WO2016183173A1

WO2016183173A1 - Antiparasitic compounds

Info

Publication number: WO2016183173A1
Application number: PCT/US2016/031814
Authority: WO
Inventors: Jason Daniel Speake; Brent Christopher Beck; Weiming Fan
Original assignee: Avista Pharma Solutions Inc
Current assignee: Avista Pharma Solutions Inc
Priority date: 2015-05-12
Filing date: 2016-05-11
Publication date: 2016-11-17
Anticipated expiration: 2017-11-12

Abstract

The invention relates to thiazole derivatives and their use to treat parasites.

Description

ANTIPARASITIC COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application

No. 62/160,188, filed May 12, 2015, the entire contents of which are hereby incorporated herein by reference.

FIELD

Disclosed herein are thiazole 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-l,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 (mGluRl). WO2002/100826 discloses the preparation of 3,5- diaryl-l,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. WO2007/087427 discloses preparation of thiazole and thiadiazole compounds for treating inflammation, immune disorders, and other diseases.

WO2005/063743 discloses synthesis of thiazole derivatives for adenosine A2A receptor antagonist. WO2001/007423 discloses preparation of heterocycles in drug compositions exhibiting thrombopoietin agonism. WO 2003/062233 discloses preparation of 2-acylaminothiazole derivatives or salts thereof as c-Mpl receptor ligands. WO 2002/062775 discloses preparation of 2-acylaminothiazole derivatives or their salts as promoters of megakaryocyte colony formation.

SUMMARY

In one aspect, provided herein are compounds of the formula (I):

wherein:

A is C=0 or S0₂;

X is R¹ or NHR¹;

R¹ - 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, -S0₂R⁵, -NR³S0₂R⁵, -S0₂NR³R⁴, -CONR³R⁴, -CONHC₆H₅, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto (-SH), thioalkyl and halogen, with the proviso that the optional substitution is not 4-[(2,4- dioxo-5-oxazolidinylidene)methyl, or with the proviso that when Z is 3- trifluoromethylphenyl, the optional substitution is not 2,5-difluoro, or with the proviso that when Z is 1 -piped dinyl, the optional substitution is not 3,5-dimethoxy;

naphthyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, - R³R⁴,

cyano, - R³COR⁵, -alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴,

-CO HC₆H5, 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, - R³R⁴, cyano, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴,

-CO HC₆H₅, 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, - R³R⁴,

cyano, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴,

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, - R³R⁴, cyano, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, 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 -CO R³R⁴; 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; Z is halo, haloalkyl, cyano, optionally substituted alkyl, alkoxy, -CO R³R⁴, optionally substituted cycloalkyl, aminoalkyl, alkylaminoalkyl, optionally substituted heterocyclyl, or optionally substituted aryl;

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, CI 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, pyranyl, furanyl, oxetanyl, azetidinyl, pyrrolidinyl.

"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, gly colic, 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-l-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-di sulfonate, 2- hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2- naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butyl acetate, 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. Internal 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 (^-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=0 or S0₂;

X is R¹ or HR¹;

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, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, hydroxy, alkoxy, haloalkyl, haloalkoxy, mercapto (-SH), thioalkyl and halogen;

-CO HC₆H₅, 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, - R³R⁴, cyano, - R³COR⁵,

alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, 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, - R³R⁴,

cyano, - R³COR⁵, -CO HC₆H₅,

alkyl, -S0₂R⁵,- R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, 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

Z is haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In one embodiment, A is C=0. In another embodiment, A is S0₂.

In one embodiment X is - HR¹. 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, -S0₂CH₃, -S0₂ H₂, -S0₂ HCH₃, -S0₂N(CH₃)₂ and - HS0₂CH₃, with the proviso that when Z is 3 -trifluoromethylphenyl, the optional substitution is not 2,5-difluoro.

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, with the proviso that when Z is 3- trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1-piperidinyl, the optional substitution is not 3,5-dimethoxy; 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 a further embodiment Z is haloalkyl or optionally substituted heterocyclyl. In yet a further embodiment Z is haloalkyl. In yet a further embodiment Z is optionally substituted heterocyclyl. In each of the embodiments discussed above, A, X, Z, R¹ and R² can be independently selected with respect to the A, X, Z, 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=0;

X is HR¹;

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, -S0₂CH₃, -S0₂ H₂, -S0₂ HCH₃, -S0₂N(CH₃)₂

and - HS0₂CH₃, with the proviso that when Z is 3-trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1- piperidinyl, the optional substitution is not 3,5-dimethoxy; 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=0;

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, -S0₂CH₃, -S0₂ H₂, -S0₂ HCH₃, -S0₂N(CH₃)₂ and - HS0₂CH₃, with the proviso that when Z is 3-trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1-piperidinyl, the optional substitution is not 3,5-dimethoxy; and

R² is hydrogen, fluoro, methyl, trifluoromethyl, methoxy,

trifluoromethoxy, morpholino, aminoalkyl or dimethylaminom ethyl.

Z is haloalkyl, cyano, optionally substituted alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl;

A is S0₂;

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, with the proviso that when Z is 3 -trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1- piperidinyl, the optional substitution is not 3,5-dimethoxy; and

R² is hydrogen. In yet a further embodiment, there are provided compounds of formula (I) wherein: A is C=0 or S0₂;

X is R¹ or HR¹;

R¹ is:

cyano, - R³COR⁵, alkyl, alkoxy, aryl, heterocyclyl, aryloxy, haloalkyl, haloalkoxy, mercapto (-SH), thioalkyl and halogen, with the proviso that when Z is 3- trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1 -piped dinyl, the optional substitution is not 3,5-dimethoxy;

R² is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl.

Z is haloalkyl, cyano, optionally substituted alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl; In one embodiment, the compounds are selected from the following compounds ("Cpd" means Compound) of Table 1 :

TABLE 1

(trifluoromethyl)benzamide

N-(4-pyrimidin-2-ylthiazol-2-yl)-4-(trifluoromethyl)benzamide

N- [5-isopropyl-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

3,5-dichloro-N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] benzamide

Nl-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzene-l,3- dicarboxamide

methyl 3- [ [5-cyano-4-(2-pyr idyl)thiazol-2- yl] carbamoyl] benzoate

N- [5-tert-butyl-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N-[5-bromo-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N- [5-phenyl-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [4-(2-pyridyl)-5-(3-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [5-chloro-4-(2-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [5-fluoro-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-(aminomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N- [5- [(dimethylamino)methyl] -4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N-[5-(acetamidomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-(methanesulfonamidomethyl)-4-(2-pyridyl)thiazol-2-yl]-4 (trifluoromethyl)benzamide

N-[5-cyano-4-(4-methoxy-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N- [5-cyano-4-(4-hydroxy-2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

[2-[5-cyano-2-[[4-(trifluoromethyl)benzoyl]amino]thiazol-4-yl]- 4-pyridyl] trifluoromethanesulfonate

N-[5-cyano-4-(4-morpholino-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-cyano-4-[4-(l-piperidyl)-2-pyridyl]thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-cyano-4-[4-(4-methylpiperazin-l-yl)-2-pyridyl]thiazol-2- yl]-4-(trifluoromethyl)benzamide

ethyl 4-(2-pyridyl)-2-[[4-

(trifluoromethyl)benzoyl]amino]thiazole-5-carboxylate

4-(2-pyridyl)-2- [ [4-(trifluoromethyl)benzoyl] amino] thiazole-5- carboxylic acid

N-methyl-4-(2-pyridyl)-2- [[4-

(trifluoromethyl)benzoyl]amino]thiazole-5-carboxamide

N,N-dimethyl-4-(2-pyridyl)-2-[[4-

(trifluoromethyl)benzoyl]amino]thiazole-5-carboxamide

N- [5-(piperidine- l-carbonyl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N-[5-(morpholine-4-carbonyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzamide

N- [4-(2-pyridyl)-5-(4-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [4-(2-pyridyl)-5-(4-pyr idyl)thiazol-2-yl] -4- (trifluoromethoxy)benzamide

3,4-dichloro-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2- yl]benzamide

4-phenoxy-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]benzamide

4-phenyl-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]benzamide

N-[4,5-bis(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

N- [4,5-bis(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzamide

N-[4,5-bis(2-pyridyl)thiazol-2-yl]-3,4-dichloro-benzamide

N- [5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl] -4

(trifluoromethyl)benzamide

3,4-dichloro-N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2- yl]benzamide

N-[4-(2-pyridyl)-5-tetrahydrofuran-3-yl-thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[4-(5-bromo-2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[4-(5-morpholino-2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]- 4-(trifluoromethyl)benzamide

N-[4-[5-(4-acetylpiperazin-l-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

N-[4-[5-(4-isopropylpiperazin-l-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

N-[4-[5-(l,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

N- [4- [5-(4-pyridyl)-2-pyridyl] -5-(trifluoromethyl)thiazol-2-yl] - 4-(trifluoromethyl)benzamide

N-[5-pyrazol-l-yl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N- [5-(4-methylpiperazin-l -yl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N- [5-mor pholino-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

N-[5-(4-acetylpiperazin-l-yl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-imidazol-l-yl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethyl)benzenesulfonamide

N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethoxy)benzenesulfonamide

N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

4-chloro-N-[5-propyl-4-(2-pyridyl)thiazol-2- yl] benzenesulfonamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzenesulfonamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzenesulfonamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethyl)benzenesulfonamide

N- [5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethoxy)benzenesulfonamide

4-chloro-N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2- yl] benzenesulfonamide

N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4-phenoxy- benzenesulfonamide

N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

71 N- [4-(2-pyridyl)-5-(4-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzenesulfonamide

72 N- [4-(2-pyridyl)-5-(4-pyr idyl)thiazol-2-yl] -4- (trifluoromethoxy)benzenesulfonamide

73 3,4-dichloro-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2- yl] benzenesulfonamide

74 N- [5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzenesulfonamide

75 N- [5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzenesulfonamide

76 3,4-dichloro-N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2- yl] benzenesulfonamide

77 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl) phenoxy]benzamide

78 3,4-dichloro-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

79 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4-[4- (trifluoromethyl)phenoxy] benzamide

80 3-phenoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl] benzamide

81 3-(4-fluorophenoxy)-N-[4-(2-pyridyl)-5- (trifluoromethyl)thiazol-2-yl]benzamide

82 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl)phenoxy] benzamide

83 3-chlor o-N- [4-(2-pyridyl)-5-(tr ifluor omethyl)thiazol-2-yl] -5- (trifluoromethyl) benzamide

84 l-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl)phenyl] urea

85 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3- (trifluoromethoxy)benzamide

86 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3- (trifluoromethyl)benzamide

87 4-tert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

88 N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

89 4-phenoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

90 3-tert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

91 4-(2,4-difluorophenoxy)-N-[4-(2-pyridyl)-5- (trifluoromethyl)thiazol-2-yl]benzamide

92 4-methoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

93 3,5-ditert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

94 N- [4-(2-pyridyl)-5-(3-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

95 N- [4-(2-pyridyl)-5-(3-pyr idyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide

96 3,4-dichloro-N-[4-(2-pyridyl)-5-(3-pyridyl)thiazol-2- yl]benzamide

97 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yl]benzamide

98 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yl]benzamide

99 4-phenoxy-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yl]benzamide

100 N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl]-4- (trifluoromethoxy) benzenesulfonamide

101 N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl]-4- (trifluoromethyl) benzenesulfonamide

102 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yl] benzenesulfonamide

103 N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl]-3- (trifluoromethyl)benzamide

104 N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl]-4- (trifluoromethoxy) benzamide

105 N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl]-4- (trifluoromethyl)benzamide

106 3,4-dichloro-N-[4-(2-pyridyl)-5-[l-(2,2,2-trifluoroacetyl)-4- piperidyl]thiazol-2-yl]benzamide

107 3,4-dichloro-N-[5-(4-piperidyl)-4-(2-pyridyl)thiazol-2- yl] benzamide

108 3,4-dichloro-N-[5-(l-methyl-4-piperidyl)-4-(2-pyridyl)thiazol-2- yl] benzamide

109 3,4-dichloro-N-[5-(l-isopropyl-4-piperidyl)-4-(2- pyr idyl)thiazol-2-yl] benzamide

110 3,4-dichloro-N-[4-(2-pyridyl)-5-[l-(3,3,3-trifluoropropanoyl)-4- piperidyl]thiazol-2-yl]benzamide

111 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -5- (trifluoromethyl)thiophene-2-carboxamide

112 4-benzyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

113 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-methoxy-5- (trifluoromethyl)benzamide

114 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4-(4- fluorophenoxy)benzamide

115 3-bromo-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

116 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-5- (trifluoromethyl)benzamide

117 3-chloro-N- [5-cyano-4-(2-pyr idyl)thiazol-2-yl] -4-fluoro- benzamide

118 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3,5- bis(trifluoromethyl)benzamide

119 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethyl)benzamide

120 3,4-dichloro-N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] benzamide

121 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethoxy)benzamide

122 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

123 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4-fluoro-2- (trifluoromethyl)benzamide

124 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -2- (trifluoromethoxy)benzamide

125 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -2-fluoro-4- (trifluoromethoxy)benzamide

126 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-fluoro-5- (trifluoromethyl)benzamide

127 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4-(l ,1 ,2,2- tetrafluoroethoxy)benzamide

128 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-(4-piperidyl)benzamide

129 3,5-ditert-butyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

130 tert-butyl-4-[4-[[5-cyano-4-(2-pyridyl)thiazol-2- yl] carbamoyl] phenyl] sulfonylpiperazine-l-carboxylate

131 tert-butyl-4-[3-[[5-cyano-4-(2-pyridyl)thiazol-2- yl]carbamoyl]phenyl]-piperidine-l-carboxylate

132 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-(3-pyridyl)benzamide

133 3-tert-butyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

134 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-(3-pyridyl)benzamide

135 3-tert-butyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

136 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3-fluoro-5- (trifluoromethyl)benzamide

137 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzamide

138 4-tert-butyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

139 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethyl)benzenesulfonamide

140 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-methoxy-benzamide

141 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethoxy)benzene sulfonamide

142 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -3- (trifluoromethoxy)benzene sulfonamide

143 4-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2- yl] benzenesulfonamide

144 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-fluoro-3-methoxy- benzamide

145 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzenesulfonamide

146 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2,5-dimethyl-furan-3- carboxamide

147 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-methyl-thiophene-2- carboxamide

148 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -2- (trifluoromethyl)benzamide

149 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-methoxy-4- (trifluoromethoxy)benzamide

150 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-piperazin-l-ylsulfonyl- benzamide

151 N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-piperazin-l-ylsulfonyl- benzamide

152 tert-butyl 4- [3- [[5-cyano-4-(2-pyridyl)thiazol-2- yl] carbamoyl] phenyl] sulfonyl piperazine-l-carboxylate

153 N-[5-cyano-4-[4-(trifluoromethyl)-2-pyridyl]thiazol-2-yl]-4- (trifluoromethyl) benzamide

154 N-[5-cyano-4-[5-(trifluoromethyl)-2-pyridyl]thiazol-2-yl]-4- (trifluoromethyl)benzamide

155 N- [5-cyano-4-(2-pyridyl)thiazol-2-yl] -4- (trifluoromethyl)benzamide The Compound numbers 1 to 155 are used to identify the above compounds hereafter. The compounds of the present invention 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):

(Π) wherein R² and Z are as defined above, with a compound of formula (III):

R^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=0 and X is NHR¹ can be prepared by the reaction of a compound of formula (II) as defined above, with a compound of formula 0=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 S0₂ and X is NHR¹ can be prepared by the reaction of a compound of formula (I) with a compound of formula X^OzNHR¹, wherein X¹ and R¹ are as defined above.

Compounds of formula (II) above are commercially available, known in the literature, or can be prepared by the methods shown. 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 the present invention used in the methods disclosed herein can be administered in certain embodiments using pesticidal compositions including at least one compound of the present invention, 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 thiazole 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-Ci₀ 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-Ci₀ glycerides or polyglyceryl-6 dioleate. 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, atachis 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-occuring 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 the present invention 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 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 present invention 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 the present invention. 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 the present invention 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 acancides 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-cypermethrin 107. Ethion 202. Phosmet

13. Alphamethrin 108. Ethiprole 203. Phosphamidon

14. Amidoflumet 109. Ethoprophos 204. Phoxim

15. Amitraz 110. Etofenprox 205. Pirimicarb

16. Anabasine 111. Etoxazole 206. Pirimiphos A

17. Avermectin Bl 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 21 1. 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. lmiprothrin 246. Sulfluramid

57. Chlorpyrifos 152. Indoxacarb 247. Sulfotep

58. Chlorpyrifos-methyl 153. insect-active fungi 248. Sulfur

59. Chromafenozide 154. insect-active nematodes 249. Sulprofos

60. Cis-Resmethrin 155. insect-active viruses 250. Tau-fluvalinate 61. Clofentezin 156. lprobenfos 251. Tebufenozide

62. Clothianidin 157. lsofenphos 252. Tebufenpyrad

63. Coumaphos 158. lsoprocarb 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. Cyfluthnn 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.

