Flavivirus inhibitor

Abstract

The present invention relates to a flavivirus NS2B-NS3 protease inhibitor, a compound that inhibits the replication of flaviviruses in cells. The compounds of the present invention are useful alone or in combination with other agents for use in the treatment of infectious diseases caused by flaviviruses, particularly dengue virus, West Nile virus, chikungunya virus, Japanese encephalitis virus.

Description

Technical Field

[0001] The present invention relates to a flavivirus NS2B-NS3 protease inhibitor, a compound that inhibits the replication of flavivirus in cells. The compounds of the present invention are useful alone or in combination with other agents for use in the treatment of infectious diseases caused by flaviviruses, particularly dengue virus, West Nile virus, Zika virus, Japanese encephalitis virus. The present invention also relates to a pharmaceutical composition comprising said compound.

Background Art

[0002] The Flavivirus genus of the Flaviviridae family contains more than 70 related arthropod-borne viruses. The most common and representative members are dengue virus (DENV) with four serotypes (DENV-1, -2, -3, and -4), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and tick-borne encephalitis virus (TBEV). These are the causative agents of viral hemorrhagic fevers and encephalitis in humans. These viruses are mainly transmitted by mosquitoes of the Aedes genus. The threat of flavivirus infections to public health continues. Mosquito-borne dengue virus serotypes 1-4 (DENV1-4) are included in the list of Category A, B, or C emerging human pathogens of the National Institute of Allergy and Infectious Disease (NIAID), along with yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). DENV causes severe diseases associated with high morbidity and mortality rates. According to the World Health Organization's estimates, more than 50 million people worldwide are affected by dengue symptoms each year, and among them, especially among children in South Asian countries, at least 250,000 cases develop into dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) that result in significant mortality. The World Health Organization estimates that 2.5 billion people (about 40% of the world's population) live in areas at high risk of dengue virus infection. It frequently breaks out in the continental United States, mainly in the southern states, as well as in Puerto Rico and Hawaii.

[0003] Zika virus (ZIKV) mainly occurred in three locations: the Pacific Islands, Brazil, and other American countries, with more than 1 million infections reported and many patients seeking medical treatment. More seriously, Zika infections are associated with severe neurological disorders with a 20-fold higher incidence, including Guillain-Barré syndrome and microcephaly in newborns with more than 4,000 cases. Zika has spread rapidly in 48 countries across the Americas and has recently been recognized to be transmitted through sexual intercourse or body fluids.

[0004] Inhibitors against two major steps of flavivirus entry: (i) molecules that block virus-receptor interaction; (ii) compounds that prevent conformational changes of viral envelope proteins in virus-host membrane fusion have been reported (ACS Infect. Dis. 2015, 1, 9, 428 - 434).

[0005] Therefore, there is a need for more effective compositions and methods for treating viral infections caused by flaviviruses. In addition to vaccine development and vector control, the search for antiviral agents that reduce symptoms in patients is a major concern. Flaviviruses share epidemiological, structural, and ecological characteristics, and it is often the case that different viruses can co-infect the same host. Therefore, the identification of broad-spectrum inhibitors is highly desirable for known flaviviruses or viruses that may potentially emerge in the future. Strategies targeting both viral and host factors have been explored to identify broad-spectrum anti-flaviviral agents (https: / / doi.org / 10.1002 / cmdc.202000464).

[0006] The flavivirus genome consists of positive-sense single-stranded RNA that consists of a single long open reading frame (ORF) approximately 11 kb in length. The single ORF encodes a polyprotein, which is further processed by host-derived proteases and the viral NS2B-NS3 complex. Flavivirus proteases are highly conserved and essential for viral replication. The viral polyprotein is processed into three structural proteins (capsid, pr-membrane, and envelope) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The three structural proteins form the viral capsid, while the seven NS proteins are involved in the membrane-bound replication complex. Of these NS proteins, only NS3 and NS5 have enzymatic functions (Pathogens 2022, 11 293). Flavivirus replication is dependent on the NS3 protease, which is a 69 kDa protein containing two domains with different enzymatic functions: the trypsin-like serine protease domain is located within the N-terminal region; simultaneously, the C-terminal region has activities of RNA helicase and RNA-stimulated NTPase. Furthermore, it binds to its cofactor, namely NS2B, and is fully activated only when forming the enzymatic complex NS2B-NS3. Considering this, the NS2B-NS3 protease represents a beneficial target for developing novel antiviral compounds that inhibit its replication complex and cause the death of flaviviruses.

[0007] Flavivirus proteases highly share structural similarities and substrate recognition profiles, which can facilitate strategies for the development of pan-flavivirus protease inhibitors. However, due to the characteristics of viral enzymes and the lack of a robust structural template, the success of various drug discovery attempts in the past decade has been limited. Small molecule, structurally diverse protease inhibitors have been reported to reach affinities in the low micromolar range. Peptide-based substrate-derived compounds are often nanomolar-level inhibitors, but their drug-likeness is highly compromised. With some exceptions, the antiviral cell activity of most of the reported compounds was incomplete and insufficient for further development. In recent years, the elucidation of inhibitor binding using different structural methods has been progressing. This is expected to lead to more rational attempts to identify various lead compounds, succeed in cell assays, and be applied to animal models and ultimately patients.

[0008] In W02021 / 175437 and W02021 / 175670, non-peptide (4-phenoxy)-phenylglycine and (4-benzyloxy)-phenylglycine derivatives are provided as inhibitors of NS2B-NS3 serine protease for use in the treatment and prevention of flavivirus infections.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0011] The present invention provides a novel series of drug-like broad-spectrum activity inhibitors of flavivirus protease.

Means for Solving the Problems

[0012] The present invention provides a series of compounds targeting NS2B-NS3 protease. The compounds of the present invention are sydnone imine derivatives and thus have a mesoionic heterocyclic core appropriately substituted with a nitrogen derivative substituent at the imino nitrogen and appropriately substituted with an alkyl aromatic or heteroaromatic substituent. The chemical species discovered in the present invention result in extremely potent ZIKV NS2B-NS3 protease inhibitors and are also active against JEV protease, dengue protease, and WNV protease. The compounds of the present invention can inhibit the replication of the above-mentioned viruses in cells.

[0013] Therefore, an object of the present invention is a compound of general formula (I)

[0014] [Chemical formula]

[0015] (wherein: m and n are each independently selected from 0, 1, and 2; preferably, m is 1 and n is 1; more preferably, m is 1 and n is 0; R 1a and R 1b are independently selected from H and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1~3 alkyl, halogen, NH 2 , NHCOCH 3 , NHCOOC 1~6 alkyl, NHC(=O)NHC 1~6 alkyl, NHSO 2 C 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 or is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R1a and R 1b are joined together to form a C 3~6 -cycloalkyl ring or a C 4~6 -heterocycloalkyl ring; or or R 1a is attached to R 3 to form a partially unsaturated aromatic or heteroaromatic bicyclic ring; or or R 1b is absent and C-R 1a is C=CH 2 ; R 2a and R 2b are independently selected from H and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1~3 alkyl, halogen, NH 2 , NHCOCH 3 , NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 or is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 2a and R 2b are joined together to form a C 3~6 -cycloalkyl ring or a C 4~6 -heterocycloalkyl ring; or or R 1a and R 2a or R 1b and R 2b any two of which are joined together to form a C 3~6 cycloalkyl or a C 3~6 heterocycloalkyl; R 3 is a heterocycloalkyl, aromatic ring or heteroaromatic ring, and each said heterocycloalkyl, aromatic ring or heteroaromatic ring is halogen, hydroxy, NH2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC(=O)NHC 1~6 alkyl, NHSO 2 C 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 , C 1~6 alkyl, haloC 1~6 alkyl, C 1~6 alkoxy, cyano, B(OH) 2 , and is optionally substituted with one or more substituents independently selected from aryl, heteroaryl, wherein said aryl or heteroaryl ring is halogen, hydroxy, cyano, NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 , C 3~6 cycloalkyl, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N - methylpiperazine, C 1~6 alkyl, C 1~6 alkoxy, each independently selected from one or more substituents, and is optionally substituted, wherein said C 1~6 alkyl, C 1~6 alkoxy is one or more halogen, hydroxy, NH 2 , NHCOCH 3 , NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 , aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N - methylpiperazine, and is optionally substituted; R 4 is a ring of formula (II):

[0016]

Chemical formula

[0017] - R 6 is CF 3 , F, Cl, CN or C 1~4 alkyl, cyclopropyl, CHF 2 ; - X is CR 7 or N; - R 7 is, independently at each occurrence, H, halogen, C 1~6 alkyl, C 1~6 alkoxy, haloC 1~6 alkyl, hydroxy; or R 4 is 4-trifluoromethylphenyl, thiophene, thiazole, imidazole, pyrazole, oxazole, oxadiazole, naphthalene, quinoline, isoquinoline, quinazoline or naphthyridine, each said ring being optionally substituted with one or more substituents selected from halogen, C 1~6 alkyl, hydroxy, haloC 1~6 alkyl, C 1~6 alkoxy, NH 2 , NHC(O)C 1~6 alkyl, CN; or R 4 is phenyl and R 3 is phenyl - heteroaryl optionally substituted with one or more substituents selected from halogen, C 1~6 alkyl, C 1~6 alkoxy; R 5 is H, C 1~6 alkyl, C 1~6 haloalkyl or halogen), or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, provided that the compounds shown below are excluded.

[0018]

Chemical Structure

[0019] Preferably, R 1b and / or R 2b is H; and / or m and n are each independently selected from 0, 1; and / or R 5 is H; more preferably, R 3 is phenyl, naphthyl, biphenyl, phenyl substituted with a heteroaromatic ring or heteroaromatic ring substituted with a second heteroaromatic ring, each said phenyl, naphthyl or heteroaromatic ring being halogen, hydroxy, cyano, B(OH) 2 , NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 , C 1~6 alkyl, C 1~6 alkoxy, pyrrolidine, piperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituents independently selected therefrom, said C 1~6 alkyl, C 1~6 alkoxy being optionally substituted with one or more halogen, hydroxy, NH 2 , N(CH 3 ) 2 , morpholine or pyrrolidine.

[0020] More preferably, R 4is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl.

[0021] Preferably, in the compound defined above, m is 1 and n is 0; R 1a is H, and R 1b is H, or C 2 alkyl optionally substituted with hydroxy or NH 1~3 is.

[0022] In a further preferred embodiment, in the compound of the present invention: i. R 3 is a) phenyl substituted with a 5- or 6-membered heteroaromatic ring, preferably phenyl selected from pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or b) A 5- or 6-membered heteroaromatic ring, preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each said 5- or 6-membered heteroaromatic ring being substituted with phenyl, isoindoline or preferably substituted with a 5- or 6-membered heteroaromatic ring selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine, a 5- or 6-membered heteroaromatic ring selected from In a) or b), each said phenyl, 5- or 6-membered heteroaromatic ring is C 1~3 alkyl, C 1~3 alkoxy, C 3~6 cycloalkyl, CF 3 , C 5~6 heterocycloalkyl, O-(CH 2 ) 2 NH 2 , O-(CH 2 ) 2 OH, hydroxy, halogen, optionally substituted with one or more substituents independently selected from; and / or ii. R 4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl; and / or iii. m is 1 and n is 0; R 1a is H, and R 1b is H, or hydroxy or NH 2 optionally substituted C 1~3 alkyl 。

[0023] In a more preferred embodiment, the present invention has the general formula (III)

[0024]

Chemical formula

[0025] or has the general formula (IV)

[0026]

Chemical formula

[0027] or has the general formula (V)

[0028]

Chemical formula

[0029] (wherein each R 3 , R 5 and X have the meanings defined above) has

[0030] Preferably, in the compound of general formula (I) or in the compound of general formula (III), (IV) or (V), R 3 is selected from the following structures

[0031]

Chemical formula

[0032] (wherein each phenyl or heteroaromatic ring is methyl, CF 3(optionally further substituted by one or two substituents independently selected from halogen, cyclopropyl, methoxy, cyano).

[0033] More preferably, in the compound of general formula (I) or in the compound of general formula (III), R 4 is selected from the following structures

[0034]

Chemical formula

[0035] In a more preferred embodiment, R 3 is

[0036]

Chemical formula

[0037] and R 4 is

[0038]

Chemical formula

[0039] and is

[0040] Preferably, the compound of the present invention is any one of the following compounds. - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl)carbamoyl)amide; - (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; - (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-Phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide - (3-(1-(3,4-Dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2,3-Dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide; - (R)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; - (3-([1,1'-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(Naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2'-Methyl-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-Benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-([1,1'-Biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2-Phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(Pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-Methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Phenyl-3-(pyrrolidin-1-yl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2,2,2-Trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Isooxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((4'-(Morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((1R,2S)-2-Phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(4-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(3-Methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-(2-Hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(5-Methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(4-(1,4-Dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,2-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-fluoro-6-oxo-1,6-dihydropyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4-(4-methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-(2-Hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-Cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl); - (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amideamide; - (S)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Isindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(2-(aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-boronopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-(2-(dimethylamino)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(2-(2-(dimethylamino)ethoxy)-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(5-Methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(5-Methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,6-Dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4,6-Dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(2-Methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(2-Methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-Methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-Methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((5-(Trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((2'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((2'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4-Cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(Pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((5-Cyclopropylpyridin-3-yl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((5-(Trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4-Cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)thiazol-5-yl)carbamoyl)amide; - (3-((5-(4-cyclopropylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)amide; - ((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2'-Methoxy-4'-methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; - (3-((5-(4-Methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3'-Methyl-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3'-Fluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)amide; - (3-((2'-chloro-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - ((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(4-chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,6-dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,6-dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((4',6'-Dimethyl-[5,5'-bipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(4,6-Dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (R)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (R)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (S)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (S)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0041] Preferably, the compounds according to the invention are NS2B-NS3 protease inhibitors of flaviviruses, preferably NS2B-NS3 protease inhibitors of dicaviruses and / or dengue viruses and / or West Nile viruses and / or Japanese encephalitis viruses, and thus inhibit the replication of said viruses in cells.

[0042] A further object of the invention is a compound as defined above for pharmaceutical use, preferably for use in the treatment and / or prevention of flavivirus infections, preferably the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0043] A further object of the invention is a compound of general formula (I) for use in the treatment of flavivirus infections, preferably the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0044] [Chemical formula]

[0045] (wherein m and n are each independently selected from 0, 1 and 2; R 1a and R 1b are independently selected from H and C 1~6 alkyl, C 1~6 alkyl is hydroxy, OC 1~3 alkyl, halogen, NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC(=O)NHC 1~6 alkyl, NHSO2 C 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 optionally substituted with one or more substituents selected from, or optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 1a及び R 1b are joined together to form a C 3~6 -cycloalkyl ring or a C 4~6 -heterocycloalkyl ring? or R 1a is R 3 bonded to form a partially unsaturated aromatic or heteroaromatic bicyclic ring? or R 1b is absent, and C-R 1a is C=CH 2 ; R 2a and R 2b are independently selected from H and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1~3 alkyl, halogen, NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 optionally substituted with one or more substituents selected from, or optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 2a and R 2b are joined together to form a C 3~6 -cycloalkyl ring or a C 4~6 -heterocycloalkyl ring? or R 1aand R 2a or R 1b and R 2b Any two of them are combined together to form C 3~6 cycloalkyl or C 3~6 heterocycloalkyl; R 3 is heterocycloalkyl, an aromatic ring or a heteroaromatic ring, and each said heterocycloalkyl, aromatic ring or heteroaromatic ring is halogen, hydroxy, NH 2 , NHCOCH 3 , NHCOOC 1~6 alkyl, NHC(=O)NHC 1~6 alkyl, NHSO 2 C 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 C 1~6 alkyl, haloC 1~6 alkyl, C 1~6 alkoxy, cyano, B(OH) 2 , aryl, heteroaryl, optionally substituted with one or more substituents independently selected therefrom, and said aryl or heteroaryl ring is halogen, hydroxy, cyano, NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 C 3~6 cycloalkyl, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N - methylpiperazine, C 1~6 alkyl, C 1~6 alkoxy, each optionally substituted with one or more substituents independently selected therefrom, and said C 1~6 alkyl, C 1~6 alkoxy is one or more halogen, hydroxy, NH 2 , NHCOCH 3 , NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl)2 and is optionally substituted with aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, and N-methylpiperazine; R 4 is halogen, hydroxy, C 1~6 alkyl, haloC 1~6 alkyl, C 1~6 alkoxy, cyano, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 and is an aromatic or heteroaromatic ring optionally substituted with one or more substituents independently selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, and N-methylpiperazine; R 5 is H, C 1~6 alkyl, C 1~6 haloalkyl or halogen), or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof. Preferably: - R 1b and R 2b are H; m and n are each independently selected from 0, 1; more preferably, m is 1 and n is 1; even more preferably, m is 1 and n is 0; and / or - R 3 is phenyl, naphthyl, biphenyl, phenyl-heteroaryl, or bis-heteroaryl, and each said phenyl, naphthyl, or heteroaryl ring is halogen, hydroxy, cyano, B(OH) 2 , NH 2 , NHCOC 1~6 alkyl, NHCOOC 1~6 alkyl, NHC 1~3 alkyl, N(C 1~3 alkyl) 2 , C 1~6 alkyl, C 1~6 alkoxy, pyrrolidine, piperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and is optionally substituted with one or more substituents independently selected therefrom, and the said C1~6 Alkyl, C 1~6 Alkoxy is optionally substituted with one or more halogens, hydroxy, NH 2 , N(CH 3 ), 2 , morpholine or pyrrolidine; and / or - R 4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl selected from.

[0046] Preferably, in the compound for use as defined above, m is 1, n is 0; R 1a is H, R 1b is H, or C 2 alkyl optionally substituted with hydroxy or NH 1~3 .

[0047] More preferably: i. R 3 is c) phenyl substituted with a 5- or 6-membered heteroaromatic ring, preferably phenyl selected from pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or d) a 5- or 6-membered heteroaromatic ring, preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each said 5- or 6-membered heteroaromatic ring being substituted with phenyl, isoindoline or preferably a 5- or 6-membered heteroaromatic ring selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine selected from; In a) or b), each said phenyl, 5- or 6-membered heteroaromatic ring is optionally substituted with one or more substituents independently selected from C 1~3 alkyl, C 1~3 alkoxy, C 3~6 cycloalkyl, CF 3 , C 5~6 heterocycloalkyl, O-(CH 2 ) 2 NH 2 、O-(CH 2 ) 2 OH, hydroxy, halogen; ii. R 4is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl; iii. m is 1 and n is 0; R 1a is H, R 1b is H, or C optionally substituted with hydroxy or NH 2 alkyl 1~3 is 。

[0048] More preferably, preferably, a compound for use in the treatment of a flavivirus infection, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus, is - (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-phenethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide selected from.

[0049] A further object of the present invention is a pharmaceutical composition comprising the compound defined above and at least one pharmaceutically acceptable excipient.

[0050] Preferably, the pharmaceutical composition is for use in the treatment and / or prevention of flavivirus infections, preferably wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0051] In a preferred embodiment, the pharmaceutical composition comprises at least one further active compound selected from the group consisting of antiviral agents, antibacterial agents, anti-inflammatory agents, analgesics and antipyretics.

[0052] A further object of the present invention is a method for synthesizing the compound of general formula (I) defined above.

DETAILED DESCRIPTION OF THE INVENTION

[0053] The present invention includes within its scope prodrugs of the compounds of formula (I). Generally, such prodrugs are functional derivatives of the compounds of formula (I) and will be readily convertible in vivo to the required compounds of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0054] Prodrugs are pharmacologically inactive derivatives of biologically active substances ("parent drugs" or "parent molecules") which are converted in the body in order to release the active drug and may have improved delivery properties compared to the parent drug molecule. The in vivo conversion may be the result of, for example, several metabolic processes, such as chemical or enzymatic hydrolysis of carboxylic acids, phosphates or sulfate esters, or reduction or oxidation of labile functional groups.

[0055] The present invention encompasses within its scope solvates of the compounds of formula (I) and salts thereof, such as solvates.

[0056] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119 - 1190), and occur as racemates, racemic mixtures, and as individual diastereomers, together with all possible isomers including optical isomers and mixtures thereof, and all such stereoisomers are included in the present invention. Further, the compounds disclosed herein may exist as tautomers, and it is intended that all tautomers be encompassed within the scope of the invention even if only one tautomeric form structure is illustrated. Specific tautomers of the compounds of the present invention are illustrated below

[0057]

Chemical formula

[0058] The compounds may exist in different isomeric forms, and all of them are included in the present invention.

[0059] If any variable appears more than once in any component, its definition at each appearance is independent of the other appearances. Also, combinations of substituents and variables are permitted only if such combinations result in stable compounds.

[0060] It should be understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art and the methods shown below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups may be present on the same carbon or on different carbons as long as a stable structure is obtained. The phrase "optionally substituted" should be considered equivalent to the phrase "unsubstituted or substituted with one or more substituents", and in such cases, preferred embodiments will have from 0 to 3 substituents. More particularly, it is from 0 to 2 substituents. Substituents on saturated, partially saturated or unsaturated heterocycles may be attached at any substitutable position.

[0061] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1 ~C 6 alkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a straight-chain or branched arrangement. For example, "C 1 ~C 6 alkyl" includes, inter alia, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, etc. The term "cycloalkyl" means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C 3~10Examples of "cycloalkyl" include cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc. In certain embodiments of the present invention, the term "cycloalkyl" includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups. For example, "cycloalkyl" as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0062] "Alkoxy" represents an alkyl group having the number of carbon atoms indicated, bonded via an oxygen bridge. Thus, "alkoxy" encompasses the definition of alkyl as described above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. A preferred alkoxy group is methoxy.

[0063] "HaloC 1~6 alkyl" and "HaloC 1~6 alkoxy" refer to a C 1~6 alkyl or C 1~6 alkoxy group in which one or more (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, especially fluorine or chlorine atoms. FluoroC 1~6 alkyl and fluoroC 1~6 alkoxy groups, especially fluoroC 1~3 alkyl and fluoroC 1~3 alkoxy groups, for example, CF 3 、CHF 2 、CH 2 F、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、OCF 3 、OCHF 2 、OCH2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , especially CF 3 , OCF 3 and OCHF 2 are preferred.

[0064] The term "hydroxy C 1~6 alkyl" means a C 1~6 alkyl group in which one or more (especially 1 to 3) hydrogen atoms are replaced by hydroxy groups. CH 2 OH, CH 2 CHOH and CHOHCH 3 are preferred.

[0065] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbocyclic ring of 6 to 10 atoms in which at least one ring is aromatic. Examples of such aryl moieties include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene. Preferred aryl groups are phenyl or naphthyl, especially phenyl.

[0066] As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein at least one ring is aromatic. In particular, the term heteroaryl includes 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein one or fewer of these is O or S; a 6-membered aromatic heterocycle containing 1, 2, or 3 nitrogen atoms; or a 7- to 13-membered aromatic heterocycle containing 5 to 10 atoms as heteroatoms independently selected from N, O, or S, and includes a 5-membered aromatic heterocycle wherein at least one ring is aromatic. Heteroaryl rings also include partially saturated bicyclic systems, such as indoline, isoindoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine; and further include tautomeric structures, such as hydroxypyrimidine and hydroxypyrimidone.

[0067] Examples of specific heteroaryls of the present invention include benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzisoxazolyl, benzisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxyxyl, furanyl, furazanyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, indolizinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxokinazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, quinolidinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, triazolyl, imidazopyridinyl, phthalazinyl, naphthyridinyl, quinazolinyl, pteridinyl, pyrimidin-4(3H)-one, and N-oxides thereof. The bond of the heterocyclic substituent may occur via a carbon atom or via a heteroatom.

[0068] Biphenyl represents a phenyl ring substituted with a further phenyl ring; phenyl-heteroaryl represents a phenyl ring substituted with a heteroaromatic ring; bisheteroaryl represents a heteroaryl substituted with a further heteroaromatic ring.

[0069] The term "heterocyclic ring" refers to a non-aromatic ring group consisting of a carbon atom and at least one heteroatom selected from nitrogen, phosphorus, oxygen, or sulfur. The heterocyclic ring may include a fused, bridged, or spiro ring system, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring group may be oxidized to various oxidation states as required. It may be a monocyclic-, bicyclic-, tricyclic-, or tetracyclic ring system. Further, the nitrogen atom may be quaternized as required.

[0070] Examples of specific heterocyclic rings of the present invention are tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolidinyl, octahydroisoindolyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azonabicycloheptanyl, azonabicyclooctanyl. The bond of the heterocyclyl substituent may occur via a carbon atom or via a heteroatom.

[0071] The preferred 4-membered saturated heterocyclic ring is azetidine.

[0072] The preferred 5-membered saturated heterocyclic ring is tetrahydrofuran.

[0073] The preferred 6-membered saturated or partially saturated heterocyclic rings are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and thiazolidinyl.

[0074] The preferred 5-membered heteroaryl groups are thienyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl, oxazolyl, triazolyl, tetrazolyl, furyl and oxadiazolyl.

[0075] The preferred 6-membered heteroaryl groups are pyridinyl and pyrimidinyl.

[0076] The preferred 8- to 10-membered heteroaryl groups are benzothienyl, indolyl, benzothiadiazolyl, benzoxadiazolyl, thiazolotriazolyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzoisoxazolyl, benzotriazolyl, dihydroisoindolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl and tetrahydroquinolinyl.

[0077] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are preferred.

[0078] Pharmaceutically acceptable salts of the compounds of the present invention may be synthesized from the compounds of the present invention containing basic or acidic moieties by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0079] Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Preferably, the pharmaceutically acceptable salts of the present invention contain 1 equivalent of the compound of formula (I) and 1, 2 or 3 equivalents of an inorganic or organic acid. More specifically, the pharmaceutically acceptable salts of the present invention are tartrate salts, trifluoroacetate salts or chloride salts.

[0080] When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganous, potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium and sodium are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, arginine, betaine, caffeine, choline, N,N 1 -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and other salts.

[0081] The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1~19.

[0082] Under physiological conditions, the deprotonated acidic moiety in the compound, for example, the carboxyl group, may be anionic, and the charge of this electron can be internally balanced against the cationic charge of the protonated or alkylated basic moiety, for example, the quaternary nitrogen atom. It should also be noted that the compounds of the present invention are potential internal salts or zwitterions.

[0083] The compounds of the present invention have been found to be useful in various applications to the health of humans and animals. The compounds of the present invention are flavivirus inhibitors and can be used in the treatment and / or prevention of flavivirus infections.

[0084] The compounds of the present invention may be administered to mammals, preferably humans, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention may be administered to animals. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0085] The present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically smooth and pleasant preparation. Tablets contain the active ingredient in a mixture of non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents such as starch, gelatin, polyvinylpyrrolidone or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated and may be coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a long period. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time delay materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0086] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily medium such as groundnut oil, liquid paraffin, or olive oil.

[0087] The aqueous suspension contains an active material in a mixture containing excipients suitable for manufacturing the aqueous suspension. Such excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and gum acacia; the dispersing agent or wetting agent may be a naturally occurring phosphatide such as lecithin, or a condensation product of an alkylene oxide and a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide and a long-chain aliphatic alcohol such as heptadecaethylene oxycetanol, or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or aspartame.

[0088] The oily suspension may be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those indicated above and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

[0089] Powders and granules of suitable dispersibility for the preparation of aqueous suspensions by adding water provide an active ingredient in a mixture containing a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents and coloring agents, may also be present. These compositions may be preserved by adding an antioxidant, such as ascorbic acid.

[0090] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phosphatides, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.

[0091] Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, flavoring agents, coloring agents and antioxidants.

[0092] The pharmaceutical composition may be in the form of a sterile aqueous solution for injection. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.

