Triazolone, tetrazolon, and imidazolon, or salts thereof, and pharmaceutical compositions containing them.

Abstract

The present technology provides triazolones, tetrazolones, and imidazolones, or their pharmaceutically acceptable salts, their preparation process, pharmaceutical compositions containing them, and their use.Triazolones, tetrazolones, and imidazolones, or their pharmaceutically acceptable salts, exhibit inhibitory activity against VAP-1, and therefore can be usefully applied to, for example, the treatment and prevention of non-alcoholic steatohepatitis (NASH).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to Korean Patent Application No. 10-2021-0052441, filed on 22 April 2021, the entirety of which is incorporated herein by reference.

[0002] (Field of Invention) This technology relates to triazolone, tetrazolon, and imidazolone, or pharmaceutically acceptable salts thereof, which have inhibitory activity against vascular adhesion protein (VAP-1), a process for preparing them, pharmaceutical compositions containing them, and their use. [Background technology]

[0003] Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO) that is abundant in human plasma. VAP-1 is an ectoenzyme containing a short cytoplasmic end, a single transmembrane domain, and a large extracellular domain with high glycosylation containing the active site. In addition to existing as a membrane-bound form in the endothelium, VAP-1 also exists as a soluble form in serum (soluble VAP-1, sVAP-1). This form has been shown to be a cleavage product from membrane-bound VAP-1 and appears to have similar characteristics to the tissue-bound form. Furthermore, while VAP-1 is normally stored in intracellular granules within endothelial cells, it has been reported that when an inflammatory response is induced in response to inflammatory stimuli, it migrates to the cell membrane, its expression is upregulated, and therefore it is expressed more strongly in inflamed tissue than in normal tissue.

[0004] The substrates of VAP-1 include endogenous methylamine and aminoacetone, as well as several xenobiotic amines such as tyramine and benzylamine.

[0005] VAP-1 has two physiological functions: firstly, amine oxidase activity as described earlier in this section, and secondly, cell adhesion activity. Due to these two activities, VAP-1 acts as a leukocyte adhesion protein at the site of inflammation, and has been shown to play an important role in the leakage of inflammatory cells [Trends Immunol. (2001) 22:211]. VAP-1-deficient transgenic mice are healthy, develop normally, are fertile, and have a normal phenotype, but show a marked reduction in inflammatory responses induced by various inflammatory stimuli [Immunity. (2005) 22:105].

[0006] In addition, the inhibitory activity of VAP-1 by antibodies or small molecules in several animal models of human diseases (e.g., carrageenan-induced peditis, oxazolone-induced colitis, lipopolysaccharide-induced pneumonia, collagen-induced arthritis, endotoxin-induced uveitis) has been shown to prevent leukocyte rolling, adhesion, and leakage, reduce levels of inflammatory cytokines and chemokines, and thereby reduce disease severity [Eur J Immunol.(2005)35:3119, J Pharmacol Exp Ther.(2005)315:553, Annu Rep Med Chem.(2007)42:229, FASEB J.(2008)22:1094]. Inflammation is the first response of the immune system to infection or irritation, and in such a process, the migration of leukocytes into tissues through circulation is a crucial step. Leukocytes first bind to adhesion proteins, then adhere to the endothelium, and then begin to pass through the blood vessel wall. VAP-1 is highly expressed in endothelial venules (HEVs), such as high endothelial venules in lymphoid organs, as well as in hepatic sinusoidal endothelial cells (HSECs), smooth muscle cells, and adipocytes. VAP-1 expression on the cell surface of endothelial cells is tightly regulated and increases during inflammation. VAP-1 activates NF-κB when present in the substrate, and NF-κB is activated within HSECs, while other adhesion molecules, E-selectin and the chemokine IL-8, are upregulated ex vivo. This suggests that VAP-1 may be an important factor in regulating the inflammatory response, and therefore, VAP-1 inhibitors appear likely to be effective anti-inflammatory agents in a wide range of human diseases.

[0007] Non-alcoholic fatty liver disease (NAFLD) histologically includes simple steatosis, non-alcoholic steatohepatitis (NASH), and cirrhosis. Among these, NASH differs from simple steatosis (non-alcoholic fatty liver, NAFL) in that it can progress to cirrhosis and hepatocellular carcinoma. In NASH, insulin resistance, along with oxidative stress, inflammatory cascades, and fibrosis, is known to play a significant role in disease progression. Elevated sVAP-1 levels have been found in NAFLD patients, and carbon tetrachloride-induced hepatic fibrosis was reduced in VAP-1 knockout (K / O) mice compared to wild-type animals. Furthermore, improvement in hepatic fibrosis by VAP-1 inhibition after administration of VAP-1 antibodies was identified by histological changes [J Clin Invest (2015) 125:501]. Therefore, VAP-1 has been found to be associated with NASH in clinical trials and animal disease models. The inhibitory activity of VAP-1 in carbon tetrachloride-induced animal models is thought to be due to a decrease in the infiltration of leukocytes such as T cells, B cells, NKT cells, and NK cells observed in hepatic fibrosis, suggesting that VAP-1 inhibitors may have the potential to treat fibrotic diseases. Therefore, substances that inhibit VAP-1 can be applied to the prevention and treatment of various inflammatory and fibrotic diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Trends Immunol. (2001) 22:211 [Non-Patent Document 2] Immunity. (2005) 22:105 [Non-Patent Document 3] Eur J Immunol.(2005)35:3119 [Non-Patent Document 4] J Pharmacol Exp Ther.(2005)315:553 [Non-Patent Document 5] Annu Rep Med Chem.(2007)42:229 [Non-Patent Document 6] FASEB J. (2008) 22:1094 [Non-Patent Document 7] J Clin Invest (2015) 125:501 [Overview of the project]

[0009] The triazolone, tetrazolon, and imidazolon, or pharmaceutically acceptable salts thereof, having a 3-fluoroallylamine group or a 3,3-difluoroallylamine group, as described herein, exhibit inhibitory activity against VAP-1. Therefore, triazolone, tetrazolon, and imidazolon, or pharmaceutically acceptable salts thereof, can be usefully used in the treatment and prevention of various VAP-1-mediated diseases, such as non-alcoholic steatohepatitis (NASH).

[0010] Therefore, this technology provides triazolone, tetrazolon, and imidazolon, or pharmaceutically acceptable salts thereof, a process for preparing them, pharmaceutical compositions containing them, and their uses.

[0011] According to one aspect of this technology, a triazolone, tetrazolon, or imidazolon, or a pharmaceutically acceptable salt thereof, is provided.

[0012] According to one aspect of this technology, a process for preparing triazolone, tetrazolon, or imidazolon, or a pharmaceutically acceptable salt thereof, is provided.

[0013] According to another aspect of this technology, a pharmaceutical composition is provided comprising triazolone, tetrazolon, or imidazolon, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0014] Another aspect of the present technology provides a therapeutic method comprising administering triazolone, tetrazolon, or imidazolon, or a pharmaceutically acceptable salt thereof.

[0015] According to another aspect of the present technology, there is provided the use of a triazolone, tetrazolone, or imidazolone, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of vascular adhesion protein-1.

[0016] According to the present technology, it has been found that triazolones, tetrazolones, and imidazolones having a 3-fluoroallylamine group or a 3,3-difluoroallylamine group, or pharmaceutically acceptable salts thereof, exhibit inhibitory activity against VAP-1. Therefore, the compounds according to the present technology or pharmaceutically acceptable salts thereof can be usefully applied to the treatment and prevention of various VAP-1-mediated diseases, such as non-alcoholic steatohepatitis (NASH).

[0017] Provided herein is a compound of formula 1,

Chemical formula

[0018] In another embodiment, the compounds provided herein are those listed in Table 1. In yet another embodiment, the compounds provided herein are those listed in Table 1, or pharmaceutically acceptable salts thereof.

[0019] In another embodiment, provided herein are pharmaceutical compositions comprising, or consisting thereof, a compound disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0020] In another embodiment, the foregoing provides a method for inhibiting vascular adhesion protein (VAP-1), comprising, or consisting thereof, administering a therapeutically effective amount of the compounds disclosed herein or a pharmaceutically acceptable salt thereof to a mammal.

[0021] In another embodiment, provided herein are methods for treating a subject requiring treatment of NASH, comprising, or consisting thereof, administering to the subject a therapeutically effective amount of a compound disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0022] In another embodiment, what is provided herein is the use of the compounds disclosed herein, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for the manufacture of a pharmaceutical product for the treatment of NASH.

[0023] In another embodiment, provided herein are compounds disclosed herein, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of NASH.

[0024] In another embodiment, provided herein are compositions disclosed herein for use in the treatment of NASH.

[0025] In another embodiment, provided herein are compounds disclosed herein, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in inhibiting VAP-1.

[0026] In another embodiment, provided herein are compositions disclosed herein for use in inhibiting VAP-1.

[0027] In another embodiment, provided herein are methods for treating a subject in need of treatment for a disease mediated by VAP-1, comprising, or consisting thereof, administering to the subject a therapeutically effective amount of a compound disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0028] In some embodiments, VAP-1-mediated diseases include: dyslipidemia, lipoprotein disorders, conditions or diseases resulting from chronic fatty and fibrous degeneration of organs due to the accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progression pathways; type 1 or type 2 diabetes mellitus; clinical complications of type 1 and type 2 diabetes mellitus; chronic intrahepatic cholestasis; extrahepatic cholestasis; hepatic fibrosis; acute intrahepatic cholestasis; obstructive or chronic inflammatory diseases resulting from inappropriate bile composition; gastrointestinal conditions with reduced intake of dietary fats and fat-soluble dietary vitamins; inflammatory bowel disease; obesity; metabolic syndromes; complex dyslipidemia; and diabetes mellitus. The group is selected from the following: disease and abnormally high obesity index; persistent infection by intracellular bacteria or parasitic protists; non-malignant hyperproliferative disorder; malignant hyperproliferative disorder; adenocarcinoma of the colon and hepatocellular carcinoma; fatty liver disease or related syndromes; hepatitis B infection; hepatitis C infection; cholestasis and fibrosis associated with alcoholic cirrhosis or viral hepatitis; hepatic failure or impaired hepatic function as a result of chronic liver disease or surgical hepatectomy; acute myocardial infarction; acute stroke; chronic obstructive arteriosclerosis; osteoarthritis; rheumatoid arthritis; psoriasis; and thrombosis (alone or in combination) occurring as an endpoint of cerebral infarction.

[0029] In another embodiment, the compound of formula 1a is provided herein. [ka] or a pharmaceutically acceptable salt thereof, in the formula, (i) X is N, and Y is N or CR 2’ And, or (ii) X is CR 3 And Y is N or CR 2 And, or (iii) Both X and Y are N, R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 Alkyl, halogen, phenyl, or benzyl, R 2’ C1~3 Alkyl, halogen, phenyl, or benzyl, R 3 is hydrogen, C 1~3 Alkyl or phenyl, n is either 0 or 1. A' is C6~C 10 The group is an aryl group or a 5-10 membered heteroaryl group, and the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S. R' is C 1~3 Selected from the group consisting of alkyl, halogen, and -R, A method for preparing a compound or a pharmaceutically acceptable salt thereof, wherein R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or unaromatic. The method is, (a) A compound of formula 2, [ka] In the formula, PG is an amino protecting group, and the compound The compound of formula 3, Z-R' (Formula 3) In the formula, Z is -B(OH)2, -B(C 1~3 Alkoxy)2, or [ka] By reacting with a compound, To obtain the compound of formula 1aa, [ka] and (b) A method comprising removing PG from the compound of formula 1aa under reaction conditions to obtain the compound of formula 1a or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0030] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “and,” and “the” refer to multiple subjects unless otherwise explicitly indicated in the context. It should also be noted that claims may be constructed to exclude any element. Therefore, this statement is intended to function as an antecedent or “negative” restriction for the use of exclusive terms such as “solely” and “only” in relation to the enumeration of claim elements.

[0031] Where used herein, the terms “comprising” or “comprises” are intended to mean that a composition or method includes the enumerated elements but does not exclude other elements. A composition or method “essentially consisting of” the elements as defined herein does not exclude other materials or processes that do not materially affect the fundamental and novel properties of the claimed art. “Consisting of” shall mean excluding other components and substantial method processes beyond trace elements. Embodiments defined by each of these conjugations are within the scope of this art. Where an embodiment is defined by one of these terms (e.g., “comprising”), it should be understood that this disclosure also includes alternative embodiments such as “consisting essentially of” and “consisting of” that embodiment.

[0032] "Substantially" or "essentially" means nearly entirely or completely, of some given quantity, for example, 95%, 96%, 97%, 98%, 99%, or more.

[0033] Where used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of a term that is not obvious to those skilled in the art, “about” will mean up to plus or minus 10% of the particular term, taking into account the context in which it is used.

[0034] Certain ranges are presented herein preceded by the term “approximately.” The term “approximately” is used herein to provide verbatim support for the exact number it precedes, and for any number that is near or approximate to the number it precedes. In determining whether a number is near or approximate to a specifically enumerated number, any unenumerated number that is near or approximate may, in the context in which the number is presented, provide a substantial equivalent of the specifically enumerated number.

[0035] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, up to one-tenth of the lower limit unit unless otherwise explicitly indicated by the context, and any other values ​​or values ​​between them within the stated range, are included in this technique. The upper and lower limits of these smaller ranges may independently be included within smaller ranges, are included in this technique, and are subject to any specifically excluded limits within the stated range. If a stated range includes one or both limits, the range excluding one or both of those limits is also included in this technique.

[0036] Generally, “substituted” refers to an organic group (e.g., an alkyl group) in which one or more bonds to hydrogen atoms contained therein are replaced by bonds to non-hydrogen or non-carbon atoms. A substituted group also includes a group in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds, including double or triple bonds, to heteroatoms. This disclosure is understood to include embodiments in which, for example, “substituted alkyl” optionally contain one or more alkenes and / or alkynes. Unless otherwise specified, a substituted group is substituted with one or more substituents. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogens (i.e., F, Cl, Br, and I), hydroxyl groups, alkoxys, alkenoxys, alkynoxys, aryloxys, aralkyloxys, heterocyclyloxys, and heterocyclylalkoxy groups, aryl groups, heteroaryl groups, cycloalkyl groups, heterocyclyl groups, carbonyl (oxo), carboxyl, esters, carbamates, urethanes, urea, oximes, hydroxylamines, alkoxyamines, aralkoxyamines, thiols, sulfides, sulfoxides, sulfones, sulfonyls, sulfonamides, amines, N-oxides, hydrazines, hydrazides, hydrazines, azides, amides, urea, amidines, guanidines, enamines, imides, isocyanates, isothiocyanates, cyanates, thiocyanates, imines, nitro groups, nitriles (i.e., CN), and the like. As used herein, "optionally substituted" groups refer to substituted or unsubstituted groups. Therefore, "replaced by choice" and "replaced or not replaced" can be used interchangeably.

