CN101316844A - Diacylglycerol Acyltransferase (DGAT) Inhibitors - Google Patents

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the substituents are as defined in the specification and claims. These compounds and pharmaceutical compositions containing them are useful in the treatment of diseases such as obesity, type II diabetes and metabolic syndrome.

Description

Diacylglycerol Acyltransferase (DGAT) Inhibitors

The present invention relates to diacylglycerol acyltransferase inhibitors. Such inhibitors include, for example, oxazole compounds, and can be used in the treatment of diseases such as obesity, type II diabetes, dyslipidemia and metabolic syndrome. The compound of the present invention is a compound of formula (I)

in:

_R is unsubstituted aryl, aryl, heteroaryl, alkyl or ring substituted with a group selected from alkyl, -O-alkyl, haloalkoxy, methoxy-ethoxy and halogen alkyl;

_R2 is C or N;

_R3 is C, N, S or O;

_R4 is C, O, S or N;

_R5 is C, N or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

或

or

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen Thiothiomorpholino, Dioxothiomorpholino, Alkyl-Carbamoyl-Alkyl-Amino, Difluoroazetidine, Ethoxyazetidine, Azetidine -3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to 6- with 1 to 3 heterocyclic atoms selected from S, N and O A membered ring, which is unsubstituted or substituted with a group selected from the group consisting of; amino, amide, -N(CH ₃ )C(O)CH ₃ , cyclopropanecarbonyl-methyl, -OCH ₃ , -OCH ₂ C (O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH; R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl , trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or with 1 to 3 A 4- to 6-membered ring of heteroatoms selected from S, N and O, unsubstituted or substituted by a group selected from the group consisting of -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ ,

-OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In addition, the present invention provides a method of treating obesity, type II diabetes or metabolic syndrome comprising the step of administering a therapeutically effective amount of a compound according to formula I to a patient in need thereof.

All documents mentioned below or relied upon are hereby expressly incorporated by reference.

Triglycerides or triacylglycerols are the major form of energy storage in eukaryotes. In mammals, these compounds are mainly synthesized in three tissues: small intestine, liver and adipocytes. Triglycerides or triacylglycerols support the following major functions: dietary fat absorption, packaging of newly synthesized fatty acids and storage in adipose tissue (see, Subauste and Burant, Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270 ).

Diacylglycerol O-acyltransferase, also known as diglyceride acyltransferase or DGAT, is an important enzyme in triglyceride synthesis. DGAT catalyzes the final rate-limiting step in the synthesis of triacylglycerols from 1,2-diacylglycerols (DAG) and long-chain fatty acyl CoAs as substrates. Thus, DGAT plays a key role in the metabolism of cellular diacylglycerols and is particularly important for triglyceride production and energy storage homeostasis (see, Mayorek et al., European Journal of Biochemistry (1989) 182, 395-400 ).

DGAT is specific for sn-1,2 diacylglycerols and will accept a wide variety of fatty acyl chain lengths (see, Farese et al., Current Opinions in Lipidology (2000) 11, 229-234). The level of DGAT activity in adipocytes increases when they differentiate in vitro, and recent evidence suggests that DGAT can be regulated in post-transcriptional adipose tissue (see, Coleman et al., Journal of Molecular Biology (1978) 253, 7256-7261 and Yu et al., Journal of Molecular Biology (2002) 277, 50876-50884). DGAT activity is mainly expressed in the endoplasmic reticulum (see, Colman, Methods in Enzymology (1992) 209, 98-104). In hepatocytes, DGAT activity has been shown to be expressed simultaneously on the cytosolic and luminal surfaces of the endoplasmic reticulum membrane (see, Owen et al., Biochemical Journal (1997) 323 (pt 1), 17-21 and Waterman et al., Journal of Lipid Research (2002) 43, 1555-156). In the liver, regulation of triglyceride synthesis and distribution, between retention as cytosolic droplets and secretion, is of primary importance for determining the rate of VLDL production (see, Shelness and Sellers, Current Opinions in Lipidology (2001) 12, 151-157 and Owen et al., Biochemical Journal (1997) 323 (pt 1), 17-21).

Two forms of DGAT were cloned and named DGAT1 and DGAT2 (see, Cases et al., Proceedings of the National Academy of Science, USA (1998) 95, 13018-13023, Lardizabal et al., Journal of Biological Chemistry (2001) 276, 38862-38869 and Cases et al., Journal of Biological Chemistry (2001) 276, 38870-38876). Although both enzymes utilize the same substrate, there is no homology between DGAT1 and DGAT2. Furthermore, although both enzymes are ubiquitously expressed, there are differences in the relative abundance of DGAT1 and DGAT2 expression in various tissues.

The gene encoding mouse DGAT1 has been used to generate DGAT knockout mice. These mice, although unable to express a functional DGAT enzyme (Dgat-/- mice), are viable and continue to synthesize triglycerides (see, Smith et al., Nature Genetics (2000) 25, 87-90). This would suggest that multiple catalytic mechanisms promote triglyceride synthesis, such as DGAT2. An alternative route has been shown to form triglycerides from two diacylglycerols through the action of diacylglycerol transacylases (see, Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210) .

Dgat-/- mice are resistant to diet-induced obesity and remain lean. When fed a high-fat diet, Dgat-/- mice maintained comparable weight to mice fed a diet with normal fat content. Dgat-/- mice also had lower tissue triglyceride levels. The increased antibody weight found in knockout mice with slightly higher food intake was due to increased energy expenditure and increased sensitivity to insulin and leptin (see, Smith et al., Nature Genetics (2000) 25, 87-90, Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192, Chen and Farese, Current Opinions in Clinical Nutrition and Metabolic Care (2002) 5, 359-363 and Chen et al., Journal of Clinical Investigation (2002) 109, 1049-1055). Compared with wild-type mice, Dgat-/- mice had a reduced rate of triglyceride absorption, increased triglyceride metabolism, and improved glucose metabolism, as well as lower glucose and insulin levels after a glucose load (see, Buhman et al., Journal of Biological Chemistry (2002) 277, 25474-25479 and Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192).

Disorders or dysregulation of triglyceride metabolism, ie both absorption as well as de novo synthesis, are implicated in the pathogenesis of various diseases. These diseases include, for example, obesity, insulin resistance syndrome, type II diabetes, dyslipidemia, metabolic syndrome (syndrome X) and coronary heart disease (see Kahn, Nature Genetics (2000) 25, 6-7, Yanovski and Yanovski, New England Journal of Medicine (2002) 346, 591-602, Lewis et al., Endocrine Reviews (2002) 23, 201, Brazil, Nature Reviews Drug Discovery (2002) 1, 408, Malloy and Kane, Advances in Internal Medicine ( 2001) 47, 111, Subauste and Burant, Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270 and Yu and Ginsberg, Annals of Medicine (2004) 36, 252-261). Compounds that can reduce the synthesis of triglycerides from diacylglycerols by inhibiting or reducing the enzyme activity of DGAT are valuable as therapeutic agents for the treatment of disorders associated with abnormal metabolism of triglycerides.

