(d,J＝9.3Hz,1H),7.50-7.39(m,1H),7.13(dd,J＝8.9,2.5Hz,1H),6.94(t,J＝6.7Hz,1H),3.89(s,3H)。

Step 3 pyridine [1,2-a ]]Benzimidazole-8-ol 21d

8-Methoxypyridine [1,2-a ] benzimidazole 21c (250mg, 1.3mmol) was dissolved in dichloromethane (5.0 mL), cooled to-20 ℃ and boron tribromide (400 μ L,4.1 mmol) was added slowly. After the addition was completed, the resulting mixture was transferred to 25 ℃ and stirred for 6 hours. Saturated sodium bicarbonate solution (15 mL) was added under ice-bath conditions, extracted with ethyl acetate (15 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1] to give the title compound 21d (112 mg, yield 48%).

Step 4N- [ 3-fluoro-2- (pyrido [1,2-a ]]Benzimidazol-8-yl-oxymethyl) allyl]Carbamic acid tert-butyl ester Esters 21e

Pyridine [1,2-a ] benzimidazol-8-ol 21d (112.0mg, 0.61mmol) was dissolved in N, N-dimethylformamide (3.0 mL), N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (170mg, 0.63mmol) and cesium carbonate (391mg, 1.20mmol) were added, and the resulting mixture was left to stand at 25 ℃ and stirred for reaction for 20 hours. To the reaction solution was added a saturated sodium chloride solution (15 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1] to give the title compound 21e (0.112 g, yield 50%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.97(t,J＝7.8Hz,1H),7.96(d,J＝15.8Hz,1H),7.70(d,J＝8.9Hz,1H),7.60(d,J＝9.2Hz,1H),7.49-7.42(m,1H),7.28-7.06(m,2H),6.97(dd,J＝20.3,13.7Hz,1H),4.80-4.45(m,2H),3.87-3.58(m,2H),1.34(d,J＝5.9Hz,9H)。

Step 5 (E) -3-fluoro-2- (pyridine [1,2-a ]]Benzoimidazol-8-yloxymethyl) prop-2-en-1-amine hydrochloride 21

N- [ 3-fluoro-2- (pyrido [1,2-a ] benzimidazol-8-yl-oxymethyl) allyl ] carbamic acid tert-butyl ester 21e (112mg, 0.3mmol) was dissolved in ethyl hydrogen chloride acetate solution (2mL, 4 mol/L) and reacted with stirring at room temperature for 14 hours. Concentration gave a pale yellow solid, which was isolated by preparative separation and ethyl hydrogen chloride solution in ethyl acetate to give the title compound 21 (40 mg, yield 43%, HPLC purity: 99.57%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.53(s,1H),8.39(d,J＝11.8Hz,3H),8.12-7.97(m,2H),7.89(d,J＝9.1Hz,1H),7.51(dd,J＝36.4,11.2Hz,2H),7.34(s,1H),7.21(s,0.5H),7.08(s,0.5H),4.83(s,2H),3.65(s,2H)。

Example 19 (E) -3-fluoro-2- [ [2- (4-pyridinyl) -6-quinolinyl ] oxymethyl ] prop-2-en-1-amine hydrochloride 22

Step 1 6-methoxy-2- (4-pyridyl) quinoline 22a

2-chloro-6-methoxy-quinoline (2.00g, 10.3mmol) was dissolved in acetonitrile (25 mL), 4-pyridineboronic acid pinacol ester (2.74g, 13.4 mmol), 1' -bis (diphenylphosphino) ferrocene-palladium dichloride dichloromethane complex (0.86g, 1.10mmol) and potassium carbonate (5.77g, 41.7mmol) in that order were added in water (20 mL), and the reaction mixture was heated to 80 ℃ under nitrogen protection and stirred for 7 hours. The reaction solution was suction-filtered through celite, washed with ethyl acetate (50 mL), the filtrate was adjusted to pH7 with hydrochloric acid (1 mol/L), the organic phase was washed with a saturated ammonium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, suction-filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/5] to give the title compound 22a (2.14 g, yield 88%) as a yellow solid.

Step 2- (4-pyridinyl) quinolin-6-ol 22b

6-methoxy-2- (4-pyridine) quinoline 22a (2.14g, 9.06mmol) is dissolved in dichloromethane (10 mL), the temperature is reduced to-20 ℃ under the protection of nitrogen, boron tribromide (3.5mL, 36mmol) is added dropwise, and the reaction solution is heated to room temperature and stirred for 3 hours. The reaction was quenched by pouring into ice water (40 mL), concentrated to remove the organic solvent, the residual aqueous phase was extracted with dichloromethane/methanol (v/v =9/1,40ml × 3), the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 22b (0.87 g, 43% yield) as a yellow solid.

