N-carbamoyl sydnone imines for use in the treatment of flavivirus infections

Abstract

The present invention pertains to compounds that inhibit Flavivirus NS2B-NS3 proteases and are potent and selective inhibitors of the West Nile virus and Zika virus. The compounds of the invention can be used alone or in combination with other agents to treat infections caused by these viruses. Additionally, the invention relates to pharmaceutical compositions containing these compounds.

Description

[0001] N-CARBAMOYL SYDNONE IMINES FOR USE IN THE TREATMENT OF FLAVIVIRUS INFECTIONS FIELD OF THE INVENTION

[0002] The present invention pertains to compounds that inhibit Flavivirus NS2B-NS3 proteases and prevent the replication of flaviviruses in cells. Specifically, these compounds are potent and selective inhibitors of the West Nile virus and Zika virus and can be used alone or in combination with other agents to treat infections caused by these viruses. Additionally, the invention relates to pharmaceutical compositions containing these compounds.

[0003] BACKGROUND

[0004] The Flavivirus genus of the Flaviviridae family includes more than 70 related arthropodborne viruses. The most common and representative members are the dengue virus (DENV) with four serotypes (DENV-1, -2, -3, and -4), Zika (ZIKV), West Nile (WNV), Japanese-encephalitis (JEV), Yellow Fever (YFV), and tick-borne encephalitis (TBEV) viruses. These are the causative agents for viral haemorrhagic fever and encephalitis in human beings. These viruses are transmitted primarily by Aedes mosquitos. Infections with flaviviruses are a continuing public health threat. There are no approved drugs for an infection caused by West Nile virus (West Nile fever), and physicians typically recommend intensive support therapy, which may involve hospitalization, intravenous fluids, use of a ventilator to assist breathing, medications to control seizures, brain swelling, nausea and vomiting, as well as the use of antibiotics to prevent secondary bacterial infections. The medical state of the art is similar for Zika virus disease. There is no vaccine or specific therapeutic treatment available. The focus is on relieving symptoms, including rest, rehydration and acetaminophen for fever and pain.

[0005] The need for Flavivirus treatments is increasing as Flaviviruses are expected to continue spreading into uninfected areas of the world and mutate under drug pressure. The medical need is particularly strong for a safe, effective, and well-tolerated anti-viral treatment, as higher viremia levels are associated with more severe disease. Further, additional treatments are necessary due to the anticipated need for combination therapies to avoid drug resistance.

[0006] The Flavivirus genome consists of a positive-sense single-stranded RNA which is ~11 kb in length, consisting 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. The flavivirus protease is highly conserved and essential for virus replication. The viral polyprotein is processed to three structural proteins (Capsid, pr-Membrane, and Envelope) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Three structural proteins form the virus shell, whereas seven NS proteins participate in the membrane- bound replication complex. Among these NS proteins, only NS3 and NS5 bear enzymatic function (Pathogens 2022, 11 293). Flaviviral replication depends on the NS3 protease, which is a 69 kDa protein with two domains that have different enzymatic functions: a trypsin-like serine protease domain located within the N-terminal region; while the C-terminal region has the activities of an RNA-helicase and an RNA-stimulated NTPase. Moreover, it is only entirely activated when associated with its cofactor, namely NS2B; forming an enzymatic complex, NS2B-NS3. Considering this, NS2B-NS3 proteases represent a valuable target for the development of new antiviral compounds, which act inhibiting their replication complex and leading to the flaviviral death.

[0007] However, the success of various drug discovery attempts during the last decade has been limited by the nature of the viral enzyme as well as a lack of robust structural templates. Small-molecule, structurally diverse protease inhibitors have been reported to reach affinities in the lower micromolar range. Peptide-based, substrate-derived compounds are often nanomolar inhibitors, however, with highly compromised drug-likeness. With some exceptions, the antiviral cellular activity of most of the reported compounds has been patchy and insufficient for further development. Recent progress has been made in the elucidation of inhibitor binding using different structural methods. This will hopefully lead to more rational attempts for the identification of various lead compounds that may be successful in cellular assays, animal models and ultimately translated to patients.

[0008] The present invention yields a novel series of drug-like, broadly active inhibitors of flavivirus proteases, more specifically of West Nile and Zika viruses proteases provide new treatments and pharmaceutical compositions to treat infections thereof. The compounds of the invention are sydnone imine derivatives having a mesoionic heterocyclic core wherein the proper selection of substituents resulted in potent, selective and brain penetrant WNV and ZIKV NS2B-NS3 protease inhibitors. The compounds of the invention are capable of inhibiting replication of the above viruses in cells.

[0009] SUMMARY OF THE INVENTION

[0010] It is therefore an object of the invention a compound of general formula (I):

[0011]

[0012] wherein

[0013] - X is C or N;

[0014] Ri is: CF3, OCF3 or cyclopropyl optionally substituted with fluorine;

[0015] R2 is: H, CH3, OCH3, Cl, NHCH3, NHC(=O)Ri2 wherein R12 is a Ci-3alkyl optionally substituted with an aromatic ring;

[0016] R3 is H or CH3 and R4 is H or CH2OH; or R3 and R4 are linked together to form a spirocyclopropyl ring;

[0017] Rs and Re are each independently selected from: H, CH3 and Cl;

[0018] R7 is selected from:

[0019] a) pyridine, optionally substituted with one or more substitents independently selected from Ci-3alkyl, Cs-ecycloalkyl, Ci-shaloalkyl, Ci-3alkoxyl, halogen, hydroxy, C i-shaloalkyl further substituted with an hydroxy group, C(O)OCi-3alkyl, C(O)OH, C(O)NHCi-3alkyl, NHC(=O)Ci-3alkyl, SO2NHC1-3alkyl, SO2C1-3alkyl, CN with the proviso that said optionally substituted pyridine is not 2- methylpyridin-3-yl and 2,4-dimethylpyridine-3-yl; or

[0020] b) pyrazole of formula (II) or (III):

[0021]

[0022] wherein:

[0023] R8 is selected from H, Ci-4alkyl optionally substituted with OH, Cs-ecycloalkyl, C3- eheterocycloalkyl and Ci-shaloalkyl optionally substituted with OH;

[0024] R9is selected from C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C1-3alkoxyl, CN and halogen;

[0025] and wherein if R9 is CH3 then Rs is not CH3 or an oxetane ring; or c) pyridazine optionally substituted with halogen, Ci-3alkyl, Ci-3alkoxyl, Ci- shaloalkyl, Cs-ecycloalkyl, CN, with the proviso that said pyridazine is a not 3- methylpyridazin-4-yl; or

[0026] d) pyrimidine of formula (IV):

[0027]

[0028] Rio (iv)

[0029] wherein Rio and Rn are each independently selected from Ci-3alkyl, Ci-shaloalkyl. Cs-ecycloalkyl, and wherein if Rio and Rn are both CH3 then in general formula (I):

[0030] ■ X is N; and / or

[0031] ■ Ri is cyclopropyl; and / or

[0032] ■ R2 is CH3, OCH3, Cl, NHCH3; and / or

[0033] ■ R5is Cl;

[0034] e) phenyl or 5 or 6 membered heteroaromatic ring selected from pyrazine, 6-oxo-l,6- dihydropyridine, imidazole and oxazole, each of said ring being optionally substituted with one or more substitents independently selected from Ci-3alkyl, Ci- shaloalkyl. Ci-3alkoxyl, halogen, hydroxy, Ci-shaloalkyl further substituted with an hydroxy group, C(O)OCi-3alkyl, C(O)OH, C(O)NHCi-3alkyl; or

[0035] or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

[0036] Preferably Ri is CF3 and R2 is H.

[0037] Preferably R3 and R4 are H.

[0038] Still preferably R7 is a pyridine ring selected from:

[0039]

[0040] (A) (B) (C) (D)

[0041] wherein:

[0042] - in structure (A) R13and R14are independently selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, halogen, and wherein one of R13 and R₁₄ is C₁₋₃haloalkyl, preferably one of R13 and R14 is trifluoromethyl or difluoromethyl; - in structure (B) Ris and Ri6 are independently selected from H, Ci-shaloalkyl and hydroxy, preferably the Ci-shaloalkyl is trifluoromethyl or difluoromethyl; more preferably Ris is trifluoromethyl or difluoromethyl and Ri6 is H;

[0043] - in structure (C) R17 is Ci-shaloalkyl. preferably trifluoromethyl or difluoromethyl;

[0044] - in structure (D) Ris is selected from Ci-3alkyl and C(=O)OH, C(=O)=CH3 and C(=O)NHCH3 and R19 is C1-3alkyl or C1-3haloalkyl.

[0045] Still preferably R? is a pyrazole of formula (II) wherein:

[0046] Rs is H, methyl, hydroxy-2-methyl-propyl, l,l-difluoro-2-hydroxy ethyl, cyclopropyl, cyclobutyl, oxetane, tetrahydropyrane, tetrahydrofurane; and

[0047] R9 is methoxy, halogen, trifluoromethyl;

[0048] or wherein:

[0049] Rs is H, hydroxy-2-methyl-propyl, cyclopropyl, cyclobutyl, tetrahydropyrane, tetrahydrofurane; and

[0050] R9 is methyl.

[0051] Still preferably R? is a pyrazole of formula (II) wherein Rs is CH3 and Ry is halogen, preferably R9 is chlorine.

[0052] Still preferably R7 is a pyrazole of formula (III) wherein Rs is Ci-3alkyl or Ci-shaloalkyl or and R9 is halogen.

[0053] Still preferably R7 is selected from: 2-(trifluoromethyl)pyridin-3-yl, 2-(difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-chloro-2-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-3-yl, 2-methoxy-4-(trifluoromethyl)pyridin-3-yl, 4- (trifluoromethyl)pyridin-2-yl, 2-trifluoromethylphenyl, 2-(difluoromethy l)-4-methylpyri din-3 -yl, 3-(difluoromethyl)pyridin-2-yl, 2-(difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-4-yl, 3-hydroxypyridin-2-yl, 1,1-difluoro-2-hydroxyethyl)pyridin-3-yl, 4-(difluoromethyl)pyridin-3-yl, 3-(difluoromethyl)pyridin-4-yl, 6-(methoxycarbonyl)-2-methylpyridin-3-yl, 6-carboxy-2-methylpyridin-3-yl, 2-methyl-6-(methylcarbamoyl)pyridin-3-yl.

[0054] Still preferably R7 is selected from: l-cyclopropyl-4-methoxy-lH-pyrazol-5-yl, 4-methoxy-l-methyl-lH-pyrazol-5-yl, l-cyclopropyl-4-methyl-lH-pyrazol-5-yl, l-cyclobutyl-4-methyl-lH-pyrazol-5-yl, l-cyclobutyl-4-methoxy-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-(4-chloro-l -(oxetan-3-yl)-lH-pyrazol-5-yl, 1 -methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl, 1 -(oxetan-3-yl)-4-(trifluoromethyl)-lH-pyrazol-5-yl, 4-fluoro-l-(oxetan-3-yl)-lH-pyrazol-5-yl, 4-chloro- 1 -methyl- lH-pyrazol-5-yl, 4-methyl- 1 -(tetrahy dro-2H-pyran-4-yl)- lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro-l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl, 4-chloro-l -(tetrahy dro-2H-pyran-4-yl)-lH-pyrazol-5-yl, 4- chloro-l-(tetrahydrofuran-3-yl)-IH-pyrazol-5-yl. 4-chloro-lH-pyrazol-5-yl, 4-chloro- 1 -(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl.

[0055] Still preferably R₇ is selected from: l,4-dimethyl-lH-imidazol-5-yl, 3 -methoxy pyridazin-4-yl, 1-cyclobutyl-4-methyl-lH-imidazol-5-yl, 2-trifluoromethylphenyl, 2-difluoromethylphenyl, 4,6-dimethylpyrimidin-5-yl, 4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl, 3- (trifluoromethyl)pyrazin-2-yl.

[0056] It is a further object of the invention a compound of general formula (I) selected from:

[0057] (3-(4-(2-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0058] (3-(4-(l,4-dimethyl-lH-imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0059] (3-(4-(l-cyclopropyl-4-methoxy-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0060] (3-(4-(4-methoxy-l-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0061] (3-(4-(l-cyclopropyl-4-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0062] (3-(4-(3-methoxypyridazin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0063] (3-(4-(l-cyclobutyl-4-methyl-lH-imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0064] (3-(4-(l-cyclobutyl-4-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0065] (3-(4-(l-cyclobutyl-4-methoxy-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0066] (3-(4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0067] (3-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0068] (3-(4-(3-(trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0069] (3-(4-(4-chloro-2-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(4-(4-chloro-l-(oxetan-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0070] (3-(4-(4-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0071] (3-(4-(l-methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0072] (3-(4-(l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0073] (3-(4-(6-oxo-2-(trifluoromethyl)-l,6-dihydropyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0074] (3-(4-(2-methoxy-4-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0075] (3-(4-(4-(trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0076] (3-((2'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0077] (3-(4-(4-fluoro-l-(oxetan-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0078] (3-((2'-(difluoromethyl)-[l,r-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0079] (3-(4-(2-(difluoromethyl)-4-methylpyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0080] (3-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)-3-methylbenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0081] (3-(4-(4-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0082] (3-(l-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0083] (3-(l-(4-(2-(difluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0084] (3-(4-(3-(difluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0085] (3-(2-chloro-4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(3-chloro-4-(4,6-dimethylpyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0086] (3-(l-(4-(2-(difluoromethyl)pyridin-3-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0087] (3-(l-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0088] (3-(4-(3-(trifluoromethyl)pyridin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0089] (3-((6-(4,6-dimethylpyrimidin-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0090] (3-((6-(4-chloro-l-methyl-lH-pyrazol-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0091] (3-((2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0092] (3-(4-(3-hydroxypyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0093] (3-(4-(4-chloro-l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0094] (3-(4-(4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0095] (3 -(4-(4-chl oro-1 -(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)benzyl)- 1,2,3 -oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0096] (3-(4-(4-chloro-l-(tetrahydrofuran-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0097] (3-(4-(3-(trifluoromethyl)pyrazin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0098] (3-(4-(2-(1,1-difluoro-2-hydroxyethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0099] (3-(4-(4-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0100] (3-(4-(4-chloro-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0101] (3-(4-(3-(difluoromethyl)pyridin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0102] (3-(4-(6-carboxy-2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0103] (3-(4-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)benzyl)-1,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0104] (3-(4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0105] (3-(4-(3-Methoxypyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0106] ((2-cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3- oxadiazol-3-ium-5-yl)amide

[0107] (3-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- cyclopropylpyridin-4-yl)carbamoyl)amide

[0108] ((2-cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(2-(difluoromethyl)pyridin-3-yl)benzyl)- 1,2,3-oxadiazol-3-ium-5-yl)amide

[0109] (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-methoxy-6- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0110] (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethoxy)pyridin-4-yl)carbamoyl)amide

[0111] (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-methyl-6- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0112] ((2-Chloro-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5- yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0113] (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (methylamino)-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0114] (3-(4-(3-(Difluoromethyl)pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0115] The compound of the invention as above defined is an inhibitor of NS2B-NS3 protease of a Flavivirus, preferably an inhibitor of the NS2B-NS3 protease of West Nile and / or Zika virus. It is a further object of the invention the compound as above defined for medical use, preferably said compound is for use in treatment and / or prevention of a Flavivirus infection, more preferably for use in the treatment and / or prevention of an infection from West Nile and Zika virus. It is a further object of the invention a pharmaceutical composition comprising the compound of the invention, either alone or in combination with one further therapeutic agent, and at least one pharmaceutically acceptable excipient.

[0116] It is a further object of the invention said pharmaceutical composition for use in the treatment and / or prevention of a Flavivirus infection, preferably wherein the Flavivirus is selected from West Nile and Zika and virus.

[0117] DETAILED DESCRIPTION OF THE INVENTION

[0118] The present invention provides inhibitors of NS2B-NS3 protease of a Flavivirus, preferably inhibitors of the NS2B-NS3 protease of Zika and / or West Nile virus, thus inhibiting replication of the above viruses in cells. More specifically, the present invention provides a specific chemotypes obtained by fine tuning the substituents on the two side of the molecule of general formula (I): the proper balance of the substituted pyridine on the urea moiety and of the aromatic / heteroaromatic ring in the bis-aromatic system provided compounds with significant selectivity versus the NS2B-NS3 proteases of West Nile virus and of Zika virus with respect to the other Flaviviruses’ proteases. Moreover, the compounds of the invention are able to penetrate the blood brain barrier to reach their target and treat the infection at the central nervous system level.

[0119] In one embodiment the invention provides a compound of general formula (I):

[0120]

[0121] In the above formula (I), X is C or N.

[0122] Preferably in formula (I) Ri is a fluoroalkyl or a fluoroalkoxy or a cycloalkyl. More specifically said Ri can be any of CF3, OCF3 or a substituted cyclopropyl. Said cyclopropyl can opionally be substituted with fluorine atoms. When the cyclopropyl is substituted with fluorine, said fluorine can be on any carbon atom of the cyclopropyl ring; preferably said fluorine is linked to the carbon atom linked to the pyridine ring. Preferably in formula (I) R2 is: H, CH3, OCH3, Cl, NHCH3, NHC(=O)Ri2 wherein R12 is a Cisalkyl optionally substituted with an aromatic ring. The definition of NHC(=O)Ri2 encompasses methylamide, ethylamide, propylamide, isopropylamide, benzylamide, phenylethylamide and the like. It is also intended that the aromatic ring can be an heteroaromatic ring and that it can be substituted by, for example, a methyl or an halogen. More preferably, R2 is H, methyl, chlorine or NHCH3; even more preferably R2 is H.

[0123] Preferably in formula (I) R3 is H or CH3 and R4 is H or CH2OH; or R3 and R4 are linked together to form a spirocyclopropyl ring; or R3 and R4 are methyl.

[0124] Preferably in formula (I) Rs and Re are each independently selected from: H, CH3 and Cl.

[0125] Preferably in formula (I) R7 is a pyridine ring. Said pyridine ring in R7 is optionally substituted with one or more substitents independently selected from Ci-salkyl, Ci-shaloalkyl, Ci-salkoxyl, halogen, hydroxy, Ci-shaloalkyl further substituted with an hydroxy group, C(O)OCi-salkyl, C(O)OH, C(O)NHCi-salkyl, NHC(=O)Ci-3alkyl, SO₂NHC₁₋₃alkyl, SO₂C₁₋₃alkyl, CN. Said optionally substituted pyridine is not 2-methy Ipyri din-3 -yl and 2,4-dimethylpyridine-3-yl, as depicted below:

[0126]

[0127] More preferably R7 is a pyridine ring selected from:

[0128]

[0129] (A) (B) (C) (D)

[0130] wherein:

[0131] - in structure (A) R13and R14are independently selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, halogen, and wherein one of R13 and R₁₄ is C₁₋₃haloalkyl, preferably one of R13 and R14 is trifluoromethyl or difluoromethyl; as indicated above, in structure (A) R13 and R14 cannot be both CH3 and / or if R13 is CH3 then R14 is not H and / or if R14 is CH3 then R13 is not H;

[0132] - in structure (B) R15 and Ri6 are independently selected from H, Ci-shaloalkyl and hydroxy, preferably the Ci-shaloalkyl is trifluoromethyl or difluoromethyl;

[0133] - in structure (C) R17 is Ci-shaloalkyl. preferably trifluoromethyl or difluoromethyl; - in structure (D) Ris is selected from Ci-3alkyl and C(=O)OH, C(=O)=CH3 and C(=O)NHCH3 and R19 is C1-3alkyl or C1-3haloalkyl.

[0134] Still preferably R7 is a substituted pyridine selected from: 2-(trifluoromethyl)pyridin-3-yl, 2-(difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-chloro-2- (trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-3-yl, 2-methoxy-4- (trifluoromethy l)pyri din-3 -yl, 4-(trifluoromethyl)pyridin-2-yl, 2-trifluoromethylphenyl, 2-(difluoromethyl)-4-methylpyridin-3-yl, 3-(difluoromethyl)pyridin-2-yl, 2- (difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-4-yl, 3-hydroxypyridin-2-yl, 1,1-difluoro-2-hydroxyethyl)pyridin-3-yl, 4-(difluoromethyl)pyridin-3-yl, 3-(difluoromethyl)pyridin-4-yl, 6-(methoxycarbonyl)-2-methylpyridin-3-yl, 6-carboxy-2-methy Ipyri din-3 -yl, 2-methyl-6-(methy Icarbamoy l)pyri din-3 -yl.