Known DGAT inhibitors include: Dibenzoxazepine Ketones (see, Ramharack, et al., EP1219716 and Burrows et al., 26 ^th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see, Fox et al., WO2004047755) , chalcones such as xanthohumol (see, Tabata et al., Phytochemistry (1997) 46, 683-687 and Casaschi et al., Journal of Nutrition (2004) 134, 1340-1346), substituted benzyl-phosphonates ( See, Kurogi et al., Journal of Medicinal Chemistry (1996) 39, 1433-1437, Goto, et al., Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Ikeda, et al., Thirteenth International Symposium on Athersclerosis (2003), Abstract 2P- 0401 and Miyata, et al., JP 2004067635), aryl alkyl acid derivatives (see Smith et al., WO2004100881 and US20040224997), furan and thiophene derivatives (see WO2004022551), pyrrolo[1,2b]pyridazine derivatives (see Fox et al., WO2005103907), and substituted sulfonamides (see Budd Haeberlein and Buckett, WO20050442500).

Also known as DGAT inhibitors are: 2-bromo-palmitic acid (see, Colman et al., Biochimica et Biophysica Acta (1992) 1125, 203-9), 2-bromo-octanoic acid (see, Mayorek and Bar-Tana , Journal of Biological Chemistry (1985) 260,6528-6532), roselipins (referring to, Noriko et al., (Journal of Antibiotics (1999) 52,815-826), amidepsin (referring to, Tomoda et al., Journal of Antibiotics (1995) 48, 942-7), isochromophilone, prenylflavonoids (see, Chung et al., Planta Medica (2004) 70, 258-260), polyacetylenes (see, Lee et al., Planta Medica (2004) 70, 197-200 ), cochlioquinones (see, Lee et al., Journal of Antibiotics (2003) 56, 967-969), tanshinones (see, Ko et al., Archives of Pharmaceutical Research (2002) 25, 446-448), gemfibrozil (see, Zhu et al., Atherosclerosis (2002) 164,221-228) and substituted quinolones (seeing, Ko, et al., Planta Medica (2002) 68,1131-1133). Antisense oligonucleotides also known as DGAT activity modulators Nucleotides (see Monia and Graham, US20040185559).

However, there is a need in the art for other DGAT inhibitors with efficacy in the treatment of metabolic disorders such as obesity, type II diabetes and metabolic syndrome. Furthermore, there is a need in the art for DGAT inhibitors with IC50 values below about 1 [mu]M.

It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. In addition, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are now described.

As used herein, the term "alkyl" refers to, for example, a branched or linear, cyclic or acyclic, saturated or unsaturated (such as alkenyl or alkynyl) hydrocarbon group, which may be substituted or un replaced. When it is a cyclic hydrocarbon group, the alkyl group is preferably C ₃ to C ₁₂ , more preferably C ₄ to C ₁₀ , more preferably C ₄ to C ₇ . When it is an acyclic hydrocarbon group, the alkyl group is preferably C ₁ to C ₁₀ , more preferably C ₁ to C ₆ , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl ( n-butyl, isobutyl or tert-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. It should therefore be understood that the term "alkyl" as used herein includes alkyl (branched or straight chain), substituted alkyl (branched or straight chain), alkenyl (branched or straight chain ), substituted alkenyl (branched or straight chain), alkynyl (branched or straight chain), substituted alkynyl (branched or straight chain), cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl. In a preferred embodiment, the term alkyl refers to the above-mentioned acyclic saturated branched or straight chain hydrocarbon groups. The above-mentioned cyclic alkyl group is preferably referred to as "cycloalkyl group".

As used herein, the term "lower alkyl" refers to, for example, branched or linear, cyclic or acyclic, saturated or unsaturated (such as alkenyl or alkynyl) hydrocarbon groups, wherein the cyclic Lower alkyl is C ₅ , C ₆ or C ₇ , and wherein said acyclic lower alkyl is C ₁ , C ₂ , C ₃ or C ₄ , and is preferably selected from: methyl, ethyl, propyl ( n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tert-butyl). Accordingly, it should be understood that the term "lower alkyl" as used herein includes, for example, lower alkyl (branched or straight chain), lower alkenyl (branched or straight chain), lower alkynyl (branched or straight chain), or straight chain), cyclo-lower alkyl, cyclo-lower alkenyl and cyclo-lower alkynyl. In a preferred embodiment, the term lower alkyl refers to the above-mentioned acyclic saturated branched or linear hydrocarbon group. The aforementioned cyclo-lower alkyl group is preferably referred to as "lower cycloalkyl group".

As used herein, the term "aryl" refers to, for example, a substituted or unsubstituted carbocyclic aromatic group such as phenyl or naphthyl, or a substituted or unsubstituted heteroaryl group containing one or more, preferably one, heteroatom A group, such as pyridyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, three Azolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzisoxazole and benzisothiazolyl. Preference is given to aryl groups which do not contain heteroatoms, especially phenyl or naphthyl. Aryl groups may be optionally substituted, for example as described below for heteroaryl groups, or as described below in the specification and claims. In a preferred embodiment, the term "heteroaryl", alone or in combination with other groups, refers to a monocyclic or bicyclic group with at least one aromatic ring of 5-12 ring atoms, which contains one, two one or three hetero ring atoms selected from N, O and S, and the remaining ring atoms are C, provided that the point of attachment of the heteroaryl is on the aromatic ring. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. The above-mentioned heteroaryl groups can be independently substituted by one, two or three substituents, preferably one or two substituents, and the substituents are selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio, amino, amino C _1-6 alkane Base, mono- or di-substituted amino-C _1-6 alkyl, nitro, cyano, acyl, carbamoyl, mono- or di-substituted amino, aminocarbonyl, mono- or di-substituted amino -Carbonyl, aminocarbonyl C _1-6 alkoxy, mono- or di-substituted amino-carbonyl-C _1-6 alkoxy, hydroxy-C _1-6 alkyl, carboxyl, C _1-6 alkoxy Carbonyl, aryl C _1-6 alkoxy, heteroaryl C _1-6 alkoxy, heterocyclyl C _1-6 alkoxy, C _1-6 alkoxycarbonyl C _1-6 alkoxy, Carbamoyl C _1-6 alkoxy and carboxy C _1-6 alkoxy, preferably selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio, amino, mono-C _1-6 alkyl substituted amino, di-C _{1 -6} alkyl substituted amino, amino C _1-6 alkyl, mono-C _1-6 alkyl substituted amino-C _1-6 alkyl, di-C _1-6 alkyl substituted amino-C _{1- 6} Alkyl, nitro, carbamoyl, mono- or di-substituted amino-carbonyl, hydroxy-C _1-6 alkyl, carboxy, C _1-6 alkoxycarbonyl and cyano.