Step 3N- [ (E) -3-fluoro-2- [ [2- (4-pyridinyl) -6-quinolinyl]Oxymethyl radical]Allyl radical]Carbamic acid tert-butyl ester Butyl ester 22c and N- [ (Z) -3-fluoro-2- [ [2- (4-pyridone)Pyridine (I)6-quinolyl-6-quinolinyl radicals]Oxymethyl radical]Allyl radical]Carbamic acid tert-butyl ester 22d

2- (4-pyridyl) quinolin-6-ol 22b (0.87g, 3.92mmol) was dissolved in N, N-dimethylformamide (20 mL), and N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (0.64g, 2.40mmol) and potassium carbonate (0.34g, 2.50mmol) were added in this order, and the resulting mixture was stirred at room temperature for 15 hours. The reaction was quenched by the addition of water (40 mL), extracted with ethyl acetate (40 mL × 3), the combined organic phases were washed successively with saturated sodium chloride solution (40 mL) and saturated ammonium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) = 1/5) ] to give the title compounds 22c (0.55 g, yield 34%) and 22d (0.25 g, yield 16%) as white solids.

MS(ESI,pos.ion)m/z:410.0[M+H] ⁺ 。

Step 4 (E) -3-fluoro-2- [ [2- (4-pyridinyl) -6-quinuclidinyl]Oxymethyl radical]Propan-2-en-1-amine hydrochloride 22

N- [ (E) -3-fluoro-2- [ [2- (4-pyridyl) -6-quinolyl ] oxymethyl ] allyl ] carbamic acid tert-butyl ester 22c (0.55g, 1.34mmol) was dissolved in ethyl acetate (15 mL), the reaction was cooled to 0 ℃, a solution of hydrogen chloride in ethyl acetate (5.0 mL,4.0 mol/L) was added dropwise, and the reaction was stirred at room temperature for 1 hour. Suction filtration gave the title compound 22 (0.23 g, yield 49%, HPLC purity: 97.78%) as a white solid.

MS(ESI,pos.ion)m/z:281.3[M-Cl] ⁺ ；

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)9.06(d,J＝6.6Hz,2H),8.81(d,J＝6.4Hz,2H),8.58(d,J＝8.7Hz,1H),8.48(d,J＝8.6Hz,1H),8.38(s,1H),8.14(d,J＝9.9Hz,3H),7.63-7.60(m,2H),7.52-7.36(m,1H),4.86(d,J＝2.4Hz,2H),3.67(s,2H)。

Example 20 (Z) -3-fluoro-2- [ [2- (4-pyridinyl) -6-quinolinyl ] oxymethyl ] prop-2-en-1-amine hydrochloride 23

The procedure described in example 19, step 4 was followed using N- [ (Z) -3-fluoro-2- [ [2- (4-pyridyl) -6-quinolyl ] oxymethyl ] allyl ] carbamic acid tert-butyl ester 22d (0.25g, 0.61mmol) in place of compound 22c to give the title compound 23 (0.11 g, yield 49%, HPLC purity: 98.54%) as a pale green solid.

MS(ESI,pos.ion)m/z:281.3[M-Cl] ⁺ ；

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)9.04(d,J＝6.6Hz,2H),8.77(d,J＝6.1Hz,2H),8.56(d,J＝8.6Hz,1H),8.46(d,J＝8.6Hz,1H),8.30(s,3H),8.16-8.11(m,1H),7.64-7.60(m,2H),7.39-7.23(m,1H),4.95(s,2H),3.62(d,J＝3.2Hz,2H)。

Example 21 (E) -3-fluoro-2- [ [2- (2-pyridyl) -6-quinolyl ] oxymethyl ] prop-2-en-1-ylamine hydrochloride 24

Step 1 6-methoxy-2- (2-pyridyl) quinoline 24a

2-chloro-6-methoxy-quinoline (1.00g, 5.16mmol) was dissolved in 1, 4-dioxane (25 mL), then 2-pyridineboronic acid (0.89g, 7.24mmol), 1' -bis (diphenylphosphine) ferrocene-palladium dichloride dichloromethane complex (0.86g, 1.0 mmol) and potassium carbonate (2.86g, 20.7 mmol) in water (20 mL) were added in sequence, and the resulting mixture was stirred at reflux for 18 hours at 80 ℃ under nitrogen protection. After cooling, suction filtration was performed on celite, the filter residue was washed with ethyl acetate (50 mL), the pH was adjusted to 7 with hydrochloric acid (1.0 mol/L), the organic phase was washed with a saturated ammonium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, suction filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =2/3] to give the title compound 24a (0.22 g, yield 18%) as a yellow solid.

Step 2- (2-pyridinyl) quinolin-6-ol 24b

6-methoxy-2- (2-pyridyl) quinoline 24a (220mg, 0.92mmol) is dissolved in dichloromethane (20 mL), the temperature is reduced to-30 ℃ under the protection of nitrogen, boron tribromide (0.65mL, 6.7 mmol) is added dropwise, and the temperature is increased to room temperature and the reaction is stirred for 5 hours. The reaction solution was quenched by pouring into ice water (30 mL), adjusting pH to 7 with saturated sodium bicarbonate solution, extracting with dichloromethane/methanol (v/v =9/1,50ml), drying the organic phase with anhydrous sodium sulfate, concentrating by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =1/1] to obtain the objective compound 24b (0.12 g, yield 59%) as a yellow solid.

