Triazolones, tetrazolones, and imidazolones, or salts thereof, and pharmaceutical compositions containing the same

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 TO RELATED APPLICATIONS) This application claims the benefit of priority to Korean Patent Application No. 10-2021-0052441, filed on April 22, 2021, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present technology relates to triazolones, tetrazolones, and imidazolones, or pharma- ceutically acceptable salts thereof, having inhibitory activity against vascular adhesion protein 1 (VAP-1), processes for their preparation, pharmaceutical compositions containing same, and uses thereof. [Background technology]

[0003] Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO) abundant in human plasma. VAP-1 is an ectoenzyme that contains a short cytoplasmic tail, a single transmembrane domain, and a large, highly glycosylated extracellular domain that contains the active center. VAP-1 exists not only in a membrane-bound form in the endothelium, but also in 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 properties to the tissue-bound form. It has also been reported that VAP-1 is normally stored in intracellular granules in endothelial cells, but that when an inflammatory response is initiated in response to an inflammatory stimulus, it is translocated to the cell membrane and its expression is upregulated, and thus it is more strongly expressed in inflamed tissues than in normal tissues.

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

[0005] VAP-1 has two physiological functions, the first being its amine oxidase activity, as mentioned earlier in this section, and the second being its cell adhesion activity. These two activities have shown that VAP-1 plays an important role in the extravasation of inflammatory cells, as it acts as an adhesion protein for leukocytes at the site of inflammation [Trends Immunol. (2001) 22:211]. VAP-1-deficient transgenic mice are healthy, develop normally, are fertile, and are phenotypically normal, but show a marked reduction in the inflammatory response elicited in response to various inflammatory stimuli [Immunity. (2005) 22:105].

[0006] In addition, inhibitory activity of VAP-1 by the use of antibodies or small molecules in several animal models of human disease (e.g., carrageenan-induced paw inflammation, oxazolone-induced colitis, lipopolysaccharide-induced lung inflammation, collagen-induced arthritis, endotoxin-induced uveitis) has been shown to prevent leukocyte rolling, adhesion, and extravasation, reduce the levels of inflammatory cytokines and chemokines, and thereby reduce the severity of the disease [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 through the circulation to tissues is a critical step. Leukocytes first bind to adhesion proteins and then adhere to the endothelium before beginning to cross the vascular 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 matrix, and NF-κB is activated in HSECs, whereas other adhesion molecules E-selectin and chemokine IL-8 are upregulated ex vivo. This suggests that VAP-1 may be an important factor for the regulation of inflammatory responses, and therefore it seems likely that VAP-1 inhibitors may be effective anti-inflammatory drugs in a wide range of human diseases.

[0007] Nonalcoholic fatty liver disease (NAFLD) includes, histologically, simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Among these, NASH, unlike simple steatosis (nonalcoholic fatty liver, NAFL), can progress to cirrhosis and hepatocellular carcinoma. In NASH, insulin resistance is known to play an important role in disease progression, along with oxidative stress, inflammatory cascade, and fibrosis. In NAFLD patients, sVAP-1 levels were found to be elevated, and carbon tetrachloride-induced liver fibrosis was reduced in VAP-1 knockout (K / O) mice compared with wild-type animals. Furthermore, the improvement of liver fibrosis by VAP-1 inhibition after administration of VAP-1 antibody was identified by histological changes [J Clin Invest (2015) 125: 501]. Thus, VAP-1 was 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 believed to be due to the reduction in the infiltration of leukocytes, such as T cells, B cells, NKT cells, and NK cells, observed in liver fibrosis, and VAP-1 inhibitors 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 Summary of the Invention

[0009] The triazolones, tetrazolones, and imidazolones having 3-fluoroallylamine groups or 3,3-difluoroallylamine groups, or their pharma- ceutically acceptable salts, described herein, exhibit inhibitory activity against VAP-1.Therefore, the triazolones, tetrazolones, and imidazolones, or their pharma- ceutically acceptable salts, can be usefully used in the treatment and prevention of various VAP-1-mediated diseases, such as nonalcoholic steatohepatitis (NASH).

[0010] Thus, the present technology provides triazolones, tetrazolones, and imidazolones, or pharma- ceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing same, and uses thereof.

[0011] According to one aspect of the present technology, there is provided a triazolone, tetrazolone, or imidazolone, or a pharma- ceutically acceptable salt thereof.

[0012] According to one aspect of the present technology, there is provided a process for the preparation of a triazolone, tetrazolone, or imidazolone, or a pharma- ceutically acceptable salt thereof.

[0013] In accordance with another aspect of the present technology, there is provided a pharmaceutical composition comprising a triazolone, tetrazolone, or imidazolone, or a pharma- ceutically acceptable salt thereof, as an active ingredient.

[0014] In accordance with another aspect of the present technology, a method of treatment is provided that includes administering a triazolone, tetrazolone, or imidazolone, or a pharma- ceutically 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 pharma- ceutically 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 3-fluoroallylamine groups or 3,3-difluoroallylamine groups, or pharma- ceutical acceptable salts thereof, exhibit inhibitory activity against VAP-1.Therefore, the compounds according to the present technology or pharma-ceutical acceptable salts thereof can be usefully applied to the treatment and prevention of various VAP-1-mediated diseases, such as nonalcoholic steatohepatitis (NASH).

[0017] Provided herein is a compound of formula 1: [ka] or a stereoisomer or a pharma- ceutically acceptable salt thereof; During the ceremony, (i) X is N and Y is N or CR 2’ or (ii) X is a CR 3 and Y is N or CR 2 or (iii) X and Y are both N; R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 alkyl, halogen, phenyl, or benzyl; R 2’ is C 1~3 alkyl, halogen, phenyl, or benzyl; R 3 is hydrogen, C 1~3 alkyl, or phenyl; n is 0 or 1, A is C6~C 10an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, the aryl group or the heteroaryl group optionally being selected from C 1~3 Substituted with 1 or 2 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 non-aromatic.

[0018] In another aspect, provided herein is a compound of Table 1. In another aspect, provided herein is a compound of Table 1, or a pharma- ceutically acceptable salt thereof.

[0019] In another aspect, provided herein is a pharmaceutical composition comprising, consisting essentially of, or consisting of a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0020] In another aspect, provided herein is a method of inhibiting vascular adhesion protein (VAP-1), comprising, consisting essentially of, or consisting of administering to a mammal a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0021] In another aspect, provided herein is a method of treating NASH in a subject in need thereof comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0022] In another aspect, provided herein is the use of a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of NASH.

[0023] In another aspect, provided herein is a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment of NASH.

[0024] In another aspect, provided herein is a composition disclosed herein for use in the treatment of NASH.

[0025] In another aspect, provided herein is a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in inhibiting VAP-1.

[0026] In another aspect, provided herein is a composition disclosed herein for use in inhibiting VAP-1.

[0027] In another aspect, provided herein is a method for treating a disease mediated by VAP-1 in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound disclosed herein, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0028] In some embodiments, the disease mediated by VAP-1 is selected from the group consisting of lipid disorders, lipoprotein disorders, conditions or diseases resulting from chronic fatty and fibrotic degeneration of organs due to accumulation of accumulated lipids, especially triglycerides, followed by activation of fibrosis-promoting pathways, type I or type II diabetes, clinical complications of type I and type II diabetes, chronic intrahepatic cholestatic conditions, extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inadequate bile composition, gastrointestinal conditions with reduced intake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, obesity, metabolic syndrome, dyslipidemia complex, diabetes mellitus, and abnormally high body mass index, persistent infection with intracellular bacteria or parasitic protozoa, nonmalignant hyperproliferative disorders, malignant hyperproliferative disorders, colorectal adenocarcinoma and hepatocellular carcinoma, fatty liver disease or related syndromes, hepatitis B infection, hepatitis C infection, cholestasis and fibrotic effects associated with alcoholic cirrhosis or viral hepatitis, liver failure or dysfunction as a result of chronic liver disease or surgical liver resection, acute myocardial infarction, acute stroke, chronic obstructive arteriosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and thrombosis occurring as an endpoint of cerebral infarction (alone or in combination).