[0135] Still preferably in formula (I) R₇ is a pyrazole of formula (II) or (III):

[0136]

[0137] In the above pyrazoles (II) and (III) Rs can be any of H, Ci-4alkyl optionally substituted with OH, C3-6cycloalkyl, Cs-eheterocycloalkyl and Ci-shaloalkyl; R₉ can be any of C₁₋₃alkyl, Ci-shaloalkyl, Ci-3alkoxyl, CN and halogen.

[0138] In the above pyrazoles (II) and (III), if R9 is CH3 then Rs is not CH3 or an oxetane ring. With this proviso, preferably R7 is a pyrazole of formula (II) wherein:

[0139] Rs is H, methyl, hydroxy-2-methyl-propyl, cyclopropyl, cyclobutyl, oxetane, tetrahydropyrane, tetrahydrofurane; and

[0140] R9 is methoxy, halogen, trifluoromethyl;

[0141] or wherein:

[0142] Rs is H, hydroxy-2-methyl-propyl, cyclopropyl, cyclobutyl, tetrahydropyrane, tetrahydrofurane; and

[0143] R9 is methyl.

[0144] Still preferably R7 is a pyrazole of formula (III) wherein Rs is Ci-3alkyl or Ci-shaloalkyl or and R9 is halogen.

[0145] Still preferably R7 is a substituted pyrazole selected from: l-cyclopropyl-4-methoxy-lH-pyrazol-5-yl, 4-methoxy-l -methyl- lH-pyrazol-5-yl, l-cyclopropyl-4-methyl-lH-pyrazol-5-yl, 1-cyclobutyl-4-methyl-lH-pyrazol-5-yl, l-cyclobutyl-4-methoxy-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-(4-chloro-l-(oxetan-3-yl)-lH-pyrazol-5-yl, l-methyl-4- (trifluoromethyl)-lH-pyrazol-5-yl, l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-pyrazol-5-yl, 4-fluoro- 1 -(oxetan-3 -y 1)- 1 H-py razol-5-y 1, 4-chloro- 1 -methy 1- IH-py razol-5-yl, 4-methyl- 1 - (tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro- l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl, 4-chloro- 1-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl, 4-chloro-l-(tetrahydrofuran-3-yl)-lH-pyrazol-5-yl, 4-chloro- lH-pyrazol-5-yl, 4-chloro- 1 -(2, 2, 2-trifluoroethyl)-lH-pyrazol-3-yl.

[0146] Still preferably in formula (I) R₇ is a pyridazine optionally substituted with halogen, Ci-3alkoxyl, Ci-shaloalkyl, Cs-ecycloalkyl, CN. Said pyridazine in R? can be substituted with one, two or three of the above indicated substituents.

[0147] Still preferably in formula (I) R₇ is a pyrimidine of formula (IV):

[0148]

[0149] % (IV).

[0150] In the above pyrimidine Rio and Rn can be any of Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl. Additionally, if Rio and Rn are both CH3 in the above pyrimidine of formula (IV), then the following conditions must be verified by general formula (I):

[0151] - X is N; and / or

[0152] Ri is cyclopropyl;

[0153] - R2 is CH3, OCH3, Cl, NHCH3; and / or

[0154] R3 is H; and / or

[0155] - R5is Cl.

[0156] Still preferably in formula (I) R7 is a phenyl, a pyrazine, a 6-oxo- 1,6-dihydropyri dine, an imidazole or an oxazole and each of said ring is optionally substituted with one or more substitents independently selected from Ci-3alkyl, Ci-shaloalkyl. Ci-3alkoxyl, halogen, hydroxy, Ci-shaloalkyl further substituted with an hydroxy group, C(O)OCi-3alkyl, C(O)OH, C(O)NHCi-3alkyl, CN, NH(CO)Ci-3alkyl.

[0157] Still preferably R₇ is selected from: l,4-dimethyl-lH-imidazol-5-yl, 3 -methoxy pyridazin-4-yl, 1-cyclobutyl-4-methyl-lH-imidazol-5-yl, 2-trifluoromethylphenyl, 2-difluoromethylphenyl, 4,6-dimethylpyrimidin-5-yl, 4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl, 3- (trifluoromethyl)pyrazin-2-yl.

[0158] In a preferred embodiment of the invention, in the compound of formula (I) Ri is CF3 and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further embodyment Ri is 1- fluoro- 1 -cyclopropyl and R2 is H. Still preferably, Ri is CF3 and R2 is OCH3; Ri is CF3 and R2 is CEL; RI is CF3 and R2 is NHCH3; Ri is CF3 and R2 is Cl; Ri is CF3 and R2 is NHCH3.

[0159] In a preferred embodiment of the invention, in the compound of formula (I) R3 and R4 are H. As explained above, the compounds of the invention can pass the blood brain barrier and this property is very important in the prevention and / or treatment of the mosquito-borne encephalitis. In an embodiment the invention provides compound according to general formula (I) characterized by a specific selection of the substituent(s) on the pyridine on the urea moiety and on the biaromatic / heteroaromatic moiety linked to the central sydnone through a methylene carbon. Said selection of substituents provided compounds able to inhibit the NS2B-NS3 protease of West Nile virus and of Zika virus with efficacy significantly higher than for the other Flaviviruses proteases. In a further embodiment the invention provides a compound as defined above for medical use, preferably for use in treatment and / or prevention of a Flavivirus infection, preferably wherein the Flavivirus is West Nile and Zika virus. In one embodiment, the Flavivirus infection is West Nile fever. In one embodiment, the Flavivirus infection is from the Zika virus.

[0160] Zika virus (ZIKV), the causative pathogen of Zika fever, is a small enveloped ss (+) RNA virus with a genome of around 11 kilobases in length that encodes a single polyprotein that is cleaved to produce 10 viral proteins. ZIKV infections in humans were sporadic before emerging in the Pacific and the Americas in the last decade. Indeed, ZIKV infection was associated with only mild illness prior to the large French Polynesian outbreak in 2013 and 2014, when severe neurological complications were reported, and the emergence in Brazil of a dramatic increase in severe congenital malformations (microcephaly) associated with ZIKV infection during pregnancy. The majority of cases (around 80%) are asymptomatic. When symptoms occur, they are typically mild, self-limiting, and similar to other arbovirus infections (e.g., DENV and CHIKV). Commonly reported symptoms include rash, fever, arthralgia and headache. Rare deaths have been described in patients infected with Zika virus. ZIKV is now known to cause fetal infection and congenital Zika syndrome, which includes microcephaly, cerebral malformations, ophthalmological and hearing defects, and arthrogryposis. Mild elevations in inflammatory markers have been described during ZIKV. Similarly to what happens in DENV infection, in ZIKV infection the interferon system is the central mediator of host defense and target of viral counterattack. A polyfunctional immune activation was seen during the acute phase of ZIKV infection, with elevated cytokine profiles associated with Th1 (IL-2), Th2 (IL-4, IL-13), Th17 (IL-17), and also Th9 (IL-9) responses (16). Increased IL-4, IL- 6, IL-8, IL-10, and IP-10 levels are also observed in ZIKV infected patients. Although no “cytokine storm” is observed in ZIKV patients, in ZIKV -infected placentas a massive inflammation has been observed, that may hamper the success of pregnancy. ZIKV perturbs the pro- / anti-inflammatory equilibrium of the placenta leading to tissue damage and massive infiltration of the villous core by inflammatory Hofbauer cells.

[0161] West Nile virus (WNV) is an important emerging neurotropic virus, responsible for increasingly severe encephalitis outbreaks in humans and horses worldwide. WNV is a member of the Flaviviridae family and is encoded by a ~ 11 kb positive-sense single-stranded RNA (ssRNA) genome. The genome is translated as a single polyprotein, and subsequent cleavage of this polyprotein by viral and host proteases generates 10 viral proteins. WNV pathogenesis follow three phases, the early phase initial infection and spread (the early phase), peripheral viral amplification (the visceral-organ dissemination phase) and neuroinvasion (the central nervous system (CNS) phase). The innate immune response, including type I interferon (IFN) and innate cell-mediated responses is responsible for the early control of WNV, whereas the adaptive immune response, including humoral and adaptive immune cell mediated responses (CD4+, CD8+ and regulatory T cells), is essential for WNV clearance and limiting possible immune response-mediated damage in the later stages of infection. The early phase after subcutaneous infection is defined by WNV replication in keratinocytes and skin-resident DCs, followed by viral amplification within the draining lymph node, which results in viremia and spread to visceral organs. The specific target cells for WNV infection are not well defined, but are thought to be subsets of DCs, macrophages and possibly neutrophils. WNV invasion of the CNS tissues (for example, the brain and spinal cord) constitutes the third phase of the infection. WNV may enter the brain through a combination of mechanisms that facilitate viral neuroinvasion, such as direct infection with or without a breakdown of the blood-brain barrier (BBB) and / or virus transport along peripheral neurons. Innate antiviral defenses are essential for the control of WNV infection, including the production of type I IFNs and pro-inflammatory cytokines, the expression of antiviral genes and the subsequent activation of the adaptive immune response. In WNV infection the innate immune activity is mainly triggered by RIG-1 like receptor (RLR) signaling, although Toll-like receptors (TLRs) could also contribute to NF-KB activation and the production of type I interferons and pro-inflammatory cytokines. DCs and macrophages, both of which are innate immune sentinel cells and target cells of WNV infection, are pivotal in linking innate and adaptive immune responses. Macrophages and DCs are readily activated by WNV, releasing pro-inflammatory cytokines and chemokines such as type I IFN, TNF, IL-Ib, CCL2, CCL3, CCL5 and IL-8. These cytokines are important in regulating innate cell-mediated responses (involving NK cells, neutrophils and gd T cells) as well as in developing adaptive immune responses. A major hallmark of WNV pathogenesis is neuroinflammation, which is caused by exaggerated innate and acquired immune response. Accumulation of inflammatory monocytes into the brain and their differentiation to macrophages and microglia can also worsen neuroinflammation and CNS injury, as demonstrated in a murine model of nonlethal WNV infection. Recognition of WNV nucleic acid in monocytes / microglia by TLRs may lead to the production of TNF-a, which results in a loss of tight junctions, allowing the entry of WNV and immune cells into the perivascular space of the brain in mice. Thus, activation of cells of the monocyte / macrophage system by WNV appears to result in important neuropathological consequences, and exaggerated innate responses may cause inflammation, altering the blood brain barrier permeability and allowing the virus to enter the CNS. Indeed, treatment of infected neuronal cells with antibodies blocking TNF-a and other pro-inflammatory mediators results in a significant reduction of WNV-mediated neuronal death, suggesting that such mediators play a major role in the pathogenesis of WNV infection in the CNS In a further embodiment the invention provides selective inhibitors of the West Nile virus and of the Zika virus protease, wherein said compounds are also able to pass the blood brain barrier. Therefore, the compounds of the invention are particularly suited for use in the treatment of the infection by West Nile virus in the central nervous system (CNS) phase.

[0162] It is a further object of the invention of a pharmaceutical composition comprising the compound as defined above and at least one pharmaceutically acceptable excipient.

[0163] Preferably the pharmaceutical composition is for use in the treatment and / or prevention of a flavivirus infection, preferably wherein the flavivirus is West Nile and Zika virus.

[0164] In a preferred embodiment, said pharmaceutical composition comprises at least one further active compound selected from the group consisting of: antivirals, antibacterials, anti-inflammatory agents, anti-pain agents and antipyretic agents.

[0165] It is a further object of the invention of a method for the synthesis of the compound of general formula (I) as defined above.

[0166] The present invention includes within its scope prodrugs of the compound of formula (I). In general, such prodrugs will be functional derivatives of the compound of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0167] A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality. The present invention includes within its scope solvates of the compound of formula (I) and salts thereof, for example, hydrates.

[0168] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and all tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. Specific tautomeric forms of compounds of the invention are depicted below:

[0169]

[0170] (i)

[0171] The compounds may exist in different isomeric forms, all of which are encompassed by the present invention.

[0172] When any variable occurs more than one time in any constituent, its definition on each occurrence is independent of every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds.

[0173] It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized from readily available starting materials by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted” should be taken to be equivalent to the phrase “unsubstituted or substituted with one or more substituents” and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents. A substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.

[0174] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “Ci-Ce alkyl” is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement. For example, “Ci-Ce alkyl” specifically includes methyl, ethyl, w-propyl, z-propyl, w-butyl. / -butyl, z-butyl, pentyl, hexyl, and so on. “Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclized alkyl and alkenyl groups. The term " Cn-m cycloalkyl" or “(Cn-Cm) cycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C3-14). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, cycloalkyl includes a single saturated carbocyclic ring of three to eight ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may optionally be substituted with one or more substituents, such as one, two, or three substituents. In some embodiments, the cycloalkyl substituent is selected from the group consisting of (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, halo, amino, mono- and di(Ci-C6)alkylamino, hetero(Ci-Ce)alkyl, acyl, aryl, and heteroaryl. A cycloalkyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the cycloalkyl group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety such as halogen, OH, cyano, methyl, trifluoromethyl, amino and the like. In some aspects, a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-l-yl). In some aspects, a cycloalkyl group is unsubstituted or not optionally substituted.

[0175] " Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, / / -propoxy. / -propoxy, w-butoxy. s-butoxy and t-butoxy. The preferred alkoxy group is methoxy.

[0176] The terms "haloCi-ealkyl" and "haloCi-ealkoxy" mean a Ci-ealkyl or Ci-ealkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are HuoroCi-ealkyl and HuoroCi-ealkoxy groups, in particular fluoroCi-salkyl and HuoroCi-salkoxy groups, for example, CF3, CHF 2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.

[0177] The term "hydroxyCi-ealkyl" means a Ci-6alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH2CHOH and CHOHCH3.

[0178] As used herein, "aryl" or “aromatic ring” is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene. The preferred aryl group is phenyl or naphthyl, especially phenyl.

[0179] As used herein, "heteroaryl" or “heteroaromatic ring” is intended to mean any stable monocyclic or bicyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein at least one ring is aromatic. In particular the term heteroaryl includes 5 membered aromatic heterocycles containing 1, 2, 3 or 4 heteroatoms independently selected fromN, O and S, but not more than one of which is O or S; 6 membered aromatic heterocycles containing 1, 2 or 3 nitrogen atoms; or a 7-13 membered aromatic heterocycle containing heteroatoms independently selected from N, O or S of 5 to 10 atoms, wherein at least one ring is aromatic. Heteroaryl ring also includes partially saturated bicyclic systems, such as indoline, isoindoline, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine; further included are tautomeric structures, such as for example hydroxypyrimidine and hydroxypyrimidones.

[0180] The terms “heterocyclic ring”, “heterocycloalkyl ring” and “cycloheteroalkyl ring” are used interchangeably in the present invention in the present invention and refer to a non-aromatic ring radical, which consists of carbon atoms and at least one heteroatom of nitrogen, phosphorus, oxygen or sulfurExamples of particular heterocyclic rings of the invention are tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl, octahydroisoindolyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.

[0181] A preferred 4-member saturated heterocycle is azetidine. A further preferred 4-membered saturated heterocycle is oxetane.

[0182] A preferred 5 -member saturated heterocycle is tetrahydrofurane.

[0183] Preferred 6 membered saturated or partially saturated heterocycles are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and thiazolidinyl.

[0184] Preferred 5 membered heteroaryls are thienyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl, oxazolyl, triazolyl, tetrazolyl, furyl and oxadiazolyl.

[0185] The preferred 6 membered heteroaryls are pyridinyl and pyrymidinyl.

[0186] Preferred 8-10 membered heteroaryls are benzothienyl, indolyl, benzothiadiazolyl, benzoxadiazolyl, thiazolotriazolyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, benzotriazolyl, dihydroisoindolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl and tetrahydroquinolinyl.

[0187] As used herein, the term 'halogen' refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are preferred.

[0188] As used herein, the term “amine” refers to linear and cyclic amines, such as methylamine, dimethylamine, diethylamine, isopropylamine, pyrrolidine, pyperidine and the like. A substutuent referred generically as “amine” indicates that an amine radical is linked through its nitrogen to the specific residue. In some instances, it is herein used the term “Ci-ealkylamine” which refers to an alkyl group substituted with an amino group, such as -CH2NH2, -CH2NHCH3, CH2NHCH2CH3, CH2-pyrrolidine, CH2-piperidine and the like.

[0189] As used herein, an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl refer to any of said ring systems as above defined being optionally substituted with groups such as halogen, hydroxy, methyl, trifluoromethyl, amino, methylamino, and the like.

[0190] The pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reaction of the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.

[0191] Thus, pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reaction of a basic instant compound with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Preferably, a pharmaceutically acceptable salt of this invention contains one equivalent of a compound of formula (I) and 1, 2 or 3 equivalents of an inorganic or organic acid. More particularly, pharmaceutically acceptable salts of this invention are the tartrate, trifluoroacetate or the chloride salts.

[0192] When the compound of the present invention is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium 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,

[0193]

[0194] -dibenzylethylenediamine. diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

[0195] The preparation of the pharmaceutically acceptable salts described above, and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.

[0196] It will also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.

[0197] The compounds of the invention find use in a variety of applications for human and animal health. The compounds of the invention are flavivirus inhibitors and can be used in the treatment and / or prevention of flavivirus infections.

[0198] The compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0199] The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, com starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water-soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.

[0200] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0201] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or / 7-propyl -hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0202] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

[0203] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0204] The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

[0205] The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.

[0206] The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution may be then introduced into a water and glycerol mixture and processed to form a microemulsion. The injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0207] Compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0208] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the invention are employed. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa buter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. When a compound according to this invention is administered into a human subject, the daily dosage regimen will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.

[0209] The instant compounds are also useful in combination with known therapeutic agents for simultaneous, separate or sequential administration.

[0210] The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the subject in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

[0211] 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.

[0212] The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. When a compound of the present invention is administered into a human subject, the daily dosage regimen will normally be determined by the prescribing physician, with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient’s symptoms. In one exemplary application, oral dosages of the present invention will range between about 0.01 mg per kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. In embodiments of the invention, the compounds of the present invention may be administered according to a dosing regimen of a daily dose. In embodiments of the invention, the compounds of the present invention may be administered according to a dosing regimen of a once daily dose, more preferably according to a twice a day (or b.i.d.) dosing regimen. In further embodiments, the compounds of the present invention may be administered according to a dosing regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. Preferred regimen is 2-5 days, or 3-5 days, or 3, 4 or 5 days, most preferably 3 days or 5 days. The dose may be a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less.

[0213] It is a further object of the invention a method treating, ameliorating or preventing a Flavivirus infection and related conditions in a subject, preferably wherein the Flavivirus is selected from the group consisting of West Nile and Zika virus, comprising administering to said subject a therapeutically effective amount of the compound as defined above.

[0214] These and other aspects of the invention will be apparent from the teachings contained herein. The invention will be illustrated by reference to the following non-limited examples.

[0215] EXAMPLES

[0216] Chemistry

[0217] General

[0218] The compounds, or pharmaceutically acceptable salts thereof, compositions, and methods described herein are further illustrated by the following non-limiting examples.