(Al ) Abamectin (A2) Albendazole (A3) Cambendazole

(A4) Closantel (A5) Diethylcarbamazine (A6) Doramectin

(A7) Emodepside (A8) Eprinomectin (A9) Febantel

(A10) Fendendazole (Al 1 ) Flubendazole (A12) Ivermectin

(A13) Levamisol (A14) Mebendazole (A15) Milbemectin

(A16) Milbemycin Oxime (A17) Morantel (A 18) 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:

(Rl ) DEET (N, N-diethyl-m-toluamide)

(R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine (R3) Cymiazole = N,- 2,3-dihydro-3-methyl-l ,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, New Jersey, 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 thiazole 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 thiazole derivative of the present invention or a pesticidally acceptable salt thereof. In another embodiment there is provided the use of a thiazole derivative of the present invention or a pesticidally acceptable salt thereof for treating or preventing parasite infection in a subject. In particular, the compounds of the present invention 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 Iyrata, O. ostertagi, O. circumcincta, Cooperia oncophora, C. pectinata, C. punctata, C.

surnabada, C. curtice a, Haemonchus contortus, H. placet, Trichostrongylus axei, T. colubriformis, T. vetrinus, Bunostomum phlebotomum, B. trigonocephalum,

Oesophagostomum radiatum, O. dentatum,.0. venulosum, O. columbianum,

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 cants, 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, Dioctophyma 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, O. 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 the present invention. 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.

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 CI 8, 3.0 x 30 mm, 1.7 μπι, was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 μΐ_^ 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 x 50 mm, 3.5 μπι, was used at a temperature of 50 °C and at a flow rate of 0.8 mL/min, 2 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 G1312Bwith 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 x 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).

Example 1 : N-[5-methyl-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide, Compound 1

5-methyl-4-(2-pyridyl)thiazol-2-amine

To a 40 mL vial was added l-Pyridin-2-yl-propan-l-one (100 mg, 0.74 mmol), thiourea (112 mg, 1.48 mmol), and anhydrous ethanol (1 mL) followed by iodine (188 mg, 0.74 mmol). The mixture was heated at 70 °C under nitrogen overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous sodium thiosulfate solution and saturated NaHCC . The organic layer was then washed with 1 N HC1. The aqueous layer was basified with saturated aqueous sodium bicarbonate to pH = 8 and extracted with EtOAc. The combined organic layer was dried over Na₂SC>4, filtered and concentrated to obtain a tan solid (104 mg), which was used without further purification. Compound 1: N-[5-methyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

To a 40 mL vial was added 5-methyl-4-(2-pyridyl)thiazol-2-amine (100 mg, 0.56 mmol), 4-trifluoromethylbenzoic acid (106 mg, 0.56 mmol), DMF (1 mL), and N,N- diisopropylethylamine (0.2 mL, 1.16 mmol) followed by addition of HATU (228 mg, 0.60 mmol). The mixture was stirred under nitrogen at RT overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3 ^χ). The combined organic layer was dried over Na₂S0₄, filtered and concentrated. The crude product was purified by flash chromatography on ISCO to obtain the product as a white solid. The white solid was dissolve in MeOH and treated with excess IN HC1. After concentration in vacuo, it gave the white solid (-101 mg, 50%) as one HC1 salt. 1H NMR (400 MHz, DMSO-^6) δ ppm 2.74 (s, 3 H) 7.41 (t, J=5.78 Hz, 1 H) 7.91 (d, J=8.25 Hz, 2 H) 7.96 - 8.10 (m, 2 H) 8.27 (d, J=8.15 Hz, 2 H) 8.66 (d, J=4.39 Hz, 1 H) 12.90 (br. s., 1 H); LCMS (M/Z): 364 (M+H).

By proceeding in a similar manner, the following Compounds were prepared: Compound 2: N-[4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

1H NMR (400 MHz, DMSO-^6) δ ppm 7.41 - 7.58 (m, 1 H) 7.92 (d, J=8.30 Hz, 2 H) 8.02 - 8.18 (m, 3 H) 8.29 (d, J=8.15 Hz, 2 H) 8.66 (d, J=4.44 Hz, 1 H) 13.11 (br. s., 1 H); LCMS (M/Z): 350 (M+H).

Compound 3: N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 0.93 (t, J=7.32 Hz, 3 H) 1.67 (sxt, J=7.40 Hz, 2 H) 3.25 (t, J=7.57 Hz, 2 H) 7.38 (t, J=5.83 Hz, 1 H) 7.91 (d, J=8.25 Hz, 2 H) 7.93 - 8.05 (m, 2 H) 8.26 (d, 7=8.15 Hz, 2 H) 8.65 (d, 7=4.93 Hz, 1 H) 12.89 (br. s., 1 H); LCMS (M/Z): 392 (M+H).

Compound 4: N-(4-pyrimidin-2-ylthiazol-2-yl)-4-(trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.41 (t, 7=4.86 Hz, 1 H) 7.91 (d, 7=8.30 Hz, 2 H) 8.15 (s, 1 H) 8.30 (d, 7=8.20 Hz, 2 H) 8.85 (d, 7=4.83 Hz, 2 H) 13.28 (br. s., 1 H); LCMS (M/Z): 351 (M+H).

Compound 5: N-[5-isopropyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H NMR (400 MHz, DMSO-^6) δ ppm 1.31 (d, 7=6.83 Hz, 6 H) 4.36 (dt, 7=13.61, 6.84 Hz, 2 H) 7.29 - 7.39 (m, 1 H) 7.86 - 8.02 (m, 4 H) 8.25 (d, 7=8.20 Hz, 2 H) 8.64 (d, 7=4.20 Hz, 1 H) 12.85 (br. s., 1 H); LCMS (M/Z): 392 (M+H).

2-amino-4-(2-pyridyl)thiazole-5-carbonitrile

To a 40 mL vial was added 3-oxo-3-(2-pyridyl)propanenitrile (1.08 g, 7.4 mmol), thiourea (1.12 g, 14.8 mmol), and pyridine (6 mL) followed by iodine (1.88 mg, 7.4 mmol). The mixture was heated at 100 °C under nitrogen for 12h. The reaction mixture was cooled to RT and diluted with EtOAc and water. The black solid was filtered. The solution was washed with saturate aqueous sodium thiosulfate solution (large excess) and some saturated NaHC0₃. The organic layer was then washed with 1 N HCl three times. Then the combined aqueous solution (HCl) was basified with saturate aqueous sodium bicarbonate to pH = 8 and extracted with EtOAc (3 χ ). The combined organic solution was dried over Na₂S0_4. After filtration and concentration, it gave the product as a brownish solid (0.41 g, 27%), which was used in the next step without further purification. 1H MR (400 MHz, DMSO-^6) δ ppm 7.43 (ddd, J=6.63, 4.62, 2.32 Hz, 1 H) 7.81 - 8.00 (m, 2 H) 8.17 (s, 2 H) 8.54 - 8.72 (m, 1 H); LCMS (M/Z): 204 (M+H).

Compound 6: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.52 (ddd, J=7.46, 4.80, 1.22 Hz, 1 H) 7.95 (d, J=8.30 Hz, 2 H) 7.98 - 8.05 (m, 1 H) 8.05 - 8.11 (m, 1 H) 8.31 (d, J=8.15 Hz, 2 H) 8.73 (d, J=4.05 Hz, 1 H) 13.81 (br. s., 1 H); LCMS (M/Z): 375 (M+H).

Compound 7: 3,5-dichloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.52 (ddd, J=7.39, 4.78, 1.34 Hz, 1 H) 7.95 (t, J=1.88 Hz, 1 H) 7.98 - 8.04 (m, 1 H) 8.04 - 8.09 (m, 1 H) 8.15(d, J=1.90 Hz, 2 H) 8.63 - 8.79 (m, 1 H) 13.72 (br. s., 1 H); LCMS (M/Z): 375 (M+H).

Compound 8: Nl-[5-cyano-4- 2-pyridyl)thiazol-2-yl]benzene-l,3-dicarboxamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.48 - 7.57 (m, 2 H) 7.66 (t, J=7.79 Hz, 1 H) 7.97 - 8.18 (m, 4 H) 8.25 (m, J=7.80 Hz, 1 H) 8.59 - 8.65 (m, 1H) 8.68 - 8.76 (m, 1 H) 13.63 (br. s., 1 H); LCMS (M/Z): 350 (M+H).

Compound 9: methyl 3-[[5-cyano-4-(2-pyridyl)thiazol-2-yl]carbamoyl]benzoate

1H MR (400 MHz, DMSO-^6) δ ppm 3.90 (s, 3 H) 7.52 (ddd, J=7.46, 4.80, 1.22 Hz, 1 H) 7.73 (t, J=7.79 Hz, 1 H) 8.01 (td, J=7.72, 1.73 Hz, 1 H)8.06 - 8.13 (m, 1 H) 8.22 (dt, J=7.82, 1.29 Hz, 1 H) 8.39 (dt, J=8.10, 1.32 Hz, 1 H) 8.70 - 8.77 (m, 2 H) 13.81 (s, 1 H); LCMS (M/Z): 365 (M+H).

5-tert-butyl-4-(2-pyridyl)thiazol-2-amine

To a solution of 3,3-dimethyl-l-(2-pyridyl)butan-l-one (264 mg, 1.5 mmol) was added HO Ac (3 mL) and Br₂ (-450 mg, 3.0 mmol). The mixture was stirred at 50 °C for 18h. LCMS indicated 70% conversion. Additional Br₂ (-230 mg, 1.5 mmol) was added. The mixture was heated for additional 8h. After the removal of solvent, it gave the brownish solid. This solid was dissolved in dioxane (4.5 mL) and pyridine (1.5 mL) and heated with thiourea (-238 mg, 3.0 mmol) at -lOOC for 30 h. LCMS indicated -15% product was formed. The bromo starting material was stable at this condition. Then additional thiourea (-228 mg, 3.0 mmol) was added. The mixture was heated at - lOOC for additional 24 h. After cooled to RT, the solid was removed and washed with MeOH. Then the organic solution was concentrated onto celite. It was purified by RP HPLC (MeOH / water / 0.1% HC0₂H). It gave the product as a yellowish solid (-30 mg, 8.5%). LCMS (M/Z): 234 (M+H).

Compound 10: N-[5-tert-butyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.38 (s, 9 H) 7.86 (d, J=8.20 Hz, 2 H) 8.08 - 8.21 (m, 3 H) 8.28 (d, J=7.66 Hz, 1 H) 8.70 (t, J=7.57 Hz, 1 H) 8.93 (d, J=5.17 Hz, 1 H); LCMS (M/Z): 406 (M+H).

Example 2: N-[5-bromo-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide, Compound 11

To a 40 mL vial was added N-[4-(2-pyridyl)thiazol-2-yl]-4-

(trifluoromethyl)benzamide (-536 mg, 1,42 mmol) and HOAc (4 mL). The mixture was cooled to about 10 °C. Then Br₂ (-244, 1.42 mmol) was added. The mixture was stirred for 30 min and LCMS indicated the reaction was complete. Then water (3 mL) and MeOH (3 mL) was added. After stirring for 5 min, the solvent was removed in vacuo. It gave the product as the light yellowish solid (0.81 g) as HBr salt. Small amount of material was converted into HC1 salt for analysis. 1H NMR (400 MHz, DMSO-^6) δ ppm 7.43 (ddd, J=6.94, 5.02, 1.61 Hz, 1 H) 7.84 - 8.09 (m, 4 H) 8.28 (d, J=8.10 Hz, 2 H) 8.68 (dd, J=4.51, 1.39, Hz, 1 H) 13.34 (br. s., 1 H); LCMS (M/Z): 428 (M+H).

Example 3: N-[5-phenyl-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide, Compound 12

To a 40 mL vial was added N-[5-bromo-4-(2-pyridyl)thiazol-2-yl]-4 - (trifluoromethyl)benzamide (25 mg, 0.05 mmol), phenylboronic acid (-18 mg, 0.15 mmol), dioxane (1 mL), KHCO3 (25 mg, 0.25 mmol), and water (0.25 mL). The reaction solution was degassed and filled with argon three times. Then PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol) was added and the solution was degassed again. The reaction was heated at 80 °C for 20h and 90 °C for 16h. LCMS indicated the reaction was complete. After work-up with EtOAc and water, the crude material was purified by silica gel chromatography (heptanes / EtOAc) and reverse phase HPLC (MeOH / H₂0 with 0.025% concentrated HC1). It gave the product as the yellowish solid (3.5 mg, -16% yield). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.54 (s, 5 H) 7.66 - 7.83 (m, 1 H) 7.83 - 7.99 (m, 3 H) 8.22 (d, J=7.81 Hz, 2 H) 8.28 - 8.48 (m, 1 H) 8.68 - 8.90 (m, 1 H); LCMS (M/Z): 426 (M+H). By proceeding in a similar manner, the following Compounds were prepared:

Compound 13: N-[4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.33 (ddd, J=7.03, 5.10, 1.59 Hz, 1 H) 7.43 (ddd, J=7.92, 4.97, 0.73 Hz, 1 H) 7.76 - 7.90 (m, 5 H) 8.24 (d, 7=8.15 Hz, 2 H) 8.40 - 8.43 (m, 1 H) 8.46 (dd, 7=4.93, 1.56 Hz, 1 H) 8.50 (dd, 7=2.22, 0.71 Hz, 1 H); LCMS (M/Z): 427 (M+H).

Compound 14: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.29 (t, 7=8.69 Hz, 2 H) 7.54 - 7.61 (m, 2 H) 7.70 - 7.80 (m, 1 H) 7.91 (d, 7=8.35 Hz, 3 H) 8.22 (d, 7=8.30 Hz, 2 H) 8.33 - 8.41 (m, 1 H) 8.72 - 8.86 (m, 1 H); LCMS (M/Z): 444 (M+H). Example 4: N-[5-chloro-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide Compound 15

A solution of N-[4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide (69 mg, 0.2 mmol) in DMF (2 raL) was treated with N-chlorosuccirsimide (-27 mg, 0.2 mmol). The reaction mixture was heated at 50 °C for lb. Then additional NCS (27 rag, 0.2 mmol) was added. The mixture was stirred, at 50 °C for additional 2h. Then it was purified by reverse phase HPLC (MeOH / H₂0) to produce the yellowish solid. The solid, was dissolved in MeOH and treated with 4N HC1 to give the light yellowish solid (- 12 mg, 14%) as HC1 salt. 1H MR (400 MHz, DMSO-^6) δ ppm 7.40 (ddd, J=6.87, 4.94, 1.66 Hz, 1 H) 7.83 - 8.01 (m, 4 H) 8.29 (d, J=8.20 Hz, 2 H) 8.67 (d, J=4.25 Hz, 1 H) 13.32 (s, 1 H); LCMS (M/Z): 384 (M+H).

Example 5: N-[5-fluoro-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide Com ound 16

To a 40mL vial was added N-[4-(2-pyridyl)thiazol-2-yl]-4-

(trifluoromethyl)benzamide (69 mg, 0.2 mmol), CH₃CN (1 mL), and DMF (1 mL) followed by Selectfluor (-71 mg, 0.2 mmol). The mixture was stirred at RT for 3 days. LCMS indicated ~70%> conversion occurred. After the removal of solvent, the residue was dissolved in DMSO and water (2 mL) and purified by RP HPLC (MeOH / water / 0.025% concentrated HC1). It gave the yellowish solid (-29 mg, 36%). 1H MR (400 MHz, DMSO-^6) δ ppm 7.37 (ddd, J=7.32, 4.86, 1.29 Hz, 1 H) 7.80 - 7.99 (m, 4 H) 8.27 (d, J=8.20 Hz, 2 H) 8.65 (d, J=4.83 Hz, 1 H) 13.14 (br. s., 1 H); LCMS (M/Z): 368 (M+H). Example 6: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Compound 17.

To a 40 mL vial was added N-[4-(2-pyridyl)thiazol-2-yl]-4-

(trifluoromethyl)benzamide (-35 mg, 0.1 mmol) in DMSO (0.5 mL) and TMSI (-60 mg) in DMSO (0.5 mL) The solution was degassed by Argon. Then Ferrocene (-6 mg, 0.03 mmol) was added followed by 30% H₂0₂ (-20 uL). The above mixture was stirred at 40-50C for 30 min. LCMS indicated the reaction was complete. The reaction mixture was cooled to RT and then purified by RP HPLC (CH₃CN / water / 0.1% HC0₂H). It gave the yellowish solid (-24 mg, 78%) as the parent form. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.43 (t, J=5.00 Hz, 1 H) 7.87 (d, J=8.25 Hz, 2 H) 7.90 - 7.98 (m, 2 H) 8.22 (d, J=8.20 Hz, 2 H) 8.64 (d, J=4.39 Hz, 1 H); LCMS (M/Z): 418 (M+H).