[0029] In another aspect, provided herein is a compound of formula 1a: [ka] or a pharma- ceutically acceptable salt thereof, wherein: (i) X is N and Y is N or CR 2’ or (ii) X is a CR 3 and Y is N or CR 2 or (iii) X and Y are both N; R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 alkyl, halogen, phenyl, or benzyl; R 2’ is C1~3 alkyl, halogen, phenyl, or benzyl; R 3 is hydrogen, C 1~3 alkyl, or phenyl; n is 0 or 1, A' is C6~C 10 an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N, and S; R' is C 1~3 is 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 non-aromatic, comprising the steps of: The method is: (a) A compound of formula 2, [ka] wherein PG is an amino protecting group; A compound of formula 3, Z-R' (Formula 3) In the formula, Z is -B(OH)2, -B(C 1~3 alkoxy)2, or [ka] and reacting a compound Obtaining a compound of formula 1aa; [ka] and (b) removing PG from the compound of formula 1aa under reaction conditions to obtain a compound of formula 1a or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] It is noted that, as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any element. Thus, this statement is intended to function as an antecedent to the use of exclusive terminology such as "solely," "only," and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0031] As used herein, the terms "comprising" or "comprises" are intended to mean that the compositions and methods include the recited elements but do not exclude other elements. A composition or method "consisting essentially of" an element as defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed technology. "Consisting of" is intended to mean excluding other components and substantial method steps beyond trace elements. Embodiments defined by each of these transitional terms are within the scope of the technology. When an embodiment is defined by one of these terms (e.g., "comprising"), it is understood that the disclosure also includes alternative embodiments such as "consisting essentially of" and "consisting of" the embodiment.

[0032] "Substantially" or "essentially" means nearly entirely or completely of any given amount, e.g., 95%, 96%, 97%, 98%, 99% or more.

[0033] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0034] Certain ranges are presented herein with numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is near or approximate to the number the term precedes. In determining whether a number is near or approximate to a specifically recited number, the unrecited number that is near or approximate may be a number that, in the context in which the number is presented, provides a substantial equivalent to the specifically recited number.

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

[0036] In general, "substituted" refers to an organic group (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to a non-hydrogen or non-carbon atom. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. The present disclosure is understood to include embodiments in which, for example, "substituted alkyl" optionally contains 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, alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups, aryl groups, heteroaryl groups, cycloalkyl groups, heterocyclyl groups, carbonyl (oxo), carboxyl, esters, carbamates, urethanes, ureas, oximes, hydroxylamines, alkoxyamines, aralkoxyamines, thiols, sulfides, sulfoxides, sulfones, sulfonyls, sulfonamides, amines, N-oxides, hydrazines, hydrazides, hydrazines, azides, amides, ureas, amidines, guanidines, enamines, imides, isocyanates, isothiocyanates, cyanates, thiocyanates, imines, nitro groups, nitriles (i.e., CN), and the like. As used herein, an "optionally substituted" group refers to a group that is substituted or unsubstituted. Thus, "optionally substituted" and "substituted or unsubstituted" can be used interchangeably.

[0037] Substituted ring groups, such as substituted cyclic, cycloalkyl, aryl, heterocyclic and heteroaryl groups, also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Thus, substituted cyclic, cycloalkyl, aryl, heterocyclic and 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 that optionally contains one or more heteroatoms. Exemplary heteroatoms include, but are not limited to, N, O, S, or B. In some embodiments, the cyclic ring optionally contains 1-5 heteroatom ring members selected from O, N, or S. In some embodiments, the cyclic ring optionally contains 1-4 heteroatom ring members selected from O, N, or S. In some embodiments, the cyclic ring optionally contains 1-3 heteroatom ring members selected from O, N, or S. Cyclic rings include aryl, cycloalkyl, and heterocyclic groups.

[0039] As used herein, an "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, azulenyl, heptalenyl, biphenyl, indecanyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbons, and in other cases, 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. The phrase "aryl group" includes groups that contain fused rings, such as fused aromatic-aliphatic ring systems (e.g., benzodioxole, indanyl, tetrahydronaphthyl, etc.), but does not include aryl groups that have other groups, such as alkyl or halo groups, attached to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups can be mono-substituted or substituted more than once. For example, mono-substituted aryl groups include, but are not limited to, di-, tri-, tetra-, pent-, or hexa-substituted phenyl or naphthyl groups, which can be substituted with substituents such as those listed above.

[0040] As used herein, the term "cycloalkyl group" refers to cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3-8 carbon ring members, while in other embodiments, the number of ring carbon atoms ranges from 3-5, 3-6, or 3-7. Cycloalkyl groups further include monocyclic, bicyclic, and polycyclic ring systems, such as, for example, bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl. In some embodiments, polycyclic cycloalkyl groups have 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 straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted two or more times, such as 2,2-, 2,3-, 2,4-2,5-, or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as, but not limited to, those listed above. In some embodiments, the cycloalkyl group has one or more alkene linkages but is not aromatic. In some embodiments, the cycloalkyl ring may be a spirocycloalkyl.

[0041] As used herein, the term "heterocyclic group" includes aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, S, or B. 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 can 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, one to five of which are heteroatoms selected from O, N, and S. Heterocyclic groups include unsaturated, partially saturated, and saturated ring systems, such as, for example, imidazolyl, imidazolinyl, and imidazolidinyl groups. The phrase "heterocyclic group" includes fused ring species including those containing fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclic groups having other groups, such as alkyl, oxo, or halo groups, attached to one of the ring members. Rather, these are referred to as "substituted heterocyclic groups."Heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiazolyl, thiazolyl, thiazolyl, thiadia ... morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzylidene, Zuthiazolyl, benzoxadiazoyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazidinyl Examples of aryl include, but are not limited to, nyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclic groups include, but are not limited to, pyridyl or piperazinyl groups which may be mono- or more than mono-substituted, for example, di-, tri-, tetra-, penta-, or hexa-substituted or di-substituted with various substituents such as those listed above.

[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, such as, but not limited to, N, O, S, or B. In some embodiments, the one or more heteroatoms are selected from N, O, or S. In some embodiments, the one to four heteroatoms are selected from N, O, or S. In some embodiments, the one to five heteroaryl groups are selected from N, O, or S. In some embodiments, heteroaryl groups contain 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 5-membered heteroaryl group has 5 ring members, a 6-membered heteroaryl group has 6 ring members, and a 9-membered heteroaryl group has 9 ring members (including but not limited to, benzothiophene). Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, 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 phrase "heteroaryl group" includes fused ring compounds such as indolyl and 2,3-dihydroindolyl, but does not include heteroaryl groups having other groups attached to one of the ring members, such as alkyl groups. Rather, heteroaryl groups having such substitutions are referred to as "substituted heteroaryl groups." Representative substituted heteroaryl groups may be substituted one or more times with a variety of substituents, such as those listed above. Azolyl groups are 5-membered heteroaryl groups containing a nitrogen atom and at least one other atom selected from nitrogen, sulfur, and oxygen as part of the ring.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 an aliphatic hydrocarbon radical, including both straight-chain and branched hydrocarbon radicals. In some embodiments, an alkyl has 1 to about 20 carbon atoms, 1 to 12 carbons, 1 to 8 carbons, 1 to 6 carbons, or 1 to 4 carbon atoms. For example, C 1~6 Alkyl refers to an aliphatic hydrocarbon having 1 to 6 carbons, including methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like.

[0044] The term "hydroxy" as used herein is defined as --OH.

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

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

[0047] Additionally, the term "amino" is defined as -NH2, and the term "alkylamino" refers to mono- or dialkyl-substituted amino.1~6 Alkylamino is mono- or di-C 1~6 In some embodiments, each alkyl in a dialkyl-substituted amino can be the same or different.

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

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

[0050] Those skilled in the art will understand that the compounds of the present technology may exhibit the phenomenon of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism.It should be understood that the formulae in this specification and claims can represent only one of the possible tautomers, conformational isomers, optical isomers, or geometric isomer forms, and that the present technology encompasses any tautomers, conformational isomers, and / or optical isomers of the compounds having one or more utilities described herein, as well as mixtures of these various different forms.

[0051] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds described herein are within the scope of the technology.

[0052] Stereoisomers of a compound, also known as "optical isomers", include all chiral, diastereomeric, and racemic forms of a structure unless a specific stereochemistry is explicitly indicated. Thus, the compounds used in the present technology include optical isomers enriched or resolved at any or all stereogenic atoms, as is clear from the depiction. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, all of which are within the scope of the present technology.

[0053] "Pharmaceutically acceptable" means that the material is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious 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 maintained by the US Food and Drug Administration.

[0054] In general, reference to certain moieties that can be protected (such as hydroxy, amine, carbonyl, etc.) includes protecting groups in some embodiments of the present disclosure. For example, in some embodiments, the -OH moieties included herein also include -OP, where P is a protecting group. Protecting groups as referred to herein, such as the amine protecting groups described herein, can be selected by those skilled in the art and include groups and strategies defined in the art, such as those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), TW Greene and PGM Wuts, 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 is the object of treatment, observation, or experiment. Unless otherwise indicated, "subject" and "patient" may be used interchangeably. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0056] The terms "therapeutically effective amount" and "effective amount" are used interchangeably and refer to an amount of a compound sufficient to effect treatment as defined below when administered in one or more doses to a patient (e.g., a human) in need of such treatment. The therapeutically effective amount will vary 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 as determined by a qualified prescriber or caregiver.

