WO2007047394A2 - Thiotriazolyl derivatives - Google Patents

Abstract

The invention relates to KvI.5 ion channel antagonists. Novel thiotriazolyl derivative compounds represented by Formula I, and synthesis and uses thereof for treating diseases mediated directly or indirectly by KvI.5 ion channels, are disclosed. Such conditions include numerous heart conditions including atrial fibrillation and other diseases; as well as epilepsy, anxiety, depression, age-related memory loss, migraine, obesity, Parkinson's disease or Alzheimer's disease. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also provided.

Description

TfflOTRIAZOLYL DERIVATIVES

RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. 119(e) to pending U.S. Patent Application No. 60/726,436, filed on October 13, 2005; which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates to thiotriazolyl derivatives which are KvI .5 ion channel modulators, e.g., antagonists, and the use of these compounds, e.g., in the treatment, modulation and/or prevention of physiological conditions such as arrhythmia associated with atrial fibrillation and other diseases regulated directly and indirectly by Kv 1.5 ion channels.

BACKGROUND OF THE INVENTION [0003] Ion channels are multi-protein structures located in the plasma membrane of nearly all biological cells. The cell membrane is a lipid bilayer that is not permeable to ions in aqueous solution. Channel proteins assemble in a multi-unit, typically circular configuration to form and ion channel, an aqueous (water-filled) pores through which ions may enter and leave a cell, thereby contributing both to the maintenance of cellular homeostasis and to the response to extracellular stimuli.

[0004] The diversity of ion channels is substantial. The channels can adopt a variety of conformations or "states"; however, ions can only flow through the channel when the pore is open. Many channels are selective and only permit passage of certain ions, differentiated either by charge, or by atomic species. Depending on the family, the open and closed state of the ion channel may also be regulated or "gated" by external factors, e.g., transmembrane potential (voltage), presence of certain chemical ligands, temperature, or mechanical stimuli transduced in the membrane. The diversity of potassium channels and their important physiological role highlights their potential as targets for developing therapeutic agents for various diseases.

[0005] The potassium channel family preferentially conducts potassium ions and is subdivided into subfamilies based on means of activation and amino acid sequence homology. One subfamily is that of the voltage-gated potassium or "Kv" channels, which open and close primarily in response to changes in transmembrane electrical potential. Accordingly, these channels are responsible for repolarizing cells in response to action potentials. There is tremendous structural and functional diversity within the Kv potassium channel superfamily, generated both by the existence of multiple genes, and by alternative splicing of RNA transcripts produced from the same gene. The amino acid sequences of the known Kv potassium channels show high similarity. The Kv channels are tetrameric assemblies of pore- forming ("α-") subunits, each possessing six α-helical transmembrane segments. In some channels, there are also four cytoplasmic (β-subunit) polypeptides.

[0006] From the MeSH ontology, the Kv family is further subdivided into voltage- gated delayed rectifier (e.g., KvLQTl), ether-a-go-go (e.g., ERG), and Shaker superfamily of channels, the prototypical member of the latter class being the Kv 1.x protein encoded by the Shaker gene in Drosophila melanogaster. The known Kv Shaker superfamily channel α- subunits fall into four sub-families named for their homology to channels first isolated from Drosophila: the KvI, or Shaker-related subfamily; the Kv2, or Shab-related subfamily; the Kv3, or Shaw-related subfamily; and the Kv4, or Shal-related subfamily. These channels activate (open), inactivate (close following opening), and recover from inactivation (become ready to open again) at a variety of rates.

[0007] Atrial fibrillation (AF) is a cardiac arrhythmia found in about 2.2 million

Americans. In AF, the normal sequence of electrical activation in the upper heart, which originates at the sinus node, proceeds throughout the atria and then passes into the atrioventricular node, is replaced by a reentrant, discordant sequence of activation. The resulting loss of electrical coordination causes blood to not be pumped completely out of the atria, leading to local stagnation and clotting, and ultimately presenting a threat to life via thromboembolic trauma, e.g., stroke or myocardial ischemia/infarction. Initiating causes of AF are varied but include rheumatic heart disease, particularly mitral stenosis, coronary heart disease, congestive or hypertrophic cardiomyopathy, mitral valve prolapse, and mitral valve annular calcification.

[0008] A number of potentially reversible, noncardiac factors are also associated with transient atrial fibrillation. The latter include hyperthyroidism, acute alcohol intoxication, cholinergic drugs, noncardiac surgery or diagnostic procedures, and pulmonary conditions leading to hypoxia. Persistent and recurring AF is most commonly associated with rheumatic heart disease; hypertension, especially when left ventricular hypertrophy is present; and chronic coronary heart disease. AF occurring in the absence of other preexisting conditions is called lone or primary AF. Other types of AF include: paroxysmal AF, which occurs intermittently and varies in frequency and duration from a few seconds to more protracted episodes lasting several hours or even days; persistent AF, usually seen in older people, often becomes the primary heart rhythm and is usually refractory to both medical and many non-pharmacologic interventions such as electrical cardioversion; neurogenic AF, which arises from an imbalance in the nervous system regulation of the heart; and adrenergic AF, a particular type of neurogenic atrial fibrillation that occurs as a result of excessive adrenaline that comes from stimulation of the sympathetic portion of the nervous system. [0009] Several approaches may be used to treat atrial fibrillation. Medication is a first step and depending on the selection of agent, can either be used for rhythm control, i.e., stop atrial fibrillation and promote normal sinus rhythm, or for "rate control", i.e., to limit the ventricular rate response to the irregular atrial activation rate. Medications in rhythm control group include drugs like amiodarone, disopyramide, calcium antagonists (verapamil, diltiazam), sotalol, dofetilide, ibutilide, flecainide, procainamide, quinidine, and propafenone. Medications in the rate control group include digoxin and beta blockers (atenolol, metoprolol, propranolol). Some agents have dual action in these categories. If such medication does not correct the problem, is contraindicated in a given patient or group, or other methods deemed beneficial, other therapies to treat AF include electrical cardioversion, radiofrequency ablation, automated implantable atrial defϊbrillators/pacemakers, and in rare cases, surgery ("MAZE" procedure) to physically disrupt electrical pathways that permit sustain atrial fibrillation.

SUMMARY OF THE INVENTION

[0010] Compounds which interact with and modulate the activity of potassium channel proteins such as potassium channels having, e.g., a KvI.5 subunit, provide targets to modulate cardiac repolarization (i.e., action potentials). In addition, such compounds can be used to diagnose and treat numerous heart conditions including atrial fibrillation; and central nervous system disorders such as epilepsy, anxiety, depression, age-related memory loss, migraine, obesity, Parkinson's disease or Alzheimer's disease; and other diseases regulated directly and indirectly by KvI.5 ion channels.

[0011] The present invention relates to the discovery of new compounds which are

KvI.5 modulators, e.g., antagonists, that can be used for treating, preventing or curing KvI.5- related conditions. In particular, it has been found that certain thiotriazolyl derivative compounds are effective KvI.5 modulators.

[0012] In an embodiment, such compounds include those having the formula

[0013] wherein

[0014] Ri and R₂ may independently be C₁-C₇ alkyl, Ci-C₇ alkyl optionally substituted with aryl; or C₃-C₁₀ alicyclic, heteroalicyclic, aryl or heteroaryl groups; wherein the alkyl, alicyclic, heteroalicyclic, aryl or heteroaryl groups are independently are optionally substituted

[0015] R₃ and R₄ may independently be hydrogen, Ci-C₆ alkyl, C3-C₁0 alicyclic, aryl, or heteroaryl; aryl(lower)alkyl; or C3-C₁0 heteroalicyclic; wherein the alkyl, alicyclic, aryl, heteroaryl, aryl(lower)alkyl, and heteroalicyclic groups independently are optionally substituted with one or more OfR₇;

[0016] R₅ may be R₈R₉NHCO, RI₀C=NNHCO, RnCONHNHCO, Ri₂NHNHCO, R₁₃CO, Ci-C₆ alkyl, Ci-C₆ alicyclic, heteroalicyclic, aryl or heteroaryl group;

[0017] R₆ and R₇ may independently be halogen, C₁-C₆ alkyl, Ci-C₆ alkoxy, aryl Ci-C₆ alkoxy, sulfonamide, or hydroxy; and

[0018] R₈, R₉, Rio, Rn, R12 and Ri₃ may be C₁-C₆ alkyl; or C₃-Ci₀ alicyclic, heteroalicyclic, aryl or heteroaryl, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci-C₆ alkyl, C₁-C₆ alkoxy, aryl C₁-C₆ alkoxy, amino, hydroxy or sulfonamide groups.

[0019] In another embodiment, such compounds include those having the formula

[0020] wherein R₁ may be straight or branched Ci-C₇ alkyl; or C3-Q₀ alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups are optionally substituted with one or more of a halogen; C₁-C₆ alkyl; C₁-C₆ alkoxy; cyano, C₁-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide; or hydroxyl group; and Ri is optionally attached via a C₁-C₂ alkyl linker in place of a direct bond; R₂ may be a C₃-C₁₀ alicyclic, heteroalicyclic, aryl, heteroaryl or fused aryl/(alicyclic or heterocyclic) ring optionally substituted with one or more of a halogen, Ci -C₃ alkyl, Cj-C₆ alkoxy, cyano, C₁-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group; and R₂ is optionally attached via a Ci-C₂ alkyl linker in place of a direct bond; R₃, R₄ and R₆ may be independently H or lower alkyl; R₅ may be a C3 -C ₁0 alicyclic, heteroalicyclic, aryl or heteroaryl group, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci-C₆ alkyl, Ci-C₆ alkoxy, cyano, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups; and R₅ is optionally attached via a Ci-C₂ alkyl linker in place of a direct bond; wherein when the straight dotted bond is absent, the dotted circular line represents a Ci- C₃ alkylene bridge; or a pharmaceutically acceptable salt thereof.

[0021] In an alternate embodiment, such compounds include those having the formula

[0022] Ri, R₂ may independently be Ci-C₇ alkyl, Ci-C₇ alkyl optionally substituted with aryl, C3-C₁0 alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alkyl, alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more OfR₆; [0023] R₆ may be halogen, Ci-C₆ alkyl, Cj-C₆ alkoxy, aryl Ci-C₆ alkoxy, sulfonamide, or hydroxy; and

[0024] R₅ may be C₁-C alkyl, C₃-C₁O alicyclic, heteroalicyclic, aryl orheteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci-C₆ alkyl, Ci-C₆ alkoxy, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups.

[0025] Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound according to Formula I, II or III to treat atrial fibrillation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier. [0026] Another aspect of the invention is a method for treating atrial fibrillation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I, II or III.

[0027] Another aspect of the invention is a composition comprising an effective amount of a compound according to Formula I, II or III to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.

[0028] Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I, II or III.

[0029] Also provided are various compounds according to Formula I, II or III and administering those compounds to a subject in need thereof to treat a disease state that is alleviated by treatment with a Kv 1.5 antagonist. Disease states that are alleviated by treatment with a KvI.5 antagonist include, but are not limited to conditions regulated directly and indirectly by Kv 1.5 ion channels, e.g., epilepsy, anxiety, depression, age-related memory loss, migraine, obesity, Parkinson's disease or Alzheimer's disease, as well as numerous heart conditions including arrhythmia, ischemia, atrial fibrillation, and other diseases.

[0030] Processes for preparing the compounds and novel intermediates are also included in the invention.

DETAILED DESCRIPTION OF THE INVENTION [0031] The features and other details of the invention will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified. [0032] Definitions

[0033] For convenience, certain terms used in the specification, examples, and appended claims are collected here.

[0034] "KvI .5 receptor modulator" or "KvI .5 modulator" includes compounds having effect at KvI.5 ion channels. KvI.5 modulators may be agonists, partial agonists or antagonists.

[0035] "Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.

[0036] "Alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups {e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched- chain alkyl groups {e.g., isopropyl, tert-butyl, isobutyl, isoamyl), cycloalkyl {e.g., alicyclic) groups {e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. "Alkyl" further includes alkyl groups which have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone {e.g., Ci-C₆ for straight chain, C3-C6 for branched chain), and more preferably four or fewer. Likewise, preferred cycloalkyls have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. " Ci-C₆ " includes alkyl groups containing one to six carbon atoms. [0037] The term "alkyl" also includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkoxyl, alkoxycarbonyl, alkoxycarbonyloxy, alkyl, alkynyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl, alkylthio, alkylthiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyloxy, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, azido, carboxylate, cyano, halogen, haloalkyl, haloalkoxy, cycloalkoxyl, acetamide, alkylacetamide, cycloalkylacetamide, amine, cycloamine, heterocyclyl, hydroxyl, nitro, phosphate, phosphonato, phosphinato, sulfates, sulfonate, sulfamoyl, sulfhydryl, sulfonamido, trifluoromethyl, alkylaryl, or an aromatic or heteroaromatic moiety, or any other substituent or its equivalent disclosed herein. Cycloalkyls can be further substituted, e.g., with the substituents described herein and or their equivalents known in the art. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). "Alkyl" also includes the side chains of natural and unnatural amino acids.

[0038] A "substituted" moiety is non-limiting as to the type of substituent. As used herein, a substituent includes any one or more chemical moieties disclosed herein, or any equivalent known in the art.

[0039] "Aryl" includes groups with aromaticity, including 5- and 6-membered "unconjugated", or single-ring, aromatic groups that may include from zero to four heteroatoms, as well as "conjugated", or multicyclic, systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, benzoxazole, benzthiazole, benzo[d][l,3]dioxole, naphthyl, quinolinyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyridinyl, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfϊnyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety, or any other substituent disclosed herein or its equivalent. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).

[0040] "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term "alkenyl" further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃- C₆ for branched chain.) Likewise, cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. The term "C₂-C₆" includes alkenyl groups containing two to six carbon atoms.

[0041] The term "alkenyl" also includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include,for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0042] "Akkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term "alkynyl" further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C3-C6 for branched chain). The term "C₂-C₆" includes alkynyl groups containing two to six carbon atoms.

[0043] The term "alkynyl" also includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0044] Unless the number of carbons is otherwise specified, "lower alkyl" includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbonatoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. [0045] "Acyl" includes compounds and moieties which contain the acyl radical

(CH₃CO-) or a carbonyl group. "Substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0046] "Acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

[0047] "Aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. [0048] "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.

[0049] The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulthydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0050] The terms "heterocyclyl" or "heterocyclic group" include closed ring structures, e.g., 3- to 10-, or 4- to 7-membered rings, which include one or more heteroatoms. Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperizine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulthydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety.

[0051] The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which 30 contain a carbon connected with a double bond to a sulfur atom.

[0052] The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group. [0053] The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above. [0054] The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

[0055] The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O.

[0056] The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term

"perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. [0057] "Polycyclyl" or "polycyclic radical" refers to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0058] "Heteroatom" includes atoms of any element other than carbon or hydrogen.

Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.

[0059] It will be noted that the structure of some of the compounds of the invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate. [0060] Combination therapy" (or "co-therapy") includes the administration of a KvI .5 modulator of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). [0061] "Combination therapy" may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.

Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.)

[0062] Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0063] An "anionic group," as used herein, refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof. "Functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents. Classical and non-classical bioisosteres are known in the art (see, e.g., Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp. 19-23). A particularly preferred anionic group is a carboxylate.

