US20170202849A1 - Antiparasitic compounds - Google Patents

Antiparasitic compounds Download PDF

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Publication number
US20170202849A1
US20170202849A1 US15/477,343 US201715477343A US2017202849A1 US 20170202849 A1 US20170202849 A1 US 20170202849A1 US 201715477343 A US201715477343 A US 201715477343A US 2017202849 A1 US2017202849 A1 US 2017202849A1
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Prior art keywords
pyridyl
thiadiazol
benzamide
trifluoromethyl
fluoro
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US15/477,343
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Hao Liu
Jessica Marie SLIGAR
Jason Daniel Speake
Joseph A. Moore, III
Brent Christopher Beck
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Avista Pharma Solutions Inc
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Avista Pharma Solutions Inc
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Assigned to ROYAL BANK OF CANADA, AS COLLATERAL AGENT reassignment ROYAL BANK OF CANADA, AS COLLATERAL AGENT FIRST LIEN PATENT SECURITY AGREEMENT Assignors: AVISTA PHARMA SOLUTIONS, INC., CAMBREX CHARLES CITY, INC.
Assigned to AVISTA PHARMA SOLUTIONS, INC. reassignment AVISTA PHARMA SOLUTIONS, INC. RELEASE OF SECOND LIEN SECURITY INTEREST IN PATENTS Assignors: ROYAL BANK OF CANADA, AS COLLATERAL AGENT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 1,2,4-thiadiazole derivatives Disclosed herein are 1,2,4-thiadiazole derivatives, compositions comprising them, processes for their preparation, intermediates useful in their synthesis, and their use as antiparasitic agents.
  • the compounds of the invention are useful in the treatment or prevention of parasitic helminth infection.
  • Parasitic helminths can cause many diseases and conditions of medical, veterinary, and agricultural importance. They can infect humans and other mammals, particularly companion animals such as dogs and cats as well as animals of agricultural importance such as sheep, cattle, horses, goats, fish, pigs, and poultry, causing many pathological effects and symptoms.
  • EP 455356 describes the preparation of 5-amino-1,2,4-thiadiazoles useful as immunosuppressants.
  • International Patent Publication No. WO 2006/033005 discloses the preparation of oxazolyl, thiazolyl or thiadiazolyl pyrimidinylamino benzamide derivatives as thrombopoietin receptor agonists.
  • WO2007/037543 discloses the preparation of biarylamide derivatives as inhibitors of metabotropic glutamate receptor 1 (mGluR1).
  • mGluR1 metabotropic glutamate receptor 1
  • WO2002/100826 discloses the preparation of 3,5-diaryl-1,2,4-oxadiazoles and analogs useful as activators of caspases and inducers of apoptosis.
  • WO1993/19054 discloses certain N-heterocyclic nitro anilines as fungicides, and refers to the use of these compounds to treat nematodes.
  • substituents R 1 , R 2 , R 3 , R 4 and R 5 can contribute to optical and/or stereoisomerism. All such forms are encompassed by exemplary embodiments described herein.
  • compositions comprising a compound of formula (I) along with a pesticidally acceptable excipient, carrier or diluent.
  • the compositions of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
  • the formulations are intended to be administered to an animal which includes but is not limited to mammals, birds and fish. Examples of mammals include but are not limited to humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or domestic birds.
  • compositions comprising a compound of formula (I) suitable for treatment of a locus that may be infected with parasites, such as a plant or animal, or for the prevention of infection of a locus with parasites.
  • a combination therapy whereby the compounds of formula (I) can be employed as such or in the form of their preparations (formulations) as combinations with other pesticidally active substances, such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators.
  • pesticidally active substances such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators.
  • the combinations may be part of the same formulation, or may be administered separately or sequentially to the locus.
  • a compound of formula (I), or a composition comprising a compound of formula (I), for use in treating or preventing parasitic infection is provided herein.
  • a compound of formula (I) for the manufacture of a medicament for use in treating or preventing parasitic infection.
  • a method of treating or preventing a parasitic infection comprising the administration of an effective amount of a compound of formula (I), or a composition comprising a compound of formula (I) to a locus.
  • any one or more aspects or features described with respect to one embodiment may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim although not originally claimed in that manner.
  • Alkoxy where described in a substituent (e.g. ‘alkoxy’, ‘haloalkoxy’) refers to the group —OR where R is alkyl. This term is illustrated by the groups methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy, cyclopentyloxy, cyclohexyloxy, 4-pyranyloxy.
  • Alkyl where described in a substituent (e.g. ‘alkyl’, ‘haloalkyl’, ‘thioalkyl’) refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably up to 6 (e.g. 1-6) carbon atoms.
  • the hydrocarbon chain can be either straight-chained or branched. This term is illustrated by the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl, cyclohexyl, cyclobutyl, cyclopentyl.
  • Halogen or “halo” where described in a substituent refers to a halogen, preferably Br, Cl or F.
  • Heterocyclyl refers to a saturated or unsaturated ring containing from 4 to 6 ring atoms and from 1 to 4 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulphur, such as pyridyl, morpholino, piperidinyl, piperizinyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl.
  • Aryl where described in a substituent (e.g. ‘aryl’, ‘aryloxy’) refers to a substituted or unsubstituted aromatic ring system of from 5 to 10 atoms, such as phenyl, naphthyl, 4-trifluoromethylphenyl.
  • a “saturated or unsaturated ring containing from 4 to 6 ring atoms” refers to a ring containing only carbon atoms, or a heterocyclic ring containing carbon atoms and non-carbon atoms (e.g. N).
  • “Pesticidally acceptable salt” refers to any salt of a compound disclosed herein which retains its biological properties and which is not toxic or otherwise undesirable for pesticidal use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art.
  • Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesul
  • Salts further include, by way of example only salts of non-toxic organic or inorganic acids, such as halides, e.g., chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate),
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966 , Angew. Chem. 78: 413-447 , Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int.
  • the compounds disclosed herein can possess one or more asymmetric centers; such compounds can therefore be produced as the individual (R)- or (S)-enantiomer or as a mixture thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • Methods for determination of stereochemistry and separation of stereoisomers are well-known in the art.
  • stereoisomers of the compounds provided herein are depicted upon treatment with base.
  • the compounds disclosed herein are “stereochemically pure”.
  • a stereochemically pure compound has a level of stereochemical purity that would be recognized as “pure” by those of skill in the art. Of course, this level of purity will be less than about 100%.
  • “stereochemically pure” designates a compound that is substantially free, i.e. at least about 85% or more, of alternate isomers.
  • the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free of other isomers.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the terms “subject” and “subjects” refer to a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human) or non-primate animal.
  • the subject is a human.
  • the subject is a companion animal such as a dog or cat.
  • the subject is an animal of agricultural importance such as a sheep, cow, horse, goat, fish, pig, or domestic fowl (such as a chicken, turkey, duck or goose).
  • A is C ⁇ O. In another embodiment, A is SO 2 .
  • X is —NHR 1 . In a further embodiment, X is R 1 .
  • R 1 is phenyl optionally substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, —SO 2 CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 and —NHSO 2 CH 3 .
  • R 1 is phenyl substituted by from 1 to 3 substituents which are the same or different selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy; or R 1 is naphthyl optionally substituted by from 1 to 3 substituents which are the same or different selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy.
  • R 2 is hydrogen or halogen. In yet a further embodiment R 2 is hydrogen.
  • A, X, R 1 and R 2 can be independently selected with respect to the A, X, R 1 , R 2 , R 3 , R 4 and R 5 substituents, respectively.
  • the compounds of formula (I) provided herein are selected from the following compounds (“Cpd” means Compound) of Table 1:
  • the compounds of formula (I) can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below.
  • R 1 and A are as defined above and X 1 is a leaving group.
  • the reaction is generally carried out in an aprotic solvent (e.g. tetrahydrofuran) at a temperature from about 0 to about 100° C.
  • aprotic solvent e.g. tetrahydrofuran
  • X 1 is a halogen, such as chlorine.
  • compounds of formula (I) in which A is C ⁇ O and X is NHR 1 can be prepared by the reaction of a compound of formula (II) as defined above, with a compound of formula O ⁇ C ⁇ NR 1 , wherein R 1 is as defined above.
  • the reaction is generally carried out in an aprotic solvent (e.g. tetrahydrofuran) at a temperature from about 0 to about 100° C.
  • compounds of formula (I) in which A is SO 2 and X is NHR 1 can be prepared by the reaction of a compound of formula (I) with a compound of formula X 1 SO 2 NHR 1 , wherein X 1 and R 1 are as defined above.
  • the compounds of formula (I) used in the methods disclosed herein can be administered in certain embodiments using pesticidal compositions including at least one compound of general formula (I), if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pesticidally acceptable carriers, such as diluents or adjuvants, or with another agent.
  • pesticidal compositions including at least one compound of general formula (I), if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pesticidally acceptable carriers, such as diluents or adjuvants, or with another agent.
  • compositions which comprise a thiadiazole derivative of formula (I) or a salt thereof, and an acceptable excipient, carrier or diluent.
  • the composition can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
  • compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets can contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use can be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin.
  • Capsules can also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • compositions can also be in the form of oil-in-water or water-in-oil emulsions.
  • the oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions can also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.
  • the composition is in the form of a microemulsion.
  • Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.
  • Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase.
  • the size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions).
  • the interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
  • the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds.
  • the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C 8 -C 10 caprylic/capric triglyceride.
  • the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
  • the aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof.
  • the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
  • Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C 8 -C 10 glycerides or polyglyceryl-6 diolcate.
  • the cosurfactants include short-chain alcohols, such as ethanol and propanol.
  • the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents can be added to provide a palatable oral preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
  • Aqueous suspensions can contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, poly
  • the aqueous suspensions can also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
  • preservatives for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
  • compositions can be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols can also be used.
  • Preservatives, such as phenol or benzyl alcohol, can be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels or pastes.
  • Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
  • acetyltributyl citrate fatty acid esters such as the dimethyl ester, di
  • plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.
  • mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.
  • Dosage forms can contain from about 0.5 mg to about 5 g of an active agent.
  • the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume.
  • the compounds of formula (I) can be employed as such or in the form of their preparations (formulations) as combinations with other pesticidally active substances, such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators.
  • pesticidally active substances such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators.
  • the compounds of formula I according to the invention may be combined with one or more agents having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents.
  • repellents By combining the compounds of the formula I with other suitable parasiticides not only the parasiticidal activity can be enhanced but the greatest part of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance.
  • Preferred groups of combination partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of formula I. Suitable partners may also be afoxolaner, sarolaner, or fluralaner or a combination thereof. Any of the individually listed agents can be used in combination with compounds of formula (I) along with any other one or more listed agents independently.
  • Suitable partners in the mixture may be biocides, e.g. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broadband insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers.
  • suitable insecticides and acaricides are shown in the following table:
  • the pharmaceutical preparation comprising the thiadiazole derivatives, for delivery to a human or other mammal is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component.
  • the unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet or lozenge itself, or it can be an appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation can be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the method of treatment are administered at an initial dosage of about 0.1 mg/kg to about 100 mg/kg per interval.
  • Preferred intervals may be daily, weekly, monthly, quarterly, semi-annually, or annually.
  • the dosages can be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound being used. Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner.
  • the treatment will be initiated with smaller dosages which are less than the optimum dose of the compound, which can be increased in small increments until the optimum effect under the particular circumstances of the infection is reached.
  • the total daily dosage can be divided and administered in portions during the day if desired.
  • a method of treating or preventing parasite infection in a subject comprising administering to the subject an effective amount of thiadiazole derivative of formula (I) or a pesticidally acceptable salt thereof.
  • a thiadiazole derivative of formula (I) or a pesticidally acceptable salt thereof for treating or preventing parasite infection in a subject.
  • the compounds of formula (I) are useful for the treatment or prophylaxis of parasitic helminth infections caused by nematodes, trematodes or cestodes, particularly in humans, companion animals, and veterinary animals, particularly dogs, cats, and agricultural livestock including cattle, sheep, goats, fish, pigs, equine and poultry.
  • diseases include ascariasis, filariasis, loaiasis, onchocerciasis, schistosomiasis, trichinelliasis and hydatid disease.
  • the compounds of the invention are especially useful for the prophylaxis and/or treatment of lymphatic filariasis, subcutaneous filariasis, serous cavity filariasis, onchocerciasis (river blindness), elephantiasis, heartworm (dogs and cats), Verminous haemorrhagic dermatitis (cattle) and ‘Summer bleeding’ (horses).
  • Examples of parasitic nematodes include, but are not limited to, Ostertagia lyrata, 0 . ostertagi, 0 . circumcincta, Cooperia oncophora, C. pectinata. C. punctata, C. surnabada, C. curticea, Haemonchus contortus, H. placei, Trichostrongylus axei, T. colubriformis, T. vetrinus, Bunostomum phlebotomum, B. trigonocephalum, Oesophagostomum radiatum, O. dentatum, O. venulosum, O.
  • duodenale Thelazia spp., Uncinaria stenocephala, Chaberia ovina, Ascaris lumbricoides, Dictyocaulus vivaparus, D. arnfieldi, D. filaria, Brugia malayi, B. timori, Dioctophymna renare, Enterobius vermicularis, Loa loa, Mansonella ozzardi, M. perstans, M. streptocerca, Necator americanus, Onchocerca volvulus, Stronglyloides stercoralis, Trichinella spiralis, T. triciura and Wuchereria bancrofti.
  • plant-damaging nematodes include, but are not limited to, the following genera: Meloidogyne, Heterodera, Ditylenchus, Aphelenchoides, Radopholus, Globodera, Pratylenchus, Longidorus and Xiphenema.
  • parasitic cestodes include, but are not limited to: Diphyllobothrium latum, D. caninum, Echinococcus granulosus, E. multilocularis, Hymenolepsis diminuta, Taenia multiceps, T. saginatus, T. serialis, T. sohum and Vampirolepis nana.
  • parasitic trematodes include, but are not limited to Clonorchis sinensis, Dicrocoelium dendriticum, an echinostome, Fasciolopsis buski, Fasciola hepatica, a heterophyid, Nanophyetus salmincola, Opisthorchis felineus, 0 . viverrini, Paragonimus kellicotti, P. westermani, Schistosoma haematobium, S. japonicum, S. mansoni, S. intercalatum and S. mekongi.
  • 2-morpholinoethanol (67 ⁇ L, 0.52 mmol) was dissolved in anhydrous DMF (1 mL) to which solution was added sodium hydride (20 mg, 60 wt % in mineral oil, 0.46 mmol). Gas evolution.
  • the mixture was stirred at 50° C. for 1 h before a solution of N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (50 mg, 0.10 mmol, in 1 mL of anhydrous DMF) was added. The mixture was then stirred at 50° C. overnight.
  • LCMS Liquid chromatography-mass spectrometry
  • An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC system with a diode array detector was used.
  • the spectrometer had an electrospray source operating in positive and negative ion mode.
  • LC was carried out using an Agilent ZORBAX XDB 50 ⁇ 2.1 mm C18 column and a 0.5 mL/minute flow rate.
  • Solvent A 95% water, 5% acetonitrile containing 0.01% formic acid;
  • Solvent B acetonitrile. The gradient was shown as below.
  • the compounds of formula (I) were tested for activity against Dirofilaria immitis.
  • Dirofilaria immitis microfilariae are isolated by filtration from blood of an infected beagle dog allowed to incubate at 37 C/5% CO 2 /95% RH in RPMI media.
  • For assay 500 microfilariae are added into 96-well plates followed by addition of compounds diluted in DMSO for single-point or dose response (5-point) analysis.
  • Ivermectin or emodepside are included as a positive control and DMSO-only wells are included as negative controls. Plates containing parasites and compounds are incubated at 37° C./5% CO 2 /95% RH for 72 hours and motility is assessed using an LCD camera imaging system. Percent motility inhibition values are generated relative to the average of the DMSO-only wells.
  • For dose response analysis data points were averaged and curve fitting software is used to generate sigmoidal curves for the determination of EC 50 values (i.e. the effective concentration to kill 50% of the organism).
  • D. immitis L3 larvae of D. immitis are isolated from infected mosquitoes and allowed to moult into L4 stages in culture. Approximately 5-10 D. immitis L4 stage parasites are added to 96-well plates containing RPMI media and incubated at 37 C/5% CO 2 /95% RH.
  • the compounds of the invention are diluted in dimethyl sulfoxide (DMSO) and added at a single dose to identify those that affect parasite motility upon microscopic inspection or automated imaging after 72 hours of incubation. Compounds with activity at that concentration are progressed to a five-point dose titration assay and evaluated by microscopic examination or automated imaging of the wells after incubation for 72 hours.
  • DMSO dimethyl sulfoxide
  • Efficacy is based on reduction in motility of the treated L4 larvae as compared to the positive (ivermectin or emodepside) and negative (DMSO) controls. Compounds are evaluated in duplicate and efficacy is reported as the lowest dose that gives 100% inhibition of parasite motility (MIC100) is reported for microscopy assays. For automated imaging assays, percent motility inhibition values are generated relative to the average of the DMSO-only wells and EC 90 or EC 50 values are generated using curve fitting software.
  • L929 fibroblasts are seeded at 2,000 cells/well and exposed to 2-fold dilutions of test compounds directly parallel to the assay for parasitic activity. Plates with parasites or L929 cells are incubated with compounds under appropriate conditions for each cell type. Tamoxifen and taxol are included as a positive control and DMSO-only wells are included as negative controls. After 72 hours of incubation, resazurin (20 ⁇ L of 12.5 mg/mL stock in phosphate buffered saline) was added to each well and plates are incubated for an additional 4-6 h.
  • the compounds of the invention demonstrated activity against D. immitis microfilariae or D. immitis L4 stage.
  • the following compounds were determined to have EC 50 values less than 5 ⁇ M: Compounds 1-47, 49-65, 67, 70, 72, 74-77, 79, 89, 91-94, 96-106, 11-14, 116, 118, 119, 121-129, 131-141, 143, 145-147.

Abstract

The invention relates to 1,2,4-thiadiazole derivatives and their use to treat parasites.

Description

    FIELD
  • Disclosed herein are 1,2,4-thiadiazole derivatives, compositions comprising them, processes for their preparation, intermediates useful in their synthesis, and their use as antiparasitic agents. In particular, the compounds of the invention are useful in the treatment or prevention of parasitic helminth infection.
    • BACKGROUND
  • There is an on-going need for new treatments for parasitic helminthic infection. Parasitic helminths (nematodes, trematodes, and cestodes) can cause many diseases and conditions of medical, veterinary, and agricultural importance. They can infect humans and other mammals, particularly companion animals such as dogs and cats as well as animals of agricultural importance such as sheep, cattle, horses, goats, fish, pigs, and poultry, causing many pathological effects and symptoms. These include, but are not limited to, malnutrition, weight loss, weakness, severe damage to tissues and organs of the infected host, elephantiasis, delayed intellectual development and other neurological effects, abdominal pain, anemia, stunting, insomnia, vomiting, diarrhoea, dermatitis, conjunctivitis, lymphangitis, meningitis, myocarditis, edema, asthma, and many others. These infections can be very debilitating and even fatal if left untreated. Parasitic nematodes can also infect plants, causing severe structural damage to roots, stems, leaves, and flowers, as well as opening a path for further infection by bacteria, fungi, and other nematodes, leading to crop damage and loss.