[0219] As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0220] Boc2O: Di-tert-butyl dicarbonate; DCM: Dichloromethane; DHP: 3,4-Dihydropyran; DIPEA: N,N-Diisopropylethylamine; DMF: Dimethylformamide; DMSO: Dimethylsulfoxide; ES+: Electrospray Positive Ionisation; EtOAc: Ethyl acetate; EtOH: Ethanol; h: Hour; HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium; HPLC: High Performance Liquid Chromatography; LiBH4: Lithium borohydride; LiOH: Lithium hydroxide; LCMS: Liquid Chromatography Mass Spectrometry; KOAc: Potassium acetate; K2CO3: Potassium carbonate; K3PO4: tripotassium phosphate; MeCN: Acetonitrile; MeOH: Methanol; min: Minute; NaH: Sodium Hydride; NH3: ammonium; NMP: N-Methylpyrrolidone; NMR: Nuclear Magnetic Resonance; NH2NH2: Hydrazine; NaCNBH3: Sodium cyanoborohydride; Pd(dppf)Cl2: (1,1'-Bis(diphenylphosphino)ferrocene)-palladium(II) dichloride; Pd(OAc)2: Palladium(II) acetate; PCy3: triclyclohexylphosphine; Py: pyridine; RP: Reverse Phase; tR: Retention time; rt: room temperature; ‘BuONO: / c / V-Butyl nitrite; TBDMS: Tert-Butyldimethylsilyl; TEA: Triethylamine; TIPS: Triisopropylsilyl ether; TFA: Trifluoroacetic acid; THF: Tetrahydrofurane; UPLC: Ultra High Performance Liquid Chromatography.

[0221] General experimental details

[0222] Solvents and reagents were obtained from commercial suppliers and were used without further purification. Flash chromatography purifications were performed on prepacked cartridges on a Biotage system. Purity of final compounds was determined using MS and UPLC. UPLC-MS analyses were performed on a Waters Acquity UPLC™, equipped with a diode array and a ZQ mass spectrometer, using an X-Terra C18 column (5 µm, 4.6 x 50 mm) or a BEH C18 column (1.7 mm, 2.1 x 50 mm). Mobile phase comprised a linear gradient of binary mixtures of H2O containing 0.1% formic acid (A), and MeCN containing 0.1% formic acid (B). The linear gradient used is: (A): 90% (0.1 min), 90%-0% (2.6 min), 0% (0.3 min), 0%-90% (0.1 min) with a 0.5 mL / min flow. The purity of final compounds was >95%. All1H spectra were recorded on Bruker AV400 spectrometer at 400 MHz except where indicated. Chemical shift (6) are reported in parts per million relative to TMS using CDCl3as a solvent or relative to the residual solvent signal using DMSO-d6. Coupling costants (J) are reported in Hertz (Hz). Multiplicities are reported as singlet (s), broad (br), doublet (d), doublet of doublet (dd), doublet of doublet of doublet (ddd), triplet (t), doublet of triplet (dt), doublet of doublet of triplet (ddt), triplet of triplet (tt), quartet (q), doublet of quartets (dq) or multiplet (m). Unless indicated, spectra were acquired at 300 K. Temperatures are expressed in degrees Celsius (°C) and are uncorrected. Unless otherwise indicated, commercially available reagents and solvents (HPLC grade) were used without further purification. Where 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 extension of the Examples herein. During any of the synthetic sequences described herein it may be necessary and / or desirable to protect sensitive or reactive groups or any of the molecules concerned, this may be achieved by means of conventional protecting groups, such as those described in Protecting Groups in Organic Synthesis (3rdEdition, Greene, T.W. and Wuts, P.G.M.; Wiley Interscience, 1999) and Protecting Groups (Kocienski, P. J.; Thieme, 1994).

[0223] Intermediates 1-24 were synthetized following the synthetic procedures described below.

[0224] Intermediates 2 & 4: l-Cyclobutyl-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- l / / -pyrazole & 4-chloro- 1 -met hyl-5-(4.4.5.5-tetraniethy 1-1.3.2-dioxaborolan-2-y 1)-1 / / -pyrazole / /

[0225] N

[0226] i\

[0227] h

[0228] Mel, CS2CO3, MeCN

[0229] 60 °C, 16 h

[0230] quant

[0231] N IT,

[0232] N'

[0233] I

[0234]

[0235] Intermediate 3 Intermediate 4

[0236] Scheme 1

[0237] Step 1A: l-Cyclobutyl-4-methyl-lH-pyr azole (Intermediate 1)

[0238] A solution of 4-methyl-1H-pyrazole (493 mg, 6 mmol) in DMF (2 mL) at 0 °C, NaH (60%, 600 mg, 15.01 mmol) was added, the resulted suspension was stirred at 0 °C for 30 min. Then bromocyclobutane (1.2 g, 9.01 mmol) was added at 0 °C and then the reaction was heated at 60 °C for 16 h. After consumption of starting material, the reaction mixture was cooled at 0 °C and subsequently quenched with water. The crude reaction was extracted with EtOAc (2x). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude compound as a colourless oil (910 mg, quant.) which was used in next step without further purification.

[0239] Step 2A: l-Cyclobutyl-4-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyr azole (Intermediate 2)

[0240] A solution of 1-cyclobutyl-4-methyl-1H-pyrazole (200 mg, 1.32 mmol) in THF (4.5 mL) at -78 °C, was treated with «-BuLi (2.5 M in hexanes, 687 pL, 1.72 mmoL) and stirred at - 78 °C for 1 h. Then 2-isopropoxy-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxoborolane (320 mg, 1.72 mmol) was added and the reaction was stirred for 1 h at - 78 °C. After checking the effective formation of the desire product, the mixture was warmed at 0 °C and subsequent quenched with NH₄Cl sat. sol. followed by HC1 (1 N) until pH = 7. The aqueous phase was then extracted with EtOAc (2x) and the resulting organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the Intermediate 2 as a yellow oil (350 mg, quant.) as a mixture of boronic ester and boronic acid (50:50 calculated by UPLC). The resulting crude compound was used in the next step without further purification. LCMS (ES+) m / z calculated for C14H23BN2O2 262.16, found 263 (M+H)+HPLC tR2.20 min (boronic ester); 180 (M+H)+HPLC tR0.80 min (boronic acid) Step IB: 4-Chloro-l-methyl-pyr azole (Intermediate 3)

[0241] A suspension of 4-methyl-1H-pyrazole (300 mg, 2.93 mmol) and CS2CO3 (1430 mg, 4.39 mmol) in acetonitrile (5.8 mL) at rt, iodomethane (830 mg, 5.85 mmol) was added. The reaction mixture was then heated to 30 °C and stirred for 16 h. The mixture was cooled to rt and then quenched with water and EtOAc. The extracted organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product as a colorless oil (170 mg, 50%) which was used in the next step without further purification. LCMS (ES+) m / z calculated for C4H5CIN2 116.55, found 196 (M+DMSO+H) HPLC tR1.13 min.

[0242] Step 2B: 4-Chloro-l-methyl-5-( 4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-lH-pyr azole (Intermediate 4)

[0243] A solution of 4-chloro-l-methyl-pyrazole (Intermediate 3, 70 mg, 0.6 mmol) in THF (2 mL) at -78 °C was treated with «-BuLi (2.5 M in hexanes, 312 pL, 0.78 mmoL) and stirred at - 78 °C for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxoborolane (145 mg, 0.78 mmol) was added and the reaction was stirred for 1 h at - 78 °C. After checking the effective formation of the desire product, the mixture was warmed at 0 °C and quenched with NH4CI sat. sol. followed by HC1 (1 N) until pH = 7. The aqueous phase was then extracted with EtOAc (2x) and the resulting organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to get the title compound as a white solid (162 mg, 72%) as mixture of boronic ester and boronic acid (5:95 calculated by UPLC). The resulting crude compound was used in the next step without further purification. 'H NMR (400 MHz, DMSO-tL) δ 7.56 (s, 1H), 3.96 (s, 3H), 1.32 (s, 12H). LCMS (ES+) m / z calculated for C10H16BCIN2O2242.51, found 243 (M+H)+. HPLC tR1.88 min (boronic ester); found 161 (M+H)+. HPLC tR0.65 min (boronic acid).

[0244] Intermediates 5-10 were prepared using the synthetic procedure described for the synthesis of Intermediate 2 or Intermediate 4 in Scheme 1 using the appropriate starting materials and CS2CO3 (1.5 equiv.) or NaH 60% dispersion in mineral oil (2.5 equiv.) as specified.

[0245] Intermediate 5: 1-Cy clobutyl-4-methoxy-5-(4, 4, 5, 5- tetramethyl- 1,3, 2-dioxaborolan-2-yl)- l / / -pyrazole

[0246] The title compound was obtained as a yellow oil (49 mg, 79% yield). The title compound was obtained as a mixture of boronic ester and boronic acid (65:35 calculated by UPLC). LCMS (ES+) m / z calculated for C14H23BN2O3278.16, found 279 (M+H)+. HPLC tR2.01 min (boronic ester); 197 (M+H)+. HPLC tR1.10 min (boronic acid).

[0247] Intermediate 6: 4-Chloro-l-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- l / / -pyrazole

[0248] The title compound was obtained as a white solid (108 mg, quant.) which was used as a crude in the next step. LCMS (ES+) m / z calculated for C12H18BCIN2O3284.55, found 203 (M+H-pinacol)+. HPLC tR0.71 min (boronic acid).

[0249] Intermediate 7: l-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)- LH-pyrazole

[0250] The title compound was obtained as a yellow oil (130 mg, quant.) and used as a crude in the next step. The title compound was obtained as a mixture of boronic ester and boronic acid (1:1 calculated by UPLC). LCMS (ES+) m / z calculated for C11H16BF3N2O2276.07, found 277 (M+H)+. HPLC tR1.99 min (boronic ester); found 195 (M+H)+. HPLC tR0.84 min (boronic acid).

[0251] Intermediate 8: l-(Oxetan-3-yl)-5-(4, 4, 5, 5- tetramethyl- 1,3, 2-dioxaborolan-2-yl)-4- (trifluoromethyl)- LH-pyrazole

[0252] The title compound was obtained as a yellow oil (162 mg, 80%) and used as a crude in the next step. The title compound was obtained as a mixture of boronic ester and boronic acid (1:1 calculated by UPLC). LCMS (ES+) m / z calculated for C13H18BF3N2O3318.10, found 319 (M+H)+. HPLC tR1.68 min (boronic ester); found 237 (M+H)+. HPLC tR0.90 min (boronic acid).

[0253] Intermediate 9: 4-Fluoro-l-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-LH-pyrazole

[0254] The title compound was obtained as a yellow oil (162 mg, 86%) as mixture of boronic ester and acid (1:1 calculated by UPLC). LCMS (ES+) m / z calculated for C12H18BFN2O3268.10, found 187 (M+H-pinacol)+. HPLC tR0.54 min (boronic acid).

[0255] Intermediate 10: 4-Chloro-l-tetrahydrofuran-3-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole

[0256] The title compound was obtained as a colorless oil (68 mg, 29%).1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 5.44-5.37 (m, 1H), 4.03-3.91 (m, 2H), 3.86-3.75 (m, 2H), 2.40-2.26 (m, 2H), 1.32 (s, 12H). LCMS (ES+) m / z calculated for C13H20BCIN2O3 298.57-300.57, found 299-301 (M+H)+. HPLC tR2.05 min.

[0257] Intermediate 11: 2-(Difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine Pd(dppf)2CI2, KOAc,

[0258] 1,4-Dioxane, 75 °C, 16 h

[0259] 33%

[0260]

[0261] Intermediate 11

[0262] Scheme 2

[0263] A suspension of 3-bromo-2-(difluoromethyl)pyridine (245 mg, 1.18 mmol), bis(pinacolato)diboron (598 mg, 2.36 mmol), Pd(dppf)Cl2(86.2 mg, 0.12 mmol) and KOAc (347 mg, 3.53 mmol) in anhydrous 1,4-dioxane (7.8 mL) was heated at 75 °C for 3 h. Then the reaction mixture was diluted with EtOAc (2x), washed with water and brine. The collected organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a colorless oil (100 mg, 33%).JH NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 1.8, 4.8 Hz, 1H), 8.13 (td, J = 0.9, 7.6 Hz, 1H), 7.61-7.57 (m, 1H), 7.21 (t, J= 54.7 Hz, 1H), 1.34 (s, 12H).19F NMR (377 MHz, DMSO-d6) δ -114.05 (s, 2F). LCMS (ES+) m / z calculated for C12H16BF2NO2255.07, found 174 (M+H-pinacol)+. HPLC tR0.82 min.

[0264] Intermediate 12 was prepared using the synthetic procedure described for the synthesis of Intermediate 11 in Scheme 2 using the appropriate starting materials.

[0265] Intermediate 12: 4,6-Dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine The title compound was obtained as a brown oil (3.0 g, 49%). 'H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 2.49-2.48 (m, 6H), 1.36 (s, 12H). LCMS (ES+) m / z calculated for C12H19BN2O2 234.10, found 235 (M+H)+. HPLC tR1.41 min.

[0266] Intermediate 13: 3-Bromo-4-(difluoromethyl)pyridine

[0267] DCM

[0268] 0 °C to rt, 1 h

[0269] 48%

[0270]

[0271] Intermediate 13

[0272] Scheme 3 A solution of diethyl(trifluorosulfuranyl)amine (0.39 mL, 2.96 mmol) in dry DCM (0.3 mL) at rt, was added dropwise to a stirring solution of 3-bromoisonicotinaldehyde (100 mg, 0.54 mmol) in dry DCM (0.7 mL) at 0 °C. The reaction was allowed to warm up to rt and stirred for 1 h before being poured in ice-cold water. A saturated aqueous solution of NaHCO3was added until pH = 8 and the solution was diluted with DCM (2x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to get the title compound as a colorless oil (54 mg, 48%). 'H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.75 (d, J= 5.0 Hz, 1H), 7.70 (d, J = 4.9 Hz, 1H), 7.19 (t, J= 53.5 Hz, 1H).19F NMR (376 MHz, DMSO-d6) δ -118.68 (s, 2F). LCMS (ES+) m / z calculated for C6H4BrF2N 206.95-208.95, found 208-210 (M+H)+. HPLC tR1.46 min

[0273] Intermediates 14 and 15 were prepared using the synthetic procedure described for the synthesis of Intermediate 13 in Scheme 3 using the appropriate starting materials.

[0274] Intermediate 14: 2-Bromo-3-(difluoromethyl)pyridine

[0275] The title compound was obtained as an orange oil (34 mg, 20%).JH NMR (400 MHz, DMSO-d6) δ 8.60-8.55 (m, 1H), 8.14-8.09 (m, 1H), 7.64 (dd, J = 4.8, 7.7 Hz, 1H), 7.16 (t, J= 53.9 Hz, 1H).

[0276] 19F NMR (376 MHz, DMSO-d6) δ -115.92 (s, 2F). LCMS (ES+) m / z calculated for C6H4BrF2N 206.95-208.95, found 208-210 (M+H)+. HPLC tR1.38 min.

[0277] Intermediate 15: 4-Bromo-3-(difluoromethyl)pyridine

[0278] The title compound was obtained as a colourless oil (125 mg, quant.). 'H NMR (400 MHz, DMSO-d6) 88.79 (s, 1H), 8.61 (d, J= 5.3 Hz, 1H), 7.90 (d, J= 5.4 Hz, 1H), 7.24 (t, J= 52 Hz,lH).19F NMR (376 MHz, DMSO-d6) δ -116.00 (s, 2F). LCMS (ES+) m / z calculated for C6H4BrF2N 206.95-208.95, found 208, 210 (M+H)+. HPLC tR1.37 min.

[0279] Intermediate 18: 4-Methyl-1-tetrahydropyran-4-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

[0280] HO

[0281] CS2CO3, MeCN n-BuLi, THF, 85 °C, 16 h - 78 °C, 3 h quant. S'° o

[0282]

[0283] Intermediate 16 Intermediate 17 Intermediate 18

[0284] Scheme 4 Step 1: 4-Methyl-l-methylsulfonyl-pyr azole (Intermediate 16)

[0285] A suspension of 4-methyl-17 / -pyrazole (300 mg, 3.65 mmol) and N,N-diethylethanamine (0.65 mL, 4.75 mmol) in dry DCM (12 mL) at 0 °C, methanesulfonyl chloride (460 mg, 4.02 mmol) was added. The resulting reaction mixture was allowed to warm up to rt and was stirred for 16 h before being quenched with water. The layer was separated, and the collected organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was used without further purification in the next step. LCMS (ES+) m / z calculated for C5H8N2O2S 160.19, found 161 (M+H)+. HPLC fe 0.85 min.

[0286] Step 2: 4-Methyl-1-tetrahydropyran-4-yl-pyrazole (Intermediate 17)

[0287] A suspension of 4-methyl-l-methylsulfonyl-pyrazole (Intermediate 16, 99 mg, 0.59 mmol), tetrahydropyran-4-ol (50 mg, 0.49 mmol) and CS2CO3 (287 mg, 0.88 mmol) in dry acetonitrile (1.6 mL) was stirred at 85 °C for 16 h, before being diluted with water and EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was used as such in step 3. LCMS (ES+) m / z calculated for C9H14N2O 166.22, found 167 (M+H)+. HPLC tR0.96 min.

[0288] Step 3: 4-Methyl-l -tetrahydropyran-4-yl-5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole (Intermediate 18)

[0289] The title compound was prepared following the procedure reported for the synthesis of Intermediate 2 (in Scheme 1, Step 2) and was obtained as a colorless oil (21.0 mg, 68%). LCMS (ES+) m / z calculated for C15H25BN2O3292.18, found 293 (M+H)+. HPLC tR1.91 min.

[0290] Intermediate 19 was prepared using the synthetic procedure described for the synthesis of Intermediate 18 in Scheme 4 using the appropriate starting materials

[0291] Intermediate 19: 4-Chloro-l-tetrahydropyran-4-yl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole

[0292] The title compound was obtained as a white solid (48 mg, 14%). 'H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 4.86-4.77 (m, 1H), 3.98 (br dd, J= 3.8, 11.4 Hz, 2H), 3.45-3.36 (m, 2H), 2.05-1.95 (m, 2H), 1.83 (br dd, J = 2.1, 12.4 Hz, 2H), 1.32 (s, 12H). LCMS (ES+) m / z calculated for C14H22BCIN2O3312.60, found 313 (M+H)+. HPLC tR2.09 min.

[0293] Intermediate 22: 4-Chloro-l-tetrahydrofuran-3-yl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole Cs2CO3, DMF rt, 16 h quant.

[0294]

[0295] Intermediate 20 Intermediate 21 Intermediate 22 Scheme 5

[0296] Step 1: l-(4-Chloropyrazol-l-yl)-2-methyl-propan-2-ol (Intermediate 20)

[0297] A suspension of 4-chloro-17 / -pyrazole (300 mg, 2.93 mmol) and CS2CO3 (846 mg, 4.39 mmol) in dry DMF (3 mL) at rt, 2,2-dimethyloxirane (632 mg, 8.78 mmol) was added. The resulting reaction mixture was stirred at rt for 16 h before being quenched with water and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a colorless oil (524 mg, quant.).JH NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.51 (s, 1H), 4.72 (s, 1H), 3.98 (s, 2H), 1.05 (s, 6H). LCMS (ES+) m / z calculated for C7H11CIN2O 174.63, found 175 (M+H)+. HPLC tR1.01 min.

[0298] Step 2: Tert-butyl-[2-(4-chloropyrazol-l-yl)-l, 1 -dimethyl-ethoxy ]-dimethyl-silane (Intermediate 21)

[0299] A stirred suspension of l-(4-chloropyrazol-l-yl)-2-methyl-propan-2-ol (Intermediate 20, 524 mg, 3.00 mmol) in dry DCM (5.8 mL) at 0 °C, was treated with 2,6-lutidine (0.5 mL, 4.39 mmol) and trifluoromethanesulfonic acid (0.8 mL, 3.51 mmol). The resulting reaction mixture was allowed to warm up to rt and stirred at rt for 16 h before being quenched with H2O and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a colorless oil (811 mg, 96%). 'H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.53 (s, 1H), 4.01 (s, 2H), 1.18 (s, 6H), 0.83 (s, 9H), 0.02 (s, 6H). LCMS (ES+) m / z calculated for C13H25ClN2OSi 288.89, found 289 (M+H)+. HPLC tR2.70 min.

[0300] Step 3: Tert-butyl-[2-[4-chloro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazol-l-yl ]-1, 1 -dimethyl-ethoxy] -dimethyl-silane (Intermediate 22)

[0301] The title compound was prepared following the procedure reported for the synthesis of Intermediate 2 (in Scheme 1, Step 2) and was obtained as a colorless oil (46 mg, 16%). 'H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 4.31 (s, 2H), 1.31 (s, 12H), 1.20 (s, 6H), 0.79 (s, 9H), 0.05 (s, 6H). LCMS (ES+) m / z calculated for C19H36BClN2O3Si 414.85, found 201 (M+H-pin-OTBDMS)+. HPLC tR1.05 min.