MS(ESI,pos.ion)m/z:223.2[M+H] ⁺ 。

Step 3N- [ (E) -3-fluoro-2- [ [2- (2-pyridinyl) -6-quinolinyl]Oxymethyl radical]Allyl radical]Carbamic acid tert-butyl Butyl ester 24c and N- [ (Z) -3-fluoro-2- [ [2- (2-pyridinyl) -6-quinolinyl]Oxymethyl radical]Allyl radical]Carbamic acid tert-butyl ester 24d

2- (2-pyridyl) quinolin-6-ol 24b (0.15g, 0.54mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (0.10g, 0.72mmol) and N- [2- (bromomethyl) -3-fluoro-allyl ] carbamic acid tert-butyl ester 1b (0.19g, 0.71mmol) were sequentially added, and the reaction solution was stirred at room temperature for 38 hours. The reaction was quenched by the addition of water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed successively with saturated ammonium chloride (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and resolved by preparative methods to give the title compounds 24c (15 mg, 6.6% yield) and 24d (10 mg, 4.4% yield) as yellow liquids.

Step 4 (E) -3-fluoro-2- [ [2- (2-pyridinyl) -6-quinuclidinyl]Oxymethyl radical]Propan-2-en-1-amine hydrochloride 24

Coupling N- [ (E) -3-fluoro-2- [ [2- (2-pyridyl) -6-quinolinyl]Oxymethyl radical]Allyl radical]Tert-butyl carbamate 24c (15mg, 0.037mmol) was dissolved in ethyl acetate (10 mL), the reaction solution was cooled to 0 ℃ and an ethyl acetate solution of hydrogen chloride (5.0 mL,4.0 mol/L) was added dropwise, followed by stirring the reaction solution at room temperature for 30 minutes. Suction filtration gave the title compound 24 (12 mg, yield 95%, HPLC purity: 96.7%) as a yellow solid. MS (ESI, pos.ion) m/z:310.1[ 2 [ M-Cl ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.85(d,J＝4.1Hz,1H),8.72(d,J＝7.9Hz,1H),8.59(d,J＝5.4Hz,1H),8.49(s,1H),8.27(d,J＝7.6Hz,3H),8.18(d,J＝9.8Hz,1H),7.77-7.70(m,1H),7.62(s,2H),7.50-7.34(m,1H),7.22(d,J＝9.0Hz,1H),4.92(d,J＝35.2Hz,2H),3.60(s,2H)。

Example 22 (Z) -3-fluoro-2- [ [2- (2-pyridyl) -6-quinolyl ] oxymethyl ] prop-2-en-1-ylamine hydrochloride 25

The procedure described in example 21, step 4 was followed using N- [ (Z) -3-fluoro-2- [ [2- (2-pyridyl) -6-quinolyl ] oxymethyl ] allyl ] carbamic acid tert-butyl ester 24d (11mg, 0.027mmol) instead of compound 24c to give the title compound 25 (9.0 mg, yield 97%, HPLC purification: 96.8%) as a pale green solid.

MS(ESI,pos.ion)m/z:310.0[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.85(d,J＝4.1Hz,1H),8.77(d,J＝6.1Hz,1H),8.73(d,J＝7.8Hz,1H),8.59(d,J＝9.9Hz,4H),8.29(t,J＝7.4Hz,1H),8.19(d,J＝9.0Hz,1H),7.75(s,1H),7.54(d,J＝60Hz,1H),7.53(s,1H),7.28(s,1H),4.89(s,2H),3.65(s,2H)。

Example 23- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy ] -3H-quinazolin-4-one hydrochloride 26

Step 1N- [ 3-fluoro-2- [ (4-oxo-3H-quinazolin-6-yl) oxymethyl group]Allyl radical]Carbamic acid tert-butyl ester 26b

6-hydroxy-3H-quinazolin-4-one (400mg, 2.47mmol) was dissolved in dimethyl sulfoxide (20 mL), potassium carbonate (465mg, 3.33mmol), tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate (400mg, 1.49mmol) were added, and the resulting mixture was stirred at room temperature for 25 hours. The reaction was quenched by the addition of water (40 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed successively with saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) =2/3] to give the title compound 26b (330 mg, yield 38%) as a white solid.

Step 2- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy]-3H-quinazolin-4-one hydrochloride 26

Tert-butyl N- [ 3-fluoro-2- [ (4-oxo-3H-quinazolin-6-yl) oxymethyl ] allyl ] carbamate 26b (260mg, 0.74mmol) was dissolved in ethyl acetate (10 mL), the temperature was reduced to 0 ℃ under nitrogen protection, a solution of hydrogen chloride in ethyl acetate (5.0 mL,4 mol/L) was added dropwise, the resulting mixture was stirred at room temperature for 8 hours to react, a white solid precipitated, filtered with suction, and treated by preparative resolution and a solution of hydrogen chloride in ethyl acetate to give the title compound 26 (23 mg, yield 10%, HPLC purity: 86.12%) as a white solid.