[0093] The sterile preparation for injection may also be a sterile oil-in-water microemulsion for injection in which the active ingredient is dissolved in the oily phase. For example, the active ingredient may first be dissolved in a mixture of soybean oil and lecithin. The oil solution may then be introduced into a mixture of water and glycerol and processed to form a microemulsion. The injection solution or microemulsion may be introduced into the patient's bloodstream by local bolus injection.

[0094] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to known fields using the suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Furthermore, sterile fixed oils have conventionally been used as solvents or suspending media. For this purpose, any brand of fixed oil containing synthetic mono- or diglycerides may be used. Furthermore, fatty acids, such as oleic acid, are recognized for use in the preparation of injectables.

[0095] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and thus will melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hardened vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0096] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. The compounds of the present invention may be administered via a nasal form through topical use of a suitable nasal vehicle and delivery device, or via a transdermal route using a transdermal skin patch well known to those skilled in the art. For administration in the form of a transdermal delivery system, the dosing of the drug will of course be continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention may also be delivered as suppositories using a base, such as cocoa butter, glycerinated gelatin, hardened vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0097] When administering a compound according to the present invention to a human subject, the daily dosage regimen will generally be determined by the prescribing physician, and the dosage will generally vary according to the age, weight, gender and response of the individual patient, as well as the severity of the patient's symptoms.

[0098] The compounds of the present invention are also useful in combination with known therapeutic agents for administration simultaneously, individually or sequentially.

[0099] As used herein, the term "administration" and variations thereof (e.g., "administering a compound") in reference to a compound of the present invention mean introducing the compound or a prodrug of the compound into the system of a subject in need of treatment. When a compound of the present invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and variations thereof are understood to include introducing the compound or its prodrug and the other agent simultaneously and sequentially.

[0100] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product directly or indirectly obtained from a combination of the specified ingredients in the specified amounts.

[0101] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other clinician.

[0102] When administering a compound of the present invention to a human subject, the daily dosage regimen will generally be determined by the prescribing physician, and the dosage will generally vary according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, the oral dosage of the present invention will range from about 0.01 mg / kg / day (mg per kg of body weight per day) to about 100 mg / kg / day, preferably between 0.01 and 10 mg / kg / day, and most preferably between 0.1 and 5.0 mg / kg / day.

[0103] A further object of the present invention is a method for treating, restoring or preventing flavivirus infections and related conditions, preferably wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus, the method comprising administering to a subject a therapeutically effective amount of a compound as defined above.

[0104] These and other aspects of the invention will become apparent from the teachings contained herein.

[0105] Chemical substance Summary The compounds or pharmaceutically acceptable salts, compositions, and methods described herein are further illustrated by the following non-limiting examples.

[0106] As used herein, the following abbreviations have the following meanings. When an abbreviation is not defined, it has its generally accepted meaning.

[0107] CDI 1,1'-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; DPPA: [azido(phenoxy)phosphoryl]oxybenzene; ES + : electrospray positive ionization; EtOAc: ethyl acetate; h: hour; HPLC: high performance liquid chromatography; LCMS: liquid chromatography mass spectrometry; MeCN: acetonitrile; MeOH: methanol; min: minute; MTBE: methyl tert-butyl ether; NMP: N-methylpyrrolidone; NMR: nuclear magnetic resonance; RP: reverse phase; t R : retention time; rt: room temperature; TBAB: tetra-n-butylammonium bromide; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra performance liquid chromatography.

[0108] Details of General Experiments Solvents and reagents were obtained from commercial suppliers and used without further purification. Silica gel chromatography purification was performed using pre-packed cartridges from Biotage system. UPLC-MS analysis was performed on a Waters Acquity UPLC (trademark) equipped with a diode array and a ZQ mass spectrometer, using an X-Terra C18 column (5 μm, 4.6 × 50 mm) or a BEH C18 column (1.7 μm, 2.1 × 50 mm). The mobile phase contained a linear gradient of a two-component mixture of H 2 O(A) and MeCN(B) containing 0.1% formic acid. The linear gradient used was: (A): 90% (0.1 min), 90% - 0% (2.6 min), 0% (0.3 min), 0% - 90% (0.1 min), at a flow rate of 0.5 mL / min. 1 H, 19 F, 13 CNMR spectra were recorded at 400, 377, and 101 MHz on a 400 MHz Bruker spectrometer. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane using CDCl 3 as the solvent, unless otherwise noted. Coupling constants (J) are reported in Hertz (Hz). Multiplicities are reported as singlet (s), broad (br), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), triplet (t), triplet of doublet (dt), or multiplet (m). Unless otherwise indicated, spectra were acquired at 300 K. Temperatures are shown in degrees Celsius (°C) and are not corrected. The reported yields are the actual isolated yields of the purified materials and are not optimized. The purity of Intermediates 1 - 10, 23 and 24 and Examples 1 - 30, 34, 38 - 43, 46 - 48, 50 - 53, 55 - 64, 67 - 69, 71 - 98, 100, 101, 103 - 115 and 117 - 124 was evaluated on a Waters Acquity UPLC (trademark) equipped with a diode array and a ZQ mass spectrometer, using a BEH C18 column (1.7 μm, 2.1 × 50 mm). The mobile phase contained H2 It included a linear gradient of a two-component mixture of O(A) and MeCN(B) containing 0.1% formic acid. The linear gradient of B used was: 10% (0.1 min), 10 - 100% (1.5 min), 100% (0.3 min), 100 - 10% (0.1 min), 0.5 mL / min flow rate, run time: 3 min. The purity of intermediates 11 - 22, 25 - 30 and Examples 30 - 32, 35 - 37, 44, 45, 49, 54, 65, 66, 70, 99, 102 and 116 was evaluated on a Waters Acquity UPLC™ equipped with a diode array and ZQ mass spectrometer, BEH C18 column (1.7 μm, 2.1×50 mm). The mobile phase was H containing 0.05% TFA 2 It included a linear gradient of a two-component mixture of O(A) and MeCN(B) containing 0.05% TFA. The linear gradient of B used was: 5% (0.1 min), 5 - 100% (2.8 min), 100% (0.2 min), 100 - 5% (0.8 min), 0.5 mL / min flow rate, run time: 3 min. Unless otherwise indicated, commercially available reagents and solvents (HPLC grade) were used without further purification. When the synthesis of intermediates and starting materials is not described, these compounds are commercially available or can be made from commercially available compounds by standard methods or by extending the examples herein. During any of the synthetic sequences described herein, it may be necessary and / or desirable to protect any highly sensitive or reactive groups or molecules of concern, which may be achieved using conventional protecting groups, e.g., those described in Protecting Groups in Organic Synthesis (3 rd Edition, Greene, T.W. and Wuts, P.G.M.; Wiley Interscience, 1999) and Protecting Groups (Kocienski, P.J.; Thieme, 1994).

Example

[0109] (Example 1) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0110] [Chemical Structure]

[0111] Step 1: 1-Phenylpropan-2-amine (Intermediate 1) Ammonium formate (24.44 g, 387.54 mmol) was dissolved in a mixture of water (9 mL) and methanol (80 mL), and the solution was treated with 1-phenylpropan-2-one (4.95 mL, 37.26 mmol) and Pd / C (10% w / w) (1.19 g, 11.18 mmol). The mixture was stirred at room temperature for 16 h, then filtered through a Celite pad and washed with methanol. The filtrate was evaporated under reduced pressure to give a white powder, which was suspended in EtOAc (150 mL) and stirred at room temperature for 1 h. The formed solid was isolated by filtration to give the desired product as a salt (4.2 g). 500 mg of the isolated product was dissolved in methanol (1.5 mL) and placed on an SCX cartridge (5 g). The resin was washed with methanol, followed by a 2M NH 3 solution in methanol. After removing the solvent under reduced pressure, the title compound was obtained as a white powder (350 mg, 58%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.30 - 7.26 (m, 2H), 7.20 - 7.17 (m, 3H), 3.03 - 2.96 (m, 1H), 2.55 - 2.48 (m, 2H), 0.95 (d, J = 4.0 Hz, 3H). LCMS (ES + ) m / z C 9 H 13 N calculated 135.10, found 136 (M+H) + . HPLC t R 0.59 min.

[0112] Step 2: 2-((1-Phenylpropan-2-yl)amino)acetonitrile (Intermediate 2) A suspension of 1-phenylpropan-2-amine (Intermediate 1) (1.31 g, 9.71 mmol) and DIPEA (3.44 mL, 19.42 mmol) in MeCN (11.8 mL) was treated with 2-bromoacetonitrile (0.47 mL, 6.8 mmol), and the reaction mixture was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure, the residue was treated with water (10 mL), and extracted with EtOAc (3 × 50 mL). The collected organic matter was washed with brine and dried over Na 2 SO 4 and evaporated under reduced pressure to give the title compound as a colorless oil (1.45 g, 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 - 7.28 (m, 2H), 7.22 - 7.18 (m, 3H), 3.73 - 3.61 (m, 2H), 2.95 - 2.90 (m, 1H), 2.77 (dd, J 1 = 4.0 Hz, J 2 = 12.0 Hz, 1H), 2.46 - 2.41 (m, 2H), 0.92 (d, J = 4.0 Hz, 3H). LCMS (ES + ) m / z Calcd for C 11 H 14 N 2 174.12, found 175 (M+H). + . HPLC t R 0.81 min.

[0113] Step 3: 5-Amino-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 3). A solution of 2-((1-phenylpropan-2-yl)amino)acetonitrile (Intermediate 2) (1.4 g, 8.03 mmol) in THF (3.9 mL) was treated with tert-butyl nitrite (3.84 mL, 32.14 mmol). The solution was stirred at room temperature for 4 h. Then 4N HCl in dioxane (13.1 mL, 52.23 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Diethyl ether was added to the mixture and the precipitate formed was collected by filtration, washed with diethyl ether to give the title compound as a white powder (1.39 g, 82%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 2H), 8.20 (s, 1H), 7.34 - 7.21 (m, 5H), 5.33 - 5.27 (m, 1H), 3.32 - 3.30 (m, 2H), 1.65 (d, J = 4.0 Hz, 3H). LCMS (ES+) m / z C 11 H 14 N 3 O + calculated for 204.11, found 204 (M+H) + . HPLC t R 0.84 min.

[0114] Step 4: (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 1) A solution of 3-(trifluoromethyl)benzoic acid (277.6 mg, 1.46 mmol) in toluene (1.7 mL, 0.016 mol) was treated with TEA (0.22 mL, 1.61 mmol) and DPPA (0.35 mL, 1.61 mmol). The mixture was heated at 70 °C for 1 h, then Intermediate 3 (175 mg, 0.730 mmol) was added and the mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, quenched by addition of 1N NaHCO 3 (aqueous solution), and extracted with EtOAc. The combined organic phases were washed with water and brine, and Na 2 SO 4It was dried and evaporated under reduced pressure. The resulting residue was triturated with petroleum ether to obtain the title compound as a pale yellow solid (258 mg, 87%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.32 (s, 1H), 8.27 (br s, 1H), 7.68 (br d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.24-7.19 (m, 4H), 5.16-5.11 (m, 1H), 3.32 (m, 2H), 1.65 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 19 H 17 F 3 N 4 O 2 calculated value for 390.13; found 391 (M+H) + . HPLC t R 2.0 min.

[0115] Examples 5, 12, 18 and 33 were synthesized according to the above procedure (Scheme 1) by reacting with appropriate starting materials.

[0116] (Example 5) (3-Phenethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-phenylethane-1-amine was reacted in Step 2, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.69 (s, 1H), 8.25 (br s, 1H), 8.24 (br s, 1H), 7.72 (br d, J = 8.3 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.35 - 7.22 (m, 6H), 4.82 (t, J = 7.1 Hz, 2H), 3.32 (t, J = 7.1 Hz, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 18 H 15 F 3 N 4 O 2 Calculated value for C + . HPLC t R 1.90 min.

[0117] (Example 12) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide When quinoline-6-carboxylic acid was reacted in Step 4, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.87 (d, J = 3.5 Hz, 1H), 8.53 - 8.51 (br m, 2H), 8.31 (s, 1H), 7.99 (br s, 2H), 7.68 - 7.65 (m, 1H), 7.33 - 7.22 (m, 5H), 5.21 - 5.16 (m, 1H), 3.34 - 3.32 (m, 2H), 1.68 (d, J = 6.6 Hz, 3H). LCMS (ES + ) m / z C 21 H 19 N 5 O 2 Calculated value for C + . HPLC t R 1.24 min.

[0118] (Example 18) (3-(Naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 4, the title compound was obtained as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.63 (br s, 1H), 8.17 (s, 1H), 8.10 (d, J = 15.5 Hz, 2H), 7.96 - 7.90 (m, 3H), 7.64 (br d, J = 8.3 Hz, 1H), 7.58 (dd, J 1 = 8.6 Hz, J 2 = 1.8 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.37 - 7.33 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.89 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 4 O 2 Calculated value for C - . HPLC t R 2.06 minutes.

[0119] (Example 33) ((3-Methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 3-methyl-5-(trifluoromethyl)benzoic acid was reacted in Step 4, the title compound was obtained as a white powder. 1 H NMR (400 MHz, DMSO-d 6) δ 9.59 (s, 1H), 8.33 (s, 1H), 8.04 (br s, 1H), 7.56 (br s, 1H), 7.32 - 7.20 (m, 5H), 7.05 (s, 1H), 5.16 - 5.11 (m, 1H), 3.35 - 3.29 (m, 2H), 2.32 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.23 (s, 3F). LCMS (ES + ) m / z C 20 H 19 F 3 N 4 O 2 Calculated value for C + . HPLC t R 2.09 minutes.

[0120] (R)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) and (S)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14)

[0121]

Chemical Structure

[0122] Step 1: (R)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) and (S)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl) ((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 1) (45 mg, 0.115 mmol) was purified by SFC (column: Chiralpak IA (cellulose) - running time 19 minutes - eluent: MeOH - method: 15% MeOH (2 minutes), 15 - 20% MeOH (8 minutes), 20% MeOH (7 minutes), 20 - 15% MeOH (1 minute), 15% MeOH (1 minute)) to obtain (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl) ((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) (the first eluted compound) as a white powder (10.2 mg, 23%) 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.6, 159.0, 141.9, 136.0, 129.4, 128.8, 128.5, 127.0, 125.7, 123.0, 121.3, 117.2, 113.6, 102.8, 62.8, 40.5, 19.3. LCMS (ES + ) m / z C 19 H 17 F 3 N 4 O 2 calculated value for 390.13; measured value 391 (M+H) + . HPLC t R 2.0 minutes, (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl) ((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14) (the second eluted compound) was obtained as a white powder (10.7 mg, 24%). LCMS (ES + )C 19 H 17 F 3 N 4 O 2 m / z calculated value for 390.13; measured value 391 (M+H) + . HPLC tR 2.0 minutes.

[0123] (Example 3) (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0124] [Chemical formula]

[0125] Step 1: 5-(1H-Imidazole-1-carboxamido)-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 4) A solution of CDI (223 mg, 1.38 mmol) in a mixture of DMF / MeCN (3 mL / 0.5 mL) was treated with Intermediate 3 (300 mg, 1.25 mmol). The solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, the title compound was obtained as a crude product and used directly in the next reaction. LCMS (ES + ) C 15 H 16 N 5 O 2 Calculated m / z for C, H, N, O: 298.13, Observed: 320 (M+Na) + . HPLC t R 1.06 minutes.

[0126] Step 2: 5-(3-Methyl-1H-imidazol-3-ium-1-carboxamido)-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride iodide (Intermediate 5) A solution of crude Intermediate 4 (417 mg, 1.25 mmol) in anhydrous MeCN (19 mL) was treated with iodomethane (0.33 mL, 5.37 mmol). The mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the title compound was obtained as a crude yellow oil and used directly in the next reaction.

[0127] Step 3: (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide (Example 3) A solution of crude intermediate 5 (60 mg, 0.13 mmol) in chloroform (1 mL) was treated with naphthalene-2-amine (18.1 mg, 0.13 mmol) in chloroform (1 mL) and DBU (0.04 mL, 0.25 mmol). The mixture was stirred overnight at reflux and then the solvent was evaporated under reduced pressure. Purification by automated RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents afforded the title compound. The fraction containing the product was lyophilized to give the title compound as a solid (28.4 mg, 60%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.56 (br s, 1H), 8.35 (s, 1H), 8.34 (br s, 1H), 7.78-7.75 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.34-7.28 (m, 3H), 7.25-7.21 (m, 3H), 5.19-5.14 (m, 1H), 3.33-3.31 (m, 2H), 1.67 (d, J = 8.0 Hz, 3H). LCMS (ES + ) m / z C 22 H 20 N 4 O 2 calculated for 372.16; found 373 (M+H) + . HPLC t R 1.93 min.

[0128] Example 4 was synthesized by reacting the appropriate starting materials according to the above procedure (Scheme 3).

[0129] (Example 4) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide In Step 3, when the intermediate 5 and 5-(trifluoromethyl)thiazol-2-amine were reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (br s, 1H), 8.46 (s, 1H), 7.92 (br d, J = 1.3 Hz, 1H), 7.32-7.20 (m, 5H), 5.25-5.19 (m, 1H), 3.36-3.30 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -59.51 (s, 3F). LCMS (ES + ) m / z C 16 H 14 F 3 N 5 O 2 S calculated value 397.08; measured value 398 (M+H) + . HPLC t R 1.91 minutes.

[0130] (Example 6) (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0131]

Chemical Structure

[0132] Step 1: 2-(Benzylamino)acetonitrile (Intermediate 6) Starting from benzylamine (1.01 mL, 9.3 mmol), the title compound was prepared using the procedure reported for the synthesis of Intermediate 2. The crude product was purified by silica gel chromatography (eluted with 100% DCM) to obtain the title compound as a colorless oil (1.06 g, 78%). 1 H NMR (400 MHz, DMSO-d 6) δ 7.36 - 7.32 (m, 4H), 7.28 - 7.23 (m, 1H), 3.76 (d, J = 8.0 Hz, 2H), 3.58 (d, J = 8.0 Hz, 2H), 3.04 - 2.98 (m, 1H). LCMS (ES + ) m / z C 9 H 10 N 2 Calculated value for 146.08, measured value 147 (M + H) + . HPLC t R 0.98 minutes.

[0133] Step 2: 5 - Amino - 3 - benzyl - 1,2,3 - oxadiazol - 3 - ium chloride (Intermediate 7) Starting from Intermediate 6, the title compound was prepared using the procedure reported for the synthesis of Intermediate 3 (877 mg, 6.0 mmol). After filtration, the title compound was obtained as a solid (786 mg, 62%). 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.84 (br s, 2H), 8.15 (br s, 1H), 7.57 - 7.45 (br m, 5H), 5.91 (br s, 2H).

[0134] Step 3: (3 - Benzyl - 1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (Example 6) A solution of 5 - Amino - 3 - benzyl - 1,2,3 - oxadiazol - 3 - ium chloride (Intermediate 7) (30 mg, 0.170 mmol) in anhydrous pyridine (1.02 mL) was cooled to 0 °C, and 1 - Isocyanato - 3 - (trifluoromethyl)benzene (0.05 mL, 0.34 mmol) was added. The reaction mixture was warmed to room temperature and left with stirring for 18 hours. After evaporating the solvent under reduced pressure, the crude product was purified by silica gel chromatography (eluting with 10 - 50% EtOAc in petroleum ether) to obtain the title compound as a solid (27.1 mg, 44%). 1 H NMR (400 MHz, DMSO - d 6) δ 9.71 (s, 1H), 8.19 (br s, 2H), 7.71 (br d, J = 8.0 Hz, 1H), 7.58-7.56 (m, 2H), 7.48-7.41 (m, 4H), 7.21 (br d, J = 8.0 Hz, 1H), 5.78 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 17 H 13 F 3 N 4 O 2 Calculated value for C + . HPLC t R 1.87 min.

[0135] Examples 2, 7, 8, 9, 10, 11, 19, 25, 27, 28, 29, 38, 46, 47, 59, 68, 69, 113, 114 and 115 were synthesized according to the above procedure (Scheme 4) by reacting with appropriate starting materials.

[0136] (Example 2) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl)carbamoyl)amide In Step 3, when Intermediate 3 and 1-isocyanato-4-(trifluoromethyl)benzene were reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.32-7.21 (m, 5H), 5.20-5.14 (m, 1H), 3.32-3.29 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6) δ -59.88 (s, 3F). LCMS (ES + ) m / z C 19 H 17 F 3 N 4 O 2 Calculated value for C + H R F

[0137] (Example 7) (3-Phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-phenyl-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.10 (br d, J = 8.1 Hz, 2H), 7.80 - 7.71 (m, 4H), 7.47 (t, J = 7.9 Hz, 1H), 7.25 (br d, J = 7.5 Hz, 1H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.25 (s, 3F). LCMS (ES + ) m / z C 16 H 11 F 3 N 4 O 2 Calculated value for C + H R F

[0138] (Example 8) ((3-Chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 1-chloro-3-isocyanatobenzene was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 8.30 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.45 (dd, J 1 = 8.3 Hz, J 2 = 1.1 Hz, 1H), 7.32 - 7.21 (m, 6H), 6.94 (dd, J 1 = 7.9 Hz, J 2 = 1.1 Hz, 1H), 5.20 - 5.12 (m, 1H), 3.33 - 3.28 (m, 2H), 1.66 (d, J = 6.6 Hz, 3H). LCMS (ES + ) m / z C 18 H 17 ClN 4 O 2 calculated value for 356.10; found 357 (M+H) + . HPLC t R 1.92 min.

[0139] (Example 9) (3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.71 (s, 1H), 8.37 (s, 1H), 8.28 (br s, 1H), 7.70 (br d, J = 8.1 Hz, 1H), 7.60 - 7.57 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.24 - 7.20 (m, 2H), 5.23 - 5.15 (m, 1H), 3.39 - 3.28 (m, 2H), 1.64 (d, J = 6.6 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 19 H 15 Cl 2 F 3 N 4 O 2 Calculated value for C + . HPLC t R 2.22 min.

[0140] (Example 10) (3-(2,3-Dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.69 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.72 (br d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.28 - 7.21 (m, 3H), 5.71 - 5.65 (m, 1H), 3.67 (dd, J 1 = 16.9 Hz, J 2 = 7.7 Hz, 2H), 3.52 (dd, J 1= 16.9 Hz, J 2 = 4.4 Hz, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.26 (s, 3F). LCMS (ES + ) m / z C 19 H 15 F 3 N 4 O 2 Calculated value for C + H R F

[0141] (Example 11) ((3-Fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide In Step 3, when Intermediate 3 and 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene were reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.71 (br d, J = 11.6 Hz, 1H), 7.32 - 7.20 (m, 5H), 7.12 (br d, J = 8.3 Hz, 1H), 5.19 - 5.14 (m, 1H), 3.33 - 3.29 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H). LCMS (ES + ) m / z C 19 H 16 F 4 N 4 O 2 Calculated value for C + H R F

[0142] (Example 19) (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.72 (br d, J = 8.3 Hz, 1H), 7.68 (br d, J = 7.7 Hz, 2H), 7.54 (br d, J = 8.1 Hz, 2H), 7.44 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.78 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 17 H 12 BrF 3 N 4 O 2 calculated value for 440.01; measured value 441 (M+H) + . HPLC t R 2.03 minutes.

[0143] (Example 25) (3-(1-Phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.72 (s, 1H), 8.24 (br s, 2H), 7.69 (br d, J = 8.1 Hz, 1H), 7.54 - 7.52 (m, 2H), 7.48 - 7.41 (m, 4H), 7.22 (br d, J = 7.7 Hz, 1H), 2.02 - 1.99 (m, 2H), 1.72 - 1.69 (m, 2H). 19 F NMR (377 MHz, DMSO - d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 19 H 15 F 3 N 4 O 2 Calculated value for C + . HPLC t R 2.03 minutes.

[0144] (Example 27) (3 - ([1,1'-Biphenyl]-3-ylmethyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 3 - ([1,1'-biphenyl]-3-ylmethyl)-5 - amino - 1,2,3 - oxadiazol - 3 - ylium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.63 (s, 1H), 8.19 (s, 1H), 8.12 (br s, 1H), 7.86 (s, 1H), 7.69 - 7.62 (m, 4H), 7.49 (br d, J = 4.8 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.37 - 7.31 (m, 2H), 7.14 (br d, J = 7.7 Hz, 1H), 5.77 (s, 2H). 19 F - NMR (377 MHz, DMSO - d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H17 F 3 N 4 O 2 Calculated value 438.13; measured value 439 (M+H) + . HPLC t R 2.20 minutes.

[0145] (Example 28) (3-(2-Phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.71 (br d, J = 8.3 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34-7.31 (m, 4H), 7.26-7.21 (m, 2H), 4.76 (br d, J = 8.1 Hz, 2H), 3.58-3.53 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 19 H 17 F 3 N 4 O 2 Calculated value 390.13; measured value 391 (M+H) + . HPLC t R 2.01 minutes.

[0146] (Example 29) (3-(Pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.80 (s, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.00 (br d, J = 7.9 Hz, 1H), 7.71 (br d, J = 8.3 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.21 (br d, J = 7.7 Hz, 1H), 5.84 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.87 (s, 3F). LCMS (ES + ) m / z C 16 H 12 F 3 N 5 O 2 Calculated value for 363.09; Measured value 364 (M+H) + . HPLC t R 1.42 minutes.

[0147] (Example 38) (3-(1-Phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.69 (s, 1H), 8.23 (br s, 1H), 8.19 (s, 1H), 7.69 (br d, J = 8.3 Hz, 1H), 7.61 (br d, J = 6.2 Hz, 2H), 7.50 - 7.41 (m, 4H), 7.22 (br d, J = 7.5 Hz, 1H), 6.16 (q, J = 6.0 Hz, 1H), 2.01 (d, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 18 H 15 F 3 N 4 O 2 Calculated value for C - . HPLC t R 1.95 min.

[0148] (Example 46) (3-(3-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a pale orange solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.27 (s, 1H), 8.21 (br s, 1H), 7.86 (br s, 1H), 7.72 (br d, J = 8.3 Hz, 1H), 7.67 (br d, J = 7.9 Hz, 1H), 7.59 (br d, J = 7.9 Hz, 1H), 7.43 (br t, J = 7.8 Hz, 2H), 7.22 (br d, J = 7.7 Hz, 1H), 5.78 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 17 H 12 BrF 3 N 4 O 2 Calculated value for C + . HPLC t R 2.07 minutes.

[0149] (Example 47) (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.22 (s, 1H), 8.21 (br s, 1H), 7.84 (br d, J = 8.6 Hz, 2H), 7.72 (br d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.22 (br d, J = 7.7 Hz, 1H), 5.75 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 17 H 12 F 3 IN 4 O 2 Calculated value for C + . HPLC t R 2.12 minutes.

[0150] (Example 59) (3-((1R,2S)-2-Phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-amino-3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 8.26 (s, 1H), 8.25 (br s, 1H), 7.69 (br d, J = 8.1 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.35 - 7.30 (m, 4H), 7.27 - 7.21 (m, 2H), 5.29 - 5.22 (m, 1H), 3.76 - 3.69 (m, 1H), 2.56 - 2.50 (m, 1H), 2.37 - 2.22 (m, 2H), 2.05 - 1.86 (m, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 21 H 19 F 3 N 4 O 2 calculated value for 416.15; found 417 (M+H) + . HPLC t R 2.15 minutes.

[0151] (Example 68) (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.72 (s, 1H), 8.24 (s, 2H), 7.70 - 7.67 (m, 3H), 7.57 (d, J = 8.6 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.16 (q, J = 7.0 Hz, 1H), 2.00 - 1.99 (m, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 18 H 14 BrF 3 N 4 O 2 Calculated value for C - . HPLC t R 2.13 minutes.