基，哌嗪基，吗啉基，硫萘基(thianaphthyl)，苯并呋喃基，异苯并呋喃基，吲哚基，羟基吲哚基，异吲哚基，吲唑基，二氢吲哚基，7-氮杂吲哚基，苯并吡喃基，香豆素基，异香豆素基，喹啉基，异喹啉基，naphthridinyl，噌啉基，喹唑啉基，吡啶并吡啶基，苯并噁嗪基，喹喔啉基，苯并吡喃基，苯并二氢吡喃基，异苯并二氢吡喃基，2，3-二氮杂萘基和咔啉基)。Alkyl and aryl groups can be substituted or unsubstituted. When substituted there will typically be, for example, 1 to 3 substituents, preferably 1 substituent. Substituents may include, for example: carbon-containing groups such as alkyl groups, aryl groups, arylalkyl groups (e.g., substituted and unsubstituted phenyl groups, substituted and unsubstituted benzyl groups); halogen atoms and halogen-containing groups such as haloalkanes (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryl oxyalkyl), aldehydes (such as formaldehyde), ketones (such as alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (such as carboxy, carboxyalkyl ), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, Aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamate (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di- Alkylaminocarbonyloxy, arylaminocarbonyloxy (arylminocarbonloxy)) and urea (e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g. amino, mono - or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azide, nitrile (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiol , thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio radical, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one, heteroatom Groups (such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidine Base, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyroneyl, pyridyl, pyrazinyl, pyridazinyl, piperidinyl, Hexahydroazepine

Base, piperazinyl, morpholinyl, thianaphthyl, benzofuryl, isobenzofuryl, indolyl, oxindolyl, isoindolyl, indazolyl, indoline Base, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl , benzoxazinyl, quinoxalinyl, benzopyranyl, chromanyl, isochromanyl, 2,3-naphthyridine and carbolinyl).

Lower alkyl may be substituted or unsubstituted, preferably unsubstituted. When substituted, there will generally be eg 1 to 3 substituents present, preferably 1 substituent.

As used herein, the term "alkoxy" refers to, for example, alkyl-O-, and "alkoyl" refers to, for example, alkyl-CO-. An alkoxy substituent or an alkoxy-containing substituent may be substituted, for example, with one or more alkyl groups.

As used herein, the term "halogen" refers to eg fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

As used herein, the term "haloalkyl" refers to an alkyl group as defined above, or preferably a lower alkyl group as defined above, which is substituted by one or more, preferably one to three, halogen atoms. Preferred examples _of haloalkyl are eg _CF3 , _CH2F , _CF3CH2- or _{CH2ClCH2 .}

As used herein, the term "haloalkoxy" refers to a group of the formula: haloalkyl-O-.

As used herein, the term "thioalkyl" refers to an alkyl group as defined above, which contains a sulfur atom. Examples of thioalkyl groups are the thioethers described below.

As used herein, the term "thioalkoxy" refers to a group of the formula: alkyl-S- or lower alkyl-S-.

As used herein, the term "thioether" refers to a group of formula: alkyl-S-alkyl- or preferably lower alkyl-S-lower alkyl. _{Examples of thioethers are eg CH3CH2SCH2CH2-} , _CH3CH2SCH2- or _{CH3SCH2- .}

As used herein, the term "amino" refers to -NH ₂ , -N(H,alkyl) or -N(alkyl) ₂ . Alkyl groups may also be replaced by lower alkyl groups.

As used herein, the term "amide" refers to aminocarbonyl, mono- or di-alkyl-aminocarbonyl. The amide group can be bound via the nitrogen atom or via the carbonyl group.

As used herein, the term "alkyl ether" refers to a group of formula: alkyl-O-alkyl- or preferably lower alkyl-O-lower alkyl. Examples of alkyl ethers are, for example, CH ₃ CH ₂ OCH ₂ CH ₂ —, CH ₃ CH ₂ OCH ₂ — or CH ₃ OCH ₂ —.

As used herein, the term "alkyl alcohol" refers to an alkyl or lower alkyl group as defined above, which is substituted with one or more, preferably one, hydroxyl group. _{Examples of} alkyl alcohols are eg _HOCH2CH2- , or _CH3CH (OH) _CH2CH2- .

As used herein, the term "acyl" refers to the group alkyl-C(O)-, lower alkyl-C(O)- or CH(O)-.

As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound of formula (I). Salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, Hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc. . Particular preference is given to fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids. Acceptable base salts include alkali metal (eg sodium, potassium), alkaline earth metal (eg calcium, magnesium) and aluminum salts.

In particular, the invention relates to compounds of formula (I):

in:

_R is unsubstituted aryl, aryl, heteroaryl, alkyl or ring substituted with a group selected from alkyl, -O-alkyl, haloalkoxy, methoxy-ethoxy and halogen alkyl;

_R2 is C or N;

_R3 is C, N, S or O;

_R4 is C, O, S or N;

_R5 is C, N or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

或

or

at least one of R ₈ or R ₉ is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azepine Cyclobutan-3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to a 6-membered ring, which is unsubstituted or substituted by a group selected from the group consisting of amino, amide, -N(CH ₃ )C(O)CH ₃ , cyclopropanecarbonyl-methyl, -OCH ₃ , - OCH ₂ C(O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered ring having 1 to 3 hetero ring atoms selected from S, N, and O, which is unsubstituted or selected from the group consisting of Group substitution: -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ , -OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

The compounds of the formula (I) are individually preferred and the physiologically acceptable salts thereof are individually preferred, with the compounds of the formula (I) being particularly preferred.

Compounds of formula (I) may possess one or more asymmetric C atoms and may thus exist as mixtures of enantiomers, mixtures of stereoisomers, or as optically pure compounds.