[0064] The term "heterocyclic group" is intended to include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, or oxygen or sulfur. Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF₃, -CN, or the like.

[0065] The present invention relates to the discovery of new compounds which are

KvI.5 modulators, e.g., antagonists, that can be used for treating, preventing or curing KvI.5- related conditions. In particular, it has been found that certain thiotriazolyl derivative compounds are effective KvI.5 modulators. In an embodiment, such compounds include those having the formula

[0066] wherein [0067] Ri and R₂ may independently be C₁-C₇ alkyl, Ci-C₇ alkyl optionally substituted with aryl; or C₃-C₁₀ alicyclic, heteroalicyclic, aryl or heteroaryl groups; wherein the alkyl, alicyclic, heteroalicyclic, aryl or heteroaryl groups are independently are optionally substituted with one or more OfR₆;

[0068] R₃ and R₄ may independently be hydrogen, Ci-C₆ alkyl, C3-Q0 alicyclic, aryl, or heteroaryl; aryl(lower)alkyl; or C3-C₁0 heteroalicyclic; wherein the alkyl, alicyclic, aryl, heteroaryl, aryl(lower)alkyl, and heteroalicyclic groups independently are optionally substitutedwith one or more of R₇; [0069] R₆ and R₇ may independently be halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryl Ci-C₆ alkoxy, sulfonamide, or hydroxy; and

[0070] R₈, R₉, Rio, Rn, Ri₂ and Ri₃ may be Cj-C₆ alkyl; or C₃-Ci₀ alicyclic, heteroalicyclic, aryl or heteroaryl, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci-C₆ alkyl, Cj-C₆ alkoxy, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups. A compound in accordance with the invention includes (E)-2-(4-cyclohexyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N'-(furan-

2-ylmethylene)acetohydrazide,

[0071] In another embodiment, such compounds include those having the formula

(II)

[0072] wherein Ri may be straight or branched Ci-C₇ alkyl; or C₃-C₁0 alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups are optionally substituted with one or more of a halogen; C]-C₆ alkyl; Ci-C₆ alkoxy; cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide; or hydroxyl group; and Ri is optionally attached via a Ci-C₂ alkyl linker in place of a direct bond; R₂ may be a C₃-C₁₀ alicyclic, heteroalicyclic, aryl, heteroaryl or fused aryl/(alicyclic or heterocyclic) ring optionally substituted with one or more of a halogen, CpC₃ alkyl, Ci-C₆ alkoxy, cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group; and R₂ is optionally attached via a Ci-C₂ alkyl linker in place of a direct bond; R₃, R₄ and R₆ may be independently H or lower alkyl; R₅ may be a C₃ -C ₁₀ alicyclic, heteroalicyclic, aryl or heteroaryl group, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Pi-C₆ alkyl, Ci-C₆ alkoxy, cyano, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups; and R₅ is optionally attached via a Ci-C₂ alkyl linker in place of a direct bond; wherein when the straight dotted bond is absent, the dotted circular line represents a C₁- C₃ alkylene bridge; or a pharmaceutically acceptable salt thereof.

[0073] In an alternate embodiment, such compounds include those having the formula

[0074] R₁, R₂ may independently be C₁-C₇ alkyl, Ci-C₇ allcyl optionally substituted with aryl, C3-C₁0 alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alkyl, alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more OfR₆;

[0075] R₆ may be halogen, Ci-C₆ alkyl, Ci-C₆ alkoxy, aryl Ci-C₆ alkoxy, sulfonamide, or hydroxy; and

[0076] R₅ may be Ci-C alkyl, C3-C₁0 alicyclic, heteroalicyclic, aryl orheteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci-C₆ alkyl, Ci-C₆ alkoxy, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups. [0077] In more particular embodiments, Ri may be, e.g., straight or branched C₁-C5 alkyl; C₃-C₇ cycloalkyl; benzyl, tolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrole, benzo[</]dioxole, benzo[d]dithiole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, or dithiolane. When substituted, the substituent may be one or more of, e.g., a halogen, Q-C3 alkyl, Ci-C₆ alkoxy, cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group.

[0078] In more particular embodiments, R₂ may be, e.g., benzyl, tolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrole, benzo[d]dioxole, benzo[</|dithiole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, or dithiolane. When substituted, the substituent may be, e.g., one or more of a halogen, C₁-C₃ alkyl, C₁-C₆ alkoxy, cyano, Cj-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group.

[0079] In more particular embodiments, R₅ may be, e.g., benzyl, tolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, or dithiolane. When substituted, the substituent may be one or more of, e.g., a halogen, C₁-C₃ alkyl, C₁-C₆ alkoxy, cyano, C₁-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group. [0080] Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound according to Formula I, II or III to treat atrial fibrillation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.

[0081] Another aspect of the invention is a method for treating atrial fibrillation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I, II or III.

[0082] Another aspect of the invention is a composition comprising an effective amount of a compound according to Formula I, II or III to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.

[0083] Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I, II or III.

[0084] Also provided are various compounds according to Formula I, II or III and administering those compounds to a subject in need thereof to treat a disease state that is alleviated by treatment with a KvI.5 antagonist. Disease states that are alleviated by treatment with a KvI.5 antagonist include, but are not limited to conditions regulated directly and indirectly by Kv 1.5 ion channels, e.g., epilepsy, anxiety, depression, age-related memory loss, migraine, obesity, Parkinson's disease or Alzheimer's disease, as well as numerous heart conditions including arrhythmia, ischemia, atrial fibrillation, and other diseases.

[0085] The regular heart beat (normal sinus rhythm) occurs when the primary periodic excitation initiated at the sinus node conducts sequentially throughout the atrial muscle, throughout the atrioventricular node, His bundle and specialized ventricular conduction fibers, and finally into the ventricular muscle proper. The normal electrical activation coordinates an efficient two-stage mechanical contraction of the heart to pump blood to the pulmonary and systemic circulation systems. Arrhythmia is a general term for the loss of normal sinus rhythm and its mechanism grossly categorized by abnormal excitation, and abnormal impulse conduction, or some combination thereof. Arrhythmia includes ventricular arrhythmia and atrial (supraventricular) arrhythmia. Arrhythmia may also be classified into supraventricular extrasystole, ventricular extrasystole, supraventricular tachycardia, WPW syndrome, atrial flutter/fibrillation, ventricular tachycardia and ventricular fibrillation.

[0086] Vaughan Williams, Singh and Houswirth have categorized antiarrhythmic agents into four classes based on their action. The Vaughan Williams classification has been utilized as a standard way of classifying antiarrhythmic agents. This method concisely expresses features of pharmacological action of various antiarrhythmic agents, and has been utilized by many physicians. This classification method roughly classifies the antiarrhythmic agents into four classes, I to IV. [0087] The antiarrhythmic agents classified into class I are medicines which have mainly a sodium channel blocking activity, and reduce the maximum upstroke velocity of depolarization at the 0-th phase of the action potential, thereby reducing the conduction speed. Class I agents are further classified into sub-classes of Ia, Ib and Ic based on their effects on the action potential duration. The class I agents have two primary adverse effects; reduced cardiac contractility and proarrhythmia. These agents indirectly reduce cardiac contractility as a result of reduced intracellular calcium concentration secondary to activation of a sodium/calcium exchange mechanism from the intracellular sodium accumulation. The sodium channel blocking activity also increases vulnerability to proarrhythmic activity by suppressing impulse conduction. [0088] The antiarrhythmic agents belonging to class II are medicines which have a β- receptor blocking activity. Stimulation of the β (βi)-receptor in the cardiac muscle cells with catecholamines activates adenylate cyclase, enhances production of cyclic AMP and increases the inward calcium current. As a result, physiological automaticity of the sinus node as well as abnormal automaticity in the morbid cardiac muscle are exacerbated. Action potential duration is also shortened by activating various ion channels related to repolarization. Although class II antiarrhythmic agents are effective against the arrhythmia related to the sympathetic nerve by their antagonistic activity against the action of catecholamines, but adverse effects, e.g., suppression of cardiac function due to β-receptor blocking activity, are cause for concern.

[0089] The antiarrhythmic agents belonging to class III are defined as medicines with a primary action to retard repolarization and prolong of the action potential duration. These agents suppress arrhythmia by prolonging the refractory period as a result of prolonging the action potential duration. Blocking action on the potassium channel appears to be mainly responsible for the principal action of these agents. "Potassium channel blocker" is often synonymous with class III agents. The class III agents are advantageous over the class I agents, as they show no suppression of cardiac contractility however, they often prolong the QT/QTc interval and lead to "Torsades de Pointes" tachyarrhythmia, a potentially lethal adverse effect common to class III agents.

[0090] The antiarrhythmic agents classified into class IV are defined as medicines which block the calcium channel as their main action. Although these agents are used for treating arrhythmia caused by acceleration of automaticity in the sinus node and arrhythmia related to the atrioventricular node, antiarrhythmic agents such as verapamil may weaken contraction force of the cardiac muscle.

[0091] Compounds of the present invention have the activity for suppressing contracture of the isolated cardiac muscle cells induced by veratrine while suppressing persistent sodium current. Therefore, the compounds according to the present invention may be also used for therapy or amelioration of disorders such as cardiac failure, angina pectoris, myocardial infarction, injury of cardiovascular system accompanied with revascularization by PTCA/PTCR/CAGB, injury of the cardiac muscle caused by ischemia-reperfusion (except severe arrhythmia), acute phase in cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head trauma, sequela of surgical operation of the brain, cerebrovascular disease such as sequela of cerebral arteriosclerosis, failure of implanted organs after implantation, symptoms caused by temporary hemostasis at surgical operation of the organs, convulsions, epilepsy, dementia (cerebrovascular and senile), neuralgia, migraine, neuropathic pain, digitalis intoxication, monkshood poisoning and pyrethroid insecticide poisoning. The compounds according to the present invention may be also used for hyperkalemic periodic paralysis, myotonia congenita, and long QT syndrome that are congenital diseases and caused by abnormal inactivation of thesodium channel due to abnormal sodium channel genes, i.e., by generation of persistent sodium current. [0092] For treating certain conditions it may be desirable to employ the compounds of the invention in conjunction with another pharmacologically active agent. The compounds of the invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use. Such combined preparations may be, for example, in the form of a twin pack.

[0093] A further aspect of the invention comprises compounds of the invention in combination with a Kv4.3 antagonist, e.g., quinidine or tedisamil.

[0094] According to a further or alternative aspect, the invention provides compounds of the invention for use in the manufacture of a medicament for the treatment or prevention of physiological disorders alleviated by treatment with a KvI .5 antagonist.

[0095] The compounds of the invention and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.

[0096] The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.

[0097] In treatment, an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. For example, in the treatment or prevention of a disorder of the central nervous system, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.01 to 1 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0098] It will be appreciated that the amount of the compound of the invention required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.

[0099] The compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein.

[00100] Aqueous compositions of the present invention comprise an effective amount of the peptides of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[00101] "Pharmaceutically or pharmacologically acceptable" include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. "Pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[00102] For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards. [00103] The compositions and combination therapies of the invention will then generally be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The preparation of an aqueous composition that contains a composition of the invention or an active component or ingredient will be known to those of skill in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.

[00104] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. [00105] Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [00106] Therapeutic or pharmacological compositions of the present invention will generally comprise an effective amount of the component(s) of the combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium. Pharmaceutically acceptable media or carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the therapeutic compositions of the present invention.

[00107] The preparation of pharmaceutical or pharmacological compositions will be known to those of skill in the art in light of the present disclosure. Typically, such compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including cremes, lotions, mouthwashes, inhalants and the like.

[00108] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00109] The preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) oragent(s) to a small area.

[00110] The use of sterile formulations, such as saline-based washes, by surgeons, physicians or health care workers to cleanse a particular area in the operating field may also be particularly useful. Therapeutic formulations in accordance with the present invention may also be reconstituted in the form of mouthwashes, or in conjunction with antifungal reagents. Inhalant forms are also envisioned. The therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as in cremes and lotions. [00111] Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5. Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of theophthalmic solution is in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.

[00112] Upon formulation, therapeutics will be administered in a manner compatible with the dosage formulation, and in such amount as is pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. [00113] In this context, the quantity of active ingredient and volume of composition to be administered depends on the host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual. [00114] A minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but would be typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals. For example, for parenteral administration, a suitably buffered, and if necessary, isotonic aqueous solution would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. One dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580).

[00115] In certain embodiments, active compounds may be administered orally. This is contemplated for agents which are generally resistant, or have been rendered resistant, to proteolysis by digestive enzymes. Such compounds are contemplated to include chemically designed or modified agents; dextrorotatory peptides; and peptide and liposomal formulations in time release capsules to avoid peptidase and lipase degradation.

[00116] Pharmaceutically acceptable salts include acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. [00117] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[00118] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[00119] The preparation of more, or highly, concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small area.

[00120] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. [00121] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.

[00122] In addition,to the compounds formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g., tablets or other solids for oral administration; liposomal formulations; time-release capsules; and any other form currently used, including cremes. [00123] Additional formulations suitable for other modes of administration include suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%.

[00124] Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.

[00125] In certain defined embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.

[00126] The tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. The pharmaceutical compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[00127] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch,lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[00128] The liquid forms in which the compositions of the invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or

[00129] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[00130] For treating clinical conditions and diseases noted above, the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[00131] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[00132] Compounds of the invention may be prepared as described in the following schemes.

[00133] Scheme 1: General Procedure of synthesis of 5, 4-disubstituted-

[l,2,4]triazoϊe-3-mercaptoacetylhydrazone

[00134] Step 1: Synthesis of Thiosemicarbazide (3): A mixture of hydrazide (1) (1 equivalent) and isothiocyanate (2) (1.1-1.3 equivalent) in ethanol or methanol (100 ml - 150 ml for 50 mmol scale) was heated at 50-80⁰C for 4-10 hr. Solid product was generated and collected by filtration. The product was washed with ether, dried under vacuum and used at the next step.

[00135] Step 2: Synthesis of 5, 4-disubstituted- [l,2,4]triazoIe-3-mercaptol (4): To a suspension of 3 (1 equivalent) in ethanol ( 50-100 ml for 50 mmol scale) was added 2N sodium hydroxide solution (10-20 equivalent). The mixture was heated at 70-90⁰C for 8-15 hours and acidified with concentrated HCl to pH 3-6. Solid was collected by filtration, washed with water, dried under vacuum used at next step.

[00136] Step 3: Synthesis of 5, 4-disubstituted- ethyl [l,2,4]triazole-3- mercaptoacetate (5): A mixture of compound 4 (1 equivalent), anhydrous K₂CO₃ (4-5 equivalent) and ethyl bromoacetate (1.1 equivalent) in dry acetone (50-100 ml for 50 mmol scale) was heated at 40-80⁰C for 4-10 hr, filtered at hot. Solvent was removed under vacuum. The solid residue was washed with ether, dried under vacuum and used next step.

[00137] Step 4: Synthesis of 5, 4-disubstituted-[l,2,4]triazole-3-mercaptoacetic acid hydrazide (6): A mixture of compound 5 (1 equivalent), hydrazine (1.1-1.3 eqivalent) in ethanol or methanol was heated at 40-80⁰C for 4-8 hr, concentrated to dryness under vacuum. The residue was crystallized from ethanol to give compound 6.