  • EP 455356 describes the preparation of 5-amino-1,2,4-thiadiazoles useful as immunosuppressants. International Patent Publication No. WO 2006/033005 discloses the preparation of oxazolyl, thiazolyl or thiadiazolyl pyrimidinylamino benzamide derivatives as thrombopoietin receptor agonists. WO2007/037543 discloses the preparation of biarylamide derivatives as inhibitors of metabotropic glutamate receptor 1 (mGluR1). WO2002/100826 discloses the preparation of 3,5-diaryl-1,2,4-oxadiazoles and analogs useful as activators of caspases and inducers of apoptosis. Journal of Medicinal Chemistry (2001), Vol. 44(5), 749-762 discloses thiazole and thiadiazole analogs as a novel class of adenosine receptor antagonists. Bioorganic & Medicinal Chemistry 21 (2013) 6385-6397 discloses structure-activity relationships of 2-aminothiazoles effective against mycobacterium tuberculosis.
  • International Patent Publication No. WO1993/19054 discloses certain N-heterocyclic nitro anilines as fungicides, and refers to the use of these compounds to treat nematodes.
    • SUMMARY
  • In one aspect, provided herein are compounds of the formula (I):
  • Figure US20170202849A1-20170720-C00001
      • wherein:
      • A is C═O or SO2;
      • X is R1 or NHR1;
      • R1 is:
        phenyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen; naphthyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, -alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
        quinoxolinyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
        quinolyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, —CONHC6H5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen; or thionyl or furyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
      • R2 is hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, aryl, heterocyclyl or —CONR3R4; or R2, together with two adjacent carbon atoms of the pyridyl ring to which it is attached, forms a saturated or unsaturated ring containing from 4 to 6 ring atoms;
      • R3 and R4, which are the same or different, each represent hydrogen or alkyl; or when R3 and R4 are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms;
      • R5 is alkyl, haloalkyl;
        or a pesticidally acceptable salt thereof.
  • In certain cases, the substituents R1, R2, R3, R4 and R5 can contribute to optical and/or stereoisomerism. All such forms are encompassed by exemplary embodiments described herein.
  • In another aspect of the invention, provided are compositions comprising a compound of formula (I) along with a pesticidally acceptable excipient, carrier or diluent. The compositions of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations. The formulations are intended to be administered to an animal which includes but is not limited to mammals, birds and fish. Examples of mammals include but are not limited to humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or domestic birds.
  • Also provided are compositions comprising a compound of formula (I) suitable for treatment of a locus that may be infected with parasites, such as a plant or animal, or for the prevention of infection of a locus with parasites.
  • In still another aspect of the present invention, there is provided a combination therapy whereby the compounds of formula (I) can be employed as such or in the form of their preparations (formulations) as combinations with other pesticidally active substances, such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators. The combinations may be part of the same formulation, or may be administered separately or sequentially to the locus.
  • In still another aspect, provided herein is a compound of formula (I), or a composition comprising a compound of formula (I), for use in treating or preventing parasitic infection.
  • In still another aspect, provided herein is the use of a compound of formula (I) for the manufacture of a medicament for use in treating or preventing parasitic infection.
  • In still another aspect, provided herein is a method of treating or preventing a parasitic infection comprising the administration of an effective amount of a compound of formula (I), or a composition comprising a compound of formula (I) to a locus.
    • DETAILED DESCRIPTION
  • It is noted that any one or more aspects or features described with respect to one embodiment may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim although not originally claimed in that manner. These and other objects and/or aspects of the present invention are explained in detail in the specification set forth below.
    • Definitions
  • When referring to the compounds and complexes disclosed herein, the following terms have the following meanings unless indicated otherwise.
  • “Alkoxy” where described in a substituent (e.g. ‘alkoxy’, ‘haloalkoxy’) refers to the group —OR where R is alkyl. This term is illustrated by the groups methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy, cyclopentyloxy, cyclohexyloxy, 4-pyranyloxy.
  • “Alkyl” where described in a substituent (e.g. ‘alkyl’, ‘haloalkyl’, ‘thioalkyl’) refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably up to 6 (e.g. 1-6) carbon atoms. The hydrocarbon chain can be either straight-chained or branched. This term is illustrated by the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl, cyclohexyl, cyclobutyl, cyclopentyl.
  • “Halogen” or “halo” where described in a substituent refers to a halogen, preferably Br, Cl or F.
  • “Heterocyclyl” refers to a saturated or unsaturated ring containing from 4 to 6 ring atoms and from 1 to 4 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulphur, such as pyridyl, morpholino, piperidinyl, piperizinyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl.
  • “Aryl” where described in a substituent (e.g. ‘aryl’, ‘aryloxy’) refers to a substituted or unsubstituted aromatic ring system of from 5 to 10 atoms, such as phenyl, naphthyl, 4-trifluoromethylphenyl.
  • A “saturated or unsaturated ring containing from 4 to 6 ring atoms” refers to a ring containing only carbon atoms, or a heterocyclic ring containing carbon atoms and non-carbon atoms (e.g. N).
  • “Pesticidally acceptable salt” refers to any salt of a compound disclosed herein which retains its biological properties and which is not toxic or otherwise undesirable for pesticidal use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and like acids.
  • Salts further include, by way of example only salts of non-toxic organic or inorganic acids, such as halides, e.g., chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like.
  • It is to be understood that compounds having the same molecular formula but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: 657-668) or can be characterized by the manner in which the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (i.e., as (+)- or (−)-isomers, respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture”.
  • In certain embodiments, the compounds disclosed herein can possess one or more asymmetric centers; such compounds can therefore be produced as the individual (R)- or (S)-enantiomer or as a mixture thereof. Unless indicated otherwise, for example by designation of stereochemistry at any position of a formula, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Methods for determination of stereochemistry and separation of stereoisomers are well-known in the art. In particular embodiments, stereoisomers of the compounds provided herein are depicted upon treatment with base.
  • In certain embodiments, the compounds disclosed herein are “stereochemically pure”. A stereochemically pure compound has a level of stereochemical purity that would be recognized as “pure” by those of skill in the art. Of course, this level of purity will be less than about 100%. In certain embodiments, “stereochemically pure” designates a compound that is substantially free, i.e. at least about 85% or more, of alternate isomers. In particular embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free of other isomers.
  • As used herein, the terms “subject” and “patient” are used interchangeably herein. The terms “subject” and “subjects” refer to a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human) or non-primate animal. In one embodiment, the subject is a human. In another embodiment, the subject is a companion animal such as a dog or cat. In a further embodiment the subject is an animal of agricultural importance such as a sheep, cow, horse, goat, fish, pig, or domestic fowl (such as a chicken, turkey, duck or goose).
    • Compounds
  • In one embodiment there are provided compounds of formula (I) wherein:
      • A is C═O or SO2;
      • X is R1 or NHR1;
      • R1 is:
        phenyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
        naphthyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, -alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
        quinoxolinyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
        quinolyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, —CONHC6H5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
      • R2 is hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; or R2, together with two adjacent carbon atoms of the pyridyl ring to which it is attached, forms a saturated or unsaturated ring containing from 4 to 6 ring atoms;
      • R3 and R4, which are the same or different, each represent hydrogen or alkyl;
      • and R5 is alkyl.
  • In one embodiment, A is C═O. In another embodiment, A is SO2.
  • In one embodiment X is —NHR1. In a further embodiment, X is R1.
  • In another embodiment, R1 is phenyl optionally substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, —SO2CH3, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2 and —NHSO2CH3.
  • In a further embodiment, R1 is phenyl substituted by from 1 to 3 substituents which are the same or different selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy; or R1 is naphthyl optionally substituted by from 1 to 3 substituents which are the same or different selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy.
  • In a further embodiment R2 is hydrogen or halogen. In yet a further embodiment R2 is hydrogen.
  • In each of the embodiments discussed above, A, X, R1 and R2 can be independently selected with respect to the A, X, R1, R2, R3, R4 and R5 substituents, respectively.
  • In yet a further embodiment, there are provided compounds of formula (I) in which:
      • A is C═O;
      • X is NHR1;
      • R1 is phenyl optionally substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen (e.g. chloro or fluoro), cyano, methyl, ethyl, methoxy, ethoxy, thiomethyl, —SO2CH3, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2 and —NHSO2CH3; and
      • R2 is hydrogen, fluoro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
  • In yet a further embodiment, there are provided compounds of formula (I) in which:
      • A is C═O;
      • X is R1;
      • R1 is phenyl substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, aryloxy, thiomethyl, —SO2CH3, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2 and —NHSO2CH3; and
      • R2 is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl.
  • In yet a further embodiment, there are provided compounds of formula (I) in which:
      • A is SO2;
      • X is R1;
      • R1 is phenyl substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, thiomethyl, methanesulfonyl, sulfonamide, methylsulfonamide, dimethylsulfonamide, and methylsulfonanilide; and
      • R2 is hydrogen.
  • In yet a further embodiment there are provided compounds of formula (I) wherein:
      • A is C═O or SO2;
      • X is R1 or NHR1;
      • R1 is:
        phenyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, alkoxy, aryl, heterocyclyl, aryloxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
      • R2 is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl.
  • In one embodiment, the compounds of formula (I) provided herein are selected from the following compounds (“Cpd” means Compound) of Table 1:
  • TABLE 1
    Cpd Name
    1 1-(4-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea
    2 1-(2-chlorophenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea
    3 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-
    (trifluoromethyl)phenyl]urea
    4 1-(3-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea
    5 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-
    (trifluoromethoxy)phenyl]urea
    6 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[3-
    (trifluoromethyl)phenyl]urea
    7 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    8 3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    9 4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    10 3-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    11 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    12 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]naphthalene-2-carboxamide
    13 4-trifluoromethoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    14 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzenesulfonamide
    15 2-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzenesulfonamide
    16 4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzenesulfonamide
    17 4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzenesulfonamide
    18 2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzenesulfonamide
    19 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-
    (trifluoromethyl)benzenesulfonamide
    20 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzenesulfonamide
    21 N-[3-(3-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    22 N-[3-(4-morpholino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    23 N-[3-[4-[benzyl(methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    24 N-[3-[4-(dimethylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    25 N-[3-[4-[2-methoxyethyl(methyl)amino]-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    26 N-[3-(5-methoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    27 N-[3-(4-methoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    28 N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    29 N-[3-(5-bromo-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    30 methyl 2-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-
    3-yl]pyridine-4-carboxylate
    31 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]isoquinoline-7-carboxamide
    32 4-acetamido-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    33 4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    34 4-nitro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    35 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]quinoxaline-6-carboxamide
    36 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-2-carboxamide
    37 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-3-carboxamide
    38 N-[3-(4-isopropyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    39 N-[3-(3-isoquinolyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    40 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    41 N-[3-(5-methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    42 3-chloro-4-fluoro-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    43 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethoxy)benzamide
    44 4-tert-butyl-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    45 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-3,5-
    bis(trifluoromethyl)benzamide
    46 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-
    (trifluoromethyl)benzamide
    47 3,4-dichloro-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    48 3-methylsulfonyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    49 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]isoquinoline-5-carboxamide
    50 3-chloro-4-(4-methylpiperazin-1-yl)-N-[3-(2-pyridyl)-1,2,4-
    thiadiazol-5-yl]benzamide
    51 methyl 4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoate
    52 4-(diethylsulfamoyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    53 4-methyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-2-
    carboxamide
    54 3-chloro-4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    55 2-fluoro-3-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    56 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-
    (trifluoromethyl)benzamide
    57 2,5-dimethyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]furan-3-
    carboxamide
    58 4-tert-butyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    59 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-1,3-benzodioxole-5-
    carboxamide
    60 3,4-dichloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    61 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3,5-
    bis(trifluoromethyl)benzamide
    62 4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    63 4-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    64 4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-
    (trifluoromethyl)benzamide
    65 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    66 4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoic acid
    67 4-iodo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    68 4-morpholino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    69 4-(morpholine-4-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    70 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]carbamoyl]benzoyl]piperazine-1-carboxylate
    71 tert-butyl 4-[[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]carbamoyl]benzoyl]amino]piperidine-1-carboxylate
    72 4-(piperidine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    73 4-(piperazine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    74 N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide
    75 4-(2-pyridylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    76 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]carbamoyl]anilino]piperidine-1-carboxylate
    77 4-phenyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    78 4-piperazin-1-yl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    79 4-(4-piperidylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    80 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]carbamoyl]phenyl]piperazine-1-carboxylate
    81 3-chloro-2-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-
    (trifluoromethyl)benzamide
    82 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(1,1,2,2-
    tetrafluoroethoxy)benzamide
    83 2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethoxy)benzamide
    84 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-(trifluoromethyl)furan-2-
    carboxamide
    85 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-
    (trifluoromethyl)thiophene-2-carboxamide
    86 4-formyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    87 4-[hydroxy(phenyl)methyl]-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    88 3-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    89 4-benzyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    90 N4-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide
    91 4-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    92 3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethoxy)benzamide
    93 N-[3-(4-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    94 4-(trifluoromethyl)-N-[3-[5-(trifluoromethyl)-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]benzamide
    95 N4-phenyl-N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide
    96 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-(trifluoromethyl)
    benzamide
    97 2-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethoxy) benzamide
    98 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-(trifluoromethoxy)
    benzamide
    99 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethoxy)
    benzamide
    100 4-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]
    benzamide
    101 3-hydroxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-
    (trifluoromethyl) thiophene-2-carboxamide
    102 4-(2,4-difluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    103 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-[4-
    (trifluoromethyl)phenoxy] benzamide
    104 N-(3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-
    (trifluoromethyl)phenoxy]benzamide
    105 3-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    106 3-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    107 N1-(4-piperidyl)-N4-[3-(2-pyridyl)-1,2,4-thiadiazol-5-
    yl]terephthalamide
    108 N-[3-(5-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    109 4-(4-piperidyloxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]pyridine-
    2-carboxamide
    110 N-[3-(6-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    111 4-(3-pyridyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl] benzamide
    112 N-[3-(5-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    113 4-(trifluoromethyl)-N-[3-(5-vinyl-2-pyridyl)-1,2,4-thiadiazol-5-
    yl]benzamide
    114 N-[3-[5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridyl]-1,2,4-thiadiazol-5-
    yl]-4-(trifluoromethyl)benzamide
    115 N-[3-(6-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    116 N-[3-[6-(3-pyridyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    117 4-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    118 4-(benzylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    119 3-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    120 N-[3-[5-(3-pyridylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    121 N-[3-(5-morpholino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    122 N-[3-[5-[2-methoxyethyl(methyl)amino]-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    123 N-[3-(5-pyrrolidin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    124 N-[3-[5-(2-pyridylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    125 N-[3-[5-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    126 tert-butyl 4-[6-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-
    thiadiazol-3-yl]-3-pyridyl]piperazine-1-carboxylate
    127 N-[3-[5-(1-piperidyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    128 N-[3-(5-anilino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    129 N-[3-[5-(4-hydroxy-1-piperidyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    130 N-[3-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    131 tert-butyl 4-[6-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-
    thiadiazol-3-yl]-2-pyridyl]piperazine-1-carboxylate
    132 N-[3-(4-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    133 N-[3-(6-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    134 N-[3-[4-(dimethylaminomethyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    135 N-[3-[4-[methyl-[2-(1-piperidyl)ethyl]amino]-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    136 N-[3-[4-[methyl(2-morpholinoethyl)amino]-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    137 N-[3-(4-pyrrolidin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    138 N-[3-[4-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    139 N-[3-[4-[2-hydroxyethyl(methyl)amino]-2-pyridyl]-1,2,4-
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    140 N-[3-[4-[2-(1-piperidyl)ethoxy]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    141 N-[3-[4-(2-methoxyethoxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    142 N-[3-[4-(2-dimethylaminoethyloxy)-2-pyridyl]-1,2,4-thiadiazol-5-
    yl]-4-(trifluoromethyl)benzamide
    143 N-[3-[4-(2,2-dimethylpropoxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    144 N-[3-[4-[(1-methyl-4-piperidyl)oxy]-2-pyridyl]-1,2,4-thiadiazol-5-
    yl]-4-(trifluoromethyl)benzamide
    145 N-[3-(4-tetrahydropyran-4-yloxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-
    4-(trifluoromethyl)benzamide
    146 N-[3-[4-(oxetan-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    147 N-[3-[4-(hydroxymethyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
  • The Compound numbers 1 to 147 are used to identify the above compounds hereafter.
  • The compounds of formula (I) can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below.
  • In general, compounds of formula (I) in which X is R1 can be prepared by the reaction of a compound of formula (II):
  • Figure US20170202849A1-20170720-C00002
  • wherein R2 is as defined above, with a compound of formula (III):

  • R1-A-X1   (III)
  • wherein R1 and A are as defined above and X1 is a leaving group. The reaction is generally carried out in an aprotic solvent (e.g. tetrahydrofuran) at a temperature from about 0 to about 100° C. In one embodiment, X1 is a halogen, such as chlorine.
  • In another aspect compounds of formula (I) in which A is C═O and X is NHR1 can be prepared by the reaction of a compound of formula (II) as defined above, with a compound of formula O═C═NR1, wherein R1 is as defined above. The reaction is generally carried out in an aprotic solvent (e.g. tetrahydrofuran) at a temperature from about 0 to about 100° C.
  • In another aspect compounds of formula (I) in which A is SO2 and X is NHR1 can be prepared by the reaction of a compound of formula (I) with a compound of formula X1SO2NHR1, wherein X1 and R1 are as defined above.
  • Compounds of formula (II) above are known in the literature or can be prepared by known methods; see for example European Patent No. 455356. Compound of formula (III) above are known in the literature or can be prepared by known methods.
    • Compositions and Methods of Administration
  • The compounds of formula (I) used in the methods disclosed herein can be administered in certain embodiments using pesticidal compositions including at least one compound of general formula (I), if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pesticidally acceptable carriers, such as diluents or adjuvants, or with another agent.
  • According to a further feature, there are provided compositions which comprise a thiadiazole derivative of formula (I) or a salt thereof, and an acceptable excipient, carrier or diluent. The composition can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
  • The composition can be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets can contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use can be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Capsules can also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • The compositions can also be in the form of oil-in-water or water-in-oil emulsions. The oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.
  • In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.
  • Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
  • In one embodiment of the oily phase, the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oily phase, the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C8-C10 caprylic/capric triglyceride. In another embodiment, the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
  • The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
  • Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 diolcate. In addition to these surfactants, the cosurfactants include short-chain alcohols, such as ethanol and propanol.
  • Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment for the amount of surfactant/cosurfactant, the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
  • Aqueous suspensions can contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring and coloring agents, can also be present.
  • Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
  • The compositions can be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols can also be used. Preservatives, such as phenol or benzyl alcohol, can be used.
  • In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
  • Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels or pastes.
  • Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
  • As vehicle or diluent, mention can be made of plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8-C12) triglycerides.
  • Dosage forms can contain from about 0.5 mg to about 5 g of an active agent.
  • In one embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume.