[0057] The term "treatment" or "treating" refers to the administration of a compound disclosed herein for the purpose of (i) delaying the onset of the disease, i.e., preventing or delaying the onset of clinical symptoms of the disease; (ii) inhibiting the disease, i.e., preventing the onset of clinical symptoms; and / or (iii) relieving the 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 commonly understood by one of ordinary skill in the art to which this technology belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present technology, representative exemplary methods and materials are described herein.

[0059] The present technology relates to a compound having inhibitory activity against VAP-1 or a pharma- ceutically 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’ or (ii) X is a CR 3 and Y is N or CR 2 or (iii) X and Y are both N; R 1 is hydrogen or fluoro, R 2 is hydrogen, C 1~3 alkyl, halogen, phenyl, or benzyl; R 2’ is C 1~3 alkyl, halogen, phenyl, or benzyl; R 3 is hydrogen, C 1~3 alkyl, or phenyl; n is 0 or 1, A is C6~C 10 an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, the aryl group or the heteroaryl group optionally being selected from C 1~3 Substituted with 1 or 2 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 non-aromatic.

[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, X and Y are both 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 It is.

[0061] In another aspect, provided herein is a compound of formula 15: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen or fluoro, R 2’ is C 1~3 alkyl, halogen, phenyl, or benzyl; n is 0 or 1, A is C6~C 10 an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, the aryl group or the heteroaryl group optionally being selected from C 1~3 Substituted with 1 or 2 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 non-aromatic, or a pharma- ceutically acceptable salt thereof.

[0062] In another aspect, provided herein is a compound of formula 16: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen or fluoro, n is 0 or 1, A is C6~C 10 an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, the aryl group or the heteroaryl group optionally being selected from C1~3 Substituted with 1 or 2 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 non-aromatic, or a pharma- ceutically acceptable salt thereof.

[0063] In another aspect, provided herein is a compound of formula 17: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen and fluoro; n is 0 or 1, A is C6~C 10 an aryl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, the aryl group or the heteroaryl group optionally being selected from C 1~3 Substituted with 1 or 2 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 non-aromatic, or a pharma- ceutically acceptable salt thereof.

[0064] In some embodiments, A is C 1~3 C6-C optionally substituted with 1 or 2 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 and phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0066] In some embodiments, A is C 1~3 phenyl 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, pyridinyl, pyrazolyl, pyridin-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl, the cyclic ring being selected from the group consisting of 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 1~3 Optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0068] In some embodiments, A is C 1~3 is thiophenyl or pyridinyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen and -R.

[0069] In some embodiments, A is C 1~3 and thiophenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R.

[0070] 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, pyridinyl, pyrazolyl, pyridin-2-onyl, benzodioxolyl, 3,4-dihydroquinolin-2-onyl, or triazolo[1,5-a]pyridinyl, 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 alkylsulfonyl, and piperazinyl.

[0071] 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, pyridinyl, pyrazolyl, pyridin-2-onyl, or 3,4-dihydroquinolin-2-onyl, and R is C 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6 In some embodiments, A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and arylsulfonyl. 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, pyridinyl, pyrazolyl, pyridin-2-onyl, or 3,4-dihydroquinolin-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 alkylsulfonyl, and piperazinyl.

[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-onyl, or 3,4-dihydroquinolin-2-onyl, and R is C 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6 In some embodiments, A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and arylsulfonyl. 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-onyl, or 3,4-dihydroquinolin-2-onyl, and R is C 1~6 Alkyl and C 1~6 and optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl.

[0073] In some embodiments, A is C 1~3 thiophenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is pyrazolyl, pyridin-2-onyl, or 3,4-dihydroquinolin-2-onyl, and R is C 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6 In some embodiments, A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and arylsulfonyl. 1~3 thiophenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R, where R is pyrazolyl, pyridin-2-onyl, or 3,4-dihydroquinolin-2-onyl, and R is C 1~6 Optionally substituted with 1 to 3 substituents independently selected from alkyl.

[0074] In some embodiments, A is C 1~3 and pyridinyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen and -R.

[0075] In some embodiments, A is C 1~3 pyridinyl 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, pyridin-2-onyl, benzodioxolyl, or 3,4-dihydroquinolin-2-onyl, and the cyclic ring is selected from the group consisting of 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 substituted or unsubstituted phenyl. In some embodiments, R is C 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6 and phenyl 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 membered heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S. In some embodiments, R is a substituted or unsubstituted 5-10 membered heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S. In some embodiments, R is a substituted or unsubstituted 5-10 membered heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S. 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6and 5-10 membered heteroaryl 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 membered heterocycle having 1-5 heteroatom ring members independently selected from O, N, and S. ... 1~6 Alkyl, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, C 1~6 A non-aromatic 3- to 12-membered heterocycle 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, pyridin-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is 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, pyridin-2-onyl, benzodioxolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is 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 alkylsulfonyl, and piperazinyl.

[0081] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridin-2-onyl, benzodioxolyl, benzoxadiazolyl, and 3,4-dihydroquinolin-2-onyl, wherein the cyclic ring is 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 pyridin-2-onyl, pyrazolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl, wherein the cyclic ring is 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, and piperazinyl.

[0083] In some embodiments, R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridin-2-onyl, benzodioxolyl, and 3,4-dihydroquinolin-2-onyl, wherein the cyclic ring is 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, and piperazinyl.

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

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

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

[0087] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1~3 In some embodiments, R 3 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 can be measured, for example, by measuring the maximum inhibitory concentration (IC 50 The IC of VAP-1 can be measured by determining 50 One method for determining 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 higher inhibitory activity" is determined by the IC50 of VAP-1 obtained from in vitro enzyme assay testing. 50 However, MAO-A's IC 50 At least 3000-fold lower than the IC of MAO-B 50 or DAO IC 50 In an alternative embodiment, "significantly higher inhibitory activity" refers to an IC50 value of at least 100-fold lower than that of VAP-1 obtained from an in vitro enzyme assay test. 50 However, MAO-A's IC 50 At least 3000-fold lower than the IC of MAO-B 50 At least 100 times lower than the IC of DAO 50 This means that the concentration is at least 100 times lower than the normal concentration.

[0091] In another embodiment, the compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, is selected from the following compounds, or a pharma- ceutically acceptable salt thereof: 2-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one, 2-[2-(aminomethyl)-3,3-difluoro-allyl]-5-methyl-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]-1,2,4-triazol-3-one, 2-[2-(aminomethyl)-3,3-difluoro-allyl]-5-methyl-4-[[5-(4-piperazin-1-ylphenyl)-2-thienyl]methyl]-1,2,4-triazol-3-one, 5-[5-[[1-[2-(aminomethyl)-3,3-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one, 2-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[5-[6-(dimethylamino)-3-pyridyl]-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one, 2-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[5-(1,3-benzodioxol-5-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one, 6-[5-[[1-[2-(aminomethyl)-3,3-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[5-[[1-[2-(aminomethyl)-3,3-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one, 2-[(E)-2-(aminomethyl)-3-fluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)-2-fluoro-phenyl]-1,2,4-triazol-3-one, 2-[(E)-2-(aminomethyl)-3-fluoro-allyl]-4-[4-(2,1,3-benzoxadiazol-5-yl)-2-fluoro-phenyl]-1,2,4-triazol-3-one, 6-[4-[1-[(E)-2-(aminomethyl)-3-fluoro-allyl]-5-oxo-1,2,4-triazol-4-yl]-3-fluoro-phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 2-[(E)-2-(aminomethyl)-3-fluoro-allyl]-4-[2-fluoro-4-(6-morpholino-3-pyridyl)phenyl]-1,2,4-triazol-3-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[3-(4-methylsulfonylphenyl)phenyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[3-(4-piperazin-1-ylphenyl)phenyl]tetrazol-5-one, 5-[3-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-ethyl-pyridin-2-one, 6-[3-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[3-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[3-(1-ethylpyrazol-4-yl)phenyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(4-methylsulfonylphenyl)phenyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(4-piperazin-1-ylphenyl)phenyl]tetrazol-5-one, 5-[4-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-ethyl-pyridin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)phenyl]tetrazol-5-one, 6-[4-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[4-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(1-ethylpyrazol-4-yl)phenyl]tetrazol-5-one, 5-[5-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-2-thienyl]-1-ethyl-pyridin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[3-methyl-6-(4-methylsulfonylphenyl)-2-pyridyl]tetrazol-5-one, 5-[6-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-1-ethyl-pyridin-2-one, 6-[6-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[6-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[3-(4-methylsulfonylphenyl)phenyl]methyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[3-(4-piperazin-1-ylphenyl)phenyl]methyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[3-[6-(dimethylamino)-3-pyridyl]phenyl]methyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[3-(1,3-benzodioxol-5-yl)phenyl]methyl]tetrazol-5-one, 6-[3-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[3-(1-ethylpyrazol-4-yl)phenyl]methyl]tetrazol-5-one, 6-[3-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one, 5-[3-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-1-ethyl-pyridin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(4-methylsulfonylphenyl)-2-thienyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(4-piperazin-1-ylphenyl)-2-thienyl]tetrazol-5-one, 5-[5-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-1-ethyl-pyridin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-[6-(dimethylamino)-3-pyridyl]-2-thienyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)-2-thienyl]tetrazol-5-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[4-(1-ethylpyrazol-4-yl)-2-thienyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]tetrazol-5-one, 5-[5-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one, 6-[5-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 6-[5-[[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]tetrazol-5-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-4-[5-(1,3-benzodioxol-5-yl)-3-pyridyl]tetrazol-5-one, 6-[5-[4-[2-(aminomethyl)-3,3-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-pyridyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one, 5-[5-[[3-[2-(aminomethyl)-3,3-difluoro-allyl]-2-oxo-imidazol-1-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one, 6-[5-[[3-[2-(aminomethyl)-3,3-difluoro-allyl]-2-oxo-imidazol-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one, 1-[2-(aminomethyl)-3,3-difluoro-allyl]-3-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]imidazol-2-one, and 1-[2-(aminomethyl)-3,3-difluoro-allyl]-3-[[5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-thienyl]methyl]imidazol-2-one.