[00138] Step 5 (Method A): Synthesis 5, 4-disubstituted-[l,2,4]triazole-3- mercaptoacetylhydrazone (7) (Method A): A mixture of compound 6 (1 equivalent), aldehydes (1.1-1.3 equivalent) in glacial acetic acid (15-40 ml for 5 mmol scale) was heated at 40-80°C for 4-9 hr, concentrated under vacuum to dryness. The residue was recrystallized from ethanol and ether solution.

[00139] Step 5 (Method B): Synthesis 5, 4-disubstituted-[l,2,4]triazoIe-3- mercaptoacetylhydrazone (7): Aldehyde (1 equivalent) was added to a solution of compound 6 (1 equivalent) dissolved or suspended in dichloromethane (50 - 100 mM soln). The reaction was allowed to stir at room temperature for 10-16 hr. The solvent was removed by rotary evaporation and the solid was suspended in diethyl ether. The solid was collected by filtration, washed with diethyl ether and dried under vacuum.

[00140] Scheme 2: Procedure for synthesis of 3-(3-Methoxy-phenyI)l,4,5,6- tetrahydro-pyridazine

[00141] Scheme 3: Synthesis of l-[3-(3-Methoxy-phenyI)-5,6-dihydro-4H- pyridazin-l-yl]-2-(4-phenyl-5-p-to!yl-4H-[l,2,4]triazol-3-ylsulfanyI)ethanone

13 14 Step 11

EXAMPLE l

[00142] [4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid furan-

2-ylmethylene-hydrazide:

[00144] Step 1. l-{4-methyl-benzoyl}-4-(2-methyI-butyl)-thiosemicarbazide: This compound was prepared essentially according to the step 1 in the general method described above (93% yield); ¹H NMR (DMSOdO): δ 10.20 (sb, IH), 9.17(sb, IH), 8.00 (sb, IH), 7.78 (d, 2H), 7.26 (d, 2H), 3.36-3.19 (m, 2H), 2.34 (s, 3H), 1.72-1.69 (m, IH), 1.36-1.30 (m, IH), 1.06-0.99 (m, IH), 0.84-0.76 (m, 6H); MS (ESI): m/z 280 (M+H)⁺. [00145] Step 2. 4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (47% yield); ¹H NMR (CDCl₃): δ 11.48 (sb, IH), 7.43-7.27 (m, 4H), 4.12-3.96 (m, 2H), 2.44 (s, 3H), 1.90-1.67 (m, IH), 1.27-1.23 (m, IH), 1.04-0.99 (m, IH), 0.78-0.68 (m, 3H); MS (ESI): m/z 262 (M+H)⁺. [00146] Step 3. [4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazol-3-ylsuIfanyl]-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (52% yield); ¹HNMR (CDCl₃): δ 7.45 (d, 2H), 7.28 (d, 2H), 4.22 (q, 2H), 4.14 (s, 2H), 3.94 (dd, IH), 3.79 (dd, IH), 2.42 (s, 3H), 1.72-1.68 (m, IH), 1.31-1.17 (m, 4H), 1.04-0.98 (m, IH), 0.77 (t, 3H), 0.68 (d, 3H); MS (ESI): m/z 348 (M+H)⁺. [00147] Step 4. [4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (76% yield); ¹HNMR (DMSO-d6): δ 9.33(sb, IH), 7.50 (d, 2H), 7.33 (d, 2H), 4.31 (sb, 2H), 3.97 (dd, IH), 3.87 (s, 2H), 3.78 (dd, IH), 2.36 (sb, 3H), 1.53-1.50 (m, IH), 1.11-1.03 (m, IH), 0.92-0.87 (m, IH), 0.65 (t, 3H), 0.55 (d, 3H); MS (ESI): m/z 334 (M+H)⁺. [00148] Step 5. [4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazol-3-yIsulfanyl]-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (49% yield); ¹H NMR (CDCl₃): δ 11.99 (sb, IH), 8.07 (s, IH), 7.49-7.26 (m, 5H), 6.79-6.73 (m, IH), 6.46-6.45 (m, IH), 3.96 (s, 2H), 3.89 (dd, IH), 3.74 (dd, IH), 2.44 (s, 3H), 1.72-1.67 (m, IH), 1.26-0.97 (m, 2H), 0.77 (t, 3H), 0.68 (d, 3H); MS (ESI): m/z 412 (M+H)⁺.

EXAMPLE 2

[00149] (4-Furan-2-ylmethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-

2-ylmethylene-hydrazide :

[00151] Step 1. l-{4-methyI-benzoyl}-4-(2-furanylmethyI)-thiosemicarbazide: This compound was prepared essentially according to the step 1 in the general method described above (93% yield); ¹H NMR (DMSO-d6): δ 10.28 (sb, IH), 9.42(sb, IH), 8.52 (sb, IH), 7.78 (d, 2H), 7.51 (m, IH), 7.26 (d, 2H), 6.35 (m, IH), 6.22 (m, IH), 4.65 (m, 2H), 2.33 (s, 3H); MS (ESI): m/z 290 (M+H)⁺.

[00152] Step 2. 4-Furan-2-ylmethyl-5-p-tolyl-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (47% yield); ¹HNMR (CDCl₃): δ 11.68 (sb, IH), 7.53-7.26 (m, 5H), 6.37-6.31 (m, 2H), 5.26 (s, 2H), 2.44 (s, 3H); MS (ESI): m/z 272 (M+H)⁺. [00153] Step 3. (4-Furan-2-yImethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (52% yield); ¹H NMR (CDCl₃): δ 7.58 (d, 2H), 7.40 (m, IH), 7.28 (d, 2H), 6.36 (m, IH), 6.27 (m, IH), 5.16 (s, 2H), 4.22 (q, 2H), 4.08 (s, 2H), 2.43 (s, 3H), 1.27 (t, 3H); MS (ESI): m/z 358 (MH-H)⁺. [00154] Step 4. (4-Furan-2-ylmethyl-5-p-toIyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (76% yield); ¹H NMR (DMSO-d6): δ 9.33(sb, IH), 7.59 (m, IH), 7.53 (d, 2H), 7.34. (d, 2H), 5.21 (s, 2H), 4.28 (sb, 2H), 3.84 (s, 2H), 2.37 (s, 3H); MS (ESI): m/z 344 (M+H)⁺.

[00155] Step 5. (4-Furan-2-ylmethyl-5-p-toIyl-4H-[l,2,4]triazoI-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (47% yield); ¹H NMR (CDCl₃): δ 11.89 (sb, IH), 8.05 (s, IH), 7.60 (d, 2H), 7.49 (m, IH), 7.42 (m, IH), 7.34 (d, 2H), 6.77 (m, IH), 6.45 (m, IH), 6.37 (m, IH), 6.32 (m, IH), 5.07 (s, 2H), 3.92 (s, 2H), 2.45 (s, 3H); MS (ESI): m/z 422 (M+H)⁺.

EXAMPLE 3 [00156] (4-Cyclopentyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethy lene-hydrazide :

[00158] Step 1 & 2. 4-Cyclopentyl-5-furan-2-yl-4H-[l,2,4]triazole-3-thioI: This compound was prepared essentially according to the step 1 and step 2 in the general method described above (79% yield); ¹H NMR (CDCl₃): δ 7.99 (d, IH), 7.05 (d, IH), 6.73-6.72 (m, IH), 5.08-5.03 (m, IH), 2.47-1.53 (m, 8H); MS (ESI): m/z 236 (M+l)⁺.

[00159] Step 3. (4-CycIopentyl-5-furan-2-yI-4H-[l,2,4]triazol-3-ylsulfanyI)-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (50% yield); ¹H NMR (CDCl₃): δ 7.59 (d, IH), 6.94 (d, IH), 6.57-6.55 (m, IH), 4.94-4.85 (m, IH), 4.22 (q, 2H), 4.19 (s, 2H), 2.16-1.61 (m, 8H), 1.29 (t, 3H); MS (ESI): m/z 322 (M+l)⁺.

[00160] Step 4. (4-CyclopentyI-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (64% yield); ¹H NMR (DMSO-d6): δ 9.36(sb, IH), 7.95 (d, IH), 6.99 (d, IH), 6.71-6.70 (m, IH), 4.84-4.75 (m, IH), 3.96 (s, 2H), 2.09-1.59 (m, 8H); MS (ESI): m/z 308 (M+l)⁺. [00161] Step 5. (4-Cyclopen1yl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (43% yield); ¹H NMR (CDCl₃): δ 11.75 (sb, IH), 8.03 (s, IH), 7.64-7.63(m, IH), 7.49 (d, IH), 6.99-6.98 (m, IH), 6.79 (d, IH), 6.61-6.60 (m, IH), 6.46-6.45 (m, IH), 4.90-4.85(m, IH), 3.99 (s, 2H), 2.11-1.61 (m, 8H); MS (ESI): m/z 386 (M+H)⁺.

EXAMPLE 4

[00162] (4-Phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- hydroxymethyl-furan-2-ylmethylene)-hydrazide:

[00164] This compound was prepared from 5-hydroxymetbyl-furan-2-carbaldehyde and

(4-phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide essentially according to the step 5 in the general method described above (45% yield); ¹H NMR (DMSO-d6): δ 11.70 (sb, 0.4H) and 11.58 (sb, 0.6H), 8.00 (s, 0.4H), 7.82 (s, 0.6H), 7.54-6.41 (m, HH), 5.40-5.37 (m, IH), 4.41-4.36 (m, 3H), 4.06 (s, IH), 2.24 (s, 3H); MS (ESI): m/z 448 (M+H)⁺.

EXAMPLE 5

[00165] (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin-3-ylmethylene-hydrazide:

[00167] This compound was prepared from (5-benzo[l,3]dioxol-5-yl-4-phenyl-4H-

[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide and pyridine-3-carbaldehyde essentially according to the step 5 in the general method described above (47%, yield); ¹H NMR (DMSO- d6): δ 11.93 (sb, 0.4H) and 11.81 (sb, 0.6H), 8.81 (s, IH), 8.58 (s, IH), 8.23 (s, 0.4H), 8.08- 8.02 (m, 1.6H), 7.54-7.41 (m, 6H), 6.87-6.77 (m, 3H), 6.00 (s, 2H)₅ 4.46 (s, 1.4H), 4.07 (s, 0.6H); MS (ESI): m/z 459(M+H)⁺.

EXAMPLE 6

[00168] [5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid (5-hydroxymethyl-furan-2-ylmethylene)-hydrazide:

[00170] This compound was prepared from 5-hydroxymethyl-furan-2-carbaldehyde and

[5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l ,2,4]triazol-3-ylsulfanyl]-acetic acid hydrazide essentially according to the step 5 in the general method described above (40% yield); ¹H NMR (DMSO-d6): δ 11.70 (sb, 0.4H) and 11.58 (sb, 0.6H), 8.00 (s, 0.4H), 7.82 (s, 0.6H), 7.54-6.41 (m, 10H), 5.40-5.37 (m, IH), 5.23-5.21 (m, IH), 4.44-4.36 (m, 5H), 4.06 (s, IH); MS (ESI): m/z 464 (M+H)⁺.

EXAMPLE 7

[00171] (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin-3-ylmethylene-hydrazide:

[00173] This compound was prepared from pyridine-3-carbaldehyde and (5- benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide essentially according to the step 5 in the general method described above (51% yield); ¹H NMR (DMSO-d6): δ 11.95 (sb, 0.4H) and 11.82 (sb, 0.6H), 8.82 (s, IH), 8.58 (s, IH), 8.24 (s, 0.4H), 8.09-8.05 (m, 1.6H), 7.46-7.43 (m, IH), 7.03-6.92 (m, 3H), 6.11 (s, 2H), 4.58 (s, 1.2H), 4.16 (s, 0.8H), 4.02-3.92 (m, IH), 2.02-1.07 (m, 10H); MS (ESI): m/z 465(M+H)⁺. EXAMPLE 8

[00174] (5-Benzo[l₅3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid

(4-methoxy-pyridin-2-ylmethylene)-hydrazide:

[00176] This compound was prepared from 4-methoxy-pyridine-2-carbaldehyde and (5- benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide essentially according to the step 5 in the general method described above (72% yield); ¹H NMR (DMSO-d6): δ 11.97 (sb, 0.4H) and 11.81 (sb, 0.6H), 8.41-6.76 (m, 12H), 6.01 (s, 2H), 4.45 (s, 1.2H), 4.08 (s, 0.8H), 3.86 (s, 3H); MS (ESI): m/z 489(M+H)⁺.

EXAMPLE 9

[00177] (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid

(5-methoxy-pyridin-3-ylmethylene)-hydrazide:

[00179] This compound was prepared from 5-methoxy-pyridine-3-carbaldehyde and (5- benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide essentially according to the step 5 in the general method described above (83% yield); ¹H NMR (DMSO-d6): δ 11.97 (sb, 0.4H) and 11.81 (sb, 0.6H), 8.42-6.76 (m, 12H), 6.01 (s, 2H), 4.45 (s, 1.2H), 4.08 (s, 0.8H), 3.86 (s, 3H); MS (ESI): m/z 489(MH-H)⁺.

EXAMPLE 10

[00180] (E)-2-(4-((Tetrahydrofuran-2-yl)methyl)-5-ρ-tolyl-4H-l,2,4-triazol-3-ylthio)-N'-

((furan-2-yl)methylene)acetohydrazide:

[00182] Step 3. Ethyl 2-(4-((tetrahydrofuran-2-yl)methyl)-5-p-tolyl-4H-l,2,4-triazol-

3-ylthio)acetate: This compound was prepared essentially according to the step 3 in the general method described above (100 % yield); ¹H NMR (CDCl₃): δ 7. 30 - 8.00 (m, 4H), 4.00 - 5.00 (m, 7H), 3.70 (m, 2H), 2.50 (m, 3H), 1.80 - 2.10 (m, 3H), 1.20 - 1.60 (m, 4H); MS (ESI): m/z 362.2 (M+H)⁺.

[00183] Step 4. 2-(4-((Tetrahydrofuran-2-yl)methyI)-5-p-tolyl-4H-l,2,4-triazol-3- ylthio) acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (58.3 % yield); ¹H NMR (DMSOd₆): δ 9.35 (s, IH), 7.55 (d, 2H), 7.35 (d, 2H), 3.30 - 4.50 (m, 9H), 2.40 (s, 3H), 1.40 - 1.90 (m, 4H); MS (ESI): m/z 348.1 (M+H)⁺.

[00184] Step 5. (E)-2-(4-((Tetrahydrofuran-2-yl)methyl)-5-p-tolyl-4H-l,2,4-triazol-

3-ylthio)-N'-((furan-2-yl)methylene)acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (57.5 % yield); ¹H NMR (CDCl₃): δ 12.10 (s, IH), 8. 05 (s, IH), 7.50 (m, 3H), 7.30 (m, 2H), 6.75 (m, IH), 6.40 (m, IH), 3.95 - 4.20 (m, 5H), 3.70 (m, 2H), 2.40 (s, 3H), 1.75 - 2.00 (m, 3H), 1.45 (m, IH); MS (ESI): m/z 426.1 (M+H)⁺.