A preferred embodiment of the invention relates to compounds of formula (I) as defined above, wherein:

_R is unsubstituted aryl or aryl substituted by a group selected from alkyl and halogen;

_R2 is C;

_R3 is N;

_R4 is O;

_R5 is C;

R is _alkyl ;

R ₇ is

或

or

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen Thiothiomorpholino, Dioxothiomorpholino, Alkyl-Carbamoyl-Alkyl-Amino, Difluoroazetidine, Ethoxyazetidine, Azetidine -3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to 6- with 1 to 3 heterocyclic atoms selected from S, N and O A membered ring, which is unsubstituted or substituted with a group selected from the group consisting of amino, amide, -N( _CH3 )C(O) _CH3 , cyclopropanecarbonyl-methyl, _-OCH3 , _-OCH2C (O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered ring having 1 to 3 hetero ring atoms selected from S, N, and O, which is unsubstituted or selected from the group consisting of Group substitution: -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ , -OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein:

_R is unsubstituted aryl or aryl substituted by a group selected from alkyl and halogen;

_R2 is C;

_R3 is O;

_R4 is N;

_R5 is C;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

或

or

at least one of R ₈ or R ₉ is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen Thiothiomorpholino, Dioxothiomorpholino, Alkyl-Carbamoyl-Alkyl-Amino, Difluoroazetidine, Ethoxyazetidine, Azetidine -3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to 6- with 1 to 3 heterocyclic atoms selected from S, N and O A membered ring, which is unsubstituted or substituted with a group selected from the group consisting of amino, amide, -N( _CH3 )C(O) _CH3 , cyclopropanecarbonyl-methyl, _-OCH3 , _-OCH2C (O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered ring having 1 to 3 hetero ring atoms selected from S, N, and O, which is unsubstituted or selected from the group consisting of Group substitution: -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ , -OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein:

_R is unsubstituted aryl, aryl, heteroaryl, alkyl or ring substituted with a group selected from alkyl, -O-alkyl, haloalkoxy, methoxy-ethoxy and halogen alkyl;

_R2 is C or N;

_R3 is C, N, S or O;

_R4 is C, O, S or N;

_R5 is C, N or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ ;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein: _R is unsubstituted aryl selected from the group consisting of alkyl, -O-alkyl, haloalkoxy, methoxy-ethyl Oxygen and halogen substituted aryl, heteroaryl, alkyl or cycloalkyl;

_R2 is C or N;

_R3 is C, N, S or O;

_R4 is C, O, S or N;

_R5 is C, N or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

at least _one of R or _R is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen Thiothiomorpholino, Dioxothiomorpholino, Alkyl-Carbamoyl-Alkyl-Amino, Difluoroazetidine, Ethoxyazetidine, Azetidine -3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to 6- with 1 to 3 heterocyclic atoms selected from S, N and O A membered ring, which is unsubstituted or substituted with a group selected from the group consisting of amino, amide, -N( _CH3 )C(O) _CH3 , cyclopropanecarbonyl-methyl, _-OCH3 , _-OCH2C (O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered ring having 1 to 3 hetero ring atoms selected from S, N, and O, which is unsubstituted or selected from the group consisting of Group substitution: -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ , -OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein:

_R is unsubstituted aryl, aryl, heteroaryl, alkyl or ring substituted with a group selected from alkyl, -O-alkyl, haloalkoxy, methoxy-ethoxy and halogen alkyl;

_R2 is C or N;

_R3 is C, N, S or O;

_R4 is C, O, S or N;

_R5 is C, N or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R ₇ is

或

or

at least _one of R or _R is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, hydroxy-dimethylethylamino, hydroxy-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxygen Thiothiomorpholino, Dioxothiomorpholino, Alkyl-Carbamoyl-Alkyl-Amino, Difluoroazetidine, Ethoxyazetidine, Azetidine -3-yloxyacetic acid tert-butyl ether, azetidin-3-yloxyacetic acid hydrochloride, or 4- to 6- with 1 to 3 heterocyclic atoms selected from S, N and O A membered ring, which is unsubstituted or substituted with a group selected from the group consisting of amino, amide, -N( _CH3 )C(O) _CH3 , cyclopropanecarbonyl-methyl, _-OCH3 , _-OCH2C (O)OC(CH ₃ ) ₃ , OCH ₂ C(O)OH, -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, -CH ₂ CH ₂ CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered ring having 1 to 3 hetero ring atoms selected from S, N, and O, which is unsubstituted or selected from the group consisting of Group substitution: -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -OCH ₂ C(O)OC(CH ₃ ) ₃ , -OCH ₂ C(O)OH and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein R ₆ is —CF ₃ .

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein R ₁₀ is -N(CH ₃ )(CH ₂ ) _n OCH ₃ , -N(CH ₃ )CH ₂ C(O)OCH ₃ , -N(CH ₃ )CH ₂ C(O)NHCH ₃ , -N(CH ₃ )C(O)CH ₃ , -N(CH ₃ )(CH ₂ ) _n CH ₃ , -NH(CH ₂ ) _n CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ ) _n OCH ₃ , diethylamino, -N(CH ₃ )C(O)CH ₂ OCH ₃ , -N(CH ₃ )CH(CH ₃ ) CH ₂ OCH ₃ , -N(CH ₃ )(CH ₂ ) _n O, -N(CH ₂ ) _n O, -NCH ₂ (CH ₃ )CH ₂ O or

-N-tetrahydropyran;

where n is 1, 2 or 3.

Preferred compounds of formula (I) as described above are those selected from the group consisting of:

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-thiazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

4-Phenyl-thiazole-2-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-pyrimidin-5-yl)-amide,

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

5-Bromo-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

5-Phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

5-Chloro-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide,

(Methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid methyl ester,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(dimethylcarbamoylmethyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide,

4-Methyl-2-phenyl-thiazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide ,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(R)-3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridine-3- base}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclopropanecarbonyl-methyl-amino)-pyridin-3-yl]-amide,

5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

5-Chloro-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide,

5-Ethyl-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide,

5-Ethyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′ -yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(butyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-propylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-thiazol-5-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide ,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-ethylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-diethylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-dimethylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclohexylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopropylamino-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclobutyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(cyclopropyl-methyl-amino)-pyrimidin-5-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]-pyridine- 3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-1-methyl-ethylamino)-pyridin-3-yl]-amide; Hydrochloride ,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-1-phenyl-ethylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyloxazole-4-carboxylic acid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide ,

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridine -3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}-amide ,

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide; trifluoro acetate,

2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

5-Phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]- Pyridin-3-yl}-amide,

1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3- base}-amide,

2-(2-Chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl }-amide,

2-(2-Chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-(2-Bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl }-amide,

2-(2-Bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide,

2-(2-Bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridine- 3-yl}-amide,

2-(2-Bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl }-amide,

2-(2-Ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3- base}-amide,

2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine -3-yl}-amide,

2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine -5-yl}-amide,

2-(2-Methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3 -base}-amide,

2-(2-Methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine-5 -base}-amide,