[0302] Intermediates 24: 4-Chloro-l-(tetrahydro-2 / f-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 / / -py razole

[0303] n-BuLi, THF,

[0304] - 78 °C, 3 h

[0305] 65% 79%

[0306]

[0307] Intermediate 23 Intermediate 24

[0308] Scheme 6

[0309] Step 1: 4-Chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (Intermediate 23)

[0310] DHP (3.2 g, 38.04 mmol) was added to 4-chloro-17 / -pyrazole (3 g, 29.26 mmol) and the resulting mixture was stirred at 140 °C for 16 h. The reaction was allowed to warm up to rt and the residue was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a colorless oil (3.5 g, 65%). LCMS (ES+) m / z calculated for C8H11CIN2O 186.64, found 209 (M+Na)+. HPLC tR1.60 min.

[0311] Step 2: 4-Chloro-l-( tetrahydro-2H-pyran-2-yl)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-IH-pyrazole (Intermediate 24)

[0312] A solution of 4-chloro-l-(tetrahydro-27 / -pyran-2-yl)-17 / -pyrazole (Intermediate 23, 2.4 g, 12.71 mmol) in THF (42 mL) at -78 °C was treated with n-BuLi (2.5 M in hexanes, 11.9 mL, 19.07 mmol) and the resulted mixture reaction was stirred at -78 °C for 1 h. Then 2-isopropoxy-4, 4,5,5-tetramethyl-l,3,2-dioxoborolane (3.1 mg, 16.52 mmol) was added and the reaction was stirred for Ih at -78 °C. After checking the effective formation of the desire product, the mixture was allowed to heat to 0 °C and quenched with NH4Clssfollowed by HC1 (1 N) until pH = 7. The mixture was then extracted with EtOAc (2x) and the resulting organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to get the residue which was purified by flash chromatography on silica gel (eluting with 0-35% EtOAc in petroleum ether) to give the title compound Intermediate 24 as a yellow oil (3.6 g, 79%). LCMS (ES+) m / z calculated for C14H22BCIN2O3312.60, found 229 (M-pinacol-H)’. HPLC tR1.20 min. Examples 1 & 8: (3-(4-(2-(Trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide & (3-(4-(l-( yclobutyl-4-inethyl-l / / -pyrazol-5-yI)benzyI)-l,2,3-oxadiazol-3-ium-5-yI)((2-(trifluoromethyI)pyridin-4-yl)carbamoyl)amide.

[0313] Triphosgene DIPEA, THF rt, 1 h 2. DIPEA, THF rt, 15 min Intermediate 26

[0314] Example 8 Pd(dppf)Cl2, K3PO4, H2O / dioxane, 75 °C, 1 h 52%

[0315]

[0316] Example 1

[0317] Scheme 7

[0318] Step 1: (3-( 4-Bromobenzyl)-l, 2, 3-oxadiazol-3-i um-5-yl)( ( 2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 26)

[0319] A solution of 2-(trifluoromethyl)pyridin-4-amine (222 mg, 1.41 mmol) and DIPEA (0.48 mL, 2.77 mmol) in dry THF (1.3 mL) was treated with triphosgene (204 mg, 0.69 mmol) and stirred at rt for 1 h. This solution was added dropwise to a stirring suspension of 5-amino-3-(4-bromobenzyl)- l,2,3-oxadiazol-3-ium chloride (Intermediate 25, 200 mg, 0.69 mmol, prepared as described in WO2023 / 227734) in dry THF (5.0 mL) followed by the addition of DIPEA (0.48 mL, 2.77 mmol) at 0 °C. The mixture was stirred at this temperature for 5 minutes before being diluted with H2O and extracted with EtOAc (2x). The collected organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as ayellow solid (190 mg, 62%). 'H NMR (400 MHz, DMSO-tfe) 810.17 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J= 1.8 Hz, 1H), 7.70-7.67 (m, 3H), 7.57-7.53 (m, 2H), 5.81 (s, 2H). LCMS (ES+) m / z calculated for Ci6HiiBrF3N5O2441.00, 443.00 found 440, 442 (M-H)'. HPLC ZR 1.81 min.

[0320] Step 2A: (3-(4-(l-Cyclobutyl-4-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 8)

[0321] A suspension of (3-(4-bromobenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 26, 30 mg, 0.07 mmol), Intermediate 2 (25.4 mg, 0.12 mmol), Pd(dppf)Cl2(5 mg, 0.01 mmol) and K3PO4 (43.2 mg, 0.2 mmol) in a mixture of 1,4-dioxane (0.8 mL) and H2O (0.1 mL) was heated at 75 °C for 1 h before being diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on C18 RP (eluting with 0-100% CH3CN in H2O) to give the title compound as a white powder (14.0 mg, 25%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.9 Hz, 1H), 7.73-7.68 (m, 3H), 7.45-7.39 (m, 3H), 5.91 (s, 2H), 4.59 (t, J= 8.3 Hz, 1H), 3.31-3.29 (m, 1H), 2.60-2.53 (m, 2H), 2.27-2.18 (m, 2H), 1.94 (s, 3H), 1.77-1.62 (m, 2H).19F NMR (377 MHz, DMSO-d6) 8 -66.93 (s, 3F). LCMS (ES+) m / z calculated for C24H22F3N7O2 497.47, found 498 (M+H)+. HPLC tR1.78 min.

[0322] Step 2B: ( 3-( 4-( 4, 4, 5, 5-Tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzyl)-l, 2, 3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 27)

[0323] A suspension of (3-(4-bromobenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 26, 192 mg, 0.43 mmol), bis(pinacolate)diboron (221 mg, 0.87 mmol), Pd(dppf)Cl2(31.8 mg, 0.04 mmol) and KOAc (128 mg, 1.3 mmol) in 1,4-dioxane (4.0 mL) was heated at 75 °C for 8 h before being diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4. filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as an orange powder (112 mg, 53%). 'H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.46 (d, J= 5.6Hz, 1H), 8.28 (s, 1H), 8.19 (d, J= 1.8 Hz, 1H), 7.75 (d, J= 8.1 Hz, 2H), 7.69 (dd, J= 5.6, 1.9 Hz, 1H), 7.57 (d, J= 8.1 Hz, 2H), 5.86 (s, 2H), 1.30 (s, 12H). LCMS (ES+) m / z calculated for C22H23BF3N5O4489.18, found 490 (M+H)+. HPLC tR2.02 min. Step 3: (3-(4-(2-(Trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 1)

[0324] The title compound was prepared following the conditions reported for the synthesis of Example 2 in Step 2A using (3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 27) and 5-bromo-4-trifluoromethylpyrimidine as starting materials. The title compound was obtained as a white powder (26.4 mg, 52%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.80 (dd, J= 1.1, 4.6 Hz, 1H), 8.47 (d, J= 5.6Hz, 1H), 8.38 (s, 1H), 8.21 (d, J= 1.8Hz, 1H), 7.96 (d, J= 8.0Hz, 1H), 7.80 (dd, J=4.6, 7.9 Hz, 1H), 7.72-7.67 (m, 3H), 7.48 (d, J= 8.1 Hz, 2H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO-d6) 8 -59.80 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C22H14F6N6O2508.38, found 509 (M+H)+. HPLC tR1.74 min.

[0325] Examples 6, 9, 11, 14, 16-17, 22, 25-28, 31-33, 39 and 42-43 were prepared using the synthetic procedure described for the synthesis of Example 8 in Step 2A Scheme 7 using the appropriate starting materials.

[0326] Example 6: (3-(4-(3-Methoxypyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0327] The title compound was obtained as a white powder (19.5 mg, 40%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.17 (d, J= 6.3 Hz, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.94 (d, J= 8.3 Hz, 2H), 7.74-7.69 (m, 3H), 7.58 (d, J= 6.3 Hz, 1H), 5.92 (s, 2H), 3.99 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F) and -74.68 (s, 6F). LCMS (ES+) m / z calculated for C21H16F3N7O3471.39, found 472 (M+H)+. HPLC tR1.14 min.

[0328] Example 9: ((3-(4-(l-Cyclobutyl-4-methoxy-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0329] The title compound obtained as a white powder (11.5 mg, 19%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J= 1.9 Hz, 1H), 7.70-7.68 (m, 3H), 7.53 (s, 1H), 7.45 (d, J= 8.3 Hz, 2H), 5.89 (s, 2H), 4.75-4.67 (m, 1H), 3.70 (s, 3H), 2.61-2.54 (m, 2H), 2.31-2.21 (m, 2H), 1.77-1.66 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F). LCMS (ES+) m / z calculated for C24H22F3N7O3513.47, found 514 (M+H)+. HPLC tR1.74 min.

[0330] Example 11: (3-(4-(4-Chloro-l-methyl-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0331] The title compound was obtained as a white powder (3.6 mg, 4%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.9Hz, 1H), 7.78-7.74 (m, J= 8.4 Hz, 2H), 7.70 (dd, J= 1.9, 5.6 Hz, 1H), 7.68 (s, 1H), 7.65-7.60 (m, 2H), 5.92 (s, 2H), 3.78 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C20H15F3N7O2477.83, found 478 (M+H)+. HPLC fa 1.61 min.

[0332] Example 14: (3-(4-(4-Chloro-l-(oxetan-3-yl)- 1 / / -pyrazol-5-yl (benzyl )- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0333] The title compound was obtained as a white powder (5.3 mg, 8%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.42 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.90 (s, 1H), 7.77-7.73 (m, J= 8.4 Hz, 2H), 7.70 (dd, J= 1.9, 5.6 Hz, 1H), 7.51-7.47 (m, 2H), 5.92 (s, 2H), 5.46-5.38 (m, 1H), 4.92 (t, J= 6.4 Hz, 2H), 4.83-4.77 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C22H17F3N7O3519.86, found 520 (M+H)+. HPLC fa 1.61 min.

[0334] Example 16: (3-(4-(l-Methyl-4-(trifluoromethyl)-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0335] The title compound was obtained as a white powder (3.2 mg, 6%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.42 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.90 (s, 1H), 7.77-7.73 (m, J= 8.4 Hz, 2H), 7.70 (dd, J= 1.9, 5.6 Hz, 1H), 7.51-7.47 (m, 2H), 5.92 (s, 2H), 5.46-5.38 (m, 1H), 4.92 (t, J= 6.4 Hz, 2H), 4.83-4.77 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -53.29 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C21H15F6N7O 511.38, found 512 (M+H)+. HPLC fa 1.70 min.

[0336] Example 17: (3-(4-(l-(Oxetan-3-yl)-4-(trifluoromethyl)-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0337] The title compound was obtained as ayellow powder (6.1 mg, 10%). 'H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.47 (d, J= 5.8 Hz, 1H), 8.43 (s, 1H), 8.20 (d, J= 11.5 Hz, 2H), 7.76-7.68 (m, 3H), 7.49 (d, J= 8.3 Hz, 2H), 5.93 (s, 2H), 5.30 (s, 1H), 4.93 (t, J= 6.4 Hz, 2H), 4.77 (t, J= 7.2 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -55.38 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C23H17F6N7O3553.42, found 554 (M+H)+. HPLC fa 1.70 min.

[0338] Example 22: (3-(4-(4-Fluoro- l-(oxetan-3-yl)- 1 / / -py razol-5-yl (benzyl )- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl).

[0339] The title compound was obtained as a white powder (2.1 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.48-8.44 (m, 1H), 8.40 (s, 1H), 8.21 (d, J= 1.9 Hz, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H), 7.70 (dd, J= 1.8, 5.6 Hz, 1H), 7.50 (d, J= 8.0 Hz, 2H), 5.92 (s, 2H), 5.53-5.45 (m, 1H), 4.93 (t, J= 6.4 Hz, 2H), 4.86-4.79 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F), -177.01 (s, IF). LCMS (ES+) m / z calculated for C22H17F4N7O3533.41, found 534 (M+H)+. HPLC tR1.54 min. Example 25: (3-(4-(4-Chloro-l-methyl-LH-pyrazol-5-yl)-3-methylbenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0340] The title compound was obtained as a white powder (5.6 mg, 13%).JH NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.46 (d, J= 5.4 Hz, 1H), 8.40 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.70 (dd, J = 1.9, 5.6 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.54 (dd, J= 1.5, 7.8 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 5.88 (s, 2H), 3.58 (s, 3H), 2.14 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -73.63 (s, 6F). LCMS (ES+) m / z calculated for C21H17CIF3N7O2491.85, found 492 (M+H)+. HPLC tR1.75 min.

[0341] Example 26: (3-(4-(4-Methyl-l-(tetrahydro-2 / 7-pyran-4-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0342] The title compound was obtained as a white powder (4.5 mg, 19%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.42 (s, 1H), 8.21-8.21 (m, 1H), 8.21 (d, J= 1.9 Hz, 1H), 7.72 (d, J= 8.3 Hz, 2H), 7.69 (d, J= 1.9 Hz, 1H), 7.48 (d, J= 8.3 Hz, 2H), 7.42 (s, 1H), 5.91 (s, 2H), 4.15 (br d, J= 11.4 Hz, 1H), 3.84-3.92 (m, 2H), 3.24-3.30 (m, 2H), 2.08 (br dd, J= 11.9, 4.6 Hz, 2H), 1.92 (s, 3H), 1.73 (br dd, J= 12.6, 2.6 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C25H24F3N7O3527.50, found 528 (M+H)+. HPLC tR1.62 min.

[0343] Example 27: (3-(l-(4-(4-Chloro-l-methyl-LH-pyrazol-5-yl)phenyl)-cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl) amide.

[0344] The title compound was obtained as a white powder (20.8 mg, 60%). 'H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.50 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.24 (d, J= 1.9 Hz, 1H), 7.71-7.62 (m, 4H), 7.62-7.56 (m, 2H), 3.78 (s, 3H), 2.11-2.03 (m, 2H), 1.86-1.78 ppm (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.91 (s, 3F). LCMS (ES+) m / z calculated for C22H17CIF3N7O2503.86, found 504 (M+H)+. HPLC tR1.85 min.

[0345] Example 28: (3-(l-(4-(2-(Difluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0346] The title compound was obtained as a white powder (28.2 mg, 60%). 'H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.77-8.73 (m, 1H), 8.49-8.45 (m, 2H), 8.24 (d, J= 1.8 Hz, 1H), 7.91-7.85 (m, 1H), 7.71-7.62 (m, 4H), 7.52-7.45 (m, 2H), 6.83 (t, J= 53.7 Hz, 1H), 2.11-2.04 (m, 2H), 1.84-1.76 ppm (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.91 (s, 3F), -111.54 (s, 2F). LCMS (ES+) m / z calculated for C24H17F5N6O2516.42, found 517 (M+H)+. HPLC tR1.80 min.

[0347] Example 31: (3-(3-Chloro-4-(4,6-dimethylpyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide. The title compound was obtained as a white powder (3.3 mg, 8%).1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.96 (s, 1H), 8.48-8.45 (m, 2H), 8.22 (d, J= 1.8 Hz, 1H), 7.96 (d, J= 1.5 Hz, 1H), 7.72-7.68 (m, 2H), 7.53 (d, J= 7.9 Hz, 1H), 5.92 (s, 2H), 2.14 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C24H17ClF3N7O2503.86, found 504 (M+H)+. HPLC tR1.52 min.

[0348] Example 32: (3-(l-(4-(2-(Difluoromethyl)pyridin-3-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-amide.

[0349] The title compound was obtained as a white powder (3.4 mg, 8%). 'H NMR (400 MHz, DMSO-d.6) 8 10.19 (s, 1H), 8.79-8.72 (m, 1H), 8.52 (s, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.24 (d, J= 1.8 Hz, 1H), 7.89 (dd, J= 0.9, 7.9 Hz, 1H), 7.77 (d, J= 8.3 Hz, 2H), 7.71-7.65 (m, 2H), 7.51 (d, J= 8.3 Hz, 2H), 6.99-6.67 (m, 1H), 6.17 (dd, J= 4.3, 9.4 Hz, 1H), 5.76 (t, J= 5.4 Hz, 1H), 4.58 (ddd, J = 5.7, 9.5, 12.0Hz, 1H), 4.14 (td, J= 4.8, 12.1 Hz, 1H).19F NMR (377 MHz, DMSO-d6) δ -66.91 (s, 3F), -111.54 (s, 2F). LCMS (ES+) m / z calculated for C23H17F5N6O3520.41, found 521 (M+H)+. HPLC tR1.55 min.

[0350] Example 33: (3-(l-(4-(4-Chloro-l-methyl-LH-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-amide.

[0351] The title compound was obtained as a white powder (1.1 mg, 2%). 'H NMR (400 MHz, DMSO-dd) 8 10.20 (br s, 1H), 8.52 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.24 (d, J= 1.9 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.70 - 7.66 (m, 2H), 7.63 (d, J= 8.4 Hz, 2H), 6.18 (dd, J= 4.3, 9.2 Hz, 1H), 4.56 (dd,.7=9.4, 12.0 Hz, 1H), 4.16 (dd, J= 4.4, 12.1 Hz, 1H), 3.78 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.91 (s, 3F). LCMS (ES+) m / z calculated for C21H17ClF3N7O3507.85, found 508 (M+H)+. HPLC tR1.60 min.

[0352] Example 39: (3-(4-(l-(2-((ter / -Butyldimethylsilyl)oxy)-2-methylpropyl)-4-chloro-127-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0353] The title compound was obtained as a white powder (7.2 mg, 19%). 'H NMR (400 MHz, DMSO-d) 8 10.18 (s, 1H), 8.45 (d, J= 5.5 Hz, 1H), 8.34 (s, 1H), 8.22 (d, J= 1.6 Hz, 1H), 7.79-7.73 (m, 3H), 7.68-7.59 (m, 3H), 5.91 (s, 2H), 4.03 (s, 2H), 1.05 (s, 6H), 0.63 (s, 9H), -0.16 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -66.94 (s, 3F). LCMS (ES+) m / z calculated for C29H35ClF3N7O3Si 649.22, found 650 (M+H)+. HPLC tR1.61 min (Method 3).

[0354] Example 42: (3-(4-(4-Chloro-l-(tetrahydro-2H-pyran-4-yl)-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0355] The title compound was obtained as a white powder (11.0 mg, 18%).1H NMR (400 MHz, DMSO-dd) 8 10.20 (s, 1H), 8.49-8.44 (m, 1H), 8.43 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.78-7.75 (m, 2H), 7.70 (dd, J= 1.8, 5.6 Hz, 1H), 7.57 (d, J= 8.1 Hz, 2H), 7.41 (s, 1H), 5.93 (s, 2H), 4.29-4.20 (m, 1H), 3.88 (br dd, J= 3.8, 11.2 Hz, 2H), 3.28 (m, 2H), 2.12-1.98 (m, 2H), 1.79 (br d, J= 10.5 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C24H21ClF3N7O3547.92, found 548 (M+H)+. HPLC tR1.75 min.

[0356] Example 43: (3-(4-(4-Chloro-l-(tetrahydrofuran-3-yl)-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0357] The title compound was obtained as awhite powder (16.8 mg, 24%). 'H NMR (400 MHz, DMSO-d6) 8 10.20 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.43 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.78-7.74 (m, 3H), 7.70 (dd, J= 1.7, 5.7 Hz, 1H), 7.56 (d, J= 8.1 Hz, 2H), 5.93 (s, 2H), 4.89-4.82 (m, 1H), 4.00-3.92 (m, 2H), 3.85-3.74 (m, 2H), 2.24 (q, J= 6.8 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C23H19ClF3N7O3533.90, found 534 (M+H)+. HPLC tR1.73 min.

[0358] Examples 2, 3-5, 7, 10, 12-13, 15, 18-21, 23-24, 29-30, 34, 38, 41, 44-46, 48-49 and 61 were prepared using the synthetic procedure described for the synthesis of Example 1 in Step 3 Scheme 7 using the appropriate starting materials.

