Flavivirus inhibitors

Abstract

The present invention relates to compounds that are flavivirus NS2B-NS3 protease inhibitors and inhibit flavivirus replication in cells. The compound provided by the invention can be independently used or combined with other medicaments for treating infections caused by flaviviruses, particularly infections caused by dengue fever virus, West Nile virus, Zika virus and Japanese encephalitis virus.

Description

Summary of the Invention

[0001] The present invention relates to compounds that act as inhibitors of the flavivirus NS2B-NS3 protease and inhibit the replication of flaviviruses in cells. The compounds of the present invention can be used alone or in combination with other agents to treat infections caused by flaviviruses, particularly infections caused by dengue fever, West Nile virus, Zika virus, and Japanese encephalitis virus. The present invention also relates to pharmaceutical compositions containing the compounds. Background Art

[0002] The genus Flavivirus of the family Flaviviridae includes more than 70 related arthropod-borne viruses. The most common and best-represented 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 primarily transmitted by Aedes mosquitoes. Flavivirus infections pose a persistent threat to public health. Mosquito-borne dengue virus serotypes 1-4 (DENV1-4), along with yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV), are listed as Category A, B, or C emerging human pathogens by the U.S. National Institute of Allergy and Infectious Diseases (NIAID). DENV can cause severe illness with significant morbidity and mortality. The World Health Organization estimates that over 50 million people worldwide experience dengue symptoms each year, with at least 250,000 developing dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), resulting in significant mortality, particularly among children in South Asia. The WHO estimates that 2.5 billion people (approximately 40% of the world's population) live in areas at high risk of contracting the dengue virus. Outbreaks frequently occur in the Americas, including the continental United States, primarily in the southern states, Puerto Rico, and Hawaii.

[0003] Zika virus (ZIKV) has caused three major outbreaks in the Pacific Islands, Brazil, and other countries in the Americas, with reported infections exceeding one million and numerous medical visits. More seriously, Zika virus infection has been linked to a 20-fold increase in the incidence of severe neurological symptoms, including Guillain-Barré syndrome, and more than 4,000 cases of microcephaly in newborns. Zika virus has rapidly spread to 48 countries in the Americas and has recently been shown to be transmissible through sexual intercourse or bodily fluids.

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

[0005] Therefore, more effective compositions and methods are needed to treat viral infections caused by flaviviruses. In addition to vaccine development and vector control, the search for antiviral drugs that can alleviate patient symptoms has also attracted much attention. Flaviviruses share common epidemiological, structural, and ecological characteristics, and different viruses can often co-infect the same host. Therefore, the identification of broad-spectrum inhibitors is highly desirable, both for known flaviviruses and for those that may emerge in the future. Strategies targeting viral and host factors are being sought to identify broad-spectrum anti-flavivirus agents (https: / / doi.org / 10.1002 / cmdc.202000464).

[0006] The flavivirus genome consists of a positive-sense single-stranded RNA of approximately 11 kb in length, which consists of a single long open reading frame (ORF). The single ORF encodes a polyprotein that is further processed by proteases from the host 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 coat, while the seven NS proteins participate in the membrane-bound replication complex. Of these NS proteins, only NS3 and NS5 have enzymatic functions (Pathogens 2022, 11 293). Flavivirus replication depends on the NS3 protease, a 69 kDa protein with two domains with different enzymatic functions: a trypsin-like serine protease domain located in the N-terminal region; and a C-terminal region with RNA helicase and RNA-stimulated NTPase activities. Furthermore, it is fully activated only when bound to its cofactor NS2B; forming the enzymatic complex NS2B-NS3. With this in mind, the NS2B-NS3 protease is an important target for the development of novel antiviral compounds that could inhibit its replication complex and lead to the death of flaviviruses.

[0007] Flavivirus proteases share a high degree of structural similarity and substrate recognition properties, which may facilitate the development of pan-flavivirus protease inhibitor strategies. However, the success of various drug discovery attempts over the past decade has been limited by the nature of the viral enzymes and the lack of robust structural templates. Structurally diverse small-molecule protease inhibitors have been reported with affinities in the low micromolar range. However, peptidyl, substrate-derived compounds are typically nanomolar inhibitors with severely compromised drug-likeness. With some exceptions, the antiviral cellular activity of most reported compounds is variable and insufficient for further development. Recently, progress has been made in elucidating inhibitor binding using different structural approaches. Hopefully, this will lead to more rational attempts to identify diverse lead compounds that may be successful in cell assays, animal models, and ultimately in patients.

[0008] WO2021 / 175437 and WO2021 / 175670 provide non-peptide (4-phenoxy)-phenylglycine and (4-benzyloxy)-phenylglycine derivatives as inhibitors of NS2B-NS3 serine proteases for the treatment and prevention of flavivirus infections.

[0009] The present invention produces a series of novel, drug-like, broadly active flavivirus protease inhibitors. Summary of the Invention

[0011] The present invention provides a series of compounds that target the NS2B-NS3 protease. The compounds of the present invention are derivatives of sydnone imine and thus possess a mesocyclic heterocyclic core appropriately substituted at the imino nitrogen with nitrogen derivative substituents and alkyl-aromatic or heteroaromatic substituents. The chemotypes discovered in the present invention produce highly potent inhibitors of the ZIKV NS2B-NS3 protease, and are also effective against JEV, dengue fever, and WNV proteases. The compounds of the present invention are capable of inhibiting the replication of these viruses in cells.

[0012] Therefore, one of the objects of the present invention is the compound of general formula (I):

[0013]

[0014] in:

[0015] 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;

[0016] R 1a and R 1b independently selected from H and C optionally substituted with one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3Alkyl, halogen, NH2, NHCOCH3, NHCOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl) 2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine;

[0017] or R 1a and R 1b connected together to form C 3-6 -cycloalkyl ring or C 4-6 -heterocycloalkyl ring;

[0018] or R 1a connected to R3 to form a partially unsaturated aromatic or heteroaromatic bicyclic ring;

[0019] or R 1b Does not exist and CR 1a is C=CH2;

[0020] R 2a and R 2b independently selected from H and C optionally substituted with one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOCH3, NHCOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl) 2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine;

[0021] or R 2a and R 2b connected together to form C 3-6 -cycloalkyl ring or C 4-6 -heterocycloalkyl ring;

[0022] or R 1a and R 2a or R 1b and R 2b Any two of them are connected together to form C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl;

[0023] R3 is a heterocycloalkyl, aromatic or heteroaromatic ring, each of which is optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from halogen, hydroxy, NH2, NHCOC 1-6Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyano, B (OH) 2, aryl, heteroaryl, wherein the aryl or heteroaryl ring is optionally substituted with one or more substituents, wherein the one or more substituents are each independently selected from 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, NHCOCH3, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 alkyl)2, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine.

[0024] R4 is a ring of formula (II):

[0025]

[0026] in

[0027] -R6 is CF3, F, Cl, CN or C 1-4 Alkyl, cyclopropyl, CHF2;

[0028] -X is CR7 or N;

[0029] -R7 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl;

[0030] or R4 is 4-trifluoromethylphenyl, thiophene, thiazole, imidazole, pyrazole, oxazole, oxadiazole, naphthalene, quinoline, isoquinoline, quinazoline or naphthyridine, wherein each ring is optionally selected from halogen, C 1-6 Alkyl, hydroxyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, NH2, NHC(O)C 1-6 Alkyl, CN is substituted with one or more substituents;

[0031] or R4 is phenyl and R3 is a phenyl-heteroaryl system, said phenyl-heteroaryl system being optionally selected from halogen, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with one or more substituents;

[0032] R5 is H, C 1-6 Alkyl, C 1-6 haloalkyl or halogen;

[0033] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof;

[0034] Provided that the following compounds are not included:

[0035]

[0036] Preferably, R 1b and / or R 2b is H; and / or m and n are each independently selected from 0, 1; and / or R5 is H; also preferably, R3 is phenyl, naphthyl, biphenyl, phenyl substituted by a heteroaromatic ring or a heteroaromatic ring substituted by a second heteroaromatic ring, wherein each phenyl, naphthyl or heteroaromatic ring is optionally substituted by one or more substituents, each of which is independently selected from halogen, hydroxyl, cyano, B(OH)2, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, N(CH3)2, morpholine or pyrrolidine.

[0037] Likewise preferably, R4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)phenyl, phenyl, 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.

[0038] Preferably, in the compounds defined above, m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 alkyl.

[0039] In other preferred embodiments, in the compounds of the present invention:

[0040] i. R3 is selected from:

[0041] a) phenyl substituted by a 5- or 6-membered heteroaromatic ring, preferably selected from the group consisting of pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or

[0042] b) a 5- or 6-membered heteroaromatic ring, preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each of said 5- or 6-membered heteroaromatic rings being substituted by phenyl, isoindoline or by a 5- or 6-membered heteroaromatic ring preferably selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine;

[0043] wherein in a) or b), each of the phenyl, 5- or 6-membered heteroaromatic rings is optionally substituted by one or more substituents independently selected from: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, CF3, C 5-6 Heterocycloalkyl, O-(CH2)2NH2, O-(CH2)2OH, hydroxyl, halogen; and / or

[0044] ii. R4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 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, phenyl, 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

[0045] iii.m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 alkyl.

[0046] In other preferred embodiments, the present invention relates to compounds having the general formula (III):

[0047]

[0048] Or having the general formula (IV):

[0049]

[0050] Or having the general formula (V):

[0051]

[0052] wherein R3, R5 and X each have the meanings as defined above.

[0053] Preferably, in the compound of formula (I) or the compound of formula (III), (IV) or (V), R3 is selected from the following structures:

[0054]

[0055] wherein each phenyl or heteroaromatic ring may be optionally further substituted by one or two substituents independently selected from methyl, CF3, halogen, cyclopropyl, methoxy, cyano.

[0056] Also preferably, in the compound having the general formula (I) or the compound having the general formula (III), R4 is selected from the following structures:

[0057]

[0058] In other preferred embodiments, R3 is:

[0059]

[0060] And R4 is:

[0061]

[0062] Preferably, the compound of the present invention is any one of the following compounds:

[0063] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl)carbamoyl)amide;

[0064] -(naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0065] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide;

[0066] -(3-benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0067] -(3-phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0068] -((3-chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0069] -(3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0070] -(3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0071] -((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0072] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide;

[0073] -(R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0074] -(S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0075] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0076] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide;

[0077] -(3-([1,1′-biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0078] -(3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0079] -(3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0080] -(3-(4-(thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0081] -(3-((2'-methyl-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0082] -(3-(4-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0083] -(3-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0084] -(3-benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0085] -(3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0086] -(3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0087] -(3-([1,1′-biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0088] -(3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0089] -(3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0090] -(R)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0091] -(S)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0092] -(R)-(3-(1-hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0093] -((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0094] -((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0095] -(3-(1-phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0096] -(3-(3-phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0097] -(S)-(3-(1-fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0098] -(3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0099] -(3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0100] -(S)-(3-(1-phenyl-3-(pyrrolidin-1-yl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0101] -(3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0102] -(3-(4-(pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0103] -(3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0104] -(R)-(3-(1-hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0105] -(3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0106] -(3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0107] -(3-(4-(isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0108] -(R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0109] -(3-(3-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0110] -(3-(3-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0111] -(3-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0112] -(3-(3-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0113] -(S)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0114] -(3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0115] -(3-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0116] -(3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0117] -(3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0118] -(3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0119] -(3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0120] -(3-(4-(pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0121] -(3-(4-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0122] -(3-(4-(2-methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0123] -(3-(4-(2-hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0124] -(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;

[0125] -(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;

[0126] -(3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0127] -(R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0128] -(S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0129] -(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;

[0130] -(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;

[0131] -(R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0132] -(R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0133] -(S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0134] -(R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0135] -(S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0136] -(S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0137] -(3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0138] -(S)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0139] -((3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0140] -(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0141] -(R)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0142] -(3-(3-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0143] -(3-(3-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0144] -(3-(4-(4-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0145] -(3-(4-(3-methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0146] -(3-(3-methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0147] -(3-(4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0148] -(3-(4-(2-(2-hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0149] -(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0150] -(3-(4-(4-cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0151] -(3-(4-(2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0152] -(3-(4-(5-methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0153] -(3-(3-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0154] -(3-(4-(1,5-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0155] -(3-(4-(1,3-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0156] -((3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0157] -(3-(4-(1,4-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0158] -(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;

[0159] -(3-((5-(pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0160] -(3-(3-methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0161] -(R)-(3-(2-amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0162] -(3-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0163] -(3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0164] -(3-(4-(1,2-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0165] -(3-(4-(4-cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0166] -(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;

[0167] -(3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0168] -(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0169] -(3-((4-(4-methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0170] -(3-(4-(4-methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0171] -(3-(4-(4-(2-hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0172] -((3-chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0173] -((3-cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl);

[0174] -(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide;

[0175] -(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;

[0176] -(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;

[0177] -(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;

[0178] -(3-((5-(isoindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0179] -(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;

[0180] -(3-((5-(2-(aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0181] -(3-((5-boropyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0182] -(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;

[0183] -(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;

[0184] -(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;

[0185] -(3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0186] -(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;

[0187] -(3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0188] -(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;

[0189] -(3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0190] -(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0191] -((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0192] -(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;

[0193] -(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;

[0194] -(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;

[0195] -(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;

[0196] -(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;

[0197] -((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;

[0198] -(3-((2'-methyl-[3,3'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0199] -(3-((4'-methyl-[3,3'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0200] -(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;

[0201] -(3-((2'-methyl-[3,3'-bipyridin-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0202] -((3-cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0203] -((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;

[0204] -(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;

[0205] -(3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0206] -((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;

[0207] -((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;

[0208] -(3-((5-(4-cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0209] -(3-((4'-methyl-[3,3'-bipyridin-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0210] -(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;

[0211] -(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;

[0212] -(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;

[0213] -(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;

[0214] -(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;

[0215] -(3-((5-(4-cyclopropylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0216] -(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;

[0217] -((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;

[0218] -(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;

[0219] -(3-((2'-methoxy-4'-methyl-[3,3'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0220] -(3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0221] -(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;

[0222] -(3-((5-(4-methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0223] -(3-((3'-methyl-[3,4'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0224] -(3-((3'-fluoro-[3,4'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0225] -(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;

[0226] -(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;

[0227] -(3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0228] -((3-(difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0229] -(3-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0230] -(3-((3',5'-difluoro-[3,4'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0231] -(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;

[0232] -(3-((2'-chloro-[3,3'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0233] -(3-((6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0234] -(3-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0235] -(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;

[0236] -(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;

[0237] -((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;

[0238] -(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;

[0239] -(3-((5-(4-chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0240] -(3-((5-(4,6-dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0241] -(3-((5-(3,6-dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0242] -((3-cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide;

[0243] -(3-((4',6'-dimethyl-[5,5'-dipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0244] -(3-((6-(4,6-dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0245] -(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide;

[0246] -(3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide;

[0247] -(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide;

[0248] -(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;

[0249] -(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;

[0250] -(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;

[0251] -(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.

[0252] Preferably, the compound is an inhibitor of the NS2B-NS3 protease of flavivirus, preferably an inhibitor of the NS2B-NS3 protease of Zika virus and / or dengue virus and / or West Nile virus and / or Japanese encephalitis virus, thereby inhibiting the replication of the above viruses in cells.

[0253] Another object of the present invention is to provide a compound as defined above for use in medicine, preferably for the treatment and / or prevention of flavivirus infection, preferably, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0254] Another object of the present invention is the compound of general formula (I):

[0255]

[0256] wherein m and n are each independently selected from 0, 1 and 2;

[0257] R 1a and R 1b independently selected from H and C optionally substituted with one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl) 2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine;

[0258] or R 1a and R 1b connected together to form C 3-6 -cycloalkyl ring or C 4-6 -heterocycloalkyl ring;

[0259] or R 1a connected to R3 to form a partially unsaturated aromatic or heteroaromatic bicyclic ring;

[0260] or R 1b Does not exist and CR 1a is C=CH2;

[0261] R 2a and R 2b independently selected from H and C optionally substituted with one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl) 2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine;

[0262] or R 2a and R 2b connected together to form C 3-6 -cycloalkyl ring or C 4-6 -heterocycloalkyl ring;

[0263] or R1a and R 2a or R 1b and R 2b Any two of them are connected together to form C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl;

[0264] R3 is a heterocycloalkyl, aromatic or heteroaromatic ring, each of which is optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from halogen, hydroxy, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyano, B (OH) 2, aryl, heteroaryl, wherein the aryl or heteroaryl ring is optionally substituted with one or more substituents, wherein the one or more substituents are each independently selected from 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, NHCOCH3, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 alkyl)2, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine substituted;

[0265] R4 is an aromatic or heteroaromatic ring optionally substituted by one or more substituents, each of which is independently selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 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;

[0266] R5 is H, C 1-6 Alkyl, C 1-6 haloalkyl or halogen;

[0267] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof for use in treating flavivirus infection, preferably, wherein the flavivirus is selected from the following group: dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0268] Preferably:

[0269] -R 1b and R 2b is H; m and n are each independently selected from 0, 1; more preferably, m is 1 and n is 1; also preferably, m is 1 and n is 0; and / or

[0270] -R3 is phenyl, naphthyl, biphenyl, phenyl-heteroaryl or bis-heteroaryl, wherein each phenyl, naphthyl or heteroaryl ring is optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, cyano, B(OH)2, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with one or more halogen, hydroxy, NH2, N(CH3)2, morpholine or pyrrolidine; and / or

[0271] -R4 is selected from 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)phenyl 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.

[0272] Preferably, in the compounds used as described above, m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 alkyl.

[0273] More preferably:

[0274] i. R3 is selected from:

[0275] c) phenyl substituted by a 5- or 6-membered heteroaromatic ring, preferably selected from the group consisting of pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or

[0276] d) a 5- or 6-membered heteroaromatic ring, preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each of said 5- or 6-membered heteroaromatic rings being substituted by phenyl, isoindoline or by a 5- or 6-membered heteroaromatic ring preferably selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine;

[0277] wherein in a) or b), each of the phenyl groups, 5- or 6-membered heteroaromatic rings is optionally substituted by one or more substituents independently selected from the group consisting of: 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, CF3, C 5-6 Heterocycloalkyl, O-(CH2)2NH2, O-(CH2)2OH, hydroxy, halogen; and

[0278] ii. R4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 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; and

[0279] iii.m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 alkyl.

[0280] Also preferably, the compound is used to treat flavivirus infection, preferably, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus, and the compound is selected from the group consisting of:

[0281] -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide;

[0282] -(3-phenylethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0283] Another object of the invention is a pharmaceutical composition comprising a compound as defined above and at least one pharmaceutically acceptable excipient.

[0284] Preferably, the pharmaceutical composition is for treating and / or preventing flavivirus infection, preferably, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

[0285] In a preferred embodiment, the pharmaceutical composition comprises at least one additional active compound selected from the group consisting of antiviral agents, antibacterial agents, anti-inflammatory agents, anti-analgesics and antipyretics.

[0286] Another object of the present invention is a process for the synthesis of the compounds of general formula (I) as defined above.

[0287] The present invention includes within its scope prodrugs of compounds of formula (I). Typically, such prodrugs will be functional derivatives of compounds of formula (I) that are readily converted into the desired compound of formula (I) in vivo. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0288] Prodrugs can be pharmacologically inert derivatives of biologically active substances ("parent drugs" or "parent molecules") that require conversion in vivo to release the active drug and have improved delivery properties compared to the parent drug molecule. The in vivo conversion can be, for example, the result of certain metabolic processes, such as chemical or enzymatic hydrolysis of carboxylic acids, phosphates or sulfates, or reduction or oxidation of sensory groups.

[0289] The present invention includes within its scope solvates, such as hydrates, of the compounds of formula (I) and salts thereof.

[0290] 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, pp. 1119-1190), and exist as racemates, racemic mixtures, and individual diastereomers, all possible isomers and mixtures thereof, including optical isomers, all of which are included in the present invention. In addition, the compounds disclosed herein may exist as tautomers, and all tautomeric forms are intended to be encompassed within the scope of the present invention, even if only one tautomeric structure is depicted. Specific tautomeric forms of the compounds of the present invention are shown below:

[0291]

[0292] The compounds may exist in different isomeric forms, all of which are encompassed by the present invention.

[0293] When any variable occurs multiple times in any constituent, its definition on each occurrence is independent at every other occurrence. Further, combinations of substituents and variables are permissible only if such combinations result in stable compounds.

[0294] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by persons of ordinary skill in the art to provide chemically stable and easily synthesized compounds from readily available starting materials by techniques known in the art and those described below. If the substituent itself is substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure can be formed. The phrase "optionally substituted" should be considered equivalent to the phrase "not substituted or substituted with one or more substituents", in which case preferred embodiments will have zero to three substituents. More specifically, there are 0-2 substituents. The substituents on saturated, partially saturated or unsaturated heterocycles can be attached to any substitutable position.

[0295] As used herein, "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc. The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C1-C6 alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc. 3-10"Cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc. In an embodiment of the present invention, "cycloalkyl" includes the above groups and further includes a monocyclic unsaturated aliphatic hydrocarbon group. For example, the "C 3-10 "Cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Preferably, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0296] "Alkoxy" refers to an alkyl group with the indicated number of carbon atoms attached through an oxygen bridge. Thus, "alkoxy" encompasses the above definition of alkyl. Examples of suitable alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy. A preferred alkoxy group is methoxy.

[0297] The term "halogenated C 1-6 Alkyl" and "halogenated C 1-6 "Alkoxy" refers to a C group in which one or more (specifically 1 to 3) hydrogen atoms have been replaced by halogen atoms (especially fluorine or chlorine atoms). 1-6 Alkyl or C 1-6 Alkoxy. Preferably fluorinated C 1-6 Alkyl and fluorinated C 1-6 Alkoxy, specifically fluorinated C 1-3 Alkyl and fluorinated C 1-3 Alkoxy, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF 3， and more particularly CF3, OCF3 and OCHF2.

[0298] The term "hydroxy C 1-6 "Alkyl" refers to a C group in which one or more (specifically 1 to 3) hydrogen atoms are replaced by hydroxy groups. 1-6 Alkyl groups are preferably CH2OH, CH2CHOH and CHOHCH3.

[0299] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms in which at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, and tetrahydrobenzo[7]annulene. Preferred aryl groups are phenyl or naphthyl, particularly phenyl.

[0300] 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. Specifically, the term heteroaryl includes a 5-membered aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, but not more than one of which is O or S; a 6-membered aromatic heterocyclic ring containing 1, 2, or 3 nitrogen atoms; or a 7- to 13-membered aromatic heterocyclic ring containing 5 to 10 heteroatoms independently selected from N, O, or S, wherein at least one ring is aromatic. Heteroaryl rings also include partially saturated bicyclic ring systems such as indoline, isoindoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine; and further include tautomeric structures such as hydroxypyrimidine and hydroxypyrimidinone.

[0301] Examples of specific heteroaryl groups of the present invention are benzimidazolyl, benzofurandiacyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzodioxazolyl, benzisoxazolyl, benzisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furanyl, furazanyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthpyridinyl, ]-one, and N-oxides thereof. Attachment of the heterocyclic substituents may be via a carbon atom or a heteroatom.

[0302] Biphenyl represents a benzene ring substituted by another benzene ring; phenyl-heteroaryl represents a benzene ring substituted by a heteroaromatic ring; and biheteroaryl represents a heteroaryl group substituted by another heteroaromatic ring.

[0303] The term "heterocycle" refers to a non-aromatic ring group consisting of carbon atoms and at least one nitrogen, phosphorus, oxygen or sulfur heteroatom. The heterocycle can be a mono-, bi-, tri- or tetracyclic ring system, which can include fused rings, bridged rings or spiro ring systems. The nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic group can optionally be oxidized to various oxidation states. In addition, the nitrogen atom can optionally be quaternized.

[0304] Examples of specific heterocycles of the present invention are tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, pyranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydroimidazoline Attachment of the heterocyclyl substituents may be through a carbon atom or a heteroatom.

[0305] A preferred 4-membered saturated heterocycle is azetidine.

[0306] A preferred 5-membered saturated heterocyclic ring is tetrahydrofuran.

[0307] Preferred 6-membered saturated or partially saturated heterocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and thiazolidinyl.

[0308] Preferred 5-membered heteroaryl groups are thienyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl, oxazolyl, triazolyl, tetrazolyl, furyl and oxadiazolyl.

[0309] Preferred 6-membered heteroaryl groups are pyridinyl and pyrimidinyl.

[0310] Preferred 8- to 10-membered heteroaryl groups are benzothiophenyl, indolyl, benzothiadiazolyl, benzodioxazolyl, thiazolotriazolyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, benzotriazolyl, dihydroisoindolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl, and tetrahydroquinolinyl.

[0311] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0312] Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or with an excess of an inorganic or organic acid that forms the desired salt in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0313] Therefore, the 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 alkaline instant compounds with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from 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, and the like. Preferably, the pharmaceutically acceptable salts of the present invention comprise one equivalent of the compound of formula (I) and 1, 2, or 3 equivalents of an inorganic or organic acid. More specifically, the pharmaceutically acceptable salt of the present invention is a tartrate, trifluoroacetate or chloride salt.

[0314] 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, iron, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N 1 -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0315] The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66: 1-19.

[0316] It should also be noted that the compounds of the present invention are potentially inner salts or zwitterions because under physiological conditions, deprotonated acidic moieties in the compounds, such as carboxyl groups, may be anionic, and this charge may be internally balanced by the cationic charge of protonated or alkylated basic moieties, such as quaternary nitrogen atoms.

[0317] The compounds of the present invention are useful in a variety of applications in human and animal health.The compounds of the present invention are flavivirus inhibitors and are useful in treating and / or preventing flavivirus infections.

[0318] According to standard pharmaceutical practice, the compounds of the present invention can be administered to mammals, preferably humans, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0319] The present invention also provides pharmaceutical compositions 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, such as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and may include one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically superior and palatable formulations. Tablets contain a mixture of the active ingredient and a pharmaceutically acceptable nontoxic excipient suitable for the preparation of tablets. These excipients may be, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrants (such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid); binders (such as starch, gelatin, polyvinyl pyrrolidone or gum arabic); and lubricants (such as magnesium stearate, stearic acid or talc). Tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, water-soluble taste-masking materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or time-delay materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0320] Preparations for oral use can also be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (for example, 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 (for example, peanut oil, liquid paraffin or olive oil).