MS(ESI,pos.ion)m/z:274.1[M-Cl] ⁺ ；

1H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.48(s,1H),8.28(s,3H),7.60(d,J＝8.8Hz,1H),7.48(d,J＝2.8Hz,1H),7.33(dd,J＝8.8,2.8Hz,1H),7.41-7.19(m,1H),4.72(s,2H),3.50(d,J＝6.0Hz,2H)。

Example 24- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy ] pyrido [2,1-b ] quinazolin-11-one hydrochloride 27 and 2- [ (Z) -2- (aminomethyl) -3-fluoro-allyloxy ] pyrido [2,1-b ] quinazolin-11-one hydrochloride 28

Step 1N- (4-methoxyphenyl) pyridin-2-amine 27b

To 4-methoxyaniline (924mg, 7.5 mmol), palladium acetate (115mg, 0.50mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (311mg, 0.48mmol) and potassium tert-butoxide (1.12g, 9.5 mmol), a solution of 2-bromopyridine (790mg, 5.0 mmol) in toluene (10 mL) was added under nitrogen, the mixture was sealed, and the mixture was stirred at 110 ℃ for 14 hours. Saturated sodium chloride solution (25 mL) was added, extraction was performed with ethyl acetate (25 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1] to give the title compound 27b (936 mg, yield 94%) as an orange-red solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.74(s,1H),8.07(d,J＝4.7Hz,1H),7.57-7.28(m,3H),6.96-6.77(m,2H),6.77-6.59(m,2H),3.71(d,J＝1.2Hz,3H)。

Step 2-Methoxypyrido [2,1-b ]]Quinazolin-11-one 27c

N- (4-methoxyphenyl) pyridin-2-amine 27b (100mg, 0.5mmol), palladium acetate (6 mg, 0.026mmol) and potassium persulfate (405mg, 1.5mmol) were dissolved in trifluoroacetic acid (2.5 mL), the atmosphere of carbon monoxide was replaced, sealing was performed, and the resulting mixture was allowed to react at 70 ℃ for 6 hours. To the reaction solution was added saturated sodium carbonate solution (50 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1] to give the title compound 27c (44 mg, yield 39%) as a yellow solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.81(d,J＝7.3Hz,1H),7.74(d,J＝9.0Hz,1H),7.68(dd,J＝15.3,5.4Hz,2H),7.58(dd,J＝9.0,2.9Hz,1H),7.52(d,J＝9.2Hz,1H),7.08(t,J＝6.7Hz,1H),3.92(s,3H)。

Step 3-Hydroxypyrido [2,1-b ]]Quinazolin-11-one 27d

2-Methoxypyrido [2,1-b ] quinazolin-11-one 27c (160mg, 0.7 mmol) was dissolved in dichloromethane (5.0 mL) and cooled to-20 deg.C, to which boron tribromide (205 μ L,2.1 mmol) was added, and then the resulting mixture was stirred at 25 deg.C for 4 hours. After cooling to 0 ℃, saturated sodium bicarbonate solution (2.5 mL) was added dropwise, extraction was performed with dichloromethane (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =3/1] to give the title compound 27d (45 mg, yield 30%) as a yellow solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.13(s,1H),8.73(d,J＝7.2Hz,1H),7.67(d,J＝8.9Hz,1H),7.59(t,J＝6.3Hz,2H),7.48-7.40(m,2H),6.99(t,J＝6.8Hz,1H)。

Step 4N- [ 3-fluoro-2- [ (11-oxopyrido [2,1-b ]]Quinazolin-2-yl) oxymethyl]Allyl radical]Carbamic acid salts of benzoic acid Tert-butyl ester 27e

2-Hydroxypyrido [2,1-b ] quinazolin-11-one 27d (45.0mg, 0.20mmol), and tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate 1b (40mg, 0.15mmol) were dissolved in N, N-dimethylformamide (3.0 mL), and cesium carbonate (79mg, 0.24mmol) was added to stir the reaction at 25 ℃ for 20 hours. To the reaction solution was added a saturated sodium chloride solution (20 mL), extracted with ethyl acetate (15 mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1] to give the title compound 27e (54 mg, yield 66%) as a yellow solid.

Step 5- [ (E) -2- (aminomethyl) -3-fluoro-allyloxy]Pyrido [2,1-b ]]Quinazolin-11-one hydrochloride 27 and 2- [ (Z) -2- (aminomethyl) -3-fluoro-allyloxy]Pyrido [2,1-b ]]Quinazolin-11-one hydrochloride 28

Tert-butyl N- [ 3-fluoro-2- [ (11-oxopyrido [2,1-b ] quinazolin-2-yl) oxymethyl ] allyl ] carbamate 27e (59mg, 0.15mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (2mL, 4 mol/L), and the resulting mixture was reacted with stirring at room temperature for 1 hour. Concentration and the resulting yellow solid was subjected to preparative resolution and treatment with a solution of hydrogen chloride in ethyl acetate to give the title compounds 27 (20 mg, yield 40%, HPLC purity: 99.62%) and 28 (12 mg, yield 24%, HPLC purity: 86.37%) as yellow solids.