[0152] (Example 69) (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 3, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.24 (s, 2H), 7.70 - 7.67 (m, 3H), 7.57 (d, J = 8.6 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.16 (q, J = 7.0 Hz, 1H), 2.00 - 1.99 (m, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 18 H 14 BrF3 N 4 O 2 Calculated value: 454.03; Measured value: 453 (M-H) - . HPLC t R 2.13 minutes

[0153] (Example 113) ((3-Chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide In Step 3, when 1-chloro-3-isocyanatobenzene and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.84 (br t, J = 2.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.46 (br d, J = 9.2 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H), 6.93 (dd, J 1 = 7.9 Hz, J 2 = 1.3 Hz, 1H), 5.85 (s, 2H), 3.94 (s, 3H), 2.39 (s, 3H). LCMS (ES + ) m / z C 22 H 19 ClN 6 O 3 Calculated value: 450.12; Measured value: 449 (M-H) - . HPLC t R 1.85 minutes

[0154] (Example 114) ((3-Cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide In Step 3, when 3-isocyanatobenzonitrile and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate were reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 8.12 (br s, 1H), 7.81 (br d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.43 (br t, J = 8.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 5.87 (s, 2H), 3.94 (s, 3H), 2.39 (s, 3H). LCMS (ES + ) m / z C 23 H 19 N 7 O 3 calculated value 441.15; measured value 442 (M+H) + . HPLC t R 1.65 minutes.

[0155] (Example 115) (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide In Step 3, when isocyanatobenzene and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate were reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.35 (br s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.21 (br t, J = 7.9 Hz, 2H), 6.90 (t, J = 7.3 Hz, 1H), 5.85 (s, 2H), 3.95 (s, 3H), 2.40 (s, 3H). LCMS (ES + ) m / z C 22 H 20 N 6 O 3 Calculated value for C - H R N

[0156] (Example 15) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0157] [Chemical formula]

[0158] A suspension of 5-(trifluoromethyl)pyridin-3-amine (135.3 mg, 0.83 mmol) and TEA (0.23 mL, 1.67 mmol) in THF (5.4 mL) was treated with triphosgene (123.8 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Diethyl ether (2 mL) was added to the mixture, and the formed salt was removed by filtration to obtain a clear solution of isocyanate in THF / ethyl ether, which was N 2It was stored below. A solution of intermediate 3 (100 mg, 0.420 mmol) in THF was treated with sodium hydride (35 mg, 1.04 mmol, 60% in mineral oil), and the mixture was stirred at room temperature for 15 minutes. After adding a solution of isocyanate in THF / ethyl ether, the reaction mixture was stirred for 6 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluting with 1% MeOH in DCM) to give the title compound as a pale beige solid (28 mg, 17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (br s, 1H), 8.89 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 7.31 - 7.19 (m, 5H), 5.20 - 5.11 (m, 1H), 3.31 (m, 2H), 1.66 (d, J = 4.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.21 (s, 3F). LCMS (ES + ) m / z C 18 H 16 F 3 N 5 O 2 Calculated value for 391.13; Measured value 392 (M+H) + . HPLC t R 1.59 minutes.

[0159] Examples 16, 34, 55, 73 and 76 were synthesized according to the above procedure (Scheme 5) by reacting with appropriate starting materials.

[0160] (Example 16) (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide When 4-(trifluoromethyl)pyridin-2-amine was reacted in Step 1, the title compound was obtained as a yellow solid. C 18 H 16 F 3 N5 O 2 Regarding LCMS (ES + ) Calculated m / z 391.13; found 392 (M+H) + . HPLC t R 1.89 minutes.

[0161] (Example 34) ((3-Methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 3-methoxy-5-(trifluoromethyl)aniline was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 8.34 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.32 - 7.20 (m, 5H), 6.76 (s, 1H), 5.17 - 5.10 (m, 1H), 3.78 (s, 3H), 3.32 - 3.29 (m, 2H), 1.66 (d, J = 6.6 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.36 (s, 3F). LCMS (ES + ) m / z C 20 H 19 F 3 N 4 O 3 Calculated value for 420.14; measured value 421 (M+H) + . HPLC t R 2.04 minutes.

[0162] (Example 55) (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 1, the title compound was obtained as a white solid.1 H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (broad singlet, 1H), 8.91 (doublet, J = 2.0 Hz, 1H), 8.55 (singlet, 1H), 8.48 (singlet, 1H), 8.27 (singlet, 1H), 7.84 (doublet, J = 8.3 Hz, 2H), 7.38 (doublet, J = 8.6 Hz, 2H), 5.77 (singlet, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.21 (singlet, 3F). LCMS (ES + ) m / z C 16 H 11 F 3 IN 5 O 2 Calculated value for 488.99; Measured value 490 (M+H) + . HPLC t R 2.00 minutes.

[0163] (Example 73) (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (broad singlet, 1H), 8.89 (doublet, J = 2.0 Hz, 1H), 8.58 (singlet, 1H), 8.47 (singlet, 1H), 8.29 (singlet, 1H), 7.68 (doublet, J = 8.6 Hz, 2H), 7.58 (doublet, J = 8.6 Hz, 2H), 6.18 (quartet, J = 7.0 Hz, 1H), 2.00 (doublet, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.22 (singlet, 3F). LCMS (ES+ ) Calculated value of m / z C 17 H 13 BrF 3 N 5 O 2 is 455.02; measured value is 455 - 457 (M+H) + . HPLC t R is 1.91 minutes.

[0164] (Example 76) (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride was reacted in Step 1, the title compound was obtained as a pale orange solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (br s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.18 (q, J = 7.0 Hz, 1H), 2.00 (d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.21 (s, 3F). LCMS (ES + ) m / z C 17 H 13 BrF 3 N 5 O 2 is 455.02; measured value is 454 - 456 (M-H) - . HPLC t R is 1.93 minutes.

[0165] (Example 17) (3-([1,1'-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0166]

Chem.

[0167] Step 1: 2-(([1,1'-Biphenyl]-4-ylmethyl)amino)acetonitrile (Intermediate 8) Starting from (4-phenylphenyl)methanamine (400 mg, 2.18 mmol), the title compound was prepared using the procedure reported for the synthesis of Intermediate 2. The crude product was purified by silica gel chromatography (eluting with 0 - 50% EtOAc in diethyl ether) to give the title compound as a white solid (339 mg, 70%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.67 - 7.62 (m, 4H), 7.48 - 7.41 (m, 4H), 7.36 (t, J = 8.0 Hz, 1H), 3.80 (br s, 2H), 3.62 (br d, J = 4.0 Hz, 2H), 3.08 (br s, 1H).

[0168] Step 2: 3-([1,1'-Biphenyl]-4-ylmethyl)-5-amino-1,2,3-oxadiazol-3-ium chloride (Intermediate 9) Starting from Intermediate 8 (339 mg, 1.53 mmol), the title compound was prepared using the procedure reported for the synthesis of Intermediate 3. After filtration, the title compound was obtained as a white powder (258 mg, 67%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (broad singlet, 2H), 8.16 (singlet, 1H), 7.76 (doublet, J = 8.0 Hz, 2H), 7.69 - 7.66 (multiplet, 4H), 7.48 (triplet, J = 8.0 Hz, 2H), 7.41 (triplet, J = 8.0 Hz, 1H), 5.96 (singlet, 2H).

[0169] Step 3: (3 - ([1,1'-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 17) Starting from intermediate 9 (50 mg, 0.200 mmol), the title compound was prepared using the procedure reported for the synthesis of Example 1. After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The fractions containing the product were lyophilized to give the title compound as a white solid (30 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (singlet, 1H), 8.24 (singlet, 1H), 8.21 (broad singlet, 1H), 7.77 - 7.66 (multiplet, 7H), 7.50 - 7.37 (multiplet, 4H), 7.22 (doublet, J = 8 Hz, 1H), 5.83 (singlet, 2H). 19 F-NMR (377 MHz, DMSO-d 6 ) δ -61.29 (singlet, 3F). LCMS (ES + ) m / z C 23 H 17 F 3 N 4 O 2 Calculated value for 438.13; Measured value 437 (M - H) - . HPLC t R 2.2 minutes.

[0170] (Example 24) (3-Benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0171] [Chemical Structure]

[0172] A solution of Example 6 (30 mg, 0.08 mmol) in chloroform (0.8 mL) was treated with parachloranil (17.4 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature for 6 h. After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The fractions containing the product were lyophilized to give the title compound as a pale yellow solid (16 mg, 49%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 8.15 (s, 1H), 7.80 (d, J = 8 Hz, 1H), 7.48 - 7.43 (m, 6H), 7.24 (d, J = 8 Hz, 1H), 5.83 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.24 (s, 3F). LCMS (ES + ) m / z C 17 H 12 ClF 3 N 4 O 2 Calculated for 396.06; Found 397 (M+H) + . HPLC t R 1.91 min.

[0173] (Example 26) (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0174] [Chemical Structure]

[0175] A solution of Example 19 (50 mg, 0.110 mmol), tetrakis(triphenylphosphine)palladium(0) (5.9 mg, 0.01 mmol), sodium carbonate (36.0 mg, 0.34 mmol) and pyrimidin-5-ylboronic acid (18.3 mg, 0.15 mmol) in dioxane (2 mL) and water (0.4 mL) in a sealed tube was heated at 80 °C for 2 h. After cooling, the reaction mixture was filtered through a Solkafloc pad and the filtrate was evaporated under reduced pressure. The residue was purified by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The fractions containing the product were lyophilized to give the title compound as a white solid (14 mg, 28%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (br s, 1H), 9.21 (s, 1H), 9.17 (s, 2H), 8.24 (s, 1H), 8.20 (s, 1H), 7.91 (d, J = 8 Hz, 2H), 7.75 (d, J = 8 Hz, 2H), 7.72 - 7.69 (m, 1H), 7.43 (t, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 5.86 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.6, 159.0, 157.5, 154.9, 141.8, 134.9, 132.8, 132.5, 130.1, 129.5, 129.1, 127.7, 125.7, 121.3, 117.3, 113.7, 104.5, 55.5. 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 6 O 2Calculated value: 440.12; Measured value: 441 (M+H) + . HPLC t R 1.62 minutes.

[0176] Examples 20, 21, 22, 23, 41, 48, 72, 74, 75, 77, 78, 93, 95, 96 and 97 were synthesized according to the above procedure (Scheme 8) by reacting with appropriate starting materials.

[0177] (Example 20) (3-(4-(Thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When thiophen-3-ylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.21 (br s, 2H), 7.95 (br s, 1H), 7.81 (br d, J = 7.7 Hz, 2H), 7.72 (br d, J = 8.3 Hz, 1H), 7.67 - 7.59 (m, 4H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.9 Hz, 1H), 5.80 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 4 O 2 Calculated value for C H F N O S: 444.09; Measured value: 443 (M-H) - . HPLC t R 2.12 minutes.

[0178] (Example 21) (3-((2'-Methyl-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When o-toluylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.28 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.64 (br d, J = 7.7 Hz, 2H), 7.44 (br d, J = 7.2 Hz, 3H), 7.30 - 7.20 (m, 5H), 5.84 (s, 2H), 2.23 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 24 H 19 F 3 N 4 O 2 Calculated value for 452.15; Measured value 451 (M - H) - . HPLC t R 2.29 minutes.

[0179] (Example 22) (3-(4-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When pyridin-3-ylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.72 (s, 1H), 8.92 (s, 1H), 8.60 (br d, J = 4.6 Hz, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 8.11 (br d, J = 7.9 Hz, 1H), 7.84 (br d, J = 7.7 Hz, 2H), 7.72 (br d, J = 7.9 Hz, 3H), 7.53 - 7.49 (m, 1H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.85 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 16 F 3 N 5 O 2 Calculated value for C - . HPLC t R 1.45 minutes.

[0180] (Example 23) (3-(4-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.69 (s, 1H), 8.19 (br s, 1H), 8.17 (br s, 2H), 7.89 (br s, 1H), 7.71 (br d, J = 8.1 Hz, 1H), 7.65 - 7.63 (m, 2H), 7.56 - 7.54 (m, 2H), 7.42 (br t, J = 8.0 Hz, 1H), 7.21 (br d, J = 7.5 Hz, 1H), 5.74 (s, 2H), 3.86 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 2 Calculated value for C - . HPLC t R 1.71 min.

[0181] (Example 41) (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (2-Methoxypyrimidin-5-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.97 (s, 2H), 8.23 (s, 1H), 8.21 (br s, 1H), 7.83 (br d, J = 8.1 Hz, 2H), 7.71 (br d, J = 8.1 Hz, 3H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.84 (s, 2H), 3.98 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES+ ) Calculated value of m / z C 22 H 17 F 3 N 6 O 3 is 470.13; measured value 469 (M-H) - . HPLC t R 1.82 minutes.

[0182] (Example 48) (3-(4-(Isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When isoxazol-4-ylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 9.51 (s, 1H), 9.21 (s, 1H), 8.21 (br s, 2H), 7.80 (br d, J = 8.3 Hz, 2H), 7.71 (br d, J = 9.2 Hz, 1H), 7.66 (br d, J = 8.3 Hz, 2H), 7.43 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.80 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 20 H 14 F 3 N 5 O 3 is 429.10; measured value 428 (M-H) - . HPLC t R 1.86 minutes.

[0183] (Example 72) (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when pyrimidin-5-ylboronic acid and (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in Scheme 1) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.20 (s, 1H), 8.17 (br s, 1H), 7.85 (br d, J = 8.1 Hz, 2H), 7.72 (br d, J = 8.1 Hz, 2H), 7.61 (br d, J = 8.6 Hz, 1H), 7.36 (br t, J = 7.9 Hz, 1H), 7.15 (br d, J = 7.5 Hz, 1H), 6.17 (q, J = 7.0 Hz, 1H), 1.99 (br d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 calculated value for 454.14; found 453 (M-H) - . HPLC t R 1.71 min.

[0184] (Example 74) (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Project 1, when pyrimidin-5-ylboronic acid and (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in Scheme 1) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.20 (s, 1H), 8.17 (br s, 1H), 7.85 (br d, J = 8.6 Hz, 2H), 7.72 (br d, J = 8.3 Hz, 2H), 7.61 (br d, J = 8.3 Hz, 1H), 7.36 (br t, J = 7.4 Hz, 1H), 7.14 (br d, J = 8.3 Hz, 1H), 6.17 (q, J = 7.2 Hz, 1H), 1.99 (br d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; Measured value 453 (M-H) - . HPLC t R 1.71 minutes.

[0185] (Example 75) (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide In Step 1, reacting pyrimidin-5-ylboronic acid and (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported in Scheme 1) gave the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (br s, 1H), 9.22 (s, 1H), 9.18 (s, 2H), 8.89 (br d, J = 2.0 Hz, 1H), 8.58 (br s, 1H), 8.47 (br s, 1H), 8.32 (s, 1H), 7.92 (br d, J = 8.3 Hz, 2H), 7.79 (br d, J = 8.3 Hz, 2H), 6.27 (q, J = 7.0 Hz, 1H), 2.07 (br d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.21 (s, 3F). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 calculated for 455.13; found 456 (M+H) + . HPLC t R 1.49 min.

[0186] (Example 77) (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide In Step 1, reacting pyrimidin-5-ylboronic acid and (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported in Scheme 1) gave the title compound as a white solid.1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (br s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.82 (br d, J = 2.0 Hz, 1H), 8.50 (br s, 1H), 8.40 (br s, 1H), 8.25 (s, 1H), 7.85 (br d, J = 8.3 Hz, 2H), 7.72 (br d, J = 8.3 Hz, 2H), 6.19 (q, J = 7.0 Hz, 1H), 1.99 (br d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.22 (s, 3F). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 Calculated value for C + . HPLC t R 1.49 min.

[0187] (Example 78) (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (3,5-dimethylisoxazol-4-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.72 (br d, J = 8.1 Hz, 1H), 7.68 (br d, J = 8.1 Hz, 2H), 7.50 (br d, J = 8.1 Hz, 2H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.83 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 5 O 3 Calculated value for C + . HPLC t R 1.92 min.

[0188] (Example 93) (3-(4-(5-Methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine was reacted in Step 1, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.76 - 7.71 (m, 3H), 7.63 (br d, J = 8.1 Hz, 2H), 7.44 (br t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 5.88 (s, 2H), 2.33 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for C + . HPLC t R 1.61 minutes.

[0189] (Example 95) (3-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (1,5-Dimethyl-1H-pyrazol-4-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.31 (br s, 2H), 7.81 (br d, J = 8.6 Hz, 1H), 7.69 (br d, J = 6.4 Hz, 3H), 7.58 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.31 (br d, J = 7.2 Hz, 1H), 5.88 (s, 2H), 3.88 (s, 3H), 2.47 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 2 Calculated value for C - . HPLC t R 1.81 minutes.

[0190] (Example 96) (3-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (1,3-Dimethyl-1H-pyrazol-4-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.21 (br s, 2H), 7.94 (s, 1H), 7.72 (br d, J = 7.9 Hz, 1H), 7.58 (br d, J = 8.1 Hz, 2H), 7.51 (br d, J = 8.1 Hz, 2H), 7.44 (br t, J = 8.1 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.77 (s, 2H), 3.79 (s, 3H), 2.30 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 2 Calculated value for 456.15; Observed value 455 (M+H) + . HPLC t R 1.79 minutes.

[0191] (Example 97) (3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When (1,3,5-Trimethyl-1H-pyrazol-4-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.26 (s, 1H), 8.21 (br s, 1H), 7.72 (br d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.44 (br t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.7 Hz, 1H), 5.80 (s, 2H), 3.70 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 23 H 21 F 3 N 6 O 2 Calculated value for C - . HPLC t R 1.81 min.

[0192] (Example 50) (3-(3-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0193]

Chemical Structure

[0194] Starting from Example 46, the title compound was prepared using the procedure reported for the synthesis of Compound 26. The crude product was purified by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as the eluent. The fractions containing the product were lyophilized to give the title compound as a white solid (18.4 mg, 37%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (br s, 1H), 9.23 (s, 1H), 9.19 (s, 2H), 8.28 (s, 1H), 8.21 (br s, 1H), 8.09 (br s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.72 - 7.62 (m, 3H), 7.43 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 5.85 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 6 O 2 Calculated value for C - H R F 1 N 6 O is 440.12; found 439 (M - H). 1 HPLC t 2 1.68 min.

[0195] Examples 51, 52, 53 and 94 were synthesized according to the above procedure (Scheme 9) by reacting appropriate starting materials.

[0196] (Example 51) (3-(3-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (3-(3-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When pyridin-3-ylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.96 (br d, J = 1.8 Hz, 1H), 8.63 (dd, J 1 = 4.8 Hz, J 2 It should be noted that there may be some minor inaccuracies in the translation due to the complexity and potential ambiguity of the original chemical text. If possible, it is advisable to cross-reference with more in-depth chemical knowledge and professional chemical dictionaries.= 1.3 Hz, 1H), 8.28 (s, 1H), 8.21 (br s, 1H), 8.17 (br d, J = 7.9 Hz, 1H), 8.02 (br s, 1H), 7.84 (br d, J = 7.0 Hz, 1H), 7.71 (br d, J = 7.9 Hz, 1H), 7.65 - 7.56 (m, 3H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.85 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 16 F 3 N 5 O 2 Calculated value for C - . HPLC t R 1.54 min.

[0197] (Example 52) (3-(3-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.21 (s, 1H), 8.20 (br s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.78 (br s, 1H), 7.71 (br d, J = 8.3 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.22 (br d, J = 7.7 Hz, 1H), 5.76 (s, 2H), 3.87 (s, 3H). 1919F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 2 calculated value 442.14; measured value 441 (M-H) - . HPLC t R 1.77 min.

[0198] (Example 53) (3-(3-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (3,5-dimethylisoxazol-4-yl)boronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.97 (s, 2H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.00 (s, 1H), 7.83 (br d, J = 6.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.62-7.60 (m, 2H), 7.43 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 5.83 (s, 2H), 3.98 (s, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 3 calculated value 470.13; measured value 469 (M-H) - . HPLC t R 1.86 min.

[0199] (Example 94) (3-(3-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Step 1 (using K in a mixture of MeOH / dioxane) Reacting (3,5-dimethylisoxazol-4-yl)boronic acid gave the title compound as a white solid. 2 CO 3 When (3,5-dimethylisoxazol-4-yl)boronic acid was reacted in Step 1 (using K in a mixture of MeOH / dioxane), the title compound was obtained as a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.64 (s, 1H), 8.21 (s, 1H), 8.13 (br s, 1H), 7.64 (br d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.51 - 7.49 (m, 2H), 7.43 - 7.40 (m, 1H), 7.36 (br t, J = 7.9 Hz, 1H), 7.14 (br d, J = 7.7 Hz, 1H), 5.76 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 5 O 3 Calculated value for C - H R F

[0200] (Example 57) (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0201] [Chemical Structure Diagram]

[0202] Starting from Example 55, the title compound was prepared using the procedure reported for the synthesis of Example 26. After purification by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents, the title compound was obtained. The fraction containing the product was lyophilized to give the title compound as a white solid (13 mg, 31%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (br s, 1H), 9.15 (s, 1H), 9.11 (s, 2H), 8.83 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 5.81 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.22 (s, 3F). LCMS (ES + ) m / z C 20 H 14 F 3 N 7 O 2 calculated for 441.12; found 442 (M+H) + . HPLC t R 1.41 min.

[0203] Examples 56, 58 and 67 were synthesized according to the above procedure (Scheme 10) by reacting with the appropriate starting materials.

[0204] (Example 56) (3-((4'-(Morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Reacting 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine in Step 1 gave the title compound as a white solid. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.77 - 7.65 (m, 7H), 7.46 - 7.40 (m, 3H), 7.22 (br d, J = 7.9 Hz, 1H), 5.83 (s, 2H), 3.58 (br s, 4H), 3.50 (br s, 2H), 2.37 (br s, 4H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 28 H 26 F 3 N 5 O 3 Calculated value for C - H R F

[0205] (Example 58) (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide In step 1, when (2-methoxypyrimidin-5-yl)boronic acid and (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported for the synthesis of Example 15) were reacted, the title compound was obtained as a white solid. 1 1H NMR (400 MHz, DMSO-d 6) δ 9.89 (broad s, 1H), 8.90 (s, 2H), 8.83 (broad d, J = 1.8 Hz, 1H), 8.48 (broad s, 1H), 8.40 (broad s, 1H), 8.22 (s, 1H), 7.76 (broad d, J = 8.3 Hz, 2H), 7.64 (broad d, J = 8.3 Hz, 2H), 5.79 (s, 2H), 3.90 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.22 (s, 3F). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 3 Calculated value for C + . HPLC t R 1.58 min.

[0206] (Example 67) (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide In Step 1, when pyridin-4-ylboronic acid and (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported for the synthesis of Example 15) were reacted, the title compound was obtained as a white solid. C 21 H 15 F 3 N 6 O 2 Regarding LCMS(ES + ) m / z calculated value 440.12; measured value 439 (M-H) - .HPLCt R 1.07 min.

[0207] (Example 60) (3-(4-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0208] [Chemical Structure]

[0209] Step 1: (3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 10) A solution of Example 19 (390 mg, 0.88 mmol) in dioxane (25 mL) was treated with bis(chloranil)palladium cyclopentyl(diphenyl)phosphanferrocene (32.8 mg, 0.04 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (246.9 mg, 0.97 mmol) and potassium acetate (260.3 mg, 2.65 mmol). The reaction mixture was refluxed for 18 h. After cooling, it was quenched with water and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na 2 SO 4 and evaporated under reduced pressure. After purification by RP (C18) silica gel (eluting with 10 - 40% MeCN in H 2 O), the title compound was obtained as a yellow solid (361 mg, 33%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (br s, 1H), 8.18 (br s, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.72 (br d, J = 9.2 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 5.81 (s, 2H), 1.29 (s, 12H). LCMS (ES + ) m / z C 23 H 24 BF 3 N 4 O 4 Calculated value of 488.18; measured value 489 (M+H) + . HPLC t R 2.24 minutes.

[0210] Step 2: (3-(4-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 60) Using the conditions reported for the synthesis of Example 26 using Intermediate 10 and 5-bromo-4-methylpyrimidine, the title compound was prepared. After purification by RP(C18) chromatography (eluting with 10 - 45% MeCN in H 2 O), the title compound was obtained. The fraction containing the product was lyophilized to give the title compound as a white solid (16 mg, 34%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (br s, 1H), 9.05 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 8.21 (br s, 1H), 7.72 (d, J = 8.3 Hz, 3H), 7.58 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.86 (s, 2H), 2.45 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 171.5, 162.7, 157.9, 155.9, 155.0, 140.7, 135.5, 132.3, 131.1, 128.7, 128.4, 128.0, 124.6, 121.9, 120.2, 116.2, 112.6, 103.5, 54.4, 21.5. 19 F NMR (377 MHz, DMSO-d 6) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; measured value 455 (M+H) + . HPLC t R 1.66 min.

[0211] Examples 39, 42, 61, 62, 63, 64, 79, 105 and 106 were synthesized according to the above procedure (Scheme 11) by reacting with appropriate starting materials.

[0212] (Example 39) (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromopyridine was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (br s, 2H), 7.92 (br s, 1H), 7.80 (br s, 1H), 7.76 (br d, J = 8.1 Hz, 2H), 7.59-7.52 (m, 5H), 7.47 (br s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.29 (br d, J = 8.1 Hz, 1H), 5.57 (s, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.71 (s, 3F). LCMS (ES + ) m / z C 22 H 16 F 3 N 5 O 2 Calculated value for 439.13; measured value 438 (M-H) - . HPLC t R 1.35 min.

[0213] (Example 42) (3-(4-(Pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-iodopyrazine was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 9.30 (s, 1H), 8.75 (s, 1H), 8.65 (br d, J = 2.4 Hz, 1H), 8.26 - 8.21 (m, 4H), 7.76 - 7.71 (m, 3H), 7.44 (t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 5.88 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 6 O 2 Calculated value for C - H R F

[0214] (Example 61) (3-(4-(Pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromopyridazine was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 9.67 (s, 1H), 9.31 (br d, J = 5.5 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.06 - 8.02 (m, 3H), 7.78 (br d, J = 8.1 Hz, 2H), 7.72 (br d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.9 Hz, 1H), 5.88 (s, 2H). 19 F NMR (377 MHz, DMSO - d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 15 F 3 N 6 O 2 Calculated value for C - . HPLC t R 1.54 min.

[0215] (Example 62) (3-(4-(4 - Methoxypyrimidin - 5 - yl)benzyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5 - bromo - 4 - methoxypyrimidine was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.66 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.14 (br s, 1H), 7.66 - 7.59 (m, 5H), 7.37 (br t, J = 8.1 Hz, 1H), 7.15 (br d, J = 7.7 Hz, 1H), 5.77 (s, 2H), 3.90 (s, 3H). 19 F NMR (377 MHz, DMSO - d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C22 H 17 F 3 N 6 O 3 Calculated value: 470.13; Measured value: 469 (M-H) - . HPLC t R 1.79 minutes.

[0216] (Example 63) (3-(4-(2-Methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromo-2-methoxypyridine was reacted in Step 2, the title compound was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.14 (br s, 1H), 7.80 (br d, J = 8.3 Hz, 2H), 7.65 - 7.62 (m, 3H), 7.36 (br t, J = 8.0 Hz, 1H), 7.26 (dd, J 1 = 5.5 Hz, J 2 = 1.5 Hz, 1H), 7.15 (br d, J = 7.7 Hz, 1H), 7.07 (s, 1H), 5.78 (s, 2H), 3.83 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 18 F 3 N 5 O 3 Calculated value: 469.14; Measured value: 468 (M-H) - . HPLC t R 1.98 minutes.