[0321] Aqueous suspensions contain a mixture of the active material and excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (for example, ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (such as sucrose, saccharin or aspartame).

[0322] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil such as liquid paraffin. Oily suspensions can contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those shown above) and flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0323] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient, which is mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are listed by those mentioned above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0324] Pharmaceutical composition of the present invention can also be the form of water-in-oil emulsion.The oil phase can be vegetable oil (for example olive oil or peanut oil), or mineral oil (for example liquid paraffin), or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide, for example soybean lecithin, and ester or partial ester derived from fatty acid and hexitol anhydride, for example sorbitan monooleate, and the condensation product of described partial ester and ethylene oxide, for example polyoxyethylene sorbitan monooleate.Emulsion can also contain sweetener, flavoring, preservative and antioxidant.

[0325] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents and an antioxidant.

[0326] The pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.

[0327] Sterile injectable formulations can also be sterile injectable oil-in-water microemulsions, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can first be dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion can be introduced into the patient's bloodstream by local bolus injection.

[0328] Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. Such suspensions can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents, as described above. Sterile injectable formulations can also be sterile injectable solutions or suspensions formulated in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Sterile, fixed oils are often used as solvents or suspending media. For this purpose, various low-irritation fixed oils can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, are also used in the preparation of injectables.

[0329] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. These materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0330] For topical use, use cream, ointment, jelly, solution or suspension etc. containing compound of the present invention.Compound of the present invention can be given with intranasal form by topical use suitable intranasal carrier and delivery device, or use the transdermal skin patch of those forms known to those of ordinary skill in the art to give by transdermal route.In order to give with the form of transdermal delivery system, in whole dosage regimen, dosage administration will certainly be continuous rather than discontinuous.Compound of the present invention can also use matrix (such as cocoa butter, glycerine gelatin, hydrogenated vegetable oil, the mixture of the polyethylene glycol of various molecular weight and the fatty acid ester of polyethylene glycol) to deliver with suppository form.

[0331] When the compounds of the invention are administered to human subjects, the daily dosage regimen will generally be determined by the prescribing physician and will generally vary according to the age, weight, sex, and response of the individual patient and the severity of the patient's symptoms.

[0332] The compounds of the present invention may also be combined with known therapeutic agents for simultaneous, separate or sequential administration.

[0333] With reference to a compound of the invention, the term "administration" and variations thereof (e.g., "administering" a compound) means introducing the compound or a prodrug of the compound into the system of a subject in need of treatment. When a compound of the 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 simultaneous or sequential introduction of the compound or its prodrug and the other agent.

[0334] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0335] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a human researcher, veterinarian, medical doctor or other clinician.

[0336] When the compounds of the present invention are administered to human subjects, 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 and the severity of the patient's symptoms. In an exemplary application, the oral dosage range of the present invention is from about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, preferably from 0.01 to 10 mg / kg / day, and most preferably from 0.1 to 5.0 mg / kg / day.

[0337] Another object of the present invention is to provide a method for treating, ameliorating or preventing flavivirus infection and related conditions, preferably, wherein the flavivirus is selected from the following group: dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus, the method comprising administering to the subject a therapeutically effective amount of a compound as defined above.

[0338] These and other aspects of the invention will be apparent from the teachings contained herein.

[0339] chemical composition

[0340] Overview

[0341] The compounds, or pharmaceutically acceptable salts thereof, compositions, and methods described herein are further illustrated by the following non-limiting examples.

[0342] As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0343] 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)acyl]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: tetrabutylammonium bromide; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra performance liquid chromatography.

[0344] Overview of experimental details

[0345] Solvents and reagents were obtained from commercial suppliers and used without further purification. Purification was performed on silica gel chromatography on prepacked columns on a Biotage system. A Waters Acquity UPLC equipped with a diode array and a ZQ mass spectrometer was used. TM UPLC-MS analysis was performed on an X-Terra C18 column (5 μm, 4.6 x 50 mm) or a BEH C18 column (1.7 μm, 2.1 x 50 mm). The mobile phase consisted of a linear gradient with a binary mixture of 0.1% formic acid in H2O (A) and 0.1% formic acid in MeCN (B). 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. Spectrophotometry was performed on a 400 MHz Bruker spectrometer at 400, 377, and 101 MHz. 1 H. 19 F. 13C NMR spectra. Chemical shifts (δ) are expressed in parts per million downfield from tetramethylsilane using CDCl3 as solvent, unless otherwise stated. Coupling constants (J) are expressed in Hertz (Hz). Multiplicities are expressed as singlet (s), broad (br), doublet (d), doublet of doublets (dd), doublet of doublets (ddd), triplet (t), doublet of triplets (dt), or multiplet (m). Spectra were acquired at 300 K unless otherwise stated. Temperatures are expressed in degrees Celsius (°C) and are uncorrected. Reported yields are actual isolated yields of purified material 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 determined on a Waters Acquity UPLC equipped with a diode array and a ZQ mass spectrometer, a BEH C18 column (1.7 μm, 2.1 x 50 mm). TM The mobile phase contained a linear gradient with a binary mixture of H2O containing 0.1% formic acid (A) and MeCN containing 0.1% formic acid (B). 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) with a flow rate of 0.5 mL / min. 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 determined on a Waters Acquity UPLC equipped with a diode array and a ZQ mass spectrometer, using a BEH C18 column (1.7 μm, 2.1 x 50 mm). TMThe mobile phase contained a linear gradient with a binary mixture of HO (A) containing 0.05% TFA 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) with a flow rate of 0.5 mL / min. Run time: 3 min. Unless otherwise stated, commercially available reagents and solvents (HPLC grade) were used without further purification. If 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 synthetic sequence described herein, it may be necessary and / or desirable to protect sensitive or reactive groups or any molecules involved, which can be achieved by means of conventional protecting groups such as those described in Protecting Groups in Organic Synthesis (3rd ed., Greene, TW and Wuts, PGM; Wiley Interscience, 1999) and Protecting Groups (Kocienski, PJ; Thieme, 1994).

[0346] Example 1: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) Carbamoyl)amide

[0347]

[0348] Solution 1

[0349] Step 1: 1-Phenylpropan-2-amine (Intermediate 1).

[0350] Ammonium formate (24.44g, 387.54mmol) is dissolved in a mixture of water (9mL) and methanol (80mL), and the solution is processed with 1-phenylpropan-2-one (4.95mL, 37.26mmol) and Pd / C (10%w / w) (1.19g, 11.18mmol). The mixture is stirred at room temperature for 16h, then filtered through a diatomaceous earth pad and washed with methanol. The filtrate is evaporated under reduced pressure to obtain a white powder, which is suspended in EtOAc (150mL), and stirred at room temperature for 1h. The solid formed by filtration is separated to obtain the required product (4.2g) of salt form. The product separated by filtration is dissolved in methanol (1.5mL) and loaded into SCX posts (5g). Resin is washed with methanol, then washed with the 2M NH3 solution in methanol. After removing the solvent under reduced pressure, the title compound is obtained as a white powder (350mg, 58%). 1H NMR (400MHz, DMSO-d6) δ7.30-7.26 (m, 2H), 7.20-7.17 (m, 3H), 3.03-2.96 (m, 1H), 2.55-2.48 (m, 2H), 0.95 (d, J = 4.0Hz, 3H). C9H 13 LCMS (ES) of N + ) m / z calculated value 135.10, (M+H) + Found 136. HPLC t R 0.59 minutes.

[0351] Step 2: 2-((1-Phenylpropan-2-yl)amino)acetonitrile (Intermediate 2).

[0352] A suspension of DIPEA (3.44 mL, 19.42 mmol) and 1-phenylpropan-2-amine (intermediate 1) (1.31 g, 9.71 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 x 50 mL). The collected organic matter was washed with salt water, dried over Na SO and evaporated under reduced pressure to obtain the title compound as a colorless oil (1.45 g, 86%). 1 H NMR (400MHz, DMSO-d6) δ7.32-7.28(m,2H),7.22-7.18(m,3H),3.73-3.61(m,2H),2.95-2. 90(m,1H),2.77(dd,J1=4.0Hz,J2=12.0Hz,1H),2.46-2.41(m,2H),0.92(d,J=4.0Hz,3H). C 11 H 14 LCMS (ES) of N2 + ) m / z calculated value 174.12, (M+H) + Found 175. HPLC t R 0.81 minutes.

[0353] Step 3: 5-amino-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 3).

[0354] 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. 4N HCl in dioxane (13.1 mL, 52.23 mmol) was then added and the reaction mixture was stirred at room temperature for 18 h. Diethyl ether was added to the mixture, and the formed precipitate was collected by filtration and washed with diethyl ether to give the title compound as a white powder (1.39 g, 82%). 1 HNMR (400MHz, DMSO-d6) δ9.71 (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 = 4.0Hz, 3H). C 11 H 14 N3O + LCMS (ES + ) m / z calculated value 204.11, (M+H) + Found 204. HPLC t R 0.84 minutes.

[0355] Step 4: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 1)

[0356] 3-(Trifluoromethyl)benzoic acid (277.6mg, 1.46mmol) solution in toluene (1.7mL, 0.016mol) is treated with TEA (0.22mL, 1.61mmol) and DPPA (0.35mL, 1.61mmol). The mixture is heated at 70°C for 1h, then intermediate 3 (175mg, 0.730mmol) is added, and the mixture is stirred at 80°C for 2h. The mixture is cooled to room temperature, 1N NaHCO (aqueous solution) is quenched, and extracted with EtOAc. The organic phase merged is washed with water and salt water, through NaSODrying and evaporated under reduced pressure. The gained residue is ground with petroleum ether to obtain the title compound, and it is light yellow solid (258mg, 87%). 1HNMR(400MHz,DMSO-d6)δ9.65(s,1H),8.32(s,1H),8.27(br s,1H),7.68(br d,J=8.0Hz,1H),7.43(t,J=8.0Hz,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=8.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,1F). C 19 H 17 F3N4O2(ES + ) m / z calculated value 390.13, (M+H) + Found 391. HPLC t R 2.0 minutes.

[0357] Examples 5, 12, 18 and 33 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 1).

[0358] Example 5: (3-phenylethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0359] Reaction with 2-phenylethan-1-amine in step 2 afforded the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.25(br s,1H),8.24(br s,1H),7.72(br d,J=8.3Hz,1H),7.44(t,J=8.0Hz,1H),7.35-7.22(m,6H),4.82(t,J=7.1Hz,2H),3.32(t,J=7.1Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,1F). C 18 H 15 F3N4O2(ES + ) m / z calculated value 376.11; (M+H) + Found 377. HPLC t R 1.90 minutes.

[0360] Example 12: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide.

[0361] Reaction with quinoline-6-carboxylic acid in step 4 afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 8.87 (d, J = 3.5Hz, 1H), 8.53-8.51 (br m,2H),8.31(s,1H),7.99(brs,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=6.6Hz,3H). C 21 H 19 LCMS (ES) of N5O2 + ) m / z calculated value 373.15, (M+H) + Found 374. HPLC t R 1.24 minutes.

[0362] Example 18: (3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0363] In step 4, reaction with 5-amino-3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium chloride affords the title compound as a white powder. 1 H NMR (400MHz, DMSO-d6) δ9.63 (br s, 1H), 8.17 (s, 1H), 8.10 (d, J = 15.5Hz, 2H), 7.96-7.90 (m, 3H), 7.64 (br d,J=8.3Hz,1H),7.58(dd,J1=8.6Hz,J2=1.8Hz,1H),7.53-7.50(m,2H),7.37-7.33(m,1H),7.14(d,J=7.7Hz,1H),5.89(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,1F). C 21 H 15 LCMS (ES) of F3N4O2 + ) m / z calculated value 412.11, (MH) - Found 411. HPLC t R 2.06 minutes.

[0364] Example 33: ((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0365] Reaction with 3-methyl-5-(trifluoromethyl)benzoic acid in step 4 afforded the title compound as a white powder. 1 H NMR(400MHz,DMSO-d6)δ9.59(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=6.8Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.23(s,1F). C 20 H 19 F3N4O2 LCMS(ES + ) m / z calculated value 404.15, (M+H) + Found 405. HPLC t R 2.09 minutes.

[0366] (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)amino Formyl) amide (Example 13) and (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(tri (4-(2-fluoromethyl)phenyl)carbamoyl)amide (Example 14)

[0367]

[0368] Option 2

[0369] 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).

[0370] (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 subjected to SFC purification (column: Chiralpak IA (cellulose) - run 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 give (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) (first eluting compound) as a white powder (10.2 mg, 23%).13 C NMR (101MHz, DMSO-d6) δ172.6,159.0,141.9,136.0,129.4,128.8,128.5,127.0,125.7,123.0,121.3,117.2,113.6,102.8,62.8,40.5,19.3. C 19 H 17 F3N4O2 LCMS(ES + ) m / z calculated value 390.13, (M+H) + Found 391. HPLC t R 2.0 minutes, and (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14) (the second eluting compound) as a white powder (10.7 mg, 24%). 19 H 17 F3N4O2 LCMS(ES + ) m / z calculated value 390.13, (M+H) + Found 391. HPLC t R 2.0 minutes.

[0371] Example 3: (Naphthalene-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl) Amide

[0372]

[0373] Option 3

[0374] Step 1: 5-(1H-imidazole-1-carboxamido)-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 4)

[0375] 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 h. After concentration under reduced pressure, the crude title compound was obtained, which was used directly in the subsequent reaction. 15 H 16 LCMS (ES) of N5O2 + ) m / z calculated value 298.13, (M+H) + Found value 320. HPLC t R 1.06 minutes.

[0376] 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).

[0377] The crude intermediate 4 (417 mg, 1.25 mmol) solution 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 crude title compound was obtained as a yellow oil, which was used directly in subsequent reactions.

[0378] Step 3: (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide (Example 3)

[0379] Thick intermediate 5 (60 mg, 0.13 mmol) solution in chloroform (1 mL) was treated with DBU (0.04 mL, 0.25 mmol) and naphthalene-2-amine (18.1 mg, 0.13 mmol) in chloroform (1 mL) and the mixture was stirred at reflux overnight, and the solvent was evaporated under reduced pressure. Water (+0.1% TFA) and MeCN (+0.1% TFA) were used as eluents (C18 column) to obtain the title compound after automatic RP-HPLC purification. The fraction containing the product was lyophilized to obtain the title compound as a solid (28.4 mg, 60%). 1 HNMR(400MHz,DMSO-d6)δ9.56(br s,1H),8.35(s,1H),8.34(br s,1H),7.78-7.75(m,2H),7.70(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.42(t,J=8.0Hz,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=8.0Hz,3H). C 22 H 20 N4O2LCMS(ES + ) m / z calculated value 372.16, (M+H) + Found 373. HPLC t R 1.93 minutes.

[0380] Example 4 was synthesized according to the above procedure (Scheme 3) via reaction with appropriate starting materials.

[0381] Example 4: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide.

[0382] Reaction of 5-(trifluoromethyl)thiazol-2-amine in step 3 with intermediate 5 gave the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ11.78(br s,1H),8.46(s,1H),7.92(br d,J=1.3Hz,1H),7.32-7.20(m,5H),5.25-5.19(m,1H),3.36-3.30(m,2H),1.67(d,J=6.8Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-59.51(s,1F). C 16 H 14 F3N5O2LCMS(ES + ) m / z calculated value 397.08, (M+H) + Found 398. HPLC t R 1.91 minutes.

[0383] Example 6: (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) Amide

[0384]

[0385] Option 4

[0386] Step 1: 2-(Benzylamino)acetonitrile (Intermediate 6)

[0387] Starting from benzylamine, the title compound (1.01 mL, 9.3 mmol) was prepared using the procedure described for the synthesis of Intermediate 2. The crude product was purified by silica gel chromatography (eluting with 100% DCM) to give the title compound as a colorless oil (1.06 g, 78%). 1 HNMR (400MHz, DMSO-d6) δ7.36-7.32(m,4H),7.28-7.23(m,1H),3.76(d,J=8.0Hz,2H),3.58(d,J=8.0Hz,2H),3.04-2.98(m,1H). C9H 10 LCMS (ES) of N2 + ) m / z calculated value 146.08, (M+H) + Found 147. HPLC t R 0.98 minutes.

[0388] Step 2: 5-amino-3-benzyl-1,2,3-oxadiazol-3-ium chloride (Intermediate 7).

[0389] Starting from Intermediate 6, the title compound (877 mg, 6.0 mmol) was prepared using the procedure described for the synthesis of Intermediate 3. The title compound was obtained as a solid after filtration (786 mg, 62%). 1 H NMR (400MHz, DMSO-d6) δ9.84(br s,2H),8.15(br s,1H),7.57-7.45(br m,5H),5.91(br s,2H).

[0390] Step 3: (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 6)

[0391] A solution of 5-amino-3-benzyl-1,2,3-oxadiazole-3-chloridium (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 stirred for 18 h. After evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (eluted with 10-50% EtOAc in petroleum ether) to give the title compound (27.1 mg, 44%) as a solid. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.19(br s,2H),7.71(br d,J=8.0Hz,1H),7.58-7.56(m,2H),7.48-7.41(m,4H),7.21(br d,J=8.0Hz,1H),5.78(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 17 H 13 F3N4O2 LCMS(ES + ) m / z calculated value 362.10, (M+H) + Found 363. HPLC t R 1.87 minutes.

[0392] 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) via reaction with appropriate starting materials.

[0393] Example 2: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl)carbamoyl)amide.

[0394] Reaction of 1-isocyanato-4-(trifluoromethyl)benzene in step 3 with intermediate 3 gave the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.29(s,1H),7.82(d,J=8.8Hz,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 = 6.8Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-59.88(s,3F). C 19 H 17 F3N4O2 LCMS(ES + ) m / z calculated value 390.13, (M+H) + Found 391. HPLC t R 2.01 minutes.

[0395] Example 7: (3-phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0396] Reaction with 5-amino-3-phenyl-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.68(s,1H),8.29(s,1H),8.10(br d,J=8.1Hz,2H),7.80-7.71(m,4H),7.47(t,J=7.9Hz,1H),7.25(br d,J=7.5Hz,1H). 19 F NMR(377MHz,DMSO-d6)δ-61.25(s,3F). C 16 H 11 F3N4O2LCMS(ES + ) m / z calculated value 348.08, (M+H) + Found 349. HPLC t R 1.85 minutes.

[0397] Example 8: ((3-chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0398] Reaction with 1-chloro-3-isocyanatobenzene in step 3 afforded the title compound as a white solid. 1 HNMR (400MHz, DMSO-d6) δ9.54 (s, 1H), 8.30 (s, 1H), 7.88 (t, J = 2.0Hz, 1H), 7.45 (dd, J1 = 8.3Hz, J2 = 1.1Hz, 1H), 7. 32-7.21(m,6H),6.94(dd,J1=7.9Hz,J2=1.1Hz,1H),5.20-5.12(m,1H),3.33-3.28(m,2H),1.66(d,J=6.6Hz,3H). C 18 H 17 ClN4O2 LCMS(ES + ) m / z calculated value 356.10, (M+H) + Found 357. HPLC t R 1.92 minutes.

[0399] Example 9: (3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0400] Reaction with 5-amino-3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.37(s,1H),8.28(br s,1H),7.70(br d,J=8.1Hz,1H),7.60-7.57(m,2H),7.45(t,J=8.0Hz,1H),7.24-7.20(m,2H),5.23-5.15(m,1H),3.39-3.28(m,2H),1.64(d,J=6.6Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 19 H 15 Cl2F3N4O2(ES + ) m / z calculated value 458.05; (M+H) + Found 459. HPLC t R 2.22 minutes.

[0401] Example 10: (3-(2,3-Dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0402] Reaction with 5-amino-3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.18(s,1H),8.07(s,1H),7.72(br d,J=8.1Hz,1H),7.44(t,J=7.9Hz,1H),7.35-7.32(m,2H),7.28-7.21(m,3H),5.71-5 .65(m,1H),3.67(dd,J1=16.9Hz,J2=7.7Hz,2H),3.52(dd,J1=16.9Hz,J2=4.4Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.26(s,3F). C 19 H 15 F3N4O2(ES + ) m / z calculated value 388.11; (M+H) + Found 389. HPLC t R 1.96 minutes.

[0403] Example 11: ((3-Fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0404] Reaction of 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene in step 3 with intermediate 3 gave the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.36(s,1H),7.96(s,1H),7.71(brd,J=11.6Hz,1H),7.32-7.20(m,5H),7.12(br d,J=8.3Hz,1H),5.19-5.14(m,1H),3.33-3.29(m,2H),1.66(d,J=6.8Hz,3H). C 19 H 16 F4N4O2 LCMS(ES + ) m / z calculated value 408.12, (M+H) + Found 409. HPLC tR 2.11 minutes.

[0405] Example 19: (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0406] Reaction with 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.23(s,1H),8.21(s,1H),7.72(br d,J=8.3Hz,1H),7.68(br d,J=7.7Hz,2H),7.54(br d,J=8.1Hz,2H),7.44(br t,J=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.78(s,2H). 19 FNMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 17 H 12 BrF3N4O2 LCMS(ES + ) m / z calculated value 440.01, (M+H) + Found 441. HPLC t R 2.03 minutes.

[0407] Example 25: (3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0408] In step 3, reaction with 5-amino-3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium chloride afforded the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.24(br s,2H),7.69(br d,J=8.1Hz,1H),7.54-7.52(m,2H),7.48-7.41(m,4H),7.22(br d,J=7.7Hz,1H),2.02-1.99(m,2H),1.72-1.69(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 19 H 15 F3N4O2(ES + ) m / z calculated value 388.11; (M+H)+ Found 389. HPLC t R 2.03 minutes.

[0409] Example 27: (3-([1,1′-biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0410] Reaction with 3-([1,1'-biphenyl]-3-ylmethyl)-5-amino-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.63(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=4.8Hz,2H),7.43(t,J=7.6Hz,2H),7.37-7.31(m,2H),7.14(br d,J=7.7Hz,1H),5.77(s,2H). 19 F-NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 17 F3N4O2 LCMS(ES + ) m / z calculated value 438.13, (M+H) + Found 439. HPLCt R 2.20 minutes.

[0411] Example 28: (3-(2-Phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0412] Reaction with 5-amino-3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.23(s,1H),8.17(s,1H),7.71(br d,J=8.3Hz,1H),7.44(t,J=8.0Hz,1H),7.34-7.31(m,4H),7.26-7.21(m,2H),4.76(br d,J=8.1Hz,2H),3.58-3.53(m,1H),1.30(d,J=7.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C19 H 17 F3N4O2 LCMS(ES + ) m / z calculated value 390.13, (M+H) + Found 391. HPLC t R 2.01 minutes.

[0413] Example 29: (3-(Pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0414] Reaction with 5-amino-3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.80(s,1H),8.64(d,J=4.8Hz,1H),8.28(s,1H),8.20(s,1H),8.00(br d,J=7.9Hz,1H),7.71(br d,J=8.3Hz,1H),7.51-7.41(m,2H),7.21(br d,J=7.7Hz,1H),5.84(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.87(s,3F). C 16 H 12 F3N5O2 LCMS(ES + ) m / z calculated value 363.09, (M+H) + Found 364. HPLC t R 1.42 minutes.

[0415] Example 38: (3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0416] Reaction with 5-amino-3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.23(br s,1H),8.19(s,1H),7.69(br d,J=8.3Hz,1H),7.61(br d,J=6.2Hz,2H),7.50-7.41(m,4H),7.22(br d, J=7.5Hz, 1H), 6.16 (q, J=6.0Hz, 1H), 2.01 (d, J=7.2Hz, 3H).19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 18 H 15 LCMS (ES) of F3N4O2 + ) m / z calculated value 376.11, (MH) - Found 375. HPLC t R 1.95 minutes.

[0417] Example 46: (3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0418] Reaction with 5-amino-3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a light orange solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),8.27(s,1H),8.21(br s,1H),7.86(br s,1H),7.72(br d,J=8.3Hz,1H),7.67(br d,J=7.9Hz,1H),7.59(br d,J=7.9Hz,1H),7.43(br t,J=7.8Hz,2H),7.22(br d,J=7.7Hz,1H),5.78(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 17 H 12 BrF3N4O2LCMS(ES + ) m / z calculated value 440.01, (M+H) + Found 441. HPLC t R 2.07 minutes.

[0419] Example 47: (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0420] Reaction with 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.22(s,1H),8.21(br s,1H),7.84(br d,J=8.6Hz,2H),7.72(br d,J=8.8Hz,1H),7.44(t,J=8.0Hz,1H),7.38(d,J=8.3Hz,2H),7.22(br d,J=7.7Hz,1H),5.75(s,2H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 17 H 12 F3IN4O2 LCMS(ES + ) m / z calculated value 488.00, (M+H) + Found 489. HPLC t R 2.12 minutes.

[0421] Example 59: (3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0422] In step 3, reaction with 5-amino-3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium chloride afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.26(s,1H),8.25(br s,1H),7.69(br d,J=8.1Hz,1H),7.43(t,J=8.0Hz,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(377MHz,DMSO-d6)δ-61.27(s,3F). C 21 H 19 F3N4O2 LCMS(ES + ) m / z calculated value 416.15, (M+H) + Found 417. HPLC t R 2.15 minutes.

[0423] Example 68: (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0424] Reaction with (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in step 3 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.24(s,2H),7.70-7.67(m,3H),7.57(d,J=8.6Hz,2H ), 7.43 (t, J = 8.0Hz, 1H), 7.22 (d, J = 7.7Hz, 1H), 6.16 (q, J = 7.0Hz, 1H), 2.00-1.99 (m, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 18 H 14 LCMS (ES) of BrF3N4O2 + ) m / z calculated value 454.03, (MH) - Found 453. HPLC t R 2.13 minutes.

[0425] Example 69: (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0426] In step 3, reaction with (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.24(s,2H),7.70-7.67(m,3H),7.57(d,J=8.6Hz,2H ), 7.43 (t, J = 7.9Hz, 1H), 7.22 (d, J = 7.7Hz, 1H), 6.16 (q, J = 7.0Hz, 1H), 2.00-1.99 (m, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 18 H 14 LCMS (ES) of BrF3N4O2 + ) m / z calculated value 454.03, (MH) - Found 453. HPLC t R2.13 minutes.