Example 7: N-[5-(aminomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Compound 18

The solution of N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide (225 mg, 0.60 mmol) in MeOH (20 mL) and THF (20 mL) was hydrogenated for about 5 cycles in H-cube at 60C and 50 bar. After removal of solvent, it gave the crude material (190 mg, 84%). A sample was further purified by reverse phase HPLC for characterization. 1H NMR (400 MHz, METHANOL-^) δ ppm 4.57 (s, 2 H) 7.69 (t, J=5.93 Hz, 1 H) 7.88 (d, J=8.20 Hz, 2 H) 8.22 (d, J=8.15 Hz, 2 H) 8.24 - 8.40 (m, 2 H) 8.79 (d, J=4.73 Hz, 1 H); LCMS (M/Z): 379 (M+H).

Example 8 : N- [5- [(dimethylamino)m ethyl] -4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Compound 19

To a 40 ml vial was added N-[5-(aminomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (-12 mg, 0.03 mmol), CH₃CN (0.5 mL), MeOH (-0.5 mL), 37% HCHO (-12 mg, 0.15 mmol), and NaC BH₃ (-27 mg, 0.45 mmol). The mixture was stirred at RT for lh. Then the solution was purified by RP HPLC (CH₃CN / water / 0.1%HC0₂H). It gave the product as the white solid (-3.0 mg, 1 formate salt from HNMR, 23%). 1H MR (500 MHz, METHANOW4) δ ppm 3.03 (s, 6 H) 4.68 (s, 2 H) 7.45 - 7.53 (m, 1 H) 7.90 (d, J=8.30 Hz, 2 H) 8.04 (t, J=7.05 Hz, 1 H) 8.24 (d, J=8.18 Hz, 2 H) 8.26 - 8.54 (m, 4 H) 8.67 - 8.81 (m, 1 H); LCMS (M/Z): 407 (M+H).

Example 9: N-[5-(acetamidomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Com ound 20

To a 40 ml vial was added N-[5-(aminomethyl)-4-(2-pyridyl)thiazol-2-yl]-4-

(trifluoromethyl)benzamide (-37 mg, 0.10 mmol), DMF (1 mL), DIPEA (-174 uL), and Ac₂0 (22 mg, 0.20 mmol). The mixture was stirred at RT for ~2h. Purification by reverse phase HPLC (CH₃CN / water / 0.1%HC0₂H) gave the product as a white solid (-14 mg, 33%). 1H NMR (400 MHz, METHANOL-^4) δ ppm 1.98 (s, 3 H) 4.96 (s, 2 H) 7.30 (dd, J=6.59, 5.03 Hz, 1 H) 7.85 (d, J=8.10 Hz, 3 H) 8.07 (d, J=7.96 Hz, 1 H) 8.18 (d, J=8.15 Hz, 2 H) 8.63 (d, J=4.49 Hz, 1 H); LCMS (M/Z): 421 (M+H).

Example 10: N-[5-(methanesulfonamidomethyl)-4-(2-pyridyl)thiazol-2-yl]-4 (trifluoromethyl)benzamide, Compound 21

To a 40 ml vial was added N-[5-(aminomethyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (-38 mg), DMF (1 mL), DIPEA (-0.17 mL), and CH₃SO₂CI (23 mg). The mixture was stirred at RT for ~2h. Then the solution was purified by RP HPLC (CH₃CN / water / 0.1%HC0₂H). It gave the product as the white solid (-9.7 mg, 21%). HNMR indicated it is a parent form. ¹H MR (400 MHz, METHANOW4) δ ppm 2.94 (s, 3 H) 4.82 (br. s., 2 H) 7.25 - 7.36 (m, 1 H) 7.80 - 7.93 (m, 3 H) 8.12 (d, J=8.00 Hz, 1 H) 8.19 (d, J=8.15 Hz, 2 H) 8.64 (d, J=4.25 Hz, 1 H); LCMS (M/Z): 457 (M+H).

Example 11 : N-[5-cyano-4-(4-morpholino-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Compound 25

To a solution of methyl 4-methoxypyridine-2-carboxylate (3.34 g, 20 mmol) in dry toluene (40 ml) under N₂ was added NaH (60% in oil, 0.80 g, 20 mmol). The mixture was heated to 80 °C and CH₃CN (-4.10 g, 100 mmol) was added slowly. The mixture was stirred for 90 min. A lot of solid (Na salt) appeared. LCMS indicated 100% conversion. The mixture was cooled to RT and dissolved in water and EtOAc. The solution was acidified to PH=~5.5. Then it was extracted with EtOAc (5x). The combined organic solution was dried over Na₂S0₄. After filtration and concentration, it gave the reddish solid (2.68 g, 76%). 1H MR (400 MHz, DMSO-^6) δ ppm 3.69 - 4.04 (m, 3 H) 4.68 (s, 2 H) 7.27 (br. s., 1 H) 7.48 (br. s., 1 H) 8.52 (d, J=5.56 Hz, 1 H); LCMS (M/Z): 177 (M+H).

2-amino-4-(4-methoxy-2-pyridyl)thiazole-5-carbonitrile

To a solution of 3-(4-methoxy-2-pyridyl)-3-oxo-propanenitrile (1.30 g, 7.4 mmol), thiourea (1.12g, 14.8 mmol, and pyridine (8 mL) was added iodine (1.88 g, 7.4 mmol). The mixture was heated at 100 °C for 2h. LCMS indicated starting material disappeared and the desired product was observed as the major product. The workup was same as before. The crude material (—1.13 g) obtained was used without further purification. LCMS (M/Z): 233 (M+H).

Compound 22: N-[5-cyano-4-(4-methoxy-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.89 (s, 3 H) 7.09 (dd, J=5.71, 2.59 Hz, 1 H) 7.62 (d, J=2.49 Hz, 1 H) 7.95 (d, J=8.30 Hz, 2 H) 8.31 (d, J=8.15 Hz, 2 H) 8.53 (d, J=5.71 Hz, 1 H) 13.77 (br. s., 1 H); LCMS (M/Z): 405 (M+H). Compound 23: N-[5-cyano-4-(4-hydroxy-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

The reaction mixture of N-[5-cyano-4-(4-methoxy-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (0.40 g, 1.0 mmol) and LiCl (0.42 g, 10 mmol) in DMF (7 mL) was heated at 140 °C for 30 min. Then it was heated at 150 °C for 70 min by Microwave (125 Power). LCMS indicated the reaction was over. The reaction mixture was treated with water (2 mL). The solution was purified by RP HPLC (MeOH / water / 0.05% concentrated HC1). It gave the yellowish solid (-294 mg, 74%) as HC1 salt. 1H MR (400 MHz, METHANOL-^) δ ppm 7.14 - 7.35 (m, 1 H) 7.80 - 8.03 (m, 3 H) 8.24 (d, 7=7.91 Hz, 2 H) 8.40 - 8.65 (m, 1 H); LCMS (M/Z): 391 (M+H).

Compound 24: [2-[5-cyano-2-[[4-(trifluoromethyl)benzoyl]amino]thiazol-4-yl]-4- pyridyl] trifluoromethanesulfonate

The solution of N-[5-cyano-4-(4-hydroxy-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (-20 mg, 0.05 mmol) and pyridine (-32 mg, 0.4 mmol) in DCM (1 mL) was cooled to 0 °C. Then (CF₃S0₂)₂0 (-28 mg, 0.1 mmol) was added. After lh, additional (CF₃S0₂)₂0 (-14 mg, 0.05 mmol) was added. The mixture was stirred at RT for additional 1 h. Then the reaction was worked up with EtOAc and 10%) NaHC0₃. The organic solution was concentrated to give the crude brownish solid (~31 mg). The material was used for next step without further purification. LCMS (M/Z): 523 (M+H).

Compound 25: N-[5-cyano-4-(4-morpholino-2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

To a 40 mL vial was added [2-[5-cyano-2-[[4-

(trifluoromethyl)benzoyl]amino]thiazol-4-yl]-4-pyridyl] trifluoromethanesulfonate (-26 mg, 0.05 mmol), DMF (1 mL), and morpholine (-0.1 mL). The reaction mixture was stirred at 80 °C for 2 h. After removal of solvent, the residue was purified by RP HPLC (MeOH / water / 0.05% concentrated HC1). It gave the yellowish solid (9.3 mg, 40%) as HC1 salt. 1H MR (400 MHz, METHANOL-^4) δ ppm 3.77 (br. s., 4 H) 3.86 (br. s, 4 H) 7.19 - 7.31 (m, 1 H) 7.85 - 7.96 (m, 3 H) 8.23 (d, J=7.86 Hz, 3 H); LCMS (M/Z): 460 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 26: N-[5-cyano-4-[4-(l-piperidyl)-2-pyridyl]thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^4) δ ppm 1.69 - 1.87 (m, 6 H) 3.79 (d, J=4.34 Hz, 4 H) 7.16 - 7.23 (m, 1 H) 7.85 (d, J=0.44 Hz, 1 H) 7.91 (d, J=8.25 Hz, 2 H) 8.11 - 8.17 (m, 1 H) 8.23 (d, J=8.20 Hz, 2 H); LCMS (M/Z): 458 (M+H). Compound 27: N-[5-cyano-4-[4-(4-methylpiperazin-l-yl)-2-pyridyl]thiazol-2-yl]- 4-(trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 3.00 (br. s., 3 H) 3.74 (br. s., 6 H) 4. (br. s., 2 H) 7.39 (br. s., 1 H) 7.91 (d, J=7.61 Hz, 2 H) 7.98 (br. s., 1 H) 8.24 (d, J=7.76 Hz, 2 H) 8.38 (br. s., 1 H); LCMS (M/Z): 473 (M+H).

Example 12: 4-(2-pyridyl)-2-[[4-(trifluoromethyl)benzoyl]amino]thiazole-5- carboxylic acid, Compound 29

Ethyl 2-amino-4-(2-pyridyl)thiazole-5-carbox late

To a solution of ethyl 3-oxo-3-(2-pyridyl)propanoate (193 mg, 1.0 mmol) in EtOAc (5 mL) was added N-Iodosuceimmide (224 mg, 1.0 mmol) and Amerlyst-15 Resin (180 mg). The mixture was stirred at RT for 30 min LCMS indicated the reaction was almost complete. After additional 30 min, the solid was removed and washed with EtOAc (5 mL). After the removal of solvent, it gave the brownish solid. This solid was dissolved in MeOH (5 mL) and treated with thiourea (152 mg, 2.0 mmol) at -60 °C for lh. LCMS indicated the reaction was complete. After the removal of solvent, the residue was used for next step without further purification. LCMS (M/Z): 250 (M+H).

Compound 28: ethyl 4-(2-pyridyl)-2-[[4- (trifluoromethyl)benzoyl]amino]thiazole-5-carboxylate

1H NMR (400 MHz, METHANOL-^) δ ppm 1.23 (t, J=7.13 Hz, 3 H) 4.24 (q, J=7.16 Hz, 2 H) 7.47 (ddd, J=7.59, 4.95, 1.17 Hz, 1 H) 7.77 - 7.83 (m, 1 H) 7.87 (d, J=8.25 Hz, 2 H) 7.89 - 7.95 (m, 1 H) 8.22 (d, J=8.20 Hz, 2 H) 8.56 - 8.65 (m, 1 H); LCMS (M/Z): 422 (M+H).

Compound 29: 4-(2-pyridyl)-2-[[4-(trifluoromethyl)benzoyl]amino]thiazole-5- carboxylic acid

The reaction mixture of ethyl 4-(2-pyridyl)-2-[[4-

(trifluoromethyl)benzoyl]amino]thiazole-5-carboxylate (126 mg, 0.30 mmol) and LiOH-H₂0 (-48 mg, 1.2 mmol) in MeOH (4 mL) and DMSO (1 mL) and H₂0 (1 mL) was stirred at RT for 1 h and LCMS indicated no reaction occurred. Then additional LiOH-H₂0 (-48 mg, 1.2 mmol) was added and the mixture was heated at 50 °C for 3h. Then the solution was cooled to RT and loaded on RP HPLC column. The column was eluted with CH₃CN and water with 0.1% formic acid. Then it was eluted with MeOH and water with 0.05% concentrated HCl. The peak on spectrum was very broad. It gave the grayish solid (95 mg, 73%) as HCL salt. 1H NMR (400 MHz, DMSO-^6) δ ppm 6.91 - 7.25 (m, 2 H) 7.74 (dd, J=6.59, 5.22 Hz, 1 H) 7.94 (d, J=8.30 Hz, 2 H) 8.26 - 8.36 (m, 3 H) 8.45 (d, J=8.05 Hz, 1 H) 8.81 (d, J=4.30 Hz, 1 H) 13.34 (s, 1 H); LCMS (M/Z): 394 (M+H). Example 13: N-methyl-4-(2-pyridyl)-2-[[4-

(trifluoromethyl)benzoyl]amino]thiazole-5-carboxamide, Compound 30

To a solution of 4-(2-pyridyl)-2-[[4-(trifluoromethyl)benzoyl]amino]thiazole-5- carboxylic acid (39 mg, 0.10 mmol) inDCM (0.5 mL) and DMF (2 mL) was added HOBt (45 mg, 0.30 mmol), MO (0.045 mL, 0.30 mmol), and 2M Me H₂ (0.15 mL, 0.3 mmol) followed by EDCI (57 mg, 0.3 mmol). The reaction was stirred at RT for 18 hour. Then DCM was removed in vacuo. The material was purified by RP HPLC (MeOH / water / 0.05% concentrated HCl). It gave the product as a yellow solid (16.7 mg, HCl salt, 40%). 1H MR (400 MHz, METHANOL-^) δ ppm 2.99 (s, 3 H) 7.88 (d, J=8.10 Hz, 2 H) 7.99 (br. s., 1 H) 8.22 (d, J=8.10 Hz, 2 H) 8.55 - 8.67 (m, 1 H) 8.81 (d, J=7.42 Hz, 1 H) 8.90 (d, J=4.30 Hz, 1 H); LCMS (M/Z): 407 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 31: N,N-dimethyl-4-(2-pyridyl)-2-[[4- (trifluoromethyl)benzoyl]amino]thiazole-5-carboxamide

1H MR (400 MHz, METHANOL-^) δ ppm 3.16 (br. s., 6 H) 7.90 (d, J=8.15 Hz, 2 H) 7.99 - 8.10 (m, 1 H) 8.21 - 8.34 (m, 3 H) 8.66 (t, J=7.52 Hz, 1 H) 8.89 (d, J=5.08 Hz, 1 H); LCMS (M/Z): 421 (M+H). Compound 32: N-[5-(piperidine-l-carbonyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 1.49 - 1.92 (m, 6 H) 3.48 - 3.93 (m, 4 H) 7.90 (d, J=8.05 Hz, 3 H) 8.13 - 8.33 (m, 3 H) 8.50 (d, J=7.61 Hz, 1 H) 8.72 - 8.91 (m, 1 H); LCMS (M/Z): 461 (M+H).

Compound 33: N-[5-(morpholine-4-carbonyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 3.47 - 3.94 (m, 8 H) 7.79 - 7.94 (m, 3 H) 8.22 (d, J=7.86 Hz, 2 H) 8.25 - 8.34 (m, 1 H) 8.46 (t, J=8.79 Hz, 1 H) 8.73 - 8.85 (m, 1 H); LCMS (M/Z): 463 (M+H).

Example 14: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide, Compound 34

2-(4-fluorophenyl)-l-(2-pyridyl)ethanone

To a solution of methyl pyridine-2-carboxylate (2.03 g, 14.8 mmol) and 2-(4- fluorophenyl)acetonitrile (2.00 g, 14.mol) in MeOH (15 mL) was added 25% NaOMe (-5.04 ml, 22.2 mmol). The mixture was heated to reflux about 3h. After cooled to RT, it was poured onto ice water. Adjust the PH to about 5-6 with concentrated HCl and collect the precipitate by vacuum filtration. Then the solid was dissolve in 48%HBr aqueous solution (50 mL) and heated to reflux for 2h. Pour the solution onto ice and adjust PH to 7 with 5N aqueous NaOH solution. Extract the aqueous solution with EtOAc. The combined organic solution was dried by Na₂SC"4. After filtration and concentration, it gave a black solid (-1.40 g, 44%). LCMS (M/Z): 215 (M+H) 5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-amine

To a solution of 2-(4-fluorophenyl)-l-(2-pyridyl)ethanone (215 mg, 1.0 mmol) in DCM (5 mL) at -5 °C was added Br₂ (-159 mg, 1.0 mmol). The mixture was stirred at RT for 3h. After the removal of solvent, the residue was dissolved in EtOH (5 mL) and stirred with thiourea (-152 mg, 2.0 mmol) at ~RT for 20 h. After the removal of solvent, It was purified by RP HPLC (MeOH / water / 0.05% concentrated HCl). It gave the product as a yellowish solid (-205 mg, 75%). LCMS (M/Z): 272 (M+H).