[0217] (Example 64) (3-(4-(2-Hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromopyridin-2-ol was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.71 (br s, 1H), 9.80 (s, 1H), 8.33 (s, 1H), 8.28 (br s, 1H), 7.86 (br d, J = 7.9 Hz, 2H), 7.82 - 7.74 (m, 3H), 7.55 - 7.49 (m, 2H), 7.30 (br d, J = 7.5 Hz, 1H), 6.69 (br s, 1H), 6.59 (d, J = 6.8 Hz, 1H), 5.92 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 16 F 3 N 5 O 3 calculated value 455.12; found 454 (M-H) - . HPLC t R 1.47 min.

[0218] (Example 79) (S)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When (S)-(3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide and 5-bromo-4-methylpyrimidine were reacted in Step 2, the title compound was obtained as a white solid. LCMS(ES + )C23 H 19 F 3 N 6 O 2 Regarding m / z calculated value 468.15; found 467 (M-H) - . HPLC t R 1.75 minutes.

[0219] (Example 105) (3-(4-(1,2-Dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromo-1,2-dimethyl-1H-imidazole was reacted in Step 2, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 7.73 - 7.64 (m, 3H), 7.52 (br d, J = 7.9 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.23 - 7.21 (m, 1H), 6.93 (s, 1H), 5.82 (s, 2H), 3.54 (s, 3H), 2.35 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 2 Calculated value 456.15; measured value 455 (M-H) - . HPLC t R 1.31 minutes.

[0220] (Example 106) (3-(4-(4-Cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromopyrimidine-4-carbonitrile was reacted in Step 2, the title compound was obtained as a beige solid. 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 14 F 3 N 7 O 2 Calculated value for 465.12; Measured value 466 (M+H) + . HPLC t R 1.84 minutes.

[0221] (Example 99) (R)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0222]

Chemical Structure

[0223] Step 1: Methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (Intermediate 11) A suspension of (-)-4-hydroxy-D-phenylglycine (5 g, 29.91 mmol) in methanol (30 mL) at 0 °C was added dropwise with thionyl chloride (2.17 mL, 29.91 mmol). The reaction mixture was stirred under reflux for 18 h, then cooled to room temperature and used as such. Then DIPEA (13 mL, 59.8 mmol) was added dropwise, followed by a solution of di-tert-butyl dicarbonate (7.18 g, 32.9 mmol) in methanol (12 mL) dropwise over 40 min. The reaction mixture was stirred at room temperature overnight. The solvent was reduced to half of its original volume, and the resulting solution was poured into water (100 mL) to form a white precipitate, which was collected by filtration. The crude product was dried under vacuum with a pump overnight to give the title compound as a white solid (7.15 g, 85%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 5.06 (d, J = 7.8 Hz, 1H), 3.59 (s, 3H), 1.38 (s, 9H). LCMS (ES + ) m / z C 14 H 19 NO 5 Calculated value for 281.13; found 282 (M+H) + . HPLC t R 1.62 min.

[0224] Step 2: tert-Butyl (R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (Intermediate 12) A solution of Intermediate 11 (1.2 g, 4.27 mmol) in anhydrous THF (30 mL) was cooled to 5 °C. 1M lithium aluminum hydride in THF (12.8 mL, 12.8 mmol) was added by slowly dropping it over 40 min while maintaining the internal reaction temperature below 15 °C. Stirring was continued for 30 min, then the reaction was quenched with saturated NH 4It was quenched carefully with Cl solution (2 mL) for 45 minutes and then with 0.3 N HCl (2 mL). Subsequently, the resulting suspension was filtered, rinsed with ethyl acetate, and 1 N HCl was added to the filtrate to adjust the aqueous layer to pH = 1. The organic extract was rinsed with water and brine and dried over MgSO 4 4. The aqueous phase was further extracted with EtOAc, and the organic phase was treated as before. The organic layers were combined, concentrated, and the title compound was obtained as a yellowish solid (927 mg, 95%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 7.06 (m, 3H), 6.67 (d, J = 8.4 Hz, 2H), 4.68 (t, J = 5.7 Hz, 1H), 4.41 (q, J = 7.2 Hz, 1H), 3.42 (t, J = 6.3 Hz, 2H), 1.36 (s, 9H). LCMS (ES + ) m / z C 13 H 19 NO 4 calculated value for 253.13; found 254 (M+H) + . HPLC t R 1.26 minutes.

[0225] Step 3: (R)-4-(4-Hydroxyphenyl)oxazolidin-2-one (Intermediate 13) A solution of Intermediate 12 (927 mg, 3.66 mmol) in THF (11 mL) was cooled to 0 °C, and thionyl chloride (0.29 mL, 4.03 mmol) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was partially concentrated under reduced pressure. The residual slurry was stirred at room temperature, and MTBE (10 mL) was added. Crystallization of the product was initiated. The slurry was stirred for 15 minutes and filtered. The filter cake was washed with MTBE (5 × 5 mL). The solid was dried to obtain the title compound as a reddish brown powder (0.63 g, 95%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.48 (s, 1H), 8.05 (s, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4.81 (t, J = 8 Hz, 1H), 4.59 (t, J = 8 Hz, 1H), 3.93 (dd, J 1 = 8 Hz, J 2 = 12 Hz, 1H). LCMS (ES + ) m / z C 9 H 9 NO 3 calculated value for C + H R NO is 179.06; found 180 (M+H)

[0226] Step 4: (R)-4-(2-Oxoxazolidin-4-yl)phenyl trifluoromethanesulfonate (Intermediate 14) To a slurry of Intermediate 13 (676 mg, 3.77 mmol) in acetonitrile (7.5 mL) was added dry pyridine (0.85 mL, 11.32 mmol). The mixture was stirred under a nitrogen atmosphere and trifluoromethanesulfonic anhydride (0.76 mL, 4.53 mmol) was added slowly while maintaining the reaction temperature at 20 °C. The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. The solvent was removed under reduced pressure and the resulting oil was taken up in DCM. The organic phase was washed with saturated NaHCO 3 solution, brine, dried over Na 2 SO 4 and then concentrated under reduced pressure to give a dark red oil. The crude product was purified by silica gel chromatography (elution gradient from 100% DCM to 15% DCM / EtOAc) to give the title compound (0.741 mg, 68%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.24 (s, 1H), 7.56 (s, 4H), 5.03 (dd, J = 8.2, 6.9 Hz, 1H), 4.69 (t, J = 8.7 Hz, 1H), 4.04 (dd, J = 8.6, 6.3 Hz, 1H). LCMS (ES +) m / z C 10 H 8 F 3 NO 5 Calculated value of S: 311.01; Measured value: 312 (M+H) + . HPLC t R 1.70 minutes.

[0227] Step 5: (R)-4-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)oxazolidin-2-one (Intermediate 15) To a pressure vessel were added Intermediate 14 (220.5 mg, 0.71 mmol) and (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (149.8 mg, 1.06 mmol) in NMP (1 mL). Then, triphenylphosphine (29.7 mg, 0.11 mmol), palladium(II) acetate (0.69 mL, 0.02 mmol) and DIPEA (0.1 mL, 0.74 mmol) were added. The reaction mixture was refluxed at 90 °C for 30 minutes in a closed vessel. The cooled reaction mixture was diluted with DCM, and the organic layer was washed with water, 5% citric acid, 3N HCl and brine. The organic phase was dried over Na 2 SO 4 and filtered, and concentrated. The crude product was purified by silica gel chromatography (eluent: from 100% DCM to 9 / 1 DCM / MeOH DCM / MeOH) to obtain the title compound as a yellow solid (278 mg), which was used as such in the next synthetic step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.49 - 7.41 (m, 4H), 5.00 (dd, J = 8.4, 6.6 Hz, 1H), 4.70 (t, J = 8.6 Hz, 1H), 4.08 (dd, J = 8.5, 6.4 Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H). LCMS (ES + ) m / z C 14 H 14 N 2 O 3 Calculated value: 258.10; Measured value: 259 (M+H) + . HPLC t R 1.41 minutes.

[0228] Step 6: tert-Butyl (R)-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-hydroxyethyl)carbamate (Intermediate 16) A mixture of Intermediate 15 (278 mg, 1.08 mmol), di-tert-butyl dicarbonate (470 mg, 2.15 mmol), and DMAP (39.5 mg, 0.32 mmol) in DCM / THF (1:1) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (30 mL), and the organic phase was washed with water and brine, and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to afford crude tert-butyl (R)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-oxooxazolidine-3-carboxylate as a pale yellow foam (357 mg). C 19 H 22 N 2 O 5 For LCMS (ES + ), calculated m / z 358.15, found 359 (M+H) + . HPLC t R 1.86 min. A mixture of this crude product and potassium carbonate (298 mg, 2.16 mmol) in MeOH (3 mL) was sonicated for 5 minutes and then stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with a small amount of water. The combined aqueous layers were extracted with EtOAc. The combined organic layers were washed with brine and evaporated to afford the title compound (327 mg, 74% over 3 steps). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.50-7.18 (m, 5H), 4.83 (br s, 1H), 4.58 (m, 1H), 3.53 (br d, J = 3.4 Hz, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.46-1.30 (m, 9H). LCMS (ES + ) m / z C 18 H 24 N 2 O 4Calculated value: 332.17; Measured value: 333 (M+H) + . HPLC t R 1.72 minutes.

[0229] Step 7: (R)-2-((tert-Butoxycarbonyl)amino)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl methanesulfonate (Intermediate 17) To a solution of Intermediate 16 (327 mg, 0.89 mmol) and TEA (0.18 mL, 1.33 mmol) in DCM (3 mL) at 0 °C was added dropwise a solution of methanesulfonyl chloride (0.082 mL, 1.07 mmol) in DCM (1 mL) over 5 minutes, and then the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with water, saturated KHSO 4 solution and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (341 mg, 93%), which was used directly in the next step. C 19 H 26 N 2 O 6 LCMS (ES + ) m / z Calculated value: 410.15; Measured value: 411 (M+H) + . HPLC t R 1.93 minutes.

[0230] Step 8: tert-Butyl (R)-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoindolin-2-yl)ethyl)carbamate (Intermediate 18) Intermediate 17 (340 mg, 0.828 mmol) in DMF (0.25 M) was added to a flask, and 1,3-dioxoindoline-2-id potassium (153 mg, 0.83 mmol) and TBAB (5.3 mg, 0.017 mmol) were added. The reaction was stirred at 60 °C for 4 hours. Then water (10 mL) was added, and the precipitated product was filtered, washed further with water, and dried under vacuum to give the title compound as a pale orange powder (264 mg, 69%). The crude product was used directly in the next synthetic step. 11H NMR (300 MHz, DMSO-d 6 ) δ 7.98 - 7.83 (m, 5H), 7.56 - 7.37 (m, 4H), 5.16 - 4.97 (m, 1H), 4.07 - 3.77 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1.27 (s, 9H). LCMS (ES + ) m / z C 26 H 27 N 3 O 5 calculated value for 461.20; measured value 462 (M + H) + . HPLC t R R 2.16 min.

[0231] Step 9: (R)-2-(2-Amino-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)isoindoline-1,3-dione hydrochloride (Intermediate 19) Intermediate 18 (260 mg, 0.572 mmol) was directly treated with 4N HCl in dioxane (1.2 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The resulting suspension was diluted with DCM (10 mL), sonicated, and filtered to obtain the title compound as a pale pink powder (108 mg, 47%). The crude product was used as is in the next step. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 8.69 (br s, 3 H), 8.02 - 7.80 (m, 4H), 7.65 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 4.67 (br dd, J = 7.9, 5.7 Hz, 1H), 4.23 - 4.04 (m, 1 H), 4.02 - 3.87 (m, 1H), 2.39 (s, 3H), 2.21 (s, 3H). LCMS (ES + ) m / z C 21 H 19 N 3 O 3 calculated value for 361.14; measured value 362 (M + H) + . HPLC t R R 1.26 min.

[0232] Step 10: (R)-2-((1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoindolin-2-yl)ethyl)amino)acetonitrile (Intermediate 20) To a suspension of Intermediate 19 (108 mg, 1.08 mmol) and DIPEA (0.18 mL, 1.03 mmol) in MeCN (2 mL) was added 2-bromoacetonitrile (0.038 mL, 0.54 mmol). The reaction mixture was heated at 60 °C for 3 h and then concentrated under reduced pressure. The resulting oil was treated with a small amount of water and extracted with EtOAc. The combined organic phases were further washed with water (3 × 3 mL) and brine, then dried over Na 2 SO 4 and concentrated under reduced pressure to afford the title compound (117 mg, 100%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.91 - 7.80 (m, 4H), 7.47 - 7.38 (m, 2H), 7.38 - 7.26 (m, 2H), 4.27 - 4.11 (m, 1H), 3.94 - 3.78 (m, 1H), 3.75 - 3.55 (m, 2H), 3.45 - 3.36 (m, 1H), 3.27 - 3.17 (m, 1H), 2.37 (s, 3H), 2.19 (s, 3H). LCMS (ES + ) m / z Calcd for C 23 H 20 N 4 O 3 400.15; Found 401 (M + H) + . HPLC t R 1.85 min.

[0233] Step 11: (R)-5-Amino-3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 21) Intermediate 20 (0.12 g, 0.29 mmol) was dissolved in DMSO (0.2 mL), and isopentyl nitrite (0.12 mL, 0.88 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine and dried over Na 2 SO 4 , concentrated under reduced pressure to give (R)-N-(cyanomethyl)-N-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoindolin-2-yl)ethyl)nitrosoamide as a yellow oil, which was used directly in the next synthetic step. C 23 H 19 N 5 O LCMS (ES + ) calculated m / z 429.14, found 430 (M + H) + . HPLC t R 1.99 min. The crude product was treated directly with 4N HCl (1.2 mL) and left without stirring at room temperature for 4 h. The mixture was concentrated under reduced pressure and DCM and diethyl ether were removed several times until a solid product was obtained. The crude product was triturated with diethyl ether to give the title compound as a beige powder (125 mg, 91%), which was used as such in the next step. C 23 H 20 N 5 O 4 430.15 LCMS (ES + ) calculated m / z; found 430 (M + H) + . HPLC t R 1.41 min.

[0234] Step 12: (R)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 22) A cooled suspension (ice bath) of Intermediate 21 (40.99 mg, 0.08 mmol) in pyridine (1.5 mL) was treated directly with 1-isocyanato-3-(trifluoromethyl)benzene (0.05 mL, 0.39 mmol). After 10 minutes, the reaction was quenched with water at 0 °C and the suspension was extracted with diethyl ether. The organic phase was washed further with water, saturated KHSO 4 solution and brine, then dried over Na 2 SO 4 and concentrated, and DCM was removed under reduced pressure using DCM to give the title compound as a solid (138 mg, 0.22 mmol), which was used directly in the next synthetic step. C 31 H 23 F 3 N 6 O 5 For LCMS (ES + ) m / z calculated 616.17; found 617 (M+H) + . HPLC t R 2.21 minutes.

[0235] Step 13: (R)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate (Example 99) A solution of Intermediate 22 (0.086 g, 0.14 mmol) in ethanol (6 mL) was treated with hydrazine hydrate (0.14 mL, 2.8 mmol) at room temperature. The reaction was stirred at 65 °C for 1 hour. The reaction was cooled to room temperature to form a white precipitate. The reaction was diluted with ethanol (5 mL) and the precipitate was filtered. The solution was concentrated under reduced pressure to give a pale yellow solid. After purification on a silica gel chromatography column using 1% DCM / MeOH aqueous eluents, the title compound was obtained. The fractions containing the product were dried under reduced pressure and then lyophilized to give the title compound as a white solid (17.4 mg, 23%). 1 H NMR (300 MHz, DMSO-d 6) δ 9.77 (s, 1H), 8.43 (s, 1H), 8.36 - 8.25 (m, 1H), 7.81 - 7.70 (m, 3H), 7.61 - 7.44 (m, 3H), 7.27 (d, J = 7.7 Hz, 1H), 5.94 (dd, J = 9.9, 4.6 Hz, 1H), 3.79 (dd, J = 13.8, 10.0 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.96 (br s, 2H). LCMS (ES + ) m / z C 23 H 21 F 3 N 6 O 3 Calculated value for C + H R F

[0236] Examples 49, 54, 65, 66, 102 and 116 were synthesized according to the above procedure (Scheme 12) by reacting with appropriate starting materials.

[0237] (Example 49) (R)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate Starting from Boc-D-phenylalaninol according to Scheme 12 (Steps 7 - 13), the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.58 (s, 1H), 8.16 (br s, 3H), 7.69 (br d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.39 - 7.12 (m, 7H), 5.27 - 5.06 (m, 1H), 3.82 - 3.64 (m, 1H), 3.58 - 3.31 (m, 3H). LCMS (ES + ) m / z C19 H 18 F 3 N 5 O 2 Calculated value: 405.14; Measured value: 406 (M+H) + . HPLC t R 2.66 min

[0238] (Example 54) (S)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate Starting from Boc-L-phenylalaninol according to Scheme 12 (Steps 7-13), the title compound was obtained as a white solid 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.58 (s, 1H), 8.16 (br s, 3H), 7.69 (br d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.37-7.10 (m, 7H), 5.27-5.06 (m, 1H), 3.82-3.64 (m, 1H), 3.56-3.28 (m, 3H). LCMS (ES + ) m / z C 19 H 18 F 3 N 5 O 2 Calculated value: 405.14; Measured value: 406 (M+H) + . HPLC t R 2.67 min

[0239] (Example 65) (S)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate Starting from (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate according to Scheme 12 (Steps 7-13), the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.21 (br s, 1H), 8.92 (br s, 1H), 8.26 (s, 1H), 8.21-8.05 (m, 4H), 7.76-7.57 (m, 5H), 7.53-7.40 (m, 3H), 7.38-7.25 (m, 4H), 5.37 (br d, J = 6.6 Hz, 1H), 3.92-3.63 (m, 1H), 3.63-3.35 (m, 3H). LCMS (ES + ) m / z C 25 H 22 F 3 N 5 O 2 calculated value for 481.17. Found 482 (M+H) + . HPLC t R 3.07 min.

[0240] (Example 66) (R)-(3-(1-([1,1'-biphenyl]-4-yl)-3-oxopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Starting from (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate according to Scheme 12 (Steps 7-13), the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6) δ 10.23 (s, 1 H), 8.94 (s, 1H), 8.26 (s, 1H), 8.20 - 8.04 (m, 3H), 7.74 - 7.58 (m, 5H), 7.55 - 7.39 (m, 3 H), 7.37 - 7.26 (m, 4H), 5.38 (q, J = 6.9 Hz, 1H), 3.91 - 3.66 (m, 1H), 3.61 - 3.32 (m, 3H). LCMS (ES + ) m / z C 25 H 22 F 3 N 5 O 2 Calculated value for C + . HPLC t R 3.08 min.

[0241] (Example 102) (R)-(3-(2-Amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate When pyrimidin-5-ylboronic acid was used according to Scheme 12 in Step 5, the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 9.22 (s, 1H), 9.16 (s, 2H), 8.38 (s, 1H), 8.30 - 8.19 (m, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.72 - 7.63 (m, 1H), 7.43 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 8.2 Hz, 1H), 5.92 (dd, J = 9.72, 4.58 Hz, 1H), 3.83 - 3.66 (m, 1H), 3.42 - 3.36 (m, 1H). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O2 Calculated value: 469.43; Measured value: 470 (M+H) + . HPLC t R 3.08 minutes

[0242] (Example 116) (S)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate Starting from 4-hydroxy-L-phenylglycine and following Scheme 12, the title compound was obtained as a white solid 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.43 (s, 1H), 8.36 - 8.25 (m, 1H), 7.81 - 7.70 (m, 3H), 7.61 - 7.44 (m, 3H), 7.27 (d, J = 7.7 Hz, 1H), 5.94 (dd, J = 9.9, 4.6 Hz, 1H), 3.79 (dd, J = 13.8, 10.0 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.96 (br s, 2H). LCMS (ES + ) m / z C 23 H 21 F 3 N 6 O 3 Calculated value: 486.16; Measured value: 487 (M+H) + . HPLC t R 2.73 minutes

[0243] (Example 88) (3-(4-(3,5-Dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0244]

Chemical Structure

[0245] H 2 In a mixture of H2O / dioxane (1:10) (1.1 mL), (3-(4-bromo-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl) ((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 23) (prepared as described in the synthesis of Example 6) (30.0 mg, 0.07 mmol), tripotassium phosphate (42.0 mg, 0.20 mmol), bis(chloranil)palladium cyclopentyl(diphenyl)phosphane ferrocene (5.5 mg, 0.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (13.0 mg, 0.09 mmol) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Solkafloc pad. The excess solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a white solid (5 mg, 16%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (br s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.71 (br d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.47-7.42 (m, 2H), 7.27-7.21 (m, 2H), 5.79 (s, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 2.01 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 20 F 3 N 5 O 3 Calculated for 471.15; found 470 (M-H) - . HPLC t R 2.03 min.

[0246] Examples 87, 100, 103, 104, 108, 109, 110, 117, 119, 120, 121 and 124 were synthesized according to the above procedure (Scheme 13) by reacting with appropriate starting materials.

[0247] (Example 87) (3-(3-Methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When pyrimidin-5-ylboronic acid was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 9.23 (s, 1H), 8.89 (s, 2H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.72 (br d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.55 (br d, J = 7.7 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.23 (br d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 2.30 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; Measured value 453 (M - H) - . HPLC t R 1.78 minutes.

[0248] (Example 100) (3-((5-(Pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, reacting pyrimidin-5-ylboronic acid with (3-((5-bromothiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) gave the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (br s, 1H), 8.91 (s, 1H), 8.89 (s, 2H), 7.98 (s, 2H), 7.82 (br s, 1H), 7.66 (s, 1H), 7.49 (br d, J = 7.9 Hz, 1H), 7.20 (br t, J = 7.7 Hz, 1H), 6.99 (br d, J = 7.2 Hz, 1H), 5.61 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 19 H 13 F 3 N 6 O 2 Calculated for C - . HPLC t R 1.65 min.

[0249] (Example 103) (3-((6-(Pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, reacting pyrimidin-5-ylboronic acid with (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) gave the title compound as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (br s, 1H), 9.47 (s, 2H), 9.28 (s, 1H), 8.97 (br s, 1H), 8.33 (br s, 1H), 8.26 - 8.19 (m, 3H), 7.72 (br d, J = 8.3 Hz, 1H), 7.44 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.93 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 20 H 14 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.51 min.

[0250] (Example 104) (3 - ((6 - (3,5 - Dimethylisoxazol - 4 - yl)pyridin - 3 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when (3,5 - dimethylisoxazol - 4 - yl)boronic acid and (3 - ((6 - bromopyridin - 3 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.89 (s, 1H), 8.34 (s, 1H), 8.22 (br s, 1H), 8.10 (br d, J = 8.3 Hz, 1H), 7.72 (br d, J = 8.6 Hz, 1H), 7.66 (br d, J = 8.1 Hz, 1H), 7.44 (br t, J = 7.9 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 5.88 (s, 2H), 2.58 (s, 3H), 2.39 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 3 Calculated value for 458.13; Observed value 457 (M-H) - . HPLC t R 1.76 min.

[0251] (Example 108) (3-((5-(Pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When pyrimidin-5-ylboronic acid and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 9.26 (br s, 1H), 9.24 (br s, 2H), 9.06 (br s, 1H), 8.39 (dd, J 1 = 8.0 Hz, J 2= 2.1 Hz, 1H), 8.24 (s, 1H), 8.20 (br s, 1H), 7.84 (br d, J = 8.1 Hz, 1H), 7.74 (br d, J = 7.9 Hz, 1H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 6.03 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 20 H 14 F 3 N 7 O 2 Calculated value for C - H R F

[0252] (Example 109) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In step 1, when (3,5-dimethylisoxazol-4-yl)boronic acid and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 8.67 (br s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 8.00 (dd, J 1 = 8.0 Hz, J 2= 2.1 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 6.00 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 3 Calculated value for C - H R F

[0253] (Example 110) (3 - ((4 - (4 - Methylpyrimidin - 5 - yl)thiophen - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when 4 - methyl - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyrimidine and (3 - ((4 - bromothiophen - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 8.13 (br s, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.68 (s, 1H), 7.65 (br s, 1H), 7.37 (br t, J = 7.9 Hz, 1H), 7.16 (br d, J = 7.7 Hz, 1H), 6.04 (s, 2H), 2.48 (s, 3H). 1919F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 20 H 15 F 3 N 6 O 2 Calculated for C - H R 1.66 min. HPLC t

[0254] (Example 117) (3-((6-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted in Step 1, the title compound was obtained as a white solid. The crude material from Step 1 was treated with HCl (4.0 M in dioxane) to give the title compound. 1 1H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.64 (br s, 1H), 8.43 (br s, 2H), 8.27 (s, 1H), 8.22 (br s, 1H), 8.13 (s, 1H), 8.01 - 7.99 (m, 1H), 7.79 (br d, J = 8.1 Hz, 1H), 7.71 (br d, J = 8.6 Hz, 1H), 7.44 (br t, J = 8.2 Hz, 1H), 7.22 (br d, J = 8.1 Hz, 1H), 5.82 (s, 2H), 4.59 - 4.52 (m, 1H), 3.46 - 3.40 (m, 2H), 3.14 - 3.06 (m, 2H), 2.29 - 2.22 (m, 2H), 2.19 - 2.11 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 24 H 23 F 3 N 8 O 2 Calculated value for 512.19; Measured value 511 (M - H) - . HPLC t R 1.28 minutes.

[0255] (Example 119) (3 - ((5 - (Isobenzindolin - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a white solid; the crude material from Step 1 was treated with HCl (4N in dioxane) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 9.47 (br s, 2H), 8.76 (br d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 8.22 (br s, 1H), 8.09 (dd, J 1 = 8.1 Hz, J 2 = 2.4 Hz, 1H), 7.81 (br d, J = 7.9 Hz, 1H), 7.73 (br d, J = 7.7 Hz, 1H), 7.56 - 7.50 (br m, 3H), 7.45 (br t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.5 Hz, 1H), 6.03 (s, 2H), 4.68 - 4.63 (m, 2H), 4.61 - 4.58 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 24 H 19 F 3 N 6 O 2 calculated value for 480.15; found 479 (M - H) - . HPLC t R 1.28 min.

[0256] (Example 120) (3-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a white solid. The crude material from Step 1 was treated with HCl (4.0 N in dioxane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.90 (br d, J = 1.8 Hz, 1H), 8.64 (br s, 1H), 8.39 (br s, 2H), 8.20 (br s, 1H), 8.17 (s, 1H), 8.12 (dd, J 1 = 8.1 Hz, J 2 = 2.2 Hz, 1H), 8.09 (s, 1H), 7.72 (br d, J = 8.1 Hz, 1H), 7.67 (br d, J = 8.1 Hz, 1H), 7.44 (br t, J = 8.0 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 5.91 (s, 2H), 4.57 - 4.50 (m, 1H), 3.75 - 3.69 (m, 1H), 3.46 - 3.39 (m, 2H), 3.15 - 3.06 (m, 2H), 2.27 - 2.22 (m, 2H), 2.17 - 2.10 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 24 H 23 F 3 N8 O 2 Calculated value 512.19; Measured value 511 (M-H) - . HPLC t R 1.20 minutes.

[0257] (Example 121) (3-((5-(2-(Aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted to give the title compound as a white solid. The crude material from Step 1 was treated with HCl (4.0 M in dioxane) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.63 (br d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 8.22 (br s, 1H), 8.12 (br s, 3H), 7.98 (dd, J 1 = 8.0 Hz, J 2 = 2.3 Hz, 1H), 7.81-7.72 (m, 2H), 7.66 (br d, J = 7.5 Hz, 1H), 7.59-7.50 (m, 2H), 7.45 (br t, J = 8.0 Hz, 1H), 7.40 (br d, J = 7.7 Hz, 1H), 7.23 (br d, J = 7.2 Hz, 1H), 6.03 (s, 2H), 4.00-3.96 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H19 F 3 N 6 O 2 Calculated value 468.15; Measured value 467 (M-H) - . HPLC t R 1.30 minutes.