EXAMPLE 11

[00185] (E)-2-(4-Cyclohexyl-5-(4-(dimethylamino)phenyl)-4H-l,2,4-triazol-3-ylthio)- N'-((furan-2-yl)methylene)acetohydrazide:

[00187] Step 3. Ethyl 2-(4-cyclohexyl-5-(4-(dimethylamino)phenyI)-4H-l,2,4-triazol-

3-ylthio)acetate: This compound was prepared essentially according to the step 3 in the general method described above (85.8 % yield); ¹H NMR (CDCl₃): δ 7. 35 (d, 2H), 6.80 (d, 2H), 4.25 (m, 4H), 4.10 (m, IH), 3.00 (s, 6H), 2.20 (m, 2H), 1.85 (m, 4H), 1.30 (m, 7H); MS (ESI): m/z 389.0 (MH-H)⁺.

[00188] Step 4. 2-(4-Cyclohexyl-5-(4-(dimethylamino)phenyl)-4H-l,2,4-triazol-3- ylthio) acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (100 % yield); ¹HNMR (DMSO-d₆): δ 9.40 (s, IH), 7.25 (d, 2H), 6.80 (d, 2H), 4.30 (bs, 2H), 3.95 (m, 3H), 2.95 (s, 6H), 2.00 (m, 2H), 1.75 (m, 4H), 1.55 (m, IH), 1.1 (m, 3H); MS (ESI): m/z 375.1 (M+H)⁺.

[00189] Step 5. (E)-2-(4-Cyclohexyl-5-(4-(dimethylamino)phenyl)-4H-l,2,4-triazol- 3-ylthio)-N'-((furan-2-yl)raethylene)acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (80 % yield); ¹H NMR (CDCl₃): δ 12.00 (s, IH), 8.05 (s, IH), 7.50 (s, IH), 7.35 (m, 2H), 6.80 (m, 3H), 6.45 (m, IH), 4.15 (m, IH), 4.00 (s, 2H), 3.05 (s, 6H), 1.85 (m, 5H), 1.70 (m, IH), 1.25 (m, 4H); MS (ESI): m/z 453.1 (M+H)⁺. EXAMPLE 12

[00190] (E)-2-(5-((Benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4-triazol-3- ylthio)-N'-benzylideneacetohydrazide:

[00192] This compound was prepared essentially according to the step 5 in the general method described above (70 % yield); ¹H NMR (DMSOd₆): δ 11.60 & 11.75 (2s, IH), 8.00 & 8.10 (2s, IH), 7.65 (m, 2H), 7.50 (m, 3H), 7.40 (m, 3H), 7.30 (m, 2H), 6.70 (d, IH), 6.45 (s, IH), 6.30 (d, IH), 5.90 (s, 2H), 4.00 & 4.40 (2s, 2H), 3.85 (s, 2H); MS (ESI): m/z 472.1 (M+H)⁺. EXAMPLE 13

[00193] (E)-2-(5-(furan-2-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-3- yl)methylene) acetohydrazide:

[00195] This compound was prepared essentially according to the step 5 in the general method described above (71 % yield); ¹H NMR (DMSO-d₆): δ 11.55 & 11.65 (2s, IH), 7.40 - 8.20 (m, 9H), 6.70 (s, IH), 6.50 (m, IH), 6.10 (m, IH), 4.00 & 4.40 (2s, 2H); MS (ESI): m/z 393.1 (M+H)⁺.

EXAMPLE 14 [00196] (E)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-

((pyrimidin-5 -yl)methylene)acetohydrazide :

[00198] This compound was prepared essentially according to the step 5 in the general method described above (73 % yield); ¹H NMR (DMSOd₆): δ 9.20 & 9.05 (2m, 2H), 8.00 & 8.25 (2s, IH), 7.55 (m, 4H), 7.40 (m, 2H), 6.80 (m, 3H), 6.00 (s, 2H), 4.10 & 4.50 (2s, 2H); MS (ESI): m/z 460.1 (M+H)⁺.

EXAMPLE 15

[00199] (E)-N'-(2-Cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H- l,2,4-triazol-3-ylthio)acetohydrazide:

[00201] This compound was prepared essentially according to the step 5 in the general method described above (75 % yield); ¹H NMR (DMSOd₆): δ 11.95 & 12.10 (2s, IH), 6.75 - 8.60 (m, 13H), 6.00 (s, 2H), 4.05 & 4.45 (2s, 2H); MS (ESI): m/z 483.1 (M+H)⁺.

EXAMPLE 16

[00202] (E)-N'-(4-cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H- l,2,4-triazol-3-ylthio)acetohydrazide:

[00204] This compound was prepared essentially according to the step 5 in the general method described above (75 % yield); ¹H NMR (DMSO-d₆): δ 8.05 & 8.25 (2s, IH), 7.85 (m, 4H), 7.60 (m, 3H), 7.40 (m, 2H), 6.80 (m, 3H), 6.00 (s, 2H), 4.05 & 4.45 (2s, 2H); MS (ESI): m/z 483.1 (M+H)⁺.

EXAMPLE 17

[00205] (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- dimethylaminoraethyl-furan-2-ylmethylene)-hydrazide:

[00207] Preparation of Dimethylaniinomethyl-furan-2-carbaIdehyde: To a solution of (5-dimethylaminomethyl-furan-2-yl)-methanol (5g, 32.21 mmol) in CH₂Cl₂ (5m mL) was added Manganese(IV) oxide (28.01g, 322.18mmol), and the suspension was stirred overnight at room temperature. The mixture was then filtered, and the residue was washed several times with CH₂Cl₂. The filtrate was concentratedunder reduced pressure and purified by column chromatography. Evaporation of appropriate fractions gave 4.80 g (97%) of pale yellow oil. ¹H NMR (400 MHz, CD₃OD): δ 9.61(s, IH), 7.22(d, J= 3.4 Hz, 1 H), 6.455(d, J= 3.4Hz, 1 H), 3.579 (s, 2 H), 2.317 (s, 6 H), MS: m/e 154.0 (M+H)⁺.

[00208] Step 5. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- dimethylaminomethyl-furan-2-ylmethylene)-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (66% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.02-7.80 (m, 3 H), (6.197-6.77 (m, 2 H), 6.46 (s, 1 H), 4.49-4.10(m, 2 H), 3.60-3.57 (m, 1 H), 2.43 (s, 3 H), 2.28 (s, 6 H), 2.20-1.15 (m, 10 H), MS: m/e 481.0 (MfH)⁺.

EXAMPLE 18 [00209] (4-Cyclopropyl-5-/?-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide :

[00211] Step 1 & 2. 4-Cyclopropyl-5-/>-tolyI-4H-[l,2,4]triazole-3-tliioϊ: This compound was prepared essentially according to the step 1 and 2 in the general method described above (91% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.64 (d, J= 7.6 Hz, 2 H), 7.35 (d, J= 8.8 Hz, 2 H), 3.25-3.19 (m, IH), 2.42 (s, 3 H), 1.15-1.01 (m, 2 H), 0.65-0.64 (m, 2 H), MS: m/e 232.0 (M+H)⁺.

[00212] Step 3. (4-Cyclopropyl-5-_Jp-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the step 1 and 2 in the general method described above (92% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.67 (d, J= 7.6 Hz, 2 H), 7.28 (d, J= 8.8 Hz, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 4.20 (s, 2 H), 3.25-3.19 (m, 1 H), 2.43 (s, 3 H), 1.32 (t, J = 6.8 Hz, 3 H), 1.06-1.06 (m, 2 H), 0.79-0.77 (m, 1 H), 0.02-0.01 (m, 1 H), MS: /w/e 318.1 (MH-H)⁺.

[00213] Step 4 . (4-Cyclopropyl-5-/?-tolyl-4H-[l,2,4]triazoI-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (95% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.80 (s, 1 H), 7.65 (d, J= 8.4 Hz, 2 H), 7.36 (d, J= 8.0 Hz, 2 H), 3.98 (s, 2 H), 3.21-3.19 (m, 1 H), 2.44 (s, 3 H), 1.09-1.08 (m, 2 H), 0.73-0.72 (m, 1 H), 0.02-0.01 (m, 2 H), MS: m/e 304.0 (M+H)⁺.

[00214] Step 5. (4-Cyclopropyl-5-/?-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (71% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.05, 7.85 (2 s, 1 H), 7.80 (s, 1 H), 7.64 (d, J= 8.4 Hz, 2 H), 7.33 (d, J= 8.0 Hz, 2 H), 6.98- 6.95 (m, 1 H), 6.61-6.60 (m, 1 H), 4.58 (s, 1 H), 4.18 (s, 1 H), 3.54-.3.52 (m, 1 H), 2.40 (s, 3 H), 1.02-1.00 (m, 2 H), 0.70-0.66 (m, 2 H), MS: m/e 382.0 (M+H)⁺.

EXAMPLE 19

[00215] (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (l-furan-2- yl-2-methyl-propylidine)-hydrazide:

[00217] Preparation of l-Furan-2-yl-2-methyl-propan-l-one: A stirred mixture of

Furan (1.08g, leq) and Isobutyric anhydride (5g, 2 eq.) were warmed to 40 ⁰C, then heating bath was removed. Orthophosphoric acid (1 mL) was added. The reaction mixture was kept at 60 ⁰C for 2h. After cooling, 15 mL of water were added and the mixture was stirred for Ih. Sat. Sodium carbonate (20 mL) was added and stirred for 24h. The reaction mixture was extracted with dichloromethane and purified by column chromatography yielded l-furan-2-yl-2-methyl- propan-1-one (1.6g, 73%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.58 (m, 1 H), 7.19-7.18 (m, 1 H), 6.54-6.52 (m, 1 H), 3.40-3.20 (m, 1 H), 1.22 (d, J= 7.2 Hz, 6 H).

[00218] Step 5. (4-CyclohexyI-5-p-tolyI-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (1- furan-2-yl-2-methyI-propylidine)-hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (66% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.82-7.81 (m, 1 H), 7.40-7.38 (m, 4 H), 7.07-7.01 (m, 1 H), 6.66-6.63 (m, 1 H), 4.53, 4.15 (2 s, 2 H), 3.09-.3.06 (m, 1 H), 2.44 (s, 3 H), 2.20-1.60 (m, 10 H), 1.24 (d, J= 7.2 Hz, 6 H), MS: m/e 466.1 (M+H)⁺.

EXAMPLE 20

[00219] (4-Cyclohexyl-5-thiophene-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide:

[00221] Step 1 & 2. 4-CyclohexyI-5-thiophen-2-yI-4Η-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the step 1 and 2 in the general method described above (90% yield). ¹H NMR (400 MHz, CDCl₃): δ 11.92 (br s, 1 H),7.59-7.57 (m, 1 H), 7.35-7.34 (m, 1 H), 7.20-7.19 (m, 1 H),4.63-4.44 (m, 1 H), 1.87-1.18 (m, 10 H), MS: m/e 266.2 (M+H)⁺.

[00222] Step 3. (4-CycIohexyI-5-thiophene-2-yl-4H-[l,2,4]triazol-3-yIsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (91% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.56 (m, 1 H), 7.34-7.33 (m, 1 H), 7.21-7.18 (m, 1 H), 4.25 (q, J= 7.2 Hz, 2 H), 4.60-4.56 (m, 1 H), 4.21 (s, 2 H), 1.34 (t, J= 6.8 Hz, 3 H), 1.86-1.19(m, 10 H), MS: m/e 352.2 (M+H)⁺. [00223] Step 4. (4-CycIohexyl-5-thiophene-2-yl-4H-[l,2,4]triazoI-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (96% yield). ¹HNMR (400 MHz, CD₃OD): δ 7.59-7.56 (m, 1 H), 7.35-7.34 (m, 1 H), 7.22-7.20 (m, 1 H),4.20-4.15 (m, 1 H), 4.05 (s, 2 H), 1.85-1.08 (m, 10 H), MS: m/e 338.1 (M+H)⁺.

[00224] Step 5. (4-Cyclohexyl-5-thiophene-2-yl-4H-[l,2,4]triazol-3-yIsuIfanyl)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (68% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.03-7.60 (m, 3 H), 7.41-7.23 (m, 2 H), 6.92-6.78 (m, 1 H), 6.54-6.52 (m, 1 H), 4.51, 4.11 (2 s, 2 H), 4.32-4.25 (m, 1 H), 2.30-1.16 (m, 10 H), MS: m/e 416.1 (M+H)⁺.

EXAMPLE 21

[00225] (4-Benzo[l,3]dioxol-5-yl-5_:p-tolyl-4H-[l,2,4]triazol-3ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide :

[00227] Step 1 and 2. 4-Benzo[l,3]dioxol-5-p-tolyl-4Η-[l,2,4]triazol-3-thiol: This compound was prepared essentially according to the step 1 and 2 in the general method described above (92% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.78(d, J= 7.2 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2 H), 7.33-7.30 (m, 3 H), 6.14 (s, 2 H), MS: m/e 312.1 (M+H)⁺.

[00228] Step 3. (4-Benzo[lβ]dioxol-5-yl-5-/>-tolyl-4H-[l,2,4]triazoI-3ylsuIfanyl)- acetic acid ethyl ester: This compound was prepared essentially according to the step 1 and 2 in the general method described above (91% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J= 7.2 Hz, 2H), 7.38 (d, J= 7.2 Hz, 2 H), 7.34-7.31 (m, 3 H), 6.15 (s, 2 H), 4.18 (q, J= 7.2 Hz, 2 H), 3.96(s, 2 H), 1.25 (t, J= 7.2 Hz, 3 H), MS: m/e 398.1(M+H)⁺.

[00229] Step 4. (4-Benzo[l,3]dioxol-5-yI-5-/?-toIyl-4H-[l,2,4]triazol-3ylsulfanyl)- acetic acid hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (95% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.33-6.82 (m, 7 H), 7.36-7.32 (m, 3 H), 6.09 (s, 2 H), 2.34 (s, 3 H)₅ MS: m/e 384.1 (M+H)⁺.

[00230] Step 5. (4-Benzo[l,3]dioxol-5-yl-5-/»-tolyl-4H-[l,2,4]triazol-3yIsulfanyI)- acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.08-6.89 (m, 9 H), 6.62-6.61 (m, 1 H), 6.15 (s, 2 H), 4.41, 4.06 (2 s, 2 H), 2.28 (s, 3 H), MS: m/e 462.1 (M+H)⁺.

EXAMPLE 22

[00231] (5-Benzo[l,3]dioxol-5-yl-4-cycloheptyl-4H-[l,2,4]triazole-3-ylsulfanyl)acetic acid furan-2-ylmethylene-hydrazide:

[00233] Step 1 and 2. 5-Benzo[l,3]dioxol-5-yl-4-cycloheptyl-4Η-[l,2,4]triazole-3- thiol: This compound was prepared essentially according to the step 1 and 2 in the general method described above (90% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.32-7.30 (m, 3 H), 6.12 (s, 2 H), 4.10 (m, 1 H), 2.20-1.10 (m, 12 H), MS: m/e 318.1 (M+H)⁺.