2-Phenyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-propyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-(2-Chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

2-(2-Bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

5-Propyl-2-tolyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-(2-Chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide,

2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(3-hydroxy-pyrrolidin-1-yl)-pyrimidin-5-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-5-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-5-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′-yl )-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-hydroxyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′-yl )-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide,

2-(2-Bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl] - amides,

2-(2-Chloro-phenyl)-5-ethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-(2-Chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

4-Methyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

4-Propyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

4-Methyl-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

4-(2-Methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-(2-Chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

2-(2-Chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

2-Phenyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-4-propyl-oxazole-5-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide,

2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}- amides,

2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide,

2-(2-Chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide,

2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide,

2-(2-Methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3 -base}-amide,

2-(2-Methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine-5 -base}-amide,

2-[2-(2-Methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl Base-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-oxo-1λ4-thiomorpholin-4-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-pyridin-3-yl]-amide ,

5-cyclohexyl-2-methyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(N-2-methoxyethyl-N-methyl)aminopyrazine]-2-yl-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(N-tetrahydropyran-4-yl)aminopyrazine]-2-yl-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(S)-(tetrahydro-furan-3-yl)amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(tetrahydro-furan-3-ylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cis-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(trans-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((1S,3S)-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((1R,3R)-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(3-(S)-methoxy-pyrrolidinyl)-pyridin-2-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-ethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-sec-butylamino)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide ,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-ethoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide,

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy) - tert-butyl acetate,

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy) - acetic acid; hydrochloride,

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid tert butyl ester,

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid; hydrochloride,

[2-(Methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy]- tert-butyl acetate,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide, and

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide,

or a medicinal salt thereof.

Particularly preferred compounds of formula (I) as described above are those selected from the group consisting of:

5-Phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide,

2-(2-Chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl }-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide, and

2-(2-Chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}- amides,

or a medicinal salt thereof.

A preferred compound of formula (I) as described above is 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide.

Another preferred compound of formula (I) as described above is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridine-3- base]-amide.

Another preferred compound of formula (I) as described above is 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl )-methyl-amino]-pyridin-3-yl}-amide.

Another preferred compound of formula (I) as described above is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxyl-1-methyl- Ethylamino)-pyridin-3-yl]-amide.

Another preferred compound of formula (I) as described above is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl -amino]-pyridin-3-yl}-amide.

Another preferred compound of formula (I) as described above is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl -amino]-pyrimidin-5-yl}-amide.

Another preferred compound of formula (I) as described above is 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy- Ethyl)-methyl-amino]-pyridin-3-yl}-amide.

Another preferred compound of formula (I) as described above is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl )-amide.

Other preferred compounds of formula (I) as described above are those of formula (I):

in:

_R is unsubstituted aryl, aryl substituted by a group selected from alkyl and halogen, heteroaryl, alkyl or cycloalkyl;

_R2 is C or N;

_R3 is C, N or O;

_R4 is C, O, S or N;

R ₅ is C or S;

_R is H, alkyl, halogen, haloalkyl, thioalkyl, alkoxy, thioalkoxy, haloalkoxy or absent;

R ₇ is

或

or

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, or has 1 to 3 selected from S , 5- or 6-membered rings of heterocyclic atoms of N and O, which are unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and - OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of amide, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Also preferred other compounds of formula (I) as described above are those wherein:

_R is unsubstituted aryl or aryl substituted by a group selected from alkyl and halogen;

_R2 is C;

_R3 is N;

_R4 is O;

_R5 is C;

R is _alkyl ;

R ₇ is

或

or

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, or has 1 to 3 selected from S , 5- or 6-membered rings of heterocyclic atoms of N and O, which are unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and - OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of amide, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Other preferred compounds of formula (I) are those wherein:

_R is unsubstituted aryl or aryl substituted by a group selected from alkyl and halogen;

_R2 is C;

_R3 is O;

_R4 is N;

_R5 is C;

_R is H, alkyl, halogen, haloalkyl, or absent;

R ₇ is

或

or

at least one of R _or ^R is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, or has 1 to 3 selected from S , 5- or 6-membered rings of heterocyclic atoms of N and O, which are unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and - OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of amide, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Other preferred compounds of formula (I) are those in which:

_R is unsubstituted aryl, aryl substituted by a group selected from alkyl and halogen, heteroaryl, alkyl or cycloalkyl;

_R2 is C or N;

_R3 is C, N or O;

_R4 is C, O, S or N;

R ₅ is C or S;

_R is H, alkyl, halogen, haloalkyl, or absent;

R ₇ is

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ ;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of amide, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Other preferred compounds of formula (I) are those in which:

_R is unsubstituted aryl, aryl substituted by a group selected from alkyl and halogen, heteroaryl, alkyl or cycloalkyl;

_R2 is C or N;

_R3 is C, N or O;

_R4 is C, O, S or N;

R ₅ is C or S;

_R is H, alkyl, halogen, haloalkyl, or absent;

R ₇ is

at least one of R _{or R} is N; and

R ₁₀ is -NR ₁₁ R ₁₂ , O-alkyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, or has 1 to 3 selected from S , 5- or 6-membered rings of heterocyclic atoms of N and O, which are unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and - OH;

R ₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered ring with 1 to 3 hetero ring atoms selected from S, N and O, which is unsubstituted or replaced by Substituted by a group selected from the group consisting of amide, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ and -OH;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Other preferred compounds of formula (I) are those in which:

_R is unsubstituted aryl, aryl substituted by a group selected from alkyl and halogen, alkyl or cycloalkyl;

_R2 is C or N;

_R3 is C, N or O;

_R4 is C, O, S or N;

R ₅ is C or S;

_R is H, alkyl, halogen, haloalkyl, or absent;

R ₇ is

或

or

at least one of R _{or R} is N; and

R ₁₀ is a 5- or 6-membered ring having 1 to 3 heterocyclic atoms selected from S, N and O, which is unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , - _CH2OH , _-CH2OCH3 and _-OH ;

R ₁₁ is a 5- or 6-membered ring having 1 to 3 heterocyclic atoms selected from S, N and O, which is unsubstituted or substituted by a group selected from the group consisting of amides, -OCH ₃ , - _CH2OH , _-CH2OCH3 and _-OH ;

R ₁₂ is H or lower alkyl;

or a medicinal salt thereof.

Preferably, R ₆ is -CF ₃ .