[0427] Example 113: ((3-chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0428] The reaction of 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetic acid and 1-chloro-3-isocyanatobenzene in step 3 gave the title compound as a white solid. 1 HNMR (400MHz, DMSO-d6) δ9.58(s,1H),8.43(s,1H),8.21(s,1H),7.84(br t,J=2.0Hz,1H),7.69(d,J=8.1Hz,2H),7.53(d,J=8.3Hz,2H),7.46(br d,J=9.2Hz,1H),7.23(t,J=8.1Hz,1H),6.93(dd,J1=7.9Hz,J2=1.3Hz,1H),5.85(s,2H),3.94(s,3H),2.39(s,3H). C 22 H 19 LCMS (ES) of ClN6O3 + ) m / z calculated value 450.12, (MH) - Found 449. HPLC t R 1.85 minutes.

[0429] Example 114: ((3-cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0430] The reaction of 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetic acid and 3-isocyanatobenzonitrile in step 3 gave the title compound as a beige solid. 1 HNMR(400MHz,DMSO-d6)δ9.74(s,1H),8.43(s,1H),8.23(s,1H),8.12(br s,1H),7.81(br d,J=8.1Hz,1H),7.69(d,J=8.1Hz,2H),7.53(d,J=8.1Hz,2H),7.43(br t,J=8.0Hz,1H),7.34(d,J=7.7Hz,1H),5.87(s,2H),3.94(s,3H),2.39(s,3H). C23 H 19 LCMS(ES) of N7O3 + ) m / z calculated value 441.15, (M+H) + Found 442. HPLC t R 1.65 minutes.

[0431] Example 115: (3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide.

[0432] Reaction of 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetic acid and benzene isocyanate in step 3 afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.35(br s,1H),8.44(s,1H),8.17(s,1H),7.69(d,J=8.3Hz,2H),7.61(d,J=7.7Hz,2H),7.54(d,J=8.3Hz,2H),7.21(br t,J=7.9Hz,2H),6.90(t,J=7.3Hz,1H),5.85(s,2H),3.95(s,3H),2.40(s,3H). C 22 H 20 LCMS (ES) of N6O3 + ) m / z calculated value 416.16, (MH) - Found 415. HPLC t R 1.61 minutes.

[0433] Example 15: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyrrolidone) 1-(2-pyridin-3-yl)carbamoyl)amide.

[0434]

[0435] Option 5

[0436] TEA (0.23mL, 1.67mmol) and 5-(trifluoromethyl)pyridine-3-amine (135.3mg, 0.83mmol) suspension in THF (5.4mL) are processed with triphosgene (123.8mg, 0.42mmol).The reaction mixture is stirred at room temperature for 10 minutes.Ether (2mL) is added to the mixture, and the salt formed is filtered to obtain a clear solution of isocyanates in THF / ether stored in N2.Intermediate 3 (100mg, 0.420mmol) solution in THF is processed with sodium hydride (35mg, 1.04mmol, mineral oil 60%), and the mixture is stirred at room temperature for 15 minutes.After being added into the isocyanate solution in THF / ether, the reaction mixture is stirred for 6h.After the solvent is evaporated under reduced pressure, the residue is purified by silica gel chromatography (eluting with 1% MeOH in DCM) to obtain the title compound (28mg, 17%) as a light beige solid. 1 H NMR(400MHz,DMSO-d6)δ9.90(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=4.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.21(s,3F). C 18 H 16 F3N5O2(ES + ) m / z calculated value 391.13; (M+H) + Found 392. HPLC t R 1.59 minutes.

[0437] Examples 16, 34, 55, 73 and 76 were synthesized according to the above procedure (Scheme 5) via reaction with appropriate starting materials.

[0438] Example 16: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide.

[0439] Reaction with 4-(trifluoromethyl)pyridin-2-amine in step 1 afforded the title compound as a yellow solid. 18 H 16 F3N5O2(ES + ) m / z calculated value 391.13; (M+H) + Found 392. HPLC t R 1.89 minutes.

[0440] Example 34: ((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0441] Reaction with 3-methoxy-5-(trifluoromethyl)aniline in step 1 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.62(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 = 6.6Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.36(s,3F). C 20 H 19 F3N4O3 LCMS(ES + ) m / z calculated value 420.14, (M+H) + Found 421. HPLC t R 2.04 minutes.

[0442] Example 55: (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0443] Reaction with 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride in step 1 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.97(br s,1H),8.91(d,J=2.0Hz,1H),8.55(s,1H),8.48(s,1H),8.27(s,1H),7.84(d,J=8.3Hz,2H),7.38(d,J=8.6Hz,2H),5.77(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.21(s,3F). C 16 H 11 F3IN5O2 LCMS(ES + ) m / z calculated value 488.99, (M+H) + Found 490. HPLC t R 2.00 minutes.

[0444] Example 73: (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0445] Reaction with (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in step 1 gave the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.96(br s,1H),8.89(d,J=2.0Hz,1H),8.58(s,1H),8.47(s,1H),8.29(s,1H),7.68(d,J= 8.6Hz, 2H), 7.58 (d, J = 8.6Hz, 2H), 6.18 (q, J = 7.0Hz, 1H), 2.00 (d, J = 7.0Hz, 3H). 19 FNMR(377MHz,DMSO-d6)δ-61.22(s,3F). C 17 H 13 BrF3N5O2 LCMS(ES + ) m / z calculated value 455.02, (M+H) + Found 455. HPLC t R 1.91 minutes.

[0446] Example 76: (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0447] Reaction with (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in step 1 afforded the title compound as a light orange solid. 1 H NMR(400MHz,DMSO-d6)δ9.96(br s,1H),8.89(d,J=2.2Hz,1H),8.58(s,1H),8.47(s,1H),8.29(s,1H),7.68(d,J= 8.6Hz, 2H), 7.58 (d, J = 8.6Hz, 2H), 6.18 (q, J = 7.0Hz, 1H), 2.00 (d, J = 7.0Hz, 3H). 19 FNMR(377MHz,DMSO-d6)δ-61.21(s,3F). C 17 H 13 LCMS (ES) of BrF3N5O2 + ) m / z calculated value 455.02, (MH)- Found 454. HPLC t R 1.93 minutes.

[0448] Example 17: (3-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoro methyl)phenyl)carbamoyl)amide

[0449]

[0450] Option 6

[0451] Step 1: 2-(([1,1'-Biphenyl]-4-ylmethyl)amino)acetonitrile (Intermediate 8).

[0452] Starting from (4-phenylphenyl)methanamine (400 mg, 2.18 mmol), the title compound was prepared using the procedure described 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 (339 mg, 70%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.67-7.62(m,4H),7.48-7.41(m,4H),7.36(t,J=8.0Hz,1H),3.80(br s,2H),3.62(br d,J=4.0Hz,2H),3.08(br s,1H).

[0453] Step 2: 3-([1,1'-Biphenyl]-4-ylmethyl)-5-amino-1,2,3-oxadiazol-3-ium chloride (Intermediate 9).

[0454] Starting from Intermediate 8, the title compound (339 mg, 1.53 mmol) was prepared using the procedure described for the synthesis of Intermediate 3. The title compound was obtained after filtration as a white powder (258 mg, 67%). 1 H NMR(400MHz,DMSO-d6)δ9.73(br s,2H),8.16(s,1H),7.76(d,J=8.0Hz,2H),7.69-7.66(m,4H),7.48(t,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),5.96(s,2H).

[0455] Step 3: (3-([1,1'-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 17).

[0456] Starting from intermediate 9, the title compound (50 mg, 0.200 mmol) was prepared using the procedure described in Synthesis Example 1. After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The fractions containing the product were lyophilized to give the title compound as a white solid (30 mg, 35%). 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.77-7.66 (m, 7H), 7.50-7.37 (m, 4H), 7.22 (d, J = 8Hz, 1H), 5.83 (s, 2H). 19 F-NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 23 H 17 LCMS (ES) of F3N4O2 + ) m / z calculated value 438.13, (MH) - Found 437. HPLC t R 2.2 minutes.

[0457] Example 24: (3-Benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)amino Formyl)amide

[0458]

[0459] Option 7

[0460] The Example 6 (30 mg, 0.08 mmol) solution in chloroform (0.8 mL) was treated with Palau'Chlor (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 using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The fraction containing the product was lyophilized to obtain the title compound as a light yellow solid (16 mg, 49%). 1 H NMR (400MHz, DMSO-d6) δ9.78 (s, 1H), 8.15 (s, 1H), 7.80 (d, J = 8Hz, 1H), 7.48-7.43 (m, 6H), 7.24 (d, J = 8Hz, 1H), 5.83 (s, 2H). 19 FNMR(377MHz,DMSO-d6)δ-61.24(s,3F). C 17 H 12 ClF3N4O2 LCMS(ES +) m / z calculated value 396.06, (M+H) + Found 397. HPLC t R 1.91 minutes.

[0461] Example 26: (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide.

[0462]

[0463] Option 8

[0464] Pyrimidine-5-ylboronic acid (18.3 mg, 0.15 mmol) and disodium carbonate (36.0 mg, 0.34 mmol) in water (0.4 mL) and dioxane (2 mL), tetrakis (triphenylphosphine) palladium (0) (5.9 mg, 0.01 mmol), Example 19 (50 mg, 0.110 mmol) solution was heated to 80 ° C in a sealed tube for 2 h. After cooling, the mixture was filtered on a cellulose pad and the filtrate was evaporated under reduced pressure. Residue was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 columns). The fraction containing the product was lyophilized to obtain the title compound as a white solid (14 mg, 28%). 1 H NMR(400MHz,DMSO-d6)δ9.71(br s,1H),9.21(s,1H),9.17(s,2H),8.24(s,1H),8.20(s,1H),7.91(d,J=8Hz,2H),7.75( d,J=8Hz,2H),7.72-7.69(m,1H),7.43(t,J=8Hz,1H),7.21(d,J=8Hz,1H),5.86(s,2H). 13 C NMR(101MHz,DMSO-d6)δ172.6,159.0,157.5,154.9,141.8,134.9,132.8,1 32.5,130.1,129.5,129.1,127.7,125.7,121.3,117.3,113.7,104.5,55.5. 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 21 H 15 F3N6O2 LCMS(ES + ) m / z calculated value 440.12, (M+H) + Found 441. HPLC t R 1.62 minutes.

[0465] 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) via reaction with appropriate starting materials.

[0466] Example 20: (3-(4-(Thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3(trifluoromethyl)phenyl)carbamoyl)amide.

[0467] Reaction with thiophen-3-ylboronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.21(br s,2H),7.95(br s,1H),7.81(br d,J=7.7Hz,2H),7.72(br d,J=8.3Hz,1H),7.67-7.59(m,4H),7.43(t,J=7.9Hz,1H),7.22(br d,J=7.9Hz,1H),5.80(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 21 H 15 LCMS (ES) of F3N4O2S + ) m / z calculated value 444.09, (MH) - Found 443. HPLC t R 2.12 minutes.

[0468] Example 21: (3-((2'-Methyl-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0469] Reaction with o-tolylboronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.28(s,1H),8.22(br s,1H),7.73(br d,J=8.1Hz,1H),7.64(brd,J=7.7Hz,2H),7.44(br d,J=7.2Hz,3H),7.30-7.20(m,5H),5.84(s,2H),2.23(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 24 H 19 LCMS (ES) of F3N4O2+ ) m / z calculated value 452.15, (MH) - Found 451. HPLC t R 2.29 minutes.

[0470] Example 22: (3-(4-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0471] Reaction with pyridin-3-ylboronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.92(s,1H),8.60(br d,J=4.6Hz,1H),8.25(s,1H),8.21(br s,1H),8.11(br d,J=7.9Hz,1H),7.84(br d,J=7.7Hz,2H),7.72(br d,J=7.9Hz,3H),7.53-7.49(m,1H),7.44(br t,J=8.0Hz,1H),7.22(br d,J=7.7Hz,1H),5.85(s,2H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 16 LCMS (ES) of F3N5O2 + ) m / z calculated value 439.13, (MH) - Found 438. HPLC t R 1.45 minutes.

[0472] Example 23: (3-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0473] Reaction with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 afforded the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.19(br s,1H),8.17(br s,2H),7.89(br s,1H),7.71(br d,J=8.1Hz,1H),7.65-7.63(m,2H),7.56-7.54(m,2H),7.42(br t,J=8.0Hz,1H),7.21(br d,J=7.5Hz,1H),5.74(s,2H),3.86(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 442.14, (MH) - Found 441. HPLC t R 1.71 minutes.

[0474] Example 41: (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0475] Reaction with (2-methoxypyrimidin-5-yl)boronic acid in step 1 afforded the title compound as a white solid. 1 HNMR(400MHz,DMSO-d6)δ9.71(s,1H),8.97(s,2H),8.23(s,1H),8.21(br s,1H),7.83(br d,J=8.1Hz,2H),7.71(br d,J=8.1Hz,3H),7.44(br t,J=8.0Hz,1H),7.22(br d,J=7.7Hz,1H),5.84(s,2H),3.98(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 22 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 470.13, (MH) - Found 469. HPLC t R 1.82 minutes.

[0476] Example 48: (3-(4-(Isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0477] Reaction with isoxazol-4-ylboronic acid in step 1 afforded the title compound as a white solid. 1 HNMR(400MHz,DMSO-d6)δ9.73(s,1H),9.51(s,1H),9.21(s,1H),8.21(br s,2H),7.80(br d,J=8.3Hz,2H),7.71(br d,J=9.2Hz,1H),7.66(br d,J=8.3Hz,2H),7.43(br t,J=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.80(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 14 LCMS (ES) of F3N5O3 + ) m / z calculated value 429.10, (MH) - Found 428. HPLC t R 1.86 minutes.

[0478] Example 72: (R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0479] Reaction of (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Scheme 1) in Step 1 and pyrimidin-5-ylboronic acid gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.14(s,1H),9.10(s,2H),8.20(s,1H),8.17(br s,1H),7.85(br d,J=8.1Hz,2H),7.72(br d, J=8.1Hz, 2H), 7.61 (br d, J=8.6Hz, 1H), 7.36 (br t, J=7.9Hz, 1H), 7.15 (br d, J=7.5Hz, 1H), 6.17 (q, J=7.0Hz, 1H), 1.99 (br d, J=7.0Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH)- Found 453. HPLC t R 1.71 minutes.

[0480] Example 74: (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0481] Reaction of (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Scheme 1) in Step 1 and pyrimidin-5-ylboronic acid gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.14(s,1H),9.10(s,2H),8.20(s,1H),8.17(br s,1H),7.85(br d,J=8.6Hz,2H),7.72(br d, J=8.3Hz, 2H), 7.61 (br d, J=8.3Hz, 1H), 7.36 (br t, J=7.4Hz, 1H), 7.14 (br d, J=8.3Hz, 1H), 6.17 (q, J=7.2Hz, 1H), 1.99 (br d, J=7.0Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.71 minutes.

[0482] 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.

[0483] Reaction of (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide in Step 1 (prepared as described in Scheme 1) and pyrimidin-5-ylboronic acid gave the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.96(br s,1H),9.22(s,1H),9.18(s,2H),8.89(br d,J=2.0Hz,1H),8.58(br s,1H),8.47(br s,1H),8.32(s,1H),7.92(br d, J=8.3Hz, 2H), 7.79 (br d, J=8.3Hz, 2H), 6.27 (q, J=7.0Hz, 1H), 2.07 (br d, J=7.0Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.21(s,3F). C 21 H 16 F3N7O2 LCMS(ES + ) m / z calculated value 455.13; (M+H) + Found 456. HPLC t R 1.49 minutes.

[0484] 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.

[0485] Reaction of (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as described in Scheme 1) in Step 1 and pyrimidin-5-ylboronic acid gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.89(br s,1H),9.14(s,1H),9.10(s,2H),8.82(br d,J=2.0Hz,1H),8.50(br s,1H),8.40(br s,1H),8.25(s,1H),7.85(br d, J=8.3Hz, 2H), 7.72 (br d, J=8.3Hz, 2H), 6.19 (q, J=7.0Hz, 1H), 1.99 (br d, J=7.0Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.22(s,3F). C 21 H 16 F3N7O2 LCMS(ES + ) m / z calculated value 455.13; (M+H) + Found 456. HPLC t R 1.49 minutes.

[0486] Example 78: (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0487] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.28(s,1H),8.21(s,1H),7.72(br d,J=8.1Hz,1H),7.68(br d,J=8.1Hz,2H),7.50(br d,J=8.1Hz,2H),7.44(br t,J=8.0Hz,1H),7.22(d,J=7.9Hz,1H),5.83(s,2H),2.41(s,3H),2.24(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 22 H 18 F3N5O3 LCMS(ES + ) m / z calculated value 457.14; (M+H) + Found 458. HPLC t R 1.92 minutes.

[0488] Example 93: (3-(4-(5-methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0489] Reaction with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine in step 1 afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(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=8.1Hz,2H),7.44(br t,J=7.5Hz,1H),7.23(d,J=7.5Hz,1H),5.88(s,2H),2.33(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 22 H 17F3N6O2 LCMS(ES + ) m / z calculated value 454.14, (M+H) + Found 455. HPLC R 1.61 minutes.

[0490] 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.

[0491] Reaction with (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.31 (br s, 2H), 7.81 (br d, J = 8.6Hz, 1H), 7.69 (br d,J=6.4Hz,3H),7.58(d,J=8.1Hz,2H),7.53(t,J=7.9Hz,1H),7.31(br d,J=7.2Hz,1H),5.88(s,2H),3.88(s,3H),2.47(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 456.15; (MH) - Found 455. HPLC t R 1.81 minutes.

[0492] 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.

[0493] Reaction with (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.21(br s,2H),7.94(s,1H),7.72(br d,J=7.9Hz,1H),7.58(br d,J=8.1Hz,2H),7.51(br d,J=8.1Hz,2H),7.44(br t,J=8.1Hz,1H),7.22(d,J=7.5Hz,1H),5.77(s,2H),3.79(s,3H),2.30(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 19 F3N6O2 LCMS(ES + ) m / z calculated value 456.15; (M+H) + Found 455. HPLC t R 1.79 minutes.

[0494] Example 97: (Trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0495] Reaction with (1,3,5-trimethyl-1H-pyrazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.26(s,1H),8.21(br s,1H),7.72(br d,J=8.6Hz,1H),7.61(d,J=8.1Hz,2H),7.44(br t,J=7.9Hz,1H),7.35(d,J=7.9Hz,2H),7.22(d,J=7.7Hz,1H),5.80(s,2H),3.70(s,3H),2.22(s,3H),2.13(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 23 H 21 LCMS (ES) of F3N6O2 + ) m / z calculated value 470.17; (MH) - Found 469. HPLC t R 1.81 minutes.

[0496] Example 50: (3-(3-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide.

[0497]

[0498] Option 9

[0499] Starting from Example 46, the title compound was prepared using the procedure described for the synthesis of compound 26. The crude product was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The fractions containing the product were lyophilized to give the title compound as a white solid (18.4 mg, 37%). 1 HNMR(400MHz,DMSO-d6)δ9.73(brs,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=7.7Hz,1H),7.72-7.62(m,3H),7.43(t,J=8.0Hz,1H),7.22(d,J=7.7Hz,1H),5.85(s,2H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 15 LCMS (ES) of F3N6O2 + ) m / z calculated value 440.12; (MH) - Found 439. HPLC t R 1.68 minutes.

[0500] Examples 51, 52, 53 and 94 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 9).

[0501] Example 51: (3-(3-(Pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0502] Reaction with pyridin-3-ylboronic acid in step 1 afforded the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.96(br d,J=1.8Hz,1H),8.63(dd,J1=4.8Hz,J2=1.3Hz,1H),8.28(s,1H),8.21(br s,1H),8.17(br d,J=7.9Hz,1H),8.02(br s,1H),7.84(br d,J=7.0Hz,1H),7.71(br d,J=7.9Hz,1H),7.65-7.56(m,3H),7.43(t,J=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.85(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 16 LCMS (ES) of F3N5O2 + ) m / z calculated value 439.13, (MH) - Found 438. HPLC t R 1.54 minutes.

[0503] Example 52: (3-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0504] Reaction with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.72(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=8.3Hz,1H),7.64(d,J=7.7Hz,1H),7.46-7.37(m,3H),7.22(br d,J=7.7Hz,1H),5.76(s,2H),3.87(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 21 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 442.14; (MH) - Found 441. HPLC t R 1.77 minutes.

[0505] Example 53: (3-(3-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0506] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.97(s,2H),8.27(s,1H),8.21(br s,1H),8.00(s,1H),7.83(br d,J=6.4Hz,1H),7.71(d,J=8.1Hz,1H),7.62-7.60(m,2H),7.43(br t,J=7.9Hz,1H),7.22(br d,J=7.5Hz,1H),5.83(s,2H),3.98(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 470.13; (MH) - Found 469. HPLC t R 1.86 minutes.

[0507] Example 94: (3-(3-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0508] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid in step 1 afforded the title compound as a white solid (using K 2 CO 3 in a MeOH / dioxane mixture). 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.21(s,1H),8.13(br s,1H),7.64(br d,J=8.1Hz,1H),7.57(s,1H),7.51-7.49(m,2H),7.43-7.40(m,1H),7.36(br t,J=7.9Hz,1H),7.14(br d,J=7.7Hz,1H),5.76(s,2H),2.35(s,3H),2.18(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C22 H 18 LCMS (ES) of F3N5O3 + ) m / z calculated value 457.14; (MH) - Found 456. HPLC t R 1.96 minutes.

[0509] Example 57: (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) pyridin-3-yl)carbamoyl)amide

[0510]

[0511] Plan 10

[0512] Starting from Example 55, the title compound was prepared using the procedure described for the synthesis of Example 26. The title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The fractions containing the product were lyophilized to give the title compound as a white solid (13 mg, 31%). 1 H NMR(400MHz,DMSO-d6)δ9.90(br s,1H),9.15(s,1H),9.11(s,2H),8.83(d,J=2.2Hz,1H),8.48(s,1H),8.40(s ,1H),8.24(s,1H),7.85(d,J=8.1Hz,2H),7.68(d,J=8.3Hz,2H),5.81(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.22(s,3F). C 20 H 14 F3N7O2 LCMS(ES + ) m / z calculated value 441.12; (M+H) + Found 442. HPLC t R 1.41 minutes.

[0513] Examples 56, 58 and 67 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 10).

[0514] Example 56: (3-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0515] Reaction with 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.1 H NMR (400MHz, DMSO-d6) δ9.73(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=7.9Hz,1H),5.83(s,2H),3.58(br s,4H),3.50(br s,2H),2.37(br s,4H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 28 H 26 LCMS (ES) of F3N5O3 + ) m / z calculated value 537.20; (MH) - Found 536. HPLC t R 1.48 minutes.

[0516] Example 58: (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0517] The title compound was obtained by reacting (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as described in Synthesis Example 15) in Step 1 with (2-methoxypyrimidin-5-yl)boronic acid as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.89(br s,1H),8.90(s,2H),8.83(brd,J=1.8Hz,1H),8.48(br s,1H),8.40(br s,1H),8.22(s,1H),7.76(br d,J=8.3Hz,2H),7.64(br d,J=8.3Hz,2H),5.79(s,2H),3.90(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.22(s,3F). C 21 H 16 F3N7O3 LCMS(ES + ) m / z calculated value 471.13; (M+H) + Found 472. HPLC t R 1.58 minutes.

[0518] Example 67: (3-(4-(Pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0519] The title compound was obtained by reacting (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as described in Synthesis Example 15) in Step 1 with pyridin-4-ylboronic acid as a white solid. 21 H 15 LCMS (ES) of F3N6O2 + ) m / z calculated value 440.12; (MH) - Found 439. HPLC t R 1.07 minutes.

[0520] Example 60: (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(tri (fluoromethyl)phenyl)carbamoyl)amide

[0521]

[0522] Plan 11

[0523] 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).

[0524] A solution of Example 19 (390 mg, 0.88 mmol) in dioxane (25 mL) was treated with bis(chloroalkyl)palladiumcyclopentyl(diphenyl)phosphine ferrocene (32.8 mg, 0.04 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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, dried over Na2SO4 and evaporated under reduced pressure. The title compound was obtained after purification on reverse phase (C18) silica gel (eluted with 10-40% MeCN in H2O) as a yellow solid (361 mg, 33%). 1H NMR (400MHz, DMSO-d6) δ9.70 (br s, 1H), 8.18 (br s, 2H), 7.75 (d, J = 7.7Hz, 2H), 7.72 (br d,J=9.2Hz,1H),7.56(d,J=7.9Hz,2H),7.43(t,J=8.1Hz,1H),7.21(d,J=7.9Hz,1H),5.81(s,2H),1.29(s,12H). C 23 H 24 BF3N4O4 LCMS(ES + ) m / z calculated value 488.18; (M+H) + Found 489. HPLC t R 2.24 minutes.

[0525] Step 2: (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 60).

[0526] The title compound was prepared using intermediate 10 and 5-bromo-4-methylpyrimidine using the conditions described for the synthesis of Example 26. The title compound was obtained after purification via RP (C18) chromatography (eluting with 10-45% MeCN in H2O). The product-containing fractions were lyophilized to give the title compound as a white solid (16 mg, 34%). 1 H NMR(400MHz,DMSO-d6)δ9.73(br s,1H),9.05(s,1H),8.62(s,1H),8.29(s,1H),8.21(br s, 1H), 7.72 (d, J = 8.3Hz, 3H), 7.58 (d, J = 8.1Hz, 2H), 7.43 (t, J = 7.9Hz, 1H), 7.22 (d, J = 7.5Hz, 1H), 5.86 (s, 2H), 2.45 (s, 3H). 13 C NMR(101MHz,DMSO-d6)δ171.5,162.7,157.9,155.9,155.0,140.7,135.5,132.3,1 31.1,128.7,128.4,128.0,124.6,121.9,120.2,116.2,112.6,103.5,54.4,21.5. 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 F3N6O2 LCMS(ES +) m / z calculated value 454.14; (M+H) + Found 455. HPLC t R 1.66 minutes.

[0527] Examples 39, 42, 61, 62, 63, 64, 79, 105 and 106 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 11).