[0037] Substituted ring groups, such as substituted rings, substituted cycloalkyls, substituted aryls, substituted heterocyclics, and substituted heteroaryl groups, also include rings and fused ring systems in which bonds to hydrogen atoms are replaced by bonds to carbon atoms. Therefore, substituted rings, substituted cycloalkyls, substituted aryls, substituted heterocyclics, and substituted heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0038] As used herein, the term “cyclic ring” refers to an aromatic or non-aromatic ring containing one or more heteroatoms of any choice. Examples of heteroatoms include, but are not limited to, N, O, S, or B. In some embodiments, the cyclic ring optionally contains 1 to 5 heteroatom ring members selected from O, N, or S. In some embodiments, the cyclic ring optionally contains 1 to 4 heteroatom ring members selected from O, N, or S. In some embodiments, the cyclic ring optionally contains 1 to 3 heteroatom ring members selected from O, N, or S. The cyclic ring includes aryl, cycloalkyl, and heterocyclic groups.

[0039] As used herein, “aryl group” refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic, and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, indecanyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbon atoms, and in other cases, the ring portion of the group contains 6 to 12 or even 6 to 10 carbon atoms. The term “aryl group” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., benzodioxole, indanyl, tetrahydronaphthyl, etc.), but does not include aryl groups having other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyls are called substituted aryl groups. Typical substituted aryl groups may be monosubstituted or substituted two or more times. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0040] As used herein, the term “cycloalkyl group” refers to cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, but is not limited to these. In some embodiments, the cycloalkyl group has 3 to 8 carbon ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include monocyclic, bicyclic, and polycyclic ring systems, such as the cross-linked cycloalkyl groups described below, and condensed rings such as dekalinyl, but is not limited to these. In some embodiments, the polycyclic cycloalkyl group has three rings. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Typical substituted cycloalkyl groups may be monosubstituted, but are not limited to those listed above, and may be substituted with substituents such as 2,2-, 2,3-, 2,4-2,5-, or 2,6-disubstituted cyclohexyl groups, which may be substituted two or more times. In some embodiments, the cycloalkyl group has one or more alkene bonds but is not aromatic. In some embodiments, the cycloalkyl ring may be a spirocycloalkyl group.

[0041] As used herein, the term “heterocyclic group” includes aromatic (also called heteroaryl) and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms such as N, O, S, or B, in no particular order. In some embodiments, heterocyclic groups contain 3 to 20 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ring members. Heterocyclic groups may have 1 to 5 heteroatom ring members selected from O, N, or S. In some embodiments, heterocyclic groups are non-aromatic rings having 3 to 12 ring members, of which 1 to 5 are heteroatoms selected from O, N, and S. Heterocyclic groups include, for example, unsaturated, partially saturated, and saturated ring systems such as imidazolyl, imidazolinyl, and imidazolidinyl groups. The term "heterocyclic group" includes fused ring species, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl, which contain fused aromatic and non-aromatic groups. This term also includes, but is not limited to, bridging polycyclic ring systems containing heteroatoms, such as quinuclidyl. However, this term does not include heterocyclic groups that have other groups, such as alkyl, oxo, or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclic groups."Heterocyclic groups include azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, and Omorpholinyl, tetrahydropyranil, tetrahydrothiopyranil, oxatian, dioxyl, dithianil, pyranil, pyridyl, pyrimidinil, pyridazinil, pyrazinil, triazinil, dihydropyridyl, dihydrodithinyl, dihydrodithionyl, homopiperazinil, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolinyl, benzotriazolyl, benzimidazolyl, benzofuranil, benzothiophenyl, benz Zuthiazolyl, benzoxadiazoyl, benzoxazinyl, benzodithinyl, benzoxathinyl, benzothiadinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidoazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazi Examples include, but are not limited to, the yl, naphthilidinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridyl, tetrahydroimidoazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Typical substituted heterocyclic groups may be monosubstituted or once hypersubstituted, and are, for example, pyridyl or piperazinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above, but are not limited to these.

[0042] As used herein, the term “heteroaryl group” refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, including but not limited to N, O, S, or B. In some embodiments, one or more heteroatoms are selected from N, O, or S. In some embodiments, one to four heteroatoms are selected from N, O, or S. In some embodiments, one to five heteroaryl groups are selected from N, O, or S. In some embodiments, a heteroaryl group contains 5 to 14 ring members, while other such groups have 5 to 6, 5 to 9, 5 to 10, 6 to 9, 6 to 10, or 6 to 14 ring members. For example, a five-membered heteroaryl group has five ring members, a six-membered heteroaryl group has six ring members, and a nine-membered heteroaryl group has nine ring members (including but not limited to benzothiophene). Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaamidolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzeneimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. The term "heteroaryl group" includes fused ring compounds such as indolyl and 2,3-dihydroindolyl, but does not include heteroaryl groups that have another group bonded to one of the ring members, such as an alkyl group. Rather, heteroaryl groups with such substitutions are called "substituted heteroaryl groups." Typical substituted heteroaryl groups can be substituted one or more times with various substituents as listed above. An azolyl group is a five-membered heteroaryl group containing a nitrogen atom and at least one other atom selected from nitrogen, sulfur, and oxygen as part of the ring.Examples of azolyl groups include imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pentazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiazole, isothiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole.

[0043] As used herein, the term "alkyl" refers to aliphatic hydrocarbon radicals that include both linear and branched hydrocarbon radicals. In some embodiments, alkyls have 1 to about 20 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. For example, C 1~6 Alkyl refers to aliphatic hydrocarbons having 1 to 6 carbon atoms, including methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, and isopentyl.

[0044] As used herein, the term "hydroxy" is defined as -OH.

[0045] As used herein, the term "alkoxy" refers to a radical formed by substituting a hydrogen atom of a hydroxyl group with an alkyl group, unless otherwise defined herein. For example, C 1~6 Examples of alkoxys include methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, and isopentyloxy.

[0046] Furthermore, the term "halogen" refers to fluorine, bromine, chlorine, and iodine.

[0047] Furthermore, the term "amino" is defined as -NH2, and the term "alkylamino" refers to mono- or dialkyl-substituted amino acids. For example, C1~6 Alkylaminos are mono- or di-C 1~6 It contains alkyl-substituted amino acids. In some embodiments, each alkyl group of the dialkyl-substituted amino acid may be the same or different.

[0048] Furthermore, the term "alkylthio" is defined as -SR (where R is alkyl), and the term "cyano" is defined as -CN.

[0049] "Alkylsulfonyl" refers to the -S(O)2R group, where R is alkyl.

[0050] Those skilled in the art will understand that the compounds of this art may exhibit phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. The formula diagrams in this specification and the claims may represent only one of the possible tautomer, conformational isomerism, optical isomerism, or geometric isomerism forms, and it should be understood that this art encompasses any tautomer, conformational isomerism, and / or optical isomerism of one or more useful compounds described herein, as well as mixtures of various different forms thereof.

[0051] As will be readily apparent to those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds described herein are within the scope of this art.

[0052] The stereoisomers of a compound, also known as an "optical isomer," include all chiral, diastereomer, and racemic forms of the structure unless a specific stereochemistry is explicitly indicated. Therefore, the compounds used in this technique, as is evident from the description, include optical isomers concentrated or decomposed at any or all stereogenic atoms. Both racemates and diastereomer mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomer or diastereomer partners, and all of these are within the scope of this technique.

[0053] "Pharmacologically acceptable" means that a material is not biologically or otherwise undesirable, for example, that can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it implies that the carrier or excipient has met the necessary standards of toxicological and manufacturing testing, or that it is included in the Inactive Ingredient Guide established by the US Food and Drug Administration.

[0054] In general, references to certain moieties that can be protected (such as hydroxy, amine, and carbonyl) include protecting groups in some embodiments of this disclosure. For example, in some embodiments, the -OH moieties included herein also include -OP, where P is a protecting group. Protecting groups such as those mentioned herein, for example, the amine protecting groups described herein, may be selected by those skilled in the art, including groups and strategies defined in the art, such as those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), T.W. Greene and P.G. M. Futs, Greene's protective groups in organic synthesis, John Wiley & Sons (2006), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions.

[0055] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. Unless otherwise indicated, "subject" and "patient" may be used interchangeably. The methods described herein may be useful in human therapeutic and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0056] The terms “therapeutic effective dose” and “effective dose” are used interchangeably and refer to the amount of a compound sufficient to provide treatment when administered in one or more doses to a patient (e.g., a human) requiring such treatment, as defined below. The therapeutic effective dose varies depending on the patient, the disease being treated, the patient’s weight and / or age, the severity of the disease, or the method of administration determined by a qualified prescriber or caregiver.

[0057] The terms “treatment” or “to treat” mean administering any of the compounds disclosed herein for the purpose of (i) delaying the onset of a disease, i.e., preventing the onset of the clinical symptoms of the disease, or delaying the onset of the disease; (ii) inhibiting a disease, i.e., preventing the onset of the clinical symptoms; and / or (iii) alleviating a disease, i.e., causing regression of the clinical symptoms or their severity.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. Any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the art, but representative exemplary methods and materials are described herein.

[0059] This technology relates to a compound having inhibitory activity against VAP-1 or a pharmaceutically acceptable salt thereof, i.e., a compound of formula 1, [ka] During the ceremony, (i) X is N, and Y is N or CR 2’ And, or (ii) X is CR 3 And Y is N or CR 2 And, or (iii) Both X and Y are N, R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 Alkyl, halogen, phenyl, or benzyl, R 2’ C 1~3 Alkyl, halogen, phenyl, or benzyl, R 3 is hydrogen, C 1~3 Alkyl or phenyl, n is either 0 or 1. A is C6~C 10 The aryl group or the 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C 1~3 It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. The present invention provides a compound in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or unaromatic.

[0060] In some embodiments, X is N and Y is N or CR 2’ In some embodiments, X is CR 3 And Y is N or CR 2 In some embodiments, both X and Y are N. In some embodiments, X is N and Y is CR 2’ In some embodiments, X is CR 3 And Y is N. In some embodiments, X is CR 3And Y is CR 2 That is the case.

[0061] In another embodiment, the compound of formula 15 is provided herein. [ka] or a pharmaceutically acceptable salt thereof During the ceremony, R 1 is hydrogen or fluoro, R 2’ C 1~3 Alkyl, halogen, phenyl, or benzyl, n is either 0 or 1. A is C6~C 10 The aryl group or the 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C 1~3 It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or unaromatic, and is a compound or a pharmaceutically acceptable salt thereof.

[0062] In another embodiment, the compound of formula 16 is provided herein. [ka] or a pharmaceutically acceptable salt thereof During the ceremony, R 1 is hydrogen or fluoro, n is either 0 or 1. A is C6~C 10 The aryl group or the 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C1~3 It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or unaromatic, and is a compound or a pharmaceutically acceptable salt thereof.

[0063] In another embodiment, the compound of formula 17 is provided herein. [ka] or a pharmaceutically acceptable salt thereof During the ceremony, R 1 These are hydrogen and fluoro, n is either 0 or 1. A is C6~C 10 The aryl group or the 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, and the aryl group or the heteroaryl group optionally contains C 1~3 It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or unaromatic, and is a compound or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, A is C 1~3 C6-C6 molecules optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. 10 It is an aryl group.

[0065] In some embodiments, A is C 1~3 This is a phenyl molecule optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0066] In some embodiments, A is C 1~3 A phenyl molecule optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, wherein R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, and the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0067] In some embodiments, A is a 5-10 membered heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, and the heteroaryl group is C 1~3 It is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0068] In some embodiments, A is C 1~3 The thiophenyl or pyridinyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0069] In some embodiments, A is C 1~3 This is a thiophenyl molecule optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0070] In some embodiments, A is C 1~3A thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, 3,4-dihydroquinoline-2-onyl, or triazolo[1,5-a]pyridinyl, where R is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls.

[0071] In some embodiments, A is C 1~3 A thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, or 3,4-dihydroquinoline-2-onyl, and R is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls. In some embodiments, A is C 1~3 A thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, or 3,4-dihydroquinoline-2-onyl, and R is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls.

[0072] In some embodiments, A is C 1~3Thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is phenyl, pyrazolyl, pyridin-2-yl, or 3,4-dihydroquinolin-2-yl, and R is C 1~6 alkyl, mono-C 1~6 alkylamino, di-C 1~6 alkylamino, C 1~6 alkylsulfonyl, and piperazinyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of. In some embodiments, A is C 1~3 Thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is phenyl, pyrazolyl, pyridin-2-yl, or 3,4-dihydroquinolin-2-yl, and R is C 1~6 alkyl and C 1~6 alkylsulfonyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of.

[0073] In some embodiments, A is C 1~3 Thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is pyrazolyl, pyridin-2-yl, or 3,4-dihydroquinolin-2-yl, and R is C 1~6 alkyl, mono-C 1~6 alkylamino, di-C 1~6 alkylamino, C 1~6 alkylsulfonyl, and piperazinyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of. In some embodiments, A is C 1~3 Thiophenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is pyrazolyl, pyridin-2-yl, or 3,4-dihydroquinolin-2-yl, and R is C 1~6 alkyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of.