Among the above compounds, preferably R ₁₀ is -N(CH ₃ )(CH ₂ ) _n OCH ₃ , -N(CH ₃ )CH ₂ C(O)OCH ₃ , -N(CH ₃ )CH ₂ C(O) NHCH ₃ , -N(CH ₃ )C(O)CH ₃ , -N(CH ₃ )(CH ₂ ) _n CH ₃ , -NH(CH ₂ ) _n CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ ) _n OCH ₃ , diethylamino, -N(CH ₃ )C(O)CH ₂ OCH ₃ , -N(CH ₃ )CH(CH ₃ )CH ₂ OCH ₃ , -N(CH ₃ )(CH ₂ ) _n O, -N(CH ₂ ) _n O, -NCH ₂ (CH ₃ ) CH ₂ O or

-N-tetrahydropyran;

where n is 1, 2 or 3.

It will be appreciated that the compounds of general formula (I) of the present invention may be derivatized at functional groups to provide derivatives which can be converted back to the parent compound in vivo.

Another embodiment of the present invention relates to a process for the preparation of a compound of formula (I) as described above, which process comprises reacting a compound of formula (II) with a compound of formula R ⁷ -NH ₂ ,

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

The reaction of the compound of formula (II) with the compound of formula R ⁷ -NH ₂ can be carried out by methods and conditions known to those skilled in the art, for example, as described in the following general methods or specific examples.

The present invention also relates to compounds of formula (I) as described above, prepared by the process defined above.

The compounds of the present invention can be prepared starting from commercially available starting materials and using general synthetic techniques and methods known to those skilled in the art. Suitable reaction schemes for the preparation of these compounds are outlined below. Further examples are in the specific examples described in detail below.

Reaction scheme 1

As shown in Scheme 1, using a method similar to that of Gilman and Burtner (see H. Gilman and RR Burtner J. Amer. Chem. Soc . 71 1213 (1949)), 2-substituted-3-furoic acids i, where R' is halogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, haloalkoxy and can be brominated at C-5 with bromine in acetic acid to give 5-bromo-furoic acid ii. Furoic acid ii can react with various amines to form amides iii, where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. A variety of standard amide bond forming conditions can be used as practiced by those skilled in the art. Typically ii and the amine _NH2R1 ', in _a suitable solvent, can be treated with a base such as triethylamine and an amide bond forming agent such as BOP, PyBroP or EDCI and HOBT ( See D. Nguyen J. Chem Soc. Perkin Trans. I 1025 (1985), J. Coste et al J. Org. Chem .592437 (1994) and M Boyeman et al Int. J. Peptide Protein Res. 37 252 (1991)) , to obtain amides iii. Use the standard palladium-catalyzed "cross-coupling" procedure (see A. Suzuki, Metal-Catalyzed Cross-Coupling Reaction, Diederich F, Stang PJ, eds, Wiley, 1998 pp 49-97 and F. Bellina et al. Synthesis 2419 (2004)) , 5-bromo-furoic acid amide iii can be heated with a commercially available substituted phenyl boronic acid or boronic acid ester in the presence of a base in an appropriate solvent with a catalytic amount of palladium to obtain iv where _R2 ' is aryl base, substituted aryl, heteroaryl, substituted heteroaryl, the base is typically aqueous sodium carbonate, the solvent is typically DME, DMF or toluene, and the palladium is typically Pd[PPh ₃ ] ₄ .

Reaction Scheme 2

As shown in Scheme 2, pyrazole vi can be prepared using a method similar to that used by Varano, F. et al. treatment to obtain pyrazole vi, wherein _R3 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, cycloalkyl, and _R4 ' is lower alkyl, preferably methyl base or ethyl, the solvent such as ethanol. Pyrazole vi can be alkylated under basic conditions, preferably sodium hydride as base, as described by Zhang, J. et al. (Bioorg. Med. Chem. Lett. 2000, 10, 2575) to obtain the predominant isomer vii .

Substituted pyrazole ester vii can be hydrolyzed by heating with a strong base, typically sodium hydroxide, in a water/organic mixed solvent, preferably methanol, to obtain pyrazole acid viii.

Pyrazole acids viii can be reacted with various amines to form amides, wherein _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically viii and the amine _NH2R1 ', in a suitable _solvent , can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT to The amide ix is obtained.

Reaction Scheme 3

As shown in Scheme 3, using a method similar to that of Plouvier et al (see B. , thioalkoxy, haloalkoxy and _R4 ' is lower alkyl, preferably methyl or ethyl, can be reacted with N-bromosuccinimide in _CCl4 at reflux to give xi. Cyclization of the ketone bromide xi with urea in a suitable solvent, preferably ethanol, preferably under heating in a microwave reactor, affords the substituted 2-aminooxazole xii. Heating xii with copper(II) bromide and tert-butyl nitrite in anhydrous acetonitrile under argon affords 2-bromo-oxazole xiii.

Substituted 2-bromo-oxazole esters xiii can be hydrolyzed to give bromo-oxazole acids xiv by heating with a strong base, typically sodium hydroxide, in an aqueous/organic mixed solvent, preferably methanol.

Oxazole acids xiv can react with various amines to form amides, where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically xiv and the amine _NH2R1 ', in an appropriate _solvent , can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT to The amide xv is obtained.

Using a standard palladium-catalyzed "cross-coupling" procedure, 2-oxazole acid amides xv can be heated with a commercially available substituted phenyl boronic acid or boronic acid ester in an appropriate solvent with a catalytic amount of palladium in the presence of a base , obtain xiv, wherein R ₂ ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, the base is typically aqueous sodium carbonate, the solvent is typically DME, DMF or toluene, the The palladium is typically Pd[PPh ₃ ] ₄ .

Reaction scheme 4

As shown in Scheme 4, ester xvii, wherein R ₄ ' is lower alkyl, preferably methyl or ethyl, and R ₅ ' is alkyl, branched chain alkyl, cycloalkyl or cycloheteroalkyl, can be Reduction with various reducing agents, preferably DIBAL, to obtain aldehydes xviii. Using methods analogous to Kretchmer and Laiter (see RA Kretchmer and RALaitar J. Org. Chem . 434596 (1978)), aldehyde xviii can be reacted with ethyl acetoacetate and a weak base such as piperidine to give xix. After heating and distillation with NBS in _CCl4 , xix affords the substituted furan xx.

Substituted esters xx can be hydrolyzed by heating with a strong base, typically sodium hydroxide, preferably methanol, to give 3-furoic acid xxi in a mixed aqueous/organic solvent.

Furoic acid xxi can react with various amines to form amides, where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically xxi and the amine _NH2R1 ', in an appropriate _solvent , can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT to The amide xxii is obtained.