[0359] Example 2: (3-(4-(l,4-Dimethyl-LH-imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0360] The title compound was obtained as a white powder (2.6 mg, 10%). 'H NMR (400 MHz, DMSO-d.6) 8 10.19 (s, 1H), 9.08 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.41 (s, 1H), 8.22 (d, J= 1.8 Hz, 1H), 7.81-7.77 (m, J= 8.3 Hz, 2H), 7.68 (dd, J= 1.9, 5.6 Hz, 1H), 7.66-7.62 (m, J= 8.4 Hz, 2H), 5.93 (s, 2H), 3.75 (s, 3H), 2.25 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F), -73.88 (s, 3F). LCMS (ES+) m / z calculated for C21H18F3N7O2457.41, found 458 (M+H)+. HPLC tR1.02 min.

[0361] Example 3: (3-(4-(l-Cyclopropyl-4-methoxy-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0362] The title compound was obtained as a white powder (4.2 mg, 12%). 'H NMR (400 MHz, DMSO-d.6) 810.18 (s, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.36 (s, 1H), 8.23-8.18 (m, 1H), 7.69 (s, 5H), 7.41 (s, 1H), 5.88 (s, 2H), 3.71 (s, 3H), 3.68 (br dd, J= 3.1, 7.3 Hz, 1H), 3.31-3.29 (m, 2H), 0.98-0.85 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C23H20F3N7O3499.45, found 500 (M+H)+. HPLC tR1.66 min.

[0363] Example 4: (3-(4-(4-Methoxy-l-methyl-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0364] The title compound was obtained as a white powder (4.0 mg, 11%). 'H NMR (400 MHz, DMSO-d) 8 10.18 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J= 1.9Hz, 1H), 7.72-7.66 (m, 3H), 7.61-7.55 (m, 2H), 7.46-7.41 (m, 2H), 5.88 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F) -74.55 (s, 3F). LCMS (ES+) m / z calculated for C21H18F3N7O3473.41, found 474 (M+H)+. HPLC tR1.51 min.

[0365] Example 5: (3-(4-(l-Cyclopropyl-4-methyl-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yI)((2-(trifluoromethyI)pyridin-4-yI)carbamoyl)amide (trifluoroacetate salt).

[0366] The title compound was obtained as a white powder (4.4 mg, 11%). 'H NMR (400 MHz, DMSO-d6) 8 10.19 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.40 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.74-7.67 (m, 3H), 7.59 (d, J= 7.7 Hz, 2H), 7.30 (s, 1H), 5.91 (s, 2H), 3.58-3.53 (m, 1H), 1.96 (s, 3H), 0.94-0.88 (m, 2H), 0.86-0.78 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F) -74.55 (s, 3F). LCMS (ES+) m / z calculated for C23H20F3N7O2483.45, found 484 (M+H)+. HPLC tR1.69 min.

[0367] Example 7: (3-(4-(l -Cyclobutyl-4-methyl-l 7 / -imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0368] The title compound was obtained as a white powder (3.0 mg, 12%). 'H NMR (400 MHz, DMSO-d.6) 8 10.20 (s, 1H), 9.31 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J= 1.8 Hz, 1H), 7.79-7.75 (m, J= 8.3 Hz, 2H), 7.68 (dd, J= 2.1, 5.7 Hz, 1H), 7.57-7.53 (m, J= 8.3 Hz, 2H), 5.93 (s, 2H), 4.71-4.67 (m, 1H), 2.41-2.31 (m, 2H), 2.24-2.21 (m, 2H), 2.20 (s, 3H), 1.75-1.72 (m, 2H).

[0369] 19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F) -73.61 (s, 6F). LCMS (ES+) m / z calculated for C24H22F3N7O2497.47, found 498 (M+H)+. HPLC tR1.10 min.

[0370] Example 10: (3-(4-(2-(Difluoromethyl)pyridin-3-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0371] The title compound was obtained as a white powder (21.0 mg, 56%).1H NMR (400 MHz, DMSO-d) 8 10.19 (s, 1H), 8.75 (dd, J= 1.4, 4.6 Hz, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.90 (d, J= 7.8 Hz, 1H), 7.75-7.66 (m, 4H), 7.51 (d, J= 8.1 Hz, 2H), 7.01-6.67 (m, 1H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -111.52 (s, 2F). LCMS (ES+) m / z calculated for C22H15F5N6O2490.39, found 491 (M+H)+. HPLC tR1.64 min.

[0372] Example 12: (3-(4-(3-(Trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0373] The title compound was obtained as a white powder (24.5 mg, 49%).1H NMR (400 MHz, DMSO-<7e) 810.19 (s, 1H), 8.92 (dd, J=0.9, 4.8 Hz, 1H), 8.46 (d, J=5.6Hz, 1H), 8.37 (s, 1H), 8.34 (dd, J= 1.2, 8.1 Hz, 1H), 8.20 (d, J= 1.9 Hz, 1H), 7.72-7.66 (m, 4H), 7.55 (d, J= 8.1 Hz, 2H), 5.93 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -56.00 (s, 3F), -66.92 (s, 3F). LCMS (ES+) m / z calculated for C22H14F6N6O2508.38, found 509 (M+H)+. HPLC tR1.69 min.

[0374] Example 13: (3-(4-(4-Chloro-2-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt). The title compound was obtained as a white powder (7.8 mg, 14%).1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.76 (d, J= 5.3 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.9 Hz, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.69 (d, J= 8.4Hz, 3H), 7.44 (d, J= 8.1 Hz, 2H), 5.93 (s, 2H).

[0375] 19F NMR (377 MHz, DMSO-rfc) 8 -60.37 (s, 3F), -66.92 (s, 3F), -74.54 (s, 3F). LCMS (ES+) m / z calculated for C22H13CIF6N6O2542.82, found 543 (M+H)+. HPLC tR1.80 min.

[0376] Example 15: (3-(4-(4-(Trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0377] The title compound was obtained as a white powder (5.5 mg, 12%). 'H NMR (400 MHz, DMSO-d.6) 8 10.19 (s, 1H), 8.90 (d, J= 5.1 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.88 (d, J= 5.3 Hz, 1H), 7.70 (d, J= 8.1 Hz, 3H), 7.50 (d, J= 8.1 Hz, 2H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO- e) 8 -57.95 (s, 3F), -66.92 (s, 3F). LCMS (ES+) m / z calculated for C22H14F6N6O2508.38, found 509 (M+H)+. HPLC tR1.74 min.

[0378] Example 18: (3-(4-(6-Oxo-2-(trifluoromethyl)-l,6-dihydropyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0379] The title compound was obtained as a white powder (5.5 mg, 12%). 'H NMR (400 MHz, DMSO-d.6) 8 11.75 (br s, 1H), 10.18 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J= 1.8 Hz, 1H), 7.75-7.67 (m, 2H), 7.65 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.1 Hz, 2H), 6.99 (d, J= 8.4 Hz, 1H), 5.89 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -59.80 (s, 3F), -66.92 (s, 3F), -74.31 (s, 3F). LCMS (ES+) m / z calculated for C22H14F6N6O3524.38, found 525 (M+H)+. HPLC tR1.52 min.

[0380] Example 19: (3-(4-(2-Methoxy-4-(trifluoromethyl)pyridin-3-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0381] The title compound was obtained as a white powder (1.6 mg, 4%). 'H NMR (400 MHz, DMSO-d.6) 8 10.20 (s, 1H), 8.47 (t, J= 5.5 Hz, 2H), 8.40 (s, 1H), 8.22 (d, J= 1.8 Hz, 1H), 7.70 (dd, J = 2.0, 5.9 Hz, 1H), 7.65-7.61 (m, J= 8.3 Hz, 2H), 7.44 (d, J= 5.4 Hz, 1H), 7.39-7.34 (m, J= 8.1 Hz, 2H), 5.89 (s, 2H), 3.68 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -57.79 (s, 3F), -66.92 (s, 3F), -74.02 (s, 3F). LCMS (ES+) m / z calculated for C23H16F6N6O3538.40, found 539 (M+H)+. HPLC tR1.93 min.

[0382] Example 20: (3-(4-(4-(Trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0383] The title compound was obtained as a white powder (2.6 mg, 6%). 'H NMR (400 MHz, DMSO-d.6) 8 10.18 (s, 1H), 8.97 (d, J= 5.1 Hz, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.35 (s, 2H), 8.29 (d, J = 8.3 Hz, 2H), 8.20 (d, J= 1.8 Hz, 1H), 7.78-7.72 (m, 3H), 7.69 (dd, J= 1.7, 5.6 Hz, 1H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -63.22 (s, 3F), -66.92 (s, 3F), -74.72 (s, 3F). LCMS (ES+) m / z calculated for C22H14F6N6O2508.38, found 509 (M+H)+. HPLC / R 1.79 min.

[0384] Example 21: (3-((2'-(Trifluoromethyl)-[l,l'-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0385] The title compound was obtained as a white powder (6.5 mg, 13%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.70 (dd, J= 1.9, 5.6 Hz, 1H), 7.65 (d, J= 8.3 Hz, 3H), 7.45-7.39 (m, 3H), 5.90 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -55.29 (s, 3F), -66.92 (s, 3F), -74.58 (s, 3F). LCMS (ES+) m / z calculated for C23H15F6N5O2509.38, found 510 (M+H)+. HPLC tR2.02 min.

[0386] Example 23: (3-((2'-(Difluoromethyl)-[l,l'-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoacetate salt).

[0387] The title compound was obtained as a white powder (23.7 mg, 47%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.47 (d, J= 5.5 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.70 (d, J= 8.0 Hz, 3H), 7.66-7.56 (m, 2H), 7.46 (d, J= 8.1 Hz, 2H), 7.41 (d, J= 7.6 Hz, 1H), 6.82 (t, J= 54.0 Hz, 1H), 5.91 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -74.58 (s, 3F), -107.20 (s, 2F). LCMS (ES+) m / z calculated for C23H16F5N5O2489.40, found 490 (M+H)+. HPLC tR1.95 min.

[0388] Example 24: (3-(4-(2-(Difluoromethyl)-4-methylpyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0389] The title compound was obtained as a white powder (18.0 mg, 27%). 'H NMR (400 MHz, DMSO- 8 10.19 (s, 1H), 8.59 (d, J= 4.9 Hz, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.42 (s, 1H), 8.21 (d, J = 1.9 Hz, 01H), 7.73-7.68 (m, 3H), 7.56 (d, J= 4.9 Hz, 1H), 7.37 (d, J= 8.1 Hz, 2H), 6.54 (d, J = 59 Hz, 1H), 5.92 (s, 2H), 2.05 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -112.07 (s, 2F). LCMS (ES+) m / z calculated for C23H17F5N6O2504.41, found 505 (M+H)+. HPLC tR1.69 min.

[0390] Example 29: (3-(4-(3-(Difluoromethyl)pyridin-2-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0391] The title compound was obtained as a white powder (25.0 mg, 62%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.84 (d, J = 4.9 Hz, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.39 (s, 1H), 8.18-8.23 (m, 2H), 7.68-7.75 (m, 3H), 7.59-7.66 (m, 3H), 7.00 (t, J= 54.1 Hz, 1H), 5.93 ppm (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -108.37 (s, 2F). LCMS (ES+) m / z calculated for C22H15F5N6O2490.30, found 491 (M+H)+. HPLC tR1.68 min.

[0392] Example 30: (3-(2-Chloro-4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide. The title compound was obtained as a white powder (25.4 mg, 39%).1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.78 (dd, J= 1.6, 4.7 Hz, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J= 1.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.72-7.66 (m, 3H), 7.51 (dd, J= 1.8, 8.0 Hz, 1H), 6.90 (t, J= 52.1 Hz, 1H), 6.05 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.91 (s, 3F), -111.48 (s, 2F). LCMS (ES+) m / z calculated for C22H14ClF5N6O2524.83, found 525 (M+H)+. HPLC tR1.74 min.

[0393] Example 34: (3-(4-(3-(Trifluoromethyl)pyridin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0394] The title compound was obtained as a white powder (25.0 mg, 62%).1H NMR (400 MHz, DMSO- e) 6 10.20 (s, 1H), 8.78 (dd, J= 1.6, 4.7 Hz, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.31 (s, 1H), 8.19 (d,.7= 1.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.83 (d, J= 8.0Hz, 1H), 7.72-7.66 (m, 3H), 7.51 (dd, J= 1.8, 8.0 Hz, 1H), 6.90 (t, J= 52.1 Hz, 1H), 6.05 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -55.43 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C22H14ClF6N6O2508.38, found 509 (M+H)+. HPLC tR1.79 min.

[0395] Example 38: (3-(4-(3-Hydroxypyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0396] The title compound was obtained as a white powder (10.9 mg, 29%).1H NMR (400 MHz, DMSO-d6) 8 10.68 (br s, 1H), 10.18 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.33 (s, 1H), 8.24-8.18 (m, 2H), 8.04 (d, J= 8.3 Hz, 2H), 7.71-7.64 (m, 3H), 7.51 (br d, J= 7.8 Hz, 1H), 7.43-7.33 (m, 1H), 5.89 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -74.57 (s, 3F). LCMS (ES+) m / z calculated for C21H15F3N6O2456.38, found 457 (M+H)+. HPLC tR1.15 min.

[0397] Example 41: (3-(4-(4-Cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0398] The title compound was obtained as a white powder (36.9 mg, 47%).1H NMR (400 MHz, DMSO-d.6) 8 10.20 (s, 1H), 9.21 (s, 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.6 Hz, 1H), 7.73 (d, J= 8.1 Hz, 2H), 7.69 (dd, J= 1.8, 5.5 Hz, 1H), 7.52 (d, J= 8.1 Hz, 2H), 5.93 (s, 2H), 1.66-1.59 (m, 1H), 1.17-1.09 (m, 2H), 1.09-1.01 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -62.26 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C24H17F6N7O2549.13, found 550 (M+H)+. HPLC tR1.96 min.

[0399] Example 44: (3-(4-(3-(T rifluoromethyl)pyrazin-2-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0400] The title compound was obtained as a white powder (3.0 mg, 6%). 'H NMR (400 MHz, DMSO-d6. 8 10.19 (s, 1H), 9.07 (d, J= 2.0 Hz, 1H), 8.90 (d, J= 2.0 Hz, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.757.68 (m, 3H), 7.68-7.63 (m, 2H), 5.94 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -62.26 (s, 3F), -66.93 (s, 3F). LCMS (ES+) m / z calculated for C21H13F6N7O2509.37, found 510 (M+H)+. HPLC tR1.71 min.

[0401] Example 45: (3-(4-(2-(l,l-Difluoro-2-hydroxyethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0402] The title compound was obtained as a white powder (8.7 mg, 37%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.70 (d, J= 4.5 Hz, 1H), 8.47 (d, J= 5.5 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.77 (dd, J= 1.5, 8.0 Hz, 1H), 7.70 (dd, J= 1.8, 5.5 Hz, 1H), 7.67-7.59 (m, 3H), 7.45 (d, J= 8.0 Hz, 2H), 5.90 (s, 2H), 5.43 (t, J= 6.4 Hz, 1H), 4.04 (dt, J= 6.5, 14.4 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F), -98.64 (s, 2F). LCMS (ES+) m / z calculated for C23H17F5N6O3520.42, found 521 (M+H)+. HPLC tR1.52 min.

[0403] Example 46: (3-(4-(4-(Difluoromethyl)pyridin-3-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0404] The title compound was obtained as a white powder (10.4 mg, 58%).1H NMR (400 MHz, DMSO-d.6) 8 10.19 (s, 1H), 8.81 (d, J= 5.1 Hz, 1H), 8.66 (s, 1H), 8.47 (d, J= 5.5 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.5 Hz, 1H), 7.76-7.68 (m, 4H), 7.55 (d, J= 8.1 Hz, 2H), 7.00 (t, J= 53.9 Hz, 1H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -108.36 (s, 2F). LCMS (ES+) m / z calculated for C22H15F5N6O2490.39, found 491 (M+H)+. HPLC tR1.70 min.

[0405] Example 48: (3-(4-(3-(Difluoromethyl)pyridin-4-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0406] The title compound was obtained as a white powder (4.5 mg, 47%). 'H NMR (400 MHz, DMSO-d.6) 8 8.21 (d, J= 1.8 Hz, 1H), 7.80-7.63 (m, 3H), 7.57-7.47 (m, 3H), 7.04 (t, J= 53.9 Hz, 1H), 5.92 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F), -109.10 (s, 2F). LCMS (ES+) m / z calculated for C22H15F5N6O2490.39, found 491 (M+H)+. HPLC tR1.66 min.

[0407] Example 49: (3-(4-(6-(Methoxycarbonyl)-2-methylpyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0408] The title compound was obtained as a white powder (30.0 mg, 29%).1H NMR (400 MHz, DMSO-d.6) 8 10.19 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.74-7.67 (m, 3H), 7.57 (d, J= 8.1 Hz, 2H), 5.91 (s, 2H), 3.90 (s, 3H), 2.50-2.49 (m, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F). LCMS (ES+) m / z calculated for C24H19F3N6O4512.40, found 513 (M+H)+. HPLC tR1.66 min.

[0409] Example 61: (3-(4-(3-(Difluoromethyl)pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide. The title compound was obtained as a white powder (39.4 mg, 63%).1H NMR (400 MHz, DMSO-d6) 8 10.19 (s, 1H), 8.97-8.94 (m, 1H), 8.85 (d, J= 2.4 Hz, 1H), 8.46 (d, J= 5.6Hz, 1H), 8.40 (s, 1H), 8.21 (d, J= 1.8 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.74 - 7.69 (m, 3H), 7.04 (t, J= 53.0 Hz, 1H), 5.95 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.92 (s, 3F) and -113.22 (s, 2F). LCMS (ES+) m / z calculated for C21H14F5N7O2491.37, found 492 (M+H)+. HPLC tR1.56 min.

[0410] Example 35: (3-((6-(4,6-Dimethylpyrimidin-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0411] Triphosgene

[0412] DIPEA, THF

[0413] rt, 1 h

[0414] 2. DIPEA, THF Intermediate 28 rt, 15 min Intermediate 29

[0415] 47%

[0416] H2O / dioxane,

[0417] 75 °C, 1 h

[0418]

[0419] 42 %

[0420] Scheme 8

[0421] Step 1: ( 3-( ( 6-Bromopyridin-3-yl)methyl)-l, 2, 3-oxadiazol-3-ium-5-yl) ((2-( trifluor omethyl)-pyridin-4-yl)carbamoyl)amide (Intermediate 29)

[0422] A solution of 2-(trifluoromethyl)pyridin-4-amine (155 mg, 1.0 mmol) and DIPEA (0.67 mL, 4.0 mmol) in dry THF (2.5 mL) was treated with triphosgene (200 mg, 0.67 mmol) and stirred at rt for 1 h. This solution was added dropwise to a stirring suspension of 5-amino-3-((6-bromopyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium trifluoromethanesulfinate (Intermediate 28, 573 mg, 1.0 mmol, prepared as described in WO2023 / 227734 from appropriated starting materials) in dry THF (7.0 mL) followed by the addition of DIPEA (0.67 mL, 4.0 mmol) at 0 °C. The mixture was stirred at this temperature for 5 minutes before being diluted with H2O and extracted with EtOAc (2x). The collected organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as an orange solid (227 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.64 (d, J= 2.3 Hz, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J= 1.8Hz, 1H), 7.97 (dd, J= 8.3, 2.6 Hz, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.69 (dd, J= 5.6, 1.9 Hz, 1H), 5.87 ppm (s, 2H). LCMS (ES+) m / z calculated for C15H10BrF3N6O2441.00-443.00, found 441 and 443 (M-H)-. HPLC fa 1.52 min.