[0074] In some embodiments, A is C 1~3 It is a pyridinyl molecule optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0075] In some embodiments, A is C 1~3 A pyridinyl molecule optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is a cyclic ring selected from the group consisting of phenyl, pyridine-2-onyl, benzodioxolyl, or 3,4-dihydroquinoline-2-onyl, and the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0076] In some embodiments, R is a substituted or unsubstituted phenyl compound. In some embodiments, R is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 This is a phenyl compound that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0077] In some embodiments, R is a substituted or unsubstituted 5-10 member heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S. In some embodiments, R has 1-5 heteroatom ring members independently selected from O, N, and S, and C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6It is a 5-10 membered heteroaryl compound that is optionally substituted with 1-3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0078] In some embodiments, R is a substituted or unsubstituted non-aromatic 3-12 member heterocycle having 1-5 heteroatom ring members independently selected from O, N, and S. In some embodiments, R has 1-5 heteroatom ring members independently selected from O, N, and S, and C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is a non-aromatic 3- to 12-membered heterocycle that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0079] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0080] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls.

[0081] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, and 3,4-dihydroquinoline-2-onyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

[0082] In some embodiments, R is a cyclic ring selected from the group consisting of pyridine-2-onyl, pyrazolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls.

[0083] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, and 3,4-dihydroquinoline-2-onyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C 1~6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyls and piperazinyls.

[0084] In some embodiments, R 1 is hydrogen. In some embodiments, R 1It is fluoro.

[0085] In some embodiments, R 2 is hydrogen, C 1~3 It is alkyl, halogen, phenyl, or benzyl. In some embodiments, R 2 is hydrogen, C 1~3 It is alkyl or halogen. In some embodiments, R 2 is phenyl or benzyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 C 1~3 It is alkyl. In some embodiments, R 2 It is hydrogen.

[0086] In some embodiments, R 2’ C 1~3 It is alkyl. In some embodiments, R 2’ is a halogen. In some embodiments, R 2’ R is phenyl. In some embodiments, R 2’ It is benzyl.

[0087] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 C 1~3 It is alkyl. In some embodiments, R 3 It is phenyl.

[0088] In some embodiments, n is 0. In some embodiments, n is 1.

[0089] The compounds provided herein are inhibitors of VAP-1. VAP-1 inhibition is, for example, achieved when the maximum inhibitory concentration (IC) is reached. 50 This can be measured by determining the IC of VAP-1. 50 One method for determining this is provided herein.

[0090] In one embodiment, the compound is an inhibitor of VAP-1. Selectivity can be determined, for example, by comparing the inhibition of VAP-1 with the inhibition of other amino oxidases, such as MAO-A (monoamine oxidase-A), MAO-B (monoamine oxidase-B), and DAO (diamine oxidase). In one embodiment, such "significantly high inhibitory activity" is determined by the IC of VAP-1 obtained from in vitro enzyme analysis (in vitro enzyme assay) tests. 50 However, the MAO-A IC 50 At least 3000 times lower than MAO-B IC 50 At least 100 times lower than, or the IC of DAO 50 This means at least 100 times lower. In an alternative embodiment, “significantly higher inhibitory activity” refers to the IC of VAP-1 obtained from in vitro enzyme analysis (in vitro enzyme assay) tests. 50 However, the MAO-A IC 50 At least 3000 times lower than MAO-B IC 50 At least 100 times lower than the IC of DAO. 50 This means it is at least 100 times lower.

[0091] In another embodiment, the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or their pharmaceutically acceptable salts. 2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-one, 2-[2-(aminomethyl)-3,3-difluoroallyl]-5-methyl-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]-1,2,4-triazole-3-one, 2-[2-(aminomethyl)-3,3-difluoroallyl]-5-methyl-4-[[5-(4-piperazine-1-ylphenyl)-2-thienyl]methyl]-1,2,4-triazole-3-one, 5-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-1-ethyl-pyridine-2-one, 2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-[6-(dimethylamino)-3-pyridyl]-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-one, 2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1,3-benzodioxol-5-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-one, 6-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-one, 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)-2-fluorophenyl]-1,2,4-triazole-3-one, 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[4-(2,1,3-benzoxadiazole-5-yl)-2-fluorophenyl]-1,2,4-triazole-3-one, 6-[4-[1-[(E)-2-(aminomethyl)-3-fluoroallyl]-5-oxo-1,2,4-triazole-4-yl]-3-fluorophenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[2-fluoro-4-(6-morpholino-3-pyridyl)phenyl]-1,2,4-triazole-3-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(4-methylsulfonylphenyl)phenyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(4-piperazine-1-ylphenyl)phenyl]tetrazole-5-one, 5-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-ethylpyridine-2-one, 6-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(1-ethylpyrazole-4-yl)phenyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-methylsulfonylphenyl)phenyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-piperazine-1-ylphenyl)phenyl]tetrazole-5-one, 5-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-ethylpyridine-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)phenyl]tetrazole-5-one, 6-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1-ethylpyrazole-4-yl)phenyl]tetrazole-5-one, 5-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-2-thienyl]-1-ethylpyridine-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-methyl-6-(4-methylsulfonylphenyl)-2-pyridyl]tetrazole-5-one, 5-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]-5-methyl-2-pyridyl]-1-ethyl-pyridine-2-one, 6-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-5-methyl-2-pyridyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-5-methyl-2-pyridyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(4-methylsulfonylphenyl)phenyl]methyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(4-piperazine-1-ylphenyl)phenyl]methyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-[6-(dimethylamino)-3-pyridyl]phenyl]methyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(1,3-benzodioxol-5-yl)phenyl]methyl]tetrazole-5-one, 6-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(1-ethylpyrazole-4-yl)phenyl]methyl]tetrazole-5-one, 6-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]phenyl]-1-methyl-3,4-dihydroquinoline-2-one, 5-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]methyl]phenyl]-1-ethylpyridine-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-methylsulfonylphenyl)-2-thienyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-piperazine-1-ylphenyl)-2-thienyl]tetrazole-5-one, 5-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-1-ethylpyridine-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-[6-(dimethylamino)-3-pyridyl]-2-thienyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)-2-thienyl]tetrazole-5-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1-ethylpyrazole-4-yl)-2-thienyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]tetrazole-5-one, 5-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]methyl]-2-thienyl]-1-ethylpyridine-2-one, 6-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 6-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]tetrazole-5-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[5-(1,3-benzodioxol-5-yl)-3-pyridyl]tetrazole-5-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-pyridyl]-8-methyl-3,4-dihydro-1H-quinoline-2-one, 5-[5-[[3-[2-(aminomethyl)-3,3-difluoroallyl]-2-oxoimidazole-1-yl]methyl]-2-thienyl]-1-ethylpyridine-2-one, 6-[5-[[3-[2-(aminomethyl)-3,3-difluoroallyl]-2-oxoimidazole-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-one, 1-[2-(aminomethyl)-3,3-difluoroallyl]-3-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]imidazole-2-one, and 1-[2-(aminomethyl)-3,3-difluoroallyl]-3-[[5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-thienyl]methyl]imidazole-2-one.

[0092] The compounds of Formula 1 in this technology may be in the form of pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” refers to a salt or zwitterionic form of the compound in this technology that is water-soluble, oil-soluble, or dispersible, suitable for the treatment of a disease without excessive toxicity, irritation, and allergic response, corresponding to a reasonable benefit / risk ratio, and effective for their intended use. Salts can be prepared during the final isolation and purification of the compound, or, for example, by reacting a suitable compound in the form of a free base with a suitable acid. Examples of such salts include conventional acid addition salts, such as those derived from inorganic acids like hydrochloric acid, bromate, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, oxalic acid, or trifluoroacetic acid. Furthermore, examples of such salts include conventional metal salt types, such as those derived from metals like lithium, sodium, potassium, magnesium, or calcium. These acid addition salts or metal salts can be prepared according to conventional methods.

[0093] Compounds of formulas 1, 15, 16, or 17 according to this technology, or their stereoisomers, or pharmaceutically acceptable salts thereof, can be prepared by various methods. For example, a compound of formula 1a according to this technology, or its stereoisomer, or a pharmaceutically acceptable salt thereof, can be prepared by a preparation process that includes the steps of reacting a compound of formula 2 with a compound of formula 3 to obtain a compound of formula 1aa, and deprotecting the compound of formula 1aa. [ka]

[0094] In formulas 1a, 1aa, 2, and 3, PG is an amine protecting group (e.g., tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl (CBZ), triphenylmethyl (trityl), etc.), and Z is a boronic acid (-B(OH)2), -B(C 1~3 Alkoxy)2, or [ka] And R 1 X, Y, n, A', and R' are the same as above.

[0095] In some embodiments, ring A' of formula 2 is further substituted with R, where R is as defined herein, and coupled with a compound of formula 3 as described herein, the resulting compound is subsequently deprotected to provide a compound of formula 1.

[0096] The reaction between the compound of formula 2 and the commercially available compound of formula 3 can be carried out via the Suzuki reaction. This reaction can be carried out using a palladium catalyst. Palladium catalysts include palladium(II) acetate (Pd(OAc))2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or palladium di[1,1'-bis(diphenylphosphino)ferrocene]dichloride (PdCl2(dppf)2). During the reaction carried out under palladium catalysis, ligands and bases can be added in addition to the palladium catalyst. The ligands include (S)-2,2-bis(diphenylphosphono)-1,1-binaphthyl (BINAP), 1,1'-bis(diphenylphosphono)ferrocene (dppf), (tri-O-tolyl)phosphine (P(O-Tol)3), etc., and the bases include inorganic bases such as cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K3PO4), sodium tert-butoxide (tert-BuONa), and potassium tert-butoxide (tert-BuOK).

[0097] The reaction may be carried out in a nonpolar organic solvent such as benzene or toluene, or in a polar solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or N,N-dimethylformamide, at a temperature in the range of 50°C to 150°C, preferably 80°C to 110°C. For example, other reaction conditions such as reaction time can be determined from the reaction conditions of the conventional Suzuki reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0098] Deprotection of compounds of formula 1aa can be carried out by conventional methods of removing the amine protecting group. For example, such deprotection can be carried out by removing the amine protecting group in the form of a free amine, or by removing it in the form of a hydrochloride salt using hydrogen chloride dissolved in an organic solvent, such as diethyl ether or 1,4-dioxane.

[0099] The compound of chemical formula 2 can be prepared by the following reaction scheme 1. [ka]

[0100] In reaction scheme 1, X, Y, n, A', R 1 , and PG are the same as defined above, and Q is a halogen (i.e., Cl or Br).

[0101] The compound of formula 10 can be converted to the compound of formula 2 via a Mitsunobu reaction with the compound of formula 11, or via a coupling reaction with the compound of formula 12.

[0102] The reaction between the compound of formula 10 and the compound of formula 11 can be carried out via the Mitsunobu reaction. For example, the reaction can be carried out using diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in the presence of triphenylphosphine or tri-n-butylphosphine. The reaction solvent may be a polar organic solvent, such as dichloromethane, dioxane, tetrahydrofuran, or dimethylformamide. The reaction may be carried out at 0°C to room temperature, or possibly at a higher temperature. Other reaction conditions, such as reaction time, can be determined from the reaction conditions of the conventional Mitsunobu reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0103] The coupling reaction between the compound of formula 10 and the compound of formula 12 can be carried out in the presence of a base and a solvent. The base may be cesium carbonate, potassium carbonate, sodium carbonate, etc., and the solvent may be an organic solvent, such as N,N-dimethylformamide, dioxane, tetrahydrofuran, etc. Furthermore, the reaction may be carried out at room temperature to 100°C.

[0104] The compound of formula 12 can be obtained by halogenation (i.e., chlorination or bromination) of the compound of formula 11. This halogenation (i.e., chlorination or bromination) can be carried out in the presence of conventional inorganic bases and organic solvents.

[0105] The compound of chemical formula 10 can be prepared by the reaction scheme 2 below. [ka]

[0106] In reaction scheme 2, R 2’ A' and n are the same as defined above. The compound of formula 6 is the same as the compound of formula 10, where X is N and Y is CR. 2’ This is the case when both X and Y are N in the compound of formula 10.

[0107] The compound of formula 9 is the compound of formula 10 in which X is CH and Y is CH, and it is commercially available or can be prepared according to methods known in the art. [ka]

[0108] The compound of Formula 4 can be converted to the compound of Formula 6 via a coupling reaction with the compound of Formula 5. The said coupling reaction can be carried out in the presence of a base and a solvent. The said base may be cesium carbonate, potassium carbonate, sodium carbonate, etc., and the said solvent may be an organic solvent such as N,N-dimethylformamide, dioxane, tetrahydrofuran, etc. Further, the said reaction may be carried out at room temperature to 100 °C.

[0109] The compound of Formula 7 can be converted to the compound of Formula 8 via a cyclization reaction. The said cyclization reaction can be carried out using trimethylsilyl azide at a temperature in the range of room temperature to 100 °C (for example, International Publication No. WO 2015 / 014283, etc.).

[0110] In some embodiments, the cyclization conditions include, consist essentially of, or consist of reacting the compound of Formula 7 with trimethylsilyl azide without a solvent at a temperature in the range of room temperature to 100 °C.

[0111] When X is N, Y is CR 2’ and n is 1, in some embodiments, the compound of Formula 2 is (a) reacting the compound of Formula 4 with

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0112] In some embodiments, both X and Y are N, and the compound of formula 2 is (a) Compound of formula 7, [ka] Reacting with trimethylsilyl azide under cyclization conditions yields the compound of formula 8. [ka] (b) The compound of formula 8 is the compound of formula 11, [ka] The compound of formula 12, [ka] In the formula, Q is a halogen, and the compound is... It is obtained by reacting the compounds under reaction conditions to obtain the compound of formula 2.

[0113] In some embodiments, X is CH, Y is CH, n is 1, and the compound of formula 2 is the compound of formula 9. [ka] Compound of formula 11, [ka] The compound of formula 12, [ka] In the formula, Q is a halogen, and the compound is... It is obtained by reacting the compounds under reaction conditions to obtain the compound of formula 2.

[0114] R 1 Compounds of formula 11 (compounds of formula 11a) in which R is hydrogen are commercially available,1 Compounds of formula 11 (compounds of formula 11b) in which is fluoro can be prepared according to the following reaction scheme 3. [ka]

[0115] In reaction scheme 3, TBDMS is the hydroxy protecting group tert-butyldimethylsilyl, and PG is the same as defined above.