[0528] Example 39: (3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0529] Reaction with 4-bromopyridine in step 2 afforded the title compound as a white solid. 1 H NMR (400MHz, CDCl3) δ8.74(br s,2H),7.92(br s,1H),7.80(br s,1H),7.76(br d,J=8.1Hz,2H),7.59-7.52(m,5H),7.47(br s, 1H), 7.39 (t, J = 7.9Hz, 1H), 7.29 (br d, J = 8.1Hz, 1H), 5.57 (s, 2H). 19 F NMR (377MHz, CDCl3) δ-62.71 (s, 3F). C 22 H 16 LCMS (ES) of F3N5O2 + ) m / z calculated value 439.13; (MH) - Found 438. HPLC t R 1.35 minutes.

[0530] Example 42: (3-(4-(Pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0531] Reaction with 2-iodopyrazine in step 2 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.30(s,1H),8.75(s,1H),8.65(br d,J=2.4Hz,1H),8.26-8.21(m,4H),7.76-7.71(m,3H),7.44(t,J=7.9Hz,1H),7.22(br d,J=7.5Hz,1H),5.88(s,2H). 19FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 15 LCMS (ES) of F3N6O2 + ) m / z calculated value 440.12; (MH) - Found 439. HPLC t R 1.76 minutes.

[0532] Example 61: (3-(4-(pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0533] Reaction with 4-bromopyridazine in step 2 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 9.67 (s, 1H), 9.31 (br d, J = 5.5Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.06-8.02 (m, 3H), 7.78 (br d,J=8.1Hz,2H),7.72(br d,J=8.1Hz,1H),7.44(t,J=7.9Hz,1H),7.22(br d,J=7.9Hz,1H),5.88(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 15 LCMS (ES) of F3N6O2 + ) m / z calculated value 440.12; (MH) - Found 439. HPLC t R 1.54 minutes.

[0534] Example 62: (3-(4-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0535] Reaction with 5-bromo-4-methoxypyrimidine in step 2 afforded the title compound as a white solid. 1HNMR(400MHz,DMSO-d6)δ9.66(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=8.1Hz,1H),7.15(br d,J=7.7Hz,1H),5.77(s,2H),3.90(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 470.13; (MH) - Found 469. HPLC t R 1.79 minutes.

[0536] Example 63: (3-(4-(2-methylpyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0537] Reaction with 4-bromo-2-methoxypyridine in step 2 afforded the title compound as a pale yellow solid. 1 HNMR(400MHz,DMSO-d6)δ9.65(s,1H),8.18(s,1H),8.17(s,1H),8.14(br s,1H),7.80(br d,J=8.3Hz,2H),7.65-7.62(m,3H),7.36(br t,J=8.0Hz,1H),7.26(dd,J1=5.5Hz,J2=1.5Hz,1H),7.15(br d,J=7.7Hz,1H),7.07(s,1H),5.78(s,2H),3.83(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 18 LCMS (ES) of F3N5O3 + ) m / z calculated value 469.14; (MH) - Found 468. HPLC t R 1.98 minutes.

[0538] Example 64: (3-(4-(2-hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0539] Reaction with 4-bromopyridin-2-ol in step 2 afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.71(br s,1H),9.80(s,1H),8.33(s,1H),8.28(br s,1H),7.86(brd,J=7.9Hz,2H),7.82-7.74(m,3H),7.55-7.49(m,2H),7.30(br d,J=7.5Hz,1H),6.69(brs,1H),6.59(d,J=6.8Hz,1H),5.92(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 16 LCMS (ES) of F3N5O3 + ) m / z calculated value 455.12; (MH) - Found 454. HPLC t R 1.47 minutes.

[0540] 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.

[0541] The title compound is obtained by reacting 5-bromo-4-methylpyrimidine in step 2 with (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. 23 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 468.15; (MH) - Found 467. HPLC t R 1.75 minutes.

[0542] 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.

[0543] Reaction with 5-bromo-1,2-dimethyl-1H-imidazole in step 2 afforded the title compound as a beige solid. 1HNMR(400MHz,DMSO-d6)δ9.73(s,1H),8.25(s,1H),8.21(br s,1H),7.73-7.64(m,3H),7.52(br d,J=7.9Hz,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(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 456.15; (MH) - Found 455. HPLC t R 1.31 minutes.

[0544] Example 106: (3-(4-(4-cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0545] Reaction with 5-bromopyrimidine-4-carbonitrile in step 2 afforded the title compound as a beige solid. 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 14 F3N7O 22 LCMS (ES + ) m / z calculated value 465.12; (M+H) + Found 466. HPLC t R 1.84 minutes.

[0546] 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.

[0547]

[0548] Plan 12

[0549] Step 1: (R)-methyl 2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (Intermediate 11)

[0550] To (-)-4-hydroxy-D-phenylglycine (5g, 29.91mmol) suspension in methanol (30mL) is dropwise added thionyl chloride (2.17mL, 29.91mmol). The reaction mixture is refluxed and stirred for 18h, then cooled to room temperature and used directly. Then DIPEA (13mL, 59.8mmol) is dropwise added, followed by dropwise addition of di-tert-butyl carbonate (7.18g, 32.9mmol) solution in methanol (12mL) within 40 minutes. The reaction mixture is stirred at room temperature overnight. The solvent is reduced to half of the original volume, and the resulting solution is poured into water (100mL), forming a white precipitate, which is collected via filtration. The crude product is dried overnight under a vacuum pump to obtain the title compound as a white solid (7.15g, 85%). 1 H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.82(d,J=8.5Hz,2H),7.61(d,J=7.8Hz ,1H),6.71(d,J=8.4Hz,2H),5.06(d,J=7.8Hz,1H),3.59(s,3H),1.38(s,9H). C 14 H 19 LCMS (ES) of NO5 + ) m / z calculated value 281.13; (M+H) + Found 282. HPLC t R 1.62 minutes.

[0551] Step 2: (R)-tert-Butyl(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (Intermediate 12).

[0552] The intermediate 11 (1.2 g, 4.27 mmol) solution in anhydrous THF (30 mL) was cooled to 5 ° C. 1M lithium aluminum hydride in THF (12.8 mL, 12.8 mmol) was slowly added dropwise over 40 minutes to keep the internal reaction temperature below 15 ° C. Stirring was continued for 30 minutes, then quenched carefully with NH4Cl saturated solution (2 mL) over 45 minutes, and then with 0.3N HCl (2 mL) to quench the reaction. The resulting suspension was then filtered and rinsed with ethyl acetate, and 1N 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 MgSO4. In addition, the aqueous phase was extracted with EtOAc, and the organic phase was processed as before. The organic layers were combined and concentrated to obtain the title compound as a light yellow solid (927 mg, 95%). 1HNMR (300MHz, DMSO-d6) δ9.21 (s, 1H), 7.06 (m, 3H), 6.67 (d, J = 8.4Hz, 2H), 4.6 8(t,J=5.7Hz,1H), 4.41(q,J=7.2Hz,1H), 3.42(t,J=6.3Hz,2H), 1.36(s,9H). C 13 H 19 LCMS (ES) of NO4 + ) m / z calculated value 253.13; (M+H) + Found 254. HPLC t R 1.26 minutes.

[0553] Step 3: (R)-4-(4-Hydroxyphenyl)oxazolidin-2-one (Intermediate 13).

[0554] The intermediate 12 (927 mg, 3.66 mmol) solution in THF (11 mL) was cooled to 0 ° C and thionyl chloride (0.29 mL, 4.03 mmol) was added dropwise. After 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. The product began to crystallize. The slurry was stirred for 15 minutes and filtered. The filter cake was washed with MTBE (5 x 5 mL). The solid was dried to obtain the title compound as a reddish-brown powder (0.63 g, 95%). 1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),8.05(s,1H),7.12(d,J=8.4Hz,2H),6.76(d,J= 8.8Hz, 2H), 4.81 (t, J = 8Hz, 1H), 4.59 (t, J = 8Hz, 1H), 3.93 (dd, J1 = 8Hz, J2 = 12Hz, 1H). C9H9NO3 LCMS(ES + ) m / z calculated value 179.06; (M+H) + Found value 180. HPLC t R 0.81 minutes.

[0555] Step 4: (R)-4-(2-Oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (Intermediate 14).

[0556] To the slurry of intermediate 13 (676 mg, 3.77 mmol) in acetonitrile (7.5 mL) was added anhydrous 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 slowly added, keeping the reaction temperature at 20 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the resulting oil was extracted with DCM. The organic phase was washed with saturated NaHCO solution, brine, and dried over Na SO, then concentrated under reduced pressure to obtain a dark red oil. The crude product was purified by silica gel chromatography (eluent gradient was 100% DCM to 15% DCM / EtOAc) to produce the title compound (0.741 mg, 68%). 1 H NMR (300MHz, DMSO-d6) δ8.24 (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). C 10 H8F3NO5S(ES + ) m / z calculated value 311.01; (M+H) + Found 312. HPLC t R 1.70 minutes.

[0557] Step 5: (R)-4-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)oxazolidin-2-one (Intermediate 15).

[0558] A pressure vessel was filled with (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (149.8 mg, 1.06 mmol) and intermediate 14 (220.5 mg, 0.71 mmol) in NMP (1 mL). 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 then added. The reaction mixture was refluxed at 90 ° C for 30 minutes in a sealed container. 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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluent DCM / MeOH was 100% DCM to 9 / 1 DCM / MeOH) to obtain the title compound as a yellow solid (278 mg), which was used directly in subsequent synthesis steps. 1HNMR(300MHz,DMSO-d6)δ8.21(s,1H),7.49-7.41(m,4H),5.00(dd,J=8.4,6.6Hz, 1H), 4.70 (t, J = 8.6Hz, 1H), 4.08 (dd, J = 8.5, 6.4Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H). C 14 H 14 LCMS (ES) of N2O3 + ) m / z calculated value 258.10; (M+H) + Found 259. HPLC t R 1.41 minutes.

[0559] Step 6: (R)-tert-Butyl(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-hydroxyethyl)carbamate (Intermediate 16).

[0560] A mixture of DMAP (39.5 mg, 0.32 mmol) and di-tert-butyl carbonate (470 mg, 2.15 mmol) and intermediate 15 (278 mg, 1.08 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 Na2SO4. The organic phase was concentrated under reduced pressure to produce crude (R)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-oxooxazolidine-3-carboxylic acid tert-butyl ester as a light yellow foam (357 mg). 19 H 22 N2O5 LCMS(ES + ) m / z calculated value 358.15, (M+H) + Found 359. HPLC t R 1.86 minutes. A mixture of potassium carbonate (298 mg, 2.16 mmol) and this crude product 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 organic phase was combined with brine and washed, and evaporated to give the title compound (327 mg, 74% over three steps). 1 H NMR (300MHz, DMSO-d6) δ7.50-7.18(m,5H),4.83(br s,1H),4.58(m,1H),3.53(br d,J=3.4Hz,2H),2.40(s,3H),2.23(s,3H),1.46-1.30(m,9H). C 18 H 24N2O4(ES + ) m / z calculated value 332.17; (M+H) + Found 333. HPLC t R 1.72 minutes.

[0561] Step 7: (R)-2-((tert-Butoxycarbonyl)amino)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl methanesulfonate (Intermediate 17).

[0562] To a solution of TEA (0.18 mL, 1.33 mmol) and intermediate 16 (327 mg, 0.89 mmol) in DCM (3 mL) was added a solution of methanesulfonyl chloride (0.082 mL, 1.07 mmol) in DCM (1 mL) dropwise over 5 minutes at 0°C, and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was washed with water, saturated KHSO4 solution, and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (341 mg, 93%), which was used directly in the subsequent step. 19 H 26 N2O6SLCMS(ES + ) m / z calculated value 410.15; (M+H) + Found 411. HPLC t R 1.93 minutes.

[0563] Step 8: (R)-tert-Butyl(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate (Intermediate 18).

[0564] Intermediate 17 (340 mg, 0.828 mmol) in DMF (0.25 M) was added to a flask, followed by potassium 1,3-dioxoisoindolin-2-ol (153 mg, 0.83 mmol) and TBAB (5.3 mg, 0.017 mmol). The reaction was stirred at 60 ° C for 4 hours. Water (10 mL) was then added, and the precipitated product was filtered, washed with water, and dried under vacuum to give the title compound as a light orange powder (264 mg, 69%). The crude product was used directly in subsequent synthesis steps. 1 H NMR (300MHz, DMSO-d6) δ7.98-7.83(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). C 26 H 27 LCMS(ES) of N3O5 +) m / z calculated value 461.20; (M+H) + Found 462. HPLC t R 2.16 minutes.

[0565] Step 9: (R)-2-(2-amino-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)isoindoline-1,3-dione hydrochloride (Intermediate 19).

[0566] Intermediate 18 (260 mg, 0.572 mmol) was treated directly with 4N HCl (1.2 mL) in dioxane at room temperature. The reaction mixture was stirred at room temperature overnight. The resulting suspension was diluted with DCM (10 mL), sonicated, and filtered to give the title compound as a light pink powder (108 mg, 47%). The crude product was used directly in subsequent steps. 1 H NMR (300MHz, DMSO-d6) δ8.69(br s,3H),8.02-7.80(m,4H),7.65(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,2H),4.67(br dd,J=7.9,5.7Hz,1H),4.23-4.04(m,1H),4.02-3.87(m,1H),2.39(s,3H),2.21(s,3H). C 21 H 19 LCMS (ES) of N3O3 + ) m / z calculated value 361.14; (M+H) + Found 362. HPLC t R 1.26 minutes.

[0567] Step 10: (R)-2-((1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)amino)acetonitrile (Intermediate 20).

[0568] To a suspension of DIPEA (0.18 mL, 1.03 mmol) and intermediate 19 (108 mg, 1.08 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 hours and then concentrated under reduced pressure. The resulting oil was treated with a small amount of water and extracted with EtOAc. The combined organic phase was washed again with water (3 x 3 mL) and saline, then dried over Na SO and concentrated under reduced pressure to obtain the title compound (117 mg, 100%). 1H NMR(300MHz,DMSO-d6)δ7.91-7.80(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). C 23 H 20 N4O3 LCMS(ES + ) m / z calculated value 400.15; (M+H) + Found 401. HPLC t R 1.85 minutes.

[0569] Step 11: (R)-5-amino-3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 21).

[0570] 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 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give (R)-N-(cyanomethyl)-N-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)nitrosamide as a yellow oil that was used directly in subsequent synthesis steps. 23 H 19 LCMS (ES) of N5O + ) m / z calculated value 429.14, (M+H) + Found 430. HPLC t R 1.99 minutes. The crude product was directly treated with 4N HCl (1.2 mL) at room temperature for 4 hours, and then at room temperature for 4 hours without stirring. The mixture was concentrated under reduced pressure and back-extracted with DCM and diethyl ether several times until a solid product was obtained. The crude product was triturated with diethyl ether to give the title compound (125 mg, 91%) as a beige powder that could be used directly in the subsequent step. 23 H 20 LCMS (ES) of N5O4 + ) m / z calculated value 430.15; (M+H) + Found 430. HPLC t R 1.41 minutes.

[0571] Step 12: (R)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 22).

[0572] A cold suspension 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) (ice bath). After 10 minutes, the reaction was quenched with water at 0°C and the suspension was extracted with ether. The organic phase was washed again with water, saturated KHSO4 solution, and brine, then dried over Na2SO4, concentrated, and back-extracted with DCM under reduced pressure to give the title compound as a solid (138 mg, 0.22 mmol), which was used directly in the subsequent synthetic steps. 31 H 23 F3N6O5 LCMS(ES + ) m / z calculated value 616.17; (M+H) + Found 617. HPLC t R 2.21 minutes.

[0573] 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).

[0574] At room temperature, intermediate 22 (0.086 g, 0.14 mmol) solution in ethanol (6 mL) was treated with hydrazine hydrate (0.14 mL, 2.8 mmol). The reactant was stirred at 65 ° C for 1 hour. The reaction was cooled to room temperature and a white precipitate was formed. The reaction was diluted with ethanol (5 mL) and the precipitate was filtered. The solution was concentrated under reduced pressure to obtain a light yellow solid. The title compound was obtained after purification by silica gel column chromatography using water DCM / MeOH 1% eluent. The fraction containing the product was dried under reduced pressure and lyophilized to obtain the title compound as a white solid (17.4 mg, 23%). 1H NMR (300MHz, DMSO-d6) δ9.77(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=9.9,4.6Hz,1H),3.79(dd,J=13.8,10.0Hz,1H),3.46-3.39(m,1H),2.46(s,3H),2.29(s,3H),1.96(br s,2H). C 23 H 21 F3N6O3 LCMS(ES + ) m / z calculated value 486.17; (M+H) + Found 487. HPLC t R 2.73 minutes.

[0575] Examples 49, 54, 65, 66, 102 and 116 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 12).

[0576] Example 49: (R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate.

[0577] Starting from Boc-D-phenylalaninol and following Scheme 12 (steps 7-13), the title compound was obtained as a white solid. 1 HNMR(300MHz,DMSO-d6)δ9.76(s,1H),8.58(s,1H),8.16(br s,3H),7.69(br d,J=8.4Hz,1H),7.46(t,J=7.9Hz,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). C 19 H 18 F3N5O2(ES + ) m / z calculated value 405.14; (M+H) + Found 406. HPLC t R 2.66 minutes.

[0578] Example 54: (S)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate.

[0579] Starting from Boc-L-phenylalaninol and following Scheme 12 (steps 7-13), the title compound was obtained as a white solid. 1 HNMR(300MHz,DMSO-d6)δ9.76(s,1H),8.58(s,1H),8.16(br s,3H),7.69(br d,J=8.4Hz,1H),7.46(t,J=7.9Hz,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). C 19 H 18 F3N5O2(ES + ) m / z calculated value 405.14; (M+H) + Found 406. HPLC t R 2.67 minutes.

[0580] 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.

[0581] Starting from tert-butyl (S)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate and following Scheme 12 (steps 7-13), the title compound was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.21(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=6.6Hz,1H),3.92-3.63(m,1H),3.63-3.35(m,3H). C 25 H 22 LCMS (ES) of F3N5O2 + ) m / z calculated value 481.17, (M+H) + Found 482. HPLC t R 3.07 minutes.

[0582] Example 66: (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.

[0583] Starting from tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate and following Scheme 12 (steps 7-13), the title compound was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.23(s,1H),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,3H),7.37-7.26(m,4H),5.38(q,J=6.9Hz,1H),3.91-3.66(m,1H),3.61-3.32(m,3H). C 25 H 22 LCMS (ES) of F3N5O2 + ) m / z calculated value 481.17, (M+H) + Found 482. HPLC t R 3.08 minutes.

[0584] 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.

[0585] Following Scheme 12 and using pyrimidin-5-ylboronic acid in step 5, the title compound was obtained as a white solid. 1 HNMR(300MHz,DMSO-d6)δ9.71(s,1H),9.22(s,1H),9.16(s,2H),8.38(s,1H),8.30-8 .19(m,1H),7.91(d,J=8.3Hz,2H),7.77(d,J=8.3Hz,2H),7.72-7.63(m,1H),7.43(br t,J=7.9Hz,1H),7.22(br d,J=8.2Hz,1H),5.92(dd,J=9.72,4.58Hz,1H),3.83-3.66(m,1H),3.42-3.36(m,1H). C 22 H 18 F3N7O2 LCMS(ES + ) m / z calculated value 469.43; (M+H) + Found 470. HPLC t R 3.08 minutes.

[0586] 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.

[0587] Starting from 4-hydroxy-L-phenylglycine, the title compound was obtained according to Scheme 12 as a white solid. 1 HNMR (300MHz, DMSO-d6) δ9.77(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. 7Hz,1H),5.94(dd,J=9.9,4.6Hz,1H),3.79(dd,J=13.8,10.0Hz,1H),3.46-3.39(m,1H),2.46(s,3H),2.29(s,3H),1.96(br s,2H). C 23 H 21 F3N6O3LCMS(ES + ) m / z calculated value 486.16; (M+H) + Found 487. HPLC t R 2.73 minutes.

[0588] Example 88: (3-(4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium- 5-amino)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0589]

[0590] Plan 13

[0591] A solution of (3,5-dimethylisoxazol-4-yl)boronic acid (13.0 mg, 0.09 mmol) and bis(chloroalkyl)palladiumcyclopentyl(diphenyl)phosphinoferrocene (5.5 mg, 0.01 mmol), tripotassium phosphate (42.0 mg, 0.20 mmol), (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) in a mixture of H2O / dioxane (1:10) (1.1 mL) was heated at 75°C for 16 h. The reaction mixture was cooled at room temperature and filtered through a pad of silica gel. 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 (5 mg, 16%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ9.72(br s,1H),8.27(s,1H),8.21(s,1H),7.71(br d,J=8.3Hz,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(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 20 LCMS (ES) of F3N5O3 + ) m / z calculated value 471.15; (MH) - Found 470. HPLC t R 2.03 minutes.

[0592] Examples 87, 100, 103, 104, 108, 109, 110, 117, 119, 120, 121 and 124 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 13).

[0593] Example 87: (3-(3-methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0594] Reaction with pyrimidin-5-ylboronic acid in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),9.23(s,1H),8.89(s,2H),8.24(s,1H),8.21(br s,1H),7.72(br d,J=8.6Hz,1H),7.59(s,1H),7.55(br d,J=7.7Hz,1H),7.46-7.42(m,2H),7.23(br d,J=7.7Hz,1H),5.82(s,2H),2.30(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.78 minutes.

[0595] Example 100: (3-((5-(Pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0596] The title compound was obtained by reacting (3-((5-bromothiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Synthesis Example 6) in Step 1 with pyrimidin-5-ylboronic acid as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.49(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=7.9Hz,1H),7.20(br t, J=7.7Hz, 1H), 6.99 (br d, J=7.2Hz, 1H), 5.61 (s, 2H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 19 H 13 LCMS (ES) of F3N6O2S + ) m / z calculated value 446.08; (MH) - Found 445. HPLC t R 1.65 minutes.

[0597] Example 103: (3-((6-(Pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0598] The title compound was obtained by reacting (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Synthesis Example 6) in Step 1 with pyrimidin-5-ylboronic acid as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(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=8.3Hz,1H),7.44(br t,J=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.93(s,2H). 19F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 20 H 14 LCMS (ES) of F3N7O2 + ) m / z calculated value 441.12; (MH) - Found 440. HPLC t R 1.51 minutes.

[0599] Example 104: (3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0600] The title compound was obtained from the reaction of (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Synthesis Example 6) in Step 1 and 3,5-dimethylisoxazol-4-yl)boronic acid as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.89(s,1H),8.34(s,1H),8.22(br s,1H),8.10(br d,J=8.3Hz,1H),7.72(br d,J=8.6Hz,1H),7.66(br d,J=8.1Hz,1H),7.44(br t,J=7.9Hz,1H),7.23(br d,J=7.9Hz,1H),5.88(s,2H),2.58(s,3H),2.39(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 21 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 458.13; (MH) - Found 457. HPLC t R 1.76 minutes.

[0601] Example 108: (3-((5-(Pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0602] The title compound was obtained by reacting (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Synthesis Example 6) in Step 1 with pyrimidin-5-ylboronic acid as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(br s,1H),9.26(br s,1H),9.24(brs,2H),9.06(br s,1H),8.39(dd,J1=8.0Hz,J2=2.1Hz,1H),8.24(s,1H),8.20(br s,1H),7.84(br d,J=8.1Hz,1H),7.74(br d,J=7.9Hz,1H),7.44(br t,J=8.0Hz,1H),7.22(brd,J=7.5Hz,1H),6.03(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 14 LCMS (ES) of F3N7O2 + ) m / z calculated value 441.12; (MH) - Found 440. HPLC t R 1.49 minutes.

[0603] 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.

[0604] The title compound was obtained from the reaction of (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as described in Synthesis Example 6) in Step 1 and 3,5-dimethylisoxazol-4-yl)boronic acid as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(br s,1H),8.67(brs,1H),8.25(s,1H),8.21(br s,1H),8.00(dd,J1=8.0Hz,J2=2.1Hz,1H),7.78-7.73(m,2H),7.44(br t,J=8.0Hz,1H),7.22(br d,J=7.7Hz,1H),6.00(s,2H),2.44(s,3H),2.26(s,3H). 19F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 21 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 458.13; (MH) - Found 457. HPLC t R 1.76 minutes.

[0605] Example 110: (3-((4-(4-methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0606] The title compound was obtained by reacting (3-((4-bromothiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in Synthesis Example 6) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.95(s,1H),8.65(s,1H),8.19(s,1H),8.13(br s,1H),7.89(d,J=1.3Hz,1H),7.68(s,1H),7.65(br s,1H),7.37(br t,J=7.9Hz,1H),7.16(br d,J=7.7Hz,1H),6.04(s,2H),2.48(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 15 LCMS (ES) of F3N6O2S + ) m / z calculated value 460.09; (MH) - Found 459. HPLC t R 1.66 minutes.

[0607] 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.

[0608]

[0266] The (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in Synthesis Example 6) was reacted with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 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 (400MHz, DMSO-d6) δ9.73(s,1H),8.74(d,J=1.8Hz,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=8.1Hz,1H),7.71(brd,J=8.6Hz,1H),7.44(br t,J=8.2Hz,1H),7.22(br d,J=8.1Hz,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 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 24 H 23 LCMS (ES) of F3N8O2 + ) m / z calculated value 512.19; (MH) - Found 511. HPLC t R 1.28 minutes.

[0609] Example 119: (3-((5-(isoindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0610] (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in Synthesis Example 6) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoindoline-2-carboxylate 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. 1HNMR(400MHz,DMSO-d6)δ9.75(br s,1H),9.47(br s,2H),8.76(br d,J=1.8Hz,1H),8.26(s,1H),8.22(br s,1H),8.09(dd,J1=8.1Hz,J2=2.4Hz,1H),7.81(br d,J=7.9Hz,1H),7.73(br d,J=7.7Hz,1H),7.56-7.50(br m,3H),7.45(br t,J=8.0Hz,1H),7.23(br d,J=7.5Hz,1H),6.03(s,2H),4.68-4.63(m,2H),4.61-4.58(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 24 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 480.15; (MH) - Found 479. HPLC t R 1.28 minutes.

[0611] 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.