[0423] Step 2: (3-((6-(4,6-Dimethylpyrimidin-5-yl)pyridin-3-yl)methyl)-l,2,3-oxad.iazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 35)

[0424] A suspension of (3-((6-bromopyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)-pyridin-4-yl)carbamoyl)amide (Intermediate 29, 50 mg, 0.1 mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (34 mg, 0.12 mmol), Pd(dppf)Cl2(7 mg, 0.01 mmol) and K3PO4 (62 mg, 0.3 mmol) in a mixture of 1,4-dioxane (0.8 mL) and H2O (0.1 mL) was heated at 75 °C for 1 h before being diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on C18 RP (eluting with 0-100% CH3CN in H2O) to give the title compound a white powder (19.0 mg, 42%). 'H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.00-8.89 (m, 2H), 8.51-8.42 (m, 2H), 8.22 (d, J= 1.4 Hz, 1H), 8.17 (dd, J= 2.2, 8.1 Hz, 1H), 7.70 (dd, J= 1.5, 5.4 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 5.97 (s, 2H), 2.20 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F). LCMS (ES+) m / z calculated for C21H17F3N8O2470.41, found 471 (M+H)+. HPLC tR1.24 min.

[0425] Examples 36 and 37 were prepared following the experimental protocol described in Scheme 8 using the appropriate starting materials.

[0426] Example 36: (3-((6-(4-Chloro-l-methyl-LH-pyrazol-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0427] The title compound was obtained as a white powder (4.1 mg, 9%).1H NMR (400 MHz, DMSO-d) 8 10.20 (s, 1H), 8.99 (d, J= 1.9 Hz, 1H), 8.49-8.44 (m, 2H), 8.23-8.19 (m, 2H), 7.86 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.70 (dd, J= 1.6, 5.8 Hz, 1H), 5.97 (s, 2H), 3.97 (s, 3H).19FNMR(377 MHz, DMSO- L) 8 -66.93 (s, 3F). LCMS (ES+) m / z calculated for C19H14CIF3N8O2478.82, found 479 (M+H)+. HPLC tR1.54 min.

[0428] Example 37: (3-((2'-(Difluoromethyl)-[2,3'-bipyridin]-5-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0429] The title compound was obtained as a white powder (7.2 mg, 19%). 'H NMR (400 MHz, DMSO-d) 810.19 (s, 1H), 8.95 (d, J= 1.6 Hz, 1H), 8.83-8.78 (m, 1H), 8.48-8.44 (m, 2H), 8.24-8.18 (m, 2H), 8.13 (d, J = 7.9 Hz, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.39-7.02 (t, J= 70.0 Hz, 1H), 5.98 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -66.93 (s, 3F), -113.78 (s, 2F). LCMS (ES+) m / z calculated for C21H14F5N7O2491.37, found 492 (M+H)+. HPLC tR1.40 min.

[0430] Example 40: (3-(4-(4-Chloro-l-(2-hydroxy-2-methylpropyl)-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide. TFA

[0431] MeCN / H2O rt, 3 h 45%

[0432]

[0433] Scheme 9

[0434] A solution of Example 39 (31 mg, 0.048 mmol,) in a mixture of MeCN / H2O (1:1, 0.3 M) at rt was treated with TFA (18 pL, 0.24 mmol). The resulting mixture reaction was then stirred for 3 h at rt. The mixture reaction was quenched with NaHCO? sat. aq. solution and diluted with EtOAc, the phases were separated and extracted with EtOAc (2x). The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to get a residue which was purified by flash chromatography on Cl 8 RP (eluting with 0-100% CH3CN in H2O) to give the title compound as a white powder (11.5 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 1.5 Hz, 1H), 7.75-7.69 (m, 4H), 7.61 (d, J = 8.3 Hz, 2H), 5.91 (s, 2H), 4.64 (s, 1H), 3.98 (s, 2H), 0.97 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -66.94 (s, 3F). LCMS (ES+) m / z calculated for C23H21ClF3N7O3535.13, found 536 (M+H)+. HPLC tR1.76 min.

[0435] Example 47 & 51: (3-(4-(4-Chloro-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide and (3-(4-(4-Chloro- 1-(2, 2, 2- trifluoroethyl)- TH-pyrazol-3-yl)benzyl)-l, 2, 3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide Example 47

[0436] CF3CH2SO3CF3

[0437] Cs2CO3, DMF,

[0438] rt, 3 h

[0439] 28%

[0440]

[0441] Example 51

[0442] Scheme 10

[0443] Step 1: ( 3-( 4-( 4-Chloro-lH-pyrazol-5-yl)benzyl)-l, 2, 3-oxadiazol-3-ium-5-yl) ((2-( trifluor o-methyl)pyridin-4-yl)carbamoyl)amide (Example 47).

[0444] A solution of Intermediate 30 (156 mg, 0.28 mmol, synthesized following the synthetic protocol described in the Scheme 7 step 2A, using the appropriate Intermediate 25) in DCM (5.0 mL, 0.05 M) at rt was treated with TFA (1.0 mL, 2.8 mmol). The resulting mixture reaction was then stirred for 1 h at rt. The excess of solvent was removed under vacuo and the resulting crude was then diluted with a EtOAc and treated with NaHC'O? sat. aq. solution, then the phases were separated and extracted with EtOAc (2x). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to get a residue which was purified by flash chromatography on C18 RP (eluting with 0-100% CHsCN in H2O) to give the title compound as a white powder (110.0 mg, 99%). 'HNMR (400 MHz, DMSO- L) 6 13.66-13.20 (m, 1H), 10.18 (s, 1H), 8.46 (d, J= 5.6 Hz. 1H), 8.35-8.31 (m, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.92 (d, J= 8.1 Hz, 1H), 7.86-7.80 (m, 1H), 7.76-7.64 (m, 3H), 5.91-5.82 (m, 2H).19F NMR (377 MHz, DMSO-t / e) 6 -66.92 (s, 3F), -108.36 (s, 2F). LCMS (ES+) m / z calculated for C19H13CIF3N7O2 463.80, found 464 (M+H)+. HPLC fe 1.65 min.

[0445] Step 2'. (3-(4-(4-Chloro-l-(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 51)

[0446] A suspension of Example 54 (20 mg, 0.04 mmol) and cesium carbonate (27 mg, 0.08 mmol) in DMF (100 pL, 0.4 M) at rt was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.0 pL. 0.05 mmol). The resulting mixture reaction was then stirred for 3 h at rt. The resulting crude was then diluted with H2O and EtOAc then the phases were separated and extracted with EtOAc (2x). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to get a residue which was purified by flash chromatography on C18 RP (eluting with 0-100% CH3CN in H2O) to give the title compound as a white powder (6.3 mg, 28%).JH NMR (400 MHz, DMSO- e) 6 10.18 (s, 1H), 8.46 (d, J= 5.6Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.20 (d, J= 1.6 Hz, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.3 Hz, 3H), 5.88 (s, 2H), 5.22 (q, J= 9.1 Hz, 2H).19F NMR (377 MHz, DMSO- e) 6 -66.92 (s, 3F), -70.12 (s, 3F). LCMS (ES+) m / z calculated for C21H14CI F6N7O2545.82, found 547 (M+H)+. HPLC tR1.95 min.

[0447] Example 52: (3-(4-(2-Methyl-6-(methylcarbamoyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0448]

[0449] Step 1: ( 3-( 4-( 6-Carboxy-2-methylpyridin-3-yl)benzyl)-l, 2, 3-oxadiazol-3-ium-5-yl) ((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 50)

[0450] A solution of Example 49 (28 mg, 0.05 mmol, synthesized following the synthetic protocol described in the Scheme 7 step 2B, using the appropriate starting materials) in a mixture of THF / H2O (1: 1, 0.5 M) at rt was treated with lithium hydroxy de monohydrate (4.5 mg, 0.06 mmol). The resulting reaction mixture was then stirred for 1 h at rt. The mixture reaction was quenched with HC1 solution (1.0 M) up to acidic pH and diluted with EtOAc, the phases were separated and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to get a residue which was purified by flash chromatography on C18 RP (eluting with 0-100% CH3CN in H2O) to give the title compound as a white powder (11.0 mg, 40%). 'H NMR (400 MHz, DMSO- e) 6 10.19 (s, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J= 1.6 Hz, 1H), 7.95 (d, J= 7.9 Hz, 1H), 7.81 (d, J= 8.0 Hz, 1H), 7.74 - 7.67 (m, 3H), 7.56 (d, J= 8.3 Hz, 2H), 5.91 (s, 2H), 2.50-2.49 (m, 3H).19F NMR (377 MHz, DMSO-t / e) 6 -66.92 (s, 3F). LCMS (ES+) m / z calculated for C23H17F3N6O4498.41, found 499 (M+H)+. HPLC / R 1.28 min.

[0451] Step 2: (3-(4-(2-Methyl-6-(methylcarbamoyl)pyridin-3-yl)benzyl)-l,2,3-oxad.iazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 52)

[0452] A solution of (3-(4-(6-carboxy-2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 50, 8.0 mg, 0.02 mmol), methylamine hydrochloride (1.6 mg, 0.02 mmol), HATU (18.3 mg, 0.05 mmol) and DIPEA (16.7 pL, 0.10 mmol) in DMF (0.3 mL) was stirred at rt for 18 h before being diluted with EtOAc and NaHCO? (sat. aqueous solution). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by automated RP-HPLC using H2O (+ 0.1% TFA) and CH3CN (+ 0.1% TFA) as eluents (Cl 8 column). Fractions containing products were lyophilized to give the title compound as a white powder (5.1 mg, 62%).1H NMR (400 MHz, DMSO-tL) 6 10.19 (s, 1H), 8.67 (br d, J= 4.9 Hz, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.38 (s, 1H), 8.25-8.17 (m, 1H), 7.92 (d, J= 7.9Hz, 1H), 7.81 (d, J= 7.9 Hz, 1H), 7.71 (br d, J= 8.0 Hz, 3H), 7.56 (d, J= 8.1 Hz, 2H), 5.91 (s, 2H), 2.85 (d, J= 4.9 Hz, 3H), 2.51-2.48 (m, 3H).19F NMR (377 MHz, DMSO- e) 8 -66.92 (s, 3F). LCMS (ES+) m / z calculated for C24H20F3N7O3 511.46, found 512 (M+H)+. HPLC fe 1.63 min.

[0453] Example 57: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethoxy)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0454] DIPEA, MeCN

[0455] 0 °C, 5 h

[0456] 1,4-dioxane / H2O 2 f-BuNO2, THF

[0457] 75 °C, 1 h, 83% rt, 30 min

[0458] 2 TFA, DCM, 3 TMSOTf, HCI 4N,

[0459] rt, 1 h 1,4-dioxane

[0460] 99% rt, 1 h

[0461] Intermediate 31 99%

[0462] Triphosgene,

[0463] DIPEA, THF

[0464] rt, 5 min

[0465] CF3SO2’

[0466] Intermediate 32 Example 57

[0467]

[0468] Scheme 12 Step 1: (4-(4,6-Dimethylpyrimidin-5-yl)phenyl)methanamine (trifluoroacetate salt) (Intermediate 31)

[0469] A degassed suspension of / c / V-butyl N- [(4-bromophenyl)methyl] carbamate (500 mg, 1.7 mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (613 mg, 1.5 mmol), Pd(dppf)Cl2(127 mg, 0.17 mmol) and K3PO4 (1.2 g, 5.2 mmol) in 1,4-dioxane (10 mL) and H2O (1.0 mL) was stirred at 75 °C for 1 h before being concentrated in vacuo to get a residue which was treated with H2O and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to get a residue which was purified by flash chromatography on silica gel (eluting with 5-100% EtOAc in petroleum ether) to give a white solid (455 mg) which was dissolved in DCM (5.8 mL) and treated with TFA (1.4 mL). The reaction mixture was stirred at rt for 1 h before being evaporated in vacuo to give the title compound as a yellow oil (570 mg, 82% over two steps). LCMS (ES+) m / z calculated for C14H18N3 213.13, found 214 (M+H)+. HPLC fa 0.34 min.

[0470] Step 2: 5-Amino-3-(4-( 4, 6-dimethylpyrimidin-5-yl)benzyl)-l, 2, 3-oxadiazol-3-ium (trifluomethanesulfonate salt) (Intermediate 32)

[0471] The title compound was prepared following the procedure reported for the synthesis of Intermediate 30 (prepared as described in WO2023 / 227734 from appropriated starting materials) obtained as a brown oil and used as such. LCMS (ES+) m / z calculated for CisHieNsO 281.13, found 282 (M+H)+. HPLC fa 0.62 min.

[0472] Step 3: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethoxy)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt) (Example 57)

[0473] The title compound was prepared as reported for the synthesis of Example 1 in Step 3, scheme 7 and obtained as a yellow powder (15.6 mg, 33%).1HNMR(400 MHz, DMSO- L) 810.14 (s, 1H), 8.90 (s, 1H), 8.36 (s, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.55 (d, J= 1.6 Hz, 1H), 7.46-7.40 (m, 3H), 5.91 (s, 2H), 2.18 (s, 6H).19F NMR (377 MHz, DMSO- e) 5 -54.78 (s, 3F), -74.70 (s, 6F). LCMS (ES+) m / z calculated for C22H18F3N7O3 485.42, found 486 (M+H)+. HPLC fa 1.45 min.

[0474] Examples 53, 56 and 58-59 were prepared using the same synthetic procedure described for the synthesis of Examples 57 Scheme 12 using the appropriate starting materials.

[0475] Example 53: ((2-Cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)amide (trifluoracetate salt). The title compound obtained as a yellow oil (10.5 mg, 45%).JH NMR (400 MHz, DMSO- L) 6 10.73 (s, 1H), 8.90 (s, 1H), 8.47 (s, 1H), 8.35 (d, J= 7.0 Hz, 1H), 7.76-7.72 (m, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.43 (d, J= 7.7 Hz, 2H), 5.95 (s, 2H), 2.23-2.19 (m, 1H), 2.18 (s, 6H), 1.33-1.25 (m, 2H), 1.03-0.95 (m, 2H).19F NMR (377 MHz, DMSO- e) 6 -74.33 (s, 3F). LCMS (ES+) m / z calculated for C24H23N7O2441.19, found 442 (M+H)+. HPLC fa 0.99 min.

[0476] Example 56: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-methoxy-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoracetate salt).

[0477] The title compound was obtained as a light-yellow powder (3.2 mg, 14%). 'H NMR (400 MHz, DMSO- L) 610.10 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 7.74-7.69 (m, 3H), 7.42 (d, J= 8.3 Hz, 2H), 7.28 (s, 1H), 5.91 (s, 2H), 3.84 (s, 3H), 2.18 (s, 6H).19F NMR (377 MHz, DMSO-tL) 6 -67.27 (s, 3F), -74.45 (s, 3F). LCMS (ES+) m / z calculated for C23H20F3N7O3 499.16, found 500 (M+H)+. HPLC fa 1.64 min.

[0478] Example 58: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2-methyl-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

[0479] The title compound was obtained as a white powder (9.6 mg, 22%). 'H NMR (400 MHz, DMSO-d6) 8 10.11 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.73-7.69 (m, J= 8.4 Hz, 2H), 7.57 (s, 1H), 7.45-7.41 (m, 2H), 5.90 (s, 2H), 2.44 (s, 3H), 2.18 (s, 6H).19FNMR(377 MHz, DMSO- / e) 8 -66.89 (s, 3F). LCMS (ES+) m / z calculated for C23H20F3N7O2 483.16, found 484 (M+H)+. HPLC tR1.41 min.

[0480] Example 59: ((2-Chloro-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)amide (trifluoracetate salt). The title compound was obtained as a white powder (3.8 mg, 14%). 'H NMR (400 MHz, DMSO-d.6) 810.42 (s, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.73-7.69 (m, J= 8.3 Hz, 2H), 7.44-7.41 (m, J= 8.1 Hz, 2H), 5.92 (s, 2H), 2.18 (s, 6H).19F NMR (377 MHz, DMSO-tL) 8 -66.26 (s, 3F), -74.75 (s, 3F). LCMS (ES+) m / z calculated for C22H17CIF3N7O2503.86, found 504 (M+H)+. HPLC fa 1.69 min.

[0481] Example 54: (3-(4-(4-Chloro-l-methyl-LH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-cyclopropylpyridin-4-yl)carbamoyl)amide (trifluoroacetate salt).

[0482]

[0483] Scheme 13

[0484] A solution of 4-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (130.0 mg, 0.48 mmol), (3-(4-bromobenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-cyclopropylpyridin-4-yl)carbamoyl)amide Intermediate 33 (prepared as reported in Scheme 7 from the corresponding commercially available starting material; 80 mg, 0.19 mmol) and K3PO4 (123.0 mg, 0.58 mmol) in 1,4-dioxane (1.3 mL) and H2O (0.3 mL) was treated with Pd(dppf)C12 (14.0 mg, 0.02 mmol), degassed and heated at 75 °C for 1 h. After cooling the mixture was treated with EtOAc and H2O and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by automated RP-HPLC using H2O (+ 0.1% TFA) and CH3CN (+ 0.1% TFA) as eluents (Cl 8 column). Fractions containing product were lyophilized to give the title compound as a powder (3.5 mg, 4%).JH NMR (400 MHz, DMSO- L) 6 10.71 (s, 1H), 8.48 (s, 1H), 8.35 (d, J= 7.0 Hz, 1H), 7.78-7.76 (m, 3H), 7.69 (s, 1H), 7.67-7.60 (m, 2H), 5.96 (s, 2H), 3.83 (s, 3H), 2.56-2.54 (m, 1H), 2.28-2.17 (m, 1H), 1.33-1.21 (m, 2H), 1.07-0.91 (m, 2H).19F NMR (377 MHz, DMSO- e) 8 -77.39 (s, 3F). LCMS (ES+) m / z calculated for C22H20CIN7O2449.89, found 450 (M+H)+. HPLC fa 1.12 min.

[0485] Examples 55 and 60 were prepared using the same synthetic procedure described for the synthesis of Examples 54 in Scheme 13 using the appropriate starting materials.

[0486] Example 55: ((2-Cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)amide.

[0487] The title compound was obtained as a white powder (15.0 mg, 27%).1H NMR (400 MHz, DMSO-d6) 89.76 - 9.52 (m, 1H), 8.82-8.70 (m, 1H), 8.37-8.25 (m, 1H), 8.14-8.05 (m, 1H), 7.97-7.86 (m, 1H), 7.76-7.60 (m, 3H), 7.57-7.39 (m, 3H), 7.35-7.19 (m, 1H), 7.00-6.61 (m, 1H), 6.01-5.82 (m, 2H), 1.94-1.86 (m, 1H), 0.89-0.81 (m, 4H).19F NMR (377 MHz, DMSO- e) 8 -111.53 (s, 2F). LCMS (ES+) m / z calculated for C24H20F2N6O2462.45, found 463 (M+H)+. HPLC fa 1.12 min. Example 60: (3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)- l,2,3-oxadiazol-3-ium-5-yl)((2- (methylamino)-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (trifluoroacetate salt). The title compound was obtained as a white powder (1.0 mg, 2%).JH NMR (400 MHz, DMSO-d6) 89.76 (s, 1H), 8.90 (s, 1H), 8.32 (s, 1H), 7.72-7.68 (m, J= 8.1 Hz, 2H), 7.44-7.40 (m, J= 8.1 Hz, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 5.89 (s, 2H), 2.76-2.69 (m, 3H), 2.18 (s, 6H).19F NMR (377 MHz, DMSO-t / e) 8 -59.71 (s, 3F), -74.52 (s, 3F). LCMS (ES+) m / z calculated for C23H21F3N8O2 498.46, found 499 (M+H)+. HPLC fa 1.50 min.

[0488] Structural properties of exemplified compounds are included in the Table 1 below.