Compound 34: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.22 - 7.35 (m, 2 H) 7.50 (d, J=8.10 Hz, 2 H) 7.54 - 7.62 (m, 2 H) 7.73 (d, J=8.20 Hz, 1 H) 7.92 (t, J=6.35 Hz, 1 H) 8.14 - 8.22 (m, 2 H) 8.37 (td, J=8.00, 1.51 Hz, 1 H) 8.79 (d, J=5.56 Hz, 1 H); LCMS (M/Z): 460 (M+H).

By proceeding in a similar manner as previous examples, the following

Compounds were prepared:

Compound 35: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.25 - 7.35 (m, 2 H) 7.54 - 7.63 (m, 2 H) 7.74 (d, J=8.25 Hz, 1 H) 7.87 - 7.96 (m, 3 H) 8.23 (d, J=8.20 Hz, 2 H) 8.32 - 8.43 (m, 1 H) 8.79 (d, J=5.32 Hz, 1 H); LCMS (M/Z): 444 (M+H).

Compound 36: N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.89 - 7.99 (m, 3 H) 8.12 (d, J=8.10 Hz, 1 H) 8.20 (d, J=6.88 Hz, 2 H) 8.26 (d, J=8.20 Hz, 2 H) 8.41 (td, J=7.94, 1.54 Hz, 1 H) 8.79 - 8.88 (m, 3 H); LCMS (M/Z): 427 (M+H).

Compound 37: N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

H MR (400 MHz, METHANOL-^) δ ppm 7.50 (d, J=8.25 Hz, 2 H) 7.91 - 8.29 (m, 6 H) 8.42 (t, J=7.88 Hz, 1 H) 8.84 (d, J=6.54 Hz, 3 H); LCMS (M/Z): 443 (M+H).

Compound 38: 3,4-dichloro-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.77 (d, J=8.44 Hz, 1 H) 7.79 - 7.88

(m, 1 H) 8.01 (dd, J=8.40, 1.42 Hz, 1 H) 8.07 - 8.12 (m, 1 H) 8.14 (d, J=6.83 Hz, 2 H) 8.23 - 8.35 (m, 2 H) 8.70 - 8.76 (m, 1 H) 8.79 (d, J=6.78 Hz, 2 H); LCMS (M/Z): 427 (M+H). Compound 39: 4-phenoxy-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.04 - 7.15 (m, 4 H) 7.19 - 7.29 (m, 1 H) 7.35 - 7.49 (m, 2 H) 7.94 (br. s., 1 H) 8.09 (d, J=8.83 Hz, 3 H) 8.17 (d, J=6.44 Hz, 2 H) 8.38 (t, J=7.91 Hz, 1 H) 8.81 (d, J=6.25 Hz, 3 H); LCMS (M/Z): 451 (M+H).

Compound 40: 4-phenyl-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.37 - 7.45 (m, 1 H) 7.45 - 7.54 (m, 2 H) 7.67 - 7.79 (m, 3 H) 7.86 (d, J=8.15 Hz, 2 H) 8.05 - 8.27 (m, 6 H) 8.61 - 8.70 (m, H) 8.76 (d, J=6.25 Hz, 2 H); LCMS (M/Z): 435 (M+H).

Compound 41: N-[4,5-bis(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.43 - 7.52 (m, 1 H) 7.56 - 7.65 (m, 1 H) 7.70 (d, J=8.35 Hz, 1 H) 7.87 - 8.00 (m, 3 H) 8.03 - 8.21 (m, 2 H) 8.30 (d, J=8.15 Hz, 2 H) 8.75 (d, J=4.78 Hz, 2 H) 13.29 (br. s., 1 H); LCMS (M/Z): 427 (M+H).

Compound 42: N-[4,5-bis(2-pyridyl)thiazol-2-yl]-4-(trifluoromethoxy)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.50 (d, J=8.83 Hz, 2 H) 7.79 (ddd, J=6.99, 5.99, 0.98 Hz, 1 H) 7.89 (ddd, J=7.04, 5.97, 1.15 Hz, 1 H) 8.18 - 8.27 (m, 3 H) 8.31 - 8.39 (m, 1 H) 8.45 (td, J=7.96, 1.66 Hz, 1 H) 8.82 (d, J=8.20 Hz, 1 H) 9.02 (t, J=6.32 Hz, 2 H); LCMS (M/Z): 443 (M+H).

Compound 43: N-[4,5-bis(2-pyridyl)thiazol-2-yl]-3,4-dichloro-benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.45 - 7.53 (m, 1 H) 7.58 - 7.66 (m, 1 H) 7.70 (d, J=8.20 Hz, 1 H) 7.84 (d, J=8.44 Hz, 1 H) 7.88 - 7.97 (m, 1 H) 8.03 - 8.12 (m, 2 H) 8.12 - 8.19 (m, 1 H) 8.39 (d, J=2.05 Hz, 1 H) 8.75 (d, J=4.93 Hz, 2 H) 13.19 (br. s., 1 H); LCMS (M/Z): 427 (M+H).

Example 15: N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl]-4

(trifluorometh l)benzamide, Compound 44

2-cyclopropyl-l-(2-pyridyl)ethanone

To a solution of 2-bromopyridine (10.2 g, 13.0 mmol) in THF (40 mL) was added isopropylMgCl (32.5 mL, 65 mmol) slowly at RT. The reaction mixture was stirred at RT for 3h. Then cyclopropylacetonitrile (5.3 g, 65 mmol) was added slowly. After addition, the mixture was stirred at RT for 18h. Then it was quenched with water (50 mL) and treated with concentrated HC1 until PH reached -7. The solution was extracted with EtOAc (3 x 75 mL). After dried over Na₂S0₄ and filtration, the solvent was removed to give the brownish oil. The crude material was further purified by silica gel chromatography (Hepanes / EtOAc). It gave the crude brownish oil (2.27 g, 21.7%). LCMS (M/Z): 162 (M+H).

5-cyclopropyl-4-(2-pyridyl)thiazol-2-amine

To a solution of 2-cyclopropyl-l-(2-pyridyl)ethanone ( 1.61 g, 10 mmol) in DCE (10 mL) at RT was added Br₂ (-1.59 g, 10 mmol). The mixture was stirred at 50 °C for 3h. After the removal of solvent, the residue was dissolved in EtOH (10 mL) and thiourea (-1.52 g, 20 mmol) was added. The mixture was heated at -80C for 3 h. After cooled to RT, celite was added and the solvent was removed. The material was loaded onto cartridge and was purified silica gel chromatography (10% MeOH in DCM with 01% saturated H₄OH / DCM). It gave the crude product (-620 mg, 28.6%). LCMS (M/Z): 218 (M+H).

Compound 44: N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.92 - 0.98 (m, 2 H) 1.34 - 1.41 (m, 2 H) 2.37 (tt, J=8.22, 5.17 Hz, 1 H) 7.90 (d, J=8.25 Hz, 2 H) 7.99 (ddd, J=7.39, 6.03, 1.32 Hz, 1 H) 8.20 (d, J=8.15 Hz, 2 H) 8.65 - 8.71 (m, 1 H) 8.71 - 8.76 (m, 1 H) 8.81 (d, J=5.32 Hz, 1 H); LCMS (M/Z): 390 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 45: 3,4-dichloro-N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2- yljbenzamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.89 - 0.98 (m, 2 H) 1.33 - 1.41 (m, 2 H) 2.35 (tt, J=8.23, 5.17 Hz, 1 H) 7.74 (d, J=8.40 Hz, 1 H) 7.90- 8.04 (m, 2 H) 8.19 (d, J=2.10 Hz, 1 H) 8.60 - 8.75 (m, 2 H) 8.81 (d, J=5.47 Hz, 1 H); LCMS (M/Z): 390 (M+H).

Compound 46: N-[4-(2-pyridyl)-5-tetrahydrofuran-3-yl-thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 2.04 - 2.18 (m, 1 H) 2.54 - 2.67 (m, 1 H) 3.86 (dd, J=8.76, 5.15 Hz, 1 H) 3.90 - 3.99 (m, 1 H) 4.08 - 4.20 (m, 2 H) 4.25 - 4.37 (m, 1 H) 7.82 - 7.94 (m, 3 H) 8.19 (d, J=8.20 Hz, 2 H) 8.28 (d, J=8.15 Hz, 1 H) 8.49 (t, J=7.54 Hz, 1 H) 8.79 (d, J=5.66 Hz, 1 H); LCMS (M/Z): 420 (M+H).

Example 16 : N- [4-(5-bromo-2-pyridyl)-5-(trifluor omethyl)thiazol-2-yl] -4- (trifluorometh l)benzamide, Compound 47

1H NMR (400 MHz, METHANOL-^) δ ppm 7.88 (d, J=8.30 Hz, 2 H) 7.98 (d, J=8.59 Hz, 1 H) 8.10 (dd, J=8.47, 2.32 Hz, 1 H) 8.22 (d, J=8.15 Hz, 2 H) 8.73 (br. s., 1 H); LCMS (M/Z): 497 (M+H).

Example 17: N-[4-(5-morpholino-2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Com ound 48

To a solution of N-[4-(5-bromo-2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (-25 mg, 0.05 mmol) and morpholine (-22 mg, 0.25 mmol) in toluene (1.5 mL) was added BINAP (16 mg, 0.025 mmol) and KO-t-Bu (23 mg, 0.20 mmol). The reaction was degassed and filled with nitrogen three times. Then Pd(OAc)2 (8.4 mg, 0.013 mmol) was added. The reaction mixture was heated at 100 °C for 2h. After work-up with EtOAC and water, the residue was purified by silica gel chromatography (EtOAc and heptanes) and then RP HPLC (MeOH and water with 0.05% concentrated HC1). It gave the yellowish solid (~3 mg, 12%) as 1 HC1 salt. 1H NMR (400 MHz, METHANOL-^) δ ppm 3.43 - 3.52 (m, 4 H) 3.81 - 3.92 (m, 4 H) 7.90 (d, J=8.30 Hz, 2 H) 7.94 - 8.10 (m, 2 H) 8.23 (d, J=8.15 Hz, 2 H) 8.38 (br. s., 1 H); LCMS (M/Z): 503 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 49: N-[4-[5-(4-acetylpiperazin-l-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 2.16 (s, 3 H) 3.49 - 3.67 (m, 4 H) 3.72 - 3.84 (m, 4 H) 7.90 (d, J=8.30 Hz, 2 H) 7.97 - 8.11 (m, 2 H) 8.22 (d, J=8.15 Hz, 2 H) 8.40 (br. s., 1 H); LCMS (M/Z): 544 (M+H).

Compound 50: N-[4-[5-(4-isopropylpiperazin-l-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2- l]-4-(trifluoromethyl)benzamide

¹H MR (400 MHz, METHANOL-^4) δ ppm 1.43 (d, J=6.69 Hz, 6 H) 3.32 - 3.47 (m, 4 H) 3.55 - 3.72 (m, 3 H) 4.22 (d, 7=11.81 Hz, 2 H) 7.85 - 7.96 (m, 3 H) 8.05 (d, J=9.13 Hz, 1 H) 8.23 (d, J=8.20 Hz, 2 H) 8.51 (br. s., 1 H); LCMS (M/Z): 544 (M+H).

Example 18: N-[4-[5-(l,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]-5- (trifluoromethyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide, Compound 51

To a solution of N-[4-(5-bromo-2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide (-30 mg, 0.05 mol) and tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (46 mg, 0.15 mmol) in EtOH (1.5 mL) and water (0.3 mL) was added KHC0₃ (50 mg, 0.5 mmol). The reaction was degassed and filled with nitrogen three times. Then PdCl₂(PPh₃)₂ (14 mg, 0.02 mmol) was added. The reaction mixture was heated at 80 °C for lh. After work-up with EtOAC and water, the residue was purified by silica gel

chromatography (EtOAc and heptanes). It gave the yellowish solid (14 mg, 46%). This material was dissolved in DCM (2 mL) and TFA (0.25 mL) was added. The reaction mixture was stirred at RT for 2h. Then the solvent was removed and the residue was purified by RP HPLC (MeOH and water with 0.05% concentrated HCl). It gave the light yellowish solid as 2 HCl salt (~8 mg, 32%). 1H MR (400 MHz, METHANOL-^) δ ppm 2.86 - 2.96 (m, 2 H) 3.53 (t, J=6.15 Hz, 2 H) 3.94 (d, J=3.12 Hz, 2 H) 6.47 - 6.54 (m, 1 H) 7.48 - 7.68 (m, 1 H) 7.90 (d, J=8.20 Hz, 2 H) 8.16 (d, J=8.20 Hz, 1 H) 8.24 (d, J=8.20 Hz, 2 H) 8.33 (dd, J=8.40, 2.15 Hz, 1 H) 8.91 (s, 1 H); LCMS (M/Z): 499 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 52: N-[4-[5-(4-pyridyl)-2-pyridyl]-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.89 (d, J=8.30 Hz, 2 H) 8.24 (d, J=8.10 Hz, 2 H) 8.33 (d, J=8.49 Hz, 1 H) 8.48 - 8.58 (m, 3 H) 8.94 (d, J=6.93 Hz, 2 H) 9.27 (d, J=2.05 Hz, 1 H); LCMS (M/Z): 495 (M+H).

Example 19: N-[5-pyrazol-l-yl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluorometh l)benzamide, Compound 53

The mixture of N-[5-bromo-4-(2-pyridyl)thiazol-2-yl]-4-(trifluoromethyl)benzamide (45 mg, 0.25 mmol), pyrazole (85 mg, 1.25 mmol), DMF (1 mL), and K₂C0₃ (103 mg, 0.75 mmol) was heated at ~115 °C for 18h. LCMS indicated the reaction was over. After workup with EtOAc and water, the residue was purified by silica gel chromatography (EtOAc and heptanes). After treatment with a few drops of concentrated HCl in MeOH and concentration, it gave the light yellowish solid (16 mg) as HCl salt. The material was further purified by RP HPLC (MeOH / water / 0.05% concentrated HCl). It gave the light yellowish solid (~9 mg, 15%) as HCl salt. 1H NMR (400 MHz, METHANOL-^) δ ppm 6.72 (t, J=2.22 Hz, 1 H) 7.74 (d, J=8.25 Hz, 1 H) 7.91 (d, J=8.25 Hz, 2 H) 7.95 - 8.03 (m, 2 H) 8.17 (d, J=2.54 Hz, 1 H) 8.24 (d, J=8.20 Hz, 2 H) 8.45 - 8.58 (m, 1 H) 8.88 (br. s., 1 H); LCMS (M/Z): 416 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 54: N-[5-(4-methylpiperazin-l-yl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 2.95 (s, 3 H) 3.33 (d, J=3.81 Hz, 1 H) 3.52 - 3.81 (m, 5 H) 5.39 (d, J=9.71 Hz, 2 H) 6.97 (t, J=6.81 Hz, 1 H) 7.24 (dd, J=9.05, 6.66 Hz, 1 H) 7.89 (d, J=8.15 Hz, 2 H) 8.09 (d, J=6.93 Hz, 1 H) 8.23 (d, J=8.05 Hz, 2 H) 8.39 (d, J=9.22 Hz, 1 H); LCMS (M/Z): 448 (M+H).

Compound 55: N-[5-morpholino-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 3.76 - 3.85 (m, 4 H) 4.20 (br. s., 4 H) 7.03 (t, J=6.52 Hz, 1 H) 7.25 (dd, J=9.37, 6.54 Hz, 1 H) 7.90 (d, J=8.30 Hz, 2 H) 8.11 (d, J=9.42 Hz, 1 H) 8.18 (d, J=7.22 Hz, 1 H) 8.24 (d, J=8.15 Hz, 2 H); LCMS (M/Z): 435 (M+H). Compound 56: N-[5-(4-acetylpiperazin-l-yl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.99 - 2.24 (m, 3 H) 3.74 (br. s., 4 H) 4.05 - 4.46 (m, 4 H) 6.96 (br. s., 1 H) 7.15 - 7.26 (m, 1 H) 7.89 (d, J=7.86 Hz, 2 H) 8.07 (d, J=6.59 Hz, 1 H) 8.17 - 8.32 (m, 3 H); LCMS (M/Z): 476 (M+H). Compound 57: N-[5-imidazol-l-yl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.31 - 7.46 (m, 1 H) 7.70 - 7.79 (m, 1 H) 7.84 - 7.92 (m, 3 H) 7.98 (br. s., 1 H) 8.07 - 8.14 (m, 1 H)8.24 (d, J=8.20 Hz, 2 H) 8.39 (br. s., 1 H) 9.43 (d, J=1.02 Hz, 1 H); LCMS (M/Z): 416 (M+H).