  • The compounds of formula (I) can be employed as such or in the form of their preparations (formulations) as combinations with other pesticidally active substances, such as, for example, insecticides, attractants, sterilants, nematicides, acaricides, fungicides, herbicides, and with safeners, fertilizers and/or growth regulators.
  • The compounds of formula I according to the invention may be combined with one or more agents having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents. By combining the compounds of the formula I with other suitable parasiticides not only the parasiticidal activity can be enhanced but the greatest part of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance. Preferred groups of combination partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of formula I. Suitable partners may also be afoxolaner, sarolaner, or fluralaner or a combination thereof. Any of the individually listed agents can be used in combination with compounds of formula (I) along with any other one or more listed agents independently.
  • Suitable partners in the mixture may be biocides, e.g. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broadband insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers. Non-limitative examples of suitable insecticides and acaricides are shown in the following table:
    • 1. Abamectin 96. Dioxathion 191. Omethoate
    • 2. Acephate 97. Disulfoton 192. Oxamyl
    • 3. Acequinocyl 98. DNOC 193. Oxydemethon M
    • 4. Acetamiprid 99. Doramectin 194. Oxydeprofos
    • 5. Acetoprole 100. DPX-HGW86 195. Parathion
    • 6. Acrinathrin 101. Edifenphos 196. Parathion-methyl
    • 7. AKD-1022 102. Emamectin 197. Permethrin
    • 8. Alanycarb 103. Empenthrin 198. Phenothrin
    • 9. Aldicarb 104. Endosulfan 199. Phenthoate
    • 10. Aldoxycarb 105. Esfenvalerat 200. Phorate
    • 11. Allethrin 106. Ethiofencarb 201. Phosalone
    • 12. Alpha-cypermenethrin 107. Ethion 202. Phosmet
    • 13. Alphamethrin 108. Ethiprole 203. Phosphamidon
    • 14. Amidoflumct 109. Ethoprophos 204. Phoxim
    • 15. Amitraz 110. Etofenprox 205. Pirimicarb
    • 16. Anabasine 111. Etoxazole 206. Pirimiphos A
    • 17. Avermectin B 112. Etrimphos 207. Pirimiphos M
    • 18. Azadirachtin 113. Fenamiphos 208. Polynactins
    • 19. Azamethiphos 114. Fenazaquin 209. Prallethrin
    • 20. Azinphos-ethyl 115. Fenbutatin oxid 210. Profenofos
    • 21. Azinphos-methyl 116. Fenitrothion 211. Profluthrin
    • 22. Azocyclotin 117. Fenobucarb 212. Promecarb
    • 23. Bacillus subtil, toxin 118. Fenothiocarb 213. Propafos
    • 24. Bacillus thuringiensis 119. Fenoxycarb 214. Propargite
    • 25. Benclothiaz 120. Fenpropathrin 215. Propoxur
    • 26. Bendiocarb 121. Fenpyroximate 216. Prothiofos
    • 27. Benfuracarb 122. Fenthion 217. Prothoate
    • 28. Bensultap 123. Fenvalerate 218. Protrifenbute
    • 29. Benzoximate 124. Fipronil 219. Pymetrozine
    • 30. Beta-cyfluthrin 125. Flonicamid 220. Pyrachlofos
    • 31. Beta-cypermethrin 126. Fluacrypyrim 221. Pyrafluprole
    • 32. Bifenazate 127. Fluazinam 222. Pyresmethrin
    • 33. Bifenthrin 128. Fluazuron 223. Pyrethrin
    • 34. Bioallethrin 129. Flubendiamide 224. Pyrethrum
    • 35. Bioresmethrin 130. Flucycloxuron 225. Pyridaben
    • 36. Bistrifluron 131. Flucythrinate 226. Pyridalyl
    • 37. BPMC 132. Flufenerim 227. Pyridaphenthion
    • 38. Brofenprox 133. Flufenoxuron 228. Pyrifluquinazon
    • 39. Bromophos A 134. Flufenprox 229. Pyrimidifen
    • 40. Bromopropylate 135. Flumethrin 230. Pyriprole
    • 41. Bufencarb 136. Fonophos 231. Pyriproxyfen
    • 42. Buprofezin 137. Formothion 232. Quinalphos
    • 43. Butocarboxim 138. Fosthiazate 233. Resmethrin
    • 44. Cadusafos 139. Fubfenprox 234. Rotenone
    • 45. Carbaryl 140. Furathiocarb 235. RU 15525
    • 46. Carbofuran 141. Gamma-cyhalothrin 236. Sabadilla
    • 47. Carbophenothion 142. Halfenprox 237. Salithion
    • 48. Carbosulfan 143. Halofenozide 238. Selamectin
    • 49. Cartap 144. HCH 239. Silafluofen
    • 50. Chloethocarb 145. Heptenophos 240. Spinetoram
    • 51. Chlorantraniliprole 146. Hexaflumuron 241. Spinosad
    • 52. Chlorethoxyfos 147. Hexythiazox 242. Spirodiclofen
    • 53. Chlorfenapyr 148. Hydramethylnon 243. Spiromesifen
    • 54. Chlorfenvinphos 149. Hydroprene 244. Spirotetramat
    • 55. Chlorfluazuron 150. Imidacloprid 245. Sulcofuron sodium
    • 56. Chlormephos 151. Imiprothrin 246. Sulfluramid
    • 57. Chlorpyrifos 152. Indoxacarb 247. Sulfotep
    • 58. Chlorpyrifos-methyl 153. insect-active fungi 248. Sulfur
    • 59. Chromafenozide 154. insect-active 249. Sulprofos nematodes
    • 60. Cis-Resmethrin 155. insect-active viruses 250. Tau-fluvalinate
    • 61. Clofentezin 156. Iprobenfos 251. Tebufenozide
    • 62. Clothianidin 157. Isofenphos 252. Tebufenpyrad
    • 63. Coumaphos 158. Isoprocarb 253. Tebupirimfos
    • 64. Cyanophos 159. Isoxathion 254. Teflubenzuron
    • 65. Cycloprothrin 160. Ivermectin 255. Tefluthrin
    • 66. Cyenopyrafen 161. Karanjin 256. Temephos
    • 67. Cyflumetofen 162. Kinoprene 257. Terbufos
    • 68. Cyfluthrin 163. Lamba-Cyhalothrin 258. Tetrachlorvinphos
    • 69. Cyhalothrin 164. Lepimectin 259. Tetradifon
    • 70. Cyhexatin 165. Lufenuron 260. Tetramethrin
    • 71. Cymiazole 166. Malathion 261. Thiacloprid
    • 72. Cypermethrin 167. Mecarbam 262. Thiamethoxam
    • 73. Cyphenothrin 168. Mesulfenphos 263. Thiocyclam
    • 74. Cyromazine 169. Metaflumizone 264. Thiodicarb
    • 75. Deltamethrin 170. Metaldehyde 265. Thiofanox
    • 76. Demeton M 171. Methamidophos 266. Thionazin
    • 77. Demeton S 172. Methidathion 267. Thiosultap
    • 78. Demeton-S-methyl 173. Methiocarb 268. Thuringiensin
    • 79. Diafenthiuron 174. Methomyl 269. Tolfenpyrad
    • 80. Diazinon 175. Methoprene 270. Tralomethrin
    • 81. Dichlofenthion 176. Methothrin 271. Transfluthrin
    • 82. Dichlorvos 177. Methoxyfenozide 272. Triarathene
    • 83. Dicofol 178. Metofluthrin 273. Triazamate
    • 84. Dicrotophos 179. Metolcarb 274. Triazophos
    • 85. Dicyclanil 180. Metoxadiazone 275. Trichlorfon
    • 86. Diethion 181. Mevinphos 276. Triflumuron
    • 87. Diflovidazin 182. Milbemectin 277. Trimethacarb
    • 88. Diflubenzuron 183. Milbemycin oxime 278. Vamidothion
    • 89. Dimefluthrin 184. Monocrotophos 279. Vaniliprole
    • 90. Dimethoate 185. Moxidectin 280. XMC (3,5,-Xylylmethylcarbamate)
    • 91. Dimethylvinphos 186. Naled 281. Xylylcarb
    • 92. Dinobuton 187. Nicotine 282. Zeta-cypermethrin
    • 93. Dinocap 188. Nitenpyram 283. Zetamethrin
    • 94. Dinotefuran 189. Novaluron 284. ZXI 8901 285. Afoxolaner 286. Sarolaner 287. fluralaner
    • 95. Diofenolan 190. Noviflumuron
    • Non-limitative examples of suitable anthelmintics are named in the following, a few representatives have anthelmintic activity in addition to the insecticidal and acaricidal activity.
    • Some of them are already listed above.
    • (A1) Abamectin (A2) Albendazole (A3) Cambendazole
    • (A4) Closantel (A5) Diethylcarbamazine (A6) Doramectin
    • (A7) Emodepside (A8) Eprinomectin (A9) Febantel
    • (A10) Fendendazole (A11) Flubendazole (A12) Ivermectin
    • (A13) Levamisol (A14) Mebendazole (A15) Milbemectin
    • (A16) Milbemycin Oxime (A17) Morantel (A18) Moxidectin
    • (A19) Nitroscanate (A20) Omphalotin (A21) Oxantel
    • (A22) Oxfendazole (A23) Oxibendazole (A24) Phenothiazine
    • (A25) Piperazine (A26) PNU-97333 (A27) PNU-141962
    • (A28) Praziquantel (A29) Pyrantel (A30) Thiabendazole
    • (A31) Triclabendazole amino acetonitrile derivatives named in WO2005044784
    • Non-limitative examples of suitable repellents and detachers are:
    • (R1) DEET (N, N-diethyl-m-toluamide)
    • (R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine (R3) Cymiazole=N,-2,3-dihydro-3-methyl-1,3-thiazol-2-ylidene-2,4-xylidene
  • The above-specified combination partners are best known to specialists in this field. Most are described in various editions of the Pesticide Manual, The British Crop Protection Council, London, and others in the various editions of The Merck Index, Merck & Co., Inc., Rahway, N.J., USA or in patent literature. Therefore, the following listing is restricted to a few places where they may be found by way of example.
  • The commercially available compounds described in the table above can be found in The Pesticide Manual, 14th Ed. (2006), The British Crop Protection Council, London except for 99, 160, 183, 185, 238, A2, A6, A8, A9, A10, A12, A13, A16, A17, A18, A22, A23, A25, A28, A29, A30, which are described in the Compendium of Veterinary Products, 9th Ed. (2006), North American Compendiums, Inc. Compounds Nos. 5, 7, 14, 66, 67, 100, 132, 163, 218, 221, 228, 230, 240, 244, 268, and 279 can be found in the Internet, for example, in the online Merck Veterinary Manual and Compendium of Pesticide Common Names.
  • The pharmaceutical preparation comprising the thiadiazole derivatives, for delivery to a human or other mammal, is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet or lozenge itself, or it can be an appropriate number of any of these in packaged form.
  • The quantity of active component in a unit dose preparation can be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
  • In therapeutic use for the treatment or prevention of a parasitic infection in a human or other mammal, the compounds utilized in the method of treatment are administered at an initial dosage of about 0.1 mg/kg to about 100 mg/kg per interval. Preferred intervals may be daily, weekly, monthly, quarterly, semi-annually, or annually. The dosages can be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound being used. Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner. Generally, the treatment will be initiated with smaller dosages which are less than the optimum dose of the compound, which can be increased in small increments until the optimum effect under the particular circumstances of the infection is reached. For convenience, the total daily dosage can be divided and administered in portions during the day if desired.
    • Methods of Treating Parasites
  • In one embodiment, there is provided a method of treating or preventing parasite infection in a subject, the method comprising administering to the subject an effective amount of thiadiazole derivative of formula (I) or a pesticidally acceptable salt thereof. In another embodiment there is provided the use of a thiadiazole derivative of formula (I) or a pesticidally acceptable salt thereof for treating or preventing parasite infection in a subject. In particular, the compounds of formula (I) are useful for the treatment or prophylaxis of parasitic helminth infections caused by nematodes, trematodes or cestodes, particularly in humans, companion animals, and veterinary animals, particularly dogs, cats, and agricultural livestock including cattle, sheep, goats, fish, pigs, equine and poultry. Such diseases include ascariasis, filariasis, loaiasis, onchocerciasis, schistosomiasis, trichinelliasis and hydatid disease.
  • The compounds of the invention are especially useful for the prophylaxis and/or treatment of lymphatic filariasis, subcutaneous filariasis, serous cavity filariasis, onchocerciasis (river blindness), elephantiasis, heartworm (dogs and cats), Verminous haemorrhagic dermatitis (cattle) and ‘Summer bleeding’ (horses).
  • Examples of parasitic nematodes include, but are not limited to, Ostertagia lyrata, 0. ostertagi, 0. circumcincta, Cooperia oncophora, C. pectinata. C. punctata, C. surnabada, C. curticea, Haemonchus contortus, H. placei, Trichostrongylus axei, T. colubriformis, T. vetrinus, Bunostomum phlebotomum, B. trigonocephalum, Oesophagostomum radiatum, O. dentatum, O. venulosum, O. columbianunm, Strongyloides papillosus, S. westeri, S. stercoralis, Nematodirus helvetianus, N. spathiger, N. filicolis, Trichuris spp., Strongylus vulgaris, S. edentatus, S. equinus, Triodontophorus spp., Oxyuris equ. Parascaris equorum, Habronema muscae, Oncocerca spp., Dirofilaria immitis, Toxocara canis, Toxascaris leonina, Ancylostoma caninum, A. braziliense, A. duodenale, Thelazia spp., Uncinaria stenocephala, Chaberia ovina, Ascaris lumbricoides, Dictyocaulus vivaparus, D. arnfieldi, D. filaria, Brugia malayi, B. timori, Dioctophymna renare, Enterobius vermicularis, Loa loa, Mansonella ozzardi, M. perstans, M. streptocerca, Necator americanus, Onchocerca volvulus, Stronglyloides stercoralis, Trichinella spiralis, T. triciura and Wuchereria bancrofti.
  • Examples of plant-damaging nematodes include, but are not limited to, the following genera: Meloidogyne, Heterodera, Ditylenchus, Aphelenchoides, Radopholus, Globodera, Pratylenchus, Longidorus and Xiphenema.
  • Examples of parasitic cestodes include, but are not limited to: Diphyllobothrium latum, D. caninum, Echinococcus granulosus, E. multilocularis, Hymenolepsis diminuta, Taenia multiceps, T. saginatus, T. serialis, T. sohum and Vampirolepis nana.
  • Examples of parasitic trematodes include, but are not limited to Clonorchis sinensis, Dicrocoelium dendriticum, an echinostome, Fasciolopsis buski, Fasciola hepatica, a heterophyid, Nanophyetus salmincola, Opisthorchis felineus, 0. viverrini, Paragonimus kellicotti, P. westermani, Schistosoma haematobium, S. japonicum, S. mansoni, S. intercalatum and S. mekongi.
    • Synthesis
  • The following Examples illustrate the synthesis of representative compounds of formula (I). These examples are not intended, nor are they to be construed, as limiting the scope of the embodiments disclosed herein. It will be clear that various embodiments may be practiced otherwise than as particularly described herein. Numerous modifications and variations are possible in view of the teachings herein and, therefore, are within the scope.
    • Example 1: 1-(4-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea (Compound 1)
  • Figure US20170202849A1-20170720-C00003
  • 3-Pyridin-2-yl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.28 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran, to which solution was added p-methoxyphenyl isocyanate (36 μL, 0.28 mmol). The mixture was stirred at 50° C. overnight. Precipitation formed which was filtered and rinsed with methanol to yield a white solid (47.9 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 6.81-7.06 (m, 2H) 7.32-7.46 (m, 2H) 7.46-7.57 (m, 1H) 7.83-8.06 (m, 1H) 8.19 (d, J=7.86 Hz, 1H) 8.60-8.90 (m, 1H) 9.12 (s, 1H) 11.49 (s, 1H); LCMS (M/Z): M+H┐+ 328.
  • By proceeding in a similar manner, the following Compounds were also prepared:
    • Compound 2: 1-(2-chlorophenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea
  • Figure US20170202849A1-20170720-C00004
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.06-7.28 (m, 1H) 7.30-7.46 (m, 1H) 7.46-7.58 (m, 2H) 7.91-8.04 (m, 1H) 8.06-8.15 (m, 1H) 8.20 (d, J=7.91 Hz, 1H) 8.57-8.80 (m, 1H) 8.91 (s, 1H) 12.05 (s, 1H); LCMS (M/Z): M+H┐+ 332.
    • Compound 3: 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-(trifluoromethyl)phenyl]urea
  • Figure US20170202849A1-20170720-C00005
  • 1H NMR (400 MHz, DMSO-d4) δ ppm 7.38-7.58 (m, 1H) 7.65-7.87 (m, 4H) 7.86-8.08 (m, 1H) 8.20 (d, J=7.86 Hz, 1H) 8.71 (d, J=3.95 Hz, 1H) 9.73 (br. s., 1H) 11.76 (s, 1H); LCMS (M/Z): M+H┐+ 366.
    • Compound 4: 1-(3-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea
  • Figure US20170202849A1-20170720-C00006
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 6.51-6.78 (m, 1H) 7.06 (d, J=8.05 Hz, 1H) 7.13-7.22 (m, 1H) 7.26 (t, J=8.15 Hz, 1H) 7.43-7.60 (m, 1H) 7.83-8.10 (m, 1H) 8.19 (d, J=7.86 Hz, 1H) 8.59-8.82 (m, 1H) 9.30 (s, 1H) 11.52 (s, 1H); LCMS (M/Z): M+H┐+ 328.
    • Compound 5: 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-(trifluoromethoxy)phenyl]urea (as the hydrochloride salt)
  • Figure US20170202849A1-20170720-C00007
  • LCMS (M/Z): 382 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (d, J=8.59 Hz, 2H) 7.52-7.69 (m, 3H) 8.06 (t, J=7.42 Hz, 1H) 8.24 (d, J=7.81 Hz, 1H) 8.71 (d, J=4.49 Hz, 1H) 9.88 (br. s., 1H).
    • Compound 6: 1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[3-(trifluoromethyl)phenyl]urea
  • Figure US20170202849A1-20170720-C00008
  • LCMS (M/Z): 366 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.22 (d, J=7.42 Hz, 1H) 7.37-7.49 (m, 2H) 7.77 (d, J=8.00 Hz, 1H) 7.88 (t, J=7.42 Hz, 1H) 8.07-8.21 (m, 2H) 8.62 (d, J=3.71 Hz, 1H).
    • Example 2: 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide (Compound 7)
  • Figure US20170202849A1-20170720-C00009
  • 3-Pyridin-2-yl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.28 mmol) and p-chlorobenzoic acid (44 mg, 0.28 mmol) were mixed in 1 mL of anhydrous dimethylformamide, to which solution was added N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) followed by addition of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to obtain Compound 7 as a white solid (53.5 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36-7.64 (m, 1H) 7.69 (d, J=8.69 Hz, 2H) 7.91-8.10 (m, 1H) 8.12-8.34 (m, 3H) 8.72 (d, J=4.00 Hz, 1H); LCMS (M/Z): M+H┐+ 317.