[0489] Example Molecule IUPAC Name Weight CF3

[0490] H (3-(4-(2- f| |N- \N(trifluoromethy l)pyridin-3 - 1 yl)benzy 1)- 1,2,3 - 508.37598 oxadiazol-3-ium-5-yl)((2- 1 ( n0

[0491] OF, xZ'v (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0492] (3 -(4-( 1,4-dimethyl- 1H- imidazol-5-yl)benzyl)- 2 l,2,3-oxadiazol-3-ium-5- 457.40853

[0493] / Xji Hx° yi)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0494] icr(3 -(4-( 1 -cyclopropy 1-4- methoxy - 1 H-py razol-5 - 3 yl)benzy 1)- 1,2,3 - 499.44521 oxadiazol-3-ium-5-yl)((2- A ° (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0495] (3 -(4-(4-methoxy - 1 - methyl- 1 H-pyrazol-5- N — v N yl)benzy 1)- 1,2,3 - 4 473.40793 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- ' ZZo yl)carbamoyl)amide

[0496]

[0497] CF:,

[0498] H / I

[0499] / / n N — (ZN (3 -(4-( 1 -cyclopropy 1-4- methy 1- 1 H-pyrazol-5- yl)benzy 1)- 1,2,3 - 483.44581 oxadiazol-3-ium-5-yl)((2- z ucM “ (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0500] CF,,

[0501] (3-(4-(3- methoxypyridazin-4- i i / \ _ / yl)benzy 1)- 1,2,3 - 471.39205 " M\X\ / XX

[0502] 1 H F^\ ° oxadiazol-3-ium-5-yl)((2- °'"' VVZN / 0(trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0503] (3 -(4-( 1 -cyclobuty 1-4- methy 1- 1 H-imidazol-5 -,N_ n / HN — / vF^ N

[0504] Z 1 \= / yl)benzy 1)- 1,2,3 - 497.47239 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- vLo0yl)carbamoyl)amide

[0505] CF,

[0506] (3 -(4-( 1 -cyclobuty 1-4- J Z^X"H / ) Z methy 1- 1 H-pyrazol-5- / / fl N (zN

[0507] \ IIN-_ / \= / yl)benzy 1)- 1,2,3 - 497.47239 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- rXMM " M C yl)carbamoyl)amide

[0508] ICF;i(3 -(4-( 1 -cyclobuty 1-4- / XX0 H / W- methoxy - 1 H-py razol-5 -Nfj, -J \= / Nyl)benzy 1)- 1,2,3 - 513.47179 oxadiazol-3-ium-5-yl)((2- X Cl H0(trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0509] (3-(4-(2- (difluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - 490.38552 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0510]

[0511] (3-(4-(4-chloro-l-methyl- lH-pyrazol-5-yl)benzyl)- l,2,3-oxadiazol-3-ium-5- NA X\ 477.82701 yi)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0512] (3-(4-(3- (trifluoromethyl)pyridin-2- O yl)benzy 1)- 1,2,3 - 508.37598 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- n yl)carbamoyl)amide

[0513] (3-(4-(4-chloro-2- A (trifluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - i n n 542.82104 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- x> yl)carbamoyl)amide

[0514] : (3 -(4-(4-chloro- 1 -(oxetan- 3-yl)-lH-pyrazol-5- yl)benzy 1)- 1,2,3 - x? oxadiazol-3-ium-5-yl)((2- 519.86369

[0515] (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0516] (3-(4-(4- (trifluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - 508.37598 ^\ oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- CVv yl)carbamoyl)amide

[0517] (3-(4-(l-methyl-4- NXv (trifluoromethyl)- 1H- pyrazol-5-yl)benzyl)-l,2,3- 511.37992 r o n oxadiazol-3-ium-5-yl)((2- x (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0518]

[0519] (3-(4-(l-(oxetan-3-yl)-4- C

[0520] N- N (trifluoromethyl)- 1H- pyrazol-5-yl)benzyl)-l,2,3- 553.4166 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0521] OF, (3-(4-(6-oxo-2- (trifluoromethy 1)- 1,6- dihy dropyridin-3 - yl)benzy 1)- 1,2,3 - 524.37538 "vLx / d

[0522] 1 T 0 F=\Goxadiazol-3-ium-5-yl)((2-cf’ V\ Jk, (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0523] CF, (3 -(4-(2-methoxy -4- (trifluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - OfN-_7 \= / N538.40196

[0524] 0 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- Ct) Hzyl)carbamoyl)amide

[0525] F“

[0526] y: CFS(3-(4-(4- (trifluoromethyl)pyridin-2- x4\ H f / C

[0527] ff F N— N yl)benzy 1)- 1,2,3 -ixN- __< \ — / 508.37598noxadiazol-3-ium-5-yl)((2- / %

[0528] 0 (trifluoromethyl)pyridin-4- IXY yl)carbamoyl)amide

[0529] (3 -((2'-(trifluoromethy 1) - / X / ^ H [l,l'-biphenyl]-4- r N — <zN

[0530] [1 J M ^ / \r=i / yl)methy 1)- 1,2,3 - \FYSFX / W 507.38792 oxadiazol-3-ium-5-yl)((2- I 1] r ° (trifluoromethyl)pyridin-4- N yl)carbamoyl)amide

[0531] (3 -(4-(4-fluoro- 1 -(oxetan- 3-yl)-lH-pyrazol-5- yl)benzy 1)- 1,2,3 - 503.40909 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0532] = PF=>

[0533] (3 -((2'-(difluoromethyl)- [l,l'-biphenyl]-4- yl)methy 1)- 1,2,3 - 489.39746 oxadiazol-3-ium-5-yl)((2- z

[0534] z° (trifluoromethyl)pyridin-4- N yl)carbamoyl)amide

[0535]

[0536] z — M F

[0537] V \\ J (3 -(4-(2-(difluoromethyl)- 4-methylpyridin-3- yl)benzy 1)- 1,2,3 - 504.4121 oxadiazol-3-ium-5-yl)((2- O N~ / V^V

[0538] \ / V 'if 1 I (trifluoromethyl)pyridin-4- ' - N 1 ll M, N

[0539] v ^Q - yl)carbamoyl)amide

[0540] CF3(3-(4-(4-chloro-l-methyl- J-< H / T \\ lH-pyrazol-5-yl)-3- k~V / N" \Nmethy Ibenzy 1) -1,2,3-NvJI ] FT— 4 V= / 491.85359 oxadiazol-3-ium-5-yl)((2- / {i i ° (trifluoromethyl)pyridin-4- X^S-" X > X z® yl)carbamoyl)amide

[0541] M CF.

[0542] _ / (3-(4-(4-methyl-l- zxMH / / ^

[0543] / / ljN~\N(tetrahydro-2H-pyran-4- yl)-lH-pyrazol-5- yl)benzy 1)- 1,2,3 - 527.49837 V z oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0544] (3-(l-(4-(4-chloro-l- methy 1- 1 H-pyrazol-5- H ff~ 1

[0545] «- — v ** yl)phenyl)cyclopropyl)- ■' U |,r_ / \= / l,2,3-oxadiazol-3-ium-5- 503.86429.< -X J \ yi)((2- (trifluoromethyl)pyridin-4-fCux> *

[0546] yl)carbamoyl)amide

[0547] (3-(l-(4-(2- (difluoromethy l)pyridin-3 - | H

[0548] xMx Jx yl)phenyl)cyclopropyl)- r jTrw> l,2,3-oxadiazol-3-ium-5- 516.4228 yi)((2- ^ 1 M1 (trifluoromethyl)pyridin-4- V* ’

[0549] v yl)carbamoyl)amide

[0550] CF, (3-(4-(3- / ' (difluoromethyl)pyridin-2-H#V\ yl)benzy 1)- 1,2,3 - f N N - N

[0551] k 1,r^J \ — / 490.38552 X. A, N — A ' ' oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- kkV. v » yl)carbamoyl)amide

[0552] N

[0553]

[0554] (3-(2-chloro-4-(2- (difluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - LK JS 524.83058 oxadiazol-3-ium-5-yl)((2- A CLX> (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0555] OF,

[0556] (3-(3-chloro-4-(4,6- N-L^( J dimethylpyrimidin-5- yl)benzy 1)- 1,2,3 - 503.86429 OX X oxadiazol-3-ium-5-yl)((2- 1 II • I - (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0557] (3-(l-(4-(2- (difluoromethy l)pyridin-3 - yl)phenyl)-2- X% hydroxyethyl)-l,2,3- 520.4115 a t T / ‘' oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-,.. / O yl)carbamoyl)amide

[0558] _ \. / f

[0559] % / *

[0560] (3-(l-(4-(4-chloro-l- methy 1- 1 H-pyrazol-5- M — r M yl)phenyl)-2- ■■ _ Y“4 hydroxyethyl)-l,2,3- 507.85299 oxadiazol-3-ium-5-yl)((2- / ' 'U (trifluoromethyl)pyridin-4- X yl)carbamoyl)amide

[0561] CF3(3-(4-(3- (trifluoromethyl)pyridin-4- i x 1hN V / / N

[0562] 1 / \ _ / yl)benzy 1)- 1,2,3 - oxadiazol-3-ium-5-yl)((2- 508.37598 1 I]0(trifluoromethyl)pyridin-4- CF, X>-'iX NX XN Z° yl)carbamoyl)amide

[0563]

[0564] (3-((6-(4,6- dimethylpyrimidin-5- yl)pyridin-3-yl)methyl)- l,2,3-oxadiazol-3-ium-5- 470.40729 / 'Xi.x^j / yi)((2- ' I J XX, ° (trifluoromethyl)pyridin-4- ^NZ" yl)carbamoyl)amide

[0565] CF, (3 -((6-(4-chloro- 1 -methyl- Z / / Y-^ [f.-^k"Hbi ( fz / X N 1 H-py razol-5 -y l)py ridin-3 - A JIN-^ / yl)methy 1)- 1,2,3 - 478.81507 oxadiazol-3-ium-5-yl)((2- ' N nVX U Y / X ° (trifluoromethyl)pyridin-4- N yl)carbamoyl)amide

[0566] (3 -((2'-(difluoromethyl)- H / F\\ [2,3'-bipyridin]-5- l J / \_ / yl)methy 1)- 1,2,3 - 491.37358 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- X CX X 'XN / ’ ° yl)carbamoyl)amide

[0567] (3-(4-(3-hydroxypyridin-2- 'N.N— \Y / N" yl)benzy 1)- 1,2,3 - oxadiazol-3-ium-5-yl)((2- 456.37741 “ Cl z, "° (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0568] (3-(4-(l-(2-((tert- butyldimethylsilyl)oxy)-2- ’J11L11methy Ipropy l)-4-chloro- zX^O-^ lH-pyrazol-5-yl)benzyl)- 650.16701 l,2,3-oxadiazol-3-ium-5- yi)((2- (trifluoromethyl)pyridin-4-,)v yl)carbamoyl)amide

[0569] H (3-(4-(4-chloro-l-(2- hydroxy-2-methylpropyl)- « i _ _hv N J-^i 3 iT Y lH-pyrazol-5-yl)benzyl)- l,2,3-oxadiazol-3-ium-5- 535.90615.cZxz yi)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0570] CF3 (3-(4-(4-cyclopropyl-6- r-’^ s-X. (trifluoromethyl)pyrimidin

[0571] -5-yl)benzyl)-l,2,3- "vX\ / Y 549.4279 oxadiazol-3-ium-5-yl)((2- A CcX ° (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0572]

[0573] OF, (3-(4-(4-chloro-l- z> X31 H

[0574] / / 7T N — V N (tetrahydro-2H-pyran-4- yl)-lH-pyrazol-5- yl)benzy 1)- 1,2,3 - 547.91685 X LJ H ° oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0575] CF:;

[0576] (3-(4-(4-chloro-l- / X-X"'Hfi v\ (tetrahy drofuran-3 -y 1) - 1 H- N 1 J \— /

[0577] pyrazol-5-yl)benzyl)-l,2,3- 533.89027 oxadiazol-3-ium-5-yl)((2- d> n > ' (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0578] CE,

[0579] (3-(4-(3- XX,H#7\

[0580] » 1 / X / (trifluoromethyl)pyrazin-2- < A. N X yl)benzy 1)- 1,2,3 - 509.36404 T n n oxadiazol-3-ium-5-yl)((2- CFaX^JT N\Z0 (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0581] CF,

[0582] (3-(4-(2-(l,l-difluoro-2- n 1 n IHH— V / / T

[0583] N hydroxy ethyl)pyridin-3 - x<n N~X( yl)benzy 1)- 1,2,3 - 520.4115 oxadiazol-3-ium-5-yl)((2- 7G\ ^T

[0584] 1 \A X

[0585] Xf s3 0(trifluoromethyl)pyridin-4- H0:yl)carbamoyl)amide

[0586] i (3-(4-(4- 1 J (difluoromethy l)pyridin-3 - yl)benzy 1)- 1,2,3 - 490,38552 oxadiazol-3-ium-5-yl)((2- _ ’•'. (trifluoromethyl)pyridin-4- \ z'= ^ — yl)carbamoyl)amide / / 7 — '

[0587]

[0588] (3-(4-(4-chloro-lH- pyrazol-5-yl)benzyl)-l,2,3- LIIS oxadiazol-3-ium-5-yl)((2- 463,80043

[0589] (trifluoromethyl)pyridin-4- _J _ \ i yl)carbamoyl)amide

[0590] ■ -

[0591] (3-(4-(3- (difluoromethyl)pyridin-4- yl)benzy 1)- 1,2,3 - 490,38552 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- 1 > yl)carbamoyl)amide

[0592] ,1

[0593] ( o- ---- (3-(4-(6- 1 (methoxy carbonyl) -2- |i j methy Ipy ridin-3 - yl)benzy 1)- 1,2,3 - 512,44067 oxadiazol-3-ium-5-yl)((2- &

[0594] I (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0595] 0

[0596] * X

[0597] (3-(4-(6-carboxy-2- methy Ipy ridin-3 - yl)benzy 1)- 1,2,3 - 498,41409 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0598] (3-(4-(4-chloro-l-(2,2,2- jQ trifluoroethyl)- IH-pyrazol- k 3-yl)benzyl)-l,2,3- 545,82498 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- r='h_1— ' yl)carbamoyl)amide

[0599]

[0600] (3-(4-(2-methyl-6- (methylcarbamoyl)pyridin- 3-yl)benzyl)-l,2,3- 511,45591 4 oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide A "

[0601] " 4 z?”-7

[0602] ((2-cyclopropylpyridin-4- yl)carbamoyl)(3-(4-(4,6- fi 4x4 4 dimethylpyrimidin-5- 441.48512 T V 4 yl)benzy 1)- 1,2,3 - 1 o A H

[0603] VVN^ / O oxadiazol-3 -ium-5 - yl)amide

[0604] (3-(4-(4-chloro-l-methyl- lH-pyrazol-5-yl)benzyl)-N4 4 l,2,3-oxadiazol-3-ium-5- 449.8929 4 4 yl)((2-cyclopropylpyridin- II 1 r \ ®

[0605] 4-yl)carbamoyl)amideA

[0606] ((2-cyclopropylpyridin-4- yl)carbamoyl)(3-(4-(2- 4 A=^ T N— G, N (difluoromethy l)pyridin-3 - 462.451411 N-4 yl)benzy 1)- 1,2,3 - oxadiazol-3 -ium-5 - Ji ] X0yl)amide

[0607] (3-(4-(4,6- Dimethy Ipy rimidin-5 - HJX yl)benzy 1)- 1,2,3 - V 4 oxadiazol-3-ium-5-yl)((2- 499,44521 methoxy-6- (trifluoromethyl)pyridin-4-441 4

[0608] yl)carbamoyl)amide

[0609]

[0610] (3-(4-(4,6- H Dimethy lpyrimidin-5 - / " A--; /

[0611] 57 yl)benzy 1)- 1,2,3 - FT K 'A1- 485,41863 oxadiazol-3-ium-5-yl)((2- (trifluoromethoxy)pyridin- \A\ / '1^r / 4-yl)carbamoyl)amide

[0612] CFa

[0613] (3-(4-(4,6- <^Nx H f / X\

[0614] ft | N: (ft N Dimethy lpyrimidin-5 - yl)benzy 1)- 1,2,3 - 58 / “ ^ oxadiazol-3-ium-5-yl)((2- 483,44581

[0615] I I i rA0methyl-6- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0616] CR ((2-Chloro-6- (trifluoromethyl)pyridin-4- n— yl)carbamoyl)(3-(4-(4,6- 59 J X / X ft. dimethylpyrimidin-5- 503,86429 yl)benzy 1)- 1,2,3 - ft iCUV oxadiazol-3 -ium-5 - yl)amide

[0617] (3-(4-(4,6- ^Cf% Dimethy lpyrimidin-5 - yl)benzy 1)- 1,2,3 - 60 ft A' oxadiazol-3-ium-5-yl)((2- 498,46045

[0618] '''j ’1 "■; -: 0 H. (methylamino)-6- (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0619] (3-(4-(3- (Difluoromethyl)pyrazin- 2-yl)benzyl)- 1,2,3 - 61 oxadiazol-3-ium-5-yl)((2- 491,37358

[0620] (trifluoromethyl)pyridin-4- yl)carbamoyl)amide

[0621]

[0622] Biology

[0623] WNV protease inhibition assay The enzyme inhibition assay was performed in 384-well flat botom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 pl. West Nile Virus (WNV) NS2B-NS3 protease, MHHHHHH (SEQ. ID. No 2; NS2B 1423-1470) - GGGGSGGGG (SEQ. ID. No 3; NS31506-1689) Accession # YP_001527877.1, R& D, cat. N. 2907-SE-020, (2 nM) was incubated with increasing inhibitor concentrations (0.097-100 pM or 0.0009-1 pM for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 9.0, 30% glycerol, 1% DMSO) for 10 minutes at 25 °C. 10 pM of pERTKR-AMC substrate (R& D, cat. N. ES013) was added and the reaction mixture incubated for additional 30 minutes at 25 °C. 10 pM of pERTKR-AMC substrate (R& D, cat. N. ESO 13) was added and the reaction mixture incubated for additional 30 minutes at 25 °C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fited by four-parameter logistic regression.

[0624] WNV replicon generation

[0625] To construct the subgenomic replicon we used the U. S. A, isolate genome (Genbank Accession Number AY646354.1, total 11.030 bp). In the replicon, the coding sequences of structural genes were removed except for 31 amino acids at the N-terminus of the capsid protein fused with 30 amino acids at the C-terminus of the E protein. These sequences were retained to preserve the correct processing and translocation of NS1 and of the non-structural polyprotein across the endothelium reticulum membrane. An EMCV IRES was placed after the stop codon of the polyprotein. The IRES drives the translation of a downstream fusion protein consisting of a luciferase (Nano-Luc) gene followed by the ubiquitin gene (UBI), and the neomycin phosphotransferase resistance gene (NEO). This fusion protein is required for reporting purposes and to confer resistance to G-418. The sub-genomic replicon was transcribed as RNA via an upstream T7 promoter and transfected in Vero cells. The stable cell line used for the WNV replication assay was generated via selection with G-418.

[0626] WNV replication inhibition assay and cell viability assay

[0627] A green monkey cell line (Vero) with a stable WNV replicon was grown and maintained in Dulbecco's modified eagle's medium (DMEM) with high glucose and pyruvate (GIBCO #41966) completed with 10% fetal bovine serum (FBS) (Gibco #10270), 1% Penicillin Streptomycin (10 mg / ml) (Gibco #14140). 0.700 mg / mL G418 solution (Sigma-Aldrich, Cat 4727894001) were used to maintain the WNV replication in the cells. The day of the experiment, compounds previously dissolved in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, D5879-1L) were transferred to a 384 black plate (Greiner #781086) using an acoustic system (Echo650, Beckman). Compounds were tested in dose response. 50 pM of example 26 (WO2023 / 227734) was used in as positive control for the WNV replication assay while 32 μM of Gambogic Acid (Sigma- Aldrich, G8171) was used as positive control for the cell viability assay. In both cases, in the negative control wells were added with 0.5% DMSO. 6000 cells / well were plated on the compound containing plates in 40 μL growth medium. 72 h after the treatment at 37 °C, 5% CO2and 90% humidity, 20 μL Nano-Glo (Promega #N1150) were added to reveal the NanoLuc signal, while 30 pL CellTiter-Glo (Promega #G7573) were added to determine the cell viability (Multiplex assay). The luminescent signal for NanoLuc was detected reading the plate on the Envision plate reading 10 minutes post detection reagent addition (luminescence was measured at 0.5 sec / well), while for cell viability (CellTiter-Glo) reading the plate after 30 minutes post addition reagent detection. Data were normalized between 0 and 100% inhibition (negative control and positive control respectively). For EC50determinations, the dose-response was fitted with a 4-p logistic regression approach using the Dotmatics Studies software.