Example 20: N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide, Compound 58

To the solution of 5-propyl-4-(2-pyridyl)thiazol-2-amine (35 mg, 0.092 mmol) in DCE (1 mL) was added Et₃N (0.028 mL, 0.20 mmol) and 4- trifluoromethylphenylsolfonyl chloride (30 mg, 0.12 mmol). The reaction was carried out at 50 °C for 20h and about 25% product formed. After the removal of solvent, the residue was dissolved in MeOH (1 mL) and purified by RP HPLC (CH₃CN and water with 0.1% HC0₂H). It gave the light yellowish solid (12.7 mg). 1H MR (400 MHz, METHANOW4) δ ppm 0.94 (t, J=7.35 Hz, 3 H) 1.66 (sxt, J=7.45 Hz, 2 H) 2.79 - 2.92 (m, 2 H) 7.38 (dd, J=7.17, 5.03 Hz, 1 H) 7.59 (d, J=7.96 Hz, 1 H) 7.82 (d, J=8.30 Hz, 2 H) 7.89 (td, J=7.81, 1.66 Hz, 1 H) 8.08 (d, J=8.25 Hz, 2 H) 8.62 (d, J=4.49 Hz, 1 H); LCMS (M/Z): 428 (M+H).

By proceeding in a similar manner, the following Compounds were prepared:

Compound 59: N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethyl)benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.84 - 1.02 (m, 3 H) 1.66 (ddt,

J=10.73, 7.18, 3.66, 3.66 Hz, 2 H) 2.87 (td, J=7.16, 3.64 Hz, 2 H) 7.39 (d, J=3.76 Hz, 1 H) 7.59 (d, J=7.61 Hz, 1 H) 7.66 - 7.77 (m, 1 H) 7.82 - 7.94 (m, 2 H) 8.15 (br. s., 2 H) 8.62 (br. s., 1 H); LCMS (M/Z): 428 (M+H).

Compound 60: N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethoxy)benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.95 (t, J=7.35 Hz, 3 H) 1.55 - 1.74 (m, 2 H) 2.78 - 2.94 (m, 2 H) 7.33 - 7.42 (m, 1 H) 7.49 (dt, J=8.27, 1.13 Hz, 1 H) 7.63 (q, J=7.96 Hz, 2 H) 7.79 (s, 1 H) 7.85 - 7.97 (m, 2 H) 8.63 (d, J=4.34 Hz, 1 H); LCMS (M/Z): 444 (M+H). Compound 61: N-[5-propyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

¹H MR (400 MHz, METHANOL-^) δ ppm 0.94 (t, J=7.35 Hz, 3 H) 1.56 - 1.72 (m, 2 H) 2.77 - 2.89 (m, 2 H) 7.32 - 7.44 (m, 3 H) 7.59 (d, J=7.96 Hz, 1 H) 7.88 (td, J=7.81, 1.81 Hz, 1 H) 7.95 - 8.08 (m, 2 H) 8.53 - 8.68 (m, 1 H); LCMS (M/Z): 444 (M+H).

Compound 62: 4-chloro-N-[5-propyl-4-(2-pyridyl)thiazol-2- yljbenzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.00 (t, J=7.27 Hz, 3 H) 1.62 - 1.83 (m, 2 H) 2.98 (t, 7=7.61 Hz, 2 H) 7.57 (d, 7=8.59 Hz, 2 H) 7.88 - 8.00 (m, 3 H) 8.17 (d, 7=8.10 Hz, 1 H) 8.59 (t, 7=7.74 Hz, 1 H) 8.77 (d, 7=5.52 Hz, 1 H); LCMS (M/Z): 394 (M+H).

Compound 63: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.10 - 7.27 (m, 2 H) 7.34 - 7.48 (m, H) 7.54 - 7.65 (m, 1 H) 7.88 (d, 7=8.35 Hz, 2 H) 7.96 (t, 7=7.54 Hz, 1 H) 8.15 (d, 7=8.25 Hz, 2 H) 8.66 (d, 7=4.59 Hz, 1 H); LCMS (M/Z): 480 (M+H).

Compound 64: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.14 - 7.27 (m, 2 H) 7.39 - 7.54 (m, 5 H) 7.68 (t, J=6.49 Hz, 1 H) 8.02 - 8.15 (m, 3 H) 8.68 (dd, J=5.47, 0.78 Hz, 1 H); LCMS (M/Z): 496 (M+H).

Compound 65: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethyl)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.13 - 7.26 (m, 2 H) 7.40 - 7.53 (m, 3 H) 7.66 - 7.74 (m, 1 H) 7.75 - 7.83 (m, 1 H) 7.96 (d, J=7.86 Hz, 1 H) 8.09 (t, J=7.54 Hz, 1 H) 8.21 - 8.28 (m, 2 H) 8.60 - 8.76 (m, 1 H); LCMS (M/Z): 480 (M+H).

Compound 66: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethoxy)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.15 - 7.26 (m, 2 H) 7.41 - 7.50 (m, 3 H) 7.57 (dt, J=8.36, 1.09 Hz, 1 H) 7.65 - 7.74 (m, 2 H) 7.85 (s, 1 H) 7.97 (d, J=7.91 Hz, 1 H) 8.07 (t, J=7.59 Hz, 1 H) 8.69 (d, J=4.73 Hz, 1 H); LCMS (M/Z): 496 (M+H). Compound 67: 4-chloro-N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2- yl] benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.15 - 7.28 (m, 2 H) 7.42 - 7.52 (m, 3 H) 7.56 - 7.63 (m, 2 H) 7.66 - 7.77 (m, 1 H) 7.92 - 8.00 (m, 2 H) 8.11 (t, J=8.10 Hz, 1 H) 8.65 - 8.73 (m, 1 H); LCMS (M/Z): 446 (M+H).

Compound 68: N-[5-(4-fluorophenyl)-4-(2-pyridyl)thiazol-2-yl]-4-phenoxy- benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.03 - 7.10 (m, 4 H) 7.18 - 7.27 (m, 3 H) 7.37 - 7.55 (m, 5 H) 7.71 (t, J=6.44 Hz, 1 H) 7.89 - 7.98 (m, 2 H) 8.11 (t, J=7.57 Hz, 1 H) 8.68 (d, J=4.78 Hz, 1 H); LCMS (M/Z): 504 (M+H).

Compound 69: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.68 (dd, J=7.32, 5.56 Hz, 1 H) 7.82 7.93 (m, 3 H) 8.08 - 8.20 (m, 3 H) 8.74 (d, J=4.64 Hz, 1 H); LCMS (M/Z): 454

(M+H). Compound 70: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.47 (d, J=8.49 Hz, 2 H) 7.68 - 7.76 (m, 1 H) 7.89 (d, J=7.96 Hz, 1 H) 8.05 (d, J=8.79 Hz, 2 H) 8.18 (t, J=7.66 Hz, 1 H) 8.75 (d, J=4.73 Hz, 1 H); LCMS (M/Z): 470 (M+H).

Compound 71: N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

¹H MR (400 MHz, METHANOL-^) δ ppm 7.65 (ddd, J=7.71, 5.08, 1.03 Hz, 1 H) 7.74 (d, J=7.96 Hz, 1 H) 7.88 (d, J=8.30 Hz, 2 H) 7.92 - 7.96 (m, 2 H) 8.05 (td, J=7.86, 1.71 Hz, 1 H) 8.16 (d, J=8.20 Hz, 2 H) 8.66 - 8.69 (m, 1 H) 8.71 - 8.75 (m, 2 H); LCMS (M/Z): 463 (M+H).

Compound 72: N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 7.47 (d, J=8.15 Hz, 2 H) 7.65 (dd, J=6.93, 5.17 Hz, 1 H) 7.75 (d, J=7.96 Hz, 1 H) 7.94 (d, J=6.88 Hz, 2 H) 8.02 - 8.11 (m, 3 H) 8.67 (d, J=4.64 Hz, 1 H) 8.72 (d, J=6.88 Hz, 2 H); LCMS (M/Z): 479 (M+H).

Compound 73: 3,4-dichloro-N-[4-(2-pyridyl)-5-(4-pyridyl)thiazol-2- yljbenzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.68 (dd, J=7.44, 5.20 Hz, 1 H) 7.72 - 7.79 (m, 2 H) 7.87 (dd, J=8.44, 2.10 Hz, 1 H) 7.95 (d, J=6.69 Hz, 2 H) 8.05 - 8.12 (m, 2 H) 8.69 (d, J=4.54 Hz, 1 H) 8.73 (d, J=6.64 Hz, 2 H); LCMS (M/Z): 463 (M+H).

Compound 74: N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.76 - 0.87 (m, 2 H) 1.21 - 1.31 (m, 2 H) 2.24 (tt, J=8.25, 5.17 Hz, 1 H) 7.82 - 7.92 (m, 3 H) 8.14 (d, J=8.30 Hz, 2 H) 8.41 - 8.58 (m, 2 H) 8.70 - 8.77 (m, 1 H); LCMS (M/Z): 426 (M+H).

Compound 75: N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.77 - 0.89 (m, 2 H) 1.16 - 1.38 (m, 2 H) 2.25 (tt, J=8.22, 5.15 Hz, 1 H) 7.47 (d, J=8.20 Hz, 2 H) 7.87 (t, J=6.08 Hz, 1 H) 8.01 - 8.14 (m, 2 H) 8.40 - 8.58 (m, 2 H) 8.73 (d, J=5.71 Hz, 1 H); LCMS (M/Z): 442 (M+H).

Compound 76: 3,4-dichloro-N-[5-cyclopropyl-4-(2-pyridyl)thiazol-2- yljbenzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 0.78 - 0.86 (m, 2 H) 1.19 - 1.30 (m, 2 H) 2.24 (tt, J=8.25, 5.17 Hz, 1 H) 7.73 (d, J=8.49 Hz, 1 H) 7.82 - 7.91 (m, 2 H) 8.08 (d, J=2.15 Hz, 1 H) 8.37 - 8.56 (m, 2 H) 8.74 (dd, J=5.74, 0.81 Hz, 1 H); LCMS (M/Z): 426 (M+H).

Example 21: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl) phenoxy]benzamide. Compound 77

4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-amine

Bring up 4-(2-pyridinyl)-l,3-thiazol-2-amine (560 mg, 3.16 mmol) in 2 mL of DMSO. Add CF3I (0.5 g/mL in DMSO, 1.92 mL, 4.92 mmol), ferrocene (192 mg, 1.03 mmol) and H₂0₂ (30% in H₂0, 200 μL). Stir the reaction at room temperature for 2 hours. Workup: Pour into Na₂S₂0₇ (sat'd, 15 mL). Extract with EtOAc (3x10 mL). Wash organic with brine. Dry over Na₂S0₄. Filter and Remove solvent. Purify using reverse phase chromatography (MeOH:H₂0) to yield 290 mg (1.18 mmol, 37.4%) of desired product. 1H MR (400 MHz, acetone) δ ppm 2.78 (s, 1 H) 7.01 (br. s., 1 H) 7.36 (ddd, J=7.42, 4.88, 1.17 Hz, 1 H) 7.81 - 7.89 (m, 1 H) 7.89 - 7.96 (m, 1 H) 8.62 (d, J=4.30 Hz, 1 H); LCMS (M/Z): 246.0 (M + H).

Compound 77: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl) phenoxy]benzamide.

Dissolve 4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-amine (50 mg, 0.204 mmol) and 3-[4-(trifluoromethyl)phenoxy]benzoic acid (69 mg, 0.245 mmol) in 1.5 ml DMF. Add HATU (78 mg, 0.204 mmol) and DIEA (70 μί, 0.408 mmol). Heat the reaction mixture to 50 °C for 40 hours. Partition between EtOAc (10 mL) and H₂0 (10 mL). Collect organic then extract aqueous with EtOAc (2x10 mL). Wash organic with brine. Dry over Na₂SC"4. Filter then remove solvent. Purify using reverse phase chromatography (H₂0:MeOH). Combine clean fractions, charge with HCl (3N) and remove solvent. 1H MR (400 MHz, acetone) δ ppm 7.26 (d, J=8.20 Hz, 2 H) 7.41 - 7.52 (m, 1 H) 7.64 - 7.72 (m, 1 H) 7.76 (d, J=8.20 Hz, 3 H) 7.98 (br. s., 1 H) 8.16 (br. s., 2 H) 8.30 - 8.42 (m, 1 H) 8.77 - 8.99 (m, 1 H); LCMS (M/Z): 509.8 (M + H).

By proceeding in a similar manner the following compounds were prepared:

Compound 78: 3,4-dichloro-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yljbenzamide

1H MR (400 MHz, DMSO-d₆) δ ppm 7.49 (d, J=3.71 Hz, 1 H) 7.88 (d, j=8.40 Hz, 1 H) 7.95 - 8.04 (m, 2 H) 8.07 - 8.16 (m, 1 H) 8.43 (d, J=1.95 Hz, 1 H) 8.71 (d, j=4.69 Hz, 1 H); LCMS (M/Z): 418.0 (M + H).

Compound 79: N- [4-(2-pyridyl)-5-(trifluor omethyl)thiazol-2-yl] -4- [4- (trifluoromethyl)phenoxy] benzamide

1H NMR (400 MHz, DMSO- ) δ ppm 7.26 (d, J=8.59 Hz, 2 H) 7.31 (d, J=8.59 Hz, 2 H) 7.49 (ddd, J=6.54, 4.69, 2.44 Hz, 1 H) 7.82 (d, J=8.59 Hz, 2 H) 7.93 - 8.06 (m, 2 H) 8.25 (d, J=8.79 Hz, 2 H) 8.70 (d, J=4.49 Hz, 1 H) 13.33 (s, 1 H); LCMS (M/Z): 510.0 (M + H).

Compound 80: 3-phenoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yljbenzamide

1H NMR (400 MHz, acetone) δ ppm 7.11 (d, J=8.00 Hz, 2 H) 7.16 - 7.26 (m, 1 H) 7.27 - 7.36 (m, 1 H) 7.44 (s, 2 H) 7.55 - 7.70 (m, 1 H) 7.83 (br. s., 2 H) 8.00 - 8.10 (m, 1 H) 8.15 - 8.28 (m, 1 H) 8.31 - 8.45 (m, 1 H) 8.85 - 9.01 (m, 1 H); LCMS (M/Z): 442.0 (M + H).

Compound 81: 3-(4-fluorophenoxy)-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol- 2-yl]benzamide

1H NMR (400 MHz, acetone) δ ppm 7.07 - 7.31 (m, 5 H) 7.54 (t, J=8.00 Hz, 1 H) 7.80 (s, 1 H) 8.08 (d, J=8.00 Hz, 2 H) 8.27 (d, J=8.00 Hz, 1 H) 8.60 (s, 1 H) 8.95 - 9.11 (m, 1 H); LCMS (M/Z): 459.9 (M + H). Compound 82: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl)phenox benzamide

1H NMR (400 MHz, acetone) δ ppm 7.26 (d, J=8.20 Hz, 2 H) 7.41 - 7.52 (m, 1 H) 7.64 - 7.72 (m, 1 H) 7.76 (d, J=8.20 Hz, 3 H) 7.98 (br. s., 1 H) 8.16 (br. s., 2 H) 8.30 - 8.42 (m, 1 H) 8.77 - 8.99 (m, 1 H); LCMS (M/Z): 509.8 (M + H). Compound 83: 3-chloro-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-5- (trifluoromethyl) benzamide

1H MR (400 MHz, acetone) δ ppm 7.78 - 7.93 (m, 1 H) 8.09 (s, 1 H) 8.16 - 8.28 (i 1 H) 8.33 - 8.44 (m, 1 H) 8.55 (s, 1 H) 8.61 (s, 1 H) 8.86 - 9.00 (m, 1 H); LCMS (M/Z): 451.8 (M + H).

Compound 84: l-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3-[4- (trifluoromethyl)phenyl] urea

1H MR (400 MHz, DMSO- ) δ ppm 7.40 - 7.53 (m, 1 H) 7.71 (s, 4 H) 7.89 - 8.09 (m, 2 H) 8.59 - 8.78 (m, 1 H) 9.89 - 10.10 (m, 1 H); LCMS (M/Z): 433.0 (M + H). Compound 85: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO- ) δ ppm 7.43 - 7.54 (m, 1 H) 7.66 - 7.78 (m, 2 H) 7.94 - 8.05 (m, 2 H) 8.10 - 8.16 (m, 1 H) 8.17 - 8.25 (m, 1 H) 8.66 - 8.75 (m, 1 H); LCMS (M/Z): 433.9 (M + H). Compound 86: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-3- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO- ) δ ppm 7.42 - 7.53 (m, 1 H) 7.79 - 7.90 (m, 1 H) 7.95 - 8.03 (m, 2 H) 8.04 - 8.11 (m, 1 H) 8.37 - 8.47 (m, 1 H) 8.50 - 8.61 (m, 1 H) 8.66 - 8.75 (m, 1 H); LCMS (M/Z): 418.0 (M + H).