[0092] The compound of formula 1 of the present technology may be in the form of a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of the compound of the present technology that is water- or oil-soluble or dispersible, suitable for treating disease without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Salts can be prepared during the final isolation and purification of the compound, or, for example, by reacting the appropriate compound in the form of a free base with a suitable acid. Such salts include conventional acid addition salts, such as salts derived from inorganic acids, such as hydrochloric acid, bromic acid, 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. In addition, such salts include conventional metal salt types, such as salts derived from metals, such as lithium, sodium, potassium, magnesium, or calcium. Such acid addition salts or metal salts can be prepared according to conventional methods.

[0093] The compound of formula 1, formula 15, formula 16, or formula 17, or its stereoisomer, or its pharma- ceutically acceptable salt, according to the present technology, can be prepared by various methods. For example, the compound of formula 1a, or its stereoisomer, or its pharma- ceutically acceptable salt, according to the present technology, can be prepared by a preparation process that includes 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 the 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 is coupled with a compound of formula 3 described herein, and the resulting compound is subsequently deprotected to provide a compound of formula 1.

[0096] The reaction of the compound of formula 2 above with the commercially available compound of formula 3 can be carried out via Suzuki reaction. The reaction can be carried out using a palladium catalyst. The palladium catalyst includes 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), etc. In addition to the palladium catalyst, a ligand and a base can be added during the reaction carried out under 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), 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 non-polar organic solvent such as benzene or toluene, or a polar solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, N,N-dimethylformamide, at a temperature ranging from 50° C. to 150° C., preferably from 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 the compound of formula 1aa can be carried out by conventional methods for removing an amine protecting group, for example, by removing the amine protecting group in the form of the free amine or in the form of the hydrochloride salt by using hydrogen chloride dissolved in an organic solvent, such as diethyl ether, 1,4-dioxane, and the like.

[0099] Compounds of formula 2 can be prepared according to Reaction Scheme 1 below. [ka]

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

[0101] Compounds of formula 10 can be converted to compounds of formula 2 via a Mitsunobu reaction with compounds of formula 11 or via a coupling reaction with compounds of formula 12.

[0102] The reaction of the compound of formula 10 with the compound of formula 11 above can be carried out via 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 can be a polar organic solvent, such as dichloromethane, dioxane, tetrahydrofuran, dimethylformamide, etc. The reaction can be carried out at 0°C to room temperature, or in some cases 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 can be cesium carbonate, potassium carbonate, sodium carbonate, etc., and the solvent can be an organic solvent, such as N,N-dimethylformamide, dioxane, tetrahydrofuran, etc. Furthermore, the reaction can be carried out at room temperature to 100°C.

[0104] The compound of formula 12 can be obtained from the halogenation (i.e., chlorination or bromination reaction) of the compound of formula 11. The halogenation (i.e., chlorination or bromination reaction) can be carried out in the presence of a conventional inorganic base and an organic solvent.

[0105] Compounds of formula 10 can be prepared according to Reaction Scheme 2 below. [ka]

[0106] In Reaction Scheme 2, R 2’ , A' and n are as defined above. The compound of formula 6 can be prepared by the compound of formula 10, where X is N and Y is CR 2’ The compound of formula 8 is the compound of formula 10 where both X and Y are N.

[0107] Compounds of formula 9, which is the compound of formula 10 where X is CH and Y is CH, are commercially available or can be made 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 coupling reaction can be carried out in the presence of a base and a solvent. The base can be cesium carbonate, potassium carbonate, sodium carbonate, etc., and the solvent can be an organic solvent, such as N,N-dimethylformamide, dioxane, tetrahydrofuran, etc. Furthermore, the reaction can be carried out at room temperature to 100°C.

[0109] Compounds of formula 7 can be converted to compounds of formula 8 via a cyclization reaction, which can be carried out using trimethylsilyl azide at temperatures ranging from room temperature to 100° C. (e.g., WO 2015 / 014283, etc.).

[0110] In some embodiments, the cyclization conditions comprise, consist essentially of, or consist of reacting a compound of formula 7 with trimethylsilyl azide in the absence of a solvent at a temperature ranging from room temperature to 100° C.

[0111] X is N and Y is CR 2’ In some embodiments where n is 1, the compound of formula 2 is (a) reacting a compound of formula 4 with [ka] reacting with a compound of formula 5, [ka] To obtain a compound of formula 6 [ka] (b) reacting a compound of formula 6 with a compound of formula 11, [ka] A compound of formula 12, [ka] wherein Q is a halogen; under reaction conditions to give a compound of formula 2.

[0112] In some embodiments, X and Y are both N, and the compound of formula 2 is (a) reacting a compound of formula 7 with [ka] Reaction with trimethylsilyl azide under cyclization conditions gives compounds of formula 8, [ka] (b) reacting a compound of formula 8 with a compound of formula 11, [ka] A compound of formula 12, [ka] wherein Q is a halogen; under reaction conditions to give a compound of formula 2.

[0113] In some embodiments, X is CH, Y is CH, n is 1, and the compound of formula 2 is a compound of formula 9, [ka] A compound of formula 11, [ka] A compound of formula 12, [ka] wherein Q is a halogen; under reaction conditions to give a compound of formula 2.

[0114] R 1 Compounds of formula 11 where R is hydrogen (compounds of formula 11a) are commercially available;1 Compounds of formula 11 where is fluoro (compounds of formula 11b) 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] Compounds of formula 13 are commercially available and can be prepared according to known methods (e.g., WO 2013 / 163675, etc.). Compounds of formula 13 can be converted to compounds of formula 14 via gem-difluoroolefination reaction. The gem-difluoroolefination reaction can be carried out using fluorinated sulfones such as difluoromethyl 2-pyridyl sulfone in the presence of a base such as potassium tert-butoxide (tert-BuOK), lithium bis(trimethylsilyl)amide (LiHMDS), etc. The reaction solvent can be an organic solvent such as N,N-dimethylformamide, tetrahydrofuran, etc., 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 through deprotection of hydroxyl protecting group (TBDMS). Deprotection of hydroxyl protecting group can be carried out according to known methods (Theodora W. Greene and Peter G. M. Wets, Protective groups in organic synthesis, 3rd Ed., 1999). For example, deprotection of hydroxyl protecting group (TBDMS) can be carried out at room temperature using organic salt such as tetrabutylammonium fluoride (TBAF) in a solvent such as dichloromethane, tetrahydrofuran, etc. W. Green; P. G. Wets, Protective Groups in Organic Synthesis, 127-141, 708-711, 1999).

[0118] The triazolones, tetrazolones, and imidazolones according to the present technology, i.e., the compounds of formula 1, or their stereoisomers, or their pharma- ceutically acceptable salts, have inhibitory activity against VAP-1, and therefore can be usefully applied to the prevention or treatment of VAP-1-mediated diseases.Preferably, the compounds of formula 1, or their stereoisomers, or their pharma-ceutically acceptable salts according to the present technology can be usefully applied to the prevention or treatment of nonalcoholic steatohepatitis (NASH).