[0258] (Example 124) (3 - ((5 - (4,5,6,7 - Tetrahydropyrazolo[1,5 - a]pyrazin - 3 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when tert - butyl 3-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)-6,7 - dihydropyrazolo[1,5 - a]pyrazine - 5(4H)-carboxylate and (3 - ((5 - bromopyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) were reacted, the title compound was obtained as a yellow solid. The crude material from Step 1 was treated with HCl (4.0 M in dioxane) to obtain the title compound. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.74 (s, 1H), 9.58 (br s, 2H), 8.71 (br d, J = 2.0 Hz, 1H), 8.20 (br s, 2H), 8.07 (s, 1H), 7.99 (dd, J 1 = 8.1 Hz, J 2 = 2.4 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.44 (br t, J = 7.9 Hz, 1H), 7.23 (br d, J = 7.7 Hz, 1H), 5.96 (s, 2H), 4.72 (br s, 2H), 4.39 (br t, J = 5.7 Hz, 2H), 3.71 (br t, J = 5.6 Hz, 2H). 19 F NMR (377 MHz, DMSO - d 6) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 8 O 2 Calculated value for 484.16; measured value 483 (M-H) - . HPLC t R 1.13 minutes.

[0259] (Example 90) (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0260]

Chemical formula

[0261] H 2 A solution of Intermediate 10 (30.0 mg, 0.07 mmol), tripotassium phosphate (42.0 mg, 0.20 mmol), bis(chloranil)palladium cyclopentyl(diphenyl)phosphane ferrocene (5.5 mg, 0.01 mmol) and 5-bromo-2-methoxy-4-methylpyrimidine (26.8 mg, 0.13 mmol) in a mixture of H2O / dioxane (1:10) (1.1 mL) was heated at 75 °C for 40 minutes. The reaction mixture was cooled to room temperature and filtered through a Solka Floc pad. The excess solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a white solid (14 mg, 43%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.84 (broad s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.84 - 7.76 (m, 3H), 7.64 (d, J = 7.9 Hz, 2H), 7.55 (broad t, J = 8.0 Hz, 1H), 7.33 (broad d, J = 7.5 Hz, 1H), 5.96 (s, 2H), 4.05 (s, 3H), 2.50 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 23 H 19 F 3 N 6 O 3 Calculated value for 484.15; Measured value 483 (M - H) - . HPLC t R 1.98 minutes.

[0262] Examples 80, 81, 82, 83, 84, 85, 86, 89, 91, 92, 98, 101, 107, 111, and 112 were synthesized according to the above procedure (Scheme 14) by reacting with appropriate starting materials.

[0263] (Example 80) ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide In Step 1, when 5-bromo-4-(trifluoromethyl)pyrimidine (using XPhos Pd G in THF 4 was used) was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.74 (s, 1H), 9.48 (s, 1H), 9.09 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J = 8.1 Hz, 3H), 7.56 (br d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.2 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 5.89 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F), -62.35 (s, 3F). LCMS (ES + ) m / z C 22 H 14 F 6 N 6 O 2 Calculated value for C + . HPLC t R 2.42 min.

[0264] (Example 81) (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Step 1, when 5-bromo-4,6-dimethylpyrimidine (using XPhos Pd G in THF 4 ) was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 8.89 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.73 - 7.70 (br m, 3H), 7.46 - 7.41 (m, 3H), 7.23 (br d, J = 7.7 Hz, 1H), 5.87 (s, 2H), 2.18 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES +) Calculated value of m / z C 23 H 19 F 3 N 6 O 2 is 468.15; measured value is 467 (M-H) - . HPLC t R is 1.69 minutes.

[0265] (Example 82) (R)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide 5-Bromo-4-methylpyrimidine and (R)-(3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in Scheme 4 starting from (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide and prepared as reported in the synthesis of Example 60) were reacted, and XPhos Pd G in THF 4 was used in Step 1, and the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.18 (br s, 1H), 7.69 (br d, J = 8.1 Hz, 2H), 7.62 (br d, J = 7.8 Hz, 1H), 7.53 (br d, J = 8.3 Hz, 2H), 7.37 (br t, J = 8.0 Hz, 1H), 7.16 (br d, J = 7.3 Hz, 1H), 6.21 - 6.16 (m, 1H), 2.39 (s, 3H), 2.00 (br d, J = 7.5 Hz, 3H). 1919F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 19 F 3 N 6 O 2 calculated value for 468.15; found 467 (M-H) - . HPLC t R 1.76 min.

[0266] (Example 83) (3-(3-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide 5-Bromo-4-methylpyrimidine and (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (starting from Example 46 and prepared as reported in the synthesis of Example 60) were reacted using XPhos Pd G in THF 4 in Step 1 to give the title compound as a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 9.07 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.21 (br s, 1H), 7.75 - 7.58 (m, 5H), 7.44 (br t, J = 8.1 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.85 (s, 2H), 2.47 (s, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2Calculated value: 454.14; Measured value: 453 (M-H) - . HPLC t R 1.72 minutes.

[0267] (Example 84) (3-(3-(4-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromo-4-methoxypyrimidine and (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared starting from Example 46 and as reported in the synthesis of Example 60) were reacted, the title compound was obtained as a white solid. XPhos Pd G in THF 4 was used in Step 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 7.87 (s, 1H), 7.72 - 7.69 (m, 2H), 7.64 - 7.55 (m, 2H), 7.43 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.84 (s, 2H), 3.99 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.30 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 3 Calculated value: 470.13; Measured value: 469 (M-H) - . HPLC t R 1.82 minutes.

[0268] (Example 85) (3-(4-(4-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React 3-bromo-4-methylpyridine with XPhos Pd G in THF 4 When used in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.45 (br d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.69 (br d, J = 8.3 Hz, 2H), 7.52 (br d, J = 8.3 Hz, 2H), 7.44 (br t, J = 8.1 Hz, 1H), 7.35 (br d, J = 5.0 Hz, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.86 (s, 2H), 2.27 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 18 F 3 N 5 O 2 Calculated value for 453.14; Measured value 452 (M-H) - . HPLC t R 1.37 minutes.

[0269] (Example 86) (3-(4-(3-Methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React 2-bromo-3-methylpyrazine; XPhos Pd G in THF 4 When used in Step 1, the title compound was obtained as an off-white solid. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (singlet, 1H), 8.58 - 8.55 (multiplet, 2H), 8.30 (singlet, 1H), 8.21 (broad singlet, 1H), 7.76 - 7.69 (multiplet, 5H), 7.44 (broad triplet, J = 7.9 Hz, 1H), 7.22 (broad doublet, J = 7.7 Hz, 1H), 5.88 (singlet, 2H), 2.57 (singlet, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (singlet, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; Measured value 453 (M - H) - . HPLC t R 1.76 minutes.

[0270] (Example 89) (3-(4-(2-(2-Hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-((5-bromo-4-methylpyrimidin-2-yl)oxy)ethan-1-ol was reacted in Step 1, the title compound was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (singlet, 1H), 8.34 (singlet, 1H), 8.20 (singlet, 1H), 8.14 (broad singlet, 1H), 7.65 - 7.60 (multiplet, 3H), 7.46 (broad doublet, J = 8.1 Hz, 2H), 7.37 (broad triplet, J = 7.8 Hz, 1H), 7.15 (broad doublet, J = 7.2 Hz, 1H), 5.78 (singlet, 2H), 4.84 - 4.80 (multiplet, 1H), 4.29 - 4.26 (multiplet, 2H), 3.68 - 3.64 (multiplet, 2H), 2.31 (singlet, 3H). 1919F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 24 H 21 F 3 N 6 O 4 calculated value for 514.16; measured value 513 (M-H) - . HPLC t R 1.68 min.

[0271] (Example 91) (3-(4-(4-Cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React 5-bromo-4-cyclopropylpyrimidine; Using XPhos Pd G in THF in Step 1, the title compound was obtained as a white solid. 4 H NMR (400 MHz, DMSO-d 1 ) δ 9.73 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.75 - 7.71 (m, 3H), 7.62 (br d, J = 8.1 Hz, 2H), 7.44 (br t, J = 7.9 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 5.88 (s, 2H), 2.06 - 1.98 (m, 1H), 1.16 - 1.10 (m, 2H), 1.06 - 1.02 (m, 2H). 6 19F NMR (377 MHz, DMSO-d 19 ) δ -61.29 (s, 3F). LCMS (ES 6 ) m / z C + ) m / z C 24 H 19 F 3 N 6 O 2 calculated value for 480.15; measured value 479 (M-H) - . HPLC t R 1.94 min.

[0272] (Example 92) (3-(4-(2-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React 3-bromo-2-methylpyridine; XPhos Pd G in THF 4 When used in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 8.40 (dd, J 1 = 4.8 Hz, J 2 = 1.8 Hz, 1H), 8.21 (s, 1H), 8.14 (br s, 1H), 7.65 (br d, J = 8.8 Hz, 1H), 7.60 (br d, J = 8.1 Hz, 2H), 7.55 (dd, J 1 = 7.7 Hz, J 2 = 1.5 Hz, 1H), 7.43 (br d, J = 8.1 Hz, 2H), 7.37 (br t, J = 8.0 Hz, 1H), 7.24 (dd, J 1 = 7.7 Hz, J 2 = 4.8 Hz, 1H), 7.15 (br d, J = 7.5 Hz, 1H), 5.78 (s, 2H), 2.35 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 18 F 3 N 5 O 2 calculated value of 453.14; measured value 452 (M-H) - . HPLC t R 1.34 minutes.

[0273] (Example 98) (3-(4-(1,4-Dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React 5-bromo-1,4-dimethyl-1H-imidazole; XPhos Pd G in THF 4 When used in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.72 (br d, J = 7.9 Hz, 1H), 7.67 (br d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.48 (br d, J = 8.1 Hz, 2H), 7.44 - 7.42 (m, 1H), 7.22 (br d, J = 7.7 Hz, 1H), 5.83 (s, 2H), 3.53 (s, 3H), 2.11 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 2 Calculated value for 456.15; Measured value 455 (M - H) - . HPLC t R 1.31 minutes.

[0274] (Example 101) (3-(3-Methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide In Project 1, when 5-bromo-4-methylpyrimidine and ((3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (starting from Intermediate 23 and prepared as reported in the synthesis of Example 60) were reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 9.08 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.22 (br s, 1H), 7.72 (br d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.52 (br d, J = 8.1 Hz, 1H), 7.44 (br t, J = 7.9 Hz, 1H), 7.31 (br d, J = 7.7 Hz, 1H), 7.23 (br d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 2.23 (s, 3H), 2.08 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 19 F 3 N 6 O 2 Calculated value for 468.15; Measured value 467 (M-H) - . HPLC t R 1.72 minutes.

[0275] (Example 107) (3-(4-(4-Fluoro-6-oxo-1,6-dihydropyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide React with 5-bromo-4,6-difluoropyrimidine; XPhos Pd G in THF 4When used in Step 1, the title compound was obtained as a pale pink solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.16 (s, 1H), 8.13 (br s, 1H), 8.05 (br s, 1H), 7.66 (br d, J = 8.8 Hz, 1H), 7.50 (br s, 4H), 7.36 (br t, J = 7.8 Hz, 1H), 7.15 (br d, J = 7.7 Hz, 1H), 5.73 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 21 H 14 F 4 N 6 O 3 Calculated value for 474.11; Observed value 473 (M-H) - . HPLC t R 1.64 minutes.

[0276] (Example 111) (3-(4-(4-Methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromo-4-methoxy-6-methylpyrimidine was reacted in Step 1, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J = 8.8 Hz, 1H), 7.65 (br d, J = 8.1 Hz, 2H), 7.46-7.40 (m, 3H), 7.23 (br d, J = 7.9 Hz, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H). 1919F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 19 F 3 N 6 O 3 Calculated value for C - H R F

[0277] (Example 112) (3-(4-(4-(2-Hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)ethan-1-ol was reacted in Step 1, the title compound was obtained as a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.64 (s, 1H), 8.62 (br s, 1H), 8.32 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J = 9.0 Hz, 1H), 7.64 (br d, J = 8.1 Hz, 2H), 7.46-7.42 (m, 3H), 7.23 (br d, J = 7.7 Hz, 1H), 5.85 (s, 2H), 4.36-4.31 (m, 2H), 3.62-3.58 (m, 2H), 2.22 (s, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 24 H 21 F 3 N 6 O 4 Calculated value for C - H R F

[0277] 514.16; found 513 (M-H). - . HPLC t R 1.63 min.

[0278] (Example 123) ((3 - ((5 - (4 - (2 - (Methyliumyl(methyl)ammonio)ethoxy)-6 - methylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide)(2,2,2 - trifluoroacetate)

[0279] [Chemical Structure]

[0280] Step 1: (3 - ((5 - Boronopyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (Example 122) A solution of bis(chloranil)palladium; cyclopentyl(diphenyl)phosphanferrocene (5.6 mg, 0.01 mmol), (3 - ((5 - bromopyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 24) (prepared as described in the synthesis of Example 6) (30.0 mg, 0.07 mmol), potassium acetate (20.0 mg, 0.20 mmol) and 4,4,5,5 - tetramethyl - 2 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)-1,3,2 - dioxaborolane (34.5 mg, 0.14 mmol) in dioxane (7.0 mL) was heated at 75 °C for 30 minutes. The reaction mixture was cooled to room temperature and filtered through a Solkafloc pad. The excess solvent was removed under reduced pressure to give the title compound as a brown oil (27.0 mg, 97%), which was used as such in the next step. 1 H NMR (400 MHz, DMSO - d 6) δ 9.73 (s, 1H), 8.75 (s, 1H), 8.21 - 8.18 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H). LCMS (ES + ) m / z C 16 H 13 BF 3 N 5 O 4 Calculated value for 407.10; Measured value 408 (M + H) + . HPLC t R 1.37 minutes.

[0281] Step 2: ((3 - ((5 - (4 - (2 - (Methyliumyl(methyl)ammonio)ethoxy) - 6 - methylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl) - 1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide)(2,2,2 - trifluoroacetate) (Example 123) Using Example 122 (48 mg, 0.12 mmol) and 2 - ((5 - bromo - 6 - methylpyrimidin - 4 - yl)oxy) - N,N - dimethylethane - 1 - amine (61 mg, 0.24 mmol), the title compound was prepared using the same conditions reported for the synthesis of Example 90. Purified by silica gel (eluting with 10% MeOH in DCM), and after freeze - drying from H 2 O / MeCN + 0.1% TFA, the title compound was obtained as a brown gummy substance (6.7 mg, 10%). 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.75 (s, 1H), 9.48 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.23 (s, 1H), 8.21 (br s, 1H), 7.98 (dd, J 1 = 8.1 Hz, J 2= 2.2 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.72 (br d, J = 8.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.01 (s, 2H), 4.64 - 4.62 (m, 2H), 3.45 - 3.41 (m, 2H), 2.68 (s, 3H), 2.67 (s, 3H), 2.28 (s, 3H); 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 25 H 25 F 3 N 8 O 3 Calculated value for C + H R F

[0282] Examples 43 and 118 were synthesized by reacting the appropriate starting materials according to the above procedure (Scheme 15).

[0283] (Example 43) (3 - ((5 - (2 - (2 - (Dimethylamino)ethoxy)-4 - methylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 2 - ((5 - bromo - 4 - methylpyrimidin - 2 - yl)oxy)-N,N - dimethylethane - 1 - amine was reacted in Step 2, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 9.48 (br s, 1H), 8.68 (br d, J = 1.8 Hz, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.20 (br s, 1H), 8.05 (dd, J 1 = 8.0 Hz, J2 = 2.3 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.01 (s, 2H), 4.43 (t, J = 5.8 Hz, 2H), 2.66 - 2.63 (m, 2H), 2.40 (s, 3H), 2.22 (s, 6H); 19 F NMR (377 MHz, DMSO - d 6 ) δ - 61.28 (s, 3F). LCMS (ES + ) m / z C 25 H 25 F 3 N 8 O 3 Calculated value of 542.20; Measured value 541 (M - H) - . HPLC t R 1.22 minutes.

[0284] (Example 118) (3 - ((5 - (1,4 - Dimethyl - 1H - imidazol - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 5 - bromo - 1,4 - dimethyl - 1H - imidazole was reacted in Step 2, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.73 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.20 (br s, 1H), 8.00 - 7.97 (m, 1H), 7.77 - 7.68 (m, 3H), 7.47 - 7.42 (m, 1H), 7.24 - 7.22 (m, 1H), 6.00 (s, 2H), 3.56 (s, 3H), 2.13 (s, 3H). 19 F NMR (377 MHz, DMSO - d 6 ) δ - 61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 18 F3 N 7 O 2 Calculated value 457.15; measured value 456 (M-H) - . HPLC t R 1.27 minutes.

[0285] (Example 31) (S)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0286]

Chemical Structure

[0287] Step 1: (S)-2-((2-Hydroxy-1-phenylethyl)amino)acetonitrile (Intermediate 25) To a suspension of (S)-2-phenylglycinol (343 mg, 2.5 mmol) and N,N-diisopropylethylamine (0.52 mL, 3 mmol) in MeCN (4 mL) was added 2-bromoacetonitrile (0.12 mL, 1.67 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting oil was treated with water (2 mL) and extracted with Et 2 O. The organic phase was washed with water (3 × 3 mL) and brine, then dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound as an oil (268 mg, 91%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43-7.16 (m, 5H), 5.02 (t, J = 5.5 Hz, 1H), 3.84-3.76 (m, 1H), 3.75-3.65 (m, 1H), 3.54-3.35 (m, 2H), 3.25-3.11 (m, 1H), 2.99 (ddd, J = 10.6, 4.6, 1.7 Hz, 1H). LCMS (ES + ) m / z C 10 H 12 N2 Calculated value of O: 176.09; Measured value: 177 (M+H) + . HPLC t R 1.35 minutes.

[0288] Step 2: (S)-N-(Cyanomethyl)-N-(2-hydroxy-1-phenylethyl)nitrosoamide (Intermediate 26) A cooled mixture (ice bath) of Intermediate 25 (268 mg, 1.52 mmol) in 3N dihydrochloride (2.03 mL, 6.08 mmol) in ethanol (2 mL) was added dropwise to a stirred and cooled (ice-salt) solution of sodium nitrite (210 mg, 3.04 mmol) in water (1.5 mL). The reaction mixture was warmed to room temperature for 1 hour. Then, brine was added thereto, and it was extracted with Et 2 O. The organic phase was washed with water and brine, and dried over Na 2 SO 4 . It was filtered and concentrated under reduced pressure to obtain the title compound as an oil, which was used as such in the next synthetic step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.56 - 7.26 (m, 5H), 5.78 (dd, J = 9.2, 5.1 Hz, 1H), 5.33 (dd, J = 5.5, 5.0 Hz, 1H), 4.68 - 4.54 (m, 2H), 4.32 - 4.23 (m, 1H), 4.03 (dt, J = 11.7, 5.0 Hz, 1H). HPLC t R 2.25 minutes.

[0289] Step 3: (S)-5-Amino-3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 27) Intermediate 26 was directly treated with 4N HCl in dioxane (1.5 mL) at room temperature to obtain a yellowish solution. After 10 minutes, the reaction mixture was diluted with Et 2 O (3 mL) and concentrated under reduced pressure. The crude product was removed using DCM and dried under a vacuum pump overnight to obtain the title compound as a white foam (286 mg, 78% over 2 steps). 11H NMR (300 MHz, DMSO-d 6 ) δ 9.73 (s, 2H), 8.22 (s, 1H), 7.71 - 7.53 (m, 2H), 7.52 - 7.41 (m, 3H), 6.21 (dd, J = 9.3, 4.2 Hz, 1H), 5.77 (br s, 1H), 4.44 (dd, J = 12.2, 9.4 Hz, 1H), 4.10 (dd, J = 12.2, 4.3 Hz, 1H). LCMS (ES+) m / z C 10 H 12 N 3 O 2 + calculated exact mass: 206.09; found 206 [M]+. HPLC t R 1.44 min.

[0290] Step 4: (S)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 31) Intermediate 27 (222 mg, 0.92 mmol) in dry methanol (3 mL) was cooled to -10 °C (ice-salt bath), and sodium acetate (82 mg, 1.01 mmol) was added. The mixture was stirred at the same temperature for 15 minutes, and 1-isocyanato-3-(trifluoromethyl)benzene (0.13 mL, 0.92 mmol) was added. The reaction was stirred at -10 °C for an additional 1 hour and then diluted with water. The precipitated product was filtered and washed with water. The crude product was purified by eluting with 99.8:0.2 DCM / MeOH on silica gel to give the title compound as a white solid (140 mg, 39%). 1 1H NMR (300 MHz, DMSO-d 6) δ 9.72 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.70 (br d, J = 8.6 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.54 - 7.36 (m, 4H), 7.22 (br d, J = 7.7 Hz, 1H), 6.02 (dd, J = 9.4, 4.2 Hz, 1H), 5.69 (br s, 1H), 4.52 (br t, J = 10.7 Hz, 1H), 4.07 (br dd, J = 11.9, 4.1 Hz, 1H). LCMS (ES + ) m / z C 18 H 15 F 3 N 4 O 3 Calculated value for 392.11; Measured value 393 (M + H) + . HPLC t R 3.12 minutes.

[0291] Examples 30, 32, and 45 were synthesized according to the above procedure (Scheme 16) by reacting with appropriate starting materials.

[0292] (Example 30) (R)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Starting from (R)-2-phenylglycinol, the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6) δ 9.72 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.70 (br d, J = 8.4 Hz, 1H), 7.62 (dd, J = 6.7, 2.9 Hz, 2H), 7.53 - 7.38 (m, 4H), 7.22 (d, J = 7.8 Hz, 1H), 6.02 (dd, J = 9.5, 4.2 Hz, 1H), 5.67 (t, J = 5.5 Hz, 1H), 4.52 (ddd, J = 12.0, 9.6, 5.8 Hz, 1H), 4.15 - 3.98 (m, 1H). LCMS (ES + ) m / z C 18 H 15 F 3 N 4 O 3 Calculated value for C + . HPLC t R 3.11 min.

[0293] (Example 32) (S)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Starting from Boc-L-phenylalaninol, the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.33 (s, 1H), 8.30 - 8.23 (m, 1H), 7.73 - 7.65 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34 - 7.16 (m, 6H), 5.89 - 5.16 (m, 1H), 5.10 - 4.94 (m, 1H), 4.05 - 3.94 (m, 1H), 3.93 - 3.84 (m, 1H), 3.34 - 3.27 (m, 2H). LCMS (ES+) m / z C 19 H 17 F 3 N 4 O 3Calculated value 406.13; measured value 407 (M+H)+. HPLC t R 3.20 minutes.

[0294] (Example 45) (R)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Starting from Boc-D-phenylalaninol, the title compound was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.34 (s, 1H), 8.30 - 8.25 (m, 1 H), 7.74 - 7.65 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34 - 7.18 (m, 6H), 5.14 - 4.93 (m, 1H), 3.92 - 3.84 (m, 1H), 3.34 - 3.26 (m, 2H). LCMS (ES+) m / z C 19 H 17 F 3 N 4 O 3 Calculated value 406.13; measured value 407 (M+H) + . HPLC t R 3.20 minutes.

[0295] (Example 35) (3-(1-Phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0296]

Chemical Structure

[0297] To an ice-cooled solution of Example 30 (20 mg, 0.05 mmol) in dry THF (0.25 mL, 0.003 mol), 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (0.04 mL, 0.06 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 40 minutes. Further, 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (0.04 mL, 0.06 mmol) was added and the mixture was stirred for an additional 30 minutes. Then, a second addition of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (0.07 mL) was made at 0 °C. The reaction mixture was stirred at 0 °C for 40 minutes and then warmed slowly overnight. The reaction mixture was quenched with NaHCO 3 (0.3 mL, saturated solution) and water and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (elution gradient from 100% petroleum ether to 70 / 30 petroleum ether / ethyl acetate) and then by reverse phase chromatography (elution gradient of 15 - 70% MeCN + 0.1% HCOOH). The pure fractions were combined and lyophilized to give the title compound as a yellow solid (1.41 mg, 8%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.81 (br s, 1H), 8.37 - 8.13 (m, 2H), 7.74 (br d, J = 7.9 Hz, 1H), 7.66 - 7.37 (m, 6H), 7.23 (br d, J = 7.4 Hz, 1H), 6.45 - 6.12 (m, 2H). LCMS (ES + ) m / z C 18 H 15 F 3 N 4 O 3 calculated value 392.11; found 393 (M + H) + . HPLC t R 3.64 minutes.

[0298] (3-(3-Phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 36) and (S)-(3-(1-Fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 37)

[0299]

Chem.

[0300] To an ice-cooled solution of Example 32 (20 mg, 0.05 mmol) in dry THF (0.25 mL, 0.003 mol) was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (0.22 mL, 0.3 mmol) dropwise. The reaction mixture was stirred at 0 °C for 40 minutes. Further, 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (0.22 mL, 0.3 mmol) was added and the reaction was stirred at 0 °C for 1 hour. Then potassium fluoride (2.9 mg, 0.05 mmol) was added and the reaction was stirred at room temperature overnight. The next day, the reaction was quenched with water and extracted with EtOAc. The organic layer was further washed with water, 1N HCl and brine, and dried over Na 2 SO 4 and filtered and concentrated to give a yellow oil. The crude product was purified by normal phase silica gel chromatography (eluent DCM + 0.5% MeOH). The product eluted first was further purified by reverse phase chromatography (elution gradient of 10 - 70% MeCN + 0.1% HCOOH) to give (3-(3-Phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 36) (0.4 mg, 2%) as a white powder. 1 1H NMR (300 MHz, DMSO-d 6) δ 9.91 - 9.58 (m, 1H), 8.46 (s, 1H), 8.26 (br s, 1H), 7.70 (br d, J = 8.2 Hz, 1H), 7.52 - 7.15 (m, 7H), 6.28 (s, 1H), 5.75 (s, 1H), 4.13 (br s, 2H). LCMS (ES + ) m / z C 19 H 15 F 3 N 4 O 2 Calculated value for C + . HPLC t R 3.66 min.

[0301] The second eluted product was further purified by reverse - phase chromatography (elution gradient of 10 - 70% MeCN + 0.1% HCOOH) to give (S)-(3-(1 - fluoro - 3 - phenylpropan - 2 - yl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 37) as a white powder (2.64 mg, 12%). 1 H NMR (300 MHz, DMSO - d 6 ) δ 9.73 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.70 (br d, J = 8.71 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.36 - 7.19 (m, 6H), 5.65 - 5.39 (m, 1H), 5.18 - 5.03 (m, 1H), 5.01 - 4.86 (m, 1H), 3.45 - 3.34 (m, 2H); 19 F NMR (282 MHz, DMSO - d 6 ) δ - 224.60 (s, 1F) - 61.29 (s, 3F). LCMS (ES + ) m / z C 19 H 16 F 4 N 4 O 2 Calculated value for C + . HPLC tR 3.62 minutes

[0302] (Example 44) (3-(2,2,2-Trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0303] [Chemical formula]

[0304] Step 1: 2-((2,2,2-Trifluoro-1-phenylethyl)amino)acetonitrile (Intermediate 28) Into a microwave vial, 2-((2,2,2-trifluoro-1-phenylethyl)amino)acetonitrile (0.25 mg, 1.44 mmol), N,N-diisopropylethylamine (0.3 mL, 1.73 mmol) and 2-bromoacetonitrile (0.07 mL, 0.96 mmol) in MeCN (2 mL) were added. The reaction mixture was heated at 100 °C for 90 minutes under microwave irradiation; then further DIPEA (300 μL) and 2-bromoacetonitrile (0.07 mL, 0.96 mmol) were added, and the reaction was heated at 100 °C for a further 30 minutes, then directly diluted with EtOAc and washed with a small amount of water and brine. The organic phase was dried over Na 2 SO 4 and filtered, concentrated under reduced pressure to give a dark brown oil, which was purified by silica gel chromatography (eluent DCM 100%) to give the title compound as a white powder (87 mg, 28%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.87 - 7.26 (m, 5H), 4.50 (q, J = 7.7 Hz, 1H), 3.90 (br s, 1 H), 3.75 - 3.61 (m, 1H), 3.56 - 3.44 (m, 1H). LCMS (ES + ) m / z C 10 H 9 F 3 N 2Calculated value: 214.07; Measured value: 215 (M+H) + . HPLC t R 1.78 minutes.