[0116] The compound of formula 13 is commercially available and can be prepared according to known methods (e.g., International Publication No. 2013 / 163675). The compound of formula 13 can be converted to the compound of formula 14 via a gem-difluoroolefination reaction. The gem-difluoroolefination reaction can be carried out using a fluorinated sulfone such as difluoromethyl 2-pyridyl sulfone in the presence of a base, such as potassium tert-butoxide (tert-BuOK) or lithium bis(trimethylsilyl)amide (LiHMDS). The reaction solvent may be an organic solvent, such as N,N-dimethylformamide or tetrahydrofuran, and the reaction can be carried out at a temperature of -40°C to 0°C (Yanchuan Zhao; Weizhou Huang; Lingui Zhu; Jinbo Hu, Organic Letters, 12, pp. 1444-1447, 2010).

[0117] The compound of Formula 14 can be converted to the compound of Formula 11b via the deprotection reaction of the hydroxyl protecting group (TBDMS). The deprotection reaction of the hydroxyl protecting group can be carried out according to known methods (Theodora W. Greene and Peter G. M. Wuts, Protective groups in organic synthesis, 3rd Ed., 1999). For example, the deprotection reaction of the hydroxyl protecting group (TBDMS) can be carried out at room temperature using an organic salt, such as tetrabutylammonium fluoride (TBAF), in a solvent such as dichloromethane, tetrahydrofuran, etc. (W. Green; P. G. M. Wuts, Protective Groups in Organic Synthesis, 127 - 141, 708 - 711, 1999).

[0118] The triazolones, tetrazolones, and imidazolones according to the present technology, namely, the compound of Formula 1, or its stereoisomers, or its pharmaceutically acceptable salts, have inhibitory activity against VAP-1, and thus can be usefully applied to the prevention or treatment of VAP-1-mediated diseases. Preferably, the compound of Formula 1 according to the present technology, or its stereoisomers, or its pharmaceutically acceptable salts, can be usefully applied to the prevention or treatment of non-alcoholic steatohepatitis (NASH).

[0119] In some embodiments, the Specified Provisions include lipid and lipoprotein disorders (such as, but not limited to, hypercholesterolemia, hypertriglyceridemia, and arteriosclerosis), conditions or diseases resulting from chronic fatty and fibrous degeneration of organs due to the accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progressive pathways (such as, but not limited to, NASH and chronic cholestasis in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes, neurodegenerative diseases such as Alzheimer's disease in the brain, and diabetic neuropathy in the peripheral nervous system), type 1 or type 2 diabetes, and clinical complications of type 1 and type 2 diabetes (diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral arterial occlusive disease).Diseases such as PAOD (but not limited to these), several forms of chronic intrahepatic or extrahepatic cholestasis, hepatic fibrosis, acute intrahepatic cholestasis, obstructive or chronic inflammatory diseases resulting from inappropriate bile composition (gallstones, also known as cholesterol gallstones, but not limited to these), gastrointestinal conditions with reduced intake of dietary fats and fat-soluble dietary vitamins, inflammatory bowel disease, obesity and metabolic syndromes (complex dyslipidemia, diabetes mellitus and abnormally high obesity index), persistent infections by intracellular bacteria or parasitic protists, non-malignant hyperproliferative disorders, malignant hyperproliferative disorders (different forms of cancer, specifically certain forms of breast cancer, liver cancer, or colon cancer, or a group consisting of hepatocellular carcinoma, colon adenoma, and polyposis). The present invention relates to the use of triazolone, tetrazolon, and imidazolon, i.e., compounds of Formula 1, or their stereoisomers, or pharmaceutically acceptable salts thereof, in the preparation of pharmaceuticals for the prevention and / or treatment of thrombosis (alone or in combination thereof) occurring as an endpoint of acute myocardial infarction, acute stroke, chronic obstructive arteriosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and cerebral infarction, including, but not limited to, disorders selected from, colorectal adenocarcinoma and hepatocellular carcinoma, particularly fatty liver disease and its associated syndromes, hepatitis B infection, hepatitis C infection, and / or cholestasis and fibrosis associated with alcoholic cirrhosis or viral hepatitis, hepatic failure or impaired hepatic function as a result of chronic liver disease or surgical hepatectomy, acute myocardial infarction, acute stroke, chronic obstructive arteriosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and cerebral infarction.

[0120] In some embodiments, the compounds and / or pharmaceutical compositions disclosed herein are used for the prevention and / or treatment of primary biliary sclerosis (PBC), primary sclerosing cholangitis (PSC), progressive inertial cholestasis (PFIC), alcohol-induced cirrhosis and associated cholestasis, as well as several forms of extrahepatic cholestatic conditions or chronic intrahepatic conditions such as hepatic fibrosis.

[0121] In some embodiments, methods for treating chronic intrahepatic conditions and / or certain forms of extrahepatic cholestasis in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the chronic intrahepatic conditions are selected from PBC, PSC, PFIC, and alcohol-induced cirrhosis and associated cholestasis.

[0122] In some embodiments, methods for treating liver fibrosis in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0123] In some embodiments, methods for treating lipid and lipoprotein disorders in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the lipid and lipoprotein disorders are selected from hypercholesterolemia, hypertriglyceridemia, and arteriosclerosis.

[0124] In some embodiments, methods are provided herein for treating a patient who requires treatment for a condition or disease resulting from chronic fatty and fibrous degeneration of an organ due to the accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progressive pathways, the methods comprising, essentially consisting of, or comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the condition or disease resulting from chronic fatty and fibrous degeneration of an organ due to the accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progressive pathways are selected from NASH and chronic cholestasis in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes, and neurodegenerative diseases. In some further embodiments, the neurodegenerative diseases are selected from Alzheimer's disease in the brain and diabetic neuropathy of the peripheral nervous system.

[0125] In some embodiments, methods are provided herein for treating patients who require treatment for type 1 or type 2 diabetes and clinical complications of type 1 and type 2 diabetes, the methods comprising, essentially comprising, or comprising administering a therapeutically effective amount of a compound or composition disclosed herein to the patient. In some embodiments, methods are provided herein for treating patients who require treatment for type 1 diabetes, the methods comprising, essentially comprising, or comprising administering a therapeutically effective amount of a compound or composition disclosed herein to the patient. In some embodiments, methods are provided herein for treating patients who require treatment for type 2 diabetes, the methods comprising, essentially comprising, or comprising administering a therapeutically effective amount of a compound or composition disclosed herein to the patient. In some embodiments, methods are provided herein for treating patients who require treatment for one or more clinical complications of type 1 and type 2 diabetes, the methods comprising, essentially comprising, or comprising administering a therapeutically effective amount of a compound or composition disclosed herein to the patient. In some embodiments, clinical complications of type 1 and type 2 diabetes are selected from diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and peripheral artery occlusive disease (PAOD), or any combination thereof.

[0126] In some embodiments, a method for treating a patient requiring treatment of acute intrahepatic cholestasis is provided herein, which includes, essentially consists of, or comprises administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0127] In some embodiments, methods are provided herein for treating in patients who require treatment of an obstructive or chronic inflammatory disease resulting from an inappropriate bile composition, the methods comprising, essentially consisting of, or comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the obstructive or chronic inflammatory disorder resulting from an inappropriate bile composition is cholelithiasis, also known as cholesterol gallstones.

[0128] In some embodiments, methods are provided herein for treating gastrointestinal conditions in patients requiring treatment of reduced dietary fat and fat-soluble dietary vitamin intake, the methods comprising, essentially consisting of, or comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0129] In some embodiments, methods for treating inflammatory bowel disease in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0130] In some embodiments, methods for treating obesity and metabolic syndrome in patients who require treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0131] In some embodiments, methods for treating an infection caused by intracellular bacteria or parasitic protists in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0132] In some embodiments, methods for treating non-malignant hyperproliferative disorders in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0133] In some embodiments, methods for treating non-malignant hyperproliferative disorders in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the malignant hyperproliferative disorder is selected from different forms of cancer, specifically certain forms of breast cancer, liver cancer, or colon cancer, or disorders selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis.

[0134] In some embodiments, methods for treating colon adenocarcinoma in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0135] In some embodiments, methods for treating hepatocellular carcinoma in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0136] In some embodiments, methods for treating fatty liver and related syndromes in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0137] In some embodiments, methods for treating hepatitis B infection in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0138] In some embodiments, methods for treating hepatitis C infection in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0139] In some embodiments, methods are provided herein for treating cholestasis and fibrotic effects associated with alcoholic cirrhosis or viral hepatitis in patients who require treatment, the methods comprising, essentially comprising, or comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0140] In some embodiments, methods for treating hepatic failure or impaired hepatic function resulting from chronic liver disease or surgical hepatectomy are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0141] In some embodiments, a method for treating acute myocardial infarction in a patient requiring treatment is provided herein, which includes, essentially consists of, or consists of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0142] In some embodiments, methods for treating acute stroke in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0143] In some embodiments, methods are provided herein for treating thrombosis occurring as an endpoint of chronic obstructive arteriosclerosis in patients who require treatment, the methods comprising, essentially comprising, or comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0144] In some embodiments, methods for treating osteoarthritis in patients who require treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0145] In some embodiments, methods for treating rheumatoid arthritis in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0146] In some embodiments, methods for treating psoriasis in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering to a patient a therapeutically effective amount of a compound or composition disclosed herein.

[0147] In some embodiments, methods for treating a patient requiring treatment for cerebral infarction are provided herein, which include, essentially consist of, or consist of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0148] Accordingly, the present invention relates to a pharmaceutical composition for inhibiting vascular adhesion protein-1 (VAP-1), comprising a therapeutically effective amount of the compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient. In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating non-alcoholic steatohepatitis (NASH), comprising a therapeutically effective amount of the compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient. In some embodiments, provided herein is a pharmaceutical composition for preventing or treating NASH, comprising, or consisting of, a therapeutically effective amount of the compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0149] In another embodiment, the Technology provides a pharmaceutical composition for preventing or treating diabetic nephropathy, comprising, essentially, or consisting of, a therapeutically effective amount of a compound of Formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0150] In another embodiment, the technology provides a pharmaceutical composition for preventing or treating primary sclerosing cholangitis, comprising, essentially, or consisting of, a therapeutically effective amount of a compound of Formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0151] In some embodiments, the compounds disclosed herein may be combined with one or more additional therapies for the prevention or treatment of diseases or conditions suitable for treatment by inhibition of VAP-1.

[0152] In some embodiments, the compositions disclosed herein contain at least one additional activator.

[0153] Exemplary additional activators include one or more ACE inhibitors, acetyl-CoA carboxylase inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), amyrin receptor agonists, angiotensin II AT-1 receptor antagonists, apoptosis signaling kinase 1 inhibitors, autotaxin inhibitors, bioactive lipids, calcitonin agonists, caspase inhibitors, caspase 3 stimulants, cathepsin inhibitors, caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulants, CNR1 inhibitors, cyclin D1 inhibitors, and cytochrome P450. 7A1 inhibitors, DGAT1 / 2 inhibitors, dipeptidyl peptidase IV inhibitors, endothialin modulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, galectin 3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 agonists, G protein-coupled bile acid receptor 1 agonists, Hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 alpha (HNF4A) modulators, hepatocyte growth factor modulators, HMG CoA reductase inhibitors, IL-10 agonists, IL-17 antagonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 44. IRAK4 inhibitors, Jak2 tyrosine kinase inhibitors, ketohexokinase inhibitors, Klotho β stimulants, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptors, LPL gene stimulants, lysophosphatidate 1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, matrix metalloproteinase (MMP) inhibitors, MEKK5 protein kinase inhibitors, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase 2 inhibitors, methyl CpG-binding protein 2 modulators, microRNA 21 (miR-21) inhibitors, mitochondrial uncoupling agents, myelin basic protein stimulants, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulants, NADPH oxidase inhibitors. Inhibitors (NOX), nicotinic acid receptor 1 agonists, P2Y13 purine receptor stimulants, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor β modulators, phospholipase C inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, PPARγ modulators, protease-activated receptor 2 antagonists, protein kinase modulators, Rho-related protein kinase inhibitors, sodium glucose transporter 2 inhibitors, SREBP transcription factor inhibitors, STAT1 inhibitors, stearoyl-CoA desaturase 1 inhibitors, cytokine signaling 1 stimulant inhibitors, cytokine signaling 3 stimulant inhibitors, transforming growth factor β (TGF-β), transforming growth factor β activated kinase 1Examples of JAK inhibitors include, but are not limited to, TAK1, thyroid hormone receptor β-agonists, TLR4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, and YAP / TAZ modulators. Examples of JAK inhibitors include, but are not limited to, prasinostat and panobinostat. A non-exclusive example of an apoptosis signal kinase inhibitor is ceroncertib.

[0154] The compound of Formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one additional activator may be administered in any order or simultaneously. Multiple activators may be provided in a single combined form or in multiple forms (for example, as a single pill or as two separate pills). One of the activators may be given in multiple doses, or both may be given in multiple doses. If not simultaneously, the timing between multiple doses may vary from more than 0 weeks to less than 4 weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents.

[0155] The pharmaceutical composition of this technology may contain pharmaceutically acceptable carriers such as diluents, disintegrants, sweeteners, lubricants, or flavoring agents, and may be formulated into oral dosage forms such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups, or into parenteral dosage forms such as liquids for external use, suspensions for external use, gels (such as ointments), inhalants, sprays, or injections. These dosage forms may be formulated in various forms, for example, single-dose or multi-dose forms.

[0156] The pharmaceutical compositions of this technology may contain excipients such as lactose and corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. Sweeteners and / or flavoring agents may be added if desired. Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO3), cremophores, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), lubricants such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, and combinations thereof.

[0157] Examples of specific carbohydrate excipients include monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melegitose, maltodextrin, dextran, and starch; and algitols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, and myo-inositol.

[0158] Examples of inorganic salts or buffering agents include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monobasic sodium phosphate, dibasic sodium phosphate, and combinations thereof.

[0159] Suitable antioxidants for use in this disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphate, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0160] Additional exemplary excipients include surfactants such as polysorbates, e.g., "Tween® 20" and "Tween® 80," as well as Pluronic® (both available from BASF, Mount Olive, NJ), such as F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidyltanolamines), fatty acids and fatty acid esters, and chelating agents such as EDTA, zinc, and other suitable cations.

[0161] Furthermore, the compositions disclosed herein may optionally contain one or more acids or bases. Non-limiting examples of acids that may be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Non-limiting examples of suitable bases include bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium sulfate, and combinations thereof.