MS(ESI,pos.ion)m/z:300.1[M-Cl] ⁺ ；

Compound 27:

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.90(d,J＝6.9Hz,1H),8.19(s,3H),7.90(s,1H),7.84(d,J＝9.0Hz,1H),7.77(d,J＝2.7Hz,1H),7.73-7.66(m,1H),7.29(d,J＝10.7Hz,1H),7.23(s,1H),7.12(d,J＝52Hz,1H),4.81(s,2H),3.67(d,J＝5.0Hz,2H)；

compound 28:

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.95(d,J＝7.3Hz,1H),8.28(s,3H),7.89(d,J＝9.0Hz,1H),7.80(d,J＝2.6Hz,1H),7.74(dd,J＝9.1,2.7Hz,1H),7.37(s,1H),7.28(d,J＝80Hz,1H),7.24(s,1H),7.11(s,1H),4.94(s,2H),3.56(s,2H)。

example 25 (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl ] oxymethyl ] prop-2-en-1-amine hydrochloride 29

Step 1N- [ (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl]Oxymethyl radical]Allyl alcohol Base (C)]Carbamic acid tert-butyl ester 29a and N- [ (Z) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinoline-6-Base (C)]Oxygen nail Base of]Allyl radical]Carbamic acid tert-butyl ester 29b

Tert-butyl N- [ 3-fluoro-2- [ [2- (4-fluorophenyl) -6-quinolinyl ] oxymethyl ] allyl ] carbamate 3d (600mg, 1.41mmol) was dissolved in tetrahydrofuran (20 mL), sodium cyanoborohydride (451mg, 7.03mmol) and acetic acid (10 mL) were added, and the reaction was stirred at room temperature for 24 hours. Saturated sodium bicarbonate solution was added to adjust pH to 7, extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (70 mL × 2), dried over anhydrous sodium sulfate, concentrated with suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1] to give the title compounds 29a (145 mg, yield 24%) and 29b (114 mg, yield 19%) as pale yellow oils.

MS(ESI,pos.ion)m/z:431.1[M+H] ⁺ 。

Step 2 (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl]Oxymethyl radical]Prop-2-ene- 1-amine hydrochloride 29

Tert-butyl N- [ (E) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl ] oxymethyl ] allyl ] carbamate 29a (114mg, 0.26mmol) was dissolved in ethyl acetate (1 mL), a solution of hydrogen chloride in methanol (2mL, 20% wt) was added, and the reaction was stirred at room temperature for 30 minutes. Concentration gave the title compound 29 (97 mg, yield 99%, HPLC: 96.80%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:331.3[M-Cl] ⁺ ；

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)8.44(s,3H),7.71(s,2H),7.28(dt,J＝51.9,40.4Hz,4H),6.94(s,2H),4.67(s,2H),4.58(d,J＝10.4Hz,1H),3.58(d,J＝5.3Hz,2H),3.01(d,J＝6.4Hz,1H),2.87(d,J＝15.3Hz,1H),2.29(s,1H),2.15(d,J＝10.4Hz,1H)。

Example 26 (Z) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl ] oxymethyl ] prop-2-en-1-ylamine hydrochloride 30

The procedure described in example 25 step 2 was followed with tert-butyl N- [ (Z) -3-fluoro-2- [ [2- (4-fluorophenyl) -1,2,3, 4-tetrahydroquinolin-6-yl ] oxymethyl ] allyl ] carbamate 29b (145mg, 0.34mmol) in place of compound 29a to give the title compound 30 (123 mg, yield 99%, HPLC purity: 97.97%) as a white solid.

MS(ESI,pos.ion)m/z:331.3[M-Cl] ⁺ ；

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)8.40(s,3H),7.69(s,2H),7.25(dd,J＝44.6,36.1Hz,4H),6.93(s,2H),4.76(s,2H),4.58(d,J＝9.3Hz,1H),3.51(s,2H),3.00(s,1H),2.87(s,1H),2.27(s,1H),2.15(s,1H)。

Example 27 (E) -3-fluoro-2- [ (2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] prop-2-en-1-amine hydrochloride 31

Step 1 6-methoxy-2-methyl-1, 2,3, 4-tetrahydroquinoline 31b

6-methoxy-2-methylquinoline (100mg, 0.57mmol) was dissolved in a mixed solvent of acetic acid (2 mL) and tetrahydrofuran (2 mL), and sodium cyanoborohydride (152mg, 2.29mmol) was added, and the reaction was stirred at room temperature for 18 hours, then warmed to 50 ℃ and stirred for 6 hours. After cooling to room temperature, the pH was adjusted to 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =6/1] to give the title compound 31b (70 mg, yield 68%) as a yellow oil.