[0305] Step 2: N-(Cyanomethyl)-N-(2,2,2-trifluoro-1-phenylethyl)nitrosoamide (Intermediate 29) Starting from Intermediate 28, the title compound was prepared using the procedure described in Step 2, Example 31. The crude product obtained as a yellow oil was used as is in the next synthetic step. C 10 H 8 F 3 N 3 LCMS (ES + ) m / z Calculated value: 243.06; Measured value: 244 (M+H) + .HPLC t R 1.91 minutes.

[0306] Step 3: 5-Amino-3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 30) Starting from Intermediate 29, the title compound was prepared using the procedure described in Step 3, Example 32, except that it was heated at 90 °C for 10 minutes. An impure crude product (30 mg) was obtained as a white solid and used as is in the next synthetic step. C 10 H 9 F 3 N 3 O + LCMS (ES + ) m / z Calculated value: 244.07; Measured value: 244 [M] + .HPLC t R 1.09 minutes.

[0307] Step 4: (3-(2,2,2-Trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 44) A mixture of Intermediate 30 (30 mg, 0.11 mmol) in pyridine (1 mL) was treated with 1-isocyanato-3-(trifluoromethyl)benzene (0.04 mL, 0.27 mmol) at 0 °C. The reaction was stirred at room temperature for 20 minutes; then diluted with DCM. The organic phase was washed with water, 1N HCl and brine; dried over Na 2 SO 4 4, filtered and concentrated under reduced pressure. After purification by reverse phase chromatography (MeCN / H 2 2O + 0.1% HCOOH), the title compound (0.62 mg, 1.25%) was obtained. The fractions containing the product were lyophilized to give the title compound as a white powder. 1 1H NMR (300 MHz, DMSO-d 6 6) δ 9.87 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.75 (br d, J = 8.0 Hz, 3H), 7.67 - 7.50 (m, 4H), 7.46 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.70 Hz, 1H). LCMS (ES + ) m / z C 18 22 12 H 6 13 4 F 2 3 + N R 3

[0308] (Example 70) (S)-(3-(1-(1,1'-Biphenyl-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0309] [Chemical Structure]

[0310] A solution of Example 65 (3.6 mg, 0.01 mmol) and sodium bicarbonate (0.3 mL, saturated solution) in THF (0.5 mL) at 0 °C was added acetyl chloride (10 μL). The reaction mixture was stirred at room temperature for 5 minutes and then diluted with EtOAc. The organic phase was washed with saturated KHSO 4 solution and brine. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The product was dissolved in MeCN / water and freeze-dried to give the title compound (2.3 mg, 40%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.70 (s, 1 H), 8.47 (s, 1 H), 8.21 (br t, J = 5.6 Hz, 1H), 7.76 - 7.59 (m, 6H), 7.52 - 7.40 (m, 4H), 7.39 - 7.30 (m, 4H), 7.23 (br d, J = 8.0 Hz, 1H), 5.12 - 4.93 (m, 1H), 3.89 - 3.76 (m, 1H), 3.74 - 3.60 (m, 1H), 1.79 (s, 3H). LCMS (ES + ) m / z C 27 H 24 F 3 N 5 O 3 calculated value 523.18; found 524 (M+H) + . HPLC t R 3.66 min.

[0311] (Example 71) (R)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide The title compound was synthesized by reacting the appropriate starting materials according to the above procedure (Scheme 20). 1 H NMR (300 MHz, DMSO-d 6) δ 9.70 (s, 1H), 8.47 (s, 1H), 8.21 (br t, J = 5.6 Hz, 1H), 7.76 - 7.59 (m, 6H), 7.52 - 7.40 (m, 4H), 7.39 - 7.30 (m, 4H), 7.23 (br d, J = 8.0 Hz, 1H), 5.12 - 4.93 (m, 1H), 3.89 - 3.76 (m, 1H), 3.74 - 3.60 (m, 1H), 1.79 (s, 3H). LCMS (ES + ) m / z C 27 H 24 F 3 N 5 O 3 Calculated value for C + . HPLC t R 3.66 min.

[0312] (Example 127) (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0313]

Chemical Structure

[0314] Step 1: 2-((4-Bromobenzyl)amino)acetonitrile (Intermediate 31) A suspension of (4-bromobenzyl)amine hydrochloride (10 g, 45 mmol) and DIPEA (31 mL, 180 mmol) in MeCN (70 mL) was treated with 2-bromoacetonitrile (3.4 mL, 49 mmol), and the reaction mixture was stirred at 60 °C for 4 h. Then, after cooling, the solvent was removed under reduced pressure, the residue was treated with water, and extracted with EtOAc. The organic phase was washed with brine and dried over Na 2 SO 4 and evaporated under reduced pressure to give the title compound as a yellow oil (9.07 g, 90%). C 9 H 9 BrN2 Regarding LCMS (ES + ) calculated m / z value 223.99, measured value 225 (M+H) + . HPLCt R 1.15 minutes

[0315] Step 2: 5-Amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 32) A solution of 2-[(4-bromophenyl)methylamino]acetonitrile (Intermediate 31, 9.07 g, 40.3 mmol) in THF (50 mL) was treated with tert-butyl nitrite (15.9 mL, 133 mmol), stirred at room temperature for 30 minutes, then diluted with EtOAc, washed with water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude material, which was dissolved in dioxane (10 mL) and treated with 4N HCl in dioxane (7.32 g, 201 mmol) and stirred at room temperature for 1 hour. The excess solvent was removed under reduced pressure, and the resulting crude compound was triturated with Et 2 O to obtain the title compound as a white powder (10.5 g, 90%). C 9 H 9 BrClN 3 Regarding LCMS (ES+) m / z calculated value 253.99 (parent), measured value 254 (M+H) + . HPLCt R 0.85 minutes

[0316] Step 3: (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 33) A solution of bis(trichloromethyl) carbonate (101.8 mg, 0.34 mmol), [5-(trifluoromethyl)-3-pyridyl]amine (111.2 mg, 0.69 mmol) and DIPEA (178 mg, 1.4 mmol) in dry THF (2.6 mL) was stirred at room temperature for 20 minutes and then added dropwise to a stirred suspension of 3-[(4-bromophenyl)methyl]-1,2,3-oxadiazol-3-ium-5-amine; hydrochloride (Intermediate 32, 100 mg, 0.34 mmol) in dry THF (2 mL) at 0 °C. DIPEA (178 mg, 1.4 mmol) was added and the reaction mixture was stirred for a further 10 minutes at room temperature, then diluted with water and extracted twice with EtOAc. The organic layer was washed with brine and dried over 2 SO 4 , filtered and concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (eluting with 0 - 100% EtOAc in petroleum ether) to give the title compound as a white powder (148 mg, 98%). C 16 H 11 BrF 3 N 5 O 2 For LCMS (ES + ), calculated m / z 441.00; found 440 - 442 (M - H) - . HPLC t R 1.79 min

[0317] Step 4: (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Example 127) In a mixture of dioxane (1 mL) and H 2 O (0.1 mL), (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 33, 25 mg, 0.06 mmol), Pd(dppf)Cl 2 (4.1 mg, 0.006 mmol), (3,5-Dimethylisoxazol-4-yl)boronic acid (15.9 mg, 0.11 mmol) and K 3PO 4 The degassed suspension of [[ID=]] (36 mg, 0.17 mmol) was stirred at 75 °C for 1 hour. After cooling, the reaction mixture was filtered through a Solkafloc pad, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluting with 0 - 100% MeCN in water) to give a pale yellow solid (12 mg). Further purification by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents gave the title compound as a white solid (4.0 mg, 14%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (br s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 7.65 (s, 1H), 7.61 - 7.52 (m, 2H), 7.50 - 7.47 (m, 1H), 5.85 (s, 2H), 2.43 (s, 3H), 2.25 (s, 3H). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 3 Calculated for 458.13; Found 459 (M + H) + . HPLC t R 1.68 min.

[0318] Example 187 was synthesized by reacting according to the above procedure (Scheme 21) with the appropriate starting materials.

[0319] (Example 187) (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide Reaction of 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine gave the title compound as a pale yellow solid. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (br s, 1H), 8.91 (s, 2H), 8.55 (br s, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.65 - 7.56 (m, 3H), 7.42 (dd, J 1 = 7.0 Hz, J 2 = 1.7 Hz, 1H), 5.86 (s, 2H), 2.19 (s, 6H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.23 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 2 Calculated value for 469.15; Observed value 468 (M - H) - . HPLC t R R 1.45 min.

[0320] (Example 130) (3 - ((5 - (4,6 - Dimethylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide

[0321] [Chemical Structure Diagram]

[0322] Using the procedure reported for the synthesis of Example 127, starting from Intermediate 24 and 4,6 - dimethyl - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyrimidine, the title compound was prepared. The title compound was obtained as a white solid (458 mg, 31%). 1 1H NMR (400 MHz, DMSO-d 6) δ 9.75 (br s, 1H), 8.93 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.97 (dd, J 1 = 8.0 Hz, J 2 = 2.3 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.74 (br d, J = 8.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H), 2.21 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 2 Calculated value for C + . HPLC t R 1.52 min.

[0323] Examples 129, 143, 170, 172, 181 and 159 were synthesized according to the above procedure (Scheme 22) by reacting Intermediate 24 with an appropriate boronic ester.

[0324] (Example 129) (3-((5-(5-Methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide Reaction of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine gave the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 9.24 (s, 1H), 9.14 (d, J = 0.8 Hz, 1H), 8.78 (dd, J1 = 2.3 Hz, J 2 = 0.7 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.16 (dd, J 1 = 8.1 Hz, J 2 = 2.3 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.05 (s, 2H), 2.34 (s, 3H). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.45 min.

[0325] (Example 143) ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 1,3,5-trimethyl(trimenthyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.53 (s, 1H), 8.23 - 8.20 (m, 2H), 7.83 (br d, J = 8.1 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.44 (br t, J = 7.9 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 5.96 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H). 19 F NMR (377 MHz, DMSO-d6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 20 F 3 N 7 O 2 Calculated value for C - H R F

[0326] (Example 170) (3 - ((3',5'-Difluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When reacted with (3,5-difluoro-4-pyridyl)boronic acid, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.81 (s, 1H), 8.73 (s, 2H), 8.30 (s, 1H), 8.20 - 8.18 (m, 2H), 7.85 (d, J = 8.1 Hz, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.45 (br t, J = 8.2 Hz, 1H), 7.23 (br d, J = 7.5 Hz, 1H), 6.06 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 13 F 5 N 6 O 2 Calculated value for C - H R F

[0327] (Example 172) (3-((2'-Chloro-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.51 (dd, J 1 = 4.8 Hz, J 2 = 1.8 Hz, 1H), 8.26 (s, 1H), 8.21 (br s, 1H), 8.11 (dd, J 1 = 8.1 Hz, J 2 = 2.1 Hz, 1H), 8.01 (dd, J 1 = 7.6 Hz, J 2 = 1.6 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 (br d, J = 8.6 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.45 (br t, J = 8.1 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 6.04 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 14 ClF 3 N 6 O 2 calculated value for 474.08; measured value 473 (M-H) - . HPLC t R 1.74 minutes.

[0328] (Example 181) (3-((5-(3,6-Dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 3,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine was reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.24 - 8.21 (m, 3H), 7.79 - 7.75 (m, 2H), 7.45 - 7.42 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 6.02 (s, 2H), 4.00 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 4 Calculated value for 501.14; Measured value 500 (M - H) - . HPLC t R 1.76 minutes.

[0329] (Example 159) (3-((2'-Methoxy-4'-methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.27 (s, 1H), 8.20 (br s, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.86 (dd, J1 = 8.1 Hz, J2 = 2.2 Hz, 1H), 7.73 - 7.71 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 5.3 Hz, 1H), 6.00 (s, 2H), 3.76 (s, 3H), 2.08 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 23 H 19 F 3 N 6 O 3 Calculated value for C - . HPLC t R 1.88 min.

[0330] (Example 134) (3 - ((5 - (2 - Methoxy - 4 - methylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide

[0331]

Chemical Structure

[0332] A degassed solution of (3 - ((5 - Boronopyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide (Example 122, 44.9 mg, 0.11 mmol) in dioxane (2.0 mL) and water (0.2 mL) was added to 5 - Bromo - 2 - methoxy - 4 - methyl - pyrimidine (46 mg, 0.23 mmol), Pd(dppf)Cl2 (8.3 mg, 0.011 mmol), K 3 PO 4 (72 mg, 0.34 mmol) was treated and heated at 85 °C for 1 hour. After cooling, the mixture was diluted with EtOAc and filtered through a cellulose pad. The excess solvent was removed under reduced pressure. After purification by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents, the title compound was obtained as a creamy solid (9.5 mg, 16%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.20 (br s, 1H), 8.05 (dd, J1 = 8.1 Hz, J2 = 2.0 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.23 (br d, J = 7.2 Hz, 1H), 6.02 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 3 calculated for 485.14; found 484 (M-H) - . HPLC t R 1.68 min.

[0333] Examples 131, 135, 138, 139, 148, 151, 155, 160, 162, 163, 164, 165, 179, 180, 177, 176, 175 and 132 were synthesized according to the above procedure (Scheme 23) by reacting Example 122 or a similar boronic acid with a suitable starting material.

[0334] (Example 131) ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 5-bromo-4-(trifluoromethyl)pyrimidine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 9.53 (s, 1H), 9.16 (s, 1H), 8.70 (br s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.08 (br d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.75 (br d, J = 8.3 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 8.8 Hz, 1H), 6.07 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F), -62.39 (s, 3F). LCMS (ES + ) m / z C 21 H 13 F 6 N 7 O 2 Calculated value for 509.10; Measured value 508 (M-H) - . HPLC t R 1.79 minutes.

[0335] (Example 135) (3-((5-(4-Methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromo-4-methoxy-6-methyl-pyrimidine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.67 (broad singlet, 1H), 8.66 (singlet, 1H), 8.50 (singlet, 1H), 8.21 (broad singlet, 1H), 8.13 (singlet, 1H), 7.88 (broad doublet, J = 8.0 Hz, 1H), 7.67 (doublet, J = 8.1 Hz, 2H), 7.37 (triplet, J = 8.0 Hz, 1H), 7.15 (doublet, J = 8.0 Hz, 1H), 5.94 (singlet, 2H), 3.79 (singlet, 3H), 2.18 (singlet, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (singlet, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 3 Calculated value for 485.14; Observed value 484 (M-H) - . HPLC t R 1.62 minutes.

[0336] (Example 138) (3 - ((2'-Methyl - [3,3'-bipyridin] - 6 - yl)methyl) - 1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 3 - bromo - 2 - methyl - pyridine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (broad singlet, 1H), 8.71 (broad singlet, 2H), 8.27 (singlet, 1H), 8.21 (broad singlet, 1H), 8.11 - 8.07 (multiplet, 2H), 7.81 (broad doublet, J = 8.0 Hz, 1H), 7.74 (broad doublet, J = 7.9 Hz, 1H), 7.69 - 7.66 (multiplet, 1H), 7.45 (triplet, J = 8.0 Hz, 1H), 7.23 (broad doublet, J = 7.9 Hz, 1H), 6.04 (singlet, 2H), 2.55 (singlet, 3H). 19 F NMR (377 MHz, DMSO-d6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; measured value 453 (M-H) - . HPLC t R 1.22 minutes.

[0337] (Example 139) (3-((4'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 3-bromo-4-methyl-pyridine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 8.72 (br s, 1H), 8.65 (br s, 2H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.09 (dd, J 1 = 8.0 Hz, J 2 = 1.9 Hz, 1H), 7.82 (br d, J = 7.9 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.7 Hz, 1H), 6.06 (s, 2H), 2.40 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17 F 3 N 6 O 2 Calculated value for 454.14; measured value 453 (M-H) - . HPLC t R 1.27 minutes.

[0338] (Example 148) (3-((5-(4-Cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromopyrimidine-4-carbonitrile was reacted, the title compound was obtained as a cream solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 9.48 (s, 1H), 9.35 (s, 1H), 8.95 (s, 1H), 8.36 (dd, J1 = 8.1 Hz, J2 = 2.2 Hz, 1H), 8.29 (s, 1H), 8.20 (br s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.74 (br d, J = 8.1 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 6.09 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 13 F 3 N 8 O 2 Calculated value for 466.11; Measured value 465 (M-H) - . HPLC t R 1.65 minutes.

[0339] (Example 151) (3-((5-(3,5-Dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromo-3,5-dimethyl-1H-pyrazole was reacted, the title compound was obtained as a cream solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (broad singlet, 1H), 8.57 (singlet, 1H), 8.24 (singlet, 1H), 8.20 (broad singlet, 1H), 7.87 (doublet, J = 8.1 Hz, 1H), 7.74 (doublet, J = 8.6 Hz, 1H), 7.69 (broad doublet, J = 7.9 Hz, 1H), 7.44 (triplet, J = 8.1 Hz, 1H), 7.23 (broad doublet, J = 7.5 Hz, 1H), 5.96 (singlet, 2H), 2.22 (singlet, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (singlet, 3F). LCMS (ES + ) m / z C 21 H 18 F 3 N 7 O 2 Calculated value for 457.15; Measured value 456 (M - H) - . HPLC t R 1.49 minutes.

[0340] (Example 155) (3 - ((5 - (4 - cyclopropylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 5 - bromo - 4 - cyclopropylpyrimidine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.74 (broad singlet, 1H), 9.03 (singlet, 1H), 8.77 (singlet, 1H), 8.62 (singlet, 1H), 8.27 (singlet, 1H), 8.21 (broad singlet, 1H), 8.14 - 8.12 (multiplet, 1H), 7.83 (doublet, J = 7.9 Hz, 1H), 7.74 (doublet, J = 8.2 Hz, 1H), 7.45 (triplet, J = 7.9 Hz, 1H), 7.23 (broad doublet, J = 7.6 Hz, 1H), 6.04 (singlet, 2H), 2.00 - 1.94 (multiplet, 1H), 1.18 - 1.13 (multiplet, 2H), 1.08 - 1.05 (multiplet, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (singlet, 3F). LCMS (ES + ) m / z C 23 H 18 F 3 N 7 O 2 Calculated value for 481.15; Observed value 480 (M - H) - . HPLC t R 1.74 minutes.

[0341] (Example 160) (3 - ((5 - (Pyridazin - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 4 - bromopyridazine was reacted, the title compound was obtained as a cream - colored solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.73 (broad singlet, 2H), 9.36 (doublet, J = 5.4 Hz, 1H), 9.15 (singlet, 1H), 8.48 (doublet, J = 2.0 Hz, 1H), 8.24 (singlet, 1H), 8.20 (singlet, 1H), 8.13 (doublet of doublets, J1 = 5.3 Hz, J2 = 2.3 Hz, 1H), 7.87 - 7.85 (multiplet, 1H), 7.76 - 7.73 (multiplet, 1H), 7.44 (triplet, J = 7.9 Hz, 1H), 7.23 - 7.22 (multiplet, 1H), 6.05 (singlet, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (singlet, 3F). LCMS (ES + ) m / z C 20 H 14 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.40 minutes.

[0342] (Example 162) (3 - ((5 - (4 - methylpyridazin - 3 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 3 - bromo - 4 - methyl - pyridazine was reacted, the title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (broad singlet, 1H), 9.14 (doublet, J = 5.3 Hz, 1H), 8.87 (doublet, J = 1.6 Hz, 1H), 8.29 (singlet, 1H), 8.24 (doublet of doublets, J 1 = 7.9 Hz, J 2 = 2.3 Hz, 1H), 8.21 (singlet, 1H), 7.82 (doublet, J = 7.9 Hz, 1H), 7.75 (broad doublet, J = 8.6 Hz, 1H), 7.71 (doublet of doublets, J 1 = 5.1 Hz, J2 = 0.8 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (br d, J = 7.9 Hz, 1H), 6.07 (s, 2H), 2.37 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.46 min.

[0343] (Example 163) (3-((3'-Methyl-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromo-3-methyl-pyridine hydrochloride was reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J1 = 8.0 Hz, J2 = 2.3 Hz, 1H), 7.77-7.73 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 5.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.03 (s, 2H), 2.27 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 22 H 17F 3 N 6 O 2 Calculated value: 454.14; Measured value: 453 (M-H) - . HPLC t R 1.25 min

[0344] (Example 164) (3-((3'-Fluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-bromo-3-fluoro-pyridine was reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (br s, 1H), 8.90 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.26-8.24 (m, 2H), 8.21 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.76-7.74 (m, 2H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.05 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 14 F 4 N 6 O 2 Calculated value: 458.11; Measured value: 457 (M-H) - . HPLC t R 1.65 min

[0345] (Example 165) (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 5-bromo-1,4-dimethyl-pyrazole was reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (br s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (dd, J1 = 8.2 Hz, J2 = 2.3 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.74 (br d, J = 8.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.04 (s, 2H), 3.74 (s, 3H), 1.99 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 18 F 3 N 7 O 2 calculated value for 457.15; measured value 456 (M-H) - . HPLC t R 1.66 min.

[0346] (Example 179) (3-((5-(4-chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide When 4-chloro-5-iodopyrimidine was reacted, the title compound was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.75 (broad s, 1H), 9.13 (s, 1H), 8.96 (s, 1H), 8.81 - 8.80 (m, 1H), 8.27 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.05 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 20 H 13 ClF 3 N 7 O 2 Calculated value for C - . HPLC t R 1.63 minutes.

[0347] (Example 180) (3 - ((5 - (4,6 - Dichloropyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide When 4,6 - dichloro - 5 - iodopyrimidine was reacted, the title compound was obtained as an off - white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (broad s, 1H), 9.02 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.10 (dd, J 1 = 8.1 Hz, J 2= 2.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.75 (br d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.06 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.27 (s, 3F). LCMS (ES + ) m / z C 20 H 12 Cl 2 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.78 min.

[0348] (Example 177) ((2-(Trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 5-bromo-4-(trifluoromethyl)pyrimidine was reacted, the title compound was obtained as a white solid. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 9.53 (s, 1H), 9.16 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.08 (dd, J1 = 8.2 Hz, J2 = 2.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.72 (dd, J1 = 5.6 Hz, J2 = 1.6 Hz, 1H), 6.11 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -62.38 (s, 3F). LCMS (ES+ ) Calculated value of m / z C 20 H 12 F 6 N 8 O 2 is 510.10; measured value is 509 (M-H) - . HPLC t R is 1.54 minutes.

[0349] (Example 176) (3-((5-(4,6-Dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide When 5-bromo-4,6-dimethyl-pyrimidine was reacted, the title compound was obtained as a white solid. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.19 (br s, 1H), 8.94 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97 (dd, J 1 = 7.9 Hz, J 2 = 2.3 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.72 (dd, J1 = 5.8 Hz, J2 = 1.8 Hz, 1H), 6.09 (s, 2H), 2.55 (s, 3H), 2.21 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 8 O 2 is 470.14; measured value is 469 (M-H) - . HPLC t R is 1.26 minutes.

[0350] (Example 175) (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide When 5-bromo-1,4-dimethyl-1H-pyrazole was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (br s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.03 (dd, J1 = 8.0 Hz, J2 = 2.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.70 (dd, J1 = 5.6 Hz, J2 = 1.6 Hz, 1H), 7.38 (s, 1H), 6.06 (s, 2H), 3.73 (s, 3H), 1.98 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 20 H 17 F 3 N 8 O 2 Calculated value for C - . HPLC t R 1.41 min.

[0351] (Example 132) (3-((5-(4,6-Dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 5-bromo-4,6-dimethyl-pyrimidine was reacted, the title compound was obtained as a white solid. C 21 H 17 F 3 N8 O 2 Regarding LCMS (ES + ) m / z calculated value 470.14; measured value 469 (M-H) - . HPLCt R 1.26 minutes.

[0352] (Example 126) (3 - ((5 - (3,5 - Dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide

[0353] [Chemical formula]

[0354] Step 1: (3 - ((5 - Bromopyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide (Intermediate 35) A solution of [5 - (trifluoromethyl)-3 - pyridyl]amine (74 mg, 0.46 mmol) and DIPEA (118 mg, 0.91 mmol) in dry THF (1.8 mL) was treated with triphosgene (68 mg, 0.23 mmol), stirred at room temperature for 30 minutes, then cooled to 0 °C, and treated dropwise with a suspension of 3 - [(5 - bromo - 2 - pyridyl)methyl]oxadiazol - 3 - ylium - 5 - amine dihydrochloride (Intermediate 34, 75 mg, 0.23 mmol; prepared as described in the synthesis of Intermediate 24) and DIPEA (118 mg, 0.91 mmol) in dry THF (1 mL). The reaction mixture was stirred at room temperature for 5 minutes, then diluted with water and extracted with EtOAC (2×). The organic layer was washed with brine and dried over Na 2 SO 4 dried, filtered, concentrated in vacuo to give a residue, which was purified by silica gel chromatography (elution gradient of 0% to 100% EtOAc in petroleum ether) to give the title compound as a white powder (49 mg, 49%). C 15 H 10 BrF3 N 6 O 5 Regarding LCMS (ES + ) calculated m / z value 442.00; measured value 441 - 443 (M - H) - .HPLCt R 1.61 minutes

[0355] Step 2: (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide (Example 126) In a mixture of dioxane (1 mL) and H 2 O (0.1 mL), [3 - [(5 - bromo - 2 - pyridyl)methyl]oxadiazol - 3 - ium - 5 - yl]-[[5 - (trifluoromethyl)-3 - pyridyl]carbamoyl]azanide (Intermediate 35, 20 mg, 0.045 mmol), Pd(dppf)Cl 2 (3.3 mg, 0.006 mmol), (3,5 - dimethylisoxazol - 4 - yl)boronic acid (12.7 mg, 0.09 mmol) and K 3 PO 4 (28.7 mg, 0.14 mmol) in a degassed suspension was stirred at 75 °C for 1 hour. After cooling, the reaction mixture was filtered through a Solka - Floc pad, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluting with 0 - 100% MeCN in water) to give the title compound as a white solid (12.0 mg, 57%). 1 H NMR (400 MHz, DMSO - d 6) δ 9.98 (br s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.67 (dd, J1 = 2.3 Hz, J2 = 0.6 Hz, 1H), 8.55 (t, J = 2.0 Hz, 1H), 8.49-8.47 (m, 1H), 8.30 (s, 1H), 8.01 (dd, J1 = 8.1 Hz, J2 = 2.3 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 6.02 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 Calculated value for 459.13; Measured value 458 (M-H) - . HPLC t R 1.52 minutes.

[0356] Examples 125, 128, 147, 150, 152, 153, 154, 156, 157, 158, 161, 166, 168 and 171 were synthesized by reacting appropriate commercially available materials according to the above procedure (Scheme 24).