[0162] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active ingredient, and the specific needs of the composition.

[0163] However, generally, the excipient is present in the composition in an amount of about 1% to about 99% by weight, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight of the excipient. Generally, the amount of excipient present in the composition of the present disclosure is selected from: at least about 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or further 95% by weight.

[0164] The compositions of this technology can be administered orally or parenterally, including by inhalation, intravenous, intraperitoneal, subcutaneous, rectal, and topical administration routes. Therefore, the compositions of this technology can be formulated in various forms, such as tablets, capsules, aqueous solutions, and suspensions. For tablets for oral administration, lactose, corn starch, and a carrier such as a lubricant, e.g., magnesium stearate, may conventionally be added. For capsules for oral administration, lactose and / or dried corn starch can be used as diluents. If an aqueous suspension is required for oral administration, the active ingredient can be combined with an emulsifier and / or suspending agent. Specific sweeteners and / or flavorings may be added, if desired. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution should be appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute should be controlled to make the preparation isotonic. The compositions of this technology may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, e.g., physiological saline with a pH level of 7.4. The solution can be introduced into the patient's intramuscular blood flow by local bolus injection.

[0165] The triazolone, tetrazolon, and imidazolon, i.e., the compounds of Formula 1, their stereoisomers, or pharmaceutically acceptable salts thereof, may be administered to a patient in an effective dose ranging from approximately 0.001 mg / kg to approximately 100 mg / kg per day. This includes 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg.

[0166] Generally, a therapeutically effective dose of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof may range from about 0.1 mg / day to 1000 mg / day, about 30 to 720 mg / day, about 60 to 600 mg / day, or about 100 to 480 mg / day, or higher total doses. In some embodiments, a therapeutically effective dose of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof may range from about 1 to 240 mg / day, about 30 to 240 mg / day, about 30 to 200 mg / day, about 30 to 120 mg / day, about 1 to 120 mg / day, about 50 to 150 mg / day, about 60 to 150 mg / day, about 60 to 120 mg / day, or about 60 to 100 mg / day, and may be administered as a single dose or in multiple doses. In some embodiments, multiple doses include doses administered two, three, or four times per day.

[0167] In some embodiments, a therapeutically effective dose of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof, is at least 0.1 mg / day, at least 0.5 mg / day, at least 1 mg / day, at least 5 mg / day, at least 10 mg / day, at least 20 mg / day, at least 30 mg / day, at least 40 mg / day, at least 50 mg / day, at least 60 mg / day, at least 70 mg / day, at least 80 mg / day, at least 90 mg / day, at least 100 mg / day, at least 110 mg / day, at least 120 mg / day, at least 130 mg / day, at least 140 mg / day, at least 150 mg / day, at least 160 mg / day, at least 170 mg / day, at least 180 mg / day, at least 190 mg / day, at least 200 mg / day, at least 225 mg / day, at least 250 mg / day, and at least 275 mg The dosage is at least 300 mg / day, at least 325 mg / day, at least 350 mg / day, at least 375 mg / day, at least 400 mg / day, at least 425 mg / day, at least 450 mg / day, at least 475 mg / day, at least 500 mg / day, at least 525 mg / day, at least 550 mg / day, at least 575 mg / day, at least 600 mg / day, at least 625 mg / day, at least 650 mg / day, at least 675 mg / day, at least 700 mg / day, at least 725 mg / day, at least 750 mg / day, at least 775 mg / day, at least 800 mg / day, at least 825 mg / day, at least 850 mg / day, at least 875 mg / day, at least 900 mg / day, at least 925 mg / day, at least 950 mg / day, at least 975 mg / day, or at least 1000 mg / day.

[0168] Naturally, the dosage may be adjusted according to the patient's age, weight, sensitivity, symptoms, or the efficacy of the compound.

[0169] In one embodiment, the technology provides a method for inhibiting vascular adhesion protein (VAP)-1 in mammals, comprising administering a therapeutically effective amount of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof to a mammal. In another embodiment, the technology provides a method for treating non-alcoholic steatohepatitis (NASH), comprising administering a therapeutically effective amount of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof to a mammal. In some embodiments, methods for treating NASH in patients requiring treatment are provided herein, which include, essentially consist of, or consist of administering a therapeutically effective amount of the compound of formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof to a subject. Examples of mammals include, but are not limited to, mice, rodents, rats, silverfish, humans, livestock, dogs, cats, sports animals, and pets.

[0170] In some embodiments, the technology provides the use of a compound of Formula 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof, for use in the preparation of pharmaceuticals for inhibiting vascular adhesion protein-1 (VAP-1) in mammals.

[0171] In one embodiment, the technology provides the use of a compound of Formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the preparation of pharmaceuticals for treating or preventing non-alcoholic steatohepatitis (NASH).

[0172] The present technology will be further described below with reference to examples and experimental examples. However, the following examples and experimental examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0173] As will be apparent to those skilled in the art by reading this disclosure, each of the individual embodiments described and illustrated herein has separate components and features that may be readily separated from or combined with any of the features of several other embodiments without departing from the scope or spirit of the Art. Any of the enumerated methods may be performed in the order of the enumerated events, or in any other logically possible order. [Examples]

[0174] The compounds prepared in the following examples were analyzed as follows. Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker 400 MHz spectrometer and an Agilent 600 MHz spectrometer, and the chemical shifts were analyzed in ppm. Furthermore, the indicated molecular weight was measured using an Agilent 1260 Infinity series liquid chromatography / mass selective detector (MSD) with an electrostatic spray interface (ESI+ represented by a [M+H]+ peak (indicating the m / z value in ESI-MS (cation)) by using a single quadrupole). Column chromatography was performed on silica gel (Merck, 70-230 mesh) (WCStill, J.Org.Chem., 43, 2923, 1978). Furthermore, the abbreviations used in the following examples are as follows: "methyl" is abbreviated as "Me", "ethyl" as "Et", "phenyl" as "Ph", "tert-butyloxycarbonyl" as "Boc", and "tert-butyldimethylsilyl" as "TBDMS". Furthermore, the starting materials for each example are known compounds synthesized according to the literature or obtained from Sigma-Aldrich.

[0175] Reference example 1. tert-butyl(E)-(2-(chloromethyl)-3-fluoroallyl)carbamate

[0176] 1.0 g of tert-butyl(E)-(3-fluoro-2-(hydroxymethyl)allyl)carbamate, 1.2 g of p-toluenesulfonyl chloride, and 0.88 mL of triethylamine were dissolved in 10.0 mL of dichloromethane, and the resulting solution was stirred at room temperature for 24 hours. Dichloromethane was added to the resulting reaction mixture. The reaction mixture was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain the title compound. 1 H-NMR(CDCl3,400MHz)δ7.61(s,1H),7.51(t,1H),7.16(s,1H),4.69(s,2H), 4.65-4.60(m,1H),3.90(s,3H),3.61-3.48(m,2H),3.41(s,3H),1.31(d,3H).

[0177] Reference example 2. tert-butyl N-[3,3-difluoro-2-(hydroxymethyl)allyl]carbamate

[0178] Step 1: tert-butyl N-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-difluoro-allyl]carbamate

[0179] Under nitrogen conditions, 2.4 g of tert-butyl N-[3-[tert-butyl(dimethyl)silyl]oxy-2-oxopropyl]carbamate and 1.0 g of 2-(difluoromethylsulfonyl)pyridine were dissolved in 34.5 mL of N,N-dimethylformamide and then cooled to -70°C. 10.4 mL of 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was slowly added dropwise to the reaction mixture. The resulting solution was stirred at -70°C for 30 minutes, and then stirred again by slowly raising the temperature to -10°C. 20 mL of ammonium chloride solution was added to the reaction mixture, followed by 20 mL of 3N hydrogen chloride solution. The reaction mixture was extracted three times with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) to obtain the title compound. 1 H-NMR (CDCl3, 400MHz) δ4.98 (s, 1H), 4.20 (s, 2H), 3.83 (s, 2H), 1.42 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H).

[0180] Step 2: tert-butyl N-[3,3-difluoro-2-(hydroxymethyl)allyl]carbamate

[0181] 426 mg of tert-butyl N-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-difluoroallyl]carbamate was dissolved in 2.0 mL of tetrahydrofuran, followed by the addition of 1.5 mL of a tetrahydrofuran solution of 1.0 M tetrabutylammonium fluoride (TBAF). The resulting solution was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture obtained in this way, and the organic layer was separated. Ethyl acetate was added to the aqueous layer of the reaction mixture, and the organic layer was separated again. The resulting organic layers were washed together with ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain the title compound. 1 H-NMR (CDCl3, 400MHz) δ4.91 (s, 1H), 4.14 (s, 2H), 3.86 (d, 2H), 3.72 (s, 1H), 1.45 (s, 9H).

[0182] Reference example 3. tert-butyl(2-(bromomethyl)-3,3-difluoroallyl)carbamate

[0183] 5.0 g of tert-butyl N-[3,3-difluoro-2-(hydroxymethyl)allyl]carbamate and 4.7 mL of triethylamine were dissolved in 100.0 mL of acetone at 0°C, and then 2.1 mL of methanesulfonyl chloride was slowly added to the mixture. The resulting solution was stirred at 0°C for 2 hours. The reaction mixture was filtered to remove the precipitated salt, and the filter cake was washed with acetone. 9.7 g of lithium bromide was added to the filtrate, and the suspension was stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture, and the contents were extracted twice with ethyl acetate. The combined organic extract was dehydrated with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound without further purification. 1 H-NMR (CDCl3, 400MHz) δ4.76 (bs, 1H), 4.05 (s, 2H), 3.88 (s, 2H), 1.45 (s, 9H).

[0184] Reference example 4.4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one

[0185] Step 1: 3-methyl-1,4-dihydro-1,2,4-triazole-5-one

[0186] 5.0 g of semicarbazide hydrochloride was dissolved in 100.0 mL of methanol. After adding 12.6 mL of trimethyl orthoacetate to the reaction solution, the solution was stirred overnight at room temperature. The reaction mixture thus obtained was concentrated and then washed with dichloromethane to obtain the title compound. 1 H-NMR (DMSO-d6, 400MHz) δ13.08(d,2H),2.02(s,3H).

[0187] Step 2: tert-butyl N-[3,3-difluoro-2-(hydroxymethyl)allyl]carbamate

[0188] 387 mg of 3-methyl-1,4-dihydro-1,2,4-triazole-5-one prepared in Step 1 and 1080 mg of potassium carbonate were dissolved in 4.0 mL of N,N-dimethylformamide, and then 1000 mg of 2-bromo-5-(bromomethyl)thiophene was added at 0°C. The resulting solution was stirred at room temperature for 3 hours. After adding distilled water, the reaction mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the title compound. 1 H-NMR(MeOD,400MHz)δ6.99(s,1H),6.91(s,1H),4.98(s,2H),2.23(s,3H)

[0189] Reference example 5.1-(5-bromothiophen-2-yl)-1,4-dihydro-5H-tetrazole-5-one

[0190] The reaction mixture of 500 mg of 5-bromothiophene-2-carbonyl chloride and 1533 mg of trimethylsilyl azide was stirred overnight at 100°C. The resulting reaction mixture was concentrated, ethyl acetate was added, and the concentrated reaction mixture was extracted three times with saturated NaHCO3 aqueous solution. The combined aqueous phase was acidified with 6N HCl aqueous solution until the pH reached 3. The aqueous phase was extracted twice with ethyl acetate. The resulting combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid. The crude solid was recrystallized with ethyl acetate to obtain the title compound. MS(ESI)m / z=247.0(M+H) +

[0191] Reference example 6.1-(3-bromophenyl)-1,4-dihydro-5H-tetrazole-5-one

[0192] The title compound was prepared in the same manner as in Reference Example 5, except that 530 mg of 3-bromobenzoyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride.

[0193] Reference example 7.1-(4-bromophenyl)-1,4-dihydro-5H-tetrazole-5-one

[0194] The title compound was prepared in the same manner as in Reference Example 5, except that 530 mg of 4-bromobenzoyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride.

[0195] Reference example 8.1-(6-bromo-3-methylpyridine-2-yl)-1,4-dihydro-5H-tetrazole-5-one

[0196] The title compound was prepared in the same manner as in Reference Example 5, except that 1000 mg of 6-bromo-3-methylpyridine-2-carbonyl chloride hydrochloride was used instead of 5-bromothiophene-2-carbonyl chloride. MS(ESI)m / z=256.0(M+H) +

[0197] Reference example 9.1-(3-bromobenzyl)-1,4-dihydro-5H-tetrazole-5-one

[0198] The title compound was prepared in the same manner as in Reference Example 5, except that 500 mg of 2-(3-bromophenyl)acetyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride. MS(ESI)m / z=255.0(M+H) +

[0199] Reference example 10.1-(4-bromothiophen-2-yl)-1,4-dihydro-5H-tetrazole-5-one

[0200] The title compound was prepared in the same manner as in Reference Example 5, except that 250 mg of 4-bromothiophene-2-carbonyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride.

[0201] Reference example 11.1-((5-bromothiophen-2-yl)methyl)-1,4-dihydro-5H-tetrazole-5-one

[0202] The title compound was prepared in the same manner as in Reference Example 5, except that 1000 mg of 2-(5-bromo-2-thienyl)acetyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride. MS(ESI)m / z=261.0(M+H) +

[0203] Reference example 12.1-(5-bromopyridine-3-yl)-1,4-dihydro-5H-tetrazole-5-one

[0204] The title compound was prepared in the same manner as in Reference Example 5, except that 1000 mg of 5-bromopyridine-3-carbonyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride.

[0205] Reference example 13.1-(4-bromo-2-fluorophenyl)-1,4-dihydro-5H-tetrazole-5-one

[0206] The title compound was prepared in the same manner as in Reference Example 5, except that 1000 mg of 4-bromo-2-fluorobenzoyl chloride was used instead of 5-bromothiophene-2-carbonyl chloride.

[0207] Reference example 14. tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0208] 637 mg of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4, 519 mg of tert-butyl N-[3,3-difluoro-2-(hydroxymethyl)allyl]carbamate prepared in Reference Example 2, and 915 mg of triphenylphosphine were dissolved in 1.0 mL of tetrahydrofuran, and the resulting solution was stirred and cooled to 0°C. 690 μL of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain the title compound. 1 H-NMR (CDCl3, 400MHz) δ6.90(d,1H),6.79(d,1H),5.57(s,1H),4.85(s,2H),4.41(s,2H),3.69(s,2H),2.20(s,3H),1.41(s,9H).