  • By proceeding in a similar manner, the following Compounds were also prepared:
    • Compound 8: 3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
  • Figure US20170202849A1-20170720-C00010
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48-7.56 (m, 1H) 7.60-7.68 (m, 1H) 7.73-7.81 (m, 1H) 7.95-8.08 (m, 1H) 8.15 (d, J=8.30 Hz, 1H) 8.20-8.31 (m, 2H) 8.73 (d, J=3.95 Hz, 1H); LCMS (M/Z): M+H┐+ 317.
    • Compound 9: 4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
  • Figure US20170202849A1-20170720-C00011
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.42-7.58 (m, 1H) 7.87-8.05 (m, 2H) 8.09 (d, 0.1=8.54 Hz, 2H) 8.25 (d, J=7.86 Hz, 1H) 8.30-8.38 (m, 2H) 8.68-8.77 (m, 1H); LCMS (M/Z): M+H┐+ 308.
    • Compound 10: 3-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
  • Figure US20170202849A1-20170720-C00012
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.62 (m, 2H) 7.62-7.75 (m, 1H) 7.91-8.12 (m, 3H) 8.25 (d, J=7.91 Hz, 1H) 8.73 (d, J=4.00 Hz, 1H) 13.89 (br. s., 1H); LCMS (M/Z): M+H┐+ 301.
    • Compound 11: N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
  • Figure US20170202849A1-20170720-C00013
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41-7.61 (m, 1H) 7.97 (d, J=7.91 Hz, 3H) 8.25 (d, J=7.86 Hz, 1H) 8.38 (d, J=8.15 Hz, 2H) 8.66-8.75 (m, 1H); LCMS (M/Z): M+H┐+ 351.
    • Compound 12: N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]naphthalene-2-carboxamide
  • Figure US20170202849A1-20170720-C00014
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48-7.57 (m, 1H) 7.62-7.75 (m, 2H) 7.96-8.03 (m, 1H) 8.05 (d, J=7.81 Hz, 1H) 8.11 (d, J=8.35 Hz, 2H) 8.18-8.25 (m, 1H) 8.27 (d, J=7.91 Hz, 1H) 8.74 (d, J=3.95 Hz, 1H) 8.92 (s, 1H) 13.94 (br. s., 1H); LCMS (M/Z): M+H┐+ 333.
    • Compound 13: 4-trifluoromethoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
  • Figure US20170202849A1-20170720-C00015
  • LCMS (M/Z): 367 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.45-7.52 (m, 2H) 7.59 (d, J=8.40 Hz, 2H) 7.95 (td, J=7.76, 1.66 Hz, 1H) 8.11-8.19 (m, 1H) 8.28 (d, J=7.81 Hz, 1H) 8.43 (d, J=8.79 Hz, 2H) 8.72 (d, J=4.30 Hz, 1H).
    • Example 3: 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide (Compound 14)
  • Figure US20170202849A1-20170720-C00016
  • 3-(Pyridin-2-yl)-1,2,4-thiadiazol-5-amine (50 mg, 0.28 mmol) was dissolved in 1.5 mL pyridine. 4-Chlorobenzenesulfonyl chloride (65 mg, 0.31 mmol) was then added. The mixture was stirred for 16 hours at room temperature. The reaction was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to obtain Compound 14 as a tan solid. LCMS (M/Z): 352 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.53-7.63 (m, 3H) 7.91 (d, J=8.64 Hz, 2H) 8.03 (td, J=7.75, 1.54 Hz, 1H) 8.24 (d, J=8.00 Hz, 1H) 8.66 (d, J=4.49 Hz, 1H).
  • By proceeding in a similar manner, the following Compounds were also prepared:
    • Compound 15: 2-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide
  • Figure US20170202849A1-20170720-C00017
  • LCMS (M/Z): 352 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.52-7.67 (m, 4H) 8.07 (td, J=7.78, 1.71 Hz, 1H) 8.17-8.28 (m, 2H) 8.64-8.73 (m, 1H).
    • Compound 16: 4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide
  • Figure US20170202849A1-20170720-C00018
  • LCMS (M/Z): 344 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.61 (ddd, J=7.57, 4.88, 1.02 Hz, 1H) 7.97-8.02 (m, 2H) 8.06 (td, J=7.80, 1.68 Hz, 1H) 8.08-8.13 (m, 2H) 8.24 (d, J=7.96 Hz, 1H) 8.68 (d, J=4.54 Hz, 1H).
    • Compound 17: 4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide
  • Figure US20170202849A1-20170720-C00019
  • LCMS (M/Z): 349 (M+H). 1H NMR (400 MHz, acetone) δ ppm 3.88 (s, 3H) 7.01-7.10 (m, 2H) 7.58 (dd, J=7.10, 5.34 Hz, 1H) 7.79-7.88 (m, 2H) 8.03 (td, J=7.76, 1.61 Hz, 1H) 8.22 (d, J=7.96 Hz, 1H) 8.67 (d, J=4.88 Hz, 1H).
    • Compound 18: 2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide
  • Figure US20170202849A1-20170720-C00020
  • LCMS (M/Z): 349 (M+H). 1H NMR (400 MHz, acetone) δ ppm 3.81 (s, 3H) 7.10 (td, J=7.63, 0.95 Hz, 1H) 7.17 (d, J=8.25 Hz, 1H) 7.52-7.64 (m, 2H) 7.96 (dd, J=7.86, 1.71 Hz, 1H) 8.05 (td, J=7.78, 1.71 Hz, 1H) 8.25 (d, J=7.91 Hz, 1H) 8.68 (d, J=4.64 Hz, 1H).
    • Compound 19: N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethyl)benzenesulfonamide
  • Figure US20170202849A1-20170720-C00021
  • LCMS (M/Z): 386 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.57-7.68 (m, 1H) 7.83-7.91 (m, 1H) 8.01 (d, J=7.81 Hz, 1H) 8.07 (t, J=7.52 Hz, 1H) 8.18 (s, 1H) 8.23 (t, J=8.40 Hz, 2H) 8.69 (d, J=4.30 Hz, 1H).
    • Compound 20: N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzenesulfonamide
  • Figure US20170202849A1-20170720-C00022
  • LCMS (M/Z): 387 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.63-7.73 (m, 1H) 7.92 (d, J=8.40 Hz, 2H) 8.02 (d, J=8.20 Hz, 2H) 8.08-8.17 (m, 1H) 8.17-8.25 (m, 1H) 8.69 (d, J=4.69 Hz, 1H).
    • Example 4: N-[3-(3-Fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (Compound 21)
  • Figure US20170202849A1-20170720-C00023
  • 3-(3-Fluoro-2-pyridyl)-1,2,4-thiadiazol-5-amine (50 mg, 0.25 mmol) was dissolved in 2 mL dichloromethane. Pyridine (25 μL, 0.30 mmol) was added followed by 4-(trifluoromethyl)benzoyl chloride (45 μL, 0.28 mmol). The mixture was stirred under nitrogen at room temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to obtain the Compound 21 as a white solid. LCMS (M/Z): 369 (M+H). 1H NMR (400 MHz, acetone) δ ppm 7.62 (dt, J=8.40, 4.20 Hz, 1H) 7.73-7.85 (m, 1H) 8.01 (d, J=8.40 Hz, 2H) 8.50 (d, J=8.00 Hz, 2H) 8.59 (d, J=4.49 Hz, 1H).
    • Synthesis 3-fluoropyridine-2-carboxamidine
  • Figure US20170202849A1-20170720-C00024
  • 3-Fluoro-2-pyridinecarbonitrile (500 mg, 4.1 mmol) and N-acetyl-L-cysteine (75 mg, 0.45 mmol) were dissolved in 4 mL methanol. Ammonium acetate (380 mg, 4.9 mmol) was added and the reaction stirred at 50° C. for 14 hours. The solution was evaporated under reduced pressure and purified by flash chromatography. The product was recovered as a tan solid (170 mg, 30%). LCMS (M/Z): 140 (M+H).
    • Synthesis of 3-(3-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-amine
  • Figure US20170202849A1-20170720-C00025
  • 3-Fluoropyridine-2-carboxamidine (150 mg, 1.07 mmol) was dissolved in 3 mL methanol. Triethylamine (150 μL, 1.07 mmol) was added, followed by N-chlorosuccinimide (145 mg, 1.07 mmol). The reaction stirred at ambient temperature for 14 hours. LCMS of crude reaction (M/Z): 174 (M+H). Potassium thiocyanate (105 mg, 1.07 mmol) was added to the reaction mixture. After 1 hour the reaction was complete. The solution was evaporated under reduced pressure and purified by flash chromatography. The product was recovered as clear oil (170 mg, 80% over 2 steps). LCMS (M/Z): 197 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (dd, J=8.20, 4.10 Hz, 1H) 7.80 (t, J=9.57 Hz, 1H) 8.06 (br. s., 2H) 8.46 (d, J=3.71 Hz, 1H).
    • Example 5: 4-methyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-2-carboxamide (Compound 53)
  • Figure US20170202849A1-20170720-C00026
  • 3-Pyridin-2-yl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.28 mmol) was placed in a vial and dissolved in dioxane (1.5 mL) and then added 3 N NaOH (1.5 mL). Then 4-methylthiophene-2-carbonyl chloride (45 mg, 0.28 mmol) was added and the reaction heated to 50° C. for 16 h. The reaction was then diluted with water and acidified with AcOH to force precipitation. The precipitates were collected by filtration. The collected solid was redissolved and concentrated onto celite (5 g). Then purified by normal phase chromatography (solvent A CH2Cl2, solvent B CH2Cl2/MeOH/NH4OH 90:10:1, gradient from 0-60% B). Collected the desired product (72 mg, 0.24 mmol, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.49 (ddd, J=7.55, 4.75, 1.12 Hz, 1H) 7.65 (s, 1H) 7.95 (td, J=7.74, 1.81 Hz, 1H) 8.13 (d, J=1.02 Hz, 1H) 8.20 (d, J=7.91 Hz, 1H) 8.62-8.74 (m, 1H) 13.75 (br. s., 1H); LCMS (M/Z): M+H+ 303.
    • Example 6: 4-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide (Compound 63)
  • Figure US20170202849A1-20170720-C00027
  • 3-Pyridin-2-yl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.28 mmol), 4-phenoxybenzoic acid (120 mg, 0.56 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (128 mg, 0.34 mmol) was placed in a vial. Then dissolved in DMF (3 mL, anhydrous), added N,N-diisopropylethylamine (98 μL, 0.56 mmol), and stirred at 50° C. for 16 h. The reaction was diluted with water and extracted with EtOAc (×3). The combined organic layers were dried and concentrated onto celite. Purified by normal phase chromatography (solvent A CH2Cl2, solvent B CH2Cl2/MeOH/NH4OH 90:10:1, gradient from 0-50% B). Collected the desired product (25.2 mg, 0.0674 mmol, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d, J=8.83 Hz, 2H) 7.16 (d, J=7.66 Hz, 2H) 7.23-7.31 (m, 1H) 7.43-7.56 (m, 3H) 7.98 (td, J=7.75, 1.73 Hz, 1H) 8.24 (d, 0.8.74 Hz, 3H) 8.72 (d, J=4.34 Hz, 1H) 13.71 (br. s., 1H); LCMS (M/Z): M+H+ 375.
    • Example 7: 4-(3-pyridyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl] benzamide (Compound 111)
  • Figure US20170202849A1-20170720-C00028
  • 4-Iodo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide (50 mg, 0.12 mmol), 3-pyridylboronic acid (30 mg, 0.24 mmol), PdCl2(dppf)CH2Cl2 (50 mg, 0.061 mmol), and Cs2CO3 (120 mg, 0.37 mmol) were placed in a vial. Then added dioxane (2 mL, degassed) and water (200 μL, degassed). The reaction was then degassed, placed under N2, and heated to 100° C. for 16 h. The reaction was cooled, added EtOAc and water, and extracted with EtOAc (×3). The combined organic layers were dried and concentrated onto celite (5 g). Purified by normal phase chromatography (solvent A CH2Cl2, solvent 13 CH2Cl2/MeOH/NH4OH 90:10:1, gradient from 0-50% B). The collected product was redissolved in CH2Cl2/MeOH and concentrated onto celite (5 g). Then further purified by reverse phase chromatography (solvent A water with 0.1% formic acid, solvent B CH3CN with 0.1% formic acid, gradient from 5-100% B). Collected the desired product (1.7 mg, 0.0047 mmol, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (ddd, J=7.44, 4.78, 0.95 Hz, 1H) 7.53 (dd, J=7.96, 4.78 Hz, 1H) 7.88-8.00 (m, 3H) 8.20 (dt, J=8.00, 1.95 Hz, 1H) 8.25 (d, J=7.86 Hz, 1H) 8.33 (d, J=8.49 Hz, 2H) 8.63 (dd, J=4.76, 1.54 Hz, 1H) 8.71 (d, J=4.00 Hz, 1H) 9.01 (d, J=1.81 Hz, 1H); LCMS (M/Z): M+H+ 360.
    • Example 8: 4-(2-pyridylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide (Compound 75)
  • Figure US20170202849A1-20170720-C00029
  • 4-Iodo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide (50 mg, 0.12 mmol), pyridin-2-amine (46 mg, 0.49 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), X-Phos (58 mg, 0.12 mmol), and NaOt-Bu (71 mg, 0.73 mmol) were placed in a vial. Then added dioxane (2 mL, anhydrous, degassed). The reaction was then degassed, placed under N2, and heated to 100° C. for 16 h. The reaction was cooled, added EtOAc and water, and extracted with EtOAc (×3). The combined organic layers were dried and concentrated onto celite (5 g). Purified by normal phase chromatography (solvent A CH2Cl2, solvent B CH2Cl2/MeOH/NH4OH 90:10:1, gradient from 0-50% B). The collected product was redissolved in CH2Cl2/MeOH and concentrated onto celite (5 g). Then further purified by reverse phase chromatography (solvent A water with 0.1% formic acid, solvent B CH3CN with 0.1% formic acid, gradient from 5-100% B). Collected the desired product (7.7 mg, 0.0206 mmol, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (ddd, J=7.49, 4.76, 0.98 Hz, 1H) 7.66 (ddd, J=8.49, 7.00, 1.93 Hz, 1H) 7.88 (d, J=8.88 Hz, 2H) 7.97 (td, J=7.72, 1.73 Hz, 1H) 8.14 (d, J=8.88 Hz, 2H) 8.21-8.30 (m, 3H) 8.71 (d, J=3.95 Hz, 1H) 9.57 (s, 1H); LCMS (M/Z): M+H+ 375.
    • Example 9: N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (Compound 28)
  • Figure US20170202849A1-20170720-C00030
  • The amine (261.4 mg, 1.02 mmol) and p-trifluoromethylbenzoic acid (194 mg, 1.02 mmol) was dissolved in anhydrous DMF (5 mL) to which mixture was added N,N-diisopropylethylamine (0.36 mL, 2.04 mmol) and HATU (387 mg, 1.02 mmol). The mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (5×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by ISCO to obtain the product (136.1 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (dd, J=5.66, 2.73 Hz, 1H) 7.66-7.79 (m, 2H) 7.99 (d, J=8.40 Hz, 2H) 8.35 (d, J=8.20 Hz, 2H) 8.77 (d, J=5.66 Hz, 1H) 8.84 (dd, J=8.49, 1.07 Hz, 1H) 8.86-8.89 (m, 1H) M+H┐+ 429
    • Example 10: N-[3-[4-[2-methoxyethyl(methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (Compound 25)
  • Figure US20170202849A1-20170720-C00031
  • The mixture of N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (30 mg, 0.063 mmol) and 2-methoxy-N-methyl-ethanamine (34 μL, 0.31 mmol) in anhydrous DMF (1 mL) was heated at 50° C. overnight. The reaction mixture was directly purified by HPLC to obtain the product (7.2 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 2H) 3.15 (s, 3H) 3.55-3.63 (m, 2H) 3.63-3.80 (m, 2H) 6.85 (d, J=3.71 Hz, 1H) 7.59 (d, J=2.73 Hz, 1H) 7.81 (d, J=8.40 Hz, 2H) 8.02-8.18 (m, 1H) 8.36 (d, J=8.00 Hz, 2H) M+H┐+ 438
    • N-[3-[4-[2-(1-piperidyl)ethoxy]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (Compound 140)
  • Figure US20170202849A1-20170720-C00032
  • 2-morpholinoethanol (67 μL, 0.52 mmol) was dissolved in anhydrous DMF (1 mL) to which solution was added sodium hydride (20 mg, 60 wt % in mineral oil, 0.46 mmol). Gas evolution. The mixture was stirred at 50° C. for 1 h before a solution of N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide (50 mg, 0.10 mmol, in 1 mL of anhydrous DMF) was added. The mixture was then stirred at 50° C. overnight. The crude mixture was directly purified by HPLC to obtain the product (11.8 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 2H) 2.76 (t, J=5.56 Hz, 2H) 3.52-3.70 (m, 4H) 4.27 (t, J=5.66 Hz, 2H) 7.02 (d, J=2.93 Hz, 1H) 7.78 (d, J=2.34 Hz, 1H) 7.85 (d, J=8.20 Hz, 2H) 8.36 (d, J=8.01 Hz, 2H) 8.46 (d, J=5.66 Hz, 1H) M+H┐+ 480
  • By proceeding in a similar manner the following compounds of the invention were prepared using the procedures described in one of Examples 1 to 10.
  • Liquid chromatography-mass spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one or more of the following Methods A, B, and C:
  • Method A:
  • Waters BEH C18, 3.0×30 mm, 1.7 μm, was used at a temperature of 50° C. and at a flow rate of 1.5 mL/min, 2 μL injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Method A details: (I) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15% (B);
  • Method B:
  • An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 μm, was used at a temperature of 50° C. and at a flow rate of 0.8 mL/min, 2 μL injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Method details: (I) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).
  • Method C:
  • An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC system with a diode array detector was used. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Agilent ZORBAX XDB 50×2.1 mm C18 column and a 0.5 mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing 0.01% formic acid; Solvent B: acetonitrile. The gradient was shown as below. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95% solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B) to 2% solvent B: 4.2-6.0 min: 2% solvent (B).