Reaction scheme 5

As shown in Scheme 5, commercially available nitroaryl halides xxiii, where A and B can be CH or N and X is F, Cl or Br, can be treated with a nucleophile and a neutralizing base in a suitable solvent, Treatment with or without heat to obtain the corresponding substituted nitroaryl xxiv where Nu can be a substituted or unsubstituted cyclic amine such as morpholine, thiomorpholine, pyrrolidine, piperidine, mono- Or di-substituted amines, amino acids or alkoxy groups, the nucleophile is typically amine or alcohol, the neutralization base is typically _Et N, the solvent is typically dichloromethane or N,N -dimethylformamide. The nitro group in compound xxiv can be reduced in a suitable solvent under hydrogen pressure, typically 50 psi, in the presence of a catalyst, typically 10% palladium on carbon, to obtain the substituted aniline xxv .

Reaction Scheme 6

As shown in Reaction Scheme 6, the monosubstituted nitroarylaniline xxvi prepared according to the steps described in Reaction Scheme 5, wherein R ₆ ' is a lower alkyl group, is prepared with an acylating agent in a suitable solvent at a catalytic amount of 4 - heating acylation in the presence of dimethylaminopyridine to obtain N-alkyl-4 nitro-aryl-amide xxvii, wherein R ₇ ' is a lower alkyl, the acylating agent is typically an acid chloride or anhydride, The solvent is typically pyridine. The nitro group in the amide xxvii is reduced in a suitable solvent, typically ethyl acetate or methanol, under hydrogen pressure, typically 50 psi, in the presence of a catalyst to obtain the aniline xxviii, so The catalyst is typically 10% palladium on carbon.

Reaction Scheme 7

As shown in Reaction Scheme 7, compound xxix prepared according to the steps described in Reaction Scheme 5 can be treated with a base and an alkylating agent in a suitable solvent to obtain N and/or O alkylated nitro compound xxx, which in turn can be Reduction under hydrogen pressure in the presence of a catalyst affords aniline xxxi, the base is typically sodium hydride, the alkylating agent is typically alkyl iodide, and the solvent is typically N,N-dimethylformaldehyde amide, the hydrogen pressure is typically 50 psi, and the catalyst is typically 10% palladium on carbon.

Reaction Scheme 8

As shown in Scheme 8, the oxazole compound xxxv can be prepared according to the method described in Org. Lett, 2003, 5 (24), 4567. Commercially available or compound xxxii prepared according to the method described in Bioorg.Med.Chem.Lett.2001, 11 (15), 1975, wherein R ₄ 'is a lower alkyl, benzyl or other protecting groups, and a strong base can be used Treatment with an anhydride or acid chloride in a suitable solvent affords the ketoester xxxiii, the strong base typically being lithium bis(trimethylsilyl)amide, where R' can be lower alkyl, cycloalkyl or cycloheteroalkane base, the solvent is typically tetrahydrofuran. Diphenylimine xxxiii can be hydrolyzed with 2N aqueous HCl in THF to give the amine HCl salt, which can be acylated with acid chloride or anhydride in the presence of pyridine in a suitable solvent to give compound xxxiv where _R3 ' is aryl , substituted aryl, heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl, and the solvent is typically dichloromethane. The oxazole ring can be generated by mixing compound xxxiv, triphenylphosphine and iodine in tetrahydrofuran under cooling. The oxazole ester xxxv can be hydrolyzed to give the oxazole-4-carboxylic acid xxxvi by treatment with a base, typically lithium hydroxide, in a water/organic mixed solvent.

Acid xxxvi can be reacted with various amines to form amides, where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically the acid xxxvi and the amine _NH2R1 ', in a suitable _solvent , can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT, to obtain amides xxxvii.

Reaction Scheme 9

Scheme 9 describes the general synthesis of oxazole amides xxxvii bearing a halogen group at C-5. Using the standard palladium-catalyzed "cross-coupling" method, according to J.Med.Chem.1971, 14 (11), 1075; Org.Lett.2002, 4 (17), 2905 and J.Org.Chem.1977, 42 , The 2-chloro-oxazole-4-carboxylic acid alkyl esters that the method described in 2429 prepares, wherein R ₄ ' is lower alkyl, preferably methyl or ethyl, can be with commercially available substituted or unsubstituted aryl Boronic acid or boronic acid ester is heated with a catalytic amount of palladium in a suitable solvent in the presence of a base to obtain xxxix, where _R2 ' is aryl, substituted aryl, heteroaryl, or substituted heteroaryl , the base is typically aqueous sodium carbonate, the solvent is typically DME, DMF or toluene, and the palladium is typically Pd(PPh ₃ ) ₄ . The oxazolate xxxix can be prepared by heating to 90°C in chloroform in the presence of a catalytic amount of concentrated sulfuric acid, using 1-chloro-pyrrolidine 2,5-dione or 1-bromo-pyrrolidine 2,5 at the C5 position - Chlorination or bromination of diketones gives compounds xxxx. Esters xxxx can be hydrolyzed to give oxazole-4-carboxylic acids xxxxi by treatment with a base, typically lithium hydroxide, in a water/organic mixed solvent.

Acids xxxxxi can be reacted with various amines to form amides where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically the acid xxxxxi and the amine _NH2R1 ', in a suitable solvent _, can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT, to obtain amides xxxvii.

Reaction Scheme 10

Scheme 10 depicts an alternative synthesis of oxazole amides xxxxvii bearing a trifluoromethyl group at C-5. Glycinate, wherein R ₄ ' is lower alkyl, preferably methyl or ethyl, acylated with an acylating agent, wherein R ₃ ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, Alkyl, or cycloalkyl. After acylation, the ester can be hydrolyzed to give the acid xxxxiii by treatment with a base, typically lithium hydroxide, in an aqueous/organic solvent, preferably methanol. Addition of excess trifluoroacetic anhydride to a solution of acid xxxxiii in acetone with cooling afforded a stable ketone hydrate, which was then refluxed in methanol for 30 minutes to afford the ketohydrate methyl ester xxxxiv. After heating with phosphorus oxychloride, compound xxxxiv cyclizes to give the substituted oxazole ester xxxxv, which in turn is hydrolyzed with a base, typically lithium hydroxide, to give the oxazole acid xxxxvi , the solvent is preferably methanol.

Oxazole acids xxxxvi can react with various amines to form amides, where _R1 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond formation conditions can be used as practiced by those skilled in the art. Typically the acid xxxxvi and the amine _NH2R1 ', in a suitable solvent _, can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBroP or EDCI and HOBT, to obtain the amide xxxxvii.