[0628] ZIKV protease expression and purification

[0629] The sequence coding for NS2B (aa 49-95, R95A) and NS3 (aa 1-170, R29G) were synthesized (GenScript, Piscataway, New Jersey, United States), cloned in pET15b vector downstream the sequence for 6 x His tag and fused by a not cleavable linker (G4SG4). The protease was expressed in E. coli BL21 (DE3) cells: bacteria were grown in LB medium at 37 °C up to 0.8 O. D. 600, then the temperature was lowered to 20 °C and protein expression induced with 0.5 mM IPTG (cat. N.

[0630] 15502, Sigma Aldrich) for 18 h. Cells were collected by centrifugation (4000 x g, 4 °C for 30 min), then re-suspended (7 ml / g of cell paste) in lysis buffer (25 mM Tris pH 8.0, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg / ml of lysozyme (cat. N. 16876, Sigma Aldrich) and 25 U / ml of benzonase (cat. N. E1014, Sigma Aldrich). After incubating at 25 °C for 30 min, cells were homogenized at 800 bars by PANDA homogenizer (GE A) then cell extract was cleared by centrifugation (32914 x g, 4 °C, Ih), brought to 500 mM NaCl then loaded on 1 ml HisTrap HP column (cat. N. 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, recombinant protein was eluted by a linear gradient up to 350 mM imidazole (cat. N. 1202, Sigma Aldrich). Fractions containing ZIKV protease were pooled and treated with 2 mM TCEP (cat. N. C4706, Sigma Aldrich) at 4 °C for 40 min, then concentrated threefold on Vivaspin 20, 3 KDa cut off device (cat. N. Z614610-48EA, Sigma Aldrich) and loaded on HiLoad 16 / 60 Superdex 75 column (cat. N. 28989333, Cytiva, Sweden) using 25 mM Tris pH 8.5, 5% glycerol and 1 mM DTT (cat. N. A2948, PanReac AppliChem) as mobile phase. Monomer peak fractions were collected, divided in small aliquots and frozen in liquid nitrogen.

[0631] ZIKV protease inhibition assay

[0632] The enzyme inhibition assay was performed in 384-well flat bottom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 pl. ZIKV NS2B-G4SG4-NS3 serine protease (MGSSHHHHHHSSGLVPRGSHMVDMYIERAGDITWEKDAEVTGNSPRLDVALDESGDF SLVEDDGPPMAGGGGSGGGGSGALWDVPAPKEVKKGETTDGVYRVMTRGLLGSTQV GVGVMQEGVFHTMWHVTKGSALRSGEGRLDPYWGDVKQDLVSYCGPWKLDAAWD GHSEVQLLAVPPGERARNIQTLPGIFKTKDGDIGAVALDYPAGTSGSPILDKCGRVIGLY GNGVVIKNGSYVSAITQGRR; SEQ. ID. No. 1) (1.25 nM) was incubated with increasing inhibitor concentrations (0.097-100 pM or 0.0009 -1 pM for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO) for 10 minutes at 25 °C. 10 pM of Bz-Nle-KRR-AMC substrate (cat. N. 4055312, Bachem) was added and the reaction mixture incubated for additional 30 minutes at 25 °C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analysed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

[0633] ZIKV replicon generation

[0634] To construct the subgenomic replicon we used the Natal RGN isolate of Asian lineage (GenBank: KU527068.1). In the replicon, the coding sequences of structural genes were removed with the exception of 31 amino acids at the N-terminus of the capsid protein fused with 32 amino acids at the C-terminus of the E protein. These sequences were retained to preserve the correct processing and translocation of NS1 and of the non-structural polyprotein across the endothelium reticulum membrane. An EMCV IRES was placed after the stop codon of the polyprotein. The IRES drives the translation of a downstream fusion protein consisting of a luciferase (Nano-Luc) gene followed by the ubiquitin gene (UBI), and the neomycin phosphotransferase resistance gene (NEO). This fusion protein is required for reporting purposes and to confer resistance to G-418. The subgenomic replicon was transcribed as RNA via an upstream T7 promoter and transfected in Vero cells. The stable cell line used for the ZIKV replication assay was generated via selection with G-418. ZIKV replication inhibition assay and cell viability assay

[0635] A green monkey cell line (Vero) with a stable ZIKV replicon was grown and maintained in Dulbecco's modified eagle's medium (DMEM) with high glucose and pyruvate (GIBCO #41966) completed with 10% fetal bovine serum (FBS) (Gibco #10270), 1% Penicillin Streptomycin (10 mg / ml) (Gibco #14140). 0.760 μg / mL G418 solution (Sigma-Aldrich, Cat 4727894001) were used to maintain the ZIKV replication in the cells. The day of the experiment, compounds previously dissolved in 100% dimethyl sulfoxide (DMSO, Sigma- Aldrich, D5879-1L) were transferred to a 384 black plate (Greiner #781086) using an acoustic system (ATS-100 EDC). Compounds were tested in dose response. 50 μM of mycophenolic acid (Sigma-Aldrich, M3536) was used in as positive control for the ZIKV replication assay while 32 μM of Gambogic Acid (Sigma-Aldrich, G8171) was used as positive control for the cell viability assay. In both cases, in the negative control wells were added with 0.5% DMSO. 8000 cells / well were plated on the compound containing plates in 40 μL growth medium. 72 h after the treatment at 37 °C, 5% CO2and 90% humidity, 20 μL Nano-Glo (Promega #N1150) were added to reveal the NanoLuc signal, while 20 μL CellTiter-Glo (Promega #G7573) were added to determine the cell viability. The luminescent signal for both assays was detected reading the plate on the Envision plate reading 10 minutes post detection reagent addition (luminescence was measured at 0.5 sec / well). Data were normalized between 0 and 100% inhibition (negative control and positive control respectively). For EC50determinations, the dose-response was fitted with a 4-p logistic regression approach using the Dotmatics Studies software. The activity of exemplified compounds is reported in the Table 2 below.

[0636] Table 2. Activity values are expressed in nanomolars, wherein: A refers to IC50or EC50in the range >0 and ≤ 75 nM; B refers to IC50or EC50in the range >75 and ≤ 150 nM; C refers to IC50or EC50in the range >150 and ≤ 300 nM; D refers to IC50or EC50in the range >300 and ≤ 600 nM; E refers to IC50or EC50> 600 nM; N / A: not available.

[0637] WNV NS3 Protease WNV Cell Nanoluc Zika NS3 Protease Zika Cell Nanoluc Example

[0638] IC50R474#12 EC50IC50EC501 A A A A 2 A B A C 3 A A A A 4 B A A B 5 A A A A

[0639]

[0640] A B B D A B A B B A A A C A A B A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A C A C B A A A E C A C C B A B B B B A D C A B A A A A C B A A A A A A B A A A B A B B A A A A C B A B A A A A B B B C C C A B A A A A A C C B A A B A A B C B C C C D E A C A

[0641]

[0642] 40 A A A A 41 A A A A 42 A A A A 43 A A A A 44 A A A A 45 A A A A 46 A A A A 47 C A A B 48 A A A A 49 A E A E 50 B E C E 51 D A A B 52 B A A A 53 A B A B 54 B C A B 55 B C B C 56 E E D D 57 D N / A D C 58 B C C B 59 D C C N / A 60 D c C C 61 A A N / A N / A

[0643]

[0644] Determination of brain penetration in CD1 Mice

[0645] Total brain levels, expressed as brain / plasma ratio (Kp, brain) were measured by Cbrain@8h / Cplasma@8h in CD1 mice after IV administration. Unbound fraction of each molecule in biological matrix was determined by in vitro plasma and brain binding assay. Kp,uu, brain was calculated by the following equation:

[0646]

[0647] Kp,uu,brain = Cbrain@8h / C plasma@8h × (fu,brain / fu, plasma)

[0648] In vitro plasma and brain binding assay was carried out on a RED (Rapid Equilibrium Dialysis) device.

[0649] Unbound fraction (fu) of each molecule in the brain homogenate and plasma were calculated by the ratio of the buffer side response to the brain homogenate / plasma side response. An IV study design was used as the in vivo screening model to identify brain penetration of each molecule. Male naive CD1 mice (n = 3) were intravenously dosed with each molecule at 0.2 mg / kg in 10% 2-hydroxypropyl-beta-cyclodextrin in 50 mM Citrate buffer pH 5.5 (w / v). At 0.083, 0.25, 0.5, 1, 2, 4, and 8 h post-dose plasma samples were collected via tail vein and brain tissue was harvested at the 8 h time point and homogenized in 3x volume of water. All samples were stored at ~−80 °C prior to LC / MS / MS analysis. At the 8 h time point, the unbound brain to plasma ratios were generated to identify molecules with Kp,uu, brain values > 0.3 which is indicative of good passive brain penetration.

[0650] Table 3.

[0651] Examples Kp,uu, brain

[0652] 1 >0.3

[0653] 10 >0.3

[0654] 11 >0.3

[0655] 29 >0.3

[0656] 36 >0.3

[0657] 44 >0.3

[0658]

[0659] 61 >0.3

[0660] *Cbrain: concentration measured in brain

[0661] *Cplasma: concentration measured in plasma

Claims

1. CLAIMS1. A compound of general formula (I):

4. 6.wherein7.- X is C or N;8.Ri is: CF3, OCF3 or cyclopropyl optionally substituted with fluorine;9.R2 is: H, CH3, OCH3, Cl, NHCH3, NHC(=O)Ri2 wherein R12 is a Ci-3alkyl optionally substituted with an aromatic ring;10.R3 is H or CH3 and R4 is H or CH2OH; or R3 and R4 are linked together to form a spirocyclopropyl ring;11.Rs and Re are each independently selected from: H, CH3 and Cl;12.R7 is selected from:13.a) pyridine, optionally substituted with one or more substitents independently selected from Ci-3alkyl, Cs-ecycloalkyl, Ci-shaloalkyl, Ci-3alkoxyl, halogen, hydroxy, C i-shaloalkyl further substituted with an hydroxy group, C(O)OCi-3alkyl, C(O)OH, C(O)NHCi-3alkyl, NHC(=O)Ci-3alkyl, SO2NHC1-3alkyl, SO2C1-3alkyl, CN with the proviso that said optionally substituted pyridine is not 2- methylpyridin-3-yl and 2,4-dimethylpyridine-3-yl; or14.b) pyrazole of formula (II) or (III):

16. 18.wherein:19.R8is selected from H, C1-4alkyl optionally substituted with OH, C3-6cycloalkyl, C3-6heterocycloalkyl and C1-3haloalkyl optionally substituted with OH;20.R9is selected from C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C1-3alkoxyl, CN and halogen; and wherein if R9 is CH3 then Rs is not CH3 or an oxetane ring; or21.c) pyridazine optionally substituted with halogen, Ci-3alkoxyl, Ci-shaloalkyl. C3- ecycloalkyl, CN; or22.d) pyrimidine of formula (IV):

24. 25.Rio (iv)26.wherein Rio and R11 are each independently selected from Ci-3alkyl, Ci-shaloalkyl. C3-6cycloalkyl, and wherein if Rio and R11 are both CH3 then in general formula (I):27.■ X is N; and / or28.■ Ri is cyclopropyl; and / or29.■ R2is CH3, OCH3, Cl, NHCH3; and / or R5is Cl;30.e) phenyl or 5 or 6 membered heteroaromatic ring selected from pyrazine, 6-oxo-l,6- dihydropyridine, imidazole and oxazole, each of said ring being optionally substituted with one or more substitents independently selected from Ci-3alkyl, Ci- shaloalkyl. Ci-3alkoxyl, halogen, hydroxy, Ci-shaloalkyl further substituted with an hydroxy group, C(O)OCi-3alkyl, C(O)OH, C(O)NHCi-3alkyl; or31.or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

2. The compound of general formula (I) according to claim 1 wherein Ri is CF3 and R2 is H.

3. The compound of general formula (I) according to claims 1 or 2 wherein R3 and R4 are H.

4. The compound of general formula (I) according to any one of previous claims wherein R7 is a pyridine ring selected from:33.R13R15R17 R1935.

36. (A) (B) (C) (D)37.wherein:38.- in structure (A) R13and R14are independently selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, halogen, and wherein one of R13 and R₁₄ is C₁₋₃haloalkyl, preferably one of R13 and R14 is trifluoromethyl or difluoromethyl; - in structure (B) Ris and Ri6 are independently selected from H, Ci-shaloalkyl and hydroxy, preferably the Ci-shaloalkyl is trifluoromethyl or difluoromethyl;39.- in structure (C) R17 is Ci-shaloalkyl. preferably trifluoromethyl or difluoromethyl;40.- in structure (D) Ris is selected from Ci-3alkyl and C(=O)OH, C(=O)=CH3 and C(=O)NHCH3 and R19 is C1-3alkyl or C1-3haloalkyl.

5. The compound of general formula (I) according to any one of claims 1 to 3 wherein:42.R? is a pyrazole of formula (II) wherein:43.Rs is H, methyl, hydroxy-2-methyl-propyl, l,l-difluoro-2-hydroxy ethyl, cyclopropyl, cyclobutyl, oxetane, tetrahydropyrane, tetrahydrofurane; and44.R9 is methoxy, halogen, trifluoromethyl;45.or wherein:46.Rs is H, hydroxy-2-methyl-propyl, cyclopropyl, cyclobutyl, tetrahydropyrane, tetrahydrofurane; and47.R9 is methyl; or48.R7is a pyrazole of formula (III) wherein R8is C1-3alkyl or C1-3haloalkyl or and R9is halogen.

6. The compound of general formula (I) according to any one of claims 1 to 4 wherein R7 is selected from: 2-(trifluoromethyl)pyridin-3-yl, 2-(difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-chloro-2-(trifluoromethyl)pyridin-3-yl, 4- (trifluoromethyl)pyridin-3-yl, 2-methoxy-4-(trifluoromethyl)pyridin-3-yl, 4- (trifluoromethyl)pyridin-2-yl, 2-trifluoromethylphenyl, 2-(difluoromethy l)-4-methylpyri din-3 -yl, 3-(difluoromethyl)pyridin-2-yl, 2-(difluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-4-yl, 3-hydroxypyridin-2-yl, 1,1-difluoro-2-hydroxyethyl)pyridin-3-yl, 4-(difluoromethyl)pyridin-3-yl, 3-(difluoromethyl)pyridin-4-yl, 6-(methoxycarbonyl)-2-methylpyridin-3-yl, 6-carboxy-2-methylpyridin-3-yl, 2-methyl-6-(methylcarbamoyl)pyridin-3-yl.

7. The compound of general formula (I) according to any one of claims 1 to 3 and 5 wherein R7 is selected from: l-cyclopropyl-4-methoxy-lH-pyrazol-5-yl, 4-methoxy-l -methyl- lH-pyrazol-5-yl, l-cyclopropyl-4-methyl-lH-pyrazol-5-yl, l-cyclobutyl-4-methyl-lH-pyrazol-5-yl, 1-cyclobutyl-4-methoxy-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-(4-chloro-l-(oxetan-3-yl)-lH-pyrazol-5-yl, l-methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl, l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-pyrazol-5-yl, 4-fluoro-l-(oxetan-3-yl)-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro-l-methyl-lH-pyrazol-5-yl, 4-chloro-l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl, 4-chloro-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl, 4-chloro-l-(tetrahydrofuran-3-yl)- 1 H-pyrazol-5-yl. 4-chloro-lH-pyrazol-5-yl, 4-chloro- 1 -(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl.

8. The compound of general formula (I) according to any one of claims 1 to 3 wherein R? is selected from: l,4-dimethyl-lH-imidazol-5-yl, 3-methoxypyridazin-4-yl, l-cyclobutyl-4-methyl-lH-imidazol-5-yl, 2-trifluoromethylphenyl, 2-difluoromethylphenyl, 4,6-dimethylpyrimidin-5-yl, 4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl, 3-(trifluoromethyl)pyrazin-2-yl.

9. The compound of general formula (I) according to claim 1 being selected from:52.(3-(4-(2-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide53.(3-(4-(l,4-dimethyl-lH-imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide54.(3-(4-(l-cyclopropyl-4-methoxy-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide55.(3-(4-(4-methoxy-l-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide56.(3-(4-(l-cyclopropyl-4-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide57.(3-(4-(3-methoxypyridazin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide58.(3-(4-(l-cyclobutyl-4-methyl-lH-imidazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide59.(3-(4-(l-cyclobutyl-4-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide60.(3-(4-(l-cyclobutyl-4-methoxy-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide61.(3-(4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide62.(3-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide63.(3-(4-(3-(trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide64.(3-(4-(4-chloro-2-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(4-(4-chloro-l-(oxetan-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide65.(3-(4-(4-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide66.(3-(4-(l-methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide67.(3-(4-(l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide68.(3-(4-(6-oxo-2-(trifluoromethyl)-l,6-dihydropyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide69.(3-(4-(2-methoxy-4-(trifluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide70.(3-(4-(4-(trifluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide71.(3-((2'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide72.(3-(4-(4-fluoro-l-(oxetan-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide73.(3-((2'-(difluoromethyl)-[l,r-biphenyl]-4-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide74.(3-(4-(2-(difluoromethyl)-4-methylpyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide75.(3-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)-3-methylbenzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide76.(3-(4-(4-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide77.(3-(l-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide78.(3-(l-(4-(2-(difluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide79.(3-(4-(3-(difluoromethyl)pyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide80.(3-(2-chloro-4-(2-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(3-chloro-4-(4,6-dimethylpyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide81.(3-(l-(4-(2-(difluoromethyl)pyridin-3-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide82.(3-(l-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide83.(3-(4-(3-(trifluoromethyl)pyridin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide84.(3-((6-(4,6-dimethylpyrimidin-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide85.(3-((6-(4-chloro-l-methyl-lH-pyrazol-5-yl)pyridin-3-yl)methyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide86.(3-((2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl)methyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide87.(3-(4-(3-hydroxypyridin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide88.(3-(4-(4-chloro-l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide89.(3-(4-(4-cyclopropyl-6-(trifluoromethyl)pyrimidin-5-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide90.(3 -(4-(4-chl oro-1 -(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)benzyl)- 1,2,3 -oxadiazol- 3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide91.(3-(4-(4-chloro-l-(tetrahydrofuran-3-yl)-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide92.(3-(4-(3-(trifluoromethyl)pyrazin-2-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide93.(3-(4-(2-(1,1-difluoro-2-hydroxyethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide94.(3-(4-(4-(difluoromethyl)pyridin-3-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide95.(3-(4-(4-chloro-lH-pyrazol-5-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide96.(3-(4-(3-(difluoromethyl)pyridin-4-yl)benzyl)-l,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide (3-(4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide97.(3-(4-(6-carboxy-2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide98.(3-(4-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)benzyl)-1,2,3-oxadiazol-3-ium- 5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide99.(3-(4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5- yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide100.(3-(4-(3-Methoxypyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide101.((2-cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3- oxadiazol-3-ium-5-yl)amide102.(3-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- cyclopropylpyridin-4-yl)carbamoyl)amide103.((2-cyclopropylpyridin-4-yl)carbamoyl)(3-(4-(2-(difluoromethyl)pyridin-3-yl)benzyl)- 1,2,3-oxadiazol-3-ium-5-yl)amide104.(3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-methoxy-6- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide105.(3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethoxy)pyridin-4-yl)carbamoyl)amide106.(3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-methyl-6- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide107.((2-Chloro-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-(4-(4,6-dimethylpyrimidin-5- yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide108.(3-(4-(4,6-Dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (methylamino)-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide109.(3-(4-(3-(Difluoromethyl)pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2- (trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

10. The compound according to any one of previous claims being an inhibitor of NS2B-NS3 protease of a Flavivirus, preferably an inhibitor of the NS2B-NS3 protease of West Nile and / or Zika virus.

11. The compound according to any one of previous claims for medical use.

12. The compound according to claim 11 for use in treatment and / or prevention of a Flavivirus infection13. The compound according to claims 11 and 12 for use in the treatment and / or prevention of an infection from West Nile and Zika virus.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, either alone or in combination with one further therapeutic agent, and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14 for use in the treatment and / or prevention of a Flavivirus infection, preferably wherein the Flavivirus is selected from West Nile and Zika and virus.

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