[00234] Step 3. 5-Benzo[l,3]dioxol-5-yl-4-cycloheptyl-4H-[l,2,4]triazole-3- ylsulfanyl)acetic acid ethyl ester: This compound was prepared essentially according to the step 1 and 2 in the general method described above (92% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.35-7.31 (m, 3 H), 6.15 (s, 2 H), 4.15 (q, J= 7.2 Hz, 2 H), 4.10 (m, 1 H), 3.98(s, 2 H), 2.05- 1.15 (m, 12 H), 1.25 (t, J= 7.2 Hz, 3 H), MS: m/e 404.1(M+H)⁺.

[00235] Step 4. S-Benzotl^dioxol-S-yM-cycloheptyMH-tl^^triazole-S- ylsulfanyl)acetic acid hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (95% yield). ¹HNMR (400 MHz, CDCl₃): δ 7.28-7.23 (m, 3 H), 6.14 (s, 2 H), 4.10 (m, 1 H), 3.99(s, 2 H), 2.08-1.19 (m, 12 H), MS: m/e 390.1(M+H)⁺. [00236] Step 5. (5-Benzo[l,3]dioxol-5-yI-4-cycloheptyl-4H-[l,2,4]triazoIe-3- ylsulfanyl)acetic acid furan-2-yImethylene-hydrazide: This compound was prepared essentially according to the step 1 and 2 in the general method described above (68% yield). ¹H NMR (400 MHz, CDCl₃): δ 11.78, 11.86 (2 s, 1 H), 8.08-7.82 (m, 2 H), 7.09-6.61 (m, 4 H), 6.63-6.61 (m, 1 H), 6.14 (s, 2 H), 4.50, 4.13 (s, 2 H), 4.14-4.12 (m, 1 H), 2.20-1.20 (m, 12 H), MS: rø/e 468.1(M+H)⁺.

EXAMPLE 23

[00237] (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazole-3-ylsulfanyl)acetic acid thiazol-2-ylmethylene-hydrazide:

[00239] This compound was prepared essentially according to the step 5 in the general method described above (67% yield). ¹HNMR (400 MHz, CDCl₃): δ 12.15, 11.96 (2 s, 1 H), 8.42, 8.20 (2s, 1 H), 7.95-6.83 (m, 10 H), 6.63-6.61 (m, 1 H), 6.02 (s, 2 H), 4.44, 4.09 (2 s, 2 H), MS: m/e 465.0(M+H)⁺.

[00240] Example 24(£)-2-(4-Cyclopentyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N^?-

((furan-2-yl)methylene)acetohydrazide:

[00242] Step 1. 4-Cyclopentyl-l-(4-methylbenzoyl)thiosemicarbazide: This compound was prepared essentially according to the step 1 in the general method described above (64 % yield); ¹H ΝMR (DMSOd₆): δ 10.2 (s, IH), 9.16 (s, IH), 7.79 (d, 2H), 7.27 (d, 2H), 4.56 (s, IH), 2.34 (s, 3H), 1.84 (m, 2H), 1.60 (m, 2H), 1.45 (m, 4H); MS (ESI): m/z 277.9 (M+H)⁺. [00243] Step 2. 4-Cyclopentyl-5-p-tolyl-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (99 % yield); ¹HNMR (DMSOd₆): δ 7.43 (d, 2H), 7.35 (d, 2H), 4.59 (m, IH), 2.51 (m, 2H), 2.37 (s, 3H), 1.82 (m, 2H), 1.73 (m, 2H), 1.44 (m, 2H). [00244] Step 3. Ethyl 2-(4-cyclopentyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)acetate:

This compound was prepared essentially according to the step 3 in the general method described above. The crude was purified by silica chromatography to collect the title compound in 18 % yield; ¹HNMR (DMSO-d₆): δ 7.40 (d, 2H), 7.30 (d, 2H), 4.54 (m, IH), 4.24 (m, 4H), 2.43 (s, 3H), 2.19 (m, 2H), 1.97 (m, 4H), 1.60 (m, 2H); MS (ESI): m/z 346.0 (M+H)⁺.

[00245] Step 4. 2-(4-CycIopentyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)acetohydrazide:

This compound was prepared essentially according to the step 4 in the general method described above with the deviation that the reaction was kept at room temperature. Followed by silica chromatography purification the title compound was collected in 49 % yield; ¹H NMR (DMSO-d₆): δ 9.37 (s, IH), 7.39 (d, 2H), 7.34 (d, 2H), 4.50 (m, IH), 4.29 (bs, IH), 3.99 (s, 2H), 2.37 (s, 3H), 2.00 (m, 4H), 1.79 (m, 2H), 1.54 (m, 2H); MS (ESI): m/z 684.7 (2M+Na)⁺.

[00246] Step 5. (JB)-2-(4-Cyclopentyl-5-p-tolyl-4H-l,2,4-triazoI-3-ylthio)-N'-((furan-

2-yI)methylene)acetohydrazide: This compound was prepared essentially according to step 5 (method B) in the general method described above. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 54 % yield; ¹H NMR (CD₃OD) mixture of tautomers: δ 8.04 (s, IH x 0.4), 7.82 (s, IH x 0.4), 7.63 (d, IH), 7.36 (m, 4H), 6.93 (s, IH x 0.4), 6.80 (s, IH x 0.4), 6.55 (m, IH)₅ 4.65 (m, IH), 4.54 (s, 2H x 0.8), 4.14 (s, 2H x 0.8), 2.43 (s, 3H), 2.19 (m, 2H), 2.12 (m, 2H), 1.90 (m, 2H), 1.61 (m, 2H); MS (ESI): m/z 410.0 (M+H)⁺.

EXAMPLE 25

[00247] (E)-2-(4-Cyclopentyl-5-p-tolyl-4H-l₅2,4-triazol-3-ylthio)-N^l-((l-methyl-lH- pyrrol-2-yl)methylene)acetohydrazide:

[00249] This compound was prepared essentially according to step 5 (method B) in the general method described above. In addition, the reaction was heated for 3h at 80 ⁰C. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 28 % yield; ¹H NMR (CDCl₃) mixture of tautomers: δ 7.99 (s, IH), 7.42 (d, 2H), 7.34 (d, 2H), 6.72 (s, IH), 6.46 (s, IH), 6.11 (s, IH), 4.58 (m, IH), 4.01 (s, 2H), 3.95 (s, 3H), 2.45 (s, 3H), 2.01 (m, 4H), 1.60 (m, 2H); MS (ESI): m/z 423.0 (M+H)⁺.

EXAMPLE 26

[00250] 2-(5-(3,4-Dimethoxybenzyl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide :

[00252] Step 1. l-(2-(3,4-Dimethoxyphenyl)acetyl)-4-phenylthiosemicarbazide: This compound was prepared essentially according to the step 1 in the general method described above (92 % yield); ¹H NMR (DMSOd₆): δ 7.42 (d, 2H), 7.33 (t, 2H), 7.19 (t, IH), 7.00 (s, IH), 6.88 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.55 (s, 2H) ; MS (ESI): m/z 345.9 (M+H)⁺.

[00253] Step 2. 5-(3,4-Dimethoxybenzyl)-4-phenyl-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (93 % yield); ¹H NMR (DMSO-d₆): δ 7.47 (m, 3H), 7.11 (d, 2H), 6.75 (d, IH)₃ 6.42 (d, IH), 6.38 (s, IH)₅ 3.84 (s, 2H), 3.72 (s, 3H), 3.64 (s, 3H); MS (ESI): m/z 328.2 (M+H)⁺.

[00254] Step 3. 2-(5-(3,4-dimethoxybenzyϊ)-4-phenyl-4H-l,2,4-triazol-3- ylthio)acetate: This compound was prepared essentially according to the step 3 in the general method described above. The crude was purified by silica chromatography to collect the title compound in 87 % yield; ¹HNMR (DMSO-d₆): δ 7.53 (m, 3H)₅ 7.26 (m, 2H)₅ 6.72 (d, IH)₅

6.38 (m, 2H)₅ 4.06 (q, 2H), 3.96 (s, 2H)₅ 3.88 (s, 2H), 3.64 (s, 3H), 3.54 (s, 3H), 1.13 (t, 3H) ; MS (ESI): m/z 414.2 (M+H)⁺.

[00255] Step 4. 4-Dimethoxybenzyl)-4-phenyl-4H-l,2,4-triazol-3- ylthio)acetohydrazide: This compound was prepared essentially according to step 4 in the general method described above with the deviation that the reaction was kept at room temperature. Followed by silica chromatography purification the title compound was collected in 83 % yield; ¹H NMR (DMSOd₆): δ 9.30 (s, IH), 7.52 (m, 3H)₅ 7.24 (m, 2H), 6.73 (d, IH),

6.39 (m, 2H), 4.24 (s, 2H), 3.88 (s, 2H), 3.77 (s, 2H)₅ 3.64 (s, 3H), 3.54 (s, 3H); MS (ESI): m/z 400.0 (M+H)⁺.

[00256] Step 5. 4-Dimethoxybenzyl)-4-phenyl-4H-l,2,4-triazol-3-yIthio)-N'-((furan-

2-yl)methyIene)acetohydrazide: This compound was prepared essentially according to step 5 (method B) in the general method described above. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 37 % yield; ¹H NMR (CD₃OD) mixture of tautomers: δ 7.99 (s, IH x 0.4), 7.77 (s, IH x 0.4), 7.65 (d, IH), 7.51 (m, 3H), 7.24 (d, IH), 7.19 (d, IH)₅ 6.95 (d, IHx 0.5), 6.79 (d, IH x 0.5), 6.73 (d, IH)₅ 6.56 (m, IH), 6.42 (m, 2H), 3.98 (s, 2H x 1.2), 3.93 (s, 2H x 0.9), 3.74 (s, 3H), 3.63 (s, 3H); MS (ESI): m/z 478.1 (M+H)⁺.

EXAMPLE 27 [00257] (E)-2-(5-Benzyl-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide:

[00259] Step 1. 4-Phenyl-l-(2-phenylacetyl)thiosemicarbazide: This compound was prepared essentially according to the step 1 in the general method described above (94 % yield); ¹H NMR (DMSOd₆): δ 7.43-7.19 (m, 1OH), 3.61 (s, 2H) ; MS (ESI): m/z 286.0

(M+H)⁺.

[00260] Step 2. 5-Benzyl-4-phenyl-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (95 % yield); ¹R NMR (DMSO-d₆): δ 7.45 (m, 3H), 7.15 (m, 5H), 6.89 (m, 2H), 3.82 (s, 2H); MS (ESI): m/z 268.3 (M+H)⁺.

[00261] Step 3. Ethyl 2-(5-benzyl-4-phenyI-4H-l,2,4-triazol-3-ylthio)acetate: This compound was prepared essentially according to the step 3 in the general method described above. The crude was purified by silica chromatography to collect the title compound in 78 % yield; ¹H NMR (DMSOd₆): δ 7.52 (m, 3H), 7.25 (m, 2H), 7.14 (m, 3H), 6.87 (m, 2H), 4.06 (q, 2H), 3.98 (s, 3H), 2.48 (s, 2H), 1.13 (t, 3H); MS (ESI): m/z 354.2 (M+H)⁺.

[00262] Step 4. 2-(5-Benzyl-4-phenyl-4H-l,2,4-triazol-3-ylthio)acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above with the deviation that the reaction was kept at room temperature. Followed by silica chromatography purification the title compound was collected in 54 % yield; ¹H NMR (DMSOd₆): δ 9.30 (s, IH), 7.50 (m, 3H), 7.22 (m, 2H), 7.14 (m, 3H), 6.87 (d, 2H), 4.24 (s, 2H), 3.95 (s, 2H), 3.78 (s, 2H); MS (ESI): m/z 340.0 (M+H)⁺.

[00263] Step 5. (E)-2-(5-Benzyl-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide: This compound was prepared essentially according to step 5 (method B) in the general method described above. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 91 % yield; ¹HNMR (CD₃OD) mixture of tautomers: δ 7.99 (s, IH x 0.4), 7.77 (s, IH x 0.4), 7.65 (d, IH), 7.48 (m, 3H), 7.16 (m, 5H), 6.86 (m, 3H), 6.56 (m, IH), 4.04 (s, 2H x 1.3), 3.98 (s, 2H x 1.1); MS (ESI): m/z 418.1 (M+H)⁺.

EXAMPLE 28

[00264] (E)-2-(5-(benzo[d][l,3]dioxol-5-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'- ((pyridin-4-yl)methylene)acetohydrazide:

[00266] This compound was prepared essentially according to step 5 (method B) in the general method described above. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 91 % yield; ¹H NMR (DMSO-d⁶) mixture of tautomers: δ 12.02 (s, IH x 0.3), 11.91 (s, IH x 0.7), 8.62 (s, 2H), 8.17 (s, IH x 0.3), 7.96 (s, IH x 0.7), 7.60 (m, 2H), 7.54 (m, 3H), 7.41 (m, 2H), 6.82 (m, 3H), 6.01 (s, 2H), 4.47 (s, 2H x 1.3), 4.08 (s, 2H x 0.6); MS (ESI): m/z 459.1 (MH-H)⁺.

EXAMPLE 29

[00267] (E)-2-(5-(benzo[d][l,3]dioxol-5-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'- ((pyridin-2-yl)methylene)acetohydrazide:

[00269] This compound was prepared essentially according to step 5 (method B) in the general method described above. The crude solid was purified by silica chromatography (5 % methanol in dichloromethane) to obtain the title compound in 30 % yield; ¹H NMR (DMSO-d⁶) mixture of tautomers: δ 11.97 (s, lH x 0.3), 11.82 (s, lH x 0.7), 8.57 (m, IH), 8.19 (m, IH x 0.3), 8.02 (m, IH x 0.7), 7.87 (m, 2H), 7.55 (m, 3H), 7.40 (m, 3H), 6.82 (m, 3H), 5.99 (s, 2H), 4.46 (s, 2H x 1.3), 4.07 (s, 2H x 1.1); MS (ESI): m/z 459.1 (M+H)⁺.

EXAMPLE 30

[00270] (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin-2-ylmethylene-hydrazide:

[00272] This compound was prepared essentially according to step 5 (method B) in the general method described above. The compound was purified by crystallization from dichloromethane (67% yield) ¹H NMR (DMSO-d⁶) mixture of tautomers: δ 12.02 (s, IH x 0.3), 11.87 (s, IH x 0.7), 8.57 (m, IH), 8.20 (s, IH x 0.3), 8.05 (s, IH x 0.7), 7.87 (m, 2H), 7.40 (m, IH), 6.97 (m, 3H), 6.12 (s, 2H), 4.60 (s, 1.3H), 4.18 (s, 0.7H), 3.96 (m, IH), 2.03 (m, 2H), 1.81 (m, 4H), 1.50 (m, IH), 1.18 (m, 3H); MS (ESI): m/z 465 (M+H)⁺.