[0119] In some embodiments, provided herein are methods for treating conditions or diseases resulting from chronic fatty and fibrotic degeneration of organs due to accumulated lipids, particularly triglycerides, accumulation and subsequent activation of fibrosis-promoting pathways, including, but not limited to, lipid and lipoprotein disorders (such as, but not limited to, hypercholesterolemia, hypertriglyceridemia, and arteriosclerosis), conditions or diseases resulting from chronic fatty and fibrotic degeneration of organs due to accumulated lipids, particularly triglycerides, accumulation and subsequent activation of fibrosis-promoting pathways (such as, but not limited to, in the liver, NASH and chronic cholestatic conditions, in the kidney, glomerulosclerosis and diabetic nephropathy, in the eye, macular degeneration and diabetic retinopathy, in the brain, neurodegenerative diseases such as Alzheimer's disease, in the peripheral nervous system, diabetic neuropathy), type I or type II diabetes and clinical complications of type I and type II diabetes, including, but not limited to, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral arterial occlusive disease.Hepatic fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inadequate bile composition (such as, but not limited to, cholelithiasis, also known as cholesterol cholelithiasis), gastrointestinal conditions with reduced intake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, obesity and metabolic syndrome (combination of dyslipidemia, diabetes mellitus and abnormally high body mass index), persistent infection with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative disorders, malignant hyperproliferative disorders (different forms of cancer, in particular certain forms of breast cancer, liver cancer or colon cancer, or the group consisting of hepatocellular carcinoma, colon adenoma and polyposis and / or pulmonary arterial fibrosis (PC) associated with hepatitis B infection, hepatitis C infection, and / or alcoholic cirrhosis or viral hepatitis, liver failure or liver dysfunction as a result of chronic liver disease or surgical liver resection, acute myocardial infarction, acute stroke, chronic obstructive arterial sclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and thrombosis occurring as an endpoint in cerebral infarction (alone or in combination), in the preparation of a medicament for the prevention and / or treatment of pulmonary arterial fibrosis (LP) associated with hepatitis B infection, hepatitis C infection, and / or pulmonary arterial fibrosis (LP), in particular pulmonary arterial fibrosis (PBA ...

[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 related cholestasis, as well as some forms of extrahepatic cholestatic conditions, or chronic intrahepatic conditions such as liver fibrosis.

[0121] In some embodiments, provided herein are methods of treating a chronic intrahepatic condition and / or some forms of extrahepatic cholestatic conditions in a patient in need thereof, the methods comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the chronic intrahepatic condition is selected from PBC, PSC, PFIC, and alcohol-induced cirrhosis and associated cholestasis.

[0122] In some embodiments, provided herein is a method of treating liver fibrosis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0123] In some embodiments, provided herein are methods of treating a lipid and lipoprotein disorder in a patient in need thereof, the methods comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein, in some embodiments, the lipid and lipoprotein disorder is selected from hypercholesterolemia, hypertriglyceridemia, and atherosclerosis.

[0124] In some embodiments, provided herein is a method for treating a condition or disease resulting from chronic fatty and fibrotic degeneration of an organ due to accumulated lipids, particularly triglycerides, and subsequent activation of fibrosis-promoting pathways in a patient in need thereof, the method comprising, consisting essentially of, or consisting of 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 fibrotic degeneration of an organ due to accumulated lipids, particularly triglycerides, and subsequent activation of fibrosis-promoting pathways is selected from NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidney, macular degeneration and diabetic retinopathy in the eye, and neurodegenerative diseases. In some further embodiments, the neurodegenerative disease is selected from Alzheimer's disease in the brain, and diabetic neuropathy in the peripheral nervous system.

[0125] In some embodiments, provided herein is a method of treating type I or type II diabetes and clinical complications of type I and type II diabetes in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, provided herein is a method of treating type I diabetes in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, provided herein is a method of treating type II diabetes in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, provided herein is a method of treating one or more clinical complications of type I and type II diabetes in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the clinical complications of type I and type II diabetes are selected from diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and peripheral arterial occlusive disease (PAOD), or any combination thereof.

[0126] In some embodiments, provided herein is a method of treating an acute intrahepatic cholestatic condition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0127] In some embodiments, provided herein is a method of treating an obstructive or chronic inflammatory disorder resulting from inappropriate bile composition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of 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 inappropriate bile composition is cholelithiasis, also known as cholesterol gallstones.

[0128] In some embodiments, provided herein is a method of treating a gastrointestinal condition in a patient in need thereof where the intake of dietary fat and fat-soluble dietary vitamins is reduced, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0129] In some embodiments, provided herein is a method of treating inflammatory bowel disease in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0130] In some embodiments, provided herein is a method of treating obesity and metabolic syndrome in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0131] In some embodiments, provided herein is a method of treating an infection by an intracellular bacterium or a parasitic protozoan in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0132] In some embodiments, provided herein is a method of treating a non-malignant hyperproliferative disorder in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0133] In some embodiments, provided herein is a method of treating a non-malignant hyperproliferative disorder in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the 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, in particular certain forms of breast cancer, liver cancer, or colon cancer, or a disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis.

[0134] In some embodiments, provided herein is a method of treating colon adenocarcinoma in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0135] In some embodiments, provided herein is a method of treating hepatocellular carcinoma in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0136] In some embodiments, provided herein is a method of treating hepatic steatosis and its associated syndromes in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0137] In some embodiments, provided herein is a method of treating a Hepatitis B infection in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0138] In some embodiments, provided herein is a method of treating a Hepatitis C infection in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0139] In some embodiments, provided herein is a method of treating cholestasis and fibrotic effects associated with alcoholic cirrhosis or viral hepatitis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0140] In some embodiments, provided herein is a method of treating liver failure or impaired liver function in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0141] In some embodiments, provided herein is a method of treating acute myocardial infarction in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0142] In some embodiments, provided herein is a method of treating acute stroke in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0143] In some embodiments, provided herein is a method of treating thrombosis occurring as an endpoint of chronic obstructive arteriosclerosis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0144] In some embodiments, provided herein is a method of treating osteoarthritis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0145] In some embodiments, provided herein is a method of treating rheumatoid arthritis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0146] In some embodiments, provided herein is a method of treating psoriasis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0147] In some embodiments, provided herein is a method of treating cerebral infarction in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

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

[0149] In another aspect, the present technology provides a pharmaceutical composition for preventing or treating diabetic nephropathy comprising, consisting essentially of, or consisting of a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

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

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

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

[0153] Exemplary additional active agents include one or more of ACE inhibitors, acetyl CoA carboxylase inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), amylin receptor agonists, angiotensin II AT-1 receptor antagonists, apoptosis signaling kinase 1 inhibitors, autotaxin inhibitors, bioactive lipids, calcitonin agonists, caspase inhibitors, caspase 3 stimulators, cathepsin inhibitors, caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, DGAT1 / 2 inhibitors, dipeptidyl peptidase IV inhibitors, endosialin 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 modulators (HNF4A), hepatocyte growth factor modulators, HMG CoA reductase inhibitors, IL-10 agonists, IL-17 antagonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 44, IRAK4 inhibitors, Jak2 tyrosine kinase inhibitors, ketohexokinase inhibitors, Klotho-β stimulators, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulators, 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 uncouplers, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase inhibitors inhibitors, NOX), nicotinic acid receptor 1 agonists, P2Y13 purinergic receptor stimulators, 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-associated protein kinase inhibitors, sodium glucose transporter 2 inhibitors, SREBP transcription factor inhibitors, STAT1 inhibitors, stearoyl-CoA desaturase 1 inhibitors, inhibitors of cytokine signaling 1 stimulators, inhibitors of cytokine signaling 3 stimulators, transforming growth factor β (TGF-β), transforming growth factor β activated kinase 1 (TGF-β),Examples of inhibitors include, but are not limited to, thyroid hormone receptor beta 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, pracinostat and panobinostat. A non-limiting example of an apoptosis signal kinase inhibitor is selonsertib.

[0154] The compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and at least one additional active agent may be administered in any order or simultaneously. The active agents may be provided in a single, combined form, or in multiple forms (as an example only, as a single pill, or as two separate pills). One of the active agents may be given in multiple doses, or both may be given in multiple doses. If not simultaneous, the timing between the 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 compositions of the present technology may include pharma- ceutically 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 parenteral dosage forms such as liquids for external use, suspensions for external use, suspensions for external use, gels (such as ointments), inhalants, sprays, injections, etc. The dosage forms may be formulated in various forms, e.g., dosage forms for single or multiple administrations.

[0156] The pharmaceutical compositions of the present technology may include excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonicity agents. If desired, sweeteners and / or flavoring agents can be added. Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophor, 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 coats, combinations thereof, and the like.

[0157] Specific carbohydrate excipients include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myo-inositol, etc.

[0158] Inorganic salts or buffers include, but are not limited to, citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

[0159] Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, low phosphates, 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," and Pluronics® 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 phosphatidylethanolamines), fatty acids and fatty acid esters, and chelating agents such as EDTA, zinc, and other such suitable cations.

[0161] In addition, the compositions disclosed herein may optionally include 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 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 agent ingredient, and particular needs of the composition.