[0612]

[0266] The (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in Synthesis Example 6) was reacted with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give the title compound as a white solid. The crude material from step 1 was treated with HCl (4.0 N in dioxane) to give the title compound. 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.90(br d,J=1.8Hz,1H),8.64(br s,1H),8.39(br s,2H),8.20(br s,1H),8.17(s,1H),8.12(dd,J1=8.1Hz,J2=2.2Hz,1H),8.09(s,1H),7.72(br d,J=8.1Hz,1H),7.67(br d,J=8.1Hz,1H),7.44(br t,J=8.0Hz,1H),7.22(br d,J=7.5Hz,1H),5.91(s,2H),4.57-4.50(m,1H),3.75-3.69(m,1H),3.4 6-3.39(m,2H),3.15-3.06(m,2H),2.27-2.22(m,2H),2.17-2.10(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 24 H 23 LCMS (ES) of F3N8O2 + ) m / z calculated value 512.19; (MH) - Found 511. HPLC t R 1.20 minutes.

[0613] Example 121: (3-((5-(2-(Aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0614] The reaction of (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in Synthesis Example 6) with tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate gave 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. 1H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 8.63 (br d, J = 1.8Hz, 1H), 8.26 (s, 1H), 8.22 (br s, 1H), 8.12 (br s,3H),7.98(dd,J1=8.0Hz,J2=2.3Hz,1H),7.81-7.72(m,2H),7.66(br d,J=7.5Hz,1H),7.59-7.50(m,2H),7.45(br t,J=8.0Hz,1H),7.40(br d,J=7.7Hz,1H),7.23(br d,J=7.2Hz,1H),6.03(s,2H),4.00-3.96(m,2H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 468.15; (MH) - Found 467. HPLC t R 1.30 minutes.

[0615] Example 124: (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.

[0616] The (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide in step 1 (prepared as described in the synthesis of Example 6) was reacted with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 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. 1HNMR(400MHz,DMSO-d6)δ9.74(s,1H),9.58(br s,2H),8.71(br d,J=2.0Hz,1H),8.20(brs,2H),8.07(s,1H),7.99(dd,J1=8.1Hz,J2=2.4Hz,1H),7.75-7.71(m,2H),7.44(br t,J=7.9Hz,1H),7.23(br d,J=7.7Hz,1H),5.96(s,2H),4.72(br s,2H),4.39(br t,J=5.7Hz,2H),3.71(br t,J=5.6Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 19 LCMS (ES) of F3N8O2 + ) m / z calculated value 484.16; (MH) - Found 483. HPLC t R 1.13 minutes.

[0617] Example 90: (3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl 1-(3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0618]

[0619] Plan 14

[0620] 5- bromo-2-methoxy-4-methylpyrimidine (26.8mg, 0.13mmol) and bis(chloroalkyl) palladium cyclopentyl(diphenyl)phosphine ferrocene (5.5mg, 0.01mmol) in H o / dioxane (1:10) (1.1mL) mixture, potassium phosphate (42.0mg, 0.20mmol), intermediate 10 (30.0mg, 0.07mmol) solution was heated at 75 DEG C for 40 minutes.The reaction mixture was cooled at room temperature and filtered on a silica gel pad. Excess solvent was removed under reduced pressure to obtain residue, which was purified by silica gel chromatography (eluting with 0-100% EtOAc in petroleum ether) to obtain the title compound (14mg, 43%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.84(br s,1H),8.53(s,1H),8.39(s,1H),8.32(s,1H),7.84-7.76(m,3H),7.64(d,J=7.9Hz,2H),7.55(br t,J=8.0Hz,1H),7.33(br d,J=7.5Hz,1H),5.96(s,2H),4.05(s,3H),2.50(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 23 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 484.15; (MH) - Found 483. HPLC t R 1.98 minutes.

[0621] Examples 80, 81, 82, 83, 84, 85, 86, 89, 91, 92, 98, 101, 107, 111 and 112 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 14).

[0622] Example 80: ((3-(Trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide.

[0623] Reaction with 5-bromo-4-(trifluoromethyl)pyrimidine (using XPhos Pd G4 in THF) in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.48(s,1H),9.09(s,1H),8.30(s,1H),8.22(br s,1H),7.73(br d,J=8.1Hz,3H),7.56(br d,J=8.1Hz,2H),7.44(t,J=8.2Hz,1H),7.23(br d,J=7.9Hz,1H),5.89(s,2H). 19 F NMR(377MHz, DMSO-d6)δ-61.29(s,3F),-62.35(s,3F). C 22 H 14 F6N6O2LCMS(ES + ) m / z calculated value 508.11; (M+H) + Found 509. HPLC t R2.42 minutes.

[0624] Example 81: (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0625] Reaction with 5-bromo-4,6-dimethylpyrimidine in step 1 (using XPhos Pd G4 in THF) afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(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=7.7Hz,1H),5.87(s,2H),2.18(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 468.15; (MH) - Found 467. HPLC t R 1.69 minutes.

[0626] 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.

[0627] In step 1, the title compound was obtained by reacting 5-bromo-4-methylpyrimidine with (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 from (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide as described in the synthesis of Example 60) using a solution of XPhos Pd G4 in THF as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.99(s,1H),8.56(s,1H),8.24(s,1H),8.18(br s,1H),7.69(br d,J=8.1Hz,2H),7.62(br d,J=7.8Hz,1H),7.53(br d,J=8.3Hz,2H),7.37(br t,J=8.0Hz,1H),7.16(br d,J=7.3Hz,1H),6.21-6.16(m,1H),2.39(s,3H),2.00(br d,J=7.5Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 468.15; (MH) - Found 467. HPLC t R 1.76 minutes.

[0628] Example 83: (3-(3-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0629] In step 1, the title compound was obtained by reacting 5-bromo-4-methylpyrimidine with (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 as described for the synthesis of Example 60 starting from Example 46) using XPhos Pd G4 solution in THF as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.72(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=8.1Hz,1H),7.22(br d,J=7.7Hz,1H),5.85(s,2H),2.47(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) -Found 453. HPLC t R 1.72 minutes.

[0630] Example 84: (3-(3-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0631] 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 as described for the synthesis of Example 60 starting from Example 46) provided the title compound as a white solid. A solution of XPhos Pd G4 in THF was used in Step 1. 1 H NMR(400MHz,DMSO-d6)δ9.72(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=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.84(s,2H),3.99(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.30(s,3F). C 22 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 470.13; (MH) - Found 469. HPLC t R 1.82 minutes.

[0632] Example 85: (3-(4-(4-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0633] XPhos Pd G4 solution in THF was used in step 1 to react with 3-bromo-4-methylpyridine to give the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),8.45(br d,J=5.0Hz,1H),8.38(s,1H),8.30(s,1H),8.22(br s,1H),7.73(br d,J=8.1Hz,1H),7.69(br d,J=8.3Hz,2H),7.52(br d,J=8.3Hz,2H),7.44(br t,J=8.1Hz,1H),7.35(br d,J=5.0Hz,1H),7.22(br d,J=7.7Hz,1H),5.86(s,2H),2.27(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 18 LCMS (ES) of F3N5O2 + ) m / z calculated value 453.14; (MH) - Found 452. HPLC t R 1.37 minutes.

[0634] Example 86: (3-(4-(3-methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0635] XPhos Pd G4 solution in THF was used in step 1 to react with 2-bromo-3-methylpyrazine to give the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),8.58-8.55(m,2H),8.30(s,1H),8.21(br s,1H),7.76-7.69(m,5H),7.44(br t,J=7.9Hz,1H),7.22(br d,J=7.7Hz,1H),5.88(s,2H),2.57(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.76 minutes.

[0636] 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.

[0637] Reaction with 2-((5-bromo-4-methylpyrimidin-2-yl)oxy)ethan-1-ol in step 1 gave the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),8.34(s,1H),8.20(s,1H),8.14(br s,1H),7.65-7.60(m,3H),7.46(br d,J=8.1Hz,2H),7.37(br t,J=7.8Hz,1H),7.15(br d,J=7.2Hz,1H),5.78(s,2H),4.84-4.80(m,1H),4.29-4.26(m,2H),3.68-3.64(m,2H),2.31(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 24 H 21 LCMS (ES) of F3N6O4 + ) m / z calculated value 514.16; (MH) - Found 513. HPLC t R 1.68 minutes.

[0638] Example 91: (3-(4-(4-cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0639] XPhos Pd G4 solution in THF was used in step 1; reaction with 5-bromo-4-cyclopropylpyrimidine afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73(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=8.1Hz,2H),7.44(br t,J=7.9Hz,1H),7.23(br d,J=7.9Hz,1H),5.88(s,2H),2.06-1.98(m,1H),1.16-1.10(m,2H),1.06-1.02(m,2H). 19F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 24 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 480.15; (MH) - Found 479. HPLC t R 1.94 minutes.

[0640] Example 92: (3-(4-(2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0641] XPhos Pd G4 solution in THF was used in step 1 to react with 3-bromo-2-methylpyridine to give the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.40 (dd, J1=4.8Hz, J2=1.8Hz, 1H), 8.21 (s, 1H), 8.14 (br s, 1H), 7.65 (br d, J=8.8Hz, 1H), 7.60 (br d,J=8.1Hz,2H),7.55(dd,J1=7.7Hz,J2=1.5Hz,1H),7.43(br d,J=8.1Hz,2H),7.37(br t,J=8.0Hz,1H),7.24(dd,J1=7.7Hz,J2=4.8Hz,1H),7.15(br d,J=7.5Hz,1H),5.78(s,2H),2.35(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 18 LCMS (ES) of F3N5O2 + ) m / z calculated value 453.14; (MH) - Found 452. HPLC t R 1.34 minutes.

[0642] 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.

[0643] XPhos Pd G4 solution in THF was used in step 1; reaction with 5-bromo-1,4-dimethyl-1H-imidazole afforded the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.30(s,1H),8.22(brs,1H),7.72(br d,J=7.9Hz,1H),7.67(br d,J=8.1Hz,2H),7.59(s,1H),7.48(br d,J=8.1Hz,2H),7.44-7.42(m,1H),7.22(br d,J=7.7Hz,1H),5.83(s,2H),3.53(s,3H),2.11(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 19 LCMS (ES) of F3N6O2 + ) m / z calculated value 456.15; (MH) - Found 455. HPLC t R 1.31 minutes.

[0644] Example 101: (3-(3-methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0645] The title compound was obtained from step 1 by reacting 5-bromo-4-methylpyrimidine with ((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 (prepared as described in Synthesis Example 60 starting from Intermediate 23) as described in Synthesis Example 60). 1 HNMR(400MHz,DMSO-d6)δ9.72(s,1H),9.08(s,1H),8.53(s,1H),8.28(s,1H),8.22(br s,1H),7.72(br d,J=7.9Hz,1H),7.59(s,1H),7.52(br d,J=8.1Hz,1H),7.44(br t,J=7.9Hz,1H),7.31(br d,J=7.7Hz,1H),7.23(br d,J=7.7Hz,1H),5.82(s,2H),2.23(s,3H),2.08(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O2 +) m / z calculated value 468.15; (MH) - Found 467. HPLC t R 1.72 minutes.

[0646] 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.

[0647] XPhos Pd G4 solution in THF was used in step 1; reaction with 5-bromo-4,6-difluoropyrimidine afforded the title compound as a light pink solid. 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),8.16(s,1H),8.13(br s,1H),8.05(br s,1H),7.66(br d,J=8.8Hz,1H),7.50(br s,4H),7.36(br t,J=7.8Hz,1H),7.15(br d,J=7.7Hz,1H),5.73(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 21 H 14 LCMS (ES) of F4N6O3 + ) m / z calculated value 474.11; (MH) - Found 473. HPLC t R 1.64 minutes.

[0648] Example 111: (3-(4-(4-methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0649] Reaction with 5-bromo-4-methoxy-6-methylpyrimidine in step 1 afforded the title compound as a white solid. 1 HNMR(400MHz,DMSO-d6)δ9.74(s,1H),8.68(s,1H),8.31(s,1H),8.22(br s,1H),7.73(br d,J=8.8Hz,1H),7.65(br d,J=8.1Hz,2H),7.46-7.40(m,3H),7.23(br d,J=7.9Hz,1H),5.84(s,2H),3.84(s,3H),2.21(s,3H). 19F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 484.15; (MH) - Found 483. HPLC t R 1.82 minutes.

[0650] 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.

[0651] Reaction with 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)ethan-1-ol in step 1 afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(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=9.0Hz,1H),7.64(br d,J=8.1Hz,2H),7.46-7.42(m,3H),7.23(br d,J=7.7Hz,1H),5.85(s,2H),4.36-4.31(m,2H),3.62-3.58(m,2H),2.22(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 24 H 21 LCMS (ES) of F3N6O4 + ) m / z calculated value 514.16; (MH) - Found 513. HPLC t R 1.63 minutes.

[0652] Example 123: ((3-((5-(4-(2-(methylimidazol-1-yl(methyl)amino)ethoxy)-6-methylpyrimidin-5-yl)pyrimidin-5-yl)pyrimidin-6 ... pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide)(2,2, 2-Trifluoroacetic acid)

[0653]

[0654] Plan 15

[0655] Step 1: (3-((5-boropyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 122)

[0656] 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) and potassium acetate (20.0 mg, 0.20 mmol) in dioxane (7.0 mL) were added to a 1% ethanol solution of (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)amine A solution of 1-(4-(4-nitro-1-yl)-2-oxo-4-oxo-2-yl)-4-nitro-2-oxo-4-oxo-6-nitro-4-nitro-6-nitro-6-nitro-6-nitro-6-nitro-6-nitro-7-nitro-7-nitro-8-nitro-6-nitro-7-nitro-8-nitro-6-nitro-7-nitro-8-nitro-6-nitro-7-nitro-8-nitro-8-nitro-7-nitro-8-nitro-8-nitro-9 ...8-nitro-9-nitro-8-nitro-8-nitro-9 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.75 (s, 1H), 8.21-8.18 (m, 3H), 7.74 (d, J = 8.0Hz ,1H),7.59(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),5.94(s,2H). C 16 H 13 BF3N5O4 LCMS(ES + ) m / z calculated value 407.10; (M+H) + Found 408. HPLC R 1.37 minutes.

[0657] Step 2: ((3-((5-(4-(2-(methylium(methyl)amino)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide)(2,2,2-trifluoroacetic acid) (Example 123)

[0658] The title compound was prepared using the same conditions described for the synthesis of Example 90 using Example 122 (48 mg, 0.12 mmol) and 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)-N,N-dimethylethan-1-amine (61 mg, 0.24 mmol). The title compound was obtained as a brown gum (6.7 mg, 10%) after purification on silica gel (eluting with 10% MeOH in DCM) and lyophilization from H2O / MeCN+0.1% TFA. 1H NMR (400MHz, DMSO-d6) δ9.75(s,1H),9.48(br s,1H),8.75(s,1H),8.63(d,J=1.8Hz,1H),8.23(s,1H),8.21(br s,1H),7.98(dd,J1=8.1Hz,J2=2.2Hz,1H),7.76(d,J=8.1Hz,1H),7.72(br d,J=8.8Hz,1H),7.44(t,J=7.9Hz,1H),7.23(d,J=7.7Hz,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(377MHz,DMSO-d6)δ-61.28(s,3F). C 25 H 25 F3N8O3 LCMS(ES + ) m / z calculated value 542.20; (M+H) + Found 543. HPLC t R 1.20 minutes.

[0659] Examples 43 and 118 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 15).

[0660] 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.

[0661] Reaction with 2-((5-bromo-4-methylpyrimidin-2-yl)oxy)-N,N-dimethylethan-1-amine in step 2 afforded the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.48(br s,1H),8.68(br d,J=1.8Hz,1H),8.48(s,1H),8.25(s,1H),8.20(br s,1H),8.05(dd,J1=8.0Hz,J2=2.3Hz,1H),7.79-7.73(m,2H),7.44(t,J=7.9Hz,1H),7.22(d,J =7.7Hz,1H),6.01(s,2H),4.43(t,J=5.8Hz,2H),2.66-2.63(m,2H),2.40(s,3H),2.22(s,6H);19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 25 H 25 LCMS (ES) of F3N8O3 + ) m / z calculated value 542.20; (MH) - Found 541. HPLC t R 1.22 minutes.

[0662] Example 118: (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.

[0663] Reaction with 5-bromo-1,4-dimethyl-1H-imidazole in step 2 afforded the title compound as a white solid. 1 HNMR(400MHz,DMSO-d6)δ9.73(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(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 457.15; (MH) - Found 456. HPLC t R 1.27 minutes.

[0664] Example 31: (S)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoro methyl)phenyl)carbamoyl)amide

[0665]

[0666] Plan 16

[0667] Step 1: (S)-2-((2-Hydroxy-1-phenylethyl)amino)acetonitrile (Intermediate 25).

[0668] To the suspension of N,N-diisopropylethylamine (0.52mL, 3mmol) and (S)-2-phenylglycinol (343mg, 2.5mmol) in MeCN (4mL) add 2-bromoacetonitrile (0.12mL, 1.67mmol). Reactant is stirred at room temperature overnight, then concentrated under reduced pressure. Gained oily matter is processed with water (2mL) and extracted with Et o. Organic phase is cleaned again with water (3x 3mL) and salt solution, then through Na sO dry, filter, and be concentrated under reduced pressure to obtain title compound (268mg, 91%), it is in oily state. 1 H NMR(300MHz,DMSO-d6)δ7.43-7.16(m,5H),5.02(t,J=5.5Hz,1H),3.84-3.76(m,1H),3.7 5-3.65(m,1H),3.54-3.35(m,2H),3.25-3.11(m,1H),2.99(ddd,J=10.6,4.6,1.7Hz,1H). C 10 H 12 N2O LCMS(ES + ) m / z calculated value 176.09; (M+H) + Found 177. HPLC t R 1.35 minutes.

[0669] Step 2: (S)-N-(Cyanomethyl)-N-(2-hydroxy-1-phenylethyl)nitriteamide (Intermediate 26).

[0670] To a stirred and cooled (cryosalt) solution of sodium nitrate (210 mg, 3.04 mmol) in water (1.5 mL) was added dropwise an ice-cold mixture (ice bath) of intermediate 25 (268 mg, 1.52 mmol) in 3N hydrogen chloride (2.03 mL, 6.08 mmol) in ethanol (2 mL). The reaction was allowed to warm to room temperature for 1 h. Then, brine was added and extracted with Et2O. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an oil, which was used directly in subsequent synthetic steps. 1 H NMR (300MHz, DMSO-d6) δ7.56-7.26 (m, 5H), 5.78 (dd, J=9.2, 5.1Hz, 1H), 5.33 (dd, J= 5.5,5.0Hz,1H),4.68-4.54(m,2H),4.32-4.23(m,1H),4.03(dt,J=11.7,5.0Hz,1H). HPLCt R 2.25 minutes.

[0671] Step 3: (S)-5-Amino-3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 27).

[0672] Intermediate 26 was treated directly with 4N HCl (1.5 mL) in dioxane at room temperature to give a pale yellow solution. After 10 minutes, the reaction mixture was diluted with Et2O (3 mL) and concentrated under reduced pressure. The crude product was stripped with DCM and dried overnight on a vacuum pump to give the title compound (286 mg, 78% over 2 steps) as a white foam. 1 H NMR(300MHz,DMSO-d6)δ9.73(s,2H),8.22(s,1H),7.71-7.53(m,2H),7.52-7.41(m,3H),6.21(d d,J=9.3,4.2Hz,1H),5.77(brs,1H),4.44(dd,J=12.2,9.4Hz,1H),4.10(dd,J=12.2,4.3Hz,1H). C 10 H 12 N3O2 + LCMS (ES + ) m / z calculated value accurate mass: 206.09; [M] + found value 206. HPLC t R 1.44 minutes.

[0673] Step 4: (S)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 31)

[0674] Intermediate 27 (222 mg, 0.92 mmol) in anhydrous methanol (3 mL) is cooled to -10 ° C (ice-salt bath), and sodium acetate (82 mg, 1.01 mmol) is added. The mixture is stirred at the same temperature for 15 minutes, and 1-isocyanato-3-(trifluoromethyl)benzene (0.13 mL, 0.92 mmol) is added. The reactant is further stirred for 1 hour at -10 ° C, then diluted with water. The precipitated product is filtered and washed with water. The crude product is purified on silica gel, eluted with DCM / MeOH 99.8:0.2 to obtain the title compound (140 mg, 39%), which is a white solid. 1H NMR (300MHz, DMSO-d6) δ9.72(s,1H),8.35(s,1H),8.25(s,1H),7.70(br d,J=8.6Hz,1H),7.66-7.56(m,2H),7.54-7.36(m,4H),7.22(br d, J=7.7Hz, 1H), 6.02 (dd, J=9.4, 4.2Hz, 1H), 5.69 (br s, 1H), 4.52 (br t, J=10.7Hz, 1H), 4.07 (br dd, J=11.9, 4.1Hz, 1H). C 18 H 15 F3N4O3(ES + ) m / z calculated value 392.11; (M+H) + Found 393. HPLC t R 3.12 minutes.

[0675] Examples 30, 32 and 45 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 16).

[0676] Example 30: (R)-(3-(2-Hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0677] Starting from (R)-2-phenylglycinol the title compound is obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ9.72(s,1H),8.35(s,1H),8.25(s,1H),7.70(br d,J=8.4Hz,1H),7.62(dd,J=6.7,2.9Hz,2H),7.53-7.38(m,4H),7.22(d,J=7.8Hz,1H),6.02(dd, J=9.5,4.2Hz,1H),5.67(t,J=5.5Hz,1H),4.52(ddd,J=12.0,9.6,5.8Hz,1H),4.15-3.98(m,1H). C 18 H 15 F3N4O3LCMS(ES + ) m / z calculated value 392.11; (M+H) + Found 393. HPLC t R 3.11 minutes.

[0678] Example 32: (S)-(3-(1-Hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0679] Starting from Boc-L-phenylalaninol the title compound is obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ9.68(s,1H),8.33(s,1H),8.30-8.23(m,1H),7.73-7.65(m,1H),7.44(t,J=8.0Hz,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). C 19 H 17 F3N4O3 LCMS(ES + ) m / z calculated value 406.13; (M+H) + Found 407. HPLC R 3.20 minutes.

[0680] Example 45: (R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0681] Starting from Boc-D-phenylalaninol the title compound is obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ9.68(s,1H),8.34(s,1H),8.30-8.25(m,1H),7.74-7.65(m,1H),7.44 (t,J=8.0Hz,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). C 19 H 17 F3N4O3LCMS(ES + ) m / z calculated value 406.13; (M+H) + Found 407. HPLC t R 3.20 minutes.

[0682] Example 35: (3-(1-phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) Carbamoyl)amide

[0683]

[0684] Plan 17

[0685] Under a nitrogen atmosphere, 1,1,1-trifluoro-N, N-bis(2-methoxyethyl)-14-sulfonamide (0.04mL, 0.06mmol) was added dropwise to an ice-cold solution of Example 30 (20mg, 0.05mmol) in anhydrous THF (0.25mL, 0.003mol). The reactant was stirred at 0°C for 40 minutes. More 1,1,1-trifluoro-N, N-bis(2-methoxyethyl)-14-sulfonamide (0.04mL, 0.06mmol) was added and stirred for another 30 minutes. Then 1,1,1-trifluoro-N, N-bis(2-methoxyethyl)-14-sulfonamide (0.07mL) was added for the second time at 0°C. The reactant was stirred at 0°C for 40 minutes and then slowly heated to room temperature overnight. The reaction mixture was quenched with NaHCO (0.3mL, saturated solution) and water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil, which was purified on a silica gel column (eluent gradient of 100% petroleum ether to 70 / 30 petroleum ether / ethyl acetate) and then subjected to reverse phase chromatography (eluent gradient of 15-70% MeCN+0.1% HCOOH). Pure fractions were combined and lyophilized to give the title compound (1.41 mg, 8%) as a yellow solid. 1 HNMR (300MHz, DMSO-d6) δ9.81 (br s, 1H), 8.37-8.13 (m, 2H), 7.74 (br d, J = 7.9Hz, 1H), 7.66-7.37 (m, 6H), 7.23 (br d, J = 7.4Hz, 1H), 6.45-6.12 (m, 2H). C 18 H 15 F3N4O3 LCMS(ES + ) m / z calculated value 392.11; (M+H) + Found 393. HPLC t R 3.64 minutes.

[0686] (3-(3-phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)amino (S)-(3-(1-fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)-1,2,3-oxadiazol-3 ...5-yl)-1,2,3-oxadiazol-3-yl)-1,2, ((3-(Trifluoromethyl)phenyl)carbamoyl)amide (Example 37)

[0687]

[0688] Plan 18

[0689] To an ice-cold solution of Example 32 (20 mg, 0.05 mmol) in anhydrous THF (0.25 mL, 0.003 mol) was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfonamide (0.22 mL, 0.3 mmol) dropwise. The reaction mixture was stirred at 0 ° C for 40 minutes. More 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfonamide (0.22 mL, 0.3 mmol) was added, and the reaction was stirred at 0 ° C for 1 h. Potassium fluoride (2.9 mg, 0.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water the next day and extracted with EtOAc. The organic layer was then washed with water, 1N HCl and brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. The crude product was purified by direct phase silica gel chromatography (eluent DCM + 0.5% MeOH). The first eluting product was then purified by reverse phase chromatography (eluent gradient 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 H NMR(300MHz,DMSO-d6)δ9.91-9.58(m,1H),8.46(s,1H),8.26(br s,1H),7.70(br d,J=8.2Hz,1H),7.52-7.15(m,7H),6.28(s,1H),5.75(s,1H),4.13(br s,2H). C 19 H 15 F3N4O2 LCMS(ES + ) m / z calculated value 388.11; (M+H) + Found 389. HPLC t R 3.66 minutes.

[0690] The second eluting product was then purified by reverse phase chromatography (eluent gradient 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) (2.64 mg, 12%) as a white powder. 1H NMR(300MHz,DMSO-d6)δ9.73(s,1H),8.43(s,1H),8.27(s,1H),7.70(br d,J=8.71Hz,1H),7.45(t,J=7.9Hz,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(282MHz,DMSO-d6)δ-224.60(s,1F)-61.29(s,3F). C 19 H 16 F4N4O2 LCMS(ES + ) m / z calculated value 408.12; (M+H) + Found 409. HPLC t R 3.62 minutes.