[0357] (Example 125) (3 - ((5 - (Pyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide When reacted with 5 - pyrimidylboronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.98 (s, 1H), 9.25 (s, 2H), 9.06 (dd, J 1 = 2.3 Hz, J 2= 0.7 Hz, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.55 (br t, J = 2.1 Hz, 1H), 8.48 (br d, J = 1.0 Hz, 1H), 8.39 (dd, J1 = 8.1 Hz, J2 = 2.4 Hz, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.53 (br s, 1H), 6.05 (s, 2H). LCMS (ES + ) m / z C 19 H 13 F 3 N 8 O 2 Calculated value for 442.11; Measured value 441 (M-H) - . HPLC t R 1.21 minutes.

[0358] (Example 128) (3 - ((5 - (5 - Methylpyridazin - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide When 4 - methyl - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyridazine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.99 (br s, 1H), 9.24 (s, 1H), 9.14 (d, J = 0.9 Hz, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.78 (dd, J1 = 2.3 Hz, J2 = 0.8 Hz, 1H), 8.55 (br t, J = 2.0 Hz, 1H), 8.50 - 8.47 (m, 1H), 8.32 (s, 1H), 8.16 (dd, J1 = 8.1 Hz, J2 = 2.3 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 6.07 (s, 2H), 2.35 (s, 3H). LCMS (ES + ) m / z C 20 H15 F 3 N 8 O 2 Calculated value 456.13; measured value 455 (M-H) - . HPLC t R 1.19 minutes

[0359] (Example 147) ((5-(Trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 1,3,5-trimethyl-4-(tetramethyl-1,3,3-dioxaborolan-2-yl)-1H-pyrazole was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (br s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.55 (br t, J = 2.1 Hz, 1H), 8.52 (dd, J 1 = 2.3 Hz, J 2 = 0.8 Hz, 1H), 8.50-8.45 (m, 1H), 8.29 (s, 1H), 7.83 (dd, J 1 = 8.1 Hz, J 2 = 2.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 5.98 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 3.14 (s, 3H). LCMS (ES + ) m / z C 21 H 19 F 3 N 8 O 2 Calculated value 472.16; measured value 471 (M-H) - . HPLC t R 1.37 minutes

[0360] (Example 150) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)amide Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid gave the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (br s, 1H), 8.67 - 8.66 (m, 1H), 8.25 (s, 1H), 8.24 - 8.21 (m, 1H), 8.00 (dd, J1 = 8.1 Hz, J2 = 2.3 Hz, 1H), 7.79 - 7.75 (m, 2H), 7.38 (t, J = 9.9 Hz, 1H), 6.00 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES + ) m / z C 21 H 16 F 4 N 6 O 3 calculated value for 476.12; found 475 (M - H) - . HPLC t R 1.77 min.

[0361] (Example 152) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid gave the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (br s, 1H), 8.67 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.01 (dd, J 1 = 8.0 Hz, J 2= 1.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.71 (br d, J = 4.8 Hz, 1H), 6.04 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 Calculated value for C - . HPLC t R 1.49 min.

[0362] (Example 153) (3 - ((5 - (3,5 - Dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - Fluoro - 5 - (trifluoromethyl)phenyl)carbamoyl)amide When reacted with (3,5 - dimethylisoxazol - 4 - yl)boronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (br s, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 8.00 (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1H), 7.90 (s, 1H), 7.78 - 7.74 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 6.02 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.54 (s, 3F). LCMS (ES + ) m / z C 21 H 16 F 4 N 6 O 3 Calculated value for C- . HPLC t R 1.86 minutes.

[0363] (Example 154) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)thiazol-5-yl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (br s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.00 (dd, J1 = 8.0 Hz, J2 = 1.7 Hz, 1H), 8.77 (d, J = 8.1 Hz, 1H), 7.52 (s, 1H), 6.05 (s, 2H), 2.43 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -58.95 (s, 3F). LCMS (ES + ) m / z C 18 H 14 F 3 N 7 O 3 S calculated value 465.08; measured value 464 (M-H) - . HPLC t R 1.60 minutes.

[0364] (Example 156) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.65 (s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.24 (s, 1H), 8.01 - 7.98 (m, 2H), 7.77 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.05 (s, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.23 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 3 Calculated value for C - . HPLC t R 1.87 min.

[0365] (Example 157) ((4-Chloro-3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.27 (s, 1H), 8.00 (dd, J1 = 7.9 Hz, J2 = 2.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.9 Hz, 1H), 6.01 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.39 (s, 3F). LCMS (ES +) Calculated value of m / z C 21 H 16 ClF 3 N 6 O 3 is 492.09; measured value 491 (M-H) - . HPLC t R 1.90 minutes.

[0366] (Example 158) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.60 (br s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 8.16 (br s, 1H), 8.00 (dd, J1 = 8.1 Hz, J2 = 1.8 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.64 (br d, J = 8.1 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -60.34 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 3 is 472.15; measured value 471 (M-H) - . HPLC t R 1.82 minutes.

[0367] (Example 161) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H), 8.00 (dd, J1 = 8.2 Hz, J2 = 2.3 Hz, 1H), 7.96 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 6.04 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.60 (s, 3F). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 Calculated value for 459.13; Measured value 458 (M-H) - . HPLC t R 1.67 minutes.

[0368] (Example 166) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.85 (br s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.01 (dd, J 1 = 7.9 Hz, J 2 = 2.3 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.78 (br d, J = 7.9 Hz, 1H), 6.07 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -52.55 (s, 3F). LCMS (ES + ) m / z C 18 H 14 F 3 N 7 O 3 S calculated value 465.08; measured value 464 (M-H) - . HPLC t R 1.65 min.

[0369] (Example 168) ((3-(Difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.61 (br s, 1H), 8.67 (dd, J 1 = 2.2 Hz, J 2 = 0.7 Hz, 1H), 8.20 (s, 1H), 8.02 - 7.97 (m, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.09 - 7.07 (m, 1H), 6.95 (s, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES+ ) Calculated value of m / z C 21 H 18 F 2 N 6 O 3 is 440.14; measured value is 439 (M-H) - . HPLC t R 1.55 minutes

[0370] (Example 171) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)amide When reacted with (3,5-dimethylisoxazol-4-yl)boronic acid, the title compound was obtained as a white solid 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.29 (s, 1H), 8.01 (dd, J 1 = 8.0 Hz, J 2 = 2.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 6.03 (s, 2H), 2.43 (s, 3H), 2.25 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -68.87 (s, 3F). LCMS (ES + ) m / z C 19 H 15 F 3 N 8 O 3 Calculated value is 460.12; measured value is 459 (M-H) - . HPLC t R 1.34 minutes

[0371] (Example 133) (3-((5-(2-Methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0372]

Chem.

[0373] Step 1: (3-((5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 36) A degassed suspension of Pd(dppf)Cl 2 (6.6 mg, 0.009 mmol), (3-((5-Bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 35, 40 mg, 0.09 mmol), 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (45.8 mg, 0.18 mmol) and KOAc (26.6 mg, 0.27 mmol) in dry dioxane (1 mL) was stirred at 75 °C for 2 h, then cooled and filtered through a Sintered Glass Filter Pad. The filtrate was concentrated in vacuo to give a residue which was used in the next step without further purification.

[0374] Step 2: (3-((5-(2-Methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Example 133) Dioxane (1 mL) and H 2(3-((5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 36, 44 mg, 0.09 mmol) in O(0.1 mL) of mixture, Pd(dppf)Cl 2 (6.6 mg, 0.01 mmol), 5-bromo-2-methoxy-4-methylpyrimidine (36.6 mg, 0.18 mmol) and K 3 PO 4 (57.3 mg, 0.27 mmol) of the degassed suspension was stirred at 75 °C for 1 h. After cooling, the reaction mixture was filtered through a Solkafloc pad and purified by RP-HPLC (C18 column) using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents to obtain the title compound as a white solid (14 mg, 30%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (br s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.68 (br s, 1H), 8.55 (br s, 1H), 8.50 (s, 1H), 8.49 - 8.45 (m, 1H), 8.30 (s, 1H), 8.08 - 8.04 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 6.04 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H). LCMS (ES + ) m / z C 21 H 17 F 3 N 8 O 3 calculated value 486.14; found 485 (M - H) - . HPLC t R 1.43 min.

[0375] Examples 136, 137, 140, 141, 144, 145, 149 and 178 were synthesized by reacting Intermediate 36 with the appropriate starting materials according to the above procedure (Scheme 25).

[0376] (Example 136) (3-((5-(4-Methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 5-bromo-4-methoxy-6-methyl-pyrimidine was reacted, the title compound was obtained as a white solid. C 21 H 17 F 3 N 8 O 3 Regarding LCMS (ES + ) m / z calculated value 486.14; measured value 485 (M-H) - . HPLC t R 1.36 minutes.

[0377] (Example 137) ((5-(Trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide When 5-bromo-4-(trifluoromethyl)-pyrimidine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (br s, 1H), 9.52 (s, 1H), 9.18 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.55 (br s, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.32 (s, 1H), 8.08 (dd, J 1 = 8.1 Hz, J 2 = 2.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H). LCMS (ES + ) m / z C 20 H 12 F 6 N 8 O 2Calculated value: 510.10; Measured value: 509 (M-H) - . HPLC t R 1.55 minutes.

[0378] (Example 140) (3-((5-(1,4-Dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 5-bromo-1,4-dimethyl-imidazole was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (br s, 1H), 8.92 (br s, 1H), 8.65 (br s, 1H), 8.55 (br s, 1H), 8.48 (br s, 1H), 8.30 (br s, 1H), 8.00 - 7.97 (m, 1H), 7.77 - 7.75 (m, 1H), 7.66 (s, 1H), 6.04 (s, 2H), 3.56 (s, 3H), 2.12 (s, 3H). LCMS (ES + ) m / z C 20 H 17 F 3 N 8 O 2 Calculated value: 458.14; Measured value: 457 (M-H) - . HPLC t R 0.94 minutes.

[0379] (Example 141) (3-((2'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 3-bromo-2-methyl-pyridine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.99 (broad singlet, 1H), 8.93 (doublet, J = 2.3 Hz, 1H), 8.66 (doublet, J = 1.6 Hz, 1H), 8.55 (broad triplet, J = 2.3 Hz, 1H), 8.52 (doublet of doublets, J1 = 4.8 Hz, J2 = 1.7 Hz, 1H), 8.48 (broad singlet, 1H), 8.31 (singlet, 1H), 8.03 (doublet of doublets, J1 = 8.0 Hz, J2 = 2.3 Hz, 1H), 7.77 (doublet, J = 8.0 Hz, 1H), 7.70 (doublet of doublets, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.36 (doublet of doublets, J1 = 7.8 Hz, J2 = 5.1 Hz, 1H), 6.04 (singlet, 2H), 2.45 (singlet, 3H). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 calculated value for 455.13; measured value 454 (M-H) - . HPLC t R 0.99 minutes.

[0380] (Example 144) (3 - ((5 - (4 - cyanopyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ylium - 5 - yl)((5 - (trifluoromethyl)pyridin - 3 - yl)carbamoyl)amide When 5 - bromo - pyrimidine - 4 - carbonitrile was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.99 (broad singlet, 1H), 9.48 (singlet, 1H), 9.36 (singlet, 1H), 8.94 (doublet of doublets, J 1 = 8.5 Hz, J 2 = 2.3 Hz, 2H), 8.55 (broad singlet, 1H), 8.48 (broad singlet, 1H), 8.36 (doublet of doublets, J 1 = 8.1 Hz, J 2= 2.3 Hz, 1H), 8.33 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 6.11 (s, 2H). LCMS (ES + ) m / z C 20 H 12 F 3 N 9 O 2 Calculated value for C - H R F

[0381] (Example 145) (3-((5-(Pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 4-bromo-pyridazine hydrobromide was reacted, the title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (br s, 1H), 9.74 (dd, J 1 = 2.5 Hz, J 2 = 1.3 Hz, 1H), 9.36 (dd, J 1 = 5.4 Hz, J 2 = 1.2 Hz, 1H), 9.15 (d, J = 1.8 Hz, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.55 (br s, 1H), 8.50 - 8.47 (m, 2H), 8.30 (s, 1H), 8.13 (dd, J 1 = 5.4 Hz, J 2 = 2.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H). LCMS (ES + ) m / z C 19 H 13 F 3 N 8 O 2 Calculated value for C - H R1:15.

[0382] (Example 149) (3 - ((4'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 3-bromo-4-methyl-pyridine was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (br s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.68 - 8.67 (m, 1H), 8.57 - 8.55 (m, 1H), 8.50 - 8.47 (m, 2H), 8.44 (s, 1H), 8.32 (s, 1H), 8.04 (dd, J 1 = 8.0 Hz, J 2 = 2.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.05 (s, 2H), 2.29 (s, 3H). LCMS (ES + ) m / z C 21 H 16 F 3 N 7 O 2 Calculated value for 455.13; Measured value 454 (M - H) - . HPLC t R 1.04 minutes.

[0383] (Example 178) (3 - ((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide When 5-bromo-1,4-dimethyl-1H-pyrazole was reacted, the title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.99 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.04 (dd, J 1 = 8.1 Hz, J 2 = 2.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 6.05 (s, 2H), 3.74 (s, 3H), 1.98 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.21 (s, 3F). LCMS (ES + ) m / z C 20 H 17 F 3 N 8 O 2 calculated value 458.14; measured value 457 (M-H) - . HPLC t R 1.40 minutes.

[0384] (Example 167) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0385] [Chemical formula]

[0386] Step 1: 2-(((5-Bromopyrimidin-2-yl)methyl)amino)acetonitrile (Intermediate 37) A suspension of (5-Bromopyrimidin-2-yl)-methanamine (500 mg, 2.7 mmol) in MeCN (1.9 mL) was treated with DIPEA (687 mg, 5.3 mmol) and 2-Bromoacetonitrile (351 mg, 2.9 mmol), stirred at 60 °C for 2 hours, then cooled, diluted with EtOAC, washed with water and brine, and dried over Na 2SO 4 It was dried with SO and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (elution gradient of 10% to 100% EtOAc in petroleum ether) to obtain the title compound as an orange powder (410 mg, 68%). 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.97 (s, 2H), 3.93 (d, J = 5.9 Hz, 2H), 3.72 (d, J = 5.8 Hz, 2H), 3.14 - 3.12 (m, 1H). LCMS (ES + ) m / z C 7 H 7 BrN 4 Calculated value for 225.99; Measured value 226 - 228 (M + H) + . HPLC t R 0.62 minutes.

[0387] Step 2: 5-Amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 38) A solution of 2-[(5-bromopyrimidin-2-yl)methylamino]acetonitrile (Intermediate 37, 390 mg, 1.72 mmol) in THF (2.2 mL) was treated with nitrous acid - {tert}-butyl ester (530 mg, 5.15 mmol), stirred at room temperature for 30 minutes, then diluted with EtOAC, washed with water and brine, and Na 2 SO 4It was dried and concentrated under reduced pressure to obtain N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitrosoamide (440 mg, 100%) as a brown residue, which was used without further purification in the next step. The obtained intermediate N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitrosoamide (440 mg, 1.72 mmol) was dissolved in dioxane (2.2 mL) and treated with trimethylsilyl trifluoromethanesulfonate (1.53 g, 6.87 mmol) and HCl (4 M in dioxane; 2.2 mL, 8.8 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour 30 minutes, quenched with water, concentrated under reduced pressure to obtain a residue, which was dissolved in a mixture of MeCN / water (1:1) and lyophilized. The title compound was obtained as a brown oily residue (1.68 g, 100%), which was used without further purification in the following step. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.57 (s, 2H), 9.10 (s, 2H), 8.10 (s, 1H), 6.22 (s, 2H). LCMS (ES + ) m / z C 7 H 7 BrClN 5 O calculated value 255.98 (parent); found 256 - 258 (M+H) + . HPLC t R 0.46 min.

[0388] Step 3: (3-((5-Bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 39) A suspension of 5-amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 38, 570 mg, 0.52 mmol) in anhydrous MeCN (1.5 mL) was treated with anhydrous pyridine (330 mg, 4.2 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (107 mg, 0.57 mmol) at 0 °C, stirred at room temperature for 5 minutes, quenched with water, and extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 , filtered, concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient of 10% to 100% EtOAc in petroleum ether) to give the title compound as a pale yellow powder (205 mg, 89%). 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.09 (s, 2H), 8.28 (s, 1H), 8.20 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.12 (s, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 15 H 10 BrF 3 N 6 O 2 calculated for 442.00; found 441 (M-H) - . HPLC t R 1.75 min.

[0389] Step 4: (3-((5-(3,5-Dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 167) In a mixture of dioxane (1 mL) and water (0.1 mL), (3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 39, 30 mg, 0.068 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (19.1 mg, 0.14 mmol), Pd(dppf)Cl 2 (5 mg, 0.0068 mmol) and K 3 PO 4 (43.1 mg, 0.20 mmol) in a degassed suspension was heated at 80 °C for 1 h and then cooled to room temperature, diluted with EtOAC, washed with water and brine, and dried over Na 2 SO 4 and evaporated in vacuo. Purification by RP-HPLC (C18 column) using water and MeCN as eluents gave the title compound as a beige solid (18 mg, 56%). 1 1H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 8.99 (s, 2H), 8.32 (s, 1H), 8.21 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.20 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 calculated for 459.13; found 458 (M-H) - . HPLC t R 1.71 min.

[0390] Examples 169, 173, 174, 183 and 184 were synthesized by reacting the appropriate starting materials according to the above procedure (Scheme 26).

[0391] (Example 169) (3-((5-(3,5-Dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide The title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (br s, 1H), 9.00 (s, 1H), 8.90 (d, J = 1.4 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.46-7.42 (m, 1H), 7.23 (br d, J = 7.8 Hz, 1H), 6.07 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 Calculated value for 459.13; Measured value 458 (M-H) - . HPLC t R 1.76 minutes.

[0392] (Example 173) (3-((6-(3,5-Dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide The title compound was obtained as an off-white solid. 1 H NMR (600 MHz, DMSO-d 6) δ 9.75 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 8.07 - 8.02 (m, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.20 (s, 2H), 2.61 (s, 3H), 2.41 (s, 3H). 19 F NMR (377 MHz, DMSO - d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3 Calculated value for C - . HPLC t R 1.64 min.

[0393] (Example 174) (3 - ((2 - (3,5 - Dimethylisoxazol - 4 - yl)pyrimidin - 5 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide The title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.74 (s, 1H), 9.10 (s, 2H), 8.37 (s, 1H), 8.23 (s, 1H), 7.72 (br d, J = 8.1 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 5.88 (s, 2H), 2.77 (s, 3H), 2.52 (s, 3H). 19 F NMR (377 MHz, DMSO - d 6 ) δ -61.29 (s, 3F). LCMS (ES + ) m / z C 20 H 16 F 3 N 7 O 3Calculated value: 459.13; Measured value: 458 (M-H) - . HPLC t R 1.83 minutes.

[0394] (Example 183) (3-((4',6'-Dimethyl-[5,5'-bipyrimidine]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide The title compound was obtained as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.96 (s, 3H), 8.36 (s, 1H), 8.21 (s, 1H), 7.76 (br d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 6.23 (s, 2H), 2.25 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 8 O 2 Calculated value: 470.14; Measured value: 469 (M-H) - . HPLC t R 1.51 minutes.

[0395] (Example 184) (3-((6-(4,6-Dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide The title compound was obtained as a light pink solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.77 (s, 1H), 9.02 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.26 (s, 2H), 2.22 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -61.28 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 8 O 2 Calculated value for C - . HPLC t R 1.43 min.

[0396] (Example 142) ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0397]

Chemical Structure

[0398] Step 1: (3-((5-Bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)carbamoyl)amide (Intermediate 40) A mixture of 3-cyclopropylaniline (62 mg, 0.47 mmol) and phosgene (280 mg, 1.4 mmol) in dry dioxane (9.3 mL) was heated at 60 °C for 20 h. After cooling, the solvent was removed under reduced pressure. The resulting 1-cyclopropyl-3-isocyanato-benzene (53.2 mg, 0.334 mmol) and anhydrous pyridine (192 mg, 2.43 mmol) were added dropwise simultaneously at 0 °C to a stirred suspension of 3-[(5-bromo-2-pyridyl)methyl]oxadiazol-3-ium-5-amine dihydrochloride (Intermediate 34, 100 mg, 0.304 mmol) in anhydrous MeCN (0.9 mL). The reaction mixture was stirred at room temperature for 5 min, then quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient of 5% to 100% EtOAc in petroleum ether) to give the title compound as a yellow powder (86 mg, 68%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.24 (br s, 1H), 8.75 (s, 1H), 8.20 (dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 8.13 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.91 (s, 2H), 1.85-1.78 (m, 1H), 0.93-0.89 (m, 2H), 0.61-0.57 (m, 2H). LCMS (ES + ) m / z C 18 H 16 BrN 5 O 2 calculated for 413.05; found 412 - 414 (M-H) - . HPLC t R 1.73 min.

[0399] Project 2: ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide (Example 142) In a mixture of dioxane (1 mL) and water (0.1 mL), (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)carbamoyl)amide (Intermediate 40, 25 mg, 0.06 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (17 mg, 0.12 mmol), Pd(dppf)Cl 2 (4.4 mg, 0.006 mmol) and K 3 PO 4 (38 mg, 0.18 mmol) in a degassed suspension was heated at 80 °C for 1.5 h, then cooled to room temperature, diluted with EtOAC, washed with water and brine, and dried over Na 2 SO 4 and evaporated in vacuo to give a crude product, which was purified by silica gel chromatography (elution gradient of 5% to 100% EtOAc in petroleum ether) to give the title compound as a yellow powder (15.5 mg, 58%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.24 (br s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 8.00 (dd, J 1 = 7.9 Hz, J 2 = 2.0 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.63 (br d, J = 7.5 Hz, 1H), 5.97 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.85 - 1.78 (m, 1H), 0.93 - 0.89 (m, 2H), 0.61 - 0.57 (m, 2H). LCMS (ES + ) m / z C 23 H 22 N6 O 3 Calculated value 430.18; measured value 429 (M-H) - . HPLC t R 1.65 minutes.

[0400] Examples 182 and 146 were synthesized by reacting appropriate starting materials according to the above procedure (Scheme 27).

[0401] (Example 182) ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide The title compound was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (br s, 1H), 8.94 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.21 (s, 1H), 7.97 (dd, J 1 = 7.9 Hz, J 2 = 2.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.63 (br d, J = 7.8 Hz, 1H), 6.02 (s, 2H), 2.21 (s, 6H), 1.85-1.78 (m, 1H), 0.93-0.89 (m, 2H), 0.61-0.57 (m, 2H). LCMS (ES + ) m / z C 24 H 23 N 7 O 2 Calculated value 441.19; measured value 440 (M-H) - . HPLC t R 1.43 minutes.

[0402] (Example 146) ((5-Cyclopropylpyridin-3-yl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide The title compound was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (br s, 1H), 8.67 (dd, J 1 = 2.3 Hz, J 2 = 0.7 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.23 (s, 1H), 8.00 (dd, J 1 = 8.1 Hz, J 2 = 2.3 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.73 (br t, J = 2.1 Hz, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.92 - 1.86 (m, 1H), 1.00 - 0.96 (m, 2H), 0.66 - 0.62 (m, 2H). LCMS (ES + ) m / z C 22 H 21 N 7 O 3 calculated value for 431.17; found 430 (M - H) - . HPLC t R 1.01 min.

[0403] (Example 185) (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0404]

Chemical Structure

[0405] Project 1: (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 41) A mixture of triphosgene (204 mg, 0.69 mmol), 2-(trifluoromethyl)pyridin-4-amine (222 mg, 1.4 mmol) and DIPEA (0.48 mL, 2.7 mmol) in dry THF (5.3 mL) was stirred at room temperature for 1 hour, then added dropwise to a stirred suspension of 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 32, 200 mg, 0.69 mmol) in dry THF (2.0 mL). The resulting mixture was treated with DIPEA (0.48 mL, 2.7 mmol) at 0 °C, stirred at room temperature for 5 minutes, diluted with water and extracted with EtOAc (2×). The collected organic layers were washed with brine and dried over 2 Na 4 SO 1 4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient of 0% to 100% EtOAc in petroleum ether) to give the title compound as a yellow powder (190 mg, 62%). 6 H NMR (400 MHz, DMSO-d + ) δ 10.17 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.70 - 7.67 (m, 3H), 7.57 - 7.53 (m, 2H), 5.81 (s, 2H). LCMS (ES 16 ) m / z C 11 H 3 BrF 5 N 2 3O3 calculated 441.00; found 440 - 442 (M-H) - . HPLC t R R 1.81 min.

[0406] Project 2: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 185) In a mixture of dioxane (1 mL) and water (0.1 mL), (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 41, 139 mg, 0.31 mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (149 mg, 0.63 mmol), Pd(dppf)Cl 2 (23 mg, 0.03 mmol) and K 3 PO 4 (200 mg, 0.94 mmol) in a degassed suspension was heated at 75 °C for 1 hour, then cooled to room temperature, diluted with EtOAC, washed with water and brine, and dried over Na 2 SO 4 and evaporated in vacuo to give a crude product, which was purified by silica gel chromatography (C18RP; elution gradient of 5% to 100% MeCN in H 2 O) to give a residue, which was dissolved in EtOAc and washed with HCl (1 N aqueous solution). The aqueous phase was neutralized with NaHCO 3 (saturated aqueous solution) and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 filtered, and concentrated in vacuo to give the title compound (70.3 mg, 48%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.90 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.72 - 7.68 (m, 3H), 7.42 (d, J = 8.1 Hz, 2H), 5.91 (s, 2H), 2.18 (s, 6H). 19 F NMR (377 MHz, DMSO-d 6) δ -66.93 (s, 3F). LCMS (ES + ) m / z C 22 H 18 F 3 N 7 O 2 Calculated value for 469.15; Measured value 468 (M-H) - . HPLC t R 1.43 minutes.

[0407] Examples 186, 189, 188, 190 and 191 were synthesized by reacting the appropriate starting materials according to the above procedure (Scheme 28).

[0408] (Example 186) (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The title compound was obtained as a white solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (br s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.68 (br d, J = 8.3 Hz, 3H), 7.50 (br d, J = 8.1 Hz, 2H), 5.87 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.93 (s, 3F). LCMS (ES + ) m / z C 21 H 17 F 3 N 6 O 3 Calculated value for 458.13; Measured value 457 (M-H) - . HPLC t R 1.68 minutes.

[0409] (Example 189) (R)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The title compound was obtained as a white solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (br s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.38 (s, 1H), 8.23 (br d, J = 1.6 Hz, 1H), 7.71 (br d, J = 8.3 Hz, 2H), 7.66 (br dd, J 1 = 5.5 Hz, J 2 = 1.6 Hz, 1H), 7.50 (br d, J = 8.2 Hz, 2H), 6.25 (q, J = 7.0 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 3 Calculated value for 472.15; Measured value 471 (M-H) - . HPLC t R 1.77 minutes.

[0410] (Example 188) (R)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The title compound was obtained as a white solid by reacting 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (br s, 1H), 8.89 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.24 (br d, J = 1.6 Hz, 1H), 7.74 (br d, J = 8.3 Hz, 2H), 7.67 (br dd, J 1 = 5.5 Hz, J 2 = 1.8 Hz, 1H), 7.43 (br d, J = 8.3 Hz, 2H), 6.29 (q, J = 7.1 Hz, 1H), 2.18 (s, 6H), 2.08 (d, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 23 H 20 F 3 N 7 O 2 calculated for 483.16; found 482 (M-H) - . HPLC t R 1.52 min.

[0411] (Example 190) (S)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The title compound was obtained as a white solid by reacting 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. 1 H NMR (400 MHz, DMSO-d 6) δ 10.18 (broad singlet, 1H), 8.90 (singlet, 1H), 8.46 (doublet, J = 5.6 Hz, 1H), 8.41 (singlet, 1H), 8.24 (broad doublet, J = 1.9 Hz, 1H), 7.74 (broad doublet, J = 8.3 Hz, 2H), 7.67 (broad doublet of doublets, J 1 = 5.6 Hz, J 2 = 1.9 Hz, 1H), 7.43 (broad doublet, J = 8.3 Hz, 2H), 6.29 (quartet, J = 6.9 Hz, 1H), 2.18 (singlet, 6H), 2.08 (doublet, J = 7.1 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (singlet, 3F). LCMS (ES + ) m / z C 23 H 20 F 3 N 7 O 2 Calculated value for C - . HPLC t R 1.51 minutes.