  • TABLE 2
    LCMS
    Mass retention
    Cpd. Name found time
    22 N-[3-(4-morpholino-2-pyridyl)-1,2,4-thiadiazol-5- 436 1.35
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.54 (br s,
    4H) 3.76 (t, J = 4.69 Hz, 4H) 7.07 (d, J = 4.10 Hz,
    1H) 7.75 (d, J = 2.34 Hz, 1H) 7.87 (d, J = 8.00 Hz,
    2H) 8.24 (d, J = 6.44 Hz, 1H) 8.36 (d, J = 8.20 Hz,
    2H) M + H┐+ 436
    23 N-[3-[4-[benzyl(methyl)amino]-2-pyridyl]-1,2,4- 470 1.63
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s,
    3H) 4.88 (s, 2H) 6.93 (d, J = 5.08 Hz, 1H)
    7.19-7.34 (m, 4H) 7.33-7.42 (m, 2H) 7.63 (s, 1H)
    7.83 (d, J = 8.20 Hz, 2H) 8.08-8.25 (m, 1H)
    8.09-8.21 (m, 1H) 8.35 (d, J = 8.20 Hz, 2H) 8.31-8.41 (m,
    1H) M + H┐+ 470
    24 N-[3-[4-(dimethylamino)-2-pyridyl]-1,2,4- 394 1.36
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (br s,
    1H) 3.25 (br s, 6H) 6.97 (d, J = 4.30 Hz, 1H)
    7.60 (br s, 1H) 7.84 (d, J = 7.81 hz, 2H) 8.14 (d, J = 6.64 Hz,
    1H) 8.36 (d, J = 8.00 Hz, 2H) M + H┐+ 408
    25 N-[3-[4-[2-methoxyethyl(methyl)amino]-2- 438 1.31
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s,
    2H) 3.15 (s, 3H) 3.55-3.63 (m, 2H)
    3.63-3.80 (m, 2H) 6.85 (d, J = 3.71 Hz, 1H) 7.59 (d, J = 2.73 Hz,
    1H) 7.81 (d, J = 8.40 Hz, 2H) 8.02-8.18 (m,
    1H) 8.36 (d, J = 8.00 Hz, 2H) M + H┐+ 438
    26 N-[3-(5-methoxy-2-pyridyl)-1,2,4-thiadiazol-5- 381 1.88
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s,
    3H) 7.54 (dd, J = 8.79, 2.93 Hz, 1H) 7.95 (d, J = 8.20 Hz,
    2H) 8.21 (d, J = 8.79 Hz, 1H) 8.31-8.46 (m,
    3H) M + H┐+ 381
    27 N-[3-(4-methoxy-2-pyridyl)-1,2,4-thiadiazol-5- 381 1.65
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s,
    3H) 7.09 (dd, J = 5.66, 2.54 Hz, 1H) 7.78 (d, J = 2.34 Hz,
    1H) 7.96 (d, J = 8.00 Hz, 2H) 8.38 (d, J = 8.20 Hz,
    2H) 8.52 (d, J = 5.86 Hz, 1H) M + H┐+ 381
    28 N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2- 485 1.91
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (dd,
    J = 5.66, 2.73 Hz, 1H) 7.66-7.79 (m, 2H) 7.99 (d,
    J = 8.40 Hz, 2H) 8.35 (d, J = 8.20 Hz, 2H) 8.77 (d,
    J = 5.66 Hz, 1H) 8.84 (dd, J = 8.49, 1.07 Hz, 1H)
    8.86-8.89 (m, 1H) M + H┐+ 429
    29 N-[3-(5-bromo-2-pyridlyl)-1,2,4-thiadiazol-5-yl]-4- 429 1.97
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (s, 2
    H) 8.11-8.19 (m, 1 H) 8.23 (d, J = 2.29 Hz, 1 H)
    8.34 (d, J = 8.20 Hz, 2 H) 8.83 (d, J = 2.25 Hz, 1 H).
    30 methyl 2-[5-[[4-(trifluoromethyl)benzoyl]amino]- 409 1.88
    1,2,4-thiadiazol-3-yl]pyridine-4-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s,
    3H) 7.88-8.00 (m, 3H) 8.38 (d, J = 8.20 Hz, 2H)
    8.71 (s, 1H) 8.93 (d, J = 5.08 Hz, 1H) M + H┐+ 409
    31 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 334 1.29
    yl]isoquinoline-7-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (dd,
    J = 6.74, 4.98 Hz, 1H) 7.93-8.05 (m, 2H) 8.18 (d,
    J = 8.59 Hz, 1H) 8.27 (d, J = 7.81 Hz, 1H) 8.46 (dd,
    J = 8.59, 1.56 Hz, 1H) 8.67 (d, J = 5.66 Hz, 1H)
    8.74 (d, J = 4.30 Hz, 1H) 9.09 (s, 1H) 9.49 (s, 1H)
    M + H┐+ 334
    32 4-acetamido-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 340 1.48
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s,
    3H) 7.59 (dd, J = 6.64, 4.88 Hz, 1H) 7.79 (d, J = 8.79 Hz,
    2H) 8.07 (td, J = 7.71, 1.56 Hz, 1H) 8.17 (d,
    J = 8.79 Hz, 2H) 8.29 (d, J = 7.81 Hz, 1H) 8.75 (d,
    J = 4.30 Hz, 1H) 10.39 (s, 1H) M + H┐+ 340
    33 4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 301 1.5
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (t,
    J = 8.79 Hz, 2H) 7.54-7.64 (m, 1H) 8.06 (td,
    J = 7.71, 1.56 Hz, 1H) 8.23-8.35 (m, 3H) 8.75 (d,
    J = 4.30 Hz, 1H) M + H┐+ 301
    34 4-nitro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 328 1.49
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (dd,
    J = 6.64, 4.88 Hz, 1H) 7.99 (td, J = 7.71, 1.56 Hz,
    1H) 8.26 (d, J = 7.81 Hz, 1H) 8.42 (s, 5H) 8.73 (d,
    J = 4.30 Hz, 1H) M + H┐+ 328
    35 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 335 1.35
    yl]quinoxaline-6-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.56 (dd,
    J = 7.03, 5.27 Hz, 1H) 8.03 (td, J = 7.71, 1.56 Hz,
    1H) 8.30 (dd, J = 8.30, 5.37 Hz, 2H) 8.53 (dd,
    J = 8.79, 1.95 Hz, 1H) 8.75 (d, J = 4.30 Hz, 1H)
    9.05 (d, J = 1.76 Hz, 1H) 9.11 (d, J = 1.37 Hz, 1H) M + H┐+
    335
    36 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene- 289 1.36
    2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.28-7.39 (m, 1H) 7.58 (dd, J = 6.83, 5.08 Hz, 1H) 8.05 (td,
    J = 7.71, 1.56 Hz, 1H) 8.10 (d, J = 4.88 Hz, 1H)
    8.27 (d, J = 7.81 Hz, 1H) 8.37 (d, J = 3.12 Hz, 1H)
    8.74 (d, J = 4.30 Hz, 1H) M + H┐+ 289
    37 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene- 289 1.92
    3-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.51-7.62 (m, 1H) 7.69-7.79 (m, 1H) 7.79-7.87 (m, 1H)
    8.05 (t, J = 7.71 Hz, 1H) 8.27 (d, J = 7.81 Hz, 1H)
    8.69-8.79 (m, 1H) M + H┐+ 289
    38 N-[3-(4-isopropyl-2-pyridyl)-1,2,4-thiadiazol-5- 393 2.04
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.17-1.44 (m, 6H) 3.07 (quin, J = 6.93 Hz, 1 H) 7.51 (d,
    J = 4.10 Hz, 1H) 8.01 (d, J = 8.20 Hz, 2H) 8.18 (s,
    1H) 8.39 (d, J = 8.20 Hz, 2H) 8.65 (d, J = 5.08 Hz,
    1H) M + H┐+ 393
    39 N-[3-(3-isoquinolyl)-1,2,4-thiadiazol-5-yl]-4- 401 1.96
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.74-7.83 (m, 1H) 7.87 (t, J = 7.22 Hz, 1H) 8.00 (d,
    J = 8.40 Hz, 2H) 8.17 (d, J = 8.20 Hz, 1H) 8.23 (d,
    J = 8.20 Hz, 1H) 8.40 (d, J = 8.20 Hz, 2H) 8.73 (s,
    1H) 9.46 (s, 1H) M + H┐+ 401
    40 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4- 369 1.86
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (td,
    J = 8.69, 2.93 Hz, 1H) 8.00 (d, J = 8.20 Hz, 2H)
    8.33 (dd, J = 8.79, 4.49 Hz, 1H) 8.38 (d, J = 8.00 Hz, 2H)
    8.73 (d, J = 2.93 Hz, 1H) M + H┐+ 369
    41 N-[3-(5-methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 365 1.88
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3
    H) 7.78 (dd, J = 8.03, 1.59 Hz, 1 H) 7.97 (d, J = 8.25 Hz,
    2 H) 8.14 (d, J = 8.00 Hz, 1 H) 8.37 (d, J = 8.15 Hz,
    2 H) 8.56 (d, J = 1.85 Hz, 1 H); LCMS (M/Z):
    M + H+ 365.
    42 3-chloro-4-fluoro-N-[3-(5-fluoro-2-pyridyl)-1,2,4- 353 1.86
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 7.66 (t,
    J = 8.88 Hz, 1 H) 7.83-7.98 (m, 1 H) 8.21 (ddd,
    J = 8.49, 4.59, 2.15 Hz, 1 H) 8.30 (dd, J = 8.79, 4.49 Hz,
    1 H) 8.44 (dd, J = 7.03, 1.95 Hz, 1 H) 8.71 (d,
    J = 2.54 Hz, 1 H); MS (M + H) = 353.0.
    43 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4- 385 1.87
    (trifluoromethoxy)benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 7.60 (d,
    J = 8.20 Hz, 2 H) 7.84-7.98 (m, 1 H) 8.33 (d,
    J = 8.79 Hz, 3 H) 8.72 (d, J = 2.73 Hz, 1 H); MS
    (M + H) = 385.0.
    44 4-tert-butyl-N-[3-(5-fluoro-2-pyridyl)-1,2,4- 357 1.99
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 1.33 (s, 9
    H) 7.62 (d, J = 8.59 Hz, 2 H) 7.83-7.98 (m, 1 H)
    8.15 (d, J = 8.40 Hz, 2 H) 8.26-8.40 (m, 1 H)
    8.71 (d, J = 2.73 Hz, 1 H); MS (M + H) = 357.0.
    45 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 437 2.05
    3,5-bis(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 7.92 (d,
    J = 2.73 Hz, 1 H) 8.26-8.37 (m, 1 H) 8.49 (s, 1 H)
    8.72 (d, J = 2.54 Hz, 1 H) 8.82 (s, 2 H); MS (M + H) =
    437.0.
    46 N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-3- 369 1.84
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 7.86 (s, 2
    H) 8.07 (s, 1 H) 8.26-8.38 (m, 1 H) 8.45 (s, 1 H)
    8.59 (s, 1 H) 8.72 (d, J = 2.93 Hz, 1 H); MS (M + H) =
    369.0.
    47 3,4-dichloro-N-[3-(5-fluoro-2-pyridyl)-1,2,4- 369 1.97
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) d ppm 7.87 (d,
    J = 8.40 Hz, 2 H) 8.07-8.19 (m, 1 H)
    8.25-8.37 (m, 1 H) 8.44 (d, J = 1.95 Hz, 1 H) 8.71 (d, J = 2.73 Hz,
    1 H); MS (M + H) = 368.9.
    48 3-methylsulfonyl-N-[3-(2-pyridyl)-1,2,4- 361 1.18
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 5.84 (br. s.,
    3 H) 7.65-7.77 (m, 1 H) 7.90 (t, J = 7.83 Hz, 1 H)
    8.17-8.29 (m, 2 H) 8.36 (d, J = 7.81 Hz, 1 H)
    8.49 (d, J = 7.91 Hz, 1 H) 8.74 (s, 1 H) 8.80 (d, J = 3.81 Hz,
    1 H); LCMS (M/Z): M + H+ 361.
    49 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 334 1.15
    yl]isoquinoline-5-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.65-7.75 (m, 1 H) 8.12 (t, J = 7.71 Hz, 1 H) 8.23 (t, J = 7.25 Hz,
    1 H) 8.38 (d, J = 7.42 Hz, 1 H) 8.71 (d, J = 7.22 Hz,
    1 H) 8.73-8.82 (m, 3 H) 8.86 (d, J = 6.83 Hz,
    1 H) 10.00 (s, 1 H); LCMS (M/Z): M + H+ 334.
    50 3-chloro-4-(4-methylpiperazin-1-yl)-N-[3-(2- 415 1.07
    pyridyl)-1,2,4-thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (d,
    J = 4.39 Hz, 3 H) 3.11-3.36 (m, 4 H) 3.52 (d,
    J = 11.32 Hz, 2 H) 3.62 (d, J = 11.96 Hz, 2 H)
    7.39 (d, J = 8.59 Hz, 1 H) 7.65 (dd, J = 6.93, 5.47 Hz, 1
    H) 8.08-8.22 (m, 2 H) 8.25-8.38 (m, 2 H)
    8.77 (d, J = 4.49 Hz, 1 H) 11.43 (br. s., 1 H); LCMS
    (M/Z): M + H+ 415.
    51 methyl 4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 341 1.6
    yl]carbamoyl]benzoate
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3
    H) 7.52-7.65 (m, 1 H) 8.08 (t, J = 7.71 Hz, 1 H)
    8.14 (d, J = 8.49 Hz, 2 H) 8.22-8.38 (m, 3 H)
    8.76 (br. s., 1 H); LCMS (M/Z): M + H+ 341.
    52 4-(diethylsulfamoyl)-N-[3-(2-pyridyl)-1,2,4- 418 1.64
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (t,
    J = 7.10 Hz, 6 H) 3.23 (q, J = 7.11 Hz, 4 H) 7.59 (br.
    s., 1 H) 8.00 (s, 2 H) 8.06 (t, J = 7.69 Hz, 1 H)
    8.29 (br. s., 1 H) 8.37 (d, J = 8.54 Hz, 2 H) 8.75 (br. s., 1
    H); LCMS (M/Z): M + H+ 418.
    53 4-methyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 3 1.54
    yl]thiophene-2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3
    H) 7.49 (ddd, J = 7.55, 4.75, 1.12 Hz, 1 H) 7.65 (s,
    1 H) 7.95 (td, J = 7.74, 1.81 Hz, 1 H) 8.13 (d,
    J = 1.02 Hz, 1 H) 8.20 (d, J = 7.91 Hz, 1 H)
    8.62-8.74 (m, 1 H) 13.75 (br. s., 1 H); LCMS (M/Z):
    M + H+ 303
    54 3-chloro-4-fluoro-N-[3-(2-pyridyl)-1,2,4- 335 1.81
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.55, 4.75, 1.12 Hz, 1 H) 7.67 (t, J = 8.91 Hz, 1
    H) 7.99 (td, J = 7.74, 1.81 Hz, 1 H) 8.16-8.28 (m,
    2 H) 8.46 (dd, J = 7.03, 2.25 Hz, 1 H)
    8.67-8.76 (m, 1 H) 13.89 (br. s., 1 H); LCMS (M/Z): M + H+
    335.
    55 2-fluoro-3-methoxy-N-[3-(2-pyridyl)-1,2,4- 331 1.41
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3
    H) 7.28-7.34 (m, 1 H) 7.35-7.40 (m, 1 H)
    7.46 (td, J = 8.08, 1.81 Hz, 1 H) 7.52 (ddd, J = 7.55, 4.75,
    1.12 Hz, 1 H) 7.99 (td, J = 7.75, 1.78 Hz, 1 H)
    8.23 (d, J = 7.91 Hz, 1 H) 8.66-8.77 (m, 1 H) 13.71 (br.
    s., 1 H); LCMS (M/Z): M + H+ 331.
    56 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3- 351 1.8
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.55, 4.75, 1.17 Hz, 1 H) 7.85 (t, J = 7.83 Hz, 1
    H) 7.99 (td, J = 7.75, 1.78 Hz, 1 H) 8.08 (d, J = 7.86 Hz,
    1 H) 8.25 (dt, J = 7.87, 0.97 Hz, 1 H) 8.46 (d,
    J = 7.96 Hz, 1 H) 8.59 (s, 1 H) 8.68-8.77 (m, 1 H)
    14.01 (s, 1 H); LCMS (M/Z): M + H+ 351.
    57 2,5-dimethyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 301 1.64
    yl]furan-3-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3
    H) 2.59 (s, 3 H) 6.92 (d, J = 0.73 Hz, 1 H)
    7.51 (ddd, J = 7.55, 4.75, 1.12 Hz, 1 H) 7.97 (td, J = 7.74,
    1.81 Hz, 1 H) 8.23 (d, J = 7.86 Hz, 1 H)
    8.68-8.75 (m, 1 H) 13.24 (s, 1 H); LCMS (M/Z): M + H+ 301.
    58 4-tert-butyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 339 1.97
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 9
    H) 7.49 (ddd, J = 7.54, 4.76, 1.17 Hz, 1 H)
    7.54-7.62 (m, 2 H) 7.95 (td, J = 7.74, 1.81 Hz, 1 H)
    8.08-8.16 (m, 2 H) 8.19-8.25 (m, 1 H) 8.65-8.72 (m,
    1 H) 13.68 (br. s., 1 H); LCMS (M/Z): M + H+ 339.
    59 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-1,3- 327 1.48
    benzodioxole-5-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 6.15 (s, 2
    H) 7.09 (d, J = 8.25 Hz, 1 H) 7.48 (ddd, J = 7.54,
    4.78, 1.10 Hz, 1 H) 7.70 (d, J = 1.76 Hz, 1 H)
    7.81 (dd, J = 8.25, 1.81 Hz, 1 H) 7.94 (td, J = 7.72, 1.78 Hz,
    1 H) 8.21 (d, J = 7.86 Hz, 1 H) 8.68 (dt, J = 4.73,
    0.83 Hz, 1 H) 13.55 (br. s., 1 H); LCMS (M/Z):
    M + H+ 327.
    60 3,4-dichloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 351 1.96
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.54, 4.76, 1.17 Hz, 1 H) 7.88 (d, J = 8.44 Hz, 1
    H) 7.98 (td, J = 7.74, 1.81 Hz, 1 H) 8.13 (dd,
    J = 8.42, 2.12 Hz, 1 H) 8.18-8.27 (m, 1 H) 8.45 (d,
    J = 2.05 Hz, 1 H) 8.67-8.76 (m, 1 H) 13.91 (br. s.,
    1 H); LCMS (M/Z): M + H+ 351.
    61 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3,5- 419 2.04
    bis(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.54, 4.76, 1.17 Hz, 1 H) 7.88 (d, J = 8.44 Hz, 1
    H) 7.98 (td, J = 7.74, 1.81 Hz, 1 H) 8.13 (dd,
    J = 8.42, 2.12 Hz, 1 H) 8.18-8.27 (m, 1 H) 8.45 (d,
    J = 2.05 Hz, 1 H) 8.67-8.76 (m, 1 H) 13.91 (br. s.,
    1 H); LCMS (M/Z): M + H+ 351.
    62 4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 313 1.49
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.87 (s, 3
    H) 7.08-7.19 (m, 2 H) 7.52 (ddd, J = 7.54, 4.76,
    1.17 Hz, 1 H) 7.98 (td, J = 7.74, 1.76 Hz, 1 H)
    8.14-8.28 (m, 3 H) 8.68-8.76 (m, 1 H) 13.61 (s, 1 H);
    LCMS (M/Z): M + H+ 313.
    63 4-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 375 1.93
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d,
    J = 8.83 Hz, 2 H) 7.16 (d, J = 7.66 Hz, 2 H)
    7.23-7.31 (m, 1 H) 7.43-7.56 (m, 3 H) 7.98 (td,
    J = 7.75, 1.73 Hz, 1 H) 8.24 (d, J = 8.74 Hz, 3 H)
    8.72 (d, J = 4.34 Hz, 1 H) 13.71 (br. s., 1 H); LCMS
    (M/Z): M + H+ 375.