[0691] Example 44: (3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl) ((3-(trifluoro methyl)phenyl)carbamoyl)amide

[0692]

[0693] Plan 19

[0694] Step 1: 2-((2,2,2-trifluoro-1-phenylethyl)amino)acetonitrile (Intermediate 28)

[0695] A microwave vial was filled with 2-bromoacetonitrile (0.07 mL, 0.96 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.73 mmol), 2-((2,2,2-trifluoro-1-phenylethyl)amino)acetonitrile (0.25 mg, 1.44 mmol) in MeCN (2 mL). The reaction mixture was heated at 100 ° C under microwave irradiation for 90 minutes; then more DIPEA (300 uL) and 2-bromoacetonitrile (0.07 mL, 0.96 mmol) were added, and the reaction was heated at 100 ° C for another 30 minutes, then directly diluted with EtOAc and washed with a small amount of water and brine. The organic phase was dried over Na2SO4, filtered and 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 (87 mg, 28%) as a white powder. 1 H NMR (300MHz, DMSO-d6) δ7.87-7.26 (m, 5H), 4.50 (q, J = 7.7Hz, 1H), 3.90 (br s, 1H), 3.75-3.61 (m, 1H), 3.56-3.44 (m, 1H). C 10H9F3N2 LCMS(ES + ) m / z calculated value 214.07; (M+H) + Found 215. HPLC t R 1.78 minutes.

[0696] Step 2: N-(Cyanomethyl)-N-(2,2,2-trifluoro-1-phenylethyl)nitriteamide (Intermediate 29).

[0697] Starting from intermediate 28, the title compound was prepared using the procedure described in step 2 of example 31. The crude product was obtained as a yellow oil, which was used directly in the subsequent synthetic step. 10 H8F3N3O LCMS(ES + ) m / z calculated value 243.06; (M+H) + Found 244. HPLC t R 1.91 minutes.

[0698] Step 3: 5-amino-3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 30).

[0699] Starting from intermediate 29, the title compound was prepared using the procedure described in step 3 of example 32, but heating at 90°C for 10 minutes. The impure crude product (30 mg) was obtained as a white solid, which was used directly in the subsequent synthetic step. 10 H9F3N3O + LCMS (ES + ) m / z calculated value 244.07; [M] + Found 244. HPLC t R 1.09 minutes.

[0700] Step 4: (3-(2,2,2-Trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 44).

[0701] 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; it was dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (0.62 mg, 1.25%) was obtained after purification by reverse phase chromatography (MeCN / H2O+0.1% HCOOH). The fractions containing the product were lyophilized to give the title compound as a white powder.1 H NMR(300MHz,DMSO-d6)δ9.87(s,1H),8.36(s,1H),8.18(s,1H),7.75(br d,J=8.0Hz,3H),7.67-7.50(m,4H),7.46(t,J=8.0Hz,1H),7.25(d,J=7.70Hz,1H). C 18 H 12 F6N4O2(ES + ) m / z calculated value 430.09; (M+H) + Found 431. HPLC t R 4.02 minutes.

[0702] Example 70: (S)-(3-(1-(1,1'-biphenyl-4-yl)-3-acetamidoprop-2-yl)-1,2,3-oxadiazole oxazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0703]

[0704] Plan 20

[0705] To a solution of sodium bicarbonate (0.3 mL, saturated solution) and Example 65 (3.6 mg, 0.01 mmol) in THF (0.5 mL) was added acetyl chloride (10 uL) at 0°C. The reaction was stirred at room temperature for 5 minutes, then diluted with EtOAc, and the organic phase was washed with saturated KHSO solution and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The product was dissolved in MeCN / water and freeze-dried to obtain the title compound (2.3 mg, 40%). 1 H NMR(300MHz, DMSO-d6)δ9.70(s,1H),8.47(s,1H),8.21(br t,J=5.6Hz,1H),7.76-7.59(m,6H),7.52-7.40(m,4H),7.39-7.30(m,4H),7.23(br d,J=8.0Hz,1H),5.12-4.93(m,1H),3.89-3.76(m,1H),3.74-3.60(m,1H),1.79(s,3H). C 27 H 24 F3N5O3 LCMS(ES + ) m / z calculated value 523.18; (M+H) + Found value 524. HPLCt R 3.66 minutes.

[0706] 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.

[0707] The title compound was synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 20). 1 HNMR(300MHz,DMSO-d6)δ9.70(s,1H),8.47(s,1H),8.21(br t,J=5.6Hz,1H),7.76-7.59(m,6H),7.52-7.40(m,4H),7.39-7.30(m,4H),7.23(br d,J=8.0Hz,1H),5.12-4.93(m,1H),3.89-3.76(m,1H),3.74-3.60(m,1H),1.79(s,3H). C 27 H 24 F3N5O3 LCMS(ES + ) m / z calculated value 523.18; (M+H) + Found 524. HPLC t R 3.66 minutes.

[0708] 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

[0709]

[0710] Plan 21

[0711] Step 1: 2-((4-bromobenzyl)amino)acetonitrile (Intermediate 31).

[0712] A suspension of DIPEA (31 mL, 180 mmol) and (4-bromobenzyl)amine hydrochloride (10 g, 45 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. After cooling, the solvent was removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The organic material was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the title compound, which was a yellow oil (9.07 g, 90%). C9H9BrN2 LCMS (ES + ) m / z calculated value 223.99; (M+H) + Found 225. HPLC t R 1.15 minutes.

[0713] Step 2: 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 32).

[0714] 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) and stirred at room temperature for 30 minutes. The mixture was then diluted with EtOAc, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to give 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. Excess solvent was removed under reduced pressure and the resulting crude compound was titrated with Et2O to give the title compound as a white powder (10.5 g, 90%). C9H9BrClN3O LCMS (ESI) + ) m / z calculated value 253.99 (parent); (M+H) + Found 254. HPLC t R 0.85 minutes.

[0715] Step 3: (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 33).

[0716] A solution of DIPEA (178 mg, 1.4 mmol) and [5-(trifluoromethyl)-3-pyridyl]amine (111.2 mg, 0.69 mmol), bis(trichloromethyl)carbonate (101.8 mg, 0.34 mmol) in anhydrous 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]oxadiazol-3-ium-5-amine; hydrochloride salt (Intermediate 32, 100 mg, 0.34 mmol) in anhydrous THF (2 mL) at 0° C. DIPEA (178 mg, 1.4 mmol) was added and the reaction mixture was stirred at room temperature for another 10 minutes before being diluted with water and extracted twice with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound (148 mg, 98%) as a white powder. 16 H 11 LCMS (ES) of BrF3N5O2 + ) m / z calculated value 441.00; (MH) - Found 440. HPLC t R 1.79 minutes.

[0717] 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).

[0718] A degassed suspension of KPO (36 mg, 0.17 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (15.9 mg, 0.11 mmol), Pd(dppf)Cl (4.1 mg, 0.006 mmol), (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) in a mixture of H0 (0.1 mL) and dioxane (1 mL) was stirred at 75°C for 1 h. After cooling, the reaction mixture was filtered over a pad of cellulose and the filtrate was evaporated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (eluting with 0-100% MeCN in water) to give a light yellow solid (12 mg). The title compound was obtained after further purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) to give the title compound as a white solid (4.0 mg, 14%). 1 H NMR(400MHz,DMSO-d6)δ9.96(br s,1H),8.91(d,J=2.0Hz,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). C 21 H 17 F3N6O3 LCMS(ES + ) m / z calculated value 458.13; (M+H) + Found 459. HPLC R 1.68 minutes.

[0719] Example 187 was synthesized according to the above procedure (Scheme 21) via reaction with appropriate starting materials.

[0720] 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.

[0721] Reaction with 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. 1 H NMR(400MHz,DMSO-d6)δ9.96(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,J1=7.0Hz,J2=1.7Hz,1H),5.86(s,2H),2.19(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.23(s,3F). C 22 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 469.15; (MH) - Found 468. HPLC t R 1.45 minutes.

[0722] Example 130: (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazole-3-yl 5-Chloronium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0723]

[0724] Plan 22

[0725] The title compound was prepared starting from intermediate 24 and 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine using the procedure described for the synthesis of Example 127. The title compound was obtained as a white solid (458 mg, 31%). 1 H NMR(400MHz,DMSO-d6)δ9.75(br s,1H),8.93(s,1H),8.59(d,J=1.8Hz,1H),8.29(s,1H),8.21(s,1H),7.97(dd,J1=8.0Hz,J2=2.3Hz,1H),7.79(d,J=8.0Hz,1H),7.74(br d,J=8.5Hz,1H),7.45(t,J=8.0Hz,1H),7.23(d,J=7.9Hz,1H),6.04(s,2H),2.21(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 18 F3N7O2 LCMS(ES + ) m / z calculated value 469.15; (M+H)+ Found 470. HPLC t R 1.52 minutes.

[0726] Examples 129, 143, 170, 172, 181 and 159 were synthesized according to the above procedure (Scheme 22) via reaction of intermediate 24 with the appropriate boronate ester.

[0727] 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.

[0728] 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(400MHz,DMSO-d6)δ9.75(br s,1H),9.24(s,1H),9.14(d,J=0.8Hz,1H),8.78(dd,J1=2.3Hz,J2=0.7Hz,1H),8.27(s,1H),8.21(s,1H),8.16(dd,J1=8.1Hz,J2= 2.3Hz, 1H), 7.83 (d, J = 7.6Hz, 1H), 7.74 (d, J = 8.9Hz, 1H), 7.45 (t, J = 8.1Hz, 1H), 7.23 (d, J = 7.8Hz, 1H), 6.05 (s, 2H), 2.34 (s, 3H). C 21 H 16 LCMS (ES) of F3N7O2 + ) m / z calculated value 455.13; (MH) - Found 454. HPLC t R 1.45 minutes.

[0729] 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.

[0730] Reaction of 1,3,5-trimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole afforded the title compound as a beige solid. 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),8.53(s,1H),8.23-8.20(m,2H),7.83(br d,J=8.1Hz,1H),7.75-7.69(m,2H),7.44(br t,J=7.9Hz,1H),7.22(br d,J=7.5Hz,1H),5.96(s,2H),3.72(s,3H),2.24(s,3H),2.14(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 20 LCMS (ES) of F3N7O2 + ) m / z calculated value 471.16; (MH) - Found 470. HPLC t R 1.61 minutes.

[0731] Example 170: (3-((3',5'-difluoro-[3,4'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0732] Reaction with (3,5-difluoro-4-pyridyl)boronic acid afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.75(s,1H),8.81(s,1H),8.73(s,2H),8.30(s,1H),8.20-8.18(m,2H),7.85(d,J=8.1Hz,1H),7.74(br d,J=8.3Hz,1H),7.45(br t,J=8.2Hz,1H),7.23(br d,J=7.5Hz,1H),6.06(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 13 LCMS (ES) of F5N6O2 + ) m / z calculated value 476.10; (MH) - Found 475. HPLC t R 1.74 minutes.

[0733] Example 172: (3-((2'-chloro-[3,3'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0734] Reaction with 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(br s,1H),8.73(d,J=2.0Hz,1H),8.51(dd,J1=4.8Hz,J2=1.8Hz,1H),8.26(s,1H),8.21(br s,1H),8.11(dd,J1=8.1Hz,J2=2.1Hz,1H),8.01(dd,J1=7.6Hz,J2=1.6Hz,1H),7.79(d,J=7.9Hz,1H),7.74(br d,J=8.6Hz,1H),7.59-7.57(m,1H),7.45(br t,J=8.1Hz,1H),7.23(br d,J=7.9Hz,1H),6.04(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 14 LCMS (ES) of ClF3N6O2 + ) m / z calculated value 474.08; (MH) - Found 473. HPLC t R 1.74 minutes.

[0735] 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.

[0736] Reaction with 3,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine afforded the title compound as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 8.86 (d, J = 2.1Hz, 1H), 8.24-8.21 (m, 3H), 7.7 9-7.75(m,2H),7.45-7.42(m,2H),7.23(d,J=7.6Hz,1H),6.02(s,2H),4.00(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 18 LCMS (ES) of F3N7O4 +) m / z calculated value 501.14; (MH) - Found value 500. HPLC t R 1.76 minutes.

[0737] Example 159: (3-((2'-methoxy-4'-methyl-[3,3'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0738] Reaction with 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.49 (d, J = 1.5Hz, 1H), 8.27 (s, 1H), 8.20 (br s,1H),8.09(d,J=5.3Hz,1H),7.86(dd,J1=8.1Hz,J2=2.2Hz,1H),7.73-7.71(m,2H),7.44(t,J= 8.0Hz, 1H), 7.22 (d, J = 7.7Hz, 1H), 7.01 (d, J = 5.3Hz, 1H), 6.00 (s, 2H), 3.76 (s, 3H), 2.08 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 484.15; (MH) - Found 483. HPLC t R 1.88 minutes.

[0739] Example 134: (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazole oxazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0740]

[0741] Plan 23

[0742] A degassed solution of (3-((5-boropyridin-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 water (0.2 mL) and dioxane (2.0 mL) was treated with 5-bromo-2-methoxy-4-methyl-pyrimidine (46 mg, 0.23 mmol), Pd(dppf)Cl2 (8.3 mg, 0.011 mmol), K3PO4 (72 mg, 0.34 mmol) and heated at 85°C for 1 h. After cooling, the mixture was diluted with EtOAc and filtered through a cellulose pad. Excess solvent was removed under reduced pressure. The title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) to afford the title compound as a cream solid (9.5 mg, 16%). 1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.68(s,1H),8.50(s,1H),8.26(s,1H),8.20(br s,1H),8.05(dd,J1=8.1Hz,J2=2.0Hz,1H),7.78(d,J=7.9Hz,1H),7.74(br d,J=8.3Hz,1H),7.44(t,J=7.9Hz,1H),7.23(br d,J=7.2Hz,1H),6.02(s,2H),3.95(s,3H),2.41(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 18 LCMS (ES) of F3N7O3 + ) m / z calculated value 485.14; (MH) - Found 484. HPLC t R 1.68 minutes.

[0743] Examples 131, 135, 138, 139, 148, 151, 155, 160, 162, 163, 164, 165, 179, 180, 177, 176, 175 and 132 were synthesized by reacting Example 122 or similar boronic acids with appropriate starting materials according to the above procedure (Scheme 23).

[0744] 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.

[0745] Reaction with 5-bromo-4-(trifluoromethyl)pyrimidine afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(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=7.9Hz,1H),7.83(d,J=8.1Hz,1H),7.75(br d,J=8.3Hz,1H),7.45(t,J=8.0Hz,1H),7.23(br d,J=8.8Hz,1H),6.07(s,2H). 19 F NMR(377MHz, DMSO-d6)δ-61.29(s,3F),-62.39(s,3F). C 21 H 13 LCMS (ES) of F6N7O2 + ) m / z calculated value 509.10; (MH) - Found value 508. HPLCt R 1.79 minutes.

[0746] 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.

[0747] Reaction with 5-bromo-4-methoxy-6-methyl-pyrimidine afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.67(br s,1H),8.66(s,1H),8.50(s,1H),8.21(br s,1H),8.13(s,1H),7.88(br d,J=8.0Hz,1H),7.67(d,J=8.1Hz,2H),7.37(t,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),5.94(s,2H),3.79(s,3H),2.18(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 18 LCMS (ES) of F3N7O3 + ) m / z calculated value 485.14; (MH) - Found 484. HPLC t R 1.62 minutes.

[0748] Example 138: (3-((2'-Methyl-[3,3'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0749] Reaction with 3-bromo-2-methyl-pyridine afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.75(br s,1H),8.71(br s,2H),8.27(s,1H),8.21(br s,1H),8.11-8.07(m,2H),7.81(br d,J=8.0Hz,1H),7.74(br d,J=7.9Hz,1H),7.69-7.66(m,1H),7.45(t,J=8.0Hz,1H),7.23(br d,J=7.9Hz,1H),6.04(s,2H),2.55(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.22 minutes.

[0750] Example 139: (3-((4'-Methyl-[3,3'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0751] Reaction with 3-bromo-4-methyl-pyridine afforded the title compound as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ9.75(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,J1=8.0Hz,J2=1.9Hz,1H),7.82(br d,J=7.9Hz,1H),7.75-7.70(m,2H),7.45(t,J=8.0Hz,1H),7.23(br d,J=7.7Hz,1H),6.06(s,2H),2.40(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.27 minutes.

[0752] 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.

[0753] Reaction with 5-bromopyrimidine-4-carbonitrile afforded the title compound as a cream-colored solid. 1 H NMR (400MHz, DMSO-d6) δ9.75(br s,1H),9.48(s,1H),9.35(s,1H),8.95(s,1H),8.36(dd,J1=8.1Hz,J2=2.2Hz,1H),8.29(s,1H),8.20(br s,1H),7.90(d,J=8.1Hz,1H),7.74(br d,J=8.1Hz,1H),7.45(t,J=8.0Hz,1H),7.23(br d,J=7.9Hz,1H),6.09(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 13 LCMS (ES) of F3N8O2 + ) m / z calculated value 466.11; (MH) - Found 465. HPLC t R 1.65 minutes.

[0754] 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.

[0755] Reaction with 4-bromo-3,5-dimethyl-1H-pyrazole afforded the title compound as a cream-colored solid. 1H NMR (400MHz, DMSO-d6) δ9.73(br s,1H),8.57(s,1H),8.24(s,1H),8.20(br s,1H),7.87(d,J=8.1Hz,1H),7.74(d,J=8.6Hz,1H),7.69(br d,J=7.9Hz,1H),7.44(t,J=8.1Hz,1H),7.23(br d,J=7.5Hz,1H),5.96(s,2H),2.22(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 457.15; (MH) - Found 456. HPLC t R 1.49 minutes.

[0756] Example 155: (3-((5-(4-Cyclopropylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0757] Reaction with 5-bromo-4-cyclopropylpyrimidine afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.74(br s,1H),9.03(s,1H),8.77(s,1H),8.62(s,1H),8.27(s,1H),8.21(br s,1H),8.14-8.12(m,1H),7.83(d,J=7.9Hz,1H),7.74(d,J=8.2Hz,1H),7.45(t,J=7.9Hz,1H),7.23(br d,J=7.6Hz,1H),6.04(s,2H),2.00-1.94(m,1H),1.18-1.13(m,2H),1.08-1.05(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 23 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 481.15; (MH) - Found 480. HPLC t R 1.74 minutes.

[0758] Example 160: (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0759] Reaction with 4-bromopyridazine afforded the title compound as a cream-colored solid. 1 H NMR(400MHz,DMSO-d6)δ9.73(br s,2H),9.36(d,J=5.4Hz,1H),9.15(s,1H),8.48(d,J=2.0Hz,1H),8.24(s,1H),8.20(s,1H),8.13(dd,J1=5.3H z,J2=2.3Hz,1H),7.87-7.85(m,1H),7.76-7.73(m,1H),7.44(t,J=7.9Hz,1H),7.23-7.22(m,1H),6.05(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 14 LCMS (ES) of F3N7O2 + ) m / z calculated value 441.12; (MH) - Found 440. HPLC t R 1.40 minutes.

[0760] Example 162: (3-((5-(4-methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0761] Reaction with 3-bromo-4-methyl-pyridazine afforded the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ9.74(br s,1H),9.14(d,J=5.3Hz,1H),8.87(d,J=1.6Hz,1H),8.29(s,1H),8.24(dd,J1=7.9Hz,J2=2.3Hz,1H),8.21(s,1H),7.82(d,J=7.9Hz,1H),7.75(br d,J=8.6Hz,1H),7.71(dd,J1=5.1Hz,J2=0.8Hz,1H),7.45(t,J=8.1Hz,1H),7.23(br d,J=7.9Hz,1H),6.07(s,2H),2.37(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C21 H 16 LCMS (ES) of F3N7O2 + ) m / z calculated value 455.13; (MH) - Found 454. HPLC t R 1.46 minutes.

[0762] Example 163: (3-((3'-Methyl-[3,4'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0763] Reaction with 4-bromo-3-methyl-pyridine hydrochloride afforded the title compound as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.74(br s,1H),8.68(d,J=2.0Hz,1H),8.56(s,1H),8.50(d,J=5.0Hz,1H),8.26(s,1H),8.20(s,1H),8.05(dd,J1=8.0Hz,J2=2.3H z,1H),7.77-7.73(m,2H),7.44(t,J=8.0Hz,1H),7.33(d,J=5.0Hz,1H),7.22(d,J=7.5Hz,1H),6.03(s,2H),2.27(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 22 H 17 LCMS (ES) of F3N6O2 + ) m / z calculated value 454.14; (MH) - Found 453. HPLC t R 1.25 minutes.

[0764] Example 164: (3-((3'-Fluoro-[3,4'-bipyridinium]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0765] Reaction with 4-bromo-3-fluoro-pyridine afforded the title compound as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ9.73(br s,1H),8.90(s,1H),8.74(d,J=2.3Hz,1H),8.58(d,J=4.9Hz,1H),8.26-8.24(m,2H),8.21(s,1H),7 .84(d,J=8.2Hz,1H),7.76-7.74(m,2H),7.45(t,J=8.1Hz,1H),7.23(d,J=7.9Hz,1H),6.05(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 14 LCMS (ES) of F4N6O2 + ) m / z calculated value 458.11; (MH) - Found 457. HPLC t R 1.65 minutes.

[0766] 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.

[0767] Reaction with 5-bromo-1,4-dimethyl-pyrazole afforded the title compound as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ9.74(br s,1H),8.69(s,1H),8.28(s,1H),8.21(s,1H),8.04(dd,J1=8.2Hz,J2=2.3Hz,1H),7.80(d,J=7.9Hz,1H),7.74(br d,J=8.6Hz,1H),7.45(t,J=7.9Hz,1H),7.39(s,1H),7.23(d,J=7.6Hz,1H),6.04(s,2H),3.74(s,3H),1.99(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 457.15; (MH) - Found 456. HPLC t R 1.66 minutes.

[0768] 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.

[0769] Reaction with 4-chloro-5-iodopyrimidine afforded the title compound as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.75(br s,1H),9.13(s,1H),8.96(s,1H),8.81-8.80(m,1H),8.27(s,1H),8.21(d,J=2.0Hz,1H),8.19(d,J=2.3Hz,1 H), 7.83 (d, J = 8.1Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.45 (t, J = 7.9Hz, 1H), 7.23 (d, J = 7.6Hz, 1H), 6.05 (s, 2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 13 LCMS (ES) of ClF3N7O2 + ) m / z calculated value 475.08; (MH) - Found 474. HPLC t R 1.63 minutes.

[0770] Example 180: (3-((5-(4,6-Dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0771] Reaction with 4,6-dichloro-5-iodopyrimidine afforded the title compound as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.76(br s,1H),9.02(s,1H),8.71(d,J=1.8Hz,1H),8.30(s,1H),8.21(s,1H),8.10(dd,J1=8.1Hz,J2=2.2Hz,1H),7.83(d,J=8.1Hz,1H),7.75(br d,J=8.3Hz,1H),7.45(t,J=7.9Hz,1H),7.23(d,J=7.6Hz,1H),6.06(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.27(s,3F). C 20 H 12 LCMS (ES) of Cl2F3N7O2+ ) m / z calculated value 509.04; (MH) - Found 508. HPLC t R 1.78 minutes.

[0772] 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.

[0773] Reaction with 5-bromo-4-(trifluoromethyl)pyrimidine afforded the title compound as a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.19(s,1H),9.53(s,1H),9.16(s,1H),8.70(d,J=2.0Hz,1H),8.47(d,J=5.6Hz,1H),8.36(s,1H),8.2 0 (d, J = 2.0Hz, 1H), 8.08 (dd, J1 = 8.2Hz, J2 = 2.3Hz, 1H), 7.83 (d, J = 7.9Hz, 1H), 7.72 (dd, J1 = 5.6Hz, J2 = 1.6Hz, 1H), 6.11 (s, 2H). 19 F NMR(377MHz,DMSO-d6)δ-62.38(s,3F). C 20 H 12 LCMS (ES) of F6N8O2 + ) m / z calculated value 510.10; (MH) - Found 509. HPLC t R 1.54 minutes.

[0774] 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.

[0775] Reaction with 5-bromo-4,6-dimethyl-pyrimidine afforded the title compound as a white solid. 1H NMR(600MHz,DMSO-d6)δ10.19(br s,1H),8.94(s,1H),8.59(d,J=2.0Hz,1H),8.47(d,J=5.6Hz,1H),8.37(s,1H),8.20(d,J=1.6Hz,1H),7.97(dd,J1=7. 9Hz, J2=2.3Hz, 1H), 7.80 (d, J=7.9Hz, 1H), 7.72 (dd, J1=5.8Hz, J2=1.8Hz, 1H), 6.09 (s, 2H), 2.55 (s, 3H), 2.21 (s, 3H). 19 FNMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 21 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 470.14; (MH) - Found 469. HPLC t R 1.26 minutes.

[0776] 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.

[0777] Reaction with 5-bromo-1,4-dimethyl-1H-pyrazole gave the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.67(d,J=2.0Hz,1H),8.45(d,J=5.6Hz,1H),8.36(s,1H),8.18(d,J=1.6Hz,1H),8.03(dd,J1=8.0Hz,J2=2.3H z, 1H), 7.80 (d, J = 8.1Hz, 1H), 7.70 (dd, J1 = 5.6Hz, J2 = 1.6Hz, 1H), 7.38 (s, 1H), 6.06 (s, 2H), 3.73 (s, 3H), 1.98 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 20 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 458.14; (MH) - Found 457. HPLC t R 1.41 minutes.

[0778] 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.

[0779] Reaction with 5-bromo-4,6-dimethyl-pyrimidine afforded the title compound as a white solid. 21 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 470.14; (MH) - Found 469. HPLC t R 1.26 minutes.

[0780] Example 126: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazole- 3-(5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0781]

[0782] Plan 24

[0783] Step 1: (3-((5-Bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 35).

[0784] DIPEA (118 mg, 0.91 mmol) and [5-(trifluoromethyl)-3-pyridinyl]amine (74 mg, 0.46 mmol) in anhydrous THF (1.8 mL) were treated with triphosgene (68 mg, 0.23 mmol), stirred at room temperature for 30 minutes, cooled to 0°C, and treated dropwise with DIPEA (118 mg, 0.91 mmol) and 3-[(5-bromo-2-pyridinyl)methyl]oxadiazol-3-ium-5-amine dihydrochloride (Intermediate 34, 75 mg, 0.23 mmol; prepared as described for the synthesis of Intermediate 24) in anhydrous THF (1 mL). The reaction mixture was stirred at room temperature for 5 minutes, diluted with water, and extracted with EtOAC (2x). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (gradient of 0% to 100% EtOAc in petroleum ether) to give the title compound (49 mg, 49%) as a white powder. 15 H 10 LCMS (ES) of BrF3N6O5 + ) m / z calculated value 442.00; (MH) - Found 441-443. HPLC t R 1.61 minutes.