[0412] (Example 191) (S)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The title compound was obtained as a pale yellow solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (broad singlet, 1H), 8.46 (doublet, J = 5.6 Hz, 1H), 8.38 (singlet, 1H), 8.23 (broad doublet, J = 1.8 Hz, 1H), 7.71 (broad doublet, J = 8.3 Hz, 2H), 7.66 (broad doublet of doublets, J 1 = 5.5 Hz, J 2= 1.9 Hz, 1H), 7.50 (broad d, J = 8.4 Hz, 2H), 6.26 (q, J = 6.8 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J = 7.1 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -66.92 (s, 3F). LCMS (ES + ) m / z C 22 H 19 F 3 N 6 O 3 Calculated value for 472.15; Measured value 471 (M-H) - . HPLC t R 1.77 minutes.

[0413] Biology Expression and purification of Zika virus protease Sequences encoding NS2B (aa49 - 95, R95A) and NS3 (aa1 - 170, R29G) were synthesized (GenScript, Piscataway, NJ, USA) and cloned into the sequence for the 6×His tag downstream of the pET15b vector, with an uncleavable linker (G 4 SG 4) were fused. Protease was expressed in E. coli BL21(DE3) cells: The bacteria were grown in LB medium at 37 °C until an OD600 of 0.8, then the temperature was lowered to 20 °C, and protein expression was induced with 0.5 mM IPTG (catalog number I5502, Sigma Aldrich) for 18 hours. The cells were collected by centrifugation (4000×g, 4 °C, 30 minutes), and then resuspended in lysis buffer (25 mM Tris pH 8.0, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (catalog number 16876, Sigma Aldrich) and 25 U / ml benzonase (catalog number E1014, Sigma Aldrich) (7 ml / g of cell paste). After incubation at 25 °C for 30 minutes, the cells were homogenized at 800 bar using a PANDA homogenizer (GEA), and then the cell extract was clarified by centrifugation (32914×g, 4 °C, 1 hour), transferred to 500 mM NaCl, and then loaded onto a 1 ml HisTrap HP column (catalog number 17-52407-01, Cytiva, Sweden) equilibrated with 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After three washing steps with 20, 30, and 50 mM imidazole, the recombinant protein was eluted with a linear gradient up to 350 mM imidazole (catalog number I202, Sigma Aldrich). The fractions containing ZIKV protease were pooled, treated with 2 mM TCEP (catalog number C4706, Sigma Aldrich) at 4 °C for 40 minutes, then concentrated to one-third using a Vivaspin 20, 3 kDa cut-off device (catalog number Z614610-48EA, Sigma Aldrich), and loaded onto a HiLoad 16 / 60 Superdex 75 column (catalog number 28989333, Cytiva, Sweden) using 25 mM Tris pH 8.5, 5% glycerol, and 1 mM DTT (catalog number A2948, Pan Reac AppliChem) as the mobile phase. The fractions of the monomer peak were collected, aliquoted in small amounts, and frozen in liquid nitrogen.

[0414] Expression and purification of DEN2V protease The expression of DEN2V serine protease was carried out as described above with some modifications (Acta Cryst. (2006). F62, 157 - 162). Sequences encoding NS2B (aa1394 - 1440, Uniprot Q91H74) and NS3 (aa1476 - 1660, Uniprot Q91H74) were synthesized (GenScript, Piscataway, New Jersey, USA), cloned into the sequence for the 6×His tag downstream of the pET15b vector, and fused with a non-cleavable linker (G4SG4). The protease was expressed in Escherichia coli BL21(DE3) cells: The bacteria were grown at 25 °C for 24 h with shaking at 300 RPM in MDG minimal non-inducing medium. Subsequently, the bacterial starter culture was diluted 1:20 in ZYM-5052 auto-inducing medium and grown for a further 24 h at 200 RPM and 25 °C. The cells were collected by centrifugation (4000×g, 4 °C, 30 min), then resuspended in lysis buffer (20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (catalog number 16876, Sigma Aldrich) and 25 U / ml benzonase (catalog number E1014, Sigma Aldrich) (7 ml / g of cell paste). After incubation at 25 °C for 30 min, the cells were homogenized at 800 bar with a PANDA homogenizer (GEA), then the cell extract was clarified by centrifugation (32914×g, 4 °C, 1 h), transferred to 500 mM NaCl, and loaded onto a 5 ml HisTrap HP column (catalog number 17525501, Cytiva, Sweden) equilibrated with 20 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two washing steps with 10 and 20 mM imidazole, the recombinant protein was eluted with a linear gradient to 440 mM imidazole (catalog number I202, Sigma Aldrich).Fractions containing DEN2V protease were pooled, concentrated to one-third using a Vivaspin 20, 3 kDa cut-off device (catalog numbers Z614610~48EA, Sigma Aldrich), and loaded onto a HiLoad 16 / 60 Superdex 75 column (catalog number 28989333, Cytiva, Sweden) using 20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol as the mobile phase. The monomer peak fractions were collected, aliquoted in small amounts, and frozen in liquid nitrogen.

[0415] Expression and purification of JEV protease The expression of JEV serine protease was performed as described above with some modifications (PLoS ONE 7(5):e36872). Sequences encoding NS2B (aa51-95, JEV genotype III strain JaOArS982, Genebank accession number: M18370) and NS3 (aa1-180, JEV genotype III strain JaOArS982, Genebank accession number: M18370) were synthesized (GenScript, Piscataway, New Jersey, USA), cloned into the sequence for the 6×His tag downstream of the pET15b vector, and fused by a cleavable linker derived from the NS2B sequence (aa121-131). The protease was expressed in Escherichia coli BL21(DE3) cells: The bacteria were grown at 25 °C for 24 h with shaking at 300 RPM in MDG minimal non-inducing medium. The bacterial starter culture was then diluted 1:20 in ZYM-5052 auto-inducing medium and grown for a further 24 h at 200 RPM and 25 °C. The cells were collected by centrifugation (4000×g, 4 °C, 30 min), then resuspended in lysis buffer (25 mM Tris pH 8.5, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (catalog number 16876, Sigma Aldrich) and 25 U / ml benzonase (catalog number E1014, Sigma Aldrich) (7 ml / g of cell paste). After incubation at 25 °C for 30 min, the cells were homogenized at 800 bar using a PANDA homogenizer (GEA), then the cell extract was clarified by centrifugation (32914×g, 4 °C, 1 h), transferred to 500 mM NaCl, and then loaded onto a 5 ml HisTrap HP column (catalog number 17525501, Cytiva, Sweden) equilibrated with 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two washing steps with 10 and 30 mM imidazole, the recombinant protein was eluted with a linear gradient to 500 mM imidazole (catalog number I202, Sigma Aldrich).Fractions containing JEV protease were pooled, then treated with 2 mM TCEP (Catalog number C4706, Sigma Aldrich) at 4 °C for 40 minutes, and finally concentrated to 1 / 3 using a Vivaspin 20, 3KDa cut-off device (Catalog number Z614610~48EA, Sigma Aldrich), and loaded onto a HiLoad 16 / 60 Superdex 75 column (Catalog number 28989333, Cytiva, Sweden) using 25 mM Tris pH 9.0, 5% glycerol, 1 mM TCEP as the mobile phase. The monomer peak fractions were collected, aliquoted into small amounts, and frozen in liquid nitrogen.

[0416] ZIKV Protease Inhibition Assay The enzyme inhibition assay was performed in a 384-well flat-bottom black polystyrene microplate (Catalog number 781900, Greiner) with a reaction volume of 20 μl. ZIKV NS2B-G 4 SG 4 -NS3 Serine Protease

[0417]

Chemical formula

[0418] (1.25 nM) was incubated at 25 °C for 10 min while increasing the concentration of the inhibitor in assay buffer (50 mM Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO) (0.097 - 100 μM or 0.0009 - 1 μM for the most active compounds). 10 μM of the Bz-Nle-KRR-AMC substrate (catalog number 4055312, Bachem) was added and the reaction mixture was incubated at 25 °C for an additional 30 min. Formation of the product was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nm) using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, California) and Vortex software (Dotmatics, Bishop's Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

[0419] DEN2V Protease Inhibition Assay The enzyme inhibition assay was performed in a 384-well flat-bottom black polystyrene microplate (catalog number 781900, Greiner) with a reaction volume of 20 μl. DEN2V NS2B-G4SG4-NS3 serine protease

[0420] [Chemical Structure]

[0421] (10 nM) was incubated at 25 °C for 10 min while increasing the concentration of the inhibitor in assay buffer (50 mM Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO) (0.097 - 100 μM or 0.0009 - 1 μM for the most active compounds). 15 μM of the Bz-Nle-KRR-AMC substrate (Catalog number 4055312, Bachem) was added and the reaction mixture was incubated at 25 °C for an additional 30 min. Formation of the product was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nm) using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bishop's Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

[0422] WNV Protease Inhibition Assay Enzyme inhibition assays were performed in a 384-well flat-bottom black polystyrene microplate (Catalog number 781900, Greiner) with a 20 μl reaction volume. West Nile virus (WNV) NS2B-NS3 protease (R&D, Catalog number 2907-SE-020) (2 nM) was incubated at 25 °C for 10 min while increasing the concentration of the inhibitor in assay buffer (50 mM Tris-HCl, pH 9.0, 30% glycerol, 1% DMSO) (0.097 - 100 μM or 0.0009 - 1 μM for the most active compounds). 10 μM of the pERTKR-AMC substrate (R&D, Catalog number ES013) was added and the reaction mixture was incubated at 25 °C for an additional 30 min. Formation of the product was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nm) using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bishop's Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

[0423] JEV Protease Inhibition Assay The enzyme inhibition assay was performed in a 384-well flat-bottom black polystyrene microplate (catalog number 781900, Greiner) with a reaction volume of 20 μl. Japanese encephalitis virus (JEV)-NS2B-NS3 protease (600 nM) was incubated at 25 °C for 10 min in assay buffer (50 mM Tris-HCl, pH 9.0, 0.1% BSA, 0.1% Triton X-100, 1% DMSO) while increasing the concentration of the inhibitor (0.097 - 100 μM or 0.009 - 1 μM for the most active compounds). 10 μM of Pyr-RTKR-AMC substrate (Bachem, catalog number 4018149) was added and the reaction mixture was incubated at 25 °C for an additional 120 min. The formation of the product was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nm) using a SPARK TM10 Tecan instrument. The results were analyzed using Prism (GraphPad, San Diego, California) and Vortex software (Dotmatics, Bishop's Stortford, UK). The dose-response curve was fitted by four-parameter logistic regression.

[0424] Generation of ZIKV Replicon To construct the subgenomic replicon, the inventors used the Asian lineage Natal RGN isolate (GenBank: KU527068.1). In the replicon, the coding sequences of the structural genes were deleted except for those in which 31 amino acids at the N-terminus of the capsid protein were fused with 32 amino acids at the C-terminus of the E protein. These sequences were retained to preserve the correct processing and translocation of NS1 and nonstructural polyproteins through the endothelial reticulum. The EMCV IRES was placed after the stop codon of the polyprotein. The IRES directs the translation of a downstream fusion protein consisting of the luciferase (Nano-Luc) gene followed by the ubiquitin gene (UBI), and the neomycin phosphotransferase resistance gene (NEO). This fusion protein is required for reporting purposes and conferring resistance to G-418. The subgenomic replicon was transcribed as RNA via the upstream T7 promoter and transfected into Vero cells. A stable cell line for use in the ZIKV replication assay was generated via selection with G-418.

[0425] ZIKV Replication Inhibition Assay and Cell Viability Assay A green monkey cell line (Vero) containing a stable ZIKV replicon was grown and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with high glucose and pyruvate (GIBCO#41966), 10% fetal bovine serum (FBS) (Gibco 10270), and 1% penicillin streptomycin (10 mg / ml) (Gibco 14140). ZIKV replication in the cells was maintained using a G418 solution (Sigma-Aldrich, catalog 4727894001) at 0.760 μg / mL. On the day of the experiment, the compound pre-dissolved in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, D5879~1L) was transferred to a 384 black plate (Greiner 781086) using an acoustic system (ATS-100EDC). Dose-response tests were performed on the compounds. A ZIKV replication assay was performed using 50 μM mycophenolic acid (Sigma-Aldrich, M3536) as a positive control, and simultaneously a cell viability assay was performed using 32 μM gambogic acid (Sigma-Aldrich, G8171) as a positive control. In both cases, 0.5% DMSO was added to the negative control wells. 8000 cells / well were plated into the compound-containing plates in 40 μL of growth medium. After treatment at 37 °C, 5% CO 2 and 90% humidity for 72 hours, 20 μL of Nano-Glo (Promega N1150) was added to reveal the NanoLuc signal, and simultaneously 20 μL of CellTiter-Glo (Promega G7573) was added to determine cell viability. Fluorescence signals for both assays were detected by reading the plates with an Envision plate reader 10 minutes after adding the detection reagents (luminescence was measured at 0.5 seconds / well). The data were normalized between 0 and 100% inhibition (from negative control to positive control respectively). For the determination of EC 50 , the dose-response was fitted to a 4-parameter logistic regression approach using Dotmatics Studies software.

[0426] Results The exemplified compounds described in this specification were tested in the assays described above. The IC calculations regarding the inhibition of ZIKV protease and replicon and the inhibition of dengue virus and West Nile virus protease are reported in Table 1 below using the following character codes: 50 The calculation results are reported in Table 1 below using the following character codes:

[0427] A: IC 50 or EC 50 is lower than 0.1 μM; B: IC 50 or EC 50 is from 0.1 μM to 1 μM; C: IC 50 or EC 50 is from 1 μM to 20 μM; D: IC 50 or EC 50 is higher than 20 μM; n.a.: not applicable.

[0428]

Table 1A

[0429]

Table 1B

[0430]

Table 1C

[0431]

Table 1D

[0432]

Table 1E

[0433]

Table 1F

[0434]

Table 1G

[0435]

Table 1H

[0436]

Table 1I

[0437]

Table 1J

[0438]

Table 1K

[0439]

Table 1L

[0440]

Table 1M

[0441]

Table 1N

[0442]

Table 1O

[0443]

Table 1P

[0444]

Table 1Q

[0445]

Table 1R

[0446]

Table 1S

[0447]

Table 1T

[0448]

Table 1U

[0449]

Table 1V

[0450]

Table 1W

Claims

1. A compound of general formula (I) 【Chemical 1】 (wherein: m and n are each independently selected from 0, 1, and 2; R 1a and R 1b are each independently selected from H and C 1～6 alkyl, and C 1～6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1～3 alkyl, halogen, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC(=O)NHC 1～6 alkyl, NHSO 2 C 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 and is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 1a and R 1b are joined together to form a C 3～6 -cycloalkyl ring or a C 4～6 -heterocycloalkyl ring; or R 1a is R 3 is attached to R to form a partially unsaturated aromatic or heteroaromatic bicyclic ring; or R 1b is absent, and C-R 1a is C=CH 2 ; R 2a and R 2b are each independently selected from H and C 1～6 alkyl, where C 1～6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1～3 alkyl, halogen, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 or is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 2a and R 2b are joined together to form a C 3～6 -cycloalkyl ring or a C 4～6 -heterocycloalkyl ring; or R 1a and R 2a or R 1b and R 2b Any two of them are combined together to form C 3～6 cycloalkyl or C 3～6 heterocycloalkyl; R 3 is a heterocycloalkyl, aromatic ring or heteroaromatic ring, and each said heterocycloalkyl, aromatic ring or heteroaromatic ring is halogen, hydroxy, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC(=O)NHC 1～6 alkyl, NHSO 2 C 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , C 1～6 alkyl, haloC 1～6 alkyl, C 1～6 alkoxy, cyano, B(OH) 2 , aryl, heteroaryl, optionally substituted with one or more substituents independently selected therefrom, and said aryl or heteroaryl ring is halogen, hydroxy, cyano, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , C 3～6 cycloalkyl, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N - methylpiperazine, C 1～6 alkyl, C 1～6 alkoxy, each independently selected from one or more substituents, optionally substituted, and said C 1～6 alkyl, C 1～6 alkoxy is one or more halogen, hydroxy, NH 2 , NHCOCH 3 , NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N - methylpiperazine, optionally substituted; R 4 is the ring of formula (II): 【Chemical 2】 - R 6 is CF 3 , F, Cl, CN or C 1～3 alkyl, cyclopropyl, CHF 2 ; and - X is CR 7 or N; - R 7 is, independently for each occurrence, selected from H, halogen, C 1～6 alkyl, C 1～6 alkoxy, haloC 1～6 alkyl, hydroxy; or or R 4 is 4-trifluoromethylphenyl, thiophene, thiazole, imidazole, pyrazole, oxazole, oxadiazole, naphthalene, quinoline, isoquinoline, quinazoline or naphthyridine, and each said ring is optionally substituted with one or more substituents selected from halogen, C 1～6 alkyl, hydroxy, haloC 1～6 alkyl, C 1～6 alkoxy, NH 2 , NHC(O)C 1～6 alkyl, CN; or R 4 is phenyl, and R 3 is a phenyl ring substituted with one or more substituents selected from halogen, C 1～6 alkyl, C 1～6 alkoxy, and optionally substituted with a heteroaromatic ring substituted with one or more substituents selected from halogen, C R 5 is H, C 1～6 alkyl, C 1～6 haloalkyl or halogen). or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, provided that the following compound: [Chemical Formula 3] is not included, a compound or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

2. - R 1b and R 2b is H; and / or - m and n are each independently selected from 0 and 1; and / or - R 5 The compound according to claim 1, wherein R is H.

3. m is 1 and n is 0; R 1a is H, and R 1b is H, or hydroxy or NH 2 optionally substituted C 1～3 alkyl, a compound according to any one of claims 1 to 2.

4. R 3 is phenyl, naphthyl, biphenyl, phenyl substituted with a heteroaromatic ring, or a heteroaromatic ring substituted with a second heteroaromatic ring, each said phenyl, naphthyl or heteroaromatic ring being halogen, hydroxy, cyano, B(OH) 2 , NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , C 1～6 alkyl, C 1～6 alkoxy, pyrrolidine, piperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituents independently selected therefrom, said C 1～6 alkyl, C 1～6 alkoxy being optionally substituted with one or more halogen, hydroxy, NH 2 , N(CH 3 ) 2 , morpholine or pyrrolidine, the compound according to any one of claims 1 to 3.

5. R 4 is a compound according to any one of claims 1 to 4, wherein R is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl.

6. - R 3 is: a) phenyl substituted with a 5- or 6-membered heteroaromatic ring, preferably phenyl selected from pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or b) a 5- or 6-membered heteroaromatic ring, preferably selected from pyridine, pyrimidine, thiophene, pyrazine, and pyridazine, each said 5- or 6-membered heteroaromatic ring being substituted with phenyl, isoindoline or preferably a 5- or 6-membered heteroaromatic ring selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine selected from; In a) or b), each said phenyl, 5- or 6-membered heteroaromatic ring is optionally substituted with one or more substituents independently selected from C 1～3 alkyl, C 1～3 alkoxy, C 3～6 cycloalkyl, CF 3 , C 5～6 heterocycloalkyl, O-(CH 2 ) 2 NH 2 , O-(CH 2 ) 2 OH, hydroxy, halogen; - R 4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl; - m is 1 and n is 0; R 1a is H, and R 1b is H, or hydroxy or NH 2 optionally substituted C 1～3 alkyl, a compound according to any one of claims 1 to 5.

7. having general formula (III) 【Chemical Formula 4】 or having general formula (IV) [Chemical Formula 5] or having general formula (V) ​ (wherein each R 3 , R 5 and X have the meanings defined in any one of claims 1 to 6) The compound according to any one of claims 1 to 6.

8. R 3 has the following structure [Chemical Formula 7] (wherein each phenyl or heteroaromatic ring may be further optionally substituted by one or two substituents independently selected from methyl, CF 3 , halogen, cyclopropyl, methoxy, and cyano) selected from, the compound according to any one of claims 1 to 7.

9. R 4 has the following structure [Chemical 8] selected from, the compound according to any one of claims 1 to 8.

10. The following list - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl)carbamoyl)amide; - (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; - (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-Phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide - (3-(1-(3,4-Dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2,3-Dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide; - (R)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; - (3-([1,1'-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(Naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2'-Methyl-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-Benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-([1,1'-Biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2-Phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(Pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-Methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(1-Phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(1-Phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Phenyl-3-(pyrrolidin-1-yl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(2,2,2-Trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(1-Methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-Amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-Iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((4'-(Morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(2-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((1R,2S)-2-Phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-([1,1'-Biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-Bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (S)-(3-(1-(4-(Pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (S)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(1-(4-(4-Methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(4-Methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(4-Methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(3-Methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-(2-Hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(2-Methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(5-Methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-(4-(1,4-Dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(3-Methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (R)-(3-(2-Amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(Pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(3,5-Dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(1,2-Dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Fluoro-6-oxo-1,6-dihydropyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4-(4-Methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-Methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4-(2-Hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-Cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl); - (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide; - (S)-(3-(2-Amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Isoindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(2-(Aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-Boronopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-(2-(Dimethylamino)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(2-(2-(dimethylamino)ethoxy)-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((2'-methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4'-methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((2'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4-Cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(Pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - ((5-Cyclopropylpyridin-3-yl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - ((5-(Trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(4-Cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((4'-Methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((4 - fluoro - 3 - (trifluoromethyl)phenyl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethyl - 1H - pyrazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((2 - (trifluoromethyl)pyridin - 4 - yl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - fluoro - 5 - (trifluoromethyl)phenyl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((2 - (trifluoromethyl)thiazol - 5 - yl)carbamoyl)amide; - (3 - ((5 - (4 - cyclopropylpyrimidin - 5 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - (trifluoromethyl)phenyl)carbamoyl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((3 - methyl - 5 - (trifluoromethyl)phenyl)carbamoyl)amide; - ((4 - chloro - 3 - (trifluoromethyl)phenyl)carbamoyl)(3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)amide; - (3 - ((5 - (3,5 - dimethylisoxazol - 4 - yl)pyridin - 2 - yl)methyl)-1,2,3 - oxadiazol - 3 - ium - 5 - yl)((4 - methyl - 3 - (trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2'-Methoxy-4'-methyl-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(Pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; - (3-((5-(4-Methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3'-Methyl-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3'-Fluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-(Difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((3',5'-Difluoro-[3,4'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)amide; - (3-((2'-Chloro-[3,3'-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(3,5-Dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((2-(3,5-Dimethylisoxazol-4-yl)pyrimidin-5-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-((5-(4,6-Dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - ((2-(Trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (3-((5-(4-Chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(4,6-Dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((5-(3,6-Dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - ((3-Cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; - (3-((4',6'-Dimethyl-[5,5'-bipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-((6-(4,6-Dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-(4-(3,5-Dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; - (R)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (R)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (S)-(3-(1-(4-(4,6-Dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; - (S)-(3-(1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide The compound of general formula (I) according to claim 1, selected from:

11. An NS2B-NS3 protease inhibitor of flavivirus, preferably an NS2B-NS3 protease inhibitor of dicavirus and / or dengue virus and / or West Nile virus and / or Japanese encephalitis virus, the compound according to any one of claims 1 to 10.

12. The compound according to any one of claims 1 to 11 for pharmaceutical use.

13. For use in the treatment and / or prevention of flavivirus infections, preferably the flavivirus is selected from the group consisting of dengue virus, West Nile virus, dicavirus and Japanese encephalitis virus, the compound according to claim 12.

14. A compound of general formula (I) for use in the treatment of flavivirus infections 【Chemical Formula 9】 (wherein: m and n are each independently selected from 0, 1, and 2; R 1a and R 1b are each independently selected from H and C 1～6 alkyl, where C 1～6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1～3 alkyl, halogen, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC(=O)NHC 1～6 alkyl, NHSO 2 C 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 and is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 1a and R 1b are joined together to form a C 3～6 -cycloalkyl ring or a C 4～6 -heterocycloalkyl ring; or R 1a is R 3 is attached to R to form a partially unsaturated aromatic or heteroaromatic bicyclic ring; or R 1b is absent, and C-R 1a is C=CH 2 ; R 2a and R 2b are each independently selected from H and C 1～6 alkyl, where C 1～6 alkyl is optionally substituted with one or more substituents selected from hydroxy, OC 1～3 alkyl, halogen, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 or is optionally substituted with one or more substituents selected from cyclic amines selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N - methylpiperazine; or R 2a and R 2b are joined together to form a C 3～6 -cycloalkyl ring or a C 4～6 -heterocycloalkyl ring; or R 1a and R 2a or R 1b and R 2b Any two of them are combined together to form C 3～6 cycloalkyl or C 3～6 heterocycloalkyl; R 3 is a heterocycloalkyl, aromatic ring or heteroaromatic ring, and each said heterocycloalkyl, aromatic ring or heteroaromatic ring is halogen, hydroxy, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC(=O)NHC 1～6 alkyl, NHSO 2 C 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 、C 1～6 alkyl, haloC 1～6 alkyl, C 1～6 alkoxy, cyano, B(OH) 2 , aryl, heteroaryl, optionally substituted with one or more substituents independently selected therefrom, and said aryl or heteroaryl ring is halogen, hydroxy, cyano, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , C 3～6 cycloalkyl, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N - methylpiperazine, C 1～6 alkyl, C 1～6 alkoxy, each independently selected from one or more substituents, optionally substituted, and said C 1～6 alkyl, C 1～6 alkoxy is one or more halogen, hydroxy, NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N - methylpiperazine, optionally substituted; R 4 is an aromatic ring or heteroaromatic ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1～6 alkyl, haloC 1～6 alkyl, C 1～6 alkoxy, cyano, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine; R 5 is H, C 1～6 alkyl, C 1～6 haloalkyl or halogen). or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, preferably, the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus, and Japanese encephalitis virus, a compound or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

15. - R 1b and R 2b is H; and / or - m and n are each independently selected from 0 and 1; and / or - R 3 is phenyl, naphthyl, biphenyl, phenyl substituted with a heteroaromatic ring, or a heteroaromatic ring substituted with a second heteroaromatic ring, each said phenyl, naphthyl or heteroaromatic ring being halogen, hydroxy, cyano, B(OH) 2 , NH 2 , NHCOC 1～6 alkyl, NHCOOC 1～6 alkyl, NHC 1～3 alkyl, N(C 1～3 alkyl) 2 , C 1～6 alkyl, C 1～6 alkoxy, pyrrolidine, piperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituents independently selected therefrom, said C 1～6 alkyl, C 1～6 alkoxy being optionally substituted with one or more halogen, hydroxy, NH 2 , N(CH 3 ) 2 , morpholine or pyrrolidine; and / or - R 4 is a compound for use according to claim 14, selected from 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridin-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridin-4-yl.

16. - m is 1 and n is 0; and / or - R 1a is H, and R 1b is H, or C 2 alkyl optionally substituted with hydroxy or NH 1～3 ; and / or - R 5 A compound for use according to any one of claims 14 or 15, wherein R is H.

17. - (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; - (3-Phenethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide A compound for use according to claim 14, selected from the group consisting of:

18. A compound according to any one of claims 14 to 17 for use in combination with at least one further therapeutic agent.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a compound for use according to any one of claims 14 to 17 and at least one pharmaceutically acceptable excipient.

20. For use in the treatment and / or prevention of flavivirus infections, preferably, the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus, and Japanese encephalitis virus, the pharmaceutical composition according to claim 19.

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