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

[0164] The compositions of the present technology can be administered orally or parenterally, including inhalation, intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Thus, the compositions of the present technology can be formulated into various forms, such as tablets, capsules, aqueous solutions, suspensions, and the like. In the case of tablets for oral administration, carriers such as lactose, corn starch, and lubricants, e.g., magnesium stearate, can be conventionally added thereto. In the case of capsules for oral administration, lactose and / or dried corn starch can be used as diluents. When an aqueous suspension is required for oral administration, the active ingredient can be combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring agents can be added thereto. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, sterile solutions of the active ingredient are usually prepared, and the pH of the solution should be suitably adjusted and buffered. For intravenous administration, the total concentration of the solutes should be controlled to render the preparation isotonic. The compositions of the present technology can be in the form of an aqueous solution containing a pharma-ceutically acceptable carrier, e.g., physiological saline having a pH level of 7.4. The solutions may be introduced into a patient's intramuscular blood stream by local bolus injection.

[0165] The triazolones, tetrazolones, and imidazolones, i.e., compounds of Formula 1, or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, may be administered to a patient in an effective amount ranging from about 0.001 mg / kg to about 100 mg / kg per day, including 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] In general, a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, will 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 more in total doses. In some embodiments, a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, will 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, administered as a single dose or multiple doses. In some embodiments, multiple administration includes two, three, or four doses per day.

[0167] In some embodiments, a therapeutically effective amount of a compound of Formula 1, or a stereoisomer thereof, or a pharma- ceutically 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, at least 275 mg / day, 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] Of course, the dosage may vary according to the age, weight, sensitivity, symptoms of the patient, or the effectiveness of the compound.

[0169] In one embodiment, the present technology provides a method for inhibiting vascular adhesion protein (VAP)-1 in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the present technology provides a method for treating non-alcoholic steatohepatitis (NASH), comprising administering to the mammal a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating NASH in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound of formula 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Mammals include, but are not limited to, mice, rodents, rats, gnats, humans, farm animals, dogs, cats, sport animals, and pets.

[0170] In some embodiments, the present technology provides the use of a compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the preparation of a medicament for inhibiting vascular adhesion protein-1 (VAP-1) in a mammal.

[0171] In one embodiment, the present technology provides the use of a compound of formula 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing nonalcoholic steatohepatitis (NASH).

[0172] The present technology will be described in more detail 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 one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the technology. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. EXAMPLES

[0174] Analysis of the compounds prepared in the following examples was carried out as follows: Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker 400 MHz spectrometer and an Agilent 600 MHz spectrometer, and chemical shifts were reported in ppm. Furthermore, the indicated molecular weights were determined by using an Agilent 1260 Infinity series liquid chromatography / mass selective detector (MSD) equipped with an electrospray interface (using a single quadrupole, the m / z values ​​in ESI+ (ESI-MS (cation) represented by [M+H]+ peaks are shown). Column chromatography was performed on silica gel (Merck, 70-230 mesh). (WC Still, J. Org. Chem., 43, 2923, 1978). Furthermore, the abbreviations used in the following examples are as follows: "methyl" is abbreviated as "Me", "ethyl" is abbreviated as "Et", "phenyl" is abbreviated as "Ph", "tert-butyloxycarbonyl" is abbreviated as "Boc", and "tert-butyldimethylsilyl" is abbreviated as "TBDMS". Furthermore, the starting materials in each example are known compounds, either 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 then concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: 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-oxo-propyl]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 in tetrahydrofuran 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 increasing 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 (developing solvent: 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-difluoro-allyl]carbamate was dissolved in 2.0 mL of tetrahydrofuran, followed by the addition of 1.5 mL of 1.0 M tetrabutylammonium fluoride (TBAF) in tetrahydrofuran, and the resulting solution was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture thus obtained, 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 organic layers thus obtained were combined, washed 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 (developing solvent: 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 precipitated salts, 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 extracts were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 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-triazol-3-one

[0185] Step 1: 3-Methyl-1,4-dihydro-1,2,4-triazol-5-one

[0186] 5.0g of semicarbazide hydrochloride was dissolved in 100.0mL of methanol. 12.6mL of trimethyl orthoacetate was added to the reaction solution, and the solution was stirred at room temperature overnight. 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-triazol-5-one prepared in step 1 and 1080 mg of potassium carbonate were dissolved in 4.0 mL of N,N-dimethylformamide, followed by the addition of 1000 mg of 2-bromo-5-(bromomethyl)thiophene at 0°C. The solution thus obtained was stirred at room temperature for 3 hours. After the addition of 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 (developing solvent: 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-tetrazol-5-one

[0190] A reaction mixture of 500 mg of 5-bromothiophene-2-carbonyl chloride and 1533 mg of trimethylsilyl azide was stirred at 100° C. overnight. After the thus obtained reaction mixture was concentrated, ethyl acetate was added and the concentrated reaction mixture was extracted three times with saturated aqueous NaHCO3 solution. The combined aqueous phase was acidified with 6N aqueous HCl until the pH reached 3. The aqueous layer was extracted twice with ethyl acetate. The thus obtained 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-tetrazol-5-one

[0192] The title compound was prepared similarly to 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-tetrazol-5-one

[0194] The title compound was prepared similarly to 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-methylpyridin-2-yl)-1,4-dihydro-5H-tetrazol-5-one

[0196] The title compound was prepared similarly to Reference Example 5, except that 1000 mg of 6-bromo-3-methyl-pyridine-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-tetrazol-5-one

[0198] The title compound was prepared similarly to 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-tetrazol-5-one

[0200] The title compound was prepared similarly to 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-tetrazol-5-one

[0202] The title compound was prepared similarly to 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-Bromopyridin-3-yl)-1,4-dihydro-5H-tetrazol-5-one

[0204] The title compound was prepared similarly to 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-tetrazol-5-one

[0206] The title compound was prepared similarly to 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-triazol-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-triazol-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 uL 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 (developing solvent: 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-tetrazol-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-bromothiophen-2-yl)-1,4-dihydro-5H-tetrazol-5-one prepared in Reference Example 5 was used instead of 4-((5-bromothiophen-2-yl)methyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one prepared in Reference Example 4.

[0211] Reference Example 16. tert-Butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-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-tetrazol-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-triazol-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-tetrazol-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-tetrazol-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-triazol-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-methylpyridin-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-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-methylpyridin-2-yl)-1,4-dihydro-5H-tetrazol-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-triazol-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-tetrazol-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-tetrazol-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-triazol-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-tetrazol-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-tetrazol-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-triazol-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-tetrazol-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-tetrazol-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-triazol-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-bromopyridin-3-yl)-5-oxo-4,5-dihydro-1H-tetrazol-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-bromopyridin-3-yl)-1,4-dihydro-5H-tetrazol-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-triazol-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-imidazol-1-yl)methyl)-3,3-difluoroallyl)carbamate

[0226] 100 mg of 3-[(5-bromo-2-thienyl)methyl]-1H-imidazol-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 solution thus obtained was stirred at room temperature overnight. The reaction mixture thus obtained was quenched with water and extracted three times with diethyl ether. 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 (developing solvent: 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-tetrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0228] The title compound was prepared in the same manner as in Reference Example 23, except that 300 mg of 1-(4-bromo-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one prepared in Reference Example 13 was used instead of 3-[(5-bromo-2-thienyl)methyl]-1H-imidazol-2-one, and 259 mg of tert-butyl (E)-(2-(chloromethyl)-3-fluoroallyl)carbamate prepared in 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-difluoro-allyl]-4-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one trifluoroacetate

[0230] Step 1: tert-Butyl (2-((4-((5-(1-ethyl-1H-pyrazol-4-yl)thiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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-triazol-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, followed by the addition of 220 μL of 1M potassium carbonate and 2 mg of palladium di[1,1′-bis(diphenylphosphino)ferrocene]dichloride (PdCl2(dppf)), and the resulting solution was stirred at 90° C. overnight. The resulting reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to give a residue. The residue thus obtained 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 (developing solvent: 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-difluoro-allyl]-4-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one trifluoroacetate

[0233] 15 mg of tert-butyl (2-((4-((5-(1-ethyl-1H-pyrazol-4-yl)thiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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 uL of trifluoroacetic acid, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture thus obtained was concentrated, followed by the addition of dichloromethane. The solution was concentrated under reduced pressure and then dried in vacuum to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: 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-difluoro-allyl]-5-methyl-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]-1,2,4-triazol-3-one trifluoroacetate

[0235] The title compound was prepared similarly to 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-dioxaborolan-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-difluoro-allyl]-5-methyl-4-[[5-(4-piperazin-1-ylphenyl)-2-thienyl]methyl]-1,2,4-triazol-3-one di-trifluoroacetate