[0209] Reference example 15. tert-butyl(2-((4-(5-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0210] The title compound was prepared in the same manner as in Reference Example 14, except that 308 mg of 1-(5-bromothiophene-2-yl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 5 was used instead of 4-((5-bromothiophene-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4.

[0211] Reference example 16. tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0212] The title compound was prepared in the same manner as in Reference Example 14, except that 300 mg of 1-(3-bromophenyl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 6 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ8.18(s,1H),7.93(d,1H),7.51(d,1H),7.35(dd,1H),4.71(s,2H),3.83(s,2H),1.35(s,9H).

[0213] Reference example 17. tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0214] The title compound was prepared in the same manner as in Reference Example 14, except that 530 mg of 1-(4-bromophenyl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 7 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1H-NMR (CDCl3, 400MHz) δ7.85(d,2H),7.61(d,2H),4.69(s,2H),3.81(s,2H),1.31(s,9H).

[0215] Reference example 18. tert-butyl(2-((4-(6-bromo-3-methylpyridine-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0216] The title compound was prepared in the same manner as in Reference Example 14, except that 660 mg of 1-(6-bromo-3-methylpyridine-2-yl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 8 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ7.59(d,1H),7.54(d,1H),4.66(s,2H),3.81(s,2H),2.26(s,3H),1.29(s,9H).

[0217] Reference example 19. tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0218] The title compound was prepared in the same manner as in Reference Example 14, except that 480 mg of 1-(3-bromobenzyl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 9 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ8.02(s,1H),7.96(d,1H),7.82-7.71(m,2H),5.79(s,2H),4.64(s,2H),3.89(s,2H),1.35(s,9H).

[0219] Reference example 20. tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0220] The title compound was prepared in the same manner as in Reference Example 14, except that 145 mg of 1-(4-bromothiophen-2-yl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 10 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ7.41 (s, 1H), 7.10 (s, 1H), 4.70 (s, 2H), 3.83 (s, 2H), 1.39 (s, 9H).

[0221] Reference example 21. tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0222] The title compound was prepared in the same manner as in Reference Example 14, except that 340 mg of 1-((5-bromothiophen-2-yl)methyl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 11 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ6.95-6.90 (m, 2H), 5.15 (s, 2H), 4.65 (s, 2H), 3.81 (s, 2H), 1.35 (s, 9H).

[0223] Reference example 22. tert-butyl(2-((4-(5-bromopyridine-3-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0224] The title compound was prepared in the same manner as in Reference Example 14, except that 140 mg of 1-(5-bromopyridine-3-yl)-1,4-dihydro-5H-tetrazole-5-one prepared in Reference Example 12 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one prepared in Reference Example 4. 1 H-NMR (CDCl3, 400MHz) δ9.18 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 4.71 (s, 2H), 3.82 (s, 2H), 1.37 (s, 9H).

[0225] Reference example 23. tert-butyl(2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0226] 100 mg of 3-[(5-bromo-2-thienyl)methyl]-1H-imidazole-2-one and 251 mg of cesium carbonate were dissolved in 2.0 mL of N,N-dimethylformamide at 0°C, followed by the addition of 116 mg of tert-butyl(2-(bromomethyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 3. The resulting solution was stirred overnight at room temperature. The resulting reaction mixture was quenched with water and extracted three times with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain the title compound.

[0227] Reference example 24. tert-butyl(E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3-fluoroallyl)carbamate

[0228] The title compound was prepared in the same manner as in Reference Example 23, except that 1-(4-bromo-2-fluorophenyl)-1,4-dihydro-5H-tetrazole-5-one, prepared in 300 mg of Reference Example 13, was used instead of 3-[(5-bromo-2-thienyl)methyl]-1H-imidazole-2-one, and tert-butyl(E)-(2-(chloromethyl)-3-fluoroallyl)carbamate, prepared in 259 mg of Reference Example 1, was used instead of tert-butyl(2-(bromomethyl)-3,3-difluoroallyl)carbamate, prepared in Reference Example 3. 1 H-NMR (CDCl3, 400MHz) δ7.48(dd,2H),7.45(s,1H),6.84(d,1H),5.01(bs,1H),4.56(s,2H),3.93(s,2H),1.42(s,9H).

[0229] Example 1. 2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-ontrifluoroacetate

[0230] Step 1: tert-butyl(2-((4-((5-(1-ethyl-1H-pyrazole-4-yl)thiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0231] 34 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14 and 16 mg of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were dissolved in 1.5 mL of 1,4-dioxane. Subsequently, 220 μL of 1 M potassium carbonate and 2 mg of palladium di[1,1'-bis(diphenylphosphino)ferrocene]dichloride (PdCl2(dppf)) were added, and the resulting solution was stirred overnight at 90°C. The resulting reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the residue. The residue obtained in this manner was dissolved in ethyl acetate, washed with distilled water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain the title compound. 1 H-NMR(CDCl3,400MHz)δ7.57(dd,1H),7.48(dd,1H),6.94(d,1H),6.89(d,1H),5.62(bs,1H) ,4.93(s,2H),4.45(s,2H),4.18(q,2H),3.72(s,2H),2.26(s,3H),1.52(t,3H),1.45(s,9H).

[0232] Step 2: 2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-ontrifluoroacetate

[0233] 15 mg of tert-butyl(2-((4-((5-(1-ethyl-1H-pyrazole-4-yl)thiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Step 1 was dissolved in 1.5 mL of dichloromethane, followed by the addition of 80 μL of trifluoroacetic acid. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated, followed by the addition of dichloromethane. The solution was concentrated under reduced pressure and then dried under vacuum to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the title compound. 1 H-NMR (MeOD, 400MHz) δ7.90(s,1H),7.67(s,1H),7.02(dd,2H),5.05(s,2H),4.56(s,2H),4.20(dd,2H),3.67(s,2H),2.30(s,3H),1.47(t,3H).

[0234] Example 2.2-[2-(aminomethyl)-3,3-difluoroallyl]-5-methyl-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]-1,2,4-triazole-3-ontrifluoroacetate

[0235] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 33 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.96(d,2H),7.85(d,2H),7.49(d,1H),7.18(d,1H),5.12(s,2H),4.57(s,2H),3.69(s,2H),3.15(s,3H),2.32(s,3H).

[0236] Example 3.2-[2-(aminomethyl)-3,3-difluoroallyl]-5-methyl-4-[[5-(4-piperazine-1-ylphenyl)-2-thienyl]methyl]-1,2,4-triazole-3-ondi-trifluoroacetate

[0237] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 46 mg of tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.52(d,2H),7.15(d,1H),7.06(m,3H),5.06(s,2H),4.56(s,2H),3.67(s,2H),3.46(t,4H),3.38(t,4H),2.31(s,3H).

[0238] Example 4.5-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-1-ethyl-pyridine-2-ontrifluoroacetate

[0239] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 29 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.98(d,1H),7.77(dd,1H),7.12(dd,2H),6.59(d,1H),5 .07(s,2H),4.56(s,2H),4.09(dd,2H),3.68(s,2H),2.30(s,3H),1.36(t,3H).

[0240] Example 5.2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-[6-(dimethylamino)-3-pyridyl]-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-ontrifluoroacetate

[0241] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 29 mg of 6-(dimethylamino)pyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ8.12(m,2H),7.28(d,1H),7.15(m,2H),5.09(s,2H),4.57(s,2H),3.69(s,2H),3.30(s,6H),2.31(s,3H).

[0242] Example 6.2-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1,3-benzodioxol-5-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazole-3-ontrifluoroacetate

[0243] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 29 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-yl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.12(d,1H),7.06(m,3H),6.83(d,1H),5.05(s,2H),4.56(s,2H),3.67(s,2H),2.30(s,3H).

[0244] Example 7.6-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0245] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 34 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.27(s,2H),7.18(d,1H),7.07(d,1H),5.06(s,2H),4.57(s,2H),3.68(s,2H),2.95(t,2H),2.57(t,2H),2.29(d,6H).

[0246] Example 8.6-[5-[[1-[2-(aminomethyl)-3,3-difluoroallyl]-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0247] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 34 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.50(d,1H),7.45(s,1H),7.23(s,1H),7.11(dd,1H),5.07(s ,2H),4.57(s,2H),3.68(s,2H),3.32(m,6H),2.95(t,2H),2.64(t,2H),2.32(s,3H).

[0248] Example 9.5-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-2-thienyl]-1-ethylpyridine-2-ontrifluoroacetate

[0249] In step 1, 50 mg of tert-butyl(2-((4-(5-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 15 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H The title compound was prepared in the same manner as in Example 1, except that it was used instead of -1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate, and 28 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.04(s,1H),7.78(d,J=8.4Hz,1H),7.38(s,1H),7.23(s,1H),6.6 0(d,J=8.4Hz,1H)4.08(q,J=7.2Hz,2H),3.72(s,2H),3.33(s,2H),1.36(t,J=7.2Hz,3H).

[0250] Example 10.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(4-methylsulfonylphenyl)phenyl]tetrazol-5-ontrifluoroacetate

[0251] In step 1, 70 mg of tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 16 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 44 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ8.16(d,J=8.0Hz,1H),8.06-7.91(m,5H),7.77(s,1H),7.69(d,J=8.0Hz,1H),3.76(s,2H),3.28(s,2H),3.11(s,3H).

[0252] Example 11.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(4-piperazine-1-ylphenyl)phenyl]tetrazol-5-ontrifluoroacetate

[0253] In step 1, 70 mg of tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 16 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole- The title compound was prepared in the same manner as in Example 1, except that 1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 61 mg of tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.10(d,J=10.0Hz,1H),7.81-7.60(m,5H),7.20-7.10(m,2 H),3.74(s,2H),3.70(s,1H),3.60-3.50(m,4H),3.45-3.37(m,4H),3.25(s,2H).

[0254] Example 12.5-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]phenyl]-1-ethyl-pyridine-2-ondi-trifluoroacetate

[0255] In step 1, 70 mg of tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 16 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 39 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.06-8.03(m,2H),7.90-7.80(m,2H),7.65-7.54(m,2H),6.66 -6.63(m,1H),4.11(q,J=7.2Hz,2H),3.76(s,2H),3.29(s,2H),1.36(t,J=7.2Hz,3H).

[0256] Example 13.6-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0257] In step 1, 70 mg of tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 16 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4 The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 45 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.10(s,1H),7.79-7.56(m,3H),7.33-7.25(m,2H),3.76 (s,2H),3.32(s,2H),2.97(d,J=6.0Hz,2H),2.56(d,J=6.0Hz,2H),2.27(s,3H).

[0258] Example 14.6-[3-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0259] In step 1, 70 mg of tert-butyl(2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 16 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that riazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 45 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.15(s,1H),7.84-7.52(m,5H),7.25-7.15(m,2H),3.76 (s,2H),3.32(s,2H),3.29(s,3H),2.96(d,J=6.0Hz,2H),2.61(d,J=6.0Hz,2H).

[0260] Example 15. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-(1-ethylpyrazole-4-yl)phenyl]tetrazol-5-ontrifluoroacetate

[0261] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1H-NMR (MeOD, 400MHz) δ8.15-8.05(m,2H),7.86(s,1H),7.71-7.49(m,3H),4.20(q,J=6.4Hz,2H),3.75(s,2H),3.28(s,2H),1.47(t,J=6.4Hz,3H).

[0262] Example 16.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-methylsulfonylphenyl)phenyl]tetrazol-5-ontrifluoroacetate

[0263] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 41 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ 8.10-8.00 (m, 4H), 7.98-7.76 (m, 4H), 3.77 (s, 2H), 3.29 (s, 2H), 3.15 (s, 3H).

[0264] Example 17.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-piperazine-1-ylphenyl)phenyl]tetrazol-5-ondi-trifluoroacetate

[0265] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole- The title compound was prepared in the same manner as in Example 1, except that 1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 56 mg of tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.91(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.59(d,J=7.6Hz,2H ),7.08(d,J=7.6Hz,2H),3.73(s,2H),3.50-3.40(m,4H),3.36-3.30(m,4H),3.27(s,2H).

[0266] Example 18. 5-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-ethylpyridine-2-ontrifluoroacetate

[0267] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 36 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.06-7.98(m,3H),7.90(d,J=8.4Hz,1H),7.80-7.70(m,2H),6.63 (d,J=8.4Hz,1H),4.10(q,J=7.6Hz,2H),3.77(s,2H),3.29(s,2H),1.38(t,J=7.6Hz,3H).

[0268] Example 19.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)phenyl]tetrazol-5-ontrifluoroacetate

[0269] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tri) carbamate prepared in Reference Example 14. The title compound was prepared in the same manner as in Example 1, except that azole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 36 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.93(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),7.13(d, J=8.4Hz,2H),6.90(d,J=8.4Hz,1H),5.92(s,2H),3.76(s,2H),3.29(s,2H).

[0270] Example 20.6-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0271] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4 The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 42 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.93(d,J=6.8Hz,2H),7.73(d,J=6.8Hz,2H),7.40-7.30(m,2H),6.47( s,1H),3.78(s,2H),3.30(s,2H),2.84(t,J=11.2Hz,2H),2.49(t,J=11.2Hz,2H),2.31(s,3H).

[0272] Example 21.6-[4-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]phenyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0273] In step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 17 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that riazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 42 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.96(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.59-7.50(m,2H),7.19(d,J =8.4Hz,1H),3.77(s,2H),3.67(s,3H),3.29(s,2H),2.96(t,J=8.4Hz,2H),2.64(t,J=8.4Hz,2H).

[0274] Example 22.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1-ethylpyrazole-4-yl)phenyl]tetrazol-5-ontrifluoroacetate

[0275] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 65 mg of tert-butyl(2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1H-NMR (MeOD, 400MHz) δ8.07(s,1H),7.90-7.84(m,3H),7.71(d,J=8.4Hz,2H),4.20(q,J=7.2Hz,2H),3.75(s,2H),3.28(s,2H),1.47(t,J=7.2Hz,3H).