    64 4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2- 369 1.56
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.55, 4.75, 1.12 Hz, 1 H) 7.77 (td, J = 8.44, 2.54 Hz,
    1 H) 7.90 (dd, J = 9.18, 2.54 Hz, 1 H)
    7.94-8.08 (m, 2 H) 8.22 (d, J = 7.91 Hz, 1 H)
    8.66-8.77 (m, 1 H) 13.95 (br. s., 1 H); LCMS (M/Z): M + H+
    367.
    65 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide 283 1.46
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.53, 4.77, 1.12 Hz, 1 H) 7.56-7.66 (m, 2 H)
    7.67-7.76 (m, 1 H) 7.99 (td, J = 7.74, 1.76 Hz, 1
    H) 8.15-8.23 (m, 2 H) 8.25 (d, J = 7.86 Hz, 1 H)
    8.65-8.78 (m, 1 H) 13.79 (br. s., 1 H); LCMS
    (M/Z): M + H+ 283.
    66 4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 327 1.35
    yl]carbamoyl]benzoic acid
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (ddd,
    J = 7.52, 4.76, 1.10 Hz, 1 H) 7.87-7.97 (m, 1 H)
    8.03 (d, J = 8.49 Hz, 2 H) 8.16-8.34 (m, 3 H)
    8.62-8.72 (m, 1 H); LCMS (M/Z): M + H+ 327.
    67 4-iodo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 408 1.79
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.54, 4.76, 1.17 Hz, 1 H) 7.90-8.05 (m, 5 H)
    8.24 (d, J = 7.86 Hz, 1 H) 8.69-8.75 (m, 1 H)
    13.85 (br. s., 1 H); LCMS (M/Z): M + H+ 408.
    68 4-morpholino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 368 1.44
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    3.24-3.40 (m, 4 H) 3.67-3.81 (m, 4 H) 7.06 (d, J = 9.13 Hz, 2
    H) 7.51 (ddd, J = 7.53, 4.75, 1.15 Hz, 1 H)
    7.97 (td, J = 7.74, 1.81 Hz, 1 H) 8.11 (d, J = 8.98 Hz,
    2 H) 8.24 (d, J = 7.86 Hz, 1 H) 8.67-8.75 (m, 1 H)
    13.41 (br. s., 1 H); LCMS (M/Z): M + H+ 368.
    69 4-(morpholine-4-carbonyl)-N-[3-(2-pyridyl)-1,2,4- 396 1.21
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    3.44-3.84 (m, 6 H) 7.45-7.55 (m, 1 H) 7.62 (d, J = 8.35 Hz, 2
    H) 7.99 (td, J = 7.74, 1.71 Hz, 1 H) 8.16-8.34 (m,
    3 H) 8.72 (d, J = 4.05 Hz, 1 H) 13.85 (br. s., 1 H);
    LCMS (M/Z): M + H+ 396.
    70 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 495 1.66
    yl]carbamoyl]benzoyl]piperazine-1-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9
    H) 3.35 (br. s., 2 H) 3.43 (br. s., 2 H) 3.62 (br. s., 2
    H) 7.53 (ddd, J = 7.54, 4.76, 1.07 Hz, 1 H) 7.63 (d,
    J = 8.40 Hz, 2 H) 7.99 (td, J = 7.72, 1.78 Hz, 1 H)
    8.21-8.30 (m, 3 H) 8.73 (d, J = 4.00 Hz, 1 H)
    13.90 (br. s., 1 H); LCMS (M/Z): M + H+ 495.
    71 tert-butyl 4-[[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 509 1.73
    yl]carbamoyl]benzoyl]amino]piperidine-1-
    carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.31-1.53 (m, 11 H) 1.81 (d, J = 9.57 Hz, 2 H) 2.86 (br. s., 2
    H) 3.86-4.08 (m, 3 H) 7.53 (ddd, J = 7.55, 4.77,
    1.10 Hz, 1 H) 7.94-8.07 (m, 3 H) 8.19-8.30 (m,
    3 H) 8.50 (d, J = 7.81 Hz, 1 H) 8.73 (d, J = 4.00 Hz,
    1 H) 13.91 (br. s., 1 H); LCMS (M/Z): M + H+ 509.
    72 4-(piperidine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4- 394 1.54
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.38-1.71 (m, 6 H) 3.25 (br. s., 2 H) 3.61 (br. s., 2 H)
    7.47-7.54 (m, 1 H) 7.57 (d, J = 8.30 Hz, 2 H) 7.99 (td,
    J = 7.72, 1.73 Hz, 1 H) 8.19-8.27 (m, 3 H) 8.73 (d,
    J = 4.10 Hz, 1 H) 13.81 (br. s., 1 H); LCMS (M/Z):
    M + H+ 394.
    73 4-(piperazine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4- 395 0.69
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    3.15-3.25 (m, 4 H) 3.77 (br. s., 4 H) 7.47 (ddd, J = 7.47, 4.81,
    1.10 Hz, 1 H) 7.53 (d, J = 8.30 Hz, 2 H) 7.95 (td,
    J = 7.71, 1.76 Hz, 1 H) 8.14-8.30 (m, 3 H)
    8.63-8.74 (m, 1 H); LCMS (M/Z): M + H+ 395
    74 N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 326
    yl]terephthalamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.61 (s, 1 H) 8.00 (td,
    J = 7.74, 1.76 Hz, 1 H) 8.05 (d, J = 8.54 Hz, 2 H)
    8.17 (s, 1 H) 8.21-8.31 (m, 3 H) 8.68-8.77 (m, 1
    H) 13.90 (br. s., 1 H); LCMS (M/Z): M + H+ 326.
    75 4-(2-pyridylamino)-N-[3-(2-pyridyl)-1,2,4- 375 1.36
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (ddd,
    J = 7.49, 4.76, 0.98 Hz, 1 H) 7.66 (ddd, J = 8.49,
    7.00, 1.93 Hz, 1 H) 7.88 (d, J = 8.88 Hz, 2 H)
    7.97 (td, J = 7.72, 1.73 Hz, 1 H) 8.14 (d, J = 8.88 Hz, 2 H)
    8.21-8.30 (m, 3 H) 8.71 (d, J = 3.95 Hz, 1 H)
    9.57 (s, 1 H); LCMS (M/Z): M + H+ 375.
    76 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 481 1.82
    yl]carbamoyl]anilino]piperidine-1-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.17-1.33 (m, 2 H) 1.34-1.50 (m, 9 H) 1.81-1.96 (m, 2 H)
    2.93 (br. s., 2 H) 3.51-3.66 (m, 1 H) 3.90 (d,
    J = 13.23 Hz, 2 H) 6.60 (s, 1 H) 6.71 (s, 2 H)
    7.51 (ddd, J = 7.55, 4.77, 1.15 Hz, 1 H) 7.90-8.05 (m, 3
    H) 8.24 (s, 1 H) 8.66-8.75 (m, 1 H); LCMS
    (M/Z): M + H+ 481.
    77 4-phenyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 359 1.91
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.40-7.48 (m, 1 H) 7.49-7.56 (m, 3 H) 7.77-7.84 (m, 2 H)
    7.92 (d, J = 8.54 Hz, 2 H) 8.00 (td, J = 7.72, 1.78 Hz,
    1 H) 8.26 (d, J = 7.86 Hz, 1 H) 8.31 (d, J = 8.54 Hz,
    2 H) 8.70-8.77 (m, 1 H) 13.84 (s, 1 H); LCMS
    (M/Z): M + H+ 359.
    78 4-piperazin-1-yl-N-[3-(2-pyridyl)-1,2,4-thiadiazol- 367 0.79
    5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (br. s.,
    4 H) 3.53-3.67 (m, 4 H) 7.14 (d, J = 9.13 Hz, 2 H)
    7.53 (dd, J = 6.61, 4.86 Hz, 1 H) 8.00 (td, J = 7.74,
    1.71 Hz, 1 H) 8.14 (d, J = 8.93 Hz, 2 H) 8.25 (d,
    J = 7.91 Hz, 1 H) 8.72 (d, J = 4.64 Hz, 1 H) 8.88 (br.
    s., 2 H) 13.49 (br. s., 1 H); LCMS (M/Z): M + H+
    367.
    79 4-(4-piperidylamino)-N-[3-(2-pyridyl)-1,2,4- 381 0.8
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (d,
    J = 10.69 Hz, 2 H) 2.07 (d, J = 12.25 Hz, 2 H)
    3.05 (t, J = 10.54 Hz, 2 H) 3.31 (d, J = 11.52 Hz, 2 H)
    3.65 (br. s., 1 H) 6.65 (d, J = 7.47 Hz, 1 H) 6.71 (d,
    J = 8.69 Hz, 2 H) 7.49 (m, J = 6.64, 4.88 Hz, 1 H)
    7.96 (td, J = 7.75, 1.64 Hz, 1 H) 8.02 (s, 2 H)
    8.23 (d, J = 7.86 Hz, 1 H) 8.34 (s, 1 H) 8.71 (d, J = 4.20 Hz,
    1 H); LCMS (M/Z): M + H+ 381.
    80 tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5- 467 1.85
    yl]carbamoyl]phenyl]piperazine-1-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9
    H) 3.38 (dd, J = 6.42, 3.59 Hz, 4 H) 3.43-3.49 (m,
    4 H) 7.05 (d, J = 9.08 Hz, 2 H) 7.50 (ddd, J = 7.50,
    4.80, 0.98 Hz, 1 H) 7.97 (td, J = 7.72, 1.73 Hz, 1 H)
    8.10 (d, J = 8.98 Hz, 2 H) 8.25 (s, 1 H) 8.71 (d,
    J = 4.05 Hz, 1 H); LCMS (M/Z): M + H+ 467.
    81 3-chloro-2-fluoro-N-[3-(2-pyridyl)-1,2,4- 403 1.87
    thiadiazol-5-yl]-5-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.46-7.55 (m, 1 H) 7.98 (td, J = 7.74, 1.76 Hz, 1 H) 8.23 (d,
    J = 7.91 Hz, 1 H) 8.31 (dd, J = 5.49, 1.98 Hz, 1 H)
    8.38 (dd, J = 6.08, 1.98 Hz, 1 H) 8.68-8.75 (m, 1
    H); LCMS (M/Z): M + H+ 403.
    82 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(1,1,2,2- 399 1.74
    tetrafluoroethoxy)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    6.68-7.05 (m, 1 H) 7.45-7.57 (m, 3 H) 7.99 (td, J = 7.75,
    1.73 Hz, 1 H) 8.24 (s, 1 H) 8.28-8.36 (m, 2 H)
    8.68-8.77 (m, 1 H) 13.88 (br. s., 1 H); LCMS
    (M/Z): M + H+ 399.
    83 2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 397 1.8
    yl]-4-(trifluoromethoxy)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3
    H) 7.08 (dd, J = 8.52, 0.85 Hz, 1 H) 7.21 (d, J = 1.81 Hz,
    1 H) 7.48 (ddd, J = 7.54, 4.76, 1.12 Hz, 1 H)
    7.82 (d, J = 8.54 Hz, 1 H) 7.95 (td, J = 7.74, 1.76 Hz,
    1 H) 8.20 (d, J = 7.91 Hz, 1 H) 8.69 (dt, J = 4.75,
    0.85 Hz, 1 H) 13.09 (br. s., 1 H); LCMS (M/Z):
    M + H+ 397.
    84 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5- 341 1.55
    (trifluoromethyl)furan-2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.46-7.59 (m, 2 H) 7.86 (d, J = 3.51 Hz, 1 H) 7.99 (td, J = 7.74,
    1.76 Hz, 1 H) 8.24 (d, J = 7.86 Hz, 1 H)
    8.68-8.77 (m, 1 H); LCMS (M/Z): M + H+ 341.
    85 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5- 357 1.84
    (trifluoromethyl)thiophene-2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (ddd,
    J = 7.49, 4.81, 0.93 Hz, 1 H) 7.91 (dd, J = 4.03, 1.00 Hz,
    1 H) 7.96 (td, J = 7.74, 1.71 Hz, 1 H) 8.21 (d,
    J = 7.86 Hz, 1 H) 8.33 (dd, J = 3.90, 1.07 Hz, 1 H)
    8.70 (d, J = 4.30 Hz, 1 H); LCMS (M/Z): M + H+
    357.
    86 4-formyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 311 1.34
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.99 (td, J = 7.75, 1.78 Hz,
    1 H) 8.06-8.14 (m, 2 H) 8.26 (d, J = 7.86 Hz,
    1 H) 8.37 (d, J = 8.25 Hz, 2 H) 8.69-8.76 (m, 1 H)
    10.14 (s, 1 H) 14.02 (s, 1 H); LCMS (M/Z): M + H+
    311.
    87 4-[hydroxy(phenyl)methyl]-N-[3-(2-pyridyl)- 389 1.62
    1,2,4-thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 5.81 (s, 1
    H) 6.09 (br. s., 1 H) 7.17-7.26 (m, 1 H) 7.32 (t,
    J = 7.54 Hz, 2 H) 7.42 (d, J = 7.22 Hz, 2 H) 7.51 (dd,
    J = 7.35, 4.95 Hz, 1 H) 7.59 (d, J = 8.20 Hz, 2 H)
    7.97 (td, J = 7.74, 1.56 Hz, 1 H) 8.14 (d, J = 8.35 Hz,
    2 H) 8.24 (d, J = 7.86 Hz, 1 H) 8.71 (d, J = 4.20 Hz,
    1 H) 13.65 (br. s., 1 H); LCMS (M/Z): M + H+ 389.
    88 3-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 363 1.76
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.58 (t, J = 7.93 Hz, 1
    H) 7.88-7.94 (m, 1 H) 7.99 (td, J = 7.74, 1.81 Hz,
    1 H) 8.15-8.21 (m, 1 H) 8.25 (d, J = 7.91 Hz, 1 H)
    8.41 (t, J = 1.78 Hz, 1 H) 8.73 (dt, J = 4.73, 0.83 Hz,
    1 H) 13.89 (br. s., 1 H); LCMS (M/Z): M + H+ 363.
    89 4-benzyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 373 1.91
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 4.06 (s, 2
    H) 7.14-7.24 (m, 1 H) 7.25-7.36 (m, 4 H)
    7.46 (d, J = 8.30 Hz, 2 H) 7.56 (br. s., 1 H)
    8.01 (t, J = 7.71 Hz, 1 H) 8.14 (d, J = 8.30 Hz, 2 H)
    8.27 (br. s., 1 H) 8.74 (br. s., 1 H) 13.72 (br. s., 1 H);
    LCMS (M/Z): M + H+ 373.
    90 N4-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 326 1.04
    yl]terephthalamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.61 (s, 1 H) 8.00 (td,
    J = 7.74, 1.76 Hz, 1 H) 8.05 (d, J = 8.54 Hz, 2 H)
    8.17 (s, 1 H) 8.21-8.31 (m, 3 H) 8.68-8.77 (m, 1
    H) 13.90 (br. s., 1 H); LCMS (M/Z): M + H+ 326.
    91 4-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 361 1.72
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.54, 4.73, 1.15 Hz, 1 H) 7.78-7.87 (m, 2 H)
    7.99 (td, J = 7.74, 1.81 Hz, 1 H) 8.08-8.17 (m, 2
    H) 8.19-8.28 (m, 1 H) 8.64-8.78 (m, 1 H)
    13.87 (s, 1 H); LCMS (M/Z): M + H+ 361.
    92 3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4- 401 1.98
    (trifluoromethoxy)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (dd,
    J = 6.66, 4.86 Hz, 1 H) 7.81 (dd, J = 8.61, 1.24 Hz, 1
    H) 7.99 (td, J = 7.72, 1.64 Hz, 1 H) 8.17-8.33 (m,
    2 H) 8.51 (d, J = 2.10 Hz, 1 H) 8.72 (d, J = 4.15 Hz,
    1 H); LCMS (M/Z): M + H+ 401.
    93 N-[3-(4-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 427 2.09
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.49-7.55 (m, 1 H) 7.56-7.63 (m, 2 H) 7.80-7.91 (m, 3 H)
    7.97 (d, J = 8.35 Hz, 2 H) 8.39 (d, J = 8.10 Hz, 2 H)
    8.53 (d, J = 1.22 Hz, 1 H) 8.78 (d, J = 5.12 Hz, 1 H);
    LCMS (M/Z): M + H+ 427.
    94 4-(trifluoromethyl)-N-[3-[5-(trifluoromethyl)-2- 419 2.03
    pyridyl]-1,2,4-thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (d,
    J = 8.35 Hz, 2 H) 8.30-8.50 (m, 4 H) 9.11 (s, 1 H);
    LCMS (M/Z): M + H+ 419.
    95 N4-phenyl-N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 402
    yl]terephthalamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.09-7.20 (m, 1 H) 7.33-7.43 (m, 2 H) 7.48-7.58 (m, 1 H)
    7.75-7.84 (m, 2 H) 8.00 (td, J = 7.74, 1.76 Hz, 1
    H) 8.15 (d, J = 8.54 Hz, 2 H) 8.27 (d, J = 7.91 Hz, 1
    H) 8.34 (d, J = 8.59 Hz, 2 H) 8.74 (d, J = 4.15 Hz, 1
    H) 10.46 (s, 1 H) 13.96 (br. s., 1 H); LCMS (M/Z):
    M + H+ 402.
    96 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2- 351
    (trifluoromethyl) benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (ddd,
    J = 7.55, 4.77, 1.15 Hz, 1 H) 7.77-7.96 (m, 4 H)
    7.99 (td, J = 7.74, 1.81 Hz, 1 H) 8.18-8.26 (m, 1
    H) 8.67-8.77 (m, 1 H) 13.92 (br. s., 1 H); LCMS
    (M/Z): M + H+ 351.
    97 2-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4- 385
    (trifluoromethoxy) benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dd,
    J = 8.69, 1.07 Hz, 1 H) 7.53 (ddd, J = 7.57, 4.76,
    1.15 Hz, 1 H) 7.66 (dd, J = 10.79, 1.56 Hz, 1 H)
    7.99 (td,
    J = 7.74, 1.76 Hz, 1 H) 8.04 (t, J = 8.35 Hz, 1 H)
    8.19-8.28 (m, 1 H) 8.69-8.77 (m, 1 H) 13.82 (br.
    s., 1 H); LCMS (M/Z): M + H+ 385.
    98 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2- 367
    (trifluoromethoxy) benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.55-7.64 (m, 2 H)
    7.70-7.81 (m, 1 H) 7.92 (dd, J = 7.61, 1.61 Hz, 1
    H) 7.98 (td, J = 7.74, 1.81 Hz, 1 H) 8.23 (d, J = 7.86 Hz,
    1 H) 8.72 (dd, J = 4.71, 0.76 Hz, 1 H) 13.84 (br.
    s., 1 H); LCMS (M/Z): M + H+ 367.
    99 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3- 367
    (trifluoromethoxy) benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.68-7.73 (m, 1 H)
    7.73-7.79 (m, 1 H) 7.99 (td, J = 7.74, 1.81 Hz, 1
    H) 8.18 (s, 1 H) 8.21-8.28 (m, 2 H)
    8.67-8.76 (m, 1 H) 13.97 (br. s., 1 H); LCMS (M/Z): M + H+
    367.