[0237] The title compound was prepared similarly to 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-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0239] The title compound was prepared similarly to 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-difluoro-allyl]-4-[[5-[6-(dimethylamino)-3-pyridyl]-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one trifluoroacetate

[0241] The title compound was prepared similarly to 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-difluoro-allyl]-4-[[5-(1,3-benzodioxol-5-yl)-2-thienyl]methyl]-5-methyl-1,2,4-triazol-3-one trifluoroacetate

[0243] The title compound was prepared similarly to 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-dioxaborolan-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-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0245] The title compound was prepared similarly to 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-difluoro-allyl]-3-methyl-5-oxo-1,2,4-triazol-4-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0247] The title compound was prepared similarly to Example 1, except that in step 1, 34 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-2-thienyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0249] In step 1, 50 mg of tert-butyl (2-((4-(5-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 15 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 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-difluoro-allyl]-4-[3-(4-methylsulfonylphenyl)phenyl]tetrazol-5-one trifluoroacetate

[0251] In step 1, 70 mg of tert-butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-dioxaborolan-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-difluoro-allyl]-4-[3-(4-piperazin-1-ylphenyl)phenyl]tetrazol-5-one trifluoroacetate

[0253] In step 1, 70 mg of tert-butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-ethyl-pyridin-2-one di-trifluoroacetate

[0255] In step 1, 70 mg of tert-butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0257] In step 1, 70 mg of tert-butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was mixed with 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 similarly to Example 1, except that 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0259] In step 1, 70 mg of tert-butyl (2-((4-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 16 was replaced with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tetrafluoroethylene)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 45 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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, and 1,2,3,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate was used instead of 1,2,3,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate ... 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-difluoro-allyl]-4-[3-(1-ethylpyrazol-4-yl)phenyl]tetrazol-5-one trifluoroacetate

[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-(3-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-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-triazol-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-difluoro-allyl]-4-[4-(4-methylsulfonylphenyl)phenyl]tetrazol-5-one trifluoroacetate

[0263] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-dioxaborolan-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-difluoro-allyl]-4-[4-(4-piperazin-1-ylphenyl)phenyl]tetrazol-5-one di-trifluoroacetate

[0265] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0267] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead 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-difluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)phenyl]tetrazol-5-one trifluoroacetate

[0269] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-trifluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of azol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-dioxaborolan-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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0271] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with 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 similarly to Example 1, except that 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0273] In step 1, 65 mg of tert-butyl (2-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 17 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tetrafluoroethylene)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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, and 42 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-4-[4-(1-ethylpyrazol-4-yl)phenyl]tetrazol-5-one trifluoroacetate

[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-tetrazol-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-triazol-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-difluoro-allyl]-4-[3-methyl-6-(4-methylsulfonylphenyl)-2-pyridyl]tetrazol-5-one trifluoroacetate

[0277] In step 1, 70 mg of tert-butyl (2-((4-(6-bromo-3-methylpyridin-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1,2,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate was used instead of 1,2,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate 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-dioxaborolan-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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0279] In step 1, 70 mg of tert-butyl (2-((4-(6-bromo-3-methylpyridin-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared similarly to Example 1, except that 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0281] In step 1, 70 mg of tert-butyl (2-((4-(6-bromo-3-methylpyridin-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-5-methyl-2-pyridyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0283] In step 1, 70 mg of tert-butyl (2-((4-(6-bromo-3-methylpyridin-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 18 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 44 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-4-[[3-(4-methylsulfonylphenyl)phenyl]methyl]tetrazol-5-one trifluoroacetate

[0285] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-dioxaborolan-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-difluoro-allyl]-4-[[3-(4-piperazin-1-ylphenyl)phenyl]methyl]tetrazol-5-one di-trifluoroacetate

[0287] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 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-difluoro-allyl]-4-[[3-[6-(dimethylamino)-3-pyridyl]phenyl]methyl]tetrazol-5-one trifluoroacetate

[0289] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-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-triazol-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 instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, except that the title compound was prepared in the same manner as in Example 1. 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-difluoro-allyl]-4-[[3-(1,3-benzodioxol-5-yl)phenyl]methyl]tetrazol-5-one trifluoroacetate

[0291] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-trifluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of azol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-dioxaborolan-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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0293] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was mixed with 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 similarly to Example 1, except that 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-difluoro-allyl]-4-[[3-(1-ethylpyrazol-4-yl)phenyl]methyl]tetrazol-5-one trifluoroacetate

[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-tetrazol-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-triazol-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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0297] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was replaced with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-tetrafluoroethylene)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 44 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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, 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]phenyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0299] In step 1, 70 mg of tert-butyl (2-((4-(3-bromobenzyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 19 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead 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-difluoro-allyl]-4-[4-(4-methylsulfonylphenyl)-2-thienyl]tetrazol-5-one trifluoroacetate

[0301] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2 The title compound was prepared similarly to Example 1, except that 1,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate was used instead of 1,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane and 14 mg of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were 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(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-difluoro-allyl]-4-[4-(4-piperazin-1-ylphenyl)-2-thienyl]tetrazol-5-one di-trifluoroacetate

[0303] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazolium)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 19 mg of tert-butyl 4-[4-(tetramethyl-1-yl)methyl-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0305] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1,2,4-triazol-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-difluoro-allyl]-4-[4-[6-(dimethylamino)-3-pyridyl]-2-thienyl]tetrazol-5-one trifluoroacetate

[0307] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-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-triazol-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 instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, except that the title compound was prepared in the same manner as in Example 1. 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-difluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)-2-thienyl]tetrazol-5-one trifluoroacetate

[0309] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0311] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-thienyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0313] In step 1, 22 mg of tert-butyl (2-((4-(4-bromothiophen-2-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 20 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2, The title compound was prepared similarly to Example 1, except that 4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 14 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-4-[4-(1-ethylpyrazol-4-yl)-2-thienyl]tetrazol-5-one trifluoroacetate

[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-tetrazol-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-triazol-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-difluoro-allyl]-4-[[5-(4-methylsulfonylphenyl)-2-thienyl]methyl]tetrazol-5-one trifluoroacetate

[0317] In step 1, 70 mg of tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 21 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1,2,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate was used instead of 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborolane and 42 mg of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (MeOD, 400MHz) δ7.90-7.70(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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0319] In step 1, 70 mg of tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 21 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared similarly to Example 1, except that 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0321] In step 1, 70 mg of tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 21 was added to tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-5-oxo-tetrazol-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0323] In step 1, 70 mg of tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 21 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 43 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-4-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]tetrazol-5-one trifluoroacetate

[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-tetrazol-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-triazol-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-difluoro-allyl]-4-[5-(1,3-benzodioxol-5-yl)-3-pyridyl]tetrazol-5-one trifluoroacetate

[0327] In step 1, 35 mg of tert-butyl (2-((4-(5-bromopyridin-3-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 22 was mixed with 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1 H-NMR (MeOD, 400MHz) δ 8.96-8.43 (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-difluoro-allyl]-5-oxo-tetrazol-1-yl]-3-pyridyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one trifluoroacetate

[0329] In step 1, 35 mg of tert-butyl (2-((4-(5-bromopyridin-3-yl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 22 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2 The title compound was prepared similarly to Example 1, except that 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, 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-difluoro-allyl]-2-oxo-imidazol-1-yl]methyl]-2-thienyl]-1-ethyl-pyridin-2-one trifluoroacetate

[0331] In step 1, 50 mg of tert-butyl (2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 23 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro- The title compound was prepared similarly to Example 1, except that 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-difluoro-allyl]-2-oxo-imidazol-1-yl]methyl]-2-thienyl]-1-methyl-3,4-dihydroquinolin-2-one trifluoroacetate

[0333] In step 1, 50 mg of tert-butyl (2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 23 was mixed with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1, The title compound was prepared similarly to Example 1, except that 2,4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 43 mg of (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-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-difluoro-allyl]-3-[[5-(1-ethylpyrazol-4-yl)-2-thienyl]methyl]imidazol-2-one trifluoroacetate

[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-imidazol-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-triazol-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-difluoro-allyl]-3-[[5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-thienyl]methyl]imidazol-2-one trifluoroacetate

[0337] In step 1, 50 mg of tert-butyl (2-((3-((5-bromothiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-3,3-difluoroallyl)carbamate prepared in Reference Example 23 was replaced with tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-trifluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of azol-1-yl)methyl)-3,3-difluoroallyl)carbamate 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-fluoro-allyl]-4-[4-(1,3-benzodioxol-5-yl)-2-fluoro-phenyl]-1,2,4-triazol-3-one hydrochloride