[0785] 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).

[0786] A degassed suspension of K3PO4 (28.7 mg, 0.14 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (12.7 mg, 0.09 mmol), Pd(dppf)Cl2 (3.3 mg, 0.006 mmol), [3-[(5-bromo-2-pyridinyl)methyl]oxadiazol-3-ium-5-yl]-[[5-(trifluoromethyl)-3-pyridinyl]carbamoyl]carbamoyl]pyridine (Intermediate 35, 20 mg, 0.045 mmol) in a mixture of H2O (0.1 mL) and dioxane (1 mL) was stirred at 75°C for 1 h. After cooling, the reaction mixture was filtered over a cellulose pad and the filtrate was evaporated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (eluting with 0-100% MeCN in water) to give the title compound as a white solid (12.0 mg, 57%). 1 H NMR(400MHz,DMSO-d6)δ9.98(br s,1H),8.92(d,J=2.3Hz,1H),8.67(dd,J1=2.3Hz,J2=0.6Hz,1H),8.55(t,J=2.0Hz,1H),8.49-8.47(m,1H),8 .30(s,1H),8.01(dd,J1=8.1Hz,J2=2.3Hz,1H),7.77(d,J=8.1Hz,1H),6.02(s,2H),2.44(s,3H),2.26(s,3H). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.52 minutes.

[0787] Examples 125, 128, 147, 150, 152, 153, 154, 156, 157, 158, 161, 166, 168 and 171 were synthesized according to the above procedure (Scheme 24) via reaction with appropriate commercial substances.

[0788] 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.

[0789] Reaction with 5-pyrimidinylboronic acid afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),9.25(s,2H),9.06(dd,J1=2.3Hz,J2=0.7Hz,1H),8.92(d,J=2.4Hz,1H),8.55(br t,J=2.1Hz,1H),8.48(br d,J=1.0Hz,1H),8.39(dd,J1=8.1Hz,J2=2.4Hz,1H),8.29(s,1H),7.84(d,J=8.1Hz,1H),7.53(br s,1H),6.05(s,2H). C 19 H 13 LCMS (ES) of F3N8O2 + ) m / z calculated value 442.11; (MH) - Found 441. HPLC t R 1.21 minutes.

[0790] Example 128: (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.

[0791] Reaction with 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 (400MHz, DMSO-d6) δ9.99(br s,1H),9.24(s,1H),9.14(d,J=0.9Hz,1H),8.93(d,J=2.3Hz,1H),8.78(dd,J1=2.3Hz,J2=0.8Hz,1H),8.55(br t,J=2.0Hz,1H),8.50-8.47(m,1H),8.32(s,1H),8.16(dd,J1=8.1Hz,J2=2.3Hz,1H),7.84(d,J=7.5Hz,1H),6.07(s,2H),2.35(s,3H). C 20 H 15 LCMS (ES) of F3N8O2 + ) m / z calculated value 456.13; (MH)- Found 455. HPLC t R 1.19 minutes.

[0792] 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.

[0793] Reaction with 1,3,5-trimethyl-4-(tetramethyl-1,3,3-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.98 (br s, 1H), 8.92 (d, J = 2.3Hz, 1H), 8.55 (br t,J=2.1Hz,1H),8.52(dd,J1=2.3Hz,J2=0.8Hz,1H),8.50-8.45(m,1H),8.29(s,1H),7.83(dd,J1= 8.1Hz, J2 = 2.3Hz, 1H), 7.70 (d, J = 7.8Hz, 1H), 5.98 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 3.14 (s, 3H). C 21 H 19 LCMS (ES) of F3N8O2 + ) m / z calculated value 472.16; (MH) - Found 471. HPLC t R 1.37 minutes.

[0794] 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.

[0795] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ9.76(br s,1H),8.67-8.66(m,1H),8.25(s,1H),8.24-8.21(m,1H),8.00(dd,J1=8.1Hz,J2=2.3H z,1H),7.79-7.75(m,2H),7.38(t,J=9.9Hz,1H),6.00(s,2H),2.44(s,3H),2.26(s,3H). C 21 H 16LCMS (ES) of F4N6O3 + ) m / z calculated value 476.12; (MH) - Found 475. HPLC t R 1.77 minutes.

[0796] 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.

[0797] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.67(s,1H),8.47(d,J=5.4Hz,1H),8.34(s,1H),8.19(s,1H),8.01(dd,J1=8.0Hz,J2=1.7Hz,1H),7.77(d,J=8.1Hz,1H),7.71(br d,J=4.8Hz,1H),6.04(s,2H),2.44(s,3H),2.26(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.49 minutes.

[0798] 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.

[0799] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.93(br s,1H),8.67(s,1H),8.27(s,1H),8.00(dd,J1=7.9Hz,J2=1.6Hz,1H),7.90(s,1H) ,7.78-7.74(m,2H),7.13(d,J=8.2Hz,1H),6.02(s,2H),2.44(s,3H),2.26(s,3H).19 F NMR(377MHz,DMSO-d6)δ-61.54(s,3F). C 21 H 16 LCMS (ES) of F4N6O3 + ) m / z calculated value 476.12; (MH) - Found 475. HPLC t R 1.86 minutes.

[0800] 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.

[0801] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.19(br s,1H),8.66(s,1H),8.34(s,1H),8.00(dd,J1=8.0Hz,J2=1.7Hz,1H),8.77(d,J=8.1Hz,1H),7.52(s,1H),6.05(s,2H),2.43(s,3H),2.26(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-58.95(s,3F). C 18 H 14 LCMS (ES) of F3N7O3S + ) m / z calculated value 465.08; (MH) - Found 464. HPLC t R 1.60 minutes.

[0802] 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.

[0803] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.67 (d, J = 2.3Hz, 1H), 8.24 (s, 1H), 8.01-7.98 (m, 2H), 7.77 (d,J=7.9Hz,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(377MHz,DMSO-d6)δ-61.23(s,3F). C 22 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 472.15; (MH) - Found 471. HPLC t R 1.87 minutes.

[0804] 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.

[0805] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ9.85(s,1H),8.67(d,J=2.0Hz,1H),8.34(d,J=2.6Hz,1H),8.27(s,1H),8.00(dd,J1 =7.9Hz, J2=2.3Hz, 1H), 7.76 (d, J = 8.3Hz, 2H), 7.56 (d, J = 8.9Hz, 1H), 6.01 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ-61.39(s,3F). C 21 H 16 LCMS (ES) of ClF3N6O3 + ) m / z calculated value 492.09; (MH) - Found 491. HPLC t R 1.90 minutes.

[0806] 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.

[0807] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.60(br s,1H),8.67(s,1H),8.23(s,1H),8.16(br s,1H),8.00(dd,J1=8.1Hz,J2=1.8Hz,1H),7.76(d,J=8.1Hz,1H),7.64(br d,J=8.1Hz,1H),7.27(t,J=8.4Hz,1H),5.99(s,2H),2.44(s,3H),2.35(s,3H),2.26(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-60.34(s,3F).C 22 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 472.15; (MH) - Found 471. HPLC t R 1.82 minutes.

[0808] 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.

[0809] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ9.82(s,1H),8.67(d,J=2.0Hz,1H),8.37(d,J=8.6Hz,1H),8.25(s,1H),8.00(dd,J1=8.2Hz,J2 =2.3Hz, 1H), 7.96 (t, J = 8.1Hz, 1H), 7.77 (d, J = 8.2Hz, 1H), 7.42 (d, J = 7.2Hz, 1H), 6.04 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ-66.60(s,3F). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.67 minutes.

[0810] 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.

[0811] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 HNMR (400MHz, DMSO-d6) δ11.85(br s,1H),8.67(d,J=2.0Hz,1H),8.40(s,1H),8.01(dd,J1=7.9Hz,J2=2.3Hz,1H),7.92(d,J=1.3Hz,1H),7.78(br d,J=7.9Hz,1H),6.07(s,2H),2.44(s,3H),2.26(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-52.55(s,3F). C 18 H 14 LCMS (ES) of F3N7O3S + ) m / z calculated value 465.08; (MH) - Found 464. HPLC t R 1.65 minutes.

[0812] 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.

[0813] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 HNMR(400MHz,DMSO-d6)δ9.61(br s,1H),8.67(dd,J1=2.2Hz,J2=0.7Hz,1H),8.20(s,1H),8.02-7.97(m,2H),7.77(d,J=7.6Hz,1H),7.67-7 .64(m,1H),7.35(t,J=7.9Hz,1H),7.09-7.07(m,1H),6.95(s,1H),5.99(s,2H),2.44(s,3H),2.26(s,3H). C 21 H 18 LCMS (ES) of F2N6O3 + ) m / z calculated value 440.14; (MH) - Found 439. HPLC tR 1.55 minutes.

[0814] 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.

[0815] Reaction with (3,5-dimethylisoxazol-4-yl)boronic acid afforded the title compound as a white solid. 1 HNMR (400MHz, DMSO-d6) δ10.26(s,1H),8.89(d,J=4.9Hz,1H),8.68(d,J=2.1Hz,1H),8.29(s,1H),8.01(dd,J 1=8.0Hz, J2=2.3Hz,1H),7.77(d,J=8.0Hz,1H),7.47(d,J=5.0Hz,1H),6.03(s,2H),2.43(s,3H),2.25(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-68.87(s,3F). C 19 H 15 LCMS (ES) of F3N8O3 + ) m / z calculated value 460.12; (MH) - Found 459. HPLC t R 1.34 minutes.

[0816] Example 133: (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazole oxazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0817]

[0818] Plan 25

[0819] 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).

[0820] A degassed suspension of KOAc (26.6 mg, 0.27 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (45.8 mg, 0.18 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), Pd(dppf)Cl (6.6 mg, 0.009 mmol) in anhydrous dioxane (1 mL) was stirred at 75 °C for 2 h, then cooled and filtered through a cellulose pad. The filtrate was concentrated in vacuo to give a residue that was used in the subsequent step without further purification.

[0821] 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).

[0822] A degassed suspension of K3PO4 (57.3 mg, 0.27 mmol) and 5-bromo-2-methoxy-4-methylpyrimidine (36.6 mg, 0.18 mmol), Pd(dppf)Cl2 (6.6 mg, 0.01 mmol), (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 a mixture of H2O (0.1 mL) and dioxane (1 mL) was stirred at 75°C for 1 h. After cooling, the reaction mixture was filtered on a cellulose pad and the title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) as a white solid (14 mg, 30%). 1 HNMR(400MHz,DMSO-d6)δ9.99(br s,1H),8.93(d,J=2.1Hz,1H),8.68(br s,1H),8.55(brs,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=8.1Hz,1H),6.04(s,2H),3.95(s,3H),2.41(s,3H). C 21 H 17 LCMS (ES) of F3N8O3+ ) m / z calculated value 486.14; (MH) - Found 485. HPLC t R 1.43 minutes.

[0823] Examples 136, 137, 140, 141, 144, 145, 149 and 178 were synthesized by reacting intermediate 36 with appropriate starting materials according to the procedure described above (Scheme 25).

[0824] 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.

[0825] Reaction with 5-bromo-4-methoxy-6-methyl-pyrimidine afforded the title compound as a white solid. 21 H 17 LCMS (ES) of F3N8O3 + ) m / z calculated value 486.14; (MH) - Found 485. HPLC t R 1.36 minutes.

[0826] 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.

[0827] Reaction with 5-bromo-4-(trifluoromethyl)-pyrimidine afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.98(br s,1H),9.52(s,1H),9.18(s,1H),8.93(d,J=2.3Hz,1H),8.70(d,J=2.1Hz,1H),8.55(br s,1H),8.48(d,J=1.0Hz,1H),8.32(s,1H),8.08(dd,J1=8.1Hz,J2=2.2Hz,1H),7.83(d,J=8.0Hz,1H),6.09(s,2H). C 20 H 12 LCMS (ES) of F6N8O2 + ) m / z calculated value 510.10; (MH) - Found 509. HPLC t R 1.55 minutes.

[0828] 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.

[0829] Reaction with 5-bromo-1,4-dimethyl-imidazole afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.99(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). C 20 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 458.14; (MH) - Found 457. HPLC t R 0.94 minutes.

[0830] 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.

[0831] Reaction with 3-bromo-2-methyl-pyridine afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.99(br s,1H),8.93(d,J=2.3Hz,1H),8.66(d,J=1.6Hz,1H),8.55(br t,J=2.3Hz,1H),8.52(dd,J1=4.8Hz,J2=1.7Hz,1H),8.48(br s,1H),8.31(s,1H),8.03(dd,J1=8.0Hz,J2=2.3Hz,1H),7.77(d,J=8.0Hz,1H),7.70(dd, J1=7.8Hz, J2=1.8Hz, 1H), 7.36(dd, J1=7.8Hz, J2=5.1Hz, 1H), 6.04(s, 2H), 2.45(s, 3H). C 21 H 16 LCMS (ES) of F3N7O2 + ) m / z calculated value 455.13; (MH) -Found 454. HPLC t R 0.99 minutes.

[0832] Example 144: (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.

[0833] Reaction with 5-bromo-pyrimidine-4-carbonitrile afforded the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.99(br s,1H),9.48(s,1H),9.36(s,1H),8.94(dd,J1=8.5Hz,J2=2.3Hz,2H),8.55(br s,1H),8.48(br s, 1H), 8.36 (dd, J1 = 8.1Hz, J2 = 2.3Hz, 1H), 8.33 (s, 1H), 7.90 (d, J = 8.1Hz, 1H), 6.11 (s, 2H). C 20 H 12 LCMS (ES) of F3N9O2 + ) m / z calculated value 467.11; (MH) - Found 466. HPLC t R 1.40 minutes.

[0834] 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.

[0835] Reaction with 4-bromopyridazine hydrobromide afforded the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ9.98(br s,1H),9.74(dd,J1=2.5Hz,J2=1.3Hz,1H),9.36(dd,J1=5.4Hz,J2=1.2Hz,1H),9.15(d,J=1.8Hz,1H),8.93(d,J=2.3Hz,1H),8.55(br s,1H),8.50-8.47(m,2H),8.30(s,1H),8.13(dd,J1=5.4Hz,J2=2.5Hz,1H),7.86(d,J=8.1Hz,1H),6.07(s,2H). C 19 H 13 LCMS (ES) of F3N8O2 + ) m / z calculated value 442.11; (MH)- Found 441. HPLC t R 1.15 minutes.

[0836] Example 149: (3-((4'-Methyl-[3,3'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide.

[0837] Reaction with 3-bromo-4-methyl-pyridine afforded the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.99(br s,1H),8.93(d,J=2.3Hz,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,1 H), 8.04 (dd, J1 = 8.0Hz, J2 = 2.4Hz, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.39 (d, J = 5.0Hz, 1H), 6.05 (s, 2H), 2.29 (s, 3H). C 21 H 16 LCMS (ES) of F3N7O2 + ) m / z calculated value 455.13; (MH) - Found 454. HPLC t R 1.04 minutes.

[0838] 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.

[0839] Reaction with 5-bromo-1,4-dimethyl-1H-pyrazole gave the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),8.93(d,J=2.0Hz,1H),8.68(d,J=2.0Hz,1H),8.55(s,1H),8.48(s,1H),8.33(s ,1H),8.04(dd,J1=8.1Hz,J2=2.2Hz,1H),7.80(d,J=8.1Hz,1H),7.39(s,1H),6.05(s,2H),3.74(s,3H),1.98(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.21(s,3F). C 20H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 458.14; (MH) - Found 457. HPLC t R 1.40 minutes.

[0840] Example 167: (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazole- 3-(trifluoromethyl)phenyl)carbamoyl)amide

[0841]

[0842] Plan 26

[0843] Step 1: 2-(((5-bromopyrimidin-2-yl)methyl)amino)acetonitrile (Intermediate 37).

[0844] A suspension of (5-bromopyrimidin-2-yl)-methylamine (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) and stirred at 60 °C for 2 h before cooling, diluting with EtOAC, washing with water, brine, drying over Na2SO4 and concentrating under reduced pressure to give a residue which was purified by silica gel chromatography (eluent gradient 10% to 100% EtOAc in petroleum ether) to give the title compound as an orange powder (410 mg, 68%). 1 HNMR (600MHz, DMSO-d6) δ8.97 (s, 2H), 3.93 (d, J = 5.9Hz, 2H), 3.72 (d, J = 5.8Hz, 2H), 3.14-3.12 (m, 1H). C7H7BrN4LCMS(ES + ) m / z calculated value 225.99; (M+H) + Found 226. HPLC t R 0.62 minutes.

[0845] Step 2: 5-amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 38).

[0846] 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 {tert}-butyl nitrite (530 mg, 5.15 mmol) and stirred at room temperature for 30 min, then diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitrosamide (440 mg, 100%) as a brown residue which was used in the subsequent step without further purification. The obtained intermediate N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitramide (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 and 30 minutes, then quenched with water, concentrated under reduced pressure to give 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 in the subsequent step without further purification. 1 H NMR (600MHz, DMSO-d6) δ9.57(s,2H),9.10(s,2H),8.10(s,1H),6.22(s,2H). C7H7BrClN5O LCMS(ES + ) m / z calculated value 255.98 (parent); (M+H) + Found 256-258. HPLC t R 0.46 minutes.

[0847] Step 3: (3-((5-Bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 39).

[0848] A suspension of 5-amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazole-3-ammonium 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. and stirred at room temperature for 5 minutes, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent gradient 10% to 100% EtOAc in petroleum ether) to give the title compound (205 mg, 89%) as a pale yellow powder. 1 H NMR(600MHz,DMSO-d6)δ9.75(s,1H),9.09(s,2H),8.28(s,1H),8.20(s,1H),7. 75(d,J=8.2Hz,1H), 7.45(t,J=8.1Hz,1H), 7.23(d,J=7.9Hz,1H), 6.12(s,2H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 15 H 10 LCMS (ES) of BrF3N6O2 + ) m / z calculated value 442.00; (MH) - Found 441. HPLC t R 1.75 minutes.

[0849] 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).

[0850] A degassed suspension of KPO (43.1 mg, 0.20 mmol) and Pd(dppf)Cl (5 mg, 0.0068 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (19.1 mg, 0.14 mmol), (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) in a mixture of water (0.1 mL) and dioxane (1 mL) was heated at 80 °C for 1 h before being cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over NaSO and evaporated in vacuo. The title compound was obtained after purification by RP-HPLC using water and MeCN as eluents (C18 column) to afford the title compound as a beige solid (18 mg, 56%). 1 H NMR(600MHz,DMSO-d6)δ9.75(br s,1H),8.99(s,2H),8.32(s,1H),8.21(s,1H),7.76(d,J=8.6Hz,1H),7.45(t ,J=8.1Hz,1H),7.23(d,J=7.9Hz,1H),6.20(s,2H),2.47(s,3H),2.28(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.71 minutes.

[0851] Examples 169, 173, 174, 183 and 184 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 26).

[0852] 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.

[0853] The title compound was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.75(br s,1H),9.00(s,1H),8.90(d,J=1.4Hz,1H),8.30(s,1H),8.21(s,1H),7.73(br d,J=8.1Hz,1H),7.46-7.42(m,1H),7.23(br d,J=7.8Hz,1H),6.07(s,2H),2.62(s,3H),2.42(s,3H). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.76 minutes.

[0854] 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.

[0855] The title compound was obtained as a beige solid. 1 H NMR(600MHz,DMSO-d6)δ9.75(s,1H),8.34(s,1H),8.21(s,1H),8.07-8.02(m,2H),7.74(d,J=8 .6Hz,1H),7.45(t,J=8.1Hz,1H),7.23(d,J=7.9Hz,1H),6.20(s,2H),2.61(s,3H),2.41(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.64 minutes.

[0856] 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.

[0857] The title compound was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.10(s,2H),8.37(s,1H),8.23(s,1H),7.72(br d,J=8.1Hz,1H),7.44(t,J=8.0Hz,1H),7.23(d,J=7.6Hz,1H),5.88(s,2H),2.77(s,3H),2.52(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-61.29(s,3F). C 20 H 16 LCMS (ES) of F3N7O3 + ) m / z calculated value 459.13; (MH) - Found 458. HPLC t R 1.83 minutes.

[0858] Example 183: (3-((4',6'-dimethyl-[5,5'-dipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

[0859] The title compound was obtained as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.96(s,3H),8.36(s,1H),8.21(s,1H),7.76(br d,J=8.3Hz,1H),7.45(t,J=7.9Hz,1H),7.23(d,J=7.1Hz,1H),6.23(s,2H),2.25(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 470.14; (MH) - Found 469. HPLC t R 1.51 minutes.

[0860] 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.

[0861] The title compound was obtained as a pale pink solid. 1H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.02(s,1H),8.41(s,1H),8.22(s,1H),8.13(d,J=8.6Hz,1H),8.06(d, J=8.6Hz,1H),7.75(d,J=8.3Hz,1H),7.45(t,J=7.9Hz,1H),7.23(d,J=7.6Hz,1H),6.26(s,2H),2.22(s,6H). 19 FNMR(377MHz,DMSO-d6)δ-61.28(s,3F). C 21 H 17 LCMS (ES) of F3N8O2 + ) m / z calculated value 470.14; (MH) - Found 469. HPLC t R 1.43 minutes.

[0862] Example 142: ((3-cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyrrolidone (2-pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0863]

[0864] Plan 27

[0865] Step 1: (3-((5-Bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)carbamoyl)amide (Intermediate 40).

[0866] The mixture of diphosgene (280mg, 1.4mmol) and 3-cyclopropylaniline (62mg, 0.47mmol) in anhydrous dioxane (9.3mL) is heated to 60°C for 20 hours. After cooling, the solvent is removed under reduced pressure. At 0°C, the 1-cyclopropyl-3-isocyanato-benzene (53.2mg, 0.334mmol) and anhydrous pyridine (192mg, 2.43mmol) obtained are added dropwise to a stirred suspension of 3-[(5-bromo-2-pyridyl)methyl]oxadiazol-3-ium-5-amine dihydrochloride (intermediate 34, 100mg, 0.304mmol) in anhydrous MeCN (0.9mL), and the reaction mixture is stirred at room temperature for 5 minutes, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent gradient 5% to 100% EtOAc in petroleum ether) to give the title compound (86 mg, 68%) as a yellow powder. 1H NMR(400MHz,DMSO-d6)δ9.24(br s,1H),8.75(s,1H),8.20(dd,J1=8.3Hz,J2=2.0Hz,1H),8.13(s,1H),7.64(d,J=8.3Hz,1H),7.41(s,1H),7.33(d,J=8.1Hz ,1H),7.06(t,J=7.9Hz,1H),6.63(d,J=7.7Hz,1H),5.91(s,2H),1.85-1.78(m,1H),0.93-0.89(m,2H),0.61-0.57(m,2H). C 18 H 16 LCMS (ES) of BrN5O2 + ) m / z calculated value 413.05; (MH) - Found 412-414. HPLC t R 1.73 minutes.

[0867] Step 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).

[0868] K3PO4 (38 mg, 0.18 mmol) and Pd(dppf)Cl2 (4.4 mg, 0.006 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (17 mg, 0.12 mmol), (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)-1,2-dopamine ... A degassed suspension of 2-(4-aminobenzoyl)-1-nitropropane (2-[4-(2-aminobenzoyl)-1-nitropropane)amide (Intermediate 40, 25 mg, 0.06 mmol) was heated at 80 °C for 1.5 h then cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and evaporated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent gradient 5% to 100% EtOAc in petroleum ether) to afford the title compound as a yellow powder (15.5 mg, 58%). 1H NMR(400MHz,DMSO-d6)δ9.24(br s,1H),8.67(s,1H),8.17(s,1H),8.00(dd,J1=7.9Hz,J2=2.0Hz,1H),7.76(d,J =8.1Hz,1H),7.41(s,1H),7.34(d,J=8.1Hz,1H),7.06(t,J=7.9Hz,1H),6.63(br d,J=7.5Hz,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). C 23 H 22 LCMS (ES) of N6O3 + ) m / z calculated value 430.18; (MH) - Found 429. HPLC R 1.65 minutes.

[0869] Examples 182 and 146 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 27).

[0870] 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.

[0871] The title compound was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ9.26(br s,1H),8.94(s,1H),8.59(d,J=1.9Hz,1H),8.21(s,1H),7.97(dd,J1=7.9Hz,J2=2.2Hz,1H) ,7.78(d,J=8.0Hz,1H),7.42(s,1H),7.34(d,J=8.1Hz,1H),7.07(t,J=7.8Hz,1H),6.63(br d,J=7.8Hz,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). C 24 H 23 LCMS (ES) of N7O2 + ) m / z calculated value 441.19; (MH) - Found 440. HPLC t R 1.43 minutes.

[0872] 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.

[0873] The title compound was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.47(br s,1H),8.67(dd,J1=2.3Hz,J2=0.7Hz,1H),8.51(d,J=2.3Hz,1H),8.23(s,1H),8.00 (dd,J1=8.1Hz,J2=2.3Hz,1H),7.96(d,J=2.0Hz,1H),7.76(d,J=8.0Hz,1H),7.73(br t,J=2.1Hz,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). C 22 H 21 LCMS(ES) of N7O3 + ) m / z calculated value 431.17; (MH) - Found 430. HPLC t R 1.01 minutes.

[0874] 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

[0875]

[0876] Plan 28

[0877] Step 1: (3-(4-Bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 41).

[0878] A mixture of DIPEA (0.48 mL, 2.7 mmol), 2-(trifluoromethyl)pyridin-4-amine (222 mg, 1.4 mmol), and triphosgene (204 mg, 0.69 mmol) in anhydrous THF (5.3 mL) was stirred at room temperature for 1 h and 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 anhydrous 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 (2x). The collected organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent gradient 0% to 100% EtOAc in petroleum ether) to give the title compound (190 mg, 62%) as a yellow powder. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.46(d,J=5.6Hz,1H),8.31(s,1H),8.20(d,J=1.8Hz,1H),7.70-7.67(m,3H),7.57-7.53(m,2H),5.81(s,2H). C 16 H 11 LCMS (ES) of BrF3N5O2 + ) m / z calculated value 441.00; (MH) - Found 440-442. HPLC t R 1.81 minutes.

[0879] Step 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).