[0276] Example 23.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[3-methyl-6-(4-methylsulfonylphenyl)-2-pyridyl]tetrazol-5-ontrifluoroacetate

[0277] In step 1, 70 mg of tert-butyl(2-((4-(6-bromo-3-methylpyridine-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 18 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1) carbamate prepared in Reference Example 14. The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 43 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.24(d,J=8.4Hz,2H),8.05(d,J=8.4Hz,1H),8.01-7.79(m ,2H),7.29(d,J=3.6Hz,1H),3.56(s,2H),3.23(s,2H),3.09(s,3H),2.32(s,3H).

[0278] Example 24. 5-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-5-methyl-2-pyridyl]-1-ethyl-pyridine-2-ontrifluoroacetate

[0279] In step 1, 70 mg of tert-butyl(2-((4-(6-bromo-3-methylpyridine-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared in the same manner as in Example 1, except that 1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 38 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.37(s,1H),8.12(d,J=9.2Hz,1H),7.88(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),6 .54(d,J=8.0Hz,1H),4.04(q,J=6.8Hz,2H),3.71(s,2H),3.26(s,2H),2.26(s,3H),1.30(t,J=6.8Hz,3H).

[0280] Example 25. 6-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-5-methyl-2-pyridyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0281] In step 1, 70 mg of tert-butyl(2-((4-(6-bromo-3-methylpyridine-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H- The title compound was prepared in the same manner as in Example 1, except that 1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 44 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.90-7.84(m,2H),7.70-7.61(m,2H),4.84(s,1H),3.73(s,2H) ,3.23(s,2H),2.93(t,J=7.6Hz,2H),2.52(t,J=7.6Hz,2H),2.27(s,3H),2.24(s,3H).

[0282] Example 26. 6-[6-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-5-methyl-2-pyridyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0283] In step 1, 70 mg of tert-butyl(2-((4-(6-bromo-3-methylpyridine-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 18 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 44 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.93-7.83(m,4H),7.14(d,J=8.4Hz,1H),3.73(s,2H),3.3 1(s,3H),3.27(s,2H),2.92(t,J=7.6Hz,2H),2.59(t,J=7.6Hz,2H),2.28(s,3H).

[0284] Example 27.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(4-methylsulfonylphenyl)phenyl]methyl]tetrazol-5-ontrifluoroacetate

[0285] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 43 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.96(d,J=8.8Hz,2H),7.80(d,J=8.8Hz,2H),7.64-7.20(m,4H),4.71(s,2H),3.63(s,2H),3.23(s,2H),3.03(s,3H).

[0286] Example 28. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(4-piperazine-1-ylphenyl)phenyl]methyl]tetrazol-5-ondi-trifluoroacetate

[0287] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole- The title compound was prepared in the same manner as in Example 1, except that 1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 59 mg of tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.54-7.33(m,6H),7.03(d,J=8.8Hz,2H),4.71(s,2H),3.62(s,2H),3.60-3.38(m,4H),3.31-3.23(m,4H),3.21(s,2H).

[0288] Example 29.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-[6-(dimethylamino)-3-pyridyl]phenyl]methyl]tetrazol-5-ontrifluoroacetate

[0289] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was used in place of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14, and 38 mg of 6-(dimethylamino)pyridine-3-boronic acid pinacol ester was used in place of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ 8.15-8.09 (m, 2H), 7.60-7.15 (m, 5H), 4.72 (s, 2H), 3.64 (s, 2H), 3.24 (s, 6H), 3.21 (s, 2H).

[0290] Example 30. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(1,3-benzodioxol-5-yl)phenyl]methyl]tetrazol-5-ontrifluoroacetate

[0291] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tri) carbamate prepared in Reference Example 14. The title compound was prepared in the same manner as in Example 1, except that azole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 38 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole.1 H-NMR(MeOD,400MHz)δ7.50-7.32(m,3H),7.24(d,J=7.6Hz,1H),7.01-6.93(m, 2H), 6.81 (d, J=7.6Hz, 1H), 5.14 (s, 2H), 4.71 (s, 2H), 3.63 (s, 2H), 3.23 (s, 2H).

[0292] Example 31.6-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]phenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0293] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4 The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 44 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.53-7.32(m,3H),7.25-7.20(m,3H),4.71(s,2H),3.63 (s,2H),3.23(s,2H),2.90(t,J=7.2Hz,2H),2.49(t,J=7.2Hz,2H),2.23(s,3H).

[0294] Example 32. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[3-(1-ethylpyrazole-4-yl)phenyl]methyl]tetrazol-5-ontrifluoroacetate

[0295] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1 H-NMR(MeOD,400MHz)δ7.95(s,1H),7.75(s,1H),7.52-7.46(m,2H),7.29(t,J=8.4Hz,1H),7.15(d ,J=8.4Hz,1H),4.72(s,2H),4.3(q,J=7.2Hz,2H),3.63(s,2H),3.23(s,2H),1.41(t,J=7.2Hz,3H).

[0296] Example 33.6-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]phenyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0297] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that riazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 44 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1 H-NMR(MeOD,400MHz)δ7.58-7.27(m,6H),7.12(d,J=8.4Hz,1H),4.71(s,2H),3.6 3(s,2H),3.31(s,3H),3.23(s,2H),2.90(t,J=6.8Hz,2H),2.56(t,J=7.2Hz,2H).

[0298] Example 34. 5-[3-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]phenyl]-1-ethylpyridine-2-ontrifluoroacetate

[0299] In step 1, 70 mg of tert-butyl(2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 19 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 38 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.00(s,1H),7.87(d,J=2.4Hz,1H),7.60-7.35(m,4H),6.64(d,J=9.2 Hz,1H),4.79(s,2H),4.20(q,J=6.8Hz,2H),3.71(s,2H),3.31(s,2H),1.39(t,J=6.8Hz,3H).

[0300] Example 35.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-methylsulfonylphenyl)-2-thienyl]tetrazol-5-ontrifluoroacetate

[0301] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2 The title compound was prepared in the same manner as in Example 1, except that 4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 14 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.90(d,J=6.4Hz,2H),7.83(d,J=6.4Hz,2H),7.80(s,1H),7.75(s,1H),3.68(s,2H),3.24(s,2H),3.05(s,3H).

[0302] Example 36.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(4-piperazine-1-ylphenyl)-2-thienyl]tetrazol-5-ondi-trifluoroacetate

[0303] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazone The title compound was prepared in the same manner as in Example 1, except that 19 mg of tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.64(s,1H),7.51(d,J=8.8Hz,2H),7.34(s,1H),6.97(d ,J=8.8Hz,2H),3.65(s,2H),3.35-3.28(m,4H),3.28-3.24(m,4H),3.20(s,2H).

[0304] Example 37. 5-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-1-ethyl-pyridine-2-ontrifluoroacetate

[0305] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H The title compound was prepared in the same manner as in Example 1, except that it was used instead of -1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate, and 12 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ8.01(s,1H),7.85(d,J=8.0Hz,1H),7.63(s,1H),7.31(s,1H),6.55( d,J=8.0Hz,1H),4.01(q,J=11.2Hz,2H),3.67(s,2H),3.23(s,2H),1.24(t,J=11.2Hz,3H).

[0306] Example 38. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-[6-(dimethylamino)-3-pyridyl]-2-thienyl]tetrazol-5-ontrifluoroacetate

[0307] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was used in place of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14, and 12 mg of 6-(dimethylamino)pyridine-3-boronic acid pinacol ester was used in place of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ8.16-8.13(m,2H),7.69(s,1H),7.58(s,1H),7.10(d,J=8.8Hz,1H),3.66(s,2H),3.24(s,2H),3.19(s,6H).

[0308] Example 39.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)-2-thienyl]tetrazol-5-ontrifluoroacetate

[0309] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4 The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 12 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.60(s,1H),7.35(s,1H),7.05(d,J=8.8Hz,2H),6.73(d,J=8.8Hz,1H),5.81(s,2H),3.67(s,2H),3.23(s,2H).

[0310] Example 40.6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0311] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 14 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.65(s,1H),7.41(s,1H),7.28-7.25(m,2H),3.67(s,2H),3 .25(s,1H),3.22(s,2H),2.89(t,J=9.2Hz,2H),2.46(t,J=9.2Hz,2H),2.20(s,3H).

[0312] Example 41.6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-thienyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0313] In step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 20 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2, The title compound was prepared in the same manner as in Example 1, except that 4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 14 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.67(s,1H),7.49-7.44(m,3H),7.05(d,J=8.4Hz,1H),3.6 7(s,2H),3.26(s,3H),3.20(s,2H),2.85(t,J=8.0Hz,2H),2.54(t,J=8.0Hz,2H).

[0314] Example 42. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[4-(1-ethylpyrazole-4-yl)-2-thienyl]tetrazol-5-ontrifluoroacetate

[0315] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 22 mg of tert-butyl(2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1H-NMR (MeOD, 400MHz) δ7.88(s,1H),7.68(s,1H),7.54(s,1H),7.27(s,1H),4.11(q,J=7.2Hz,2H),3.66(s,2H),3.24(s,2H),1.38(t,J=7.2Hz,3H).

[0316] Example 43.1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]tetrazol-5-ontrifluoroacetate

[0317] In step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 21 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1 The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 42 mg of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.90-7.70(m,4H),7.34(s,1H),7.13(s,1H),4.67(s,2H),3.70(s,2H),3.25(s,2H),3.04(s,3H).

[0318] Example 44. 5-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]-2-thienyl]-1-ethylpyridine-2-ontrifluoroacetate

[0319] In step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 21 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared in the same manner as in Example 1, except that 1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 37 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.88(s,1H),6.67(d,J=9.2Hz,1H),7.07-7.03(m,2H),6.49(d,J=9.2 Hz,1H),4.68(s,2H),3.97(q,J=8.0Hz,2H),3.60(s,2H),3.21(s,2H),1.26(t,J=8.0Hz,3H).

[0320] Example 45.6-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazol-1-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0321] In step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 21 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H- The title compound was prepared in the same manner as in Example 1, except that 1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 43 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.20-7.18(m,2H),7.08(s,1H),7.01(s,1H),4.67(s,2H),3 .59(s,2H),3.20(s,2H),2.85(t,J=8.0Hz,2H),2.46(t,J=8.0Hz,2H),2.17(s,3H).

[0322] Example 46.6-[5-[[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0323] In step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 21 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 43 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.42-7.36(m,2H),7.13(s,1H),7.05-7.01(m,2H),4.68(s,2H) ,3.60(s,2H),3.26(s,3H),3.20(s,2H),2.85(t,J=6.8Hz,2H),2.53(t,J=6.8Hz,2H).

[0324] Example 47. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]tetrazol-5-ontrifluoroacetate

[0325] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 70 mg of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 21 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1H-NMR(MeOD,400MHz)δ7.79(s,1H),7.56(s,1H),6.97(d,J=3.6Hz,1H),6.90(d,J=3.6Hz, 1H),4.67(s,2H),4.08(q,J=7.6Hz,2H),3.54(s,2H),3.20(s,2H),1.36(t,J=7.6Hz,3H).

[0326] Example 48. 1-[2-(aminomethyl)-3,3-difluoroallyl]-4-[5-(1,3-benzodioxol-5-yl)-3-pyridyl]tetrazol-5-ontrifluoroacetate

[0327] In step 1, 35 mg of tert-butyl(2-((4-(5-bromopyridine-3-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 22 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 19 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ8.96-8.43(m,3H),7.15-6.89(m,3H),5.95(s,2H),3.67(s,2H),3.25(s,2H).

[0328] Example 49.6-[5-[4-[2-(aminomethyl)-3,3-difluoroallyl]-5-oxotetrazole-1-yl]-3-pyridyl]-8-methyl-3,4-dihydro-1H-quinoline-2-ontrifluoroacetate

[0329] In step 1, 35 mg of tert-butyl(2-((4-(5-bromopyridine-3-yl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 22 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2 The title compound was prepared in the same manner as in Example 1, except that ,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 22 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ9.09(s,1H),8.87(s,1H),8.56(s,1H),7.50-7.45(m,2H),3 .78(s,2H),3.32(s,2H),2.86(t,J=6.8Hz,2H),2.60(t,J=6.8Hz,2H),2.18(s,3H).

[0330] Example 50. 5-[5-[[3-[2-(aminomethyl)-3,3-difluoroallyl]-2-oxoimidazole-1-yl]methyl]-2-thienyl]-1-ethyl-pyridine-2-ontrifluoroacetate

[0331] In step 1, 50 mg of tert-butyl(2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 23 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared in the same manner as in Example 1, except that 1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 27 mg of 1-ethyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.94(d,J=2.4Hz,1H),7.75(d,J=9.2Hz,1H),7.10(d,J=3.6Hz,1H),7.02(d,J=3.6Hz,1H), 6.71-6.67(m,2H),6.66(d,J=9.2Hz,1H),4.93(s,2H),4.06(q,J=7.6Hz,2H),3.40(s,2H),1.33(t,J=7.6Hz,3H).

[0332] Example 51.6-[5-[[3-[2-(aminomethyl)-3,3-difluoroallyl]-2-oxoimidazole-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinoline-2-ontrifluoroacetate

[0333] In step 1, 50 mg of tert-butyl(2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 23 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 43 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(MeOD,400MHz)δ7.47(d,J=8.0Hz,1H),7.43(s,1H),7.19(d,J=3.2Hz,1H),7.10(d,J=8.0Hz,1H),7.03(d,J=3.2Hz, 1H),6.62-6.56(m,2H),4.42(s,2H),3.60(s,2H),3.34(s,3H),3.29(s,2H),2.92(t,J=7.2Hz,2H),2.61(t,J=7.2Hz,2H).

[0334] Example 52. 1-[2-(aminomethyl)-3,3-difluoroallyl]-3-[[5-(1-ethylpyrazole-4-yl)-2-thienyl]methyl]imidazole-2-ontrifluoroacetate

[0335] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 50 mg of tert-butyl(2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 23 was used instead of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. 1 H-NMR(MeOD,400MHz)δ7.85(s,1H),7.63(s,1H),6.78-6.72(m,2H),5.98(s,1H),5.92(s, 1H),4.91(s,2H),4.16(q,J=7.2Hz,2H),3.80(s,2H),3.30(s,2H),1.44(t,J=7.2Hz,3H).