Compound 87: 4-tert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

1H MR (400 MHz, DMSO- ) δ ppm 1.32 (s, 9 H) 7.44 - 7.53 (m, 1 H) 7.56 - 7.66 (m, 2 H) 7.93 - 8.05 (m, 2 H) 8.07 - 8.19 (m, 2 H) 8.65 - 8.75 (m, 1 H); LCMS (M/Z): 406.0 (M + H). Compound 88: N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO- ) δ ppm 7.43 - 7.52 (m, 1 H) 7.54 - 7.65 (m, 2 H) 7.92 - 8.06 (m, 2 H) 8.22 - 8.33 (m, 2 H) 8.67 - 8.74 (m, 1 H); LCMS (M/Z): 433.9 (M + H). Compound 89: 4-phenoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

1H NMR (400 MHz, acetone) δ ppm 7.06 (d, J=8.79 Hz, 2 H) 7.14 (d, J=7.61 Hz, 2 H) 7.21 - 7.34 (m, 1 H) 7.42 - 7.57 (m, 2 H) 7.84 - 7.99 (m, 1 H) 8.21 (d, J=7.81 Hz, 1 H) 8.31 (d, J=8.79 Hz, 2 H) 8.45 (s, 1 H) 8.85 - 9.08 (m, 1 H); LCMS (M/Z): 442.0 (M + H).

Compound 90: 3-tert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yljbenzamide

1H NMR (400 MHz, acetone) δ ppm 1.40 (s, 9 H) 7.44 - 7.59 (m, 1 H) 7.71 - 7.81 (m, 1 H) 7.84 - 7.96 (m, 1 H) 8.04 - 8.15 (m, 1 H) 8.16 - 8.27 (m, 1 H) 8.33 (s, 1 H) 8.39 - 8.52 (m, 1 H) 8.85 - 9.02 (m, 1 H); LCMS (M/Z): 406.0 (M + H).

Compound 91: 4-(2,4-difluorophenoxy)-N-[4-(2-pyridyl)-5- (trifluoromethyl)thiazol-2- l]benzamide

1H MR (400 MHz, acetone) δ ppm 7.03 - 7.20 (m, 3 H) 7.29 (br. s., 1 H) 7.36 - 7 (m, 1 H) 7.72 - 7.85 (m, 1 H) 8.16 (s, 1 H) 8.30 (d, J=8.79 Hz, 3 H) 8.79 - 8.96 (m H); LCMS (M/Z): 477.8 (M + H).

Compound 92: 4-methoxy-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.87 (s, 3 H) 7.11 (d, J=8.79 Hz, 2 H) 7.49 (dt, J=4.34, 2.22 Hz, 1 H) 7.91 - 8.05 (m, 2 H) 8.17 (d, J=8.98 Hz, 2 H) 8.70 (d, J=4.69 Hz, 1 H) 13.15 (s, 1 H); LCMS (M/Z): 380.0 (M + H).

Compound 93: 3,5-ditert-butyl-N-[4-(2-pyridyl)-5-(trifluoromethyl)thiazol-2- yl]benzamide

1H MR (400 MHz, acetone) δ ppm 1.40 (s, 18 H) 7.55 - 7.67 (m, 1 H) 7.79 - 7.88 (m, 1 H) 8.13 (d, J=1.56 Hz, 4 H) 8.73 - 8.84 (m, 1 H); LCMS (M/Z): 462.0 (M + H).

Example 22: N-[4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide, Compound 94.

l-(2-pyridy -2-(3-pyridyl)ethanone

Bring up Methyl picolinate (714 ijL, 5.92 mmol) and pyridine-3-acetonitrile (700 mg, 5.92 mmol) in MeOH (21 mL). Add NaOMe (25%, 4.0 mL, 17.8 mmol). Heat the reaction to reflux for 3 hours. Pour into ice water. Extract with EtOAc (3x 50 mL). Wash with brine. Dry over Na₂SC"4. Filter and remove solvent. Purify using reverse phase chromatography (MeOH:H₂0).

Bring up the intermediate in HBr (48%, 20 mL). Heat the reaction to 70 °C for 30 minutes. Workup: Pour into ice water, Neutralize to ~pH 7 using 10% NaOH.

Remove water in vacuo and purify using reverse phase chromatography (MeOH:H₂0) to yield 250 mg of product. LCMS (M/Z): 199.2 (M + H).

4-(2-pyridyl)-5- 3-pyridyl)thiazol-2-amine

Bring up l-(2-pyridyl)-2-(3-pyridyl)ethanone (250 mg, 1.26 mmol) in DCE (4.0 mL). Cool to 0 °C and add bromine (65 μΕ, 1.26 mmol). Stir at room temperature overnight. Remove solvent. Dissolve in EtOH (4.0 mL) and charge with thiourea (192 mg, 2.52 mmol). Stir at room temperature for 16 hours. Remove solvent and purify using normal phase conditions (DCM/MeOH/NH₄OH) to isolate 150 mg of clean product. LCMS (M/Z): 255.4 (M + H).

Compound 94: N-[4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-yl]-4- (trifluorometh l)benzamide

Dissolve 4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-amine (50 mg, 0.197) and 4- trifluorobenzoic acid (42 mg, 0.218 mmol) in 3.0 ml DMF. Add HATU (90 mg, 0.236 mmol) and DIEA (70 μΐ_^, 0.394 mmol). Stir the reaction mixture at room temperature for 16 hours. Partition between EtOAc (15 mL) and H₂0 (15 mL). Collect organic then extract aqueous with EtOAc (2x10 mL). Wash organic with brine. Dry over Na₂S0₄. Filter then remove solvent. Purify using reverse phase chromatography

(MeOH:H₂0). Combine clean fractions, charge with HCl (3N) and remove solvent to isolate the product as a white solid (16 mg). 1H MR (400 MHz, METHANOL-^) δ ppm 7.77 - 7.87 (m, 1 H) 7.93 (d, J=8.40 Hz, 2 H) 7.98 - 8.06 (m, 1 H) 8.08 - 8.17 (m, 1 H) 8.28 (d, J=8.20 Hz, 3 H) 8.72 (d, J=8.20 Hz, 2 H) 8.92 (d, J=5.66 Hz, 1 H) 9.15 (s, 1 H); LCMS (M/Z): 427.0 (M + H).

By proceeding in a similar manner, the following compounds were prepared.

Compound 95: N-[4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.77 - 7.87 (m, 1 H) 7.93 (d, J=8.40 Hz, 2 H) 7.98 - 8.06 (m, 1 H) 8.08 - 8.17 (m, 1 H) 8.28 (d, J=8.20 Hz, 3 H) 8.72 (d, J=8.20 Hz, 2 H) 8.92 (d, J=5.66 Hz, 1 H) 9.15 (s, 1 H); LCMS (M/Z): 427.0 (M + H). Compound 96: 3,4-dichloro-N- 4-(2-pyridyl)-5-(3-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 7.77 (d, J=8.40 Hz, 1 H) 7.90 - 8.07 (m, 3 H) 8.20 (br. s., 1 H) 8.27 (s, 1 H) 8.42 (br. s., 1 H) 8.80 (d, J=7.81 Hz, 1 H) 8.84 - 8.94 (m, 1 H) 8.99 (d, J=5.27 Hz, 1 H) 9.21 (s, 1 H); LCMS (M/Z): 427.0 (M + H).

Example 23: 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- l]benzamide, Compound 97.

l-(2-pyridyl)- -tetrahydropyran-4-yl-ethanone

Bring up methyl picolinate (880 i|L , 7.30 mmol) and tetrahydropyran-4-yl acetonitrile (910 mg, 7.30 mmol) in THF (20 mL) under anhydrous conditions. Add NaH (60%, 870 mg, 21.75 mmol). Stir at room temp overnight. Quench with 10% HC1. Dilute with H₂0 (50 mL). Extract with EtOAc (3 x 50 mL). Wash organic with brine and dry over Na₂S0₄. Filter and remove solvent.

Bring up residue in HBr (48%, 25 mL). Heat the reaction to 70 °C for 30 minutes. Workup: Pour into ice water, Neutralize to ~pH 7 using 10% NaOH. Dilute with H₂0 (50 mL). Extract with EtOAc (3 x 50 mL). Wash with brine and dry over Na₂S0₄. Filter and remove solvent. Purify using reverse phase chromatography (MeOH:H₂0) to yield 820 mg of product. LCMS (M/Z): 206.4 (M + H). 4-(2-pyridyl -5-tetrahydropyran-4-yl-thiazol-2-amine

Bring up l-(2-pyridyl)-2-tetrahydropyran-4-yl-ethanone (820 mg, 4.00 mmol) and bromine (200 mg, 4.0 mmol) in DCE (16 mL). Stir at room temp for 60 hours.

Remove solvent. Bring up in EtOH (16 mL) and charge with thiourea (600 mg, 8.0 mmol). Stir at room temperature for 16 hours. Remove solvent. Purify using normal phase conditions (DCM:MeOH:NH₄OH) to isolate 250 mg of clean compound. LCMS (M/Z): 262.2 (M + H).

Compound 97: 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yljbenzamide

Bring up 4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-amine (75 mg, 0.460 mmol). 3,4-dichlorobenzoic acid (105 mg, 0.550 mmol), HATU (210 mg, 0.550 mmol) and DIEA (160 μΕ, 0.918 mmol)in 2 ml DMF. Stir at room temperature overnight. Partition between EtOAc (15 mL) and H₂0 (15 mL). Collect organic then extract aqueous with EtOAc (2x10 mL). Wash organic with brine. Dry over Na₂S0₄. Filter then remove solvent. Purify using reverse phase chromatography (MeOH:H₂0). Combine clean fractions and convert to HCl salt by adding 3N HCl. Remove solvent to yield 23.0 mg of off white solid. ¹H MR (400 MHz, METHANOL-^) δ ppm 1.92 (dd, J=12.59, 3.81 Hz, 2 H) 2.01 - 2.14 (m, 2 H) 3.55 - 3.78 (m, 3 H) 4.08 (dd, J=11.52, 3.51 Hz, 2 H) 7.77 (d, J=8.40 Hz, 1 H) 7.94 - 8.08 (m, 2 H) 8.23 (d, 7=1.95 Hz, 1 H) 8.35 (d, 7=8.20 Hz, 1 H) 8.62 - 8.74 (m, 1 H) 8.88 (d, 7=5.86 Hz, 1 H); LCMS (M/Z): 434.0 (M + H).

By proceeding in a similar manner, the following compounds were prepared.

Compound 98: 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yljbenzamide

¹H MR (400 MHz, METHANOL-^) δ ppm 1.92 (dd, 7=12.59, 3.81 Hz, 2 H) 2.01 - 2.14 (m, 2 H) 3.55 - 3.78 (m, 3 H) 4.08 (dd, 7=11.52, 3.51 Hz, 2 H) 7.77 (d, 7=8.40 Hz, 1 H) 7.94 - 8.08 (m, 2 H) 8.23 (d, 7=1.95 Hz, 1 H) 8.35 (d, 7=8.20 Hz, 1 H) 8.62 - 8.74 (m, 1 H) 8.88 (d, 7=5.86 Hz, 1 H); LCMS (M/Z): 434.0 (M + H).

Compound 99: 4-phenoxy-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yljbenzamide

¹H MR (400 MHz, METHANOL-^) δ ppm 1.86 - 2.00 (m, 2 H) 2.02 - 2.16 (m, 2 H) 3.56 - 3.83 (m, 3 H) 4.01 - 4.18 (m, 2 H) 7.13 (d, 7=8.40 Hz, 4 H) 7.22 - 7.33 (m, 1 H) 7.37 - 7.56 (m, 2 H) 7.93 - 8.16 (m, 3 H) 8.28 - 8.44 (m, 1 H) 8.60 - 8.76 (m, 1 H) 8.79 - 8.95 (m, 1 H); LCMS (M/Z): 458.2 (M+H).

Compound 100 : N- [4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl] -4- (trifluoromethoxy) benzenesulfonamide

1H NMR (400 MHz, METHANOL-^) δ ppm 1.78 (dd, J=12.50, 3.90 Hz, 2 H) 1.87 - 2.07 (m, 2 H) 3.41 - 3.63 (m, 3 H) 4.00 (dd, J=l 1.52, 3.71 Hz, 2 H) 7.48 (d, J=8.40 Hz, 2 H) 7.79 - 7.91 (m, 1 H) 7.99 - 8.17 (m, 3 H) 8.38 - 8.56 (m, 1 H) 8.79 (d, J=5.27 Hz, 1 H); LCMS (M/Z): 486.2 (M + H).

Compound 101 : N- [4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl] -4- (trifluoromethyl) benzenesulfonamide

1H MR (400 MHz, DMSO- ) δ ppm 1.60 (dd, J=12.40, 4.00 Hz, 2 H) 1.81 (d, J=10.74 Hz, 2 H) 3.36 (t, J=l 1.13 Hz, 2 H) 3.58 - 3.76 (m, 1 H) 3.90 (dd, J=l 1.32, 3.51 Hz, 2 H) 7.43 (dd, J=7.13, 4.98 Hz, 1 H) 7.67 (d, J=8.00 Hz, 1 H) 7.88 - 8.00 (m, 3 H) 8.06 (d, J=8.20 Hz, 2 H) 8.68 (d, J=4.10 Hz, 1 H); LCMS (M/Z): 470.2 (M + H).

Compound 102: 3,4-dichloro-N-[4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2- yl] benzenesulfonamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.70 - 1.86 (m, 2 H) 1.91 (br. s., 2 H) 3.17 - 3.28 (m, 1 H) 3.51 (d, J=10.93 Hz, 3 H) 3.89 - 4.11 (m, 2 H) 7.75 (d, J=8.40 Hz, 1 H) 7.87 (dd, J=8.49, 1.85 Hz, 2 H) 8.08 (d, 7=1.95 Hz, 2 H) 8.39 - 8.55 (m, 1 H) 8.74 - 8.86 (m, 1 H); LCMS (M/Z): 470.0 (M + H).

Compound 103 : N- [4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl] -3- (trifluoromethyl)benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.85 - 2.02 (m, 2 H) 2.02 - 2.16 (m, 2 H) 3.56 - 3.78 (m, 3 H) 4.08 (dd, 7=11.52, 3.71 Hz, 2 H) 7.73 - 7.89 (m, 1 H) 7.95 - 8.10 (m, 2 H) 8.29 - 8.44 (m, 3 H) 8.71 (td, 7=8.00, 1.37 Hz, 1 H) 8.89 (d, 7=5.66 Hz, 1 H); LCMS (M/Z): 434.6. (M + H).

Compound l04: N- [4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl] -4- (trifluoromethoxy) benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.94 (dd, 7=12.59, 3.81 Hz, 2 H) 2.02 - 2.14 (m, 2 H) 3.57 - 3.80 (m, 3 H) 4.09 (dd, 7=11.52, 3.51 Hz, 2 H) 7.52 (d, 7=8.40 Hz, 2 H) 8.04 (s, 1 H) 8.19 (d, 7=8.59 Hz, 2 H) 8.37 (d, 7=8.20 Hz, 1 H) 8.71 (s, 1 H) 8.88 (d, 7=5.47 Hz, 1 H); LCMS (M/Z): 450.2 (M + H).

Compound l05: N- [4-(2-pyridyl)-5-tetrahydropyran-4-yl-thiazol-2-yl] -4- (trifluoromethyl)benzamide

1H NMR (400 MHz, METHANOL-^) δ ppm 1.84 - 2.02 (m, 2 H) 2.06 (br. s., 2 H) 3.67 (d, J=11.13 Hz, 3 H) 4.08 (br. s., 2 H) 7.93 (d, J=8.20 Hz, 2 H) 8.02 - 8.12 (m, 1 H) 8.24 (d, J=8.01 Hz, 2 H) 8.32 - 8.44 (m, 1 H) 8.66 - 8.81 (m, 1 H) 8.84 - 8.96 (m, 1 H); LCMS (M/Z): 434.0 (M + H).

Example 24: 3,4-dichloro-N-[5-(l-methyl-4-piperidyl)-4-(2-pyridyl)thiazol-2-yl] benzamide Compound 108

2-(4-piperidyl)-l-(2-pyridyl)ethanone

Bring up methyl picolinate (4.16 mL, 34.5 mmol) and N-boc-4- cyanonmethylpiperidine (7.75 g, 34.5 mmol) in DMF (100 mL). Add sodium hydride (60%, 4.5g, 103 mmol). Stir at room temperature for 16 hours. Pour into water.