[0880] A degassed suspension of K3PO4 (200 mg, 0.94 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (149 mg, 0.63 mmol), (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) in a mixture of water (0.1 mL) and dioxane (1 mL) was heated at 75°C for 1 h then cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and evaporated in vacuo to give the crude product which was purified by silica gel chromatography (C18 The product was purified by HPLC (HPLC elution gradient: 5% to 100% MeCN in H₂O) to afford a residue which was dissolved in EtOAc and washed with HCl (1N aqueous solution). The aqueous phase was neutralized with NaHCO₃ (saturated aqueous solution) and extracted with EtOAc. The organic phase was dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (70.3 mg, 48%). 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.90(s,1H),8.47(d,J=5.6Hz,1H),8.41(s,1H),8 .21(d,J=1.9Hz,1H),7.72-7.68(m,3H),7.42(d,J=8.1Hz,2H),5.91(s,2H),2.18(s,6H). 19 F NMR(377MHz,DMSO-d6)δ-66.93(s,3F). C 22 H 18 LCMS (ES) of F3N7O2 + ) m / z calculated value 469.15; (MH) - Found 468. HPLC t R 1.43 minutes.

[0881] Examples 186, 189, 188, 190 and 191 were synthesized via reaction with appropriate starting materials according to the above procedure (Scheme 28).

[0882] 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.

[0883] The title compound was obtained as a white solid via reaction with (3,5-dimethylisoxazol-4-yl)boronic acid. 1HNMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.46(d,J=5.6Hz,1H),8.37(s,1H),8.21(s,1H),7.68(br d,J=8.3Hz,3H),7.50(br d,J=8.1Hz,2H),5.87(s,2H),2.41(s,3H),2.24(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-66.93(s,3F). C 21 H 17 LCMS (ES) of F3N6O3 + ) m / z calculated value 458.13; (MH) - Found 457. HPLC t R 1.68 minutes.

[0884] 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.

[0885] The title compound was obtained as a white solid via reaction with (3,5-dimethylisoxazol-4-yl)boronic acid. 1 HNMR (400MHz, DMSO-d6) δ10.17(br s,1H),8.46(d,J=5.6Hz,1H),8.38(s,1H),8.23(br d,J=1.6Hz,1H),7.71(br d,J=8.3Hz,2H),7.66(br dd, J1=5.5Hz, J2=1.6Hz, 1H), 7.50 (br d, J=8.2Hz, 2H), 6.25 (q, J=7.0Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J=7.0Hz, 3H). 19 FNMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 22 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 472.15; (MH) - Found 471. HPLC t R 1.77 minutes.

[0886] 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.

[0887] The title compound was obtained as a light yellow solid via reaction with 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. 1 H NMR (400MHz, DMSO-d6) δ10.18(br s,1H),8.89(s,1H),8.46(d,J=5.6Hz,1H),8.41(s,1H),8.24(br d,J=1.6Hz,1H),7.74(br d,J=8.3Hz,2H),7.67(br dd, J1=5.5Hz, J2=1.8Hz, 1H), 7.43 (br d, J=8.3Hz, 2H), 6.29 (q, J=7.1Hz, 1H), 2.18 (s, 6H), 2.08 (d, J=7.0Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 23 H 20 LCMS (ES) of F3N7O2 + ) m / z calculated value 483.16; (MH) - Found 482. HPLC t R 1.52 minutes.

[0888] 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.

[0889] The title compound was obtained as a light yellow solid via reaction with 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. 1H NMR (400MHz, DMSO-d6) δ10.18(br s,1H),8.90(s,1H),8.46(d,J=5.6Hz,1H),8.41(s,1H),8.24(br d,J=1.9Hz,1H),7.74(br d,J=8.3Hz,2H),7.67(br dd, J1=5.6Hz, J2=1.9Hz, 1H), 7.43 (br d, J=8.3Hz, 2H), 6.29 (q, J=6.9Hz, 1H), 2.18 (s, 6H), 2.08 (d, J=7.1Hz, 3H). 19 F NMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 23 H 20 LCMS (ES) of F3N7O2 + ) m / z calculated value 483.16; (MH) - Found 482. HPLC t R 1.51 minutes.

[0890] 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.

[0891] The title compound was obtained as a light yellow solid via reaction with (3,5-dimethylisoxazol-4-yl)boronic acid. 1 HNMR (400MHz, DMSO-d6) δ10.17(br s,1H),8.46(d,J=5.6Hz,1H),8.38(s,1H),8.23(br d,J=1.8Hz,1H),7.71(br d,J=8.3Hz,2H),7.66(br dd, J1=5.5Hz, J2=1.9Hz, 1H), 7.50 (brd, J=8.4Hz, 2H), 6.26 (q, J=6.8Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J=7.1Hz, 3H). 19 FNMR(377MHz,DMSO-d6)δ-66.92(s,3F). C 22 H 19 LCMS (ES) of F3N6O3 + ) m / z calculated value 472.15; (MH) - Found 471. HPLC t R 1.77 minutes.

[0892] biology

[0893] Expression and purification of ZIKV protease

[0894] The coding sequences of NS2B (amino acids 49-95, R95A) and NS3 (amino acids 1-170, R29G) were synthesized (GenScript, Piscataway, NJ, USA) and cloned into the pET15b vector downstream of a 6x His tag sequence and fused via a non-cleavable linker (G4SG4). The protease was expressed in Escherichia coli BL21 (DE3) cells: bacteria were grown in LB medium at 37°C to an OD600 of 0.8, then the temperature was reduced to 20°C and protein expression was induced by treatment with 0.5 mM IPTG (Cat. No. I5502, Sigma Aldrich) for 18 hours. Cells were collected by centrifugation (4000 x g, 4°C, 30 min) and resuspended (7 ml / g cell slurry) in lysis buffer (25 mM Tris pH 8.0, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (Cat. No. 16876, Sigma-Aldrich) and 25 U / ml Benzonase (Cat. No. E1014, Sigma-Aldrich). After incubation at 25°C for 30 minutes, the cells were homogenized at 800 bar using a PANDA homogenizer (GEA) and the cell extracts were clarified by centrifugation (32914 x g, 4°C, 1 h) to 500 mM NaCl and then loaded onto a 1 ml HisTrap HP column (Cat. No. 17-52407-01, Cytiva, Sweden) equilibrated in 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After three wash steps at 20, 30 and 50 mM imidazole, the recombinant protein was eluted via a linear gradient up to 350 mM imidazole (Cat. No. I202, Sigma Aldrich). Fractions containing ZIKV protease were pooled, treated with 2 mM TCEP (Cat. No. C4706, Sigma-Aldrich) for 40 minutes at 4°C, and then concentrated threefold on a Vivaspin 20, 3 kDa cutoff device (Cat. No. Z614610-48EA, Sigma-Aldrich) before being loaded onto a HiLoad 16 / 60 Superdex 75 column (Cat. No. 28989333, Stovan, Sweden) using 25 mM Tris pH 8.5, 5% glycerol, and 1 mM DTT (Cat. No. A2948, PanReac AppliChem) as the mobile phase. Monomer peak fractions were collected, aliquoted, and frozen in liquid nitrogen.

[0895] Expression and purification of DEN2V protease

[0896] The expression of the DEN2V serine protease was performed as previously described (Acta Cryst. (2006). F62, 157-162) with little modification. The coding sequences of NS2B (amino acids 1394-1440, Uniprot Q91H74) and NS3 (amino acids 1476-1660, Uniprot Q91H74) were synthesized (GenScript, Piscataway, NJ, USA) and cloned into the pET15b vector downstream of the 6x His tag sequence and fused via a non-cleavable linker (G4SG4). The protease was expressed in Escherichia coli BL21 (DE3) cells: the bacteria were grown in MDG minimal non-inducing medium at 25°C with shaking at 300 RPM for 24 hours. The bacterial starter was then diluted 1:20 in ZYM-5052 autoinduction medium and cultured for an additional 24 hours at 25°C with 200 RPM. Cells were collected via centrifugation (4000 x g, 4°C, 30 minutes) and resuspended (7 ml / g cell slurry) in lysis buffer (20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (Cat. No. 16876, Sigma-Aldrich) and 25 U / ml Benzonase (Cat. No. E1014, Sigma-Aldrich). After incubation at 25°C for 30 minutes, cells were homogenized at 800 bar using a PANDA homogenizer (GEA) and the cell extract was clarified by centrifugation (32914 x g, 4°C, 1 h) to 500 mM NaCl and then loaded onto a 5 ml HisTrap HP column (Cat. No. 17525501, Stovepipe, Sweden) equilibrated in 20 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two washing steps at 10 and 20 mM imidazole, the recombinant protein was eluted via a linear gradient up to 440 mM imidazole (Cat. No. I202, Sigma Aldrich). Fractions containing the DEN2V protease were pooled, concentrated three-fold on a Vivaspin 20, 3 kDa cutoff device (Cat. No. Z614610-48EA, Sigma Aldrich), and then loaded onto a HiLoad 16 / 60 Superdex 75 column (Cat. No. 28989333, Stovian, Sweden) using 20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol as the mobile phase. The monomer peak fraction was collected, aliquoted and frozen in liquid nitrogen.

[0897] Expression and purification of JEV protease

[0898] JEV serine protease expression was performed as previously described (PLoS ONE 7(5):e36872) with minimal changes. The coding sequences for NS2B (amino acids 51-95, JEV genotype III strain JaOArS 982, Genebank accession number: M18370) and NS3 (amino acids 1-180, JEV genotype III strain JaOArS 982, Genebank accession number: M18370) were synthesized (GenScript, Piscataway, NJ, USA) and cloned into the pET15b vector downstream of a 6x His tag sequence and fused via a cleavable linker from the NS2B sequence (amino acids 121-131). The protease was expressed in Escherichia coli BL21 (DE3) cells: the bacteria were grown in MDG minimal non-inducing medium at 25°C with shaking at 300 RPM for 24 h. The bacterial starter was then diluted 1:20 in ZYM-5052 autoinduction medium and cultured for an additional 24 h at 200 RPM at 25° C. The cells were collected by centrifugation (4000×g, 4° C., 30 min) and resuspended (7 ml / g cell slurry) in lysis buffer (25 mM Tris pH 8.5, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml lysozyme (Cat. No. 16876, Sigma-Aldrich) and 25 U / ml Benzonase (Cat. No. E1014, Sigma-Aldrich). After incubation at 25 ° C for 30 minutes, the cells were homogenized with a PANDA homogenizer (GEA) at 800 bar and the cell extract was clarified by centrifugation (32914×g, 4 ° C, 1 h) to 500 mM NaCl and then loaded onto a 5 ml HisTrap HP column (catalog number 17525501, Stovan, Sweden) equilibrated in 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two washing steps at 10 and 30 mM imidazole, the recombinant protein was eluted via a linear gradient up to 500 mM imidazole (catalog number I202, Sigma Aldrich). Fractions containing JEV protease were pooled, treated with 2 mM TCEP (Cat. No. C4706, Sigma-Aldrich) at 4°C for 40 minutes, then concentrated three-fold on a Vivaspin 20, 3 kDa cutoff device (Cat. No. Z614610-48EA, Sigma-Aldrich) and loaded onto a HiLoad 16 / 60 Superdex 75 column (Cat. No. 28989333, Stovan, Sweden) using 25 mM Tris pH 9.0, 5% glycerol and 1 mM TCEP as the mobile phase. Monomer peak fractions were collected, aliquoted and frozen in liquid nitrogen.

[0899] ZIKV protease inhibition assay

[0900] Enzyme inhibition assays were performed in 384-well flat-bottom black polystyrene microplates (Cat. No. 781900, Greiner) in a reaction volume of 20 μl. ZIKV NS2B-G4SG4-NS3 serine protease (MGSSHHHHHHSSGLVPRGSHMVDMYIERAGDITWEKDAEVTGNSPRLDVALD ESGDFSLVEDDGPPMAGGGGSGGGGSGALWDVPAPKEVKKGETTDGVYRVMTRGLLGSTQVGVGVMQEGVFHTMWHVTKGSALRSGEGRLDPYWGDVKQDLVSYCGPWKLDAAWDGHSEVQLLAVPPGERARNIQTLPGIFKTKDGDIGAVALDYPAGTSGSPILDKCGRVIGLYGNGVVIKNGSYVSAITQGRR; SEQ.ID.No. 1) (1.25 nM) was mixed with increasing concentrations of inhibitor (0.097-100 μM or 0.0009-1 μM for the most active compound) in assay buffer (50 mM Tris-HCl, pH 7.5). 8.5, 1% glycerol, 1mM CHAPS, 1% DMSO) were incubated at 25°C for 10 minutes. 10 μM Bz-Nle-KRR-AMC substrate (Cat. No. 4055312, Bachem) was added and the reaction mixture was incubated at 25°C for another 30 minutes. Product formation was assessed 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.

[0901] DEN2V protease inhibition assay

[0902] Enzyme inhibition assays were performed in 384-well flat-bottom black polystyrene microplates (Cat. No. 781900, Greiner) in a reaction volume of 20 μl. DEN2V NS2B-G4SG4-NS3 serine protease (MGSSHHHHHHSSGLVPRGSHMADLELERAADVRWEEQAEISGSSPILSITISE DGSMSIKNEEEEQTLGGGGSGGGGAGVLWDVPSPPPVGKAELEDGAYRIKQKGILGYSQIGAGVYKEGTFHTMWHVTRGAVLMHKGKRIEPSWADVKKDLISYGGGWKLEGEWKEGEEVQVLALEPGKNPRAVQTKPGLFKTNTGTIGAVSLDFSPGTSGSPIVDKKGKVVGLYGNGVVTRSGAYVSAIAQTEKSIEDNPEIEDDIFRK; SEQ ID No 2) (10 nM) was mixed with increasing concentrations of inhibitor (0.097-100 μM or 0.0009-1 μM for the most active compound) in assay buffer (50 mM The cells were incubated at 25°C for 10 minutes in a 5% PBS (Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO). 15 μM Bz-Nle-KRR-AMC substrate (Cat. No. 4055312, Bachem) was added and the reaction mixture was incubated for another 30 minutes at 25°C. Product formation was assessed 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.

[0903] WNV protease inhibition assay

[0904] Enzyme inhibition assays were performed in 384-well flat-bottom black polystyrene microplates (Cat. No. 781900, Greiner) with a reaction volume of 20 μl. West Nile virus (WNV) NS2B-NS3 protease (R&D, Cat. No. 2907-SE-020) (2 nM) was incubated with increasing concentrations of inhibitor (0.097-100 μM or 0.0009-1 μM for the most active compound) in assay buffer (50 mM Tris-HCl, pH 9.0, 30% glycerol, 1% DMSO) at 25°C for 10 minutes. 10 μM pERTKR-AMC substrate (Cat. No. ES013) was added, and the reaction mixture was incubated for an additional 30 minutes at 25°C. Product formation was assessed by fluorescence measurement (excitation 360 nm, emission 465 nM) using a SPARK™10 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.

[0905] JEV protease inhibition assay

[0906] Enzyme inhibition assays were performed in 384-well flat-bottom black polystyrene microplates (Cat. No. 781900, Greiner) with a reaction volume of 20 μl. Japanese encephalitis virus (JEV)-NS2B-NS3 protease (600 nM) was incubated with increasing concentrations of inhibitor (0.097-100 μM or 0.009-1 μM for the most active compound) in assay buffer (50 mM Tris-HCl, pH 9.0, 0.1% BSA, 0.1% Triton X-100, 1% DMSO) at 25°C for 10 minutes. 10 μM Pyr-RTKR-AMC substrate (Bachem, Cat. No. 4018149) was added, and the reaction mixture was incubated for an additional 120 minutes at 25°C. Product formation was assessed by fluorescence measurement (excitation 360 nm, emission 465 nM) using a SPARK™10 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.

[0907] Generation of ZIKV replicons

[0908] To construct a subgenomic replicon, we used the Natal RGN isolate of the Asian lineage (GenBank: KU527068.1). In this replicon, the coding sequence of the structural gene was removed, but the 31 amino acids at the N-terminus of the capsid protein were fused to the 32 amino acids at the C-terminus of the E protein. These sequences were retained to maintain the correct processing and translocation of NS1 and non-structural polyproteins on the endothelial membrane. The EMCV IRES is located after the stop codon of the polyprotein. IRES drives the translation of the downstream fusion protein, which consists of the luciferase (Nano-Luc) gene, the ubiquitin gene (UBI) and the neomycin phosphotransferase resistance gene (NEO). This fusion protein is necessary for reporting purposes and conferring resistance to G-418. The subgenomic replicon was transcribed into RNA by the upstream T7 promoter and transfected into Vero cells. Stable cell lines for ZIKV replication experiments were generated via G-418 selection.

[0909] ZIKV replication inhibition assay and cell viability assay

[0910] Green monkey cell lines (Vero) harboring stable ZIKV replicons were grown and maintained in Dulbecco's modified Eagle's medium (DMEM) containing high glucose and pyruvate (GIBCO #41966), supplemented with 10% fetal bovine serum (FBS) (GIBCO #10270), 1% penicillin-streptomycin (10 mg / ml) (GIBCO #14140). A 0.760 μg / mL G418 solution (Sigma-Aldrich, catalog number 4727894001) was used to maintain ZIKV replication in the cells. On the day of the experiment, compounds previously dissolved in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, D5879-1L) were transferred to 384 black plates (Grener #781086) using an acoustic system (ATS-100EDC). Compounds were tested for dose response. 50 μM mycophenolic acid (Sigma Aurich, M3536) was used as a positive control for the ZIKV replication assay, while 32 μM gambogic acid (Sigma Aurich, G8171) was used as a positive control for the cell viability assay. In both cases, 0.5% DMSO was added to the negative control wells. 8,000 cells / well were plated in a culture dish containing the compound in 40 μL growth medium. After 72 h of treatment at 37°C, 5% CO2 and 90% humidity, 20 μL Nano-Glo (Promega #N1150) was added to visualize the NanoLuc signal, while 20 μL CellTiter-Glo (Promega #G7573) was added to determine cell viability. The luminescent signal for both assays was detected by reading the plate on the Envision plate 10 minutes after the addition of the detection reagent (luminescence measurement speed was 0.5 seconds / well). The data were normalized between 0 and 100% inhibition (negative and positive controls, respectively). For EC 50 The dose-response ratio was determined using Dotmatics Studies software and a 4-p logistic regression method was used to fit the dose-response ratio.

[0911] result

[0912] The exemplary compounds described herein were tested in the above assays. Table 1 below reports the IC values ​​for ZIKV protease and replicon inhibition and dengue virus and West Nile virus protease inhibition. 50 Calculate the result using the following letter codes:

[0913] A:IC 50 or EC 50 Less than 0.1 μM; B: IC 50 or EC 50 0.1 to 1 μM; C: IC 50 or EC 501 to 20 μM; D: IC 50 or EC 50 Above 20 μM; na: not applicable.

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

Claims

1. A compound having the general formula (I): in: m and n are each independently selected from 0, 1 and 2; R 1a and R 1b independently selected from H and C optionally substituted by one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 alkyl)2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 1a and R 1b Connect together to form C 3-6 -cycloalkyl ring or C 4-6 - a heterocycloalkyl ring; or R 1a connected to R3 to form a partially unsaturated aromatic or heteroaromatic bicyclic ring; or R 1b Does not exist and CR 1a C=CH2; R 2a and R 2b independently selected from H and C optionally substituted by one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 alkyl)2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 2a and R 2b Connect together to form C 3-6 -cycloalkyl ring or C 4-6 - a heterocycloalkyl ring; or R 1a and R 2a or R 1b and R 2b Any two of them are connected together to form C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl; R3 is a heterocycloalkyl, aromatic or heteroaromatic ring, each of which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyano, B(OH)2, aryl, heteroaryl, wherein the aryl or heteroaryl ring is optionally substituted by one or more substituents, each of which is independently selected from halogen, hydroxyl, cyano, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, NHCOCH3, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 alkyl)2, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine; R4 is a ring of formula (II): in -R6 is CF3, F, Cl, CN or C 1-3 Alkyl, cyclopropyl, CHF2; -X is CR7 or N; -R7 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl; or R4 is 4-trifluoromethylphenyl, thiophene, thiazole, imidazole, pyrazole, oxazole, oxadiazole, naphthalene, quinoline, isoquinoline, quinazoline or naphthyridine, wherein each ring is optionally selected from halogen, C 1-6 Alkyl, hydroxyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, NH2, NHC(O)C 1-6 Alkyl, CN is substituted with one or more substituents; or R4 is phenyl and R3 is a phenyl ring substituted with a heteroaromatic ring, wherein the heteroaromatic ring is optionally selected from halogen, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with one or more substituents; R5 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 compounds are not included:

2. The compound according to claim 1, wherein: -R 1b and R 2b is H; and / or - m and n are each independently selected from 0, 1; and / or -R5 is H.

3. A compound according to any one of the preceding claims, wherein m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxyl or NH2 1-3 alkyl.

4. A compound according to any one of the preceding claims, wherein R3 is phenyl, naphthyl, biphenyl, phenyl substituted with a heteroaromatic ring, or a heteroaromatic ring substituted with a second heteroaromatic ring, wherein each of the phenyl, naphthyl or heteroaromatic ring is optionally substituted with one or more substituents, each of the one or more substituents being independently selected from halogen, hydroxyl, cyano, B(OH)2, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, N(CH3)2, morpholine or pyrrolidine.

5. A compound according to any one of the preceding claims, wherein R4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropane phenyl, 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. A compound according to any one of the preceding claims, wherein: -R3 is selected from: a) phenyl substituted by a 5- or 6-membered heteroaromatic ring, the 5- or 6-membered heteroaromatic ring preferably being selected from the group consisting of: pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or b) a 5- or 6-membered heteroaromatic ring, which is preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each of which is substituted by phenyl, isoindolinone or by a 5- or 6-membered heteroaromatic ring preferably selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine; Wherein in a) or b), each of the phenyl, 5- or 6-membered heteroaromatic rings is optionally substituted by one or more substituents independently selected from the following: 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, CF3, C 5-6 Heterocycloalkyl, O-(CH2)2NH2, O-(CH2)2OH, hydroxyl, halogen; and -R4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-3-yl, phenyl, 3-(trifluoromethyl)phenyl, 4-(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 -m is 1 and n is 0; R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 alkyl.

7. A compound according to any one of the preceding claims, having the general formula (III): Or having the general formula (IV): Or having the general formula (V): wherein R3, R5 and X each have the meaning as defined in any one of the preceding claims.

8. A compound according to any one of the preceding claims, wherein R 3 Select from the following structures: Each phenyl or heteroaromatic ring may be optionally further substituted by one or two substituents independently selected from methyl, CF3, halogen, cyclopropyl, methoxy, cyano.

9. A compound according to any one of the preceding claims, wherein R4 is selected from the following structures:

10. The compound of claim 1 having the general formula (I), which is selected from 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)acyl amine; -(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-methylpyridin-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-oxadiazole -3-carbamido-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-boropyridin-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)pyridine -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'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; -(3-((4'-methyl-[3,3'-bipyridinyl]-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'-bipyridinyl]-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'-bipyridinyl]-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'-bipyridinyl]-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'-bipyridinyl]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; -(3-((3'-fluoro-[3,4'-bipyridinyl]-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)pyridine -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'-bipyridinyl]-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'-bipyridinyl]-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'-dipyrimidinyl]-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-(trifluoro methyl)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.

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

12. A compound according to any one of the preceding claims for use in medicine.

13. Use of the compound according to claim 12 in the treatment and / or prevention of flavivirus infection, preferably, wherein the flavivirus is selected from the following group: dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

14. A compound having the general formula (I): in: m and n are each independently selected from 0, 1 and 2; R 1a and R 1b independently selected from H and C optionally substituted by one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 1a and R 1b Connect together to form C 3-6 -cycloalkyl ring or C 4-6 - a heterocycloalkyl ring; or R 1a connected to R3 to form a partially unsaturated aromatic or heteroaromatic bicyclic ring; or R 1b Does not exist and CR 1a C=CH2; R 2a and R 2b independently selected from H and C optionally substituted by one or more substituents selected from 1-6 Alkyl: hydroxyl, OC 1-3 Alkyl, halogen, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine; or R 2a and R 2b Connect together to form C 3-6 -cycloalkyl ring or C 4-6 - a heterocycloalkyl ring; or R 1a and R 2a or R 1b and R 2b Any two of them are connected together to form C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl; R3 is a heterocycloalkyl, aromatic or heteroaromatic ring, each of which is optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from halogen, hydroxy, NH2, NHCOC 1-6 Alkyl, NHCOOC 1-6 Alkyl, NHC(=O)NHC 1-6 Alkyl, NHSO2C 1-6 Alkyl, NHC 1-3 Alkyl, N(C 1-3 Alkyl)2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyano, B(OH)2, aryl, heteroaryl, wherein the aryl or heteroaryl ring is optionally substituted with one or more substituents, wherein the one or more substituents are each independently selected from halogen, hydroxyl, cyano, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, 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; R4 is an aromatic or heteroaromatic ring optionally substituted by one or more substituents, each of which is independently selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 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; R5 is H, C 1-6 Alkyl, C 1-6 Haloalkyl or halogen; or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, for use in treating a flavivirus infection, preferably, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

15. The compound for use according to claim 14, wherein: -R 1b and R 2b is H; and / or - m and n are each independently selected from 0, 1; and / or - R3 is phenyl, naphthyl, biphenyl, phenyl substituted by a heteroaromatic ring, or a heteroaromatic ring substituted by a second heteroaromatic ring, wherein each phenyl, naphthyl or heteroaromatic ring is optionally substituted by one or more substituents, each of which is independently selected from halogen, hydroxyl, cyano, B(OH)2, NH2, 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, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, NH2, N(CH3)2, morpholine or pyrrolidine; and / or -R4 is selected from 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)phenyl 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. A compound for use according to any one of claims 14 and 15, wherein: - m is 1 and n is 0; and / or -R 1a H and R 1b is H or C optionally substituted by hydroxy or NH2 1-3 Alkyl; and / or -R5 is H.

17. The compound for use according to claim 14, which is selected from: -(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; -(3-phenylethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide.

18. A compound according to any one of claims 14 to 17 in combination with at least one other 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. The pharmaceutical composition according to claim 19, for use in treating and / or preventing flavivirus infection, preferably, wherein the flavivirus is selected from the group consisting of dengue virus, West Nile virus, Zika virus and Japanese encephalitis virus.

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