MS(ESI,pos.ion)m/z:178.2[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)6.66-6.59(m,2H),6.48(d,J＝8.3Hz,1H),3.76(s,3H),3.41-3.31(m,1H),3.26(s,1H),2.88(ddd,J＝17.3,11.6,5.9Hz,1H),2.74(ddd,J＝16.6,5.2,3.3Hz,1H),1.94(ddt,J＝11.9,5.8,2.9Hz,1H),1.67-1.54(m,1H),1.23(d,J＝6.3Hz,3H)。

Step 2-methyl-1, 2,3, 4-tetrahydroquinolin-6-ol 31c

6-methoxy-2-methyl-1, 2,3, 4-tetrahydroquinoline 31b (1.7g, 9.6 mmol) was dissolved in dichloromethane (20 mL), boron tribromide (3.8mL, 39mmol) was added dropwise at 0 deg.C, stirring was continued for 1 hour, quenched by pouring into ice water (40 mL), the pH was adjusted to 7 with saturated sodium bicarbonate solution, extraction was performed with ethyl acetate (60 mL. Times.3), the combined organic phases were washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 31c (1.6 g, yield 100%) as a yellow oil.

MS(ESI,pos.ion)m/z:164.1[M+H] ⁺ 。

Step 3 tert-butyl 6-hydroxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylate 31d

2-methyl-1, 2,3, 4-tetrahydroquinolin-6-ol 31c (184mg, 1.13mmol) was dissolved in tetrahydrofuran (6 mL), and an aqueous solution (1 mL) of sodium hydroxide (138mg, 3.38mmol) and di-tert-butyl dicarbonate (0.52mL, 2.2mmol) were added, and the reaction was stirred at room temperature for 18 hours. The reaction was quenched by the addition of water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =9/1] to give the title compound 31d (200 mg, yield 67%) as a white solid.

MS(ESI,pos.ion)m/z:264.3[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)6.63(d,J＝6.3Hz,2H),6.48-6.34(m,1H),5.59(s,1H),3.28(s,2H),2.78-2.55(m,2H),1.87-1.74(m,1H),1.46(s,9H),1.13(d,J＝6.2Hz,3H)。

Step 4- [ (E) -2- [ (tert-butoxycarbonylamino) methyl group]-3-fluoro-allyloxy]-2-methyl-3, 4-dihydro- 2H-quinoline-1-carboxylic acid tert-butyl ester 31e and 6- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl]-3-fluoro-allyloxy]-2-A 3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester 31f

Tert-butyl 6-hydroxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylate 31d (500mg, 1.9mmol), tert-butyl N- [2- (bromomethyl) -3-fluoro-allyl ] carbamate (60mg, 2.09mmol) were dissolved in N, N-dimethylformamide (10 mL), cesium carbonate (1.26g, 3.79mmol) was added, and the reaction was stirred at 50 ℃ for 48 hours. Cooled to room temperature, quenched by addition of water (20 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phases washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue subjected to silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =9/1] to give the title compounds 31e (98 mg, yield 11%) and 31f (35 mg, yield 3.9%) as yellow oils.

MS(ESI,pos.ion)m/z:451.2[M+H] ⁺ 。

Step 5 (E) -3-fluoro-2- [ (2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl]Propan-2-en-1-amine salts Acid salt 31g

Tert-butyl 6- [ (E) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylate 31H (98mg, 0.22mmol) was dissolved in ethyl acetate (1 mL), and a solution of hydrogen chloride in ethyl acetate (2mL, 4 mol/L) was added and the reaction was stirred at room temperature for 1 hour. Concentration gave the title compound 31 (62 mg, yield 99%, HPLC purity: 98.42%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:251.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.42(s,4H),7.13(d,1H),6.61(s,3H),3.65(s,2H),3.51(s,2H),2.73(d,J＝29.0Hz,3H),1.75(s,1H),1.24-1.16(m,4H)。

Example 28 (Z) -3-fluoro-2- [ (2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) oxymethyl ] prop-2-en-1-amine hydrochloride 32

The procedure described in example 27, step 5 was repeated except for using 6- [ (Z) -2- [ (tert-butoxycarbonylamino) methyl ] -3-fluoro-allyloxy ] -2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester 31f (35mg, 0.078mmol) instead of the compound 31a to give the title compound 32 (22 mg, yield 98%, HPLC purity: 93.65%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:251.1[M-Cl] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.30(s,4H),7.30-7.12(m,1H),6.55(s,3H),4.12(s,2H),3.98(s,2H),2.72(dd,J＝18.8,5.7Hz,3H),1.74(s,1H),1.38(t,J＝24.2Hz,1H),1.16(d,J＝17.3Hz,3H)。

Activity test example I assay of human recombinant SSAO/VAP-1 inhibitory Activity

The test purpose is as follows: the following method was used to determine the inhibitory activity of the compounds of the present invention against human recombinant SSAO/VAP-1.

Test materials:

human recombinant SSAO/VAP-1 (VAP-1, human) was purchased from Sigma, cat. No. SRP6241;

red Monoamine oxide Assay Kit available from Invitrogen, cat. No. A12214;

384 well plates from Corning, cat.no.6005174;

red Hydrogen Peroxeperoxidase Assay Kit was purchased from Invitrogen, cat. No. A22188.