[0339] In step 1, 50 mg of tert-butyl (E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 24 was added to tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2, The title compound was prepared similarly to Example 1, except that 4-triazol-1-yl)methyl)-3,3-difluoroallyl)carbamate was used instead of 4-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 35 mg of 2-(1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were 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) 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-fluoro-allyl]-4-[4-(2,1,3-benzoxadiazol-5-yl)-2-fluoro-phenyl]-1,2,4-triazol-3-one hydrochloride

[0341] In step 1, 50 mg of tert-butyl (E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3-fluoroallyl) carbamate prepared in Reference Example 24 was used instead of tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-3,3-difluoroallyl) carbamate prepared in Reference Example 14, and 23 mg of benzo[c][1,2,5]oxadiazol-5-ylboronic acid was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, except that the title compound was prepared in the same manner as in Example 1. 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-fluoro-allyl]-5-oxo-1,2,4-triazol-4-yl]-3-fluoro-phenyl]-8-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride

[0343] In step 1, 50 mg of tert-butyl (E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 24 was added to tert-butyl (2-((4-((5-bromothiophen-2-yl)methyl)-3-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 14. The title compound was prepared similarly to Example 1, except that 1,2,4-triazol-1-yl)methyl-3,3-difluoroallyl)carbamate was used instead of 1,2,4-triazole-1-yl)methyl-3,3-difluoroallyl)carbamate 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-fluoro-allyl]-4-[2-fluoro-4-(6-morpholino-3-pyridyl)phenyl]-1,2,4-triazol-3-one hydrochloride

[0345] In step 1, 50 mg of tert-butyl (E)-(2-((4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-3-fluoroallyl)carbamate prepared in Reference Example 24 was added to 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 similarly to Example 1, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 41 mg of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-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] Example compounds are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] * Compounds were isolated as either the free base or as salts as described in Examples 1-57.

[0347] Experimental Example 1: Activity evaluation against amine oxidase

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

[0349] In addition, the compounds of this technology were evaluated for their activity against recombinant human MAO-A (monoamine oxidase-A, Sigma-Aldrich) and recombinant human MAO-B (monoamine oxidase-B, Sigma-Aldrich) using 0.5 mM tyramine and 1 mM benzylamine as substrates, respectively, in a manner similar to that used to evaluate the activity against recombinant human VAP-1. The compounds of this technology were also evaluated for their activity against recombinant human DAO (diamine oxidase, R&D systems) using 1 mM putrescine as a substrate in a manner similar to that used to evaluate the activity of recombinant human VAP-1.

[0350] The results obtained by evaluating the activity against 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 according to the present technology have excellent inhibitory activity against VAP-1, among various amine oxidases.

Claims

1. A compound of formula 1, 【Chemistry 28】 or a pharma- ceutically acceptable salt thereof, During the ceremony, (i) X is N and Y is N or CR ２’ or (ii) X is CR ３ and Y is N or CR ２ or (iii) X and Y are both N; R １ is hydrogen or fluoro, R ２ is hydrogen, C １～３ alkyl, halogen, phenyl, or benzyl; R ２’ is C １～３ alkyl, halogen, phenyl, or benzyl; R ３ is hydrogen, C １～３ alkyl, or phenyl; n is 0 or 1; A is C ６ ~C １０ an aryl group or a 5-10 membered heteroaryl group, said heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, said aryl group or said heteroaryl group optionally having １～３ Substituted with 1 or 2 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 said cyclic ring is aromatic or non-aromatic, or a pharma- ceutically acceptable salt thereof.

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

3. A is C １～３ 2. The compound of claim 1, which is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen and -R, or a pharma- ceutically acceptable salt thereof.

4. A is a 5-10 membered heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, said heteroaryl group being １～３ 2. The compound of claim 1, or a pharma- ceutically 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, C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, and -R.

6. R is, substituted or unsubstituted phenyl; a substituted or unsubstituted 5-10 membered heteroaryl having 1-5 heteroatom ring members independently selected from O, N, and S; or The compound according to any one of claims 1 to 5, 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, or a pharma- ceutically acceptable salt thereof.

7. R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridin-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl, said cyclic ring being １～６ Alkyl, mono-C １～６ Alkylamino, di-C １～６ Alkylamino, C １～６ 6. The compound according to any one of claims 1 to 5, optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl, piperazinyl, and morpholinyl, or a pharma- ceutically acceptable salt thereof.

8. A compound of formula 15, 【Chemical 29】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ is hydrogen or fluoro, R ２’ is C １～３ alkyl, halogen, phenyl, or benzyl; n is 0 or 1; A is C ６ ~C １０ an aryl group or a 5-10 membered heteroaryl group, said heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, said aryl group or said heteroaryl group optionally having １～３ Substituted with 1 or 2 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 said cyclic ring is aromatic or non-aromatic, or a pharma- ceutically acceptable salt thereof.

9. A compound of formula 16, 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ is hydrogen or fluoro, n is 0 or 1; A is C ６ ~C １０ an aryl group or a 5-10 membered heteroaryl group, said heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S, said aryl group or said heteroaryl group optionally having １～３ Substituted with 1 or 2 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 said cyclic ring is aromatic or non-aromatic, or a pharma- ceutically acceptable salt thereof.

10. A compound of formula 17, 【Chemistry 31】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ is hydrogen and fluoro; n is 0 or 1; A is C ６ ~C １０ an aryl group or a 5-10 membered heteroaryl group, said heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N, or S, said aryl group or said heteroaryl group optionally having １～３ Substituted with 1 or 2 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 said cyclic ring is aromatic or non-aromatic, or a pharma- ceutically acceptable salt thereof.

11. The compound is 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】

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

14. A composition for use in the treatment of a disease mediated by VAP-1, said composition comprising a compound according to any one of claims 1 to 5 and 8 to 11 or a pharma- ceutically acceptable salt thereof, said disease mediated by VAP-1 being selected from the group consisting of lipid disorders, lipoprotein disorders, conditions or diseases resulting from chronic fatty and fibrotic degeneration of organs due to accumulation of accumulated lipids, especially triglycerides, followed by activation of fibrosis-promoting pathways, diabetes mellitus type I or II, clinical complications of diabetes mellitus type I and II, chronic intrahepatic cholestatic conditions, extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inadequate bile composition, reduced intake of dietary fat and fat-soluble dietary vitamins. and / or a combination thereof.

15. Formula 1a 【Chemistry 32】 or a pharma- ceutically acceptable salt thereof, wherein (i) X is N and Y is N or CR ２’ or (ii) X is CR ３ and Y is N or CR ２ or (iii) X and Y are both N; R １ is hydrogen or fluoro, R ２ is hydrogen, C １～３ alkyl, halogen, phenyl, or benzyl; R ２’ is C １～３ alkyl, halogen, phenyl, or benzyl; R ３ is hydrogen, C １～３ alkyl, or phenyl; n is 0 or 1; A' is C ６ ~C １０ an aryl group or a 5-10 membered heteroaryl group, said heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, and S; R' is C １～３ is selected from the group consisting of alkyl, halogen, and -R; 1. A method for preparing a compound, or a pharma- ceutically 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 said cyclic ring is aromatic or non-aromatic, comprising the steps of: The method comprises: (a) a compound of formula 2, 【Chemical 33】 wherein PG is an amino protecting group; A compound of formula 3, Z-R' (Formula 3) In the formula, Z is -B(OH) ２ , -B(C １～３ Alkoxy) ２ or 【Chemical 34】 and reacting a compound Obtaining a compound of formula 1aa; 【Chemistry 35】 and (b) removing PG from said compound of formula 1aa under reaction conditions to obtain said compound of formula 1a or a pharma- ceutically acceptable salt thereof.

16. X is N and Y is CR ２’ and n is 1, and the compound of formula 2 is (a) reacting a compound of formula 4 with 【Chemical 36】 reacting with a compound of formula 5, 【Chemical 37】 To obtain a compound of formula 6, 【Chemical Formula 38】 (b) reacting the compound of formula 6 with a compound of formula 11, 【Chemical Formula 39】 A compound of formula 12, 【Chemistry 40】 wherein Q is a halogen; 16. The method of claim 15, wherein the compound of formula 2 is obtained by reacting under reaction conditions to obtain the compound of formula 2.

17. X and Y are both N, and the compound of formula 2 is (a) reacting a compound of formula 7 with 【Chemistry 41】 Reaction with trimethylsilyl azide under cyclization conditions gives compounds of formula 8: 【Chemistry 42】 (b) reacting the compound of formula 8 with a compound of formula 11, 【Chemistry 43】 A compound of formula 12, 【Chemistry 44】 wherein Q is a halogen; 16. The method of claim 15, wherein the compound of formula 2 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 is 【Chemistry 45】 A compound of formula 11, 【Chemistry 46】 A compound of formula 12, 【Chemistry 47】 wherein Q is a halogen; 16. The method of claim 15, wherein the compound of formula 2 is obtained by reacting under reaction conditions to obtain the compound of formula 2.

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