EXAMPLE 31

[00273] (E)-N'-(3-Cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H- l,2,4-triazol-3-ylthio)acetohydrazide:

[00275] This compound was prepared essentially according to step 5 (method B) in the general method described above. The compound was purified by crystallization from dichloromethane (65% yield) ¹H NMR (DMSO-d⁶) mixture of tautomers: δ 11.96 (s, 0.3H), 11.81 (s, 0.7H), 8.23-7.40 (m, 10H), 6.88-6.77 (m, 3H), 6.01 (s, 2H), 4.47 (s, 1.3H), 4.07 (s, 0.7H); MS (ESI): m/z 483 (M+H)⁺. EXAMPLE 32

[00276] (S-Benzotl^Jdioxol-S-yl^-phenyl-ffi-tl^^jtriazol-S-ylsulfanyO-acetic acid

( 1 H-pyrrol-2-ylmethylene)-hydrazide :

[00278] This compound was prepared essentially according to step 5 (method B) in the general method described above. The compound was purified by crystallization from dichloromethane (56% yield). ¹H NMR (DMSO-d⁶) mixture of tautomers: δ 11.45 (s, 0.4H), 11.39 (s, 0.4H), 11.33 (s, 0.6H), 11.27 (s, 0.6H), 8.01 (s, 0.4H), 1.81 (s, 0.6H), 7.55-7.41 (m, 3H), 7.40-7.39 (m, 2H), 6.91-6.69 (m, 4), 6.46 (s, 0.4H), 6.41 (s, 0.6H), 6.10 (s, IH), 6.01 (s, 2H), 4.41 (s, 1.3H), 4.03 (s, 0.7H); MS (ESI): m/z 447 (M+H)⁺.

EXAMPLE 33

[00279] (S-Benzotl^Jdioxol-S-yl^-phenyl^H-tl^^ltriazol-S-ylsulfanyO-acetic acid

(6-cyano-pyridin-2-ylmethylene)-hydrazide,

[00281] This compound was prepared essentially according to step 5 (method B) in the general method described above. The compound was purified by crystallization from dichloromethane (53% yield). ¹H NMR (DMSO-d⁶): δ 12.00 (s, IH), 9.35 (s, IH), 8.2-6.80 (m, 12H), 6.02 (s, 2H), 3.91 (s, 2H).

EXAMPLE 34 [00282] (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide :

[00284] Step 1. l-{Benzo[l,3]dioxole-5-carboxyloyl}-4-cyclohexylthiosemicarbazide:

This compound was prepared essentially according to the general method described above (90% yield); ¹U NMR (DMSO-d6): δ 10.07 (sb, IH), 9.11(sb, IH), 7.66 (sb, IH), 7.48 (d, IH), 7.42 (s, IH), 6.99 (d, IH), 6.09 (s, 2H), 4.10 (m, IH), 1.75-1.53 (m, 5H), 1.31-1.00 (m, 5H); MS (ESI): m/z 322 (M+H)⁺.

[00285] Step 2. 5-Benzo[l,3]dioxol-5-yl-4-cyclohexyI-4H-[l,2,4]triazole-3-thiol : This compound was prepared essentially according to the general method described above (73% yield); ¹H NMR (DMSO-d6): δ 13.76 (sb, IH), 7.09-6.98 (m, 3H), 6.12 (s, 2H), 4.10 (m, IH), 1.75-1.00 (m, 10H); MS (ESI): m/z 304 (M+H)⁺.

[00286] Step 3. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3- ylsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the general method described above (81% yield); ¹HNMR (CDCl₃): δ 6.98-6.91(m, 3H), 6.08 (s, 2H), 4.25-4.21 (m, 4H), 4.08 (m, IH), 1.60-1.90 (m, 6H), 1.34-1.20 (m, 7H); MS (ESI): m/z 390 (MfH)⁺.

[00287] Step 4. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3- ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the general method described above (93% yield); ¹HNMR (DMSO-d6): δ 9.40(sb, IH), 6.92-7.10 (m, 3H), 6.15 (s, 2H), 4.30 (sb, 2H), 3.97 (s 2H), 3.90-3.95 (m, IH), 2.02-1.00 (m, 10H); MS (ESI): m/z 377 (M+H)⁺.

[00288] Step 5. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3- ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the general method described above (83% yield); ¹H NMR (CDCl₃): δ 11.98 (sb, IH), 8.05 9s, IH), 7.50 (s, IH), 6.98-6.90 (m, 3H), 6.80 (d, IH), 6.45 (d, IH), 6.10 (s, 2H), 4.08-4.02 (m, IH), 4.02 (s, 2H), 2.20-1.10 (m, 10H); MS (ESI): m/z 454 (M+H)⁺. EXAMPLE 35

[00289] (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide:

[00291] Step 1. l-{Benzo[l,3]dioxole-5-carboxyloyI}-4-phenylthiosemicarbazide:

This compound was prepared essentially according to the general method described above (97% yield); ¹HNMR (DMSO-d6): δ 10.35 (sb, IH), 9.74(sb, IH), 9.64 (sb, IH), 7.53-7.00 (m, 8H), 6.09 (s, 2H); MS (ESI): m/z 316 (M+H)⁺.

[00292] Step 2. 5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the general method described above (73% yield); ¹HNMR (DMSO-d6): δ 13.76 (sb, IH), 7.48-7.46 (m, 3H), 7.33-7.31 (m, 2H), 6.82- 6.76 (m, 3H), 6.00 (s, 2H); MS (ESI): m/z 298 (M+H)⁺.

[00293] Step 3. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)- acetic acid ethyl ester: This compound was prepared essentially according to the general method described above (45% yield); ¹H NMR (DMSO-d6): δ 7.60-7.55 (m, 3H), 7.42-7.38 (m, 2H), 6.90-6.75 (m, 3H), 6.00 (s, 2H), 4.17-4.08 (m, 4H), 1.19 (t, 3H); MS (ESI): m/z 384 (MfH)⁺.

[00294] Step 4. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)- acetic acid hydrazide: This compound was prepared essentially according to the general method described above (87% yield); ¹H NMR (DMSO-d6): δ 9.35 (sb, IH), 7.60-7.55 (m, 3H), 7.42-7.38 (m, 2H), 6.90-6.78 (m, 3H), 4.25 (s, 2H), 3.85 (s, 2H), 3.30 (sb, 2H); MS (ESI): m/z 370 (M+H)⁺.

[00295] Step 5. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)- acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the general method described above (76% yield); ¹H NMR (CDCl₃): δ 11.79 (sb, IH), 8.16 (s, IH), 7.60-6.49 (m, HH), 5.98 (s, 2H), 3.95 (s, 2H); MS (ESI): m/z 448 (M+H)⁺. EXAMPLE 36

[00296] Step 5. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (4-dimethylamino-benzylidene)-hydrazide,

[00298] This compound was prepared essentially according to the general method described above (63% yield); ¹H NMR (DMSO-d6): δ 11.40 (sb, IH), 7.82 (s, IH), 7.54-7.40 (m, 7H), 6.86-6.69 (m, 5H), 6.00 (s, 2H), 4.40 (s, 2H), 2.94 (s, 6H); MS (ESI): m/z 501 (M+H)⁺.

EXAMPLE 37 [00299] 5-Cyclohexyl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide :

[00301] Step 1. l-cyclohexylcarboxyloyl}-4-phenylthiosemicarbazide: This compound was prepared essentially according to the general method described above (97% yield); ¹HNMR (DMSO-d6): δ 9.80 (sb, IH), 9.70(sb, IH), 9.50 (sb, IH), 7.60-7.15 (m, 5H), 2.29-1.92(m, IH) 1.82-1.10 (m, 10H); MS (ESI): m/z 278 (M+H)⁺.

[00302] Step 2. 5-Cyclohexyl-4-phenyI-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the general method described above (53% yield); ¹H NMR (DMSO-d6): δ 13.76 (sb, IH), 7.56-7..35 (m, 5H), 2.34-2.29 (m, IH), 1.70-0.99 (m, 10H); MS (ESI): m/z 260 (M+H)⁺. [00303] Step 3. (5-Cyclohexyl-4-phenyl-4H-[l,2,4]triazol-3-yIsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the general method described above (35% yield); ¹H NMR (CDCl₃): δ 7.56-7.55 (m, 3H), 7.28-7.26 (m, 2H), 4.20 (q, 2H), 4.00 (s, 2H), 2.49-2.44 (m, IH), 1.81-1.09 (m, 10H); MS (ESI): m/z 346 (M+H)⁺. [00304] Step 4. (5-CyclohexyI-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the general method described above (63% yield); ¹HNMR (DMSO-d6): δ 9.30 (sb, IH), 7.65-7.55 (m, 3H), 7.42- 7.38 (m, 2H), 6.90-6.78 (m, 3H), 4.35 (sb, 2H), 3.80 (s, 2H), 2.50-2.40 (m, IH), 1.80-1.00 (m, 10H); MS (ESI): m/z 332 (M+H)⁺. [00305] Step 5. (5-Cyclohexyl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyI)-acetic acid furan-2-ylmethylene-hydrazide: This compound was prepared essentially according to the general method described above (41% yield); ¹HNMR (CDCl₃): δ 11.80 (sb, IH), 8.18 (s, IH), 7.60-7.23 (m, 5H), 6.81 (d, IH), 6.50 (d, IH), 3.95 (s, 2H), 2.60-2.50 (m, IH), 1.90-1.10 (m, 10H); MS (ESI): m/z 410 (M+H)⁺. EXAMPLE 38

[00306] (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- hydroxymethyl-furan-2~ylmethylene)-hydrazide:

[00308] Step 1. l-p-toloyl-4-cyclohexylthiosemicarbazide: This compound was prepared essentially according to the general method described above (90% yield); ¹H NMR (DMSO-d6): δ 10.16 (sb, IH), 9.15(sb, IH), 7.80-7.78 (m, 2H), 7.66 (sb, IH), 7.28-7.26 (m, 2H), 4.10 (m, IH), 2.34 (s, 3H), 1.80-1.00 (m, 10H); MS (ESI): m/z 292 (M+H)⁺.

[00309] Step 2. 4-CycIohexyl-5-p-tolyl-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the general method described above (53% yield); ¹HNMR (DMSO-d6): δ 13.80 (sb, IH), 7.40 (d, 2H), 7.35 (d, 2H), 4.30-4.20 (m, IH), 2.40 (s, 3H), 1.75- 0.90 (m, 10H); MS (ESI): m/z 274 (M+H)⁺. [00310] Step 3. (4-CyclohexyI-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the general method described above (55% yield); ¹H NMR (CDCl₃): δ 7.60-7.25 (m, 5H), 4.30-4.22 (m, 4H), 2.45(s, 3H), 2.22-2.10 (m, IH), 1.90-1.09 (m, 10H); MS (ESI): m/z 382 (M+H)⁺. [00311] Step 4. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the general method described above (63% yield); ¹HNMR (DMSO-d6): δ 9.25 (sb, IH), 7.35 (d, 2H), 7.30 (d, 2H), 4.10-4.00 (m, IH), 3.95 (s, 2H), 2.45 (s, 2H), 2.20-1.08 (m, 10H); MS (ESI): m/z 368 (M+H)⁺.

[00312] Step 5. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- hydroxymethyI-furan-2-yImethylene)-hydrazide: This compound was prepared essentially according to the general method described above (52% yield); ¹H NMR (CDCl₃): δ 12.05 (sb, IH), 7.99 (s, IH), 7.40-7.33 (m, 4H), 6.69 (d, IH), 6.35 (d, IH), 4.63 (s, 2H),4.11-4.06 (m, IH), 4.00 (s, 2H), 2.46 (s, 3H), 2.20-1.10 (m, 10H); MS (ESI): m/z 454 (M+H)⁺.

EXAMPLE 39 [00313] [5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid furan-2-ylmethylene-hydrazide :

[00315] Step 1. l-{4-Hydroxymethyl-benzoyl}-4-phenyIthiosemicarbazide: This compound was prepared essentially according to the general method described above (91% yield); ¹B NMR (DMSO-d6): δ 10.45 (sb, IH), 9.80(sb, IH), 9.64 (sb, IH), 7.90-7.10 (m, 9H), 5.35 (sb, IH), 4.58 (s, 2H); MS (ESI): m/z 302 (M+H)⁺

[00316] Step 2. [4-(5-Mercapto-4-phenyl-4H-[l,2,4]triazol-3-yl)-phenyl]-methanol:

This compound was prepared essentially according to the general method described above (50% yield); ¹H NMR (DMSO-d6): δ 13.80 (sb, IH), 7.50-7.20 (m, 9H), 5.23 (s, IH), 4.43 (s, 2H); MS (ESI): m/z 284 (M+H)⁺. [00317] Step 3. [5-(4-HydroxymethyI-phenyl)-4-phenyl-4H-[l,2,4]triazol-3- ylsulfanyl]-acetic acid ethyl ester: This compound was prepared essentially according to the general method described above (55% yield); ¹HNMR (CDCl₃): δ 7.50-7.24 (m, 9H), 4.66 (s, 2H), 4.23 (t, 2H), 4.11 (s, 2H), 1.28 (t, 3H); MS (ESI): m/z 370 (M+H)⁺. [00318] Step 4. [5-(4-HydroxymethyI-phenyl)-4-phenyl-4H-[l,2,4]triazol-3- ylsulfanyl]-acetic acid hydrazide: This compound was prepared essentially according to the general method described above (63% yield); ¹H NMR (DMSO-d6): δ 9.33(sb, IH), 7.53-7.22 (m, 9H), 5.20 (s, IH), 4.43 (s, 2H), 4.27 (sb, 2H), 3.87(s, 2H); MS (ESI): m/z 356 (M+H)⁺.

[00319] Step 5. [5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l,2,4]triazol-3- ylsulfanyl] -acetic acid furan-2-ylmethyIene-hydrazide: This compound was prepared essentially according to the general method described above (50% yield); ¹H NMR (CDCl₃): δ 11.06 (sb, IH), 7.78 (s, IH), 7.81-7.24 (m, 9H), 6.87 (d, IH), 6.59 (d, IH), 5.21 (sb, IH), 4.44 (s, 2H), 4. 40(s, 2H); MS (ESI): m/z 434 (M+H)⁺.

EXAMPLE 40 [00320] (4-Isobutyl-5-p-tolyl-4H[l,2₅4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide :

[00322] Stepl &2. 4-Isobutyl-5-p-tolyI-4H-[l,2,4]triazole-3-thiol: The title compound was synthesized in a similar manner to that outlined for general procedure step 1 and 2 except that cyclohexyl isocyanate was replaced by Isobutyl isocyanate (91% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.79(d, J= 7.2 Hz, 2H), 7.38 (d, J= 7.2 Hz, 2 H), 3.50 (d, 6.8 Hz, 2 H), 2.40 (s, 3 H), 2.01 (m, 1 H), 0.84 (d, J = 6.8 Hz, 6 H), MS: m/e 248.2 (M+H)⁺.

[00323] Step 3. (4-IsobutyI-5-p-tolyl-4H[l,2,4]triazol-3-yIsuIfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (90% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.78(d, J= 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2 H), 4.18 (q, J= 7.2 Hz , 2 H), 4.01 (s, 2 H), 3.51 (d, J= 6.8 Hz, 2 H), 2.40 (s, 3 H), 2.01 (m, 1 H), 1.27 (t, J= 5.2 Hz, 3 H), 0.84 (d, J= 6.8 Hz, 6 H), MS: m/e 334.2 (M+H)⁺. [00324] Step 4. (4-Isobutyl-5-p-tolyl-4H[l,2,4]triazol-3-yIsulfanyI)-acetic hydrazide:

This compound was prepared essentially according to the step 4 in the general method described above (94% yield). ¹HNMR (400 MHz, DMSO): δ 7.77(d, J= 7.2 Hz, 2H), 7.38(d, J = 7.2 Hz, 2 H)₅ 4.20 (br s, 2 H), 4.00 (s, 2 H)₅ 3.50 (d, J= 6.8 Hz, 2 H), 2.40 (s, 3 H), 2.01 (m, 1 H), 0.84 (d, J= 6.8 Hz, 6 H)₅ MS: m/e 320.2 (M+H)⁺.