    100 4-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4- 393
    thiadiazol-5-yl] benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (d,
    J = 8.83 Hz, 2 H) 7.17-7.25 (m, 2 H)
    7.26-7.37 (m, 2 H) 7.49 (dd, J = 6.56, 4.81 Hz, 1 H) 7.96 (td,
    J = 7.72, 1.68 Hz, 1 H) 8.19-8.30 (m, 3 H) 8.70 (d,
    J = 4.05 Hz, 1 H); LCMS (M/Z): M + H+ 393.
    101 3-hydroxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]- 373
    5-(trifluoromethyl) thiophene-2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d,
    J = 0.98 Hz, 1 H) 7.58 (ddd, J = 7.54, 4.83, 1.05 Hz,
    1 H) 8.03 (td, J = 7.75, 1.73 Hz, 1 H) 8.27 (d,
    J = 7.91 Hz, 1 H) 8.73 (dt, J = 4.78, 0.83 Hz, 1 H);
    LCMS (M/Z): M + H+ 373.
    102 4-(2,4-difluorophenoxy)-N-[3-(2-pyridyl)-1,2,4- 411
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d,
    J = 8.83 Hz, 2 H) 7.16-7.27 (m, 1 H)
    7.37-7.62 (m, 3 H) 7.97 (td, J = 7.74, 1.76 Hz, 1 H)
    8.17-8.29 (m, 3 H) 8.67-8.75 (m, 1 H) 13.72 (br. s., 1
    H); LCMS (M/Z): M + H+ 411.
    103 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-[4- 443
    (trifluoromethyl)phenoxy] benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.25-7.30 (m, 2 H) 7.32 (d, J = 8.54 Hz, 2 H) 7.52 (ddd,
    J = 7.52, 4.78, 1.07 Hz, 1 H) 7.83 (d, J = 8.64 Hz, 2
    H) 7.99 (td, J = 7.74, 1.76 Hz, 1 H) 8.25 (d, J = 7.91 Hz,
    1 H) 8.27-8.34 (m, 2 H) 8.73 (d, J = 4.00 Hz,
    1 H) 13.79 (s, 1 H); LCMS (M/Z): M + H+ 443.
    104 N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4- 443
    (trifluoromethyl)phenoxy]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.26 (d,
    J = 8.49 Hz, 2 H) 7.45-7.56 (m, 2 H) 7.69 (t,
    J = 7.98 Hz, 1 H) 7.79 (d, J = 8.64 Hz, 2 H)
    7.92-8.01 (m, 2 H) 8.03-8.11 (m, 1 H) 8.23 (d, J = 7.86 Hz,
    1 H) 8.66-8.76 (m, 1 H) 13.85 (br. s., 1 H);
    LCMS (M/Z): M + H+ 443.
    105 3-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4- 393
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.13-7.21 (m, 2 H) 7.25-7.32 (m, 2 H) 7.35 (ddd, J = 8.16,
    2.48, 0.68 Hz, 1 H) 7.52 (ddd, J = 7.54, 4.76, 1.12 Hz,
    1 H) 7.61 (t, J = 8.00 Hz, 1 H) 7.73-7.80 (m, 1
    H) 7.92-8.03 (m, 2 H) 8.24 (d, J = 7.86 Hz, 1 H)
    8.72 (dt, J = 4.70, 0.82 Hz, 1 H) 13.83 (br. s., 1 H);
    LCMS (M/Z): M + H+ 393.
    106 3-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 375
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.06-7.15 (m, 2 H) 7.17-7.27 (m, 1 H) 7.36 (ddd, J = 8.16,
    2.45, 0.71 Hz, 1 H) 7.42-7.48 (m, 2 H) 7.52 (ddd,
    J = 7.54, 4.76, 1.12 Hz, 1 H) 7.62 (t, J = 8.00 Hz, 1
    H) 7.76-7.84 (m, 1 H) 7.93-8.04 (m, 2 H)
    8.24 (d, J = 7.86 Hz, 1 H) 8.68-8.75 (m, 1 H) 13.83 (s,
    1 H); LCMS (M/Z): M + H+ 375.
    107 N1-(4-piperidyl)-N4-[3-(2-pyridyl)-1,2,4- 409
    thiadiazol-5-yl]terephthalamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.71-1.89 (m, 2 H) 2.02 (d, J = 11.37 Hz, 2 H) 3.11 (t,
    J = 11.35 Hz, 2 H) 3.49 (d, J = 12.50 Hz, 2 H)
    4.03-4.19 (m, 1 H) 7.42 (dd, J = 6.54, 4.98 Hz, 1 H)
    7.84-7.96 (m, 3 H) 8.16-8.29 (m, 3 H) 8.49 (d,
    J = 7.47 Hz, 1 H) 8.67 (d, J = 4.20 Hz, 1 H); LCMS
    (M/Z): M + H+ 409.
    108 N-[3-(5-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol- 435
    5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (br. s.,
    4 H) 3.43-3.60 (m, 4 H) 7.52 (d, J = 8.59 Hz, 1 H)
    7.96 (d, J = 8.30 Hz, 2 H) 8.10 (d, J = 3.51 Hz, 1 H)
    8.34 (d, J = 8.15 Hz, 2 H) 8.45 (br. s., 1 H) 8.89 (br.
    s., 2 H) 13.91 (br. s., 1 H); LCMS (M/Z): M + H+
    435.
    109 4-(4-piperidyloxy)-N-[3-(2-pyridyl)-1,2,4- 383
    thiadiazol-5-yl]pyridine-2-carboxamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.70-1.84 (m, 2 H) 1.90 (s, 3 H) 2.14 (d, J = 11.62 Hz, 2 H)
    3.10 (t, J = 9.18 Hz, 2 H) 3.24-3.36 (m, 2 H)
    4.87 (d, J = 3.51 Hz, 1 H) 7.13 (dd, J = 5.59, 2.51 Hz, 1
    H) 7.44 (dd, J = 6.91, 5.20 Hz, 1 H) 7.80 (d, J = 2.44 Hz,
    1 H) 7.93 (t, J = 7.03 Hz, 1 H) 8.23 (d, J = 7.91 Hz,
    1 H) 8.50 (d, J = 5.56 Hz, 1 H) 8.68 (d, J = 4.05 Hz,
    1 H); LCMS (M/Z): M + H+ 383.
    110 N-[3-(6-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol- 435
    5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    3.19-3.26 (m, 4 H) 3.73-3.87 (m, 4 H) 7.00 (d, J = 8.40 Hz, 1
    H) 7.61 (d, J = 7.32 Hz, 1 H) 7.69-7.80 (m, 1 H)
    7.89 (d, J = 8.30 Hz, 2 H) 8.36 (d, J = 8.10 Hz, 2 H);
    LCMS (M/Z): M + H+ 435.
    111 4-(3-pyridyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 360
    yl] benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (ddd,
    J = 7.44, 4.78, 0.95 Hz, 1 H) 7.53 (dd, J = 7.96, 4.78 Hz,
    1 H) 7.88-8.00 (m, 3 H) 8.20 (dt, J = 8.00,
    1.95 Hz, 1 H) 8.25 (d, J = 7.86 Hz, 1 H) 8.33 (d,
    J = 8.49 Hz, 2 H) 8.63 (dd, J = 4.76, 1.54 Hz, 1 H)
    8.71 (d, J = 4.00 Hz, 1 H) 9.01 (d, J = 1.81 Hz, 1 H);
    LCMS (M/Z): M + H+ 360.
    112 N-[3-(5-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 427
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.42-7.51 (m, 3 H) 7.55 (t, J = 7.49 Hz, 4 H) 7.78-7.87 (m, 2
    H) 7.95 (d, J = 8.30 Hz, 2 H) 8.22-8.29 (m, 1 H)
    8.30-8.35 (m, 1 H) 8.39 (d, J = 8.10 Hz, 2 H)
    9.04 (d, J = 1.90 Hz, 1 H); LCMS (M/Z): M + H+ 427.
    113 4-(trifluoromethyl)-N-[3-(5-vinyl-2-pyridyl)-1,2,4- 377
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 5.50 (d,
    J = 11.23 Hz, 1 H) 6.09 (d, J = 17.77 Hz, 1 H)
    6.87 (dd, J = 17.74, 11.10 Hz, 1 H) 7.98 (d, J = 8.35 Hz, 2
    H) 8.12 (dd, J = 8.27, 2.17 Hz, 1 H) 8.23 (d, J = 8.20 Hz,
    1 H) 8.38 (d, J = 8.15 Hz, 2 H) 8.79 (d, J = 1.95 Hz,
    1 H); LCMS (M/Z): M + H+ 377.
    114 N-[3-[5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridyl]- 433
    1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (d,
    J = 1.66 Hz, 2 H) 3.86 (t, J = 5.42 Hz, 2 H) 4.27 (d,
    J = 2.64 Hz, 2 H) 6.53 (br. s., 1 H) 7.96 (d, J = 8.30 Hz,
    2 H) 8.02 (dd, J = 8.27, 2.27 Hz, 1 H) 8.23 (s, 1
    H) 8.39 (s, 2 H) 8.83 (d, J = 1.90 Hz, 1 H); LCMS
    (M/Z): M + H+ 433.
    115 N-[3-(6-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 427
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    7.42-7.60 (m, 3 H) 7.99 (d, J = 7.57 Hz, 2 H) 8.09 (br. s., 2 H)
    8.13-8.26 (m, 3 H) 8.39 (d, J = 7.61 Hz, 2 H)
    14.03 (s, 1 H); LCMS (M/Z): M + H+ 427.
    116 N-[3-[6-(3-pyridyl)-2-pyridyl]-1,2,4-thiadiazol-5- 428
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d,
    J = 7.81 Hz, 2 H) 8.11 (br. s., 1 H) 8.23 (br. s., 1 H)
    8.29-8.45 (m, 5 H) 9.07 (br. s., 2 H) 9.66 (br. s., 1
    H); LCMS (M/Z): M + H+ 428.
    117 4-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 374
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.03 (t,
    J = 7.32 Hz, 1 H) 7.12 (d, J = 8.88 Hz, 2 H) 7.22 (d,
    J = 7.52 Hz, 2 H) 7.31-7.39 (m, 2 H) 7.51 (ddd,
    J = 7.50, 4.77, 1.05 Hz, 1 H) 7.98 (td, J = 7.74, 1.76 Hz,
    1 H) 8.10 (d, J = 8.83 Hz, 2 H) 8.24 (d, J = 7.86 Hz,
    1 H) 8.68-8.75 (m, 1 H) 8.91 (s, 1 H)
    13.42 (s, 1 H); LCMS (M/Z): M + H+ 374.
    118 4-(benzylamino)-N-[3-(2-pyridyl)-1,2,4- 388
    thiadiazol-5-yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 4.39 (d,
    J = 5.95 Hz, 2 H) 6.68 (d, J = 8.83 Hz, 2 H)
    7.17-7.41 (m, 7 H) 7.50 (dd, J = 6.83, 4.98 Hz, 1 H)
    7.90-8.03 (m, 3 H) 8.23 (d, J = 7.86 Hz, 1 H) 8.70 (d,
    J = 4.10 Hz, 1 H); LCMS (M/Z): M + H+ 388.
    119 3-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5- 374
    yl]benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 6.91 (t,
    J = 7.30 Hz, 1 H) 7.16 (d, J = 7.61 Hz, 2 H)
    7.24-7.33 (m, 3 H) 7.41 (t, J = 7.86 Hz, 1 H) 7.50 (dd,
    J = 7.03, 5.03
    Hz, 1 H) 7.65 (d, J = 7.66 Hz, 1 H) 7.87 (s, 1 H)
    7.97 (td, J = 7.70, 1.54 Hz, 1 H) 8.24 (d, J = 7.86 Hz,
    1 H) 8.44 (s, 1 H) 8.71 (d, J = 4.34 Hz, 1 H); LCMS
    (M/Z): M + H+ 374.
    120 N-[3-[5-(3-pyridylamino)-2-pyridyl]-1,2,4- 443
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (dd,
    J = 8.27, 4.51 Hz, 1 H) 7.55-7.66 (m, 2 H) 7.82 (d,
    J = 8.25 Hz, 2 H) 8.08-8.17 (m, 2 H) 8.36 (d,
    J = 8.00 Hz, 2 H) 8.44 (dd, J = 4.71, 2.81 Hz, 2 H)
    8.78 (s, 1 H) 11.94 (br. s., 1 H); LCMS (M/Z):
    M + H+ 443.
    121 N-[3-(5-morpholino-2-pyridyl)-1,2,4-thiadiazol-5- 436
    yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (br. s.,
    4 H) 3.70-3.82 (m, 4 H) 7.44 (dd, J = 8.86, 2.95 Hz,
    1 H) 7.94 (d, J = 8.35 Hz, 2 H) 8.09 (d, J = 8.79 Hz,
    1 H) 8.37 (d, J = 8.15 Hz, 2 H) 8.41 (d, J = 2.83 Hz,
    1 H); LCMS (M/Z): M + H+ 436.
    122 N-[3-[5-[2-methoxyethyl(methyl)amino]-2- 438
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.03 (s, 3
    H) 3.26 (s, 3 H) 3.49-3.57 (m, 2 H) 3.61 (d,
    J = 5.22 Hz, 2 H) 7.19 (dd, J = 8.96, 3.05 Hz, 1 H)
    7.97 (d, J = 8.35 Hz, 2 H) 8.04 (d, J = 8.88 Hz, 1 H)
    8.20 (d, J = 2.93 Hz, 1 H) 8.37 (d, J = 8.15 Hz, 2 H);
    LCMS (M/Z): M + H+ 438.
    123 N-[3-(5-pyrrolidin-1-yl-2-pyridyl)-1,2,4- 420
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.92-2.05 (m, 4 H) 3.35-3.39 (m, 4 H) 7.00 (dd, J = 8.79,
    2.93 Hz, 1 H) 7.93 (d, J = 8.30 Hz, 2 H) 8.02 (d,
    J = 2.68 Hz, 1 H) 8.06 (s, 1 H) 8.37 (d, J = 8.10 Hz,
    2 H); LCMS (M/Z): M + H+ 420.
    124 N-[3-[5-(2-pyridylamino)-2-pyridyl]-1,2,4- 443
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 6.86 (dd,
    J = 6.74, 5.32 Hz, 1 H) 6.94 (s, 1 H) 7.58-7.70 (m,
    1 H) 7.92 (d, J = 8.35 Hz, 2 H) 8.16 (d, J = 8.74 Hz,
    1 H) 8.25 (dd, J = 5.00, 1.49 Hz, 1 H) 8.38 (d,
    J = 8.15 Hz, 2 H) 8.47 (dd, J = 8.74, 2.64 Hz, 1 H)
    8.86 (d, J = 2.54 Hz, 1 H) 9.54 (s, 1 H); LCMS
    (M/Z): M + H+ 443.
    125 N-[3-[5-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4- 449
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3
    H) 2.57-2.68 (m, 4 H) 3.33-3.41 (m, 4 H)
    7.44 (dd, J = 8.79, 2.93 Hz, 1 H) 7.95 (d, J = 8.20 Hz, 2
    H) 8.08 (d, J = 8.79 Hz, 1 H) 8.37 (d, J = 8.20 Hz, 2
    H) 8.41 (d, J = 2.93 Hz, 1 H); LCMS (M/Z): M + H+
    449.
    126 tert-butyl 4-[6-[5-[[4- 535
    (trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-
    3-yl]-3-pyridyl]piperazine-1-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9
    H) 3.42-3.58 (m, 4 H) 7.45 (dd, J = 8.88, 2.93 Hz,
    1 H) 7.98 (d, J = 8.35 Hz, 2 H) 8.09 (d, J = 8.79 Hz,
    1 H) 8.37 (d, J = 8.20 Hz, 2 H) 8.42 (d, J = 2.88 Hz,
    1 H) 13.94 (br. s., 1 H); LCMS (M/Z): M + H+ 535.
    127 N-[3-[5-(1-piperidyl)-2-pyridyl]-1,2,4-thiadiazol- 434
    5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s.,
    6 H) 3.22-3.40 (m, 4 H) 7.26 (br. s., 1 H)
    7.41 (dd, J = 8.91, 2.95 Hz, 1 H) 7.97 (s, 2 H) 8.07 (s, 1
    H) 8.27-8.45 (m, 3 H) 13.90 (br. s., 1 H); LCMS
    (M/Z): M + H+ 434.
    128 N-[3-(5-anilino-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 442
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (t,
    J = 7.32 Hz, 1 H) 7.21 (d, J = 7.57 Hz, 2 H)
    7.30-7.37 (m, 2 H) 7.58 (dd, J = 8.69, 2.78 Hz, 1 H)
    7.98 (d, J = 8.35 Hz, 2 H) 8.10 (d, J = 8.69 Hz, 1 H)
    8.38 (d, J = 8.15 Hz, 2 H) 8.43 (d, J = 2.73 Hz, 1 H)
    8.76 (s, 1 H) 13.91 (br. s., 1 H); LCMS (M/Z): M + H+
    442.
    129 N-[3-[5-(4-hydroxy-1-piperidyl)-2-pyridyl]-1,2,4- 450
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (dtd,
    J = 12.86, 9.34, 9.34, 3.86 Hz, 2 H) 1.78-1.89 (m,
    2 H) 3.05 (ddd, J = 12.81, 9.96, 2.95 Hz, 2 H)
    3.64-3.78 (m, 3 H) 4.74 (d, J = 3.37 Hz, 1 H) 7.42 (dd,
    J = 8.93, 2.98 Hz, 1 H) 7.96 (d, J = 8.35 Hz, 2 H)
    8.05 (d, J = 8.83 Hz, 1 H) 8.29-8.44 (m, 3 H);
    LCMS (M/Z): M + H+ 450.
    130 N-[3-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4- 449
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 4
    H) 2.32 (s, 3 H) 2.54 (br. s., 4 H) 3.62 (br. s., 4 H)
    6.92 (d, J = 8.44 Hz, 1 H) 7.53 (d, J = 7.32 Hz, 1 H)
    7.62-7.73 (m, 1 H) 7.90 (d, J = 8.25 Hz, 2 H)
    8.37 (d, J = 8.15 Hz, 2 H); LCMS (M/Z): M + H+ 449.
    131 tert-butyl 4-[6-[5-[[4- 535
    (trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-
    3-yl]-2-pyridyl]piperazine-1-carboxylate
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9
    H) 3.46 (d, J = 5.12 Hz, 4 H) 3.60 (br. s., 4 H)
    6.96 (d, J = 8.44 Hz, 1 H) 7.54 (d, J = 7.27 Hz, 1 H)
    7.67-7.79 (m, 1 H) 7.96 (d, J = 8.35 Hz, 2 H) 8.37 (d,
    J = 8.15 Hz, 2 H); LCMS (M/Z): M + H+ 535.
    132 N-[3-(4-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 365
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3
    H) 7.34 (d, J = 4.69 Hz, 1 H) 7.97 (d, J = 7.81 Hz, 2
    H) 8.10 (s, 1 H) 8.38 (d, J = 8.20 Hz, 2 H) 8.57 (d,
    J = 4.88 Hz, 1 H) M + H┐+ 365.