Benzylamine hydrochloride (Benzylamine hydrochloride) was purchased from Sigma, cat.no. b5136-25G;

DMSO (Dimethyl Sulfoxide) was purchased from Sigma, cat. No. D2650-100ML;

the test method comprises the following steps:

test compounds were dissolved in DMSO and diluted 4-fold for a total of 10 concentrations. In 384-well plates, 25. Mu.L of human recombinant SSAO/VAP-1 (1.6. Mu.g/mL) was added to each well. 100nL of different concentrations of test compound were added to each well containing human recombinant SSAO/VAP-1 and incubated at room temperature for 30min. After 30min incubation, 25. Mu.L of the suspension was added

Red Monoamine Oxidase Assay Kit (reaction mixture containing 200. Mu.M Amplex Red reagent,1U/mL HRP and 1mM benzylamine hydrochloride) was added to the corresponding wells and incubated for 60min at room temperature in the dark. After 60min, fluorescence values (RFU) were read using an Envision of Perkinelmer at excitation 530-560nm and emission 590 nm. The IC was calculated using Graph Pad Prism 5 software to plot curves ₅₀ The value is obtained. The results are shown in table 1, and the compound corresponding to the compound number in table 1 is a compound of the same compound number in the preparation example:

table 1: the compounds provided in the examples of the present invention have inhibitory activity against human recombinant SSAO/VAP-1

Compound number	SSAO/VAP-1 (human recombinant protein) IC 50 /nM
		1	2.437
2	0.675
		7	0.45
8	0.81
		9	1.43
22	0.49
		23	0.37

The test results show that: the compound has obvious inhibition effect on human recombinant SSAO/VAP-1.

2. Assay for SSAO/VAP-1 inhibitory Activity in rat adipose tissue homogenate

The test purpose is as follows: the following method was used to determine the inhibitory activity of the compounds of the present invention on SSAO/VAP-1 in rat fat homogenates.

Test materials:

N-piperazine-N-ethanesulfonic acid SODIUM SALT (HEPES SODIUM SALT) available from AMRESCO, cat. No.0485-500G;

EDTA (Ethylenediaminetetraacetic acid ) was purchased from Sigma, cat. No. eds-100G;

sucrose (Sucrose) was purchased from Sigma, cat.no. v900116;

PMSF (Phenylmethanesulfonyl fluoride) purchased from Beyotime, cat.no. st506;

beta-Glycerophosphate disodium salt hydrate (beta-glycophosphophosphate dihydrate) purchased from Sigma, cat.no. G5422-25G;

eugenine hydrochloride (Pargyline hydrochloride) was purchased from Sigma, cat. No. P8013-500MG;

DMSO (Dimethyl Sulfoxide) was purchased from Sigma, cat. No. D2650-100ML;

benzylamine hydrochloride (Benzylamine hydrochloride) was purchased from Sigma, cat.no. b5136-25G;

96-well plates were purchased from COSTAR, cat.No.3631;

red Hydrogen Peroxeperoxidase Assay Kit was purchased from Invitrogen, cat. No. A22188.

The test method comprises the following steps:

abdominal fat from Sprague Dawley rats, a SSAO/VAP-1 rich tissue, was surgically excised. For each gram of rat abdominal adipose tissue, 5ml HES buffer (20 mM N-piperazine-N-ethanesulfonic acid) was addedSodium salt, 1mM EDTA,250mM sucrose, 1 XPSF and 100mM beta-glycerophosphate disodium salt hydrate, pH 7.4). Adipose tissue was homogenized using a Bertin Precellys 24 multifunctional sample homogenizer from Bertin Technologies for 3min, the adipose tissue homogenate was centrifuged at 4 ℃ at 20000g for 10min, and the intermediate clear supernatant was taken. The supernatant was incubated with 0.5mM of perhexiline hydrochloride in HES buffer for 30min at 37 ℃. After 30min incubation, 25 μ Ι _ of adipose tissue supernatant was added to a standard 96-well plate. Test compounds were dissolved in DMSO and diluted 6 concentrations. 25 μ L of test compound at various concentrations were added to each well containing the adipose tissue supernatant and incubated at 37 ℃ for 30min. After incubation, 50. Mu.L of the reaction mixture containing 80. Mu.M benzylamine hydrochloride (containing 100. Mu.M)

Red and 0.2U/mL HRP,/>

Red Hydrogen peroxiredoxin Assay Kit) was added to the respective wells and incubated at 37 ℃ for 30min. After 30min, fluorescence values (RFU) were read at excitation 540nm and emission 580nm using a PHERAStar FSX microplate reader from BMG LABTECH. The IC was calculated using Graph Pad Prism 5 software to plot curves ₅₀ The value is obtained. The results are shown in table 2, and the compound numbers in table 2 correspond to the compound numbers in the preparation examples:

table 2: the compounds provided in the examples of the present invention have inhibitory activity against SSAO/VAP-1 in adipose tissue homogenates

Compound numbering	SSAO/VAP-1 (adipose homogenate) IC 50 /nM
		1	9.332
2	6.726
		7	6.226
8	6.729
		22	9.234
23	7.117

The test results show that: the compound has obvious inhibition effect on the SSAO/VAP-1 of the adipose tissue homogenate.

3. Pharmacokinetic determination of Compounds of the invention

Measurement purpose the following method was used to determine the pharmacokinetics of the compounds of the present invention.