[00325] Step 5. (4-Isobutyl-5-p-tolyl-4H[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-

2-ylmethylene-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (70% yield). ¹H NMR (400 MHz₅ CD₃OD): δ 8.00 (s, 1 H), 7.70-7.25 (m, 6 H)₅ 6.60 (m, 1 H), 4.00 (s, 2 H), 3.97 (d, J= 6.8 Hz, 2 H), 2. 40 (s, 3 H), 1.89 (m, 1 H)₅ 0.75 (d, J= 6.8 Hz, 6 H), MS: m/e 398.1 (M+H)⁺.

EXAMPLE 41

[00326] (4-Cyclohexyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-ylsulfanyl)-acetic acid furan-

2-ylmethylene-hydrazide :

[00328] Step 1 & 2.4-Cyclohexyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol: This compound was prepared essentially according to the step 1 and 2 in the general method described above (92% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.65 (m, 2 H)₅ 8.00 (m, IH)₅ 7.60(m, 1 H)₅ 4.40 (m, 1 H), 2.01 (br s, 1 H), 1.80-0.86 (m, 10 H), MS: m/e 261.0 (M+H)⁺.

[00329] Step 3. 4-Cyclohexyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-ylsuIfanyl)-acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (92% yield). ¹H NMR (400 MHz₅ CD₃OD): δ 8.85 (m, 2 H), 7.90 (m, 1 H), 7.50(m, 1 H), 4.20 (q, J= 7.2 Hz, 2 H), 4.19 (m, 1 H), 4.00 (s, 2 H), 1.80-0.86 (m, 10 H), 1.28 (t, J= 7.2 Hz, 3 H), MS: m/e 347.1 (M+H)⁺.

[00330] Step 4. (4-Cyclohexyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-ylsulfanyl)-acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (95% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.84 (m, 2 H), 7.91 (m, 1 H), 7.52(m, 1 H), 4.14 (m, 1 H), 4.00 (s, 2 H), 1.80-0.86 (m, 10 H), MS: m/e 333.1 (M+H)⁺.

[00331] Step 5. (4-Cyclohexyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-ylsulfanyI)-acetic acid furan-2-yImethylene-hydrazide: This compound was prepared essentially according to 5 the step 5 in the general method described above (70% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.80 (m, 3 H), 7.92 (m, 1 H), 7.45(m, 2 H), 6.45(m, 1 H), 4.20 (br s, 1 H), 4.04 (m, 1 H), 4.00 (s, 2 H), 1.90-0.96 (m, 10 H), MS: m/e 411.1 (M+H)⁺.

EXAMPLE 42

[00332] [5-(4-Hydroxy-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid o furan-2-ylmethylene-hydrazide,

[00334] Step 1 & 2. 4-(5-Mercapto-4-phenyl-4H-[l,2,4]triazol-3-yl)-phenol: This compound was prepared essentially according to the step 1 and 2 in the general method described above (90% yield). ¹HNMR (400 MHz, CD₃OD): δ 7.50 (m, 3 H), 7.30 (m, 2 H), 5 7.14(d, J= 8.4 Hz, 2 H), 7.67(d, J= 8.4 Hz, 2 H), MS: m/e 270.1 (M+H)⁺.

[00335] Step 3. [5-(4-Hydroxy-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-yIsulfanyl]- acetic acid ethyl ester: This compound was prepared essentially according to the step 3 in the general method described above (92% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.55 (m, 3 H), 7.35(m, 2 H), 7.20 (d, J= 9.2 Hz, 2 H), 6.70 (d, J= 8.8 Hz, 2 H), 4.17 (q, J= 7.2 Hz, 2 H), 0 3.97(s, 2 H), 1.24 (t, J= 7.2 Hz, 3 H), MS: m/e 356.1 (M+H)⁺.

[00336] Step 4. [5-(4-Hydroxy-phenyl)-4-phenyl-4H-[l,2,4]triazoI-3-ylsulfanyI]- acetic acid hydrazide: This compound was prepared essentially according to the step 4 in the general method described above (91% yield). ¹HNMR (400 MHz, DMSO): δ 7.59 (m, 3 H), 7.39(m, 2 H), 7.13 (d, J= 8.4 Hz, 2 H), 6.66 (d, J= 8.8 Hz, 2 H), 4.26 (br s, 2 H), 3.83 (s, 2 H), 5 MS: m/e 342.0 (M+H)⁺. [00337] Step 5. [5-(4-Hydroxy-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-yIsulfanyl]- acetic acid furan-2-yImethylene-hydrazide: This compound was prepared essentially according to the step 5 in the general method described above (65% yield). ¹H NMR (400 MHz, DMSO): δ 7.80 (m, 1 H), 7.58 (m, 3 H), 7.38(m, 3 H), 7.13 (d, J= 8.4 Hz, 2 H), 6.66 (d, J= 8.8 Hz, 2 H), 6.62 (m, 1 H), 4.40 (br s, 2 H), 4.00 (s, 2 H), MS: m/e 420.0 (M+H)⁺.

EXAMPLE 43

[00338] l-[3-(3-Methoxy-phenyl)-5,6-dihydro-4H-pyridazin-l-yl]-2-(4-phenyl-5-p- tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)ethanone:

[00340] Step 6 & 7. 4~(3-Methoxy-phenyl)-4-oxo-butyric acid: To a suspension of 3-

(3-Methoxy-phenyl)-3-oxo-propionic acid ethyl ester (5g, 1 equivalent) in tetrahydrofuran (100 mL) was added NaH (0.647 g, 1.2 equivalent) portionwise. Then after 20 minutes, ethyl bromoacetate was added dropwise and stirred for 5h. The mixture was quenched with ice and extracted with ethyl acetate. The organic portion was dried and evaporated. The crude material 5g (1 eq) was dissolved in mixture of THF (80 mL), Water 10 mL and Methanol (10 mL).The reaction mixture was stirred at room temperature for 2 h. The mixture was eacidfied with 6N HCl to pH 3. The mixture was extracted with ethyl acetate and dried. Evaporation of the solvent yielded 4-(3-Methoxy-phenyl)-4-oxo-butyric acid (90%)as pure product. ¹H NMR (400 MHz, CDCl₃): δ 7.60-7.10 (m, 4 H), 3.85 (s, 3 H), 3.30 (t, J= 6.4 Hz, 2 H), 2.81 (t, J= 6.8 Hz, 2 H), MS: m/e 208.9 (M+)

[00341] Step 8. 6-(3-Methoxy-phenyl)-4,5-dihydro-2H-pyridazin-3-one: A solution of 4-(3-Methoxy-phenyl)-4-oxo-butyric acid (3g, 1 eq) and hydrazine hydrate (1.38 g, 3 eq) in ethanol (50 mL) was stirred at reflux temperature for 3 hr. The mixture was chilled and filtered to give 6-(3-Methoxy-phenyl)-4,5-dihydro-2H-pyridazin-3-one (2.5 g, 85%). ¹H NMR (400 MHz₅ CDCl₃): δ 8.62 (br s, 1 H), 7.40-6.85 (m, 4 H), 3.86 (s, 3 H), 3.00-2.80 (m, 2 H), 2.79- 2.60 (m, 2 H), MS: m/e 205.1 (M+H)⁺.

[00342] Step 9. 3-(3-Methoxy-phenyl)l,4,5,6-tetrahydro-pyridazine: A solution of 6-

(3-Methoxy-phenyl)-4,5-dihydro-2H-pyridazin-3-one (2 g, 1 eq) was added drowise to the solution of Lithium Aluminiumhydride (0.372 g, leq) in THF (30 niL). The reaction mixture was refluxed for 5 hr. The reaction mixture was quenched with water (0.4 mL), 15 % NaOH (0.4 mL) and water (1.2 mL). Filtration of crude mixture gave 3-(3-Methoxy-phenyl)l,4,5,6- tetrahydro-pyridazine (1.6 g, 86%). ¹HNMR (400 MHz, CDCl₃): δ 7.26-6.82 (m, 4 H), 3.82 (s, 3 H), 3.15 (t, J= 5.2 Hz, 2 H), 2.57 (t, J= 7.2 Hz, 2 H), 2.09-2.06 (m, 2 H), MS: m/e 191.1 (MH-H)⁺.

[00343] Step 10. 4-Phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid: A solution of (4-Phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester (3 g, 1 eq) was treated with 10% NaOH (50 mL) and refluxed for 2 hr. The reaction mixture was acidified with 6N HCl and extracted with ethyl acetate. Evaporation of the organic solvent yielded 4- Phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (2.5 g, 90%) as pure product. ¹H NMR (400 MHz, DMSO): δ 7.58-7.30 (m, 5 H), 7.20, 7.15 (2 d, J= 7.2 Hz, 4 H), 3.96 (s, 2 H), 2.57 (t, J= 7.2 Hz, 2 H), 2.09-2.06 (m, 2 H), MS: m/e 326.1 (MH-H)⁺.

[00344] Step 11. l-[3-(3-Methoxy-phenyI)-5,6-dihydro-4H-pyridazin-l-yl]-2-(4- phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)ethanone: 4-Phenyl-5-p-tolyl-4H- [l,2,4]triazol-3-ylsulfanyl)-acetic acid (0.2 g, 1 eq) was dissolved in DMF (10 mL). To this solution EDCI (0.235 g, 2 eq), 3-(3-Methoxy-phenyl)l,4,5,6-tetrahydro-pyridazine (0.116 g) and catalytic amount of DMAP were added. The reaction mixture was stirred for 5 hr. Extracted with DCM , dried and evaporation gave l-[3-(3-Methoxy-phenyl)-5,6-dihydro-4H- pyridazin-l-yl]-2-(4-phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)ethanone (0.140 g, 45%). ¹H NMR (400 MHz, CD₃OD): δ 7.60-6.30 (m, 8 H), 7.18, 7.11 (2 d, J= 7.2 Hz, 4 H), 6.98- 6.97 (m, 1 H), 3.81 (s, 3 H), 3.79 (t, J= 6 Hz, 2 H)₅ 2.70 (t, J= 6.4 Hz, 2 H), 2.57 (t, J = 7.2 Hz, 2 H), 2.07-2.01 (m, 2 H), MS: m/e 498.1 (MH-H)⁺.

EXAMPLE 44

[00345] 2-(4-Phenyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N-(benzyloxy)acetamide: 6 039945

[00347] This compound was prepared essentially according to step 11 in the general method described above (64% yield); ¹HNMR (CDCl₃): δ 10.80(s, IH), 7. 60-7.10 (m, 14H), 5.0 (s, 2H), 3.8 (s, 2H), 2.40 (s, 3H); MS (ESI): m/z 431.1 (M+H)⁺.

EXAMPLE 45

[00348] (E)-2-(4-Cyclohexyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)-2-methylpropanehydrazide,

[00350] Step 3. Ethyl 2-(4-cyclohexyl-5-p-toIyl-4H-l,2,4-triazol-3-yIthio)-2- methylpropanoate: This compound was prepared essentially according to the step 3 in the general method described above (100% yield); ¹H NMR (CDCl₃): δ 7.40 (d, 2H), 7.30 (d, 2H), 4.20 (m, 3H), 2.40 (s, 3H), 2.10-1.05 (m, 19H); MS (ESI): m/z 388.5 (M+H)⁺.

[00351] Step 4. 2-(4-Cyclohexyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-2- methylpropanehydrazide: This compound was prepared essentially according to the step 4 in the general method described above (68% yield); ¹H NMR (CDCl₃): δ 7.30 (m, 4H), 4.40 (m, IH), 2.50 (s, 3H), 2.4-1.0 (m, 16H); MS (ESI): m/z 374.2 (M+H)⁺.

[00352] Step 5. (E)-2-(4-Cyclohexyl-5-p-tolyl-4H-l,2,4-triazol-3-yIthio)-N'-((furan-

2-yl)methylene)-2-methyIpropanehydrazide: This compound was prepared essentially according to the step 5 in the general method described above (84% yield); ¹H NMR (CDCl₃): δ 11.80 (s, IH), 8. 60 (s, IH), 7.60 (s, IH), 7.30 (m, 4H), 6.9 (s, IH), 6.60 (s, IH), 4.40 (m, IH), 2.40 (s, 3H)₅ 2.4-1.0 (m, 16H); MS (ESI): m/z 451.58 (M+H)⁺. 45

EXAMPLE 46

[00353] (E)-2-(4-Cyclohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide:

[00355] Step 2. 4-CycIohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (74% yield); ¹HNMR (CDCl₃): δ 11.70 (s, IH), 7.50 (m, 2H), 7.20 (m, 2H), 4.40 (m, IH), 2.40-1.00 (m, 10H); MS (ESI): m/z 278.0 (MH-H)⁺.

[00356] Step 3. Ethyl 2-(4-cyclohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazol-3- ylthio)acetate: This compound was prepared essentially according to the step 3 in the general method described above (53% yield); ¹H NMR (CDCl₃): δ 7.50 (m, 2H), 7.20 (t, 2H), 4.25 (m, 4H), 4.0 (m, IH), 2.15 (m, 2H), 1.90 (m, 4H), 1.3 (m, 7H); MS (ESI): m/z 364.1 (M+H)⁺.

[00357] Step 4. 2-(4-Cyclohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazol-3- ylthio)acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (73% yield); ¹H NMR (CDCl₃): δ 9.20 (s, IH), 7.50 (m, IH), 7.25 (m, 2H), 3.90 (m, 5H), 2.10 (m, 2H), 1.90 (m, 4H), 1.2 (m, 4H); MS (ESI): m/z 350.0 (M+H)⁺.

[00358] Step 5. (E)-2-(4-Cyclohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazol-3-ylthio)-

N'-((furan-2-yl)methylene)acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (68% yield); ¹H NMR (CDCl₃): δ 11.90 (s, IH)₅ 8. 10 (s, IH), 7.50 (m, 3H), 7.30 (m, 2H), 6.80 (s, IH), 6.50 (s, IH), 4.00 (m, 3H), 2.10 (m, 2H), 1.90 (m, 4H), 1.2 (m, 4H); MS (ESI): m/z 428.0 (M+H)⁺.

EXAMPLE 47

[00359] (E)-2-(5-Phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene) acetohydrazide:

[00361] Step 2. 5-Phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (86% yield); ¹H NMR (DMSO-d₆): δ 8.65 (d, IH), 8.55 (s, IH), 7.90 (m, IH), 7.55 (m, IH), 7.45 (m, IH), 7.35 (m, 4H); MS (ESI): m/z 255.2 (M+H)⁺.