    133 N-[3-(6-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]- 365
    4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.56 (s, 3
    H) 7.39 (d, J = 7.81 Hz, 1 H) 7.87 (t, J = 7.71 Hz, 1
    H) 8.00 (d, J = 8.20 Hz, 2 H) 8.07 (d, J = 7.42 Hz, 2
    H) 8.39 (d, J = 8.20 Hz, 2 H) M + H┐+ 365.
    134 N-[3-[4-(dimethylaminomethyl)-2-pyridyl]-1,2,4- 408
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s,
    2H) 2.24 (s, 7H) 3.56 (s, 2H) 7.37 (d, J = 4.10 Hz,
    1H) 7.89 (d, J = 8.40 Hz, 2H) 8.24 (s, 1H) 8.37 (d,
    J = 8.20 Hz, 2H) 8.61 (d, J = 4.88 Hz, 1H) M + H┐+
    408.
    135 N-[3-[4-[methyl-[2-(1-piperidyl)ethyl]amino]-2- 491
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (d,
    J = 4.69 Hz, 2H) 1.47 (d, J = 4.88 Hz, 4H) 2.44 (br s,
    4H) 2.52-2.56 (m, 2H) 3.16 (s, 3H) 3.68 (t,
    J = 6.44 Hz, 2H) 6.86 (dd, J = 6.64, 2.34 Hz, 1H)
    7.58 (d, J = 2.54 Hz, 1H) 7.81 (d, J = 8.20 Hz, 2H)
    8.13 (d, J = 6.64 Hz, 1H) 8.36 (d, J = 8.00 Hz, 2H)
    M + H┐+ 491.
    136 N-[3-[4-[methyl(2-morpholinoethyl)amino]-2- 493
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s,
    2H) 2.45 (br s, 5H) 2.52-2.55 (m, 2H) 3.12 (s,
    3H) 3.30-3.37 (m, 4H) 3.53-3.59 (m, 4H)
    3.65 (t, J = 6.54 Hz, 2H) 6.78 (dd, J = 6.25, 2.54 Hz, 1H)
    7.57 (d, J = 2.54 Hz, 1H) 7.80 (d, J = 8.20 Hz, 2H)
    8.15 (d, J = 6.44 Hz, 1H) 8.36 (d, J = 8.00 Hz, 2H)
    M + H┐+ 493
    137 N-[3-(4-pyrrolidin-1-yl-2-pyridyl)-1,2,4- 420
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (t,
    J = 6.35 Hz, 4H) 3.51 (br s, 4H) 6.72 (d, J = 4.30 Hz,
    1H) 7.44 (d, J = 2.34 Hz, 1H) 7.81 (d, J = 8.20 Hz,
    2H) 8.13 (d, J = 6.64 Hz, 1H) 8.36 (d, J = 8.20 Hz,
    2H) M + H┐+ 420
    138 N-[3-[4-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4- 449
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    2.70-2.96 (m, 6H) 3.04-3.28 (m, 3H) 3.55-3.80 (m, 4H)
    4.43 (br s, 1H) 7.37 (dd, J = 6.93, 2.05 Hz, 1H)
    7.82 (d, J = 2.34 Hz, 1H) 8.02 (d, J = 8.20 Hz, 2H)
    8.33-8.45 (m, 3H) M + H┐+ 449.
    139 N-[3-[4-[2-hydroxyethyl(methyl)amino]-2- 424
    pyridyl]-1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s,
    3H) 3.65-3.82 (m, 4H) 7.84 (d, J = 8.00 Hz, 1H)
    8.01 (d, J = 8.20 Hz, 2H) 8.06 (d, J = 8.00 Hz, 1H)
    8.21 (d, J = 7.22 Hz, 1H) 8.39 (d, J = 8.20 Hz, 2H)
    M + H┐+ 424.
    140 N-[3-[4-[2-(1-piperidyl)ethoxy]-2-pyridyl]-1,2,4- 480
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s,
    2H) 2.76 (t, J = 5.56 Hz, 2H) 3.52-3.70 (m, 4H)
    4.27 (t, J = 5.66 Hz, 2H) 7.02 (d, J = 2.93 Hz, 1H)
    7.78 (d, J = 2.34 Hz, 1H) 7.85 (d, J = 8.20 Hz, 2H)
    8.36 (d, J = 8.01 Hz, 2H) 8.46 (d, J = 5.66 Hz, 1H)
    M + H┐+ 480.
    141 N-[3-[4-(2-methoxyethoxy)-2-pyridyl]-1,2,4- 425
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 3.33 (s,
    3H) 3.65-3.80 (m, 2H) 4.34-4.48 (m, 3H)
    7.37 (d, J = 3.90 Hz, 1H) 7.88 (d, J = 1.76 Hz, 1H)
    8.01 (d, J = 8.20 Hz, 2H) 8.39 (d, J = 8.20 Hz, 2H)
    8.64 (d, J = 6.25 Hz, 1H) M + H┐+ 425.
    142 N-[3-[4-(2-dimethylaminoethyloxy)-2-pyridyl]- 438
    1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (d,
    J = 3.90 Hz, 6H) 3.59 (br s, 2H) 4.66 (br s, 2H)
    7.83 (d, J = 8.20 Hz, 2H) 8.00 (d, J = 8.00 Hz, 2H)
    8.07 (d, J = 8.00 Hz, 2H) 8.40 (d, J = 8.01 Hz, 2H) M + H┐+
    438.
    143 N-[3-[4-(2,2-dimethylpropoxy)-2-pyridyl]-1,2,4- 437
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s,
    9H) 3.94 (s, 2H) 7.36 (br s, 1H) 7.90 (br s, 1H)
    8.04 (d, J = 8.00 Hz, 2H) 8.39 (d, J = 8.01 Hz, 2H)
    8.61 (br s, 1H) M + H┐+ 437.
    144 N-[3-[4-[(1-methyl-4-piperidyl)oxy]-2-pyridyl]- 464
    1,2,4-thiadiazol-5-yl]-4-
    (trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.88-2.13 (m, 2H) 2.15-2.32 (m, 2H) 2.71 (d, J = 12.10 Hz,
    3H) 3.13 (br s, 2H) 3.27 (br s, 2H) 4.78-4.94 (m,
    1H) 5.04 (br s, 1H) 7.18-7.31 (m, 1H)
    7.74-7.87 (m, 1H) 7.97 (d, J = 5.66 Hz, 2H) 8.36 (d,
    J = 5.66 Hz, 2H) 8.57 (br s, 1H) M + H┐+ 464.
    145 N-[3-(4-tetrahydropyran-4-yloxy-2-pyridyl)-1,2,4- 451
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    1.64-1.76 (m, 2H) 2.01-2.09 (m, 2H) 3.46-3.61 (m, 2H)
    3.83-3.93 (m, 2H) 4.98 (dt, J = 8.15, 4.22 Hz, 1H)
    7.38 (d, J = 4.69 Hz, 1H) 7.85 (d, J = 2.34 Hz, 1H)
    8.01 (d, J = 8.20 Hz, 2H) 8.39 (d, J = 8.00 Hz, 2H)
    8.61 (d, J = 6.05 Hz, 1H) M + H┐+ 451.
    146 N-[3-[4-(oxetan-3-yloxy)-2-pyridyl]-1,2,4- 423
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm
    3.61-3.82 (m, 2H) 3.84-3.97 (m, 1H) 3.97-4.09 (m, 1H)
    4.91-5.10 (m, 1H) 7.43 (d, J = 3.71 Hz, 1H)
    7.94 (s, 1H) 8.01 (d, J = 8.20 Hz, 2H) 8.39 (d, J = 8.20 hz,
    2H) 8.64 (d, J = 6.25 Hz, 1H) M + H┐+ 423.
    147 N-[3-[4-(hydroxymethyl)-2-pyridyl]-1,2,4- 381
    thiadiazol-5-yl]-4-(trifluoromethyl)benzamide
    1H NMR (400 MHz, DMSO-d6) δ ppm 4.62 (br s,
    2H) 5.49 (br s, 1H) 7.31 (d, J = 4.49 Hz, 1H)
    7.78 (d, J = 8.20 Hz, 2H) 8.22 (s, 1H) 8.36 (d, J = 8.01 Hz,
    2H) 8.56 (d, J = 4.88 Hz, 1H) M + H┐+ 381.
  • 3-Pyridin-2-yl-[1,2,4]thiadiazol-5-ylamine was obtained from commercial sources.
    • Parasiticidal Activity
  • The compounds of formula (I) were tested for activity against Dirofilaria immitis.
  • Dirofilaria immitis Microfilariae Motility Assay
  • Dirofilaria immitis microfilariae are isolated by filtration from blood of an infected beagle dog allowed to incubate at 37 C/5% CO2/95% RH in RPMI media. For assay 500 microfilariae are added into 96-well plates followed by addition of compounds diluted in DMSO for single-point or dose response (5-point) analysis. Ivermectin or emodepside are included as a positive control and DMSO-only wells are included as negative controls. Plates containing parasites and compounds are incubated at 37° C./5% CO2/95% RH for 72 hours and motility is assessed using an LCD camera imaging system. Percent motility inhibition values are generated relative to the average of the DMSO-only wells. For dose response analysis, data points were averaged and curve fitting software is used to generate sigmoidal curves for the determination of EC50 values (i.e. the effective concentration to kill 50% of the organism).
  • Dirofilaria immitis L4 Stage Assay
  • L3 larvae of D. immitis are isolated from infected mosquitoes and allowed to moult into L4 stages in culture. Approximately 5-10 D. immitis L4 stage parasites are added to 96-well plates containing RPMI media and incubated at 37 C/5% CO2/95% RH. The compounds of the invention are diluted in dimethyl sulfoxide (DMSO) and added at a single dose to identify those that affect parasite motility upon microscopic inspection or automated imaging after 72 hours of incubation. Compounds with activity at that concentration are progressed to a five-point dose titration assay and evaluated by microscopic examination or automated imaging of the wells after incubation for 72 hours. Efficacy is based on reduction in motility of the treated L4 larvae as compared to the positive (ivermectin or emodepside) and negative (DMSO) controls. Compounds are evaluated in duplicate and efficacy is reported as the lowest dose that gives 100% inhibition of parasite motility (MIC100) is reported for microscopy assays. For automated imaging assays, percent motility inhibition values are generated relative to the average of the DMSO-only wells and EC90 or EC50 values are generated using curve fitting software.
    • L929 Mouse Fibroblast Cytotoxicity Assay
  • For evaluation of mammalian cell cytotoxicity, L929 fibroblasts are seeded at 2,000 cells/well and exposed to 2-fold dilutions of test compounds directly parallel to the assay for parasitic activity. Plates with parasites or L929 cells are incubated with compounds under appropriate conditions for each cell type. Tamoxifen and taxol are included as a positive control and DMSO-only wells are included as negative controls. After 72 hours of incubation, resazurin (20 μL of 12.5 mg/mL stock in phosphate buffered saline) was added to each well and plates are incubated for an additional 4-6 h. To assess cell viability, fluorescence is read in the EnVision® plate reader (Perkin Elmer, Waltham, Mass.) at an excitation wavelength of 530 nm and emission of 590 nm. Data points are averaged and curve-fitting software is used to generate sigmoidal dose-response curves for the determination of IC50 values.
  • Generally, at concentrations of 100 μM or less, the compounds of the invention demonstrated activity against D. immitis microfilariae or D. immitis L4 stage. The following compounds were determined to have EC50 values less than 5 μM: Compounds 1-47, 49-65, 67, 70, 72, 74-77, 79, 89, 91-94, 96-106, 11-14, 116, 118, 119, 121-129, 131-141, 143, 145-147.
  • All publications, patents and patent applications cited in this specification are incorporated herein by reference in their entireties as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. While the foregoing has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof.

Claims (9)

1-18. (canceled)
19. A method for controlling parasites at a locus which comprises applying to the locus an effective amount of a thiadiazole derivative of formula (I)
Figure US20170202849A1-20170720-C00033
wherein:
A is C═O or SO2;
X is R1 or NHR1;
R1 is:
phenyl optionally substituted by from one to three substituents, which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl and halogen;
naphthyl optionally substituted by from one to three substituents, which are the same or different, each independently selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl and halogen;
quinoxolinyl optionally substituted by from one to three substituents, which are the same or different, each independently selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl and halogen;
quinolinyl optionally substituted by from one to three substituents, which are the same or different, each independently selected from the group consisting nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl and halogen;
or thionyl or furyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, —SO2R5, —NR3SO2R5, —SO2NR3R4, —CONR3R4, —CONHC6H5, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
R2 is hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy, aminoalkyl, alkylaminoalkyl, aryl, heterocyclyl or —CONR3R4; or R2, together with two adjacent carbons of the pyridyl ring to which it is attached, forms a saturated or unsaturated ring containing from 4 to 6 ring atoms;
R3 and R4, which are the same or different, each independently represent hydrogen or alkyl; or when R3 and R4 are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms
R5 is alkyl or haloalkyl;
or a pesticidally acceptable salt thereof.
20. The method of claim 19 wherein controlling parasites comprises treating or preventing parasite infection in a subject in need thereof.
21. The method of claim 19, wherein:
A is C═O;
X is R1;
R1 is phenyl substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, aryloxy, thiomethyl, —SO2CH3, —SO2NH2, —SO2NHCH3, —SO2N(CH3)2 and —NHSO2CH3; and
R2 is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl.
22. The method of claim 19, wherein:
A is SO2;
X is R1;
R1 is phenyl substituted by from one to three substituents which are the same or different selected from the group consisting of trifluoromethyl, trifluoromethoxy, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, thiomethyl, methanesulfonyl, sulfonamide, methylsulfonamide, dimethylsulfonamide, and methylsulfonanilide; and
R2 is hydrogen.
23. The method of claim 19, wherein:
A is C═O or SO2;
X is R1 or NHR1;
R1 is:
phenyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, —NR3R4, cyano, —NR3COR5, alkyl, alkoxy, aryl, heterocyclyl, aryloxy, haloalkyl, haloalkoxy, mercapto (—SH), thioalkyl and halogen;
R2 is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl.
24. The method of claim 19, wherein the compound is selected from one or more of:
1-(4-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea;
1-(2-chlorophenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea;
1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-(trifluoromethyl)phenyl]urea;
1-(3-methoxyphenyl)-3-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]urea;
1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-(trifluoromethoxy)phenyl]urea;
1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[3-(trifluoromethyl)phenyl]urea;
4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]naphthalene-2-carboxamide;
4-trifluoromethoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;
2-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;
4-cyano-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;
4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;
2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethyl)benzenesulfonamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzenesulfonamide;
N-[3-(3-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(4-morpholino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[benzyl(methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(dimethylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[2-methoxyethyl)methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-methoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(4-methoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(triazolo[4,5-b]pyridin-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-bromo-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
methyl 2-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-3-yl]pyridine-4-carboxylate;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]isoquinoline-7-carboxamide;
4-acetamido-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-nitro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]quinoxaline-6-carboxamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-2-carboxamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-3-carboxamide;
N-[3-(4-isopropyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(3-isoquinolyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
3-chloro-4-fluoro-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)benzamide;
4-tert-butyl-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-3,5-bis(trifluoromethyl)benzamide;
N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethyl)benzamide;
3,4-dichloro-N-[3-(5-fluoro-2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-methylsulfonyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]isoquinoline-5-carboxamide;
3-chloro-4-(4-methylpiperazin-1-yl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
methyl 4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoate;
4-(diethylsulfamoyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-methyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]thiophene-2-carboxamide;
3-chloro-4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
2-fluoro-3-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethyl)benzamide;
2,5-dimethyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]furan-3-carboxamide;
4-tert-butyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-1,3-benzodioxole-5-carboxamide;
3,4-dichloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3,5-bis(trifluoromethyl)benzamide;
4-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-(trifluoromethyl)benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoic acid;
4-iodo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-morpholino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-(morpholine-4-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoyl]piperazine-1-carboxylate;
tert-butyl 4-[[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]benzoyl]amino]piperidine-1-carboxylate;
4-(piperidine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-(piperazine-1-carbonyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide;
4-(2-pyridylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]anilino]piperidine-1-carboxylate;
4-phenyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-piperazin-1-yl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-(4-piperidylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
tert-butyl 4-[4-[[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]carbamoyl]phenyl]piperazine-1-carboxylate;
3-chloro-2-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-(trifluoromethyl)benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(1,1,2,2-tetrafluoroethoxy)benzamide;
2-methoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-(trifluoromethyl)furan-2-carboxamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-(trifluoromethyl)thiophene-2-carboxamide;
4-formyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-[hydroxy(phenyl)methyl]-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-benzyl-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N4-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide;
4-bromo-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)benzamide;
N-[3-(4-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
4-(trifluoromethyl)-N-[3-[5-(trifluoromethyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]benzamide;
N4-phenyl-N1-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-(trifluoromethyl) benzamide;
2-fluoro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy) benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-2-(trifluoromethoxy) benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-(trifluoromethoxy) benzamide;
4-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl] benzamide;
3-hydroxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-5-(trifluoromethyl) thiophene-2-carboxamide;
4-(2,4-difluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-[4-(trifluoromethyl)phenoxy] benzamide;
N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]-3-[4-(trifluoromethyl)phenoxy]benzamide;
3-(4-fluorophenoxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-phenoxy-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N1-(4-piperidyl)-N4-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]terephthalamide;
N-[3-(5-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
4-(4-piperidyloxy)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]pyridine-2-carboxamide;
N-[3-(6-piperazin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
4-(3-pyridyl)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl] benzamide;
N-[3-(5-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
4-(trifluoromethyl)-N-[3-(5-vinyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-[5-(3,6-dihydro-2H-pyran-4-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(6-phenyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[6-(3-pyridyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
4-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
4-(benzylamino)-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
3-anilino-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide;
N-[3-[5-(3-pyridylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-morpholino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[5-[2-methoxyethyl(methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-pyrrolidin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[5-(2-pyridylamino)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[5-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
tert-butyl 4-[6-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-3-yl]-3-pyridyl]piperazine-1-carboxylate;
N-[3-[5-(1-piperidyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(5-anilino-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[5-(4-hydroxy-1-piperidyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
tert-butyl 4-[6-[5-[[4-(trifluoromethyl)benzoyl]amino]-1,2,4-thiadiazol-3-yl]-2-pyridyl]piperazine-1-carboxylate;
N-[3-(4-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(6-Methyl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(dimethylaminomethyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[methyl-[2-(1-piperidyl)ethyl]amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[methyl(2-morpholinoethyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(4-pyrrolidin-1-yl-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(4-methylpiperazin-1-yl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[2-hydroxyethyl(methyl)amino]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[2-(1-piperidyl)ethoxy]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(2-methoxyethoxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(2-dimethylaminoethyloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(2,2-dimethylpropoxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-[(1-methyl-4-piperidyl)oxy]-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-(4-tetrahydropyran-4-yloxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide;
N-[3-[4-(oxetan-3-yloxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide; and
N-[3-[4-(hydroxymethyl)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-4-(trifluoromethyl)benzamide,
or a pesticidally acceptable salt thereof.
25. The method of claim 19, wherein the parasite is a helminth.
26. The method of claim 19, wherein the parasite is dirofilaria immitis.
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