Neutralize to pH ~7 using 10% HCl. Extract with EtOAc (3 x 20 mL). Wash with brine. Dry over Na₂SC"4. Filter and remove solvent. Bring up in HBr (48%, 40 mL). Heat the reaction mixture to 70 °C for 30 minutes. Pour into water (100 mL).

Neutralize to pH of 7. Remove aqueous in vacuo. Bring up in DCM/MeOH (3 mL). Filter off salts. Use the crude material for the next step.

2,2,2-trifluoro- 1- [4- [2-oxo-2-(2-pyr idyl)ethyl] - 1-piperidyl] ethanone

Bring up 2-(4-piperidyl)-l-(2-pyridyl)ethanone (-34.5 mmol) in DCE (200 mL). Cool to 0 C. Charge with TEA (14.4 mL, 103 mmol) and slowly add trifluoroacetic anhydride (9.75 mL, 69 mmol) dissolve in DCE (25 mL). Stir at room temperature for 16 hours. Remove solvent and purify using normal phase chromatography

(DCM:MeOH:NH₄OH) to yield 7.0 grams of off white solid. 1H NMR (400 MHz, METHANOL-^) δ ppm 1.29 (td, 7=12.69, 3.90 Hz, 2 H) 1.82 - 1.95 (m, 2 H) 2.32 (td, 7=7.22, 3.71 Hz, 1 H) 2.90 (t, 7=12.98 Hz, 1 H) 3.17 (d, 7=6.83 Hz, 2 H) 3.24 - 3.34 (m, 1 H) 3.97 (d, 7=13.67 Hz, 1 H) 4.41 (dd, 7=13.18, 1.85 Hz, 1 H) 7.55 - 7.70 (m, 1 H) 7.94 - 8.15 (m, 2 H) 8.68 (d, 7=4.69 Hz, 1 H); LCMS (M/Z): 301.4 (M + H). l-[4-[2-amino-4-(2-pyridyl)thiazol-5-yl]-l-piperidyl]-2,2,2-trifluoro-ethanone

Bring up 2,2,2-trifluoro- l-[4-[2-oxo-2-(2-pyridyl)ethyl]-l -piped dyl]ethanone (7.0 g, 23.3 mmol) in DCE (100 mL). Slowly add bromine (1.2 mL, 23.3 mmol) dissolved in DCE (25 mL) using addition funnel. Stir at 55 °C for 16 hours. Remove solvent in vacuo. Bring up residue in EtOH and charge with thiourea. Stir at room temperature for 16 hours. Remove solvent and purify using normal phase chromatography (DCM:MeOH: H₄OH) to isolate 3.1 grams of white solid. 1H MR (400 MHz, METHANOL-^) δ ppm 1.49 - 1.68 (m, 2 H) 2.17 (br. s., 2 H) 2.82 - 3.02 (m, 1 H) 4.00 - 4.23 (m, 2 H) 4.50 - 4.64 (m, 1 H) 7.30 (s, 1 H) 7.71 - 7.92 (m, 2 H) 8.60 (d, J=4.69 Hz, 1 H); LCMS (M/Z): 357.0 (M + H).

Compoundl06: 3,4-dichloro-N-[4-(2-pyridyl)-5-[l-(2,2,2-trifluoroacetyl)-4- iperidyl]thiazol-2-yl]benzamide

Dissolve l-[4-[2-amino-4-(2-pyridyl)thiazol-5-yl]-l-piperidyl]-2,2,2-trifluoro- ethanone (3.1 g, 8.70 mmol) in DMF (80 mL). Add 3,4-dichlorobenzoic acid (2.0 g, 10.44 mmol), HATU (5.0 g, 13.0 mmol) and DIEA (3.0 mL, 17.0 mmol). Stir at room temperature overnight. Dilute with H20 (500 mL). Extract with EtOAc (3 x 500 mL). Wash organic with brine and dry over Na₂S0₄. Filter and remove solvent. Purify using normal phase chromatography (DGVLMeOH: H₄OH) to yield 3.0 grams of white solid. 1H MR (400 MHz, METHANOL-^) δ ppm 1.67 (br. s., 2 H) 2.22 (br. s., 2 H) 2.96 (s, 1 H) 3.31 - 3.44 (m, 1 H) 3.97 - 4.15 (m, 1 H) 4.30 - 4.43 (m, 1 H) 4.49 - 4.64 (m, 1 H) 7.20 - 7.31 (m, 1 H) 7.67 (d, J=8.40 Hz, 1 H) 7.82 (d, J=1.76 Hz, 1 H) 7.91 (dd, J=8.49, 2.05 Hz, 1 H) 8.00 (d, J=8.20 Hz, 1 H) 8.16 (d, J=2.15 Hz, 1 H) 8.59 (d, J=4.10 Hz, 1 H); LCMS (M/Z): 528.8 (M + H).

Compound 107: 3,4-dichloro-N-[5-(4-piperidyl)-4-(2-pyridyl)thiazol-2- yl]benzamide

Dissolve 3,4-dichloro-N-[4-(2-pyridyl)-5-[l-(2,2,2-trifluoroacetyl)-4- piperidyl]thiazol-2-yl]benzamide (3.0 g, 5.67 mmol) in MeOH (25 mL). Charge with NaOH (10%, 25 mL). Stir at room temperature for 30 minutes. Dilute with H₂0 (50 mL) and adjust pH to ~7 using HCl (10%). Extract with EtOAc (3 x 100 mL). Wash with brine and dry over Na₂S0₄. Filter and remove solvent. Purify using normal phase conditions (DCM:MeOH:NH₄OH) to yield 1.9 grams of white solid. 1H NMR (400 MHz, DMSO-i¾) δ ppm 1.61 (dd, J=12.30, 3.12 Hz, 2 H) 1.98 (br. s., 2 H) 2.73 (t, J=l 1.52 Hz, 2 H) 3.03 - 3.27 (m, 2 H) 4.06 - 4.21 (m, 1 H) 7.18 (dd, J=6.64, 5.27 Hz, 1 H) 7.63 (d, J=8.40 Hz, 1 H) 7.78 (d, J=1.37 Hz, 1 H) 7.90 - 8.02 (m, 2 H) 8.25 (d, J=1.56 Hz, 1 H) 8.53 (d, J=4.10 Hz, 1 H); LCMS (M/Z): 433.0 (M + H).

Compound 108: 3,4-dichloro-N-[5-(l-methyl-4-piperidyl)-4-(2-pyridyl)thiazol-2- yl] benzamide

Dissolve 3,4-dichloro-N-[5-(4-piperidyl)-4-(2-pyridyl)thiazol-2-yl]benzamide (25 mg, 0.058 mmol) in MeOH (2 mL). Charge with formaldehyde (37%, 7 μί), NaCNBH₃ (1.0 M in THF, 174 μΕ, 0.174 mmol) and acetic acid (2 drops). Stir at room

temperature for 16 hours. Remove solvent and purify using reverse phase

chromatography (MeOH:H₂0). Combine clean fractions and convert to HCl salt by adding 3N HCl. Remove solvent to yield 2.7 mg of off white solid. 1H NMR (400 MHz, METHANOL-^) δ ppm 2.02 - 2.23 (m, 2 H) 2.38 - 2.54 (m, 2 H) 2.97 (s, 3 H) 3.24 - 3.32 (m, 2 H) 3.58 - 3.78 (m, 2 H) 4.04 - 4.23 (m, 1 H) 7.63 - 7.85 (m, 2 H) 7.93 - 8.07 (m, 1 H) 8.23 (d, 7=1.76 Hz, 3 H) 8.69 - 8.86 (m, 1 H); LCMS (M/Z): 447.0 (M + H). By proceeding in a similar manner, the following compounds were prepared.

Compound 109: 3,4-dichloro-N-[5-(l-isopropyl-4-piperidyl)-4-(2-pyridyl)thiazol- 2-yl]benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.45 (d, 7=6.44 Hz, 6 H) 2.08 - 2.34 (m, 2 H) 2.40 - 2.61 (m, 2 H) 3.37 (s, 3 H) 3.56 - 3.71 (m, 3 H) 7.79 (d, 7=8.20 Hz, 1 H) 7.94 - 8.08 (m, 2 H) 8.24 (d, 7=1.56 Hz, 1 H) 8.36 - 8.49 (m, 1 H) 8.61 - 8.73 (m, 1 H) 8.84 - 8.95 (m, 1 H); LCMS (M/Z): 475.6 (M + H). Compound 110: 3,4-dichloro-N-[4-(2-pyridyl)-5-[l-(3,3,3-trifluoropropanoyl)-4- piperidyl]thiazol-2-yl]benzamide

1H MR (400 MHz, METHANOL-^) δ ppm 1.59 - 1.76 (m, 1 H) 1.77 - 1.95 (m, 1 H) 2.19 (d, 7=10.93 Hz, 2 H) 2.79 - 2.97 (m, 1 H) 3.36 - 3.45 (m, 1 H) 3.49 - 3.69 (m, 3 H) 3.74 - 3.91 (m, 1 H) 3.98 - 4.20 (m, 1 H) 4.63 - 4.78 (m, 1 H) 7.73 (d, 7=8.20 Hz, 1 H) 7.97 (d, 7=8.00 Hz, 2 H) 8.20 (s, 1 H) 8.26 - 8.42 (m, 1 H) 8.60 (br. s., 1 H); LCMS (M/Z): 543.6 (M + H).

By proceeding in a similar manner to previous examples, the following

compounds were prepared. Compound 111: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-5- (trifluoromethyl)thiophene-2-carboxamide

1H MR (400 MHz, acetone) δ ppm 7.61 - 7.89 (m, 2 H) 8.14 - 8.41 (m, 2 H) 8.45 - 8.59 (m, 1 H) 8.74 - 8.98 (m, 1 H); LCMS (M/Z): 381.0 (M + H).

Compound 112: 4-benzyl-N- [5-c ano-4-(2-pyridyl)thiazol-2-yl] benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 4.02 - 4.11 (m, 2 H) 7.14 - 7.24 (m, 1 H) 7.25 - 7.35 (m, 4 H) 7.41 - 7.49 (m, 2 H) 7.50 - 7.59 (m, 1 H) 7.98 - 8.07 (m, 1 H) 8.07 - 8.20 (m, 3 H) 8.68 - 8.83 (m, 1 H); LCMS (M/Z): 397.0 (M + H).

Compound 113: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-methoxy-5- (trifluoromethyl)benzamide

1H MR (400 MHz, acetone) δ ppm 4.02 (s, 3 H) 7.42 - 7.50 (m, 1 H) 7.53 (s, 1 H) 7.90 - 8.03 (m, 2 H) 8.04 - 8.15 (m, 2 H) 8.72 (d, J=4.49 Hz, 1 H). Compound 114: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-(4- fluorophenoxy)benzamide

1H NMR (400 MHz, acetone) δ ppm 7.13 (d, J=8.79 Hz, 2 H) 7.18 - 7.34 (m, 4 H) 7.48 (d, J=2.15 Hz, 1 H) 7.97 (d, J=1.17 Hz, 1 H) 8.07 (d, J=7.81 Hz, 1 H) 8.26 (d, J=8.79 Hz, 2 H) 8.72 (d, J=4.30 Hz, 1 H); LCMS (M/Z): 417.0 (M + H).

Compound 115: 3-bromo-N- 5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.49 - 7.61 (m, 2 H) 7.90 (d, J=7.81 Hz, 1 H) 8.04 (d, J=1.17 Hz, 1 H) 8.07 - 8.20 (m, 2 H) 8.37 (s, 1 H) 8.75 (d, J=4.30 Hz, 1 H) 13.51 - 13.81 (m, 1 H); LCMS (M/Z): 386.8 (M + H).

Compound 116: 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-5- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.46 - 7.60 (m, 1 H) 7.94 - 8.15 (m, 2 H) 8.18 - 8.27 (m, 1 H) 8.38 - 8.55 (m, 2 H) 8.69 - 8.81 (m, 1 H); LCMS (M/Z): 409.0 (M +

Compound 117: 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-fluoro- benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.52 (br. s., 1 H) 7.64 (br. s., 1 H) 7.93 - 8.11 (m, 2 H) 8.16 (br. s., 1 H) 8.41 (d, J=4.30 Hz, 1 H) 8.73 (br. s., 1 H); LCMS (M/Z): 359.0 (M + H).

Compound 118: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3,5- bis(trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.56 (d, J=5.27 Hz, 1 H) 7.96 - 8.18 (m, 2 H) 8.48 (s, 1 H) 8.69 - 8.87 (m, 3 H); LCMS (M/Z): 442.9 (M + H).

Compound 119: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethyl)benzamid

1H MR (400 MHz, DMSO-^6) δ ppm 7.54 (br. s., 1 H) 7.75 - 7.91 (m, 1 H) 7.95 - 8.18 (m, 3 H) 8.42 (d, J=7.03 Hz, 1 H) 8.55 (s, 1 H) 8.75 (br. s., 1 H); LCMS (M/Z): 375.0 (M + H).

Compound 120: 3,4-dichloro-N-[5-c ano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.45 - 7.61 (m, 1 H) 7.81 - 7.94 (m, 1 H) 8.09 (br. s., 2 H) 8.43 (br. s., 1 H) 8.74 (br. s., 1 H); LCMS (M/Z): 375.0 (M + H).

Compound 121: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.50 - 7.60 (m, 1 H) 7.68 - 7.78 (m, 2 H) 8.00 - 8.08 (m, 1 H) 8.09 - 8.17 (m, 2 H) 8.17 - 8.23 (m, 1 H) 8.71 - 8.79 (m, 1 H); LCMS (M/Z): 391.0 (M + H).

Compound 122: 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.49 - 7.59 (m, 1 H) 7.77 - 7.86 (m, 1 H) 8.00 - 8.07 (m, 1 H) 8.08 - 8.15 (m, 1 H) 8.19 - 8.30 (m, 1 H) 8.44 - 8.55 (m, 1 H) 8.70 - 8.81 (m, 1 H); LCMS (M/Z): 424.8 (M + H).

Compound 123: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-fluoro-2- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.46 - 7.59 (m, 1 H) 7.69 - 7.81 (m, 1 H) 7.83 - 7.93 (m, 1 H) 7.95 - 8.12 (m, 3 H) 8.69 - 8.79 (m, 1 H); LCMS (M/Z): 393.0 (M + H).

Compound 124: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.43 - 7.65 (m, 3 H) 7.69 - 7.80 (m, 1 H) 7.82 - 7.92 (m, 1 H) 7.96 - 8.14 (m, 2 H) 8.64 - 8.83 (m, 1 H); LCMS (M/Z): 391.0 (M + H).

Compound 125: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-fluoro-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.34 - 7.48 (m, 1 H) 7.49 - 7.58 (m, 1 H) 7.59 - 7.71 (m, 1 H) 7.90 - 8.17 (m, 3 H) 8.63 - 8.82 (m, 1 H); LCMS (M/Z): 409.0 (M + H). Compound 126: 3-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-fluoro-5- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.47 - 7.60 (m, 1 H) 8.06 (br. s., 2 H) 8.21 8.30 (m, 1 H) 8.35 - 8.46 (m, 1 H) 8.68 - 8.82 (m, 1 H); LCMS (M/Z): 477.2 (M +

Compound 127: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-(l, 1,2,2- tetrafluoroethoxy)benzamide

1H MR (400 MHz, acetone) δ ppm 6.34 - 6.80 (m, 1 H) 7.36 - 7.67 (m, 3 H) 7.89 - 8.02 (m, 1 H) 8.08 (d, J=7.81 Hz, 1 H) 8.35 (d, J=8.59 Hz, 2 H) 8.73 (d, J=4.10 Hz, 1 H); LCMS (M/Z): 423.0 (M + H).

Compound 128: N-[5-cyano-4- 2-pyridyl)thiazol-2-yl]-3-(4-piperidyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 1.83 - 2.06 (m, 4 H) 2.89 - 3.11 (m, 3 H) 3.31 - 3.46 (m, 2 H) 7.47 - 7.65 (m, 3 H) 8.04 (s, 3 H) 8.09 - 8.17 (m, 1 H) 8.69 - 8.80 (m, 1 H) 8.88 - 9.02 (m, 1 H) 9.03 - 9.18 (m, 1 H); LCMS (M/Z): 390.0 (M + H).

Compound 129: 3,5-ditert-butyl-N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 1.35 (s, 18 H) 7.49 - 7.59 (m, 1 H) 7.66 - 7.74 (m, 1 H) 8.02 (d, J=1.37 Hz, 3 H) 8.08 - 8.18 (m, 1 H) 8.69 - 8.80 (m, 1 H); LCMS (M/Z): 419.0 (M + H).