[00362] Step 3. Ethyl 2-(5-phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazol-3-ylthio)acetate:

This compound was prepared essentially according to the step 3 in the general method described above (100% yield); ¹HNMR (CDCl₃): δ 8.75 (m, IH), 8.55 (s, IH), 7.65 (m, IH), 7.45 (m, IH), 7.40-7.20 (m, 5H), 4.25 (q, 2H), 4.10 (s, 2H); MS (ESI): m/z 341.1 (MfH)⁺. [00363] Step 4. 2-(5-Phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazol-3- ylthio)acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (80% yield); ¹H NMR (DMSO-d₆): δ 9.25 (s, IH), 8.75 (m, IH), 8.65 (m, IH), 7.95 (m, IH), 7.60 (m, IH), 7.35 (m, 5H), 4.30 (bs, 2H) 3.85 (s, 2H); MS (ESI): m/z 327.0 (M+H)⁺. [00364] Step 5. (E)-2-(5-Phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazol-3-ylthio)-N'-

((furan-2-yl)methylene) acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (71% yield); ¹H NMR (DMSOd₆): δ 11.60 (s, IH)₅ 8. 70 (m, IH), 7.95 (m, IH), 7.80 (s, 2H), 7.60 (m, IH), 7.35 (m, 5H), 6.90 (s, IH), 6.60 (s, IH), 4.40 (s, 2H); MS (ESI): m/z 405.1 (M+H)⁺. EXAMPLE 48

[00365] (E)-2-(5-(Furan-2-yl)-4-(phenyl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide:

[00367] Step 2. 5-(Furan-2-yl)-4-(phenyl)-4H-l,2,4-triazole-3-thiol: This compound was prepared essentially according to the step 2 in the general method described above (75% yield); ¹H NMR (DMSO-d₆): δ 7.80 (s, IH), 7.60 (m, 3H), 7.40 (m, 2H), 6.50 (m, IH), 5.80 (m, IH), 3.30 (s, IH); MS (ESI): m/z 244.2 (M)⁺.

[00368] Step 3. Ethyl 2-(5-(furan-2-yI)-4-(phenyl)-4H-l,2,4-triazol-3-ylthio)acetate:

This compound was prepared essentially according to the step 3 in the general method described above (99% yield); ¹HNMR (DMSOd₆): δ 7.75 (s, IH), 7.60 (m, 3H), 7.30 (m, 2H), 6.50 (m, IH), 6.15 (m, IH), 4.10 (q, 2H), 1.15 (t, 3H); MS (ESI): m/z 330.1 M⁺. [00369] Step 4.2-(5-(Furan-2-yl)-4-(phenyl)-4H-l,2,4-triazoI-3- ylthio)acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (82% yield); ¹HNMR (DMSOd₆): δ 9.35 (s, IH), 7.75 (s, IH), 7.60 (m, 3H), 7.45 (m, 2H), 4.30 (bs, 2H) 3.85 (s, 2H); MS (ESI): m/z 316.0 M⁺.

[00370] Step 5. (E)-2-(5-(Furan-2-yl)-4-(phenyl)-4H-l,2,4-triazol-3-ylthio)-N'- ((furan-2-yl)methylene)acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (64% yield); ¹H NMR (DMSOd₆): δ 11.60 (s, IH), 7. 90 (s, IH), 7.75 (m, IH), 7.60 (m, 4H), 7.50 (m, 2H), 6.90 (m, IH), 6.60 (m, IH), 6.50 (m, IH), 6.10 (m, IH), 4.40 (s, 2H); MS (ESI): m/z 394.0 M⁺.

EXAMPLE 49 [00371] (E)-2-(5-(βenzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4-triazol-3- ylthio)-N^<-((flιran-2-yl)methylene)acetohydrazide:

[00373] Step 2. 5-((Benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4-triazole-3- thiol: This compound was prepared essentially according to the step 2 in the general method described above (82% yield); ¹H NMR (DMSOd₆): δ 13.80 (s, IH), 7.50 (m, 3H), 7.20 (m, 2H), 6.70 (d, IH), 6.45 (s, IH), 6.35 (d, IH), 5.90 (s, 2H), 3.75 (s, 2H); MS (ESI): m/z 312.2 (M+H)⁺.

[00374] Step 3. Ethyl 2-(5-((benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4- triazol-3-ylthio) acetate: This compound was prepared essentially according to the step 3 in the general method described above (96% yield); ¹H NMR (CDCl₃): δ 7. 50 (m, 3H), 7.05 (m, 2H), 6.60 (m, IH), 6.50 (s, IH), 6.30 (m, IH), 5.95 (s, 2H), 4.20 (q, 2H), 4.05 (s, 2H), 3.95 (s, 2H) 1.15 (t, 3H); MS (ESI): m/z 398.1 (M+H)⁺.

[00375] Step 4. 2-(5-((Benzo[d] [l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4-triazol-3- ylthio) acetohydrazide: This compound was prepared essentially according to the step 4 in the general method described above (100% yield); ¹H NMR (CDCl₃): δ 9.20 (s, IH), 7.50 (m, 3H), 7.05 (m, 2H), 6.60 (m, IH), 6.50 (m, IH), 6.35 (m, IH), 5.95 (s, 2H), 3.95 (m, 4H), 3.80 (s, 2H); MS (ESI): m/z 384.0 (M+H)⁺.

[00376] Step 5. (E)-2-(5-((Benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4- triazol-3-ylthio)-N'-((furan-2-yl)methylene)acetohydrazide: This compound was prepared essentially according to the step 5 in the general method described above (60% yield); ¹H NMR (DMSO-d₆): δ 11.60 (s, IH), 7. 80 (d, IH), 7.50 (m, 3H), 7.30 (m, 2H), 6.90 (m, IH), 6.65 (m, IH), 6.60 (m, IH), 6.45 (s, IH), 6.30 (m, IH), 5.90 (s, 2H), 4.30 (s, 2H), 3.80 (s, IH); MS (ESI): m/z 462.0 (M+H)⁺ [00377] EQUIVALENTS

[00378] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the invention and are covered by the following claims. Various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. Other aspects, advantages, and modifications are within the scope of the invention. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the invention and embodiments thereof.

Claims

CLAIMSWhat is claimed is:

1. A compound having the formula

wherein

^■ Ri is selected from the group consisting of straight or branched Ci-C₇ alkyl; and C₃ -C io alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups are optionally substituted with one or more of a halogen; Ci-Cg alkyl; Cj-C₆ alkoxy; cyano, Cj-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide; or hydroxyl group; and Ri is optionally attached via a C₁-C₂ alkyl linker in place of a direct bond;

^■ R₂ is a C₃-C₁0 alicyclic, heteroalicyclic, aryl, heteroaryl or fused aryl/(alicyclic or heterocyclic) ring optionally substituted with one or more of a halogen, Ci -C₃ alkyl, Cj-C₆ alkoxy, cyano, C]-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group; and R₂ is optionally attached via a C₁-C₂ alkyl linker in place of a direct bond;

^■ R3, R₄ and R₆ are independently H or lower alkyl;

■ R5 is selected from the group consisting Of C₃-Ci_O alicyclic, heteroalicyclic, aryl or heteroaryl groups, wherein the alicyclic, heteroalicyclic, aryl or heteroaryl groups independently are optionally substituted with one or more halogen, Ci- C₆ alkyl, Ci-C₆ alkoxy, cyano, aryl Ci-C₆ alkoxy, amino, hydroxy or sulfonamide groups; and R₅ is optionally attached via a Cj-C₂ alkyl linker in place of a direct bond; wherein when the straight dotted bond is absent, the dotted circular line represents a C₁-C₃ alkylene bridge; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Ri is selected from the group consisting of straight or branched C₁-C5 alkyl; C₃-C₇ cycloalkyl; benzyl, tolyl, fϊiranyl, thiophene, imidazolyl, oxazόlyl, thiazolyl, triazolyl, pyrrole, benzo[c(|dioxole, benzo[</]dithiole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, and dithiolane.

3. The compound of claim 2, wherein Rj is substituted with one or more of a halogen, C₁- C₃ alkyl, Ci-C₆ alkoxy, cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group.

4. The compound of claim 1, wherein R₂ is selected from the group consisting of benzyl, tolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrole, benzo[cf]dioxole, benzo[d]dithiole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, and dithiolane.

5. The compound of claim 2, wherein R₂ is substituted with one or more of a halogen, C₁- C3 alkyl, C]-C₆ alkoxy, cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group.

6. The compound of claim 1, wherein R₅ is selected from the group consisting of benzyl, tolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrole, lower hydroxyalkyl-subsitituted benzyl, lower hydroxyalkyl-subsitituted benzyl, pyridinyl, pyrimidinyl, triazine, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophene, and dithiolane.

7. The compound of claim 2, wherein R₅ is substituted with one or more of a halogen, Q- C3 alkyl, C₁-C₆ alkoxy, cyano, Ci-C₆ hydroxyalkyl; amino, lower alkylamino or lower dialkylamino; sulfonamide, or hydroxyl group.

8. A method of treating a condition regulated directly or indirectly by KvI .5 ion channels, comprising administering to a patient in need thereof a composition comprising the compound of claim 1 in an amount effective to treat said condition.

9. The method of claim 8, wherein said condition is selected from the group consisting of epilepsy, anxiety, depression, age-related memory loss, migraine, obesity, Parkinson's disease or Alzheimer's disease.

10. The method of claim 8, wherein said condition is selected from the group consisting of atrial fibrillation, arrhythmia, myocardial ischemia, and ventricular fibrillation.

11. [4-(2-Methyl-butyl)-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

12. (4-Furan-2-ylmethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

13. (4-Cyclopentyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

14. (4-Phenyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5-hydroxymethyl-furan- 2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

15. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin- 3-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

16. [5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid (5- hydroxymethyl-furan-2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

17. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin-3-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

18. (5-Benzo[l _J3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (4- methoxy-pyridin-2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

19. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- methoxy-pyridin-3-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

20. (E)-2-(4-((Tetrahydrofuran-2-yl)methyl)-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan- 2-yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

21. (E)-2^(4-Cyclohexyl-5-(4-(dimethylamino)phenyl)-4H-l,2,4-triazol-3-ylthio)-N'- ((furan-2-yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

22. (E)-2-(5-((Benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2_s4-triazol-3-ylthio)-N¹- benzylideneacetohydrazide, or a pharmaceutically acceptable salt thereof.

23. (E)-2-(5-(furan-2-yl)-4-phenyl-4H-l,2₅4-triazol-3-ylthio)-N'-((furan-3-yl)methylene) acetohydrazide, or a pharmaceutically acceptable salt thereof.

24. (E)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((pyrimidin- 5-yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

25. (E)-N'-(2-Cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H-l,2,4- triazol-3-ylthio)acetohydrazide, or a pharmaceutically acceptable salt thereof.

26. (E)-N'-(4-cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H-l,2,4- triazol-3-ylthio)acetohydrazide, or a pharmaceutically acceptable salt thereof.

27. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5- dimethylaminomethyl-furan-2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

28. (4-Cyclopropyl-5-/»-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

29. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (l-furan-2-yl-2- methyl-propylidine)-hydrazide, or a pharmaceutically acceptable salt thereof.

30. (4-CycIohexyl-5-thiophene-2-yl-4H-[l,2,4]triazol-3-ylsuIfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

31. (4-Benzo[l,3]dioxol-5-yl-5-/7-tolyl-4H-[l,2,4]triazol-3ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a phaπnaceutically acceptable salt thereof.

32. (5-Benzo[l,3]dioxol-5-yl-4-cycloheptyl-4H-[l,2,4]triazole-3-ylsulfanyl)acetic acid furan-2-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

33. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazole-3-ylsulfanyl)acetic acid thiazol- 2-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

34. (E)-2-(4-Cyclopentyl-5-p-tolyl-4Η-l ,2,4-triazol-3-ylthio)-N'-((l -methyl- lH-pyrrol-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

35. 2-(5-(3,4-Dimethoxybenzyl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

36. (E)-2-(5-Benzyl-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

37. (E)-2-(5-(benzo[d][l,3]dioxol-5-yl)-4-phenyl-4H-l₅2,4-triazol-3-ylthio)-N'-((pyridin-4- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

38. (E)-2-(5-(benzo[d][l,3]dioxol-5-yl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'-((pyridin-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

39. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid pyridin-2-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

40. (E)-N'-(3-Cyanobenzylidene)-2-(5-(benzo[d][l,3]dioxol-6-yl)-4-phenyl-4H-l₅2,4- triazol-3-ylthio)acetohydrazide, or a pharmaceutically acceptable salt thereof.

41. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (IH- pyrrol-2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

42. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (6- cyano-pyridin-2-ylmethylene)-hydrazide₅ or a pharmaceutically acceptable salt thereof.

43. (5-Benzo[l,3]dioxol-5-yl-4-cyclohexyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

44. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

45. (5-Benzo[l,3]dioxol-5-yl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (4- dimethylamino-benzylidene)-hydrazide, or a pharmaceutically acceptable salt thereof.

46. 5-Cyclohexyl-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene- hydrazide, or a pharmaceutically acceptable salt thereof.

47. (4-Cyclohexyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetic acid (5-hydroxymethyl- furan-2-ylmethylene)-hydrazide, or a pharmaceutically acceptable salt thereof.

48. [5-(4-Hydroxymethyl-phenyl)-4-phenyl-4H-[l,2,4]triazol-3-ylsulfanyl]-acetic acid furan-2-ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

49. (4-Isobutyl-5 -p-tolyl-4H[ 1 ,2,4]triazol-3 -ylsulfanyl)-acetic acid furan-2-ylmethylene- hydrazide, or a pharmaceutically acceptable salt thereof.

50. (4-Isobutyl-5-p-tolyl-4H[l,2,4]triazol-3-ylsulfanyl)-acetic acid furan-2-ylmethylene- hydrazide, or a pharmaceutically acceptable salt thereof.

51. [5-(4-Ηydroxy-phenyl)-4-phenyl-4Η-[l,2,4]triazol-3-ylsulfanyl]-acetic acid furan-2- ylmethylene-hydrazide, or a pharmaceutically acceptable salt thereof.

52. l-[3-(3-Methoxy-phenyl)-5,6-dihydro-4H-pyridazin-l-yl]-2-(4-phenyl-5-p-tolyl-4H- [l,2,4]triazol-3-ylsulfanyl)ethanone, or a pharmaceutically acceptable salt thereof.

53. 2-(4-Phenyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N-(benzyloxy)acetamide, or a pharmaceutically acceptable salt thereof.

54. (E)-2-(4-Cyclohexyl-5-p-tolyl-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2-yl)methylene)-2- methylpropanebydrazide, or a pharmaceutically acceptable salt thereof.

55. (E)-2-(4-Cyclohexyl-5-(4-fluorophenyl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

56. (E)-2-(5-Phenyl-4-(pyridin-3-yl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2-yl)methylene) acetohydrazide, or a pharmaceutically acceptable salt thereof.

57. (E)-2-(5-(Furan-2-yl)-4-(phenyl)-4H-l,2,4-triazol-3-ylthio)-N'-((furan-2- yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.

58. (E)-2-(5-((Benzo[d][l,3]dioxol-5-yl)methyl)-4-phenyl-4H-l,2,4-triazol-3-ylthio)-N'- ((furan-2-yl)methylene)acetohydrazide, or a pharmaceutically acceptable salt thereof.