[0336] Example 53.1-[2-(aminomethyl)-3,3-difluoroallyl]-3-[[5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-thienyl]methyl]imidazole-2-ontrifluoroacetate

[0337] In step 1, 50 mg of tert-butyl(2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in reference example 23 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tri) carbamate prepared in reference example 14. The title compound was prepared in the same manner as in Example 1, except that azole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 22 mg of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5,a]pyridine was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1 H-NMR(MeOD,400MHz)δ8.75(d,J=6.8Hz,1H),8.40(s,1H),7.88-7.49(m,3H),7.16(d,J=3. 2Hz, 1H), 6.80 (d, J=3.2Hz, 1H), 6.00-5.92 (m, 1H), 5.02 (s, 2H), 3.82 (s, 2H), 3.31 (s, 2H).

[0338] Example 54. 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[4-(1,3-benzodioxol-5-yl)-2-fluorophenyl]-1,2,4-triazole-3-onhydrochloride

[0339] In step 1, 50 mg of tert-butyl(E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3-fluoroallyl)carbamate prepared in reference example 24 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2, The title compound was prepared in the same manner as in Example 1, except that 4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 35 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole. 1 H-NMR (DMSO-d6,400MHz) δ7.82(d,1H),7.71(s,2H),7.42(s,1H),7.36(d,1H),7.30(d,1H),7.05(d,1H),6.10(s,2H),4.79(d,2H),3.58(s,2H).

[0340] Example 55. 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[4-(2,1,3-benzoxadiazole-5-yl)-2-fluorophenyl]-1,2,4-triazole-3-onhydrochloride

[0341] The title compound was prepared in the same manner as in Example 1, except that in Step 1, 50 mg of tert-butyl(E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 24 was used in place of tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14, and 23 mg of benzo[c][1,2,5]oxadiazole-5-ylboronic acid was used in place of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (DMSO-d6,400MHz) δ8.54(s,1H),8.23(d,1H),8.16-8.08(m,2H),7.98(d,1H),7.87(t,1H),7.37(d,1H),4.80(s,2H),3.58(s,2H).

[0342] Example 56.6-[4-[1-[(E)-2-(aminomethyl)-3-fluoroallyl]-5-oxo-1,2,4-triazole-4-yl]-3-fluorophenyl]-8-methyl-3,4-dihydro-1H-quinoline-2-onhydrochloride

[0343] In step 1, 50 mg of tert-butyl(E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 24 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1 The title compound was prepared in the same manner as in Example 1, except that 2,4-triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 41 mg of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-boronic acid pinacol ester was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(DMSO-d6,400MHz)δ9.61(s,1H),7.83(d,1H),7.72(s,2H),7.50(d,2H), 7.36(d,1H),4.79(s,2H),3.57(s,2H),2.95(t,2H),2.50(t,2H),2.30(s,3H).

[0344] Example 57. 2-[(E)-2-(aminomethyl)-3-fluoroallyl]-4-[2-fluoro-4-(6-morpholino-3-pyridyl)phenyl]-1,2,4-triazole-3-onhydrochloride

[0345] In step 1, 50 mg of tert-butyl(E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazole-1-yl)methyl)-3-fluoroallyl)carbamate prepared in reference example 24 is used to prepare tert-butyl(2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- The title compound was prepared in the same manner as in Example 1, except that triazole-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead, and 41 mg of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)morpholine was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR(DMSO-d6,400MHz)δ8.38(d,1H),8.35(s,1H),7.84(t,2H),7.80(d,1H), 7.47(d,1H),7.32(d,1H),4.79(s,2H),3.88(d,4H),3.79(s,2H),3.75(d,4H).

[0346] The compounds used in the examples are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] * The compounds were isolated as either free bases or salts, as described in Examples 1 to 57.

[0347] Experimental Example 1: Activity Evaluation of Amine Oxidase

[0348] The activity of compounds produced using this technique against recombinant human VAP-1 (R&D systems) was evaluated by measuring the level of hydrogen peroxide in a horseradish peroxidase (HRP) binding reaction using the Amplex Red Hydrogen Peroxide Assay Kit (Molecular Probes, Invitrogen, USA). The experiment was performed at room temperature using benzylamine as the substrate. In the HRP binding reaction, hydrogen peroxide oxidation of 10-acetyl-3,7-dihydroxyphenoxazine (Amplex Red reagent) produces resorphine, a highly fluorescent compound. Briefly, the test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 20 mM. Dose-response evaluation was performed by 1:3 serial dilutions in DMSO, thereby creating an 8-point curve. The upper concentration was controlled according to the potency of the compound, and then diluted with reaction buffer to obtain a final DMSO concentration of less than 1%. Human VAP-1 purified in 50 mM sodium phosphate buffer (pH 7.4) was added to each well of a black 96-well plate. Test compounds dissolved in DMSO were incubated with human VAP-1 enzyme at 37°C for 30 minutes. After 30 minutes of incubation, a reaction mixture containing 50 mM sodium phosphate buffer (pH 7.4), 1 mM benzylamine, and 200 μM Amplex Red reagent prepared from 1 U / mL HRP was added to each well. A microplate reader (Flexstation3, Molecular Devices) was used under wavelength conditions of excitation at 544 nm and emission reading at 590 nm, and fluorescence intensity was measured at multiple time points over 1–2 hours. The inhibitory effect of the compound was measured as a percentage decrease in signal rate compared to a control group without the inhibitor (diluted DMSO only). The data were fixed to a logistic model with four variable values, and IC was performed using the GraphPad Prism program. 50 The value was calculated.

[0349] Furthermore, the activity of compounds produced using this technology against recombinant human MAO-A (monoamine oxidase-A, Sigma-Aldrich) and recombinant human MAO-B (monoamine oxidase-B, Sigma-Aldrich) was evaluated using 0.5 mM tyramine and 1 mM benzylamine, respectively, in the same manner as the activity evaluation method for recombinant human VAP-1. The activity of compounds produced using this technology against recombinant human DAO (diamine oxidase, R&D systems) was also evaluated using 1 mM putrescine as a substrate, in the same manner as the activity evaluation method for recombinant human VAP-1.

[0350] The results obtained by evaluating the activity of the above enzymes are shown in Table 2 below. [Table 2-1] [Table 2-2]

[0351] The results in Table 2 above show that the compounds produced by this technology exhibit superior inhibitory activity against VAP-1 among various amine oxidases. The present invention provides, for example, the following items: (Item 1) Compound of formula 1, [ka] or a pharmaceutically acceptable salt thereof During the ceremony, (i) X is N, and Y is N or CR 2’ And, or (ii) X is CR 3 And Y is N or CR 2 And, or (iii) Both X and Y are N, R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 Alkyl, halogen, phenyl, or benzyl, R 2’ C 1~3 Alkyl, halogen, phenyl, or benzyl, R 3 is hydrogen, C 1~3 Alkyl or phenyl, n is either 0 or 1. A is C 6 ~C 10 The aryl group or the 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C 1~3 It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic. (Item 2) A, C 1~3 C is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. 6 ~C 10 A compound listed in item 1, or a pharmaceutically acceptable salt thereof, which is an aryl group. (Item 3) A, C 1~3 A compound or pharmaceutically acceptable salt thereof described in item 1 or item 2, which is a phenyl compound optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. (Item 4) A is a 5-10 membered heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, wherein the heteroaryl group is C 1~3 A compound described in item 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. (Item 5) A is thiophenyl or pyridinyl, and A is C 1~3 A compound described in item 1 or item 4, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. (Item 6) A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1 to 5, wherein R is a substituted or unsubstituted phenyl. (Item 7) A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 5, wherein R is a substituted or unsubstituted 5-10 member heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S. (Item 8) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 5, wherein R is a substituted or unsubstituted non-aromatic 3 to 12-membered heterocycle having 1 to 5 heteroatom ring members independently selected from O, N, and S. (Item 9) R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is C 1~6 Alkyl, Mono-C 1~6 Alkylamino, di-C 1~6 Alkylamino, C1~6 A compound described in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl. (Item 10) Compound of formula 15,

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Claims

1. Compound of formula 1, 【Chemistry 28】 or a pharmaceutically acceptable salt thereof During the ceremony, (i) X is N, and Y is N or CR ２’ And, or (ii) X is CR ３ And Y is N or CR ２ And, or (iii) Both X and Y are N, R １ is hydrogen or fluoro, R ２ is hydrogen, C １～３ Alkyl, halogen, phenyl, or benzyl, R ２’ C １～３ Alkyl, halogen, phenyl, or benzyl, R ３ is hydrogen, C １～３ alkyl, or phenyl, and n is either 0 or 1, A is C ６ ~C １０ The aryl group or the 5-10 membered heteroaryl group, wherein the heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C １～３ It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.

2. A is C １～３ C is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. ６ ~C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is an aryl group.

3. A is C １～３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

4. A is a 5-10 membered heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, wherein the heteroaryl group is C １～３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

5. A is thiophenyl or pyridinyl, and C １～３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R.

6. R is, It is a substituted or unsubstituted phenyl. A substituted or unsubstituted 5-10 member heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S, or A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted non-aromatic 3 to 12-membered heterocycle having 1 to 5 heteroatom ring members independently selected from O, N, and S.

7. R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinoline-2-onyl, and triazolo[1,5-a]pyridinyl, and the cyclic ring is C １～６ Alkyl, mono-C １～６ Alkylamino, D-C １～６ Alkylamino, C １～６ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, optionally substituted with one to three substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl.

8. Compound of formula 15, 【Chemistry 29】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ is hydrogen or fluoro, R ２’ C １～３ Alkyl, halogen, phenyl, or benzyl, n is either 0 or 1, A is C ６ ~C １０ The aryl group or the 5-10 membered heteroaryl group, wherein the heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C １～３ It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.

9. Compound of formula 16, 【Transformation 30】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ is hydrogen or fluoro, n is either 0 or 1, A is C ６ ~C １０ The aryl group or the 5-10 membered heteroaryl group, wherein the heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S, and the aryl group or the heteroaryl group optionally contains C １～３ It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.

10. Compound of formula 17, 【Chemistry 31】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ These are hydrogen and fluoro, n is either 0 or 1, A is C ６ ~C １０ The aryl group or the 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, or S, and the aryl group or the heteroaryl group optionally contains C １～３ It is substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.

11. The aforementioned compound, Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-7 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and 8 to 11 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. A composition for use in inhibiting vascular adhesion protein-1 (VAP-1), comprising a compound according to any one of claims 1 to 5 and 8 to 11 or a pharmaceutically acceptable salt thereof.

14. A composition for use in the treatment of a disease mediated by VAP-1, wherein the composition comprises a compound according to any one of claims 1 to 5 and 8 to 11 or a pharmaceutically acceptable salt thereof, wherein the disease mediated by VAP-1 is a condition or disease resulting from chronic fatty and fibrous degeneration of organs due to lipid disorders, lipoprotein disorders, accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progressive pathways; type I or type II diabetes mellitus; clinical complications of type I and type II diabetes mellitus; chronic intrahepatic cholestasis; extrahepatic cholestasis; hepatic fibrosis; acute intrahepatic cholestasis; obstructive or chronic inflammatory diseases resulting from inappropriate bile composition; and reduced intake of dietary fats and fat-soluble dietary vitamins. A composition selected from the group consisting of gastrointestinal conditions, inflammatory bowel disease, obesity, metabolic syndromes, dyslipidemia, diabetes and abnormally high obesity index, persistent infection by intracellular bacteria or parasitic protists, non-malignant hyperproliferative disorder, malignant hyperproliferative disorder, adenocarcinoma of the colon and hepatocellular carcinoma, fatty liver disease or related syndromes, hepatitis B infection, hepatitis C infection, cholestasis and fibrosis associated with alcoholic cirrhosis or viral hepatitis, hepatic failure or impaired hepatic function as a result of chronic liver disease or surgical hepatectomy, acute myocardial infarction, acute stroke, chronic obstructive arteriosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and thrombosis (alone or in combination thereof) occurring as an endpoint of cerebral infarction.

15. Formula 1a 【Chemistry 32】 A compound of, or a pharmaceutically acceptable salt thereof, wherein, (i) X is N, and Y is N or CR ２’ And, or (ii) X is CR ３ And Y is N or CR ２ And, or (iii) Both X and Y are N, R １ is hydrogen or fluoro, R ２ is hydrogen, C １～３ Alkyl, halogen, phenyl, or benzyl, R ２’ C １～３ Alkyl, halogen, phenyl, or benzyl, R ３ is hydrogen, C １～３ Alkyl or phenyl, n is either 0 or 1, A' is C ６ ~C １０ The group is an aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S. R' is C １～３ Selected from the group consisting of alkyl, halogen, and -R, A method for preparing a compound or a pharmaceutically acceptable salt thereof, wherein R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or non-aromatic, The aforementioned method, (a) A compound of formula 2, 【Transformation 33】 In the formula, PG is an amino protecting group, and the compound is The compound of formula 3, Z-R' (Formula 3) In the formula, Z is -B(OH) ２ , -B(C １～３ Alkyl(alkoxy) ２ , or 【Transformation 34】 By reacting with a compound, To obtain the compound of formula 1aa, 【Chemistry 35】 and (b) A method comprising removing PG from the compound of formula 1aa under reaction conditions to obtain the compound of formula 1a or a pharmaceutically acceptable salt thereof.

16. X is N and Y is CR ２’ And n is 1, and the compound of formula 2 is, (a) The compound of formula 4, 【Transformation 36】 React with the compound in formula 5, 【Chemistry 37】 Obtaining the compound of formula 6, 【Transformation 38】 (b) The compound of formula 6 is the compound of formula 11, 【Chemistry 39】 The compound of formula 12, 【Chemistry 40】 In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.

17. Both X and Y are N, and the compound of formula 2 is, (a) The compound of formula 7, 【Chemistry 41】 By reacting with trimethylsilyl azide under cyclization conditions, the compound of formula 8 is obtained. 【Chemistry 42】 (b) The compound of formula 8 is the compound of formula 11, 【Chemistry 43】 The compound of formula 12, 【Chemistry 44】 In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.

18. X is CH, Y is CH, n is 1, and the compound of formula 2 is, The compound of formula 9, 【Chemistry 45】 Compound of formula 11, 【Chemistry 46】 The compound of formula 12, 【Chemistry 47】 In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.

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