Compound 130: tert-butyl-4-[4-[[5-cyano-4-(2-pyridyl)thiazol-2- yl]carbamoyl]phenyl]sulfon lpiperazine-l-carboxylate

1H MR (400 MHz, DMSO-^6) δ ppm 1.33 (s, 9 H) 2.94 (t, J=4.39 Hz, 4 H) 3.40 (d, J=4.30 Hz, 4 H) 7.46 - 7.59 (m, 1 H) 7.92 (d, J=8.40 Hz, 2 H) 7.98 - 8.07 (m, 1 H)

8.10 (s, 1 H) 8.37 (d, J=8.40 Hz, 2 H) 8.68 - 8.82 (m, 1 H); LCMS (M/Z): 555.0 (M + H).

Compound 131: tert-butyl-4-[3-[[5-cyano-4-(2-pyridyl)thiazol-2- yl] carbamoyl] phenyl] piperidine-l-carbox late

1H MR (400 MHz, DMSO-^6) δ ppm 1.36 - 1.51 (m, 9 H) 1.53 - 1.70 (m, 2 H) 1.72 - 1.92 (m, 2 H) 2.70 - 2.92 (m, 2 H) 3.99 - 4.24 (m, 2 H) 7.45 - 7.65 (m, 3 H) 7.93 - 7.99 (m, 1 H) 7.99 - 8.07 (m, 1 H) 8.13 (br. s., 2 H) 8.66 - 8.83 (m, 1 H); LCMS (M/Z): 490.0 (M + H).

Compound 132: N-[5-cyano-4- 2-pyridyl)thiazol-2-yl]-3-(3-pyridyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.50 - 7.60 (m, 2 H) 7.69 - 7.77 (m, 1 H) 7.99 - 8.10 (m, 2 H) 8.10 - 8.19 (m, 2 H) 8.22 - 8.28 (m, 1 H) 8.56 - 8.61 (m, 1 H) 8.62 - 8.68 (m, 1 H) 8.70 - 8.82 (m, 1 H) 9.01 - 9.14 (m, 1 H); LCMS (M/Z): 384.0 (M + H). Compound 133: 3-tert-butyl-N- 5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 1.36 (s, 9 H) 7.52 (d, J=7.61 Hz, 2 H) 7.67 - 7.77 (m, 1 H) 7.92 - 7.99 (m, 1 H) 7.99 - 8.07 (m, 1 H) 8.08 - 8.16 (m, 1 H) 8.21 (s, 1 H) 8.66 - 8.82 (m, 1 H) 13.48 - 13.71 (m, 1 H); LCMS (M/Z): 363.0 (M + H).

Compound 134: N-[5-cyano-4- 2-pyridyl)thiazol-2-yl]-3-(3-pyridyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.50 - 7.60 (m, 2 H) 7.69 - 7.77 (m, 1 H) 7.99 - 8.10 (m, 2 H) 8.10 - 8.19 (m, 2 H) 8.22 - 8.28 (m, 1 H) 8.56 - 8.61 (m, 1 H) 8.62 - 8.68 (m, 1 H) 8.70 - 8.82 (m, 1 H) 9.01 - 9.14 (m, 1 H); LCMS (M/Z): 384.0 (M + H). Compound 135: 3-tert-butyl-N- 5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

Compound 136: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-fluoro-5- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.45 - 7.61 (m, 1 H) 7.93 - 8.14 (m, 3 H) 8.26 (d, J=8.98 Hz, 1 H) 8.40 (s, 1 H) 8.74 (d, J=3.90 Hz, 1 H); LCMS (M/Z): 393.0 (M + H).

Compound 137: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.44 - 7.68 (m, 3 H) 8.11 (d, J=7.22 Hz, 2 H) 8.29 (d, J=7.81 Hz, 2 H) 8.75 (br. s., 1 H); LCMS (M/Z): 391.0 (M + H). Compound 138: 4-tert-butyl-N- 5-cyano-4-(2-pyridyl)thiazol-2-yl]benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 1.32 (s, 9 H) 7.46 - 7.57 (m, 1 H) 7.60 (d, J=8.20 Hz, 2 H) 7.95 - 8.07 (m, 1 H) 8.12 (d, J=8.00 Hz, 3 H) 8.58 - 8.84 (m, 1 H); LCMS (M/Z): 363.0 (M + H). Compound 139: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethyl)benzenesulfonamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.50 - 7.62 (m, 1 H) 7.75 - 7.89 (m, 1 H) 7.94 - 8.07 (m, 3 H) 8.08 - 8.13 (m, 1 H) 8.14 - 8.26 (m, 1 H) 8.63 - 8.77 (m, 1 H); LCMS (M/Z): 411.0 (M + H).

Compound 140: N-[5-cyano-4- 2-pyridyl)thiazol-2-yl]-4-methoxy-benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.87 (s, 3 H) 7.05 - 7.20 (m, 2 H) 7.48 - 7. (m, 1 H) 7.98 - 8.07 (m, 1 H) 8.09 - 8.14 (m, 1 H) 8.15 - 8.23 (m, 2 H) 8.70 - 8.80 1 H); LCMS (M/Z): 337.0 (M + H).

Compound 141: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethoxy)benzene sulfonamide

¹H MR (400 MHz, DMSO-^6) δ ppm 7.57 (d, J=8.98 Hz, 3 H) 7.94 - 8.10 (m, 4 H) 8.72 (d, J=4.49 Hz, 1 H); LCMS (M/Z): 426.9 (M + H). Compound 142: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3- (trifluoromethoxy)benzene sulfonamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.52 - 7.61 (m, 1 H) 7.67 (s, 1 H) 7.70 - 7.81 (m, 2 H) 7.91 (d, J=7.81 Hz, 1 H) 7.96 - 8.11 (m, 2 H) 8.72 (d, J=4.49 Hz, 1 H); LCMS (M/Z): 427.0 (M + H).

Compound 143: 4-chloro-N-[5-cyano-4-(2-pyridyl)thiazol-2- yljbenzenesulfonamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.51 - 7.60 (m, 1 H) 7.65 (d, J=8.59 Hz, 2 H) 7.89 (d, J=8.59 Hz, 2 H) 7.99 (s, 2 H) 8.67 - 8.78 (m, 1 H); LCMS (M/Z): 377.0 (M + H).

Compound 144: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-fluoro-3-methoxy- benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.91 (s, 3 H) 7.31 (d, J=5.66 Hz, 2 H) 7.39 7.49 (m, 1 H) 7.50 - 7.61 (m, 1 H) 8.06 (s, 2 H) 8.68 - 8.79 (m, 1 H); LCMS (M/Z): 355.0 (M + H). Compound 145: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzenesulfonamide

1H MR (400 MHz, acetone) δ ppm 7.37 (br. s., 1 H) 7.79 (d, J=8.20 Hz, 2 H) 7.84 - 7.94 (m, 1 H) 8.10 (d, J=7.81 Hz, 3 H) 8.50 - 8.73 (m, 1 H); LCMS (M/Z): 410.9 (M + H).

Compound 146: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2,5-dimethyl-furan-3- carboxamide

1H MR (400 MHz, DMSO-^6) δ ppm 2.23 - 2.31 (m, 3 H) 2.58 (s, 3 H) 6.86 - 6.97 (m, 1 H) 7.47 - 7.59 (m, 1 H) 7.94 - 8.05 (m, 1 H) 8.06 - 8.16 (m, 1 H) 8.67 - 8.81 (m, 1 H); LCMS (M/Z): 325.0 (M + H).

Compound 147: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-methyl-thiophi carboxamide

1H MR (400 MHz, DMSO-^6) δ ppm 2.28 (s, 3 H) 7.46 - 7.58 (m, 1 H) 7.63 - 7.72 (m, 1 H) 7.97 - 8.06 (m, 1 H) 8.07 - 8.14 (m, 1 H) 8.17 (s, 1 H) 8.68 - 8.83 (m, 1 H); LCMS (M/Z): 327.0 (M + H).

Compound 148: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 7.49 - 7.60 (m, 1 H) 7.87 (s, 3 H) 7.90 - 7.96 (m, 1 H) 8.04 (s, 2 H) 8.67 - 8.81 (m, 1 H); LCMS (M/Z): 375.0 (M + H). Compound 149: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-2-methoxy-4- (trifluoromethoxy)benzamide

1H MR (400 MHz, acetone) δ ppm 4.25 (s, 3 H) 7.14 - 7.22 (m, 1 H) 7.29 (s, 1 H) 7.46 - 7.54 (m, 1 H) 7.99 (d, J=1.56 Hz, 1 H) 8.13 (d, J=8.01 Hz, 1 H) 8.24 (d, J=8.79 Hz, 1 H) 8.73 (d, J=4.30 Hz, 1 H); LCMS (M/Z): 421.0 (M + H).

Compound 150: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4-piperazin-l-ylsulfonyl- benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.08 - 3.32 (m, 8 H) 7.45 - 7.61 (m, 1 H) 7.96 - 8.07 (m, 3 H) 8.09 - 8.16 (m, 1 H) 8.38 - 8.50 (m, 2 H) 8.68 - 8.85 (m, 1 H) 9.13 - 9.37 (m, 2 H); LCMS (M/Z): 455.0 (M + H).

Compound 151: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-3-piperazin-l-ylsulfonyl- benzamide

1H MR (400 MHz, DMSO-^6) δ ppm 3.06 - 3.34 (m, 8 H) 7.48 - 7.61 (m, 1 H) 7.87 - 7.99 (m, 1 H) 8.11 (s, 3 H) 8.45 - 8.53 (m, 1 H) 8.54 - 8.63 (m, 1 H) 8.68 - 8.83 (m, 1 H) 9.20 - 9.42 (m, 2 H); LCMS (M/Z): 455.0 (M + H).

Compound 152: tert-butyl 4-[3-[[5-cyano-4-(2-pyridyl)thiazol-2- yl]carbamoyl]phenyl]sulfonyl iperazine-l-carboxylate

1H MR (400 MHz, DMSO-^6) δ ppm 1.33 (s, 9 H) 2.84 - 3.00 (m, 4 H) 3.38 - 3.49 (m, 4 H) 7.47 - 7.58 (m, 1 H) 7.80 - 7.90 (m, 1 H) 7.95 - 8.07 (m, 2 H) 8.09 - 8.16 (m, 1 H) 8.41 - 8.47 (m, 1 H) 8.48 - 8.56 (m, 1 H) 8.67 - 8.82 (m, 1 H); LCMS (M/Z): 555.0 (M + H).

Compound 153 : N- [5-cyano-4- [4-(trifluor omethyl)-2-pyridyl] thiazol-2-yl] -4- (trifluoromethyl) benzamide

1H MR (400 MHz, acetone) δ ppm 7.85 (d, J=4.69 Hz, 1 H) 7.99 (d, J=8.00 Hz, 2 H) 8.30 (s, 1 H) 8.45 (d, J=8.20 Hz, 2 H) 9.02 (d, J=5.08 Hz, 1 H); LCMS (M/Z): 442.8 (M + H). Compound l54: N- [5-cyano-4- [5-(trifluor omethyl)-2-pyridyl] thiazol-2-yl] -4- (trifluoromethyl)benzamide

1H MR (400 MHz, acetone) δ ppm 7.99 (d, J=8.00 Hz, 2 H) 8.24 - 8.31 (i 8.33 - 8.39 (m, 1 H) 8.42 (s, 2 H) 9.02 - 9.12 (m, 1 H).

Compound 155: N-[5-cyano-4-(2-pyridyl)thiazol-2-yl]-4- (trifluoromethyl)benzamide

1H MR (400 MHz, DMSO- ) δ ppm 7.55 (dd, J=6.93, 5.37 Hz, 1 H) 7.98 (d, J=8.20 Hz, 2 H) 8.04 (td, J=7.71, 1.56 Hz, 1 H) 8.09 - 8.14 (m, 1 H) 8.34 (d, J=8.20 Hz, 2 H) 8.76 (d, J=4.88 Hz, 1 H) LC/MS M+H? 375.

Parasiticidal Activity

The compounds of the present invention 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 37C/5%C0₂/95%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%C0₂/95%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 im itis 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 37C/5%C0₂/95%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 (MIC 100) 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 μΙ_, 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 En Vision® plate reader (Perkin Elmer, Waltham, MA) 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 μΜ 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 μΜ:

Compounds 1-7, 9-19,21-22, 24-28, 30-56, 58-92, 94-138, 140-142, 144, 147-148, 151-153, and 155.

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

1. A compound of formula (I)

(I)

wherein:

A is C=0 or S0₂;

X is R¹ or HR¹;

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,

- R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl, and halogen,

with the proviso that the optional substitution is not 4-[(2,4-dioxo-5- oxazolidinylidene)methyl, or

with the proviso that when Z is 3-trifluoromethylphenyl, the optional substitution is not 2,5-difluoro, or

with the proviso that when Z is 1 -piped dinyl, the optional substitution is not 3,5-dimethoxy;

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, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴,

-CO HC₆H5, 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, - R³R⁴, cyano, - R³COR⁵,alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴,

-CO R³R⁴, -CO HC₆H₅, 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, - R³R⁴, cyano, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴,

-CO HC₆H₅, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, haloalkyl, haloalkoxy, mercapto, thioalkyl and halogen;

or thionyl or furyl, each optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of nitro, - R³R⁴, cyano, - R³COR⁵, alkyl, -S0₂R⁵, - R³S0₂R⁵, -S0₂ R³R⁴, -CO R³R⁴, -CO HC₆H₅, 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 -CO R³R⁴; 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;

Z is halo, haloalkyl, cyano, optionally substituted alkyl, alkoxy, -CO R³R⁴, optionally substituted cycloalkyl, aminoalkyl, alkylaminoalkyl, optionally substituted heterocyclyl, or optionally substituted aryl;

or a pesticidally acceptable salt thereof.

2. The compound of claim 1, where R² is hydrogen or halogen.

3. The compound of claim 1, where R¹ is phenyl substituted by from one to three substituents which are the same or different, each selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy, with the proviso that when Z is 3-trifluoromethylphenyl, the optional substitution is not 2,5-difluoro or with the proviso that when Z is 1-piperidinyl, the optional substitution is not 3,5-dimethoxy; or R¹ is naphthyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of halogen, cyano, haloalkyl, alkoxy and haloalkoxy.

4. The compound of claim 1, where:

A is C=0;

X is HR¹;

R¹ is phenyl optionally substituted by from one to three substituents which are the same or different, each selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, cyano, methyl, ethyl, methoxy, ethoxy,

thiomethyl, -S0₂CH₃, -S0₂ H₂, -S0₂ HCH₃, -S0₂N(CH₃)₂ and - HS0₂CH₃, with the proviso that when Z is 3-trifluoromethylphenyl, the optional substitution is not 2,5-difluoro;

and R² is hydrogen, fluoro, methyl, trifluoromethyl, methoxy or

trifluoromethoxy;

and Z is haloalkyl, cyano, optionally substituted alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl.

5. The compound of claim 1, where:

A is C=0;

X is R¹;

R² is hydrogen, fluoro, methyl, trifluoromethyl, methoxy,

trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl;

Z is haloalkyl, cyano, optionally substituted alkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl.

6. The compound of claim 1, where:

- I l l - A is S0₂;

X is R¹;

trifluoromethoxy, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, thiomethyl, methanesulfonyl, sulfonamide, methylsulfonamide, dimethylsulfonamide, and methylsulfonanilide; and

R² is hydrogen

Z is haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl.

7. The compound of claim 1, where:

A is C=0 or S0₂;

X is R¹ or HR¹;

R^l is:

cyano, - R³COR⁵, alkyl, alkoxy, aryl, heterocyclyl, aryloxy, haloalkyl, haloalkoxy, mercapto (-SH), thioalkyl and halogen;

R² is hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, morpholino, aminoalkyl or dimethylaminomethyl;

8. A compound selected from a compound listed in Table 1.

9. A compound selected from the group consisting of Compounds 1-7, 9-19, 21- 22, 24-28, 30-56, 58-93, 94-138, 140-142, 144, 147-148, 151-153, and 155.

10. A pesticidal composition comprising a compound of claim 1 and a pesticidally acceptable carrier.

11. A compound of claim 1 or a composition of claim 10 in combination with one or more other pesticidally active substances.

12. A method for controlling parasites at a locus which comprises applying to the locus an effective amount of a thiazole derivative of formula (I) as defined in claim 1 or a pestici dally acceptable salt thereof or a composition of claim 10.

13. A method of treating or preventing parasite infection in a subject, the method comprising administering to the subject an effective amount of a thiazole derivative of formula (I) as defined in claim 1 or a pesticidally acceptable salt thereof or a composition of claim 10.

14. A compound of claim 1 or a composition of claim 10 for use in treating or preventing parasitic infection.

15. The method of claim 13 or the compound or composition of claim 14, wherein the parasite is a helminth.

16. The method of claim 13 or the compound or composition of claim 14, wherein the parasite is dirofilaria immitis.

17. A compound of claim 1 or a composition of claim 10 for use in medicine.

18. A method of manufacturing a compound of formula (I) of claim 1 in which X is R¹, comprising reacting a compound of formula (II):

R -A-X