Test materials:

the used experimental reagents and test articles are as follows: propranolol (internal standard), methanol, ammonium acetate, K ₂ EDTA (potassium ethylene diamine tetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), kolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;

SD rat: male, 180-220g,7-8 weeks old, purchased from Schleik laboratory animals, inc., hunan.

The test method comprises the following steps:

1. preparation of test article

The test solution is prepared as 5% DMSO +5% by weight of KolliphorHS15+90% physiological saline, adjusted specifically to the dissolution profile of each compound, so that the compound is completely dissolved.

2. Design of animal experiment

3. Animal administration dose meter

Group of	Sex	Number of animals	Administration dosage	Concentration of drug administration	Volume of administration
						I.v. was injected intravenously.	Male sex	3	1mg/kg	1mg/mL	1mL/kg
P.o was administered orally.	Male sex	3	5mg/kg	1mg/mL	5mL/kg

4. Solution preparation

(1) Preparing a stock solution of a test sample: accurately weighing a proper amount of test sample, dissolving the test sample in DMSO, diluting the test sample to 1mg/mL by using acetonitrile, and shaking up to obtain the test sample. Storing at-20 deg.C for use.

(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL of the stock solution of Propranol was precisely aspirated, and the solution was diluted to 100ng/mL with water.

5. Sample analysis

Processing a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis on the sample by a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode, and calculating the concentration of the result by using instrument quantitative software.

6. Plasma sample pretreatment

Accurately sucking 30 μ L of plasma sample, adding 250 μ L of internal standard, and mixing by vortex. Extracting with 1mL MTBE once, centrifuging at 13000rpm for 2min at 4 deg.C, sucking supernatant 800. Mu.L, volatilizing in a 96-well nitrogen blower, re-dissolving the residue with 150. Mu.L methanol/water =50/50, vortex mixing, and injecting sample with 8. Mu.L.

7. Preparation of Standard samples

Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with the plasma concentrations of 3,5, 10, 30, 100, 300, 1000, 3000, 5000 and 10000ng/mL, performing double-sample analysis on each concentration according to the operation of plasma sample pretreatment, and establishing a standard curve.

8. Analytical method

The LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.

9. Data processing

Pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.

The test result shows that the compound of the invention has excellent pharmacokinetics.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. A compound which is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of a compound of formula (II),

wherein, the first and the second end of the pipe are connected with each other,

x is-CH =;

R ⁵ is H, D, F, cl, br, I, C _1-6 Alkyl, phenyl or pyridyl, wherein said C _1-6 Alkyl, phenyl and pyridyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br or I；

R ⁶ Is H or D;

or R ⁵ 、R ⁶ And together with the carbon atom to which they are each attached form cyclohexyl or phenyl; wherein the cyclohexyl or phenyl is each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br or I;

R ¹ is H or D;

R ² is F;

R ³ and R ⁴ Each independently is H or D.

2. The compound of claim 1, wherein R ⁵ Is H, D, F, cl, br, I, C _1-4 Alkyl, phenyl or pyridyl, wherein said C _1-4 Alkyl, phenyl and pyridyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br or I.

3. The compound of claim 1, wherein R ⁵ Is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, phenyl, or pyridinyl, wherein the methyl, ethyl, n-propyl, isopropyl, phenyl, and pyridinyl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, or I.

4. A compound having the structure of one of:

/>

or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide or mesylate salt.

6. A pharmaceutical composition comprising a compound of any one of claims 1-5, further comprising a pharmaceutically acceptable carrier, excipient, or combination thereof.

7. Use of a compound according to any one of claims 1-5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for inhibiting SSAO/VAP-1; or for the prevention, treatment or alleviation of diseases associated with or modulated by SSAO/VAP-1 protein.

8. Use according to claim 7, wherein the disease associated with or modulated by SSAO/VAP-1 protein is an inflammatory and/or inflammation-related disease, diabetes and/or diabetes-related disease, a psychiatric disorder, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection.

9. The use according to claim 8, wherein the inflammatory disease and/or inflammation-related disease is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease; the diabetes and/or diabetes-related diseases are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema; the psychiatric disorder is major depression, bipolar depression or attention deficit hyperactivity disorder; the ischemic disease is stroke and/or complications thereof, myocardial infarction and/or complications thereof, or destruction of tissue by inflammatory cells after stroke; the fibrosis is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity-induced fibrosis; the vascular disease is atherosclerosis, chronic heart failure or congestive heart failure.

10. The use according to claim 9, wherein the arthritis is osteoarthritis, rheumatoid arthritis or juvenile rheumatoid arthritis; systemic inflammatory syndrome is systemic inflammatory sepsis; inflammatory bowel disease is irritable bowel disease; 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; the respiratory disease is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis or bronchiectasis; the eye disease is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation caused by angiogenesis and/or lymphangiogenesis, or macular degeneration; the skin diseases are contact dermatitis, skin inflammation, psoriasis or eczema; the neuroinflammatory disease is Parkinson disease, alzheimer disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis;

wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related negative cirrhosis or primary liver cancer.