Reaction Scheme 11

As shown in Scheme 11, according to the method described in Int.J.Peptide Protein Res.1989, 33 , 353, the commercially available amino acid xxxxviii, wherein R' can be lower alkyl, cycloalkyl, or cycloheteroalkane , can be acylated with an acylating agent, typically an acid chloride or anhydride. Using the method described in J. Chem. Soc. Chem. Commun. 1995, 2335, the acid xxxxix can be treated with excess oxalyl chloride under heating in a solvent such as tetrahydrofuran to obtain the cyclized oxazole 1 by reacting with 1-hydroxy -Pyrrolidine-2,5-dione and a base such as triethylamine are directly converted to the active ester li by heating in acetonitrile.

Oxazole acids li can be reacted with various amines to form amides lii by heating in a suitable solvent, typically acetonitrile, wherein R ₁ ' is aryl, substituted aryl, heteroaryl, substituted hetero Aryl, cycloalkyl or cycloheteroalkyl.

Scheme 12

As shown in Scheme 12, aromatic heterocyclic amine lvi can be prepared by Curtius rearrangement. Commercially available methyl arylhaloformates liiii (where X can be nitrogen) are reacted with a nucleophile Nu, typically an amine or an alcohol, in the presence of a base such as triethylamine. Nucleophilic amines can be acyclic, cyclic, substituted or unsubstituted, or heterocyclic. The obtained ester liv can be saponified to obtain the corresponding formic acid, which is converted to the isocyanate intermediate by a Curtius rearrangement reaction in the presence of diphenylphosphoryl azide and a suitable base such as triethylamine. The isocyanate intermediate can be reacted with an alcohol (where _R8 ' can be tert-butyl or benzyl) to give the corresponding carbamate lv. Finally, tert-butyl or benzyl carbamates can be deprotected under acidic conditions such as trifluoroacetic acid or under palladium-catalyzed hydrogenation to afford the desired aromatic heterocyclic amine lvi.

Scheme 13

As shown in Scheme 13, amide lix, wherein R ₃ ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl, wherein R ₁ ' can be aryl, Substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl, R' can be lower alkyl, cycloalkyl, cycloheteroalkyl or absent, and _R3 ' can be Aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl can be prepared from commercially available substituted aromatic acids lviii, wherein R ₈ ', R ₉ ', R ₁₀ ', and R ₁₁ ' can independently be N, C, or S, also prepared from commercially available esters lvii after hydrolysis, wherein R ₄ ' is lower alkyl, preferably methyl or ethyl, and various amine. A variety of standard amide bond formation conditions practiced by those skilled in the art can be used. Typically, the acid lviii and the amine _NH2R1 ', can be treated with a base such as triethylamine and an amide bond forming reagent such as BOP, PyBrop, or EDCI and HOBT _in an appropriate solvent to obtain the amide lix.

As noted above, the novel compounds of the present invention have been found to inhibit hepatic diacylglycerol acyltransferase activity. The compounds according to the invention can therefore be used for the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, in particular for the therapeutic and/or prophylactic treatment of obesity, type II diabetes, dyslipidemia and Metabolic syndrome.

Accordingly, the present invention also relates to a pharmaceutical composition comprising a compound as defined above together with a pharmaceutically acceptable carrier and/or adjuvant.

Likewise, the invention includes compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, in particular for the treatment of And/or therapeutically active substances for the prophylactic treatment of obesity, type II diabetes, dyslipidemia and metabolic syndrome.

In another preferred embodiment of the present invention, the present invention relates to a method for the therapeutic and/or prophylactic treatment of diseases modulated by diacylglycerol acyltransferase inhibitors, in particular for the therapeutic and/or prophylactic A method for the treatment of obesity, type II diabetes and metabolic syndrome, the method comprising administering to humans or animals a therapeutically effective amount of a compound as defined above. Preferred is a method as defined above, wherein the therapeutically effective amount of said compound is in an amount from about 1 mg to about 1000 mg/day, more preferably in an amount from about 1 mg to about 500 mg/day.

The invention also includes the use of compounds as defined above in the therapeutic and/or prophylactic treatment of diseases modulated by diacylglycerol acyltransferase inhibitors, in particular in the therapeutic and/or prophylactic treatment of obesity, type II diabetes, dyslipidemia syndrome and metabolic syndrome.

The present invention also relates to the use of compounds as described above in the preparation for the treatment and/or prophylactic treatment of diseases modulated by diacylglycerol acyltransferase inhibitors, in particular for the treatment and/or prophylactic treatment of obesity, type II diabetes , for use in the treatment of dyslipidemia and metabolic syndrome. Such agents include compounds as described above.

With regard to the compositions, uses and methods described above, obesity, type II diabetes, dyslipidemia and metabolic syndrome individually constitute respectively preferred diseases.

In the method of practicing the present invention, an effective amount of any compound of the present invention, or a combination of any compounds of the present invention, or a pharmaceutically acceptable salt thereof, can be administered by any of the commonly used and acceptable methods known in the art. species, administered alone or in combination. Thus, a compound or composition may be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lotion ), transdermally (eg, by skin electroporation) or by inhalation (eg, by aerosol), and in solid, liquid or gaseous dosage forms, including tablets and suspensions. Administration can be carried out in a single unit dosage form under continuous treatment, or in a single dose treatment ad libitum. Therapeutic compositions may also be in the form of oily emulsions or dispersions incorporating lipophilic salts such as pamoic acid, or in the form of biodegradable sustained release compositions for subcutaneous or intramuscular administration.

Useful pharmaceutical carriers for preparing compositions thereof can be solid, liquid or gaseous; thus, compositions can take the form of tablets, pills, capsules, suppositories, powders, enteric-coated or other protective formulations (e.g. bound on ion exchange resins or encapsulated in lipoprotein capsules), sustained release formulations, solutions, suspensions, elixirs, aerosols, etc. The carrier can be selected from various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose and glycols are preferred liquid carriers, especially (when isotonic with blood) for injectable solutions. For example, formulations for intravenous administration comprise: a sterile aqueous solution of one or more active ingredients prepared by dissolving one or more solid active ingredients in water to prepare an aqueous solution, and rendering the solution sterile. Prepared. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silicon dioxide, magnesium stearate, sodium stearate, glyceryl monostearate , Sodium Chloride, Dry Skim Milk, Glycerin, Propylene Glycol, Water, Ethanol, etc. The composition may contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences, by E.W. Martin. In any event, such compositions will contain an effective amount of the active compound together with a suitable carrier to produce a suitable dosage form for suitable administration to a subject.

The dosage of the compound of the present invention depends on many factors, such as the mode of administration, the age and weight of the subject, and the condition of the patient to be treated, and will ultimately be determined by the attending physician or veterinarian. Such an amount of active compound as determined by the attending physician or veterinarian is referred to herein and in the claims as an "effective amount". For example, the dosage of a compound of the invention will typically be in the range of about 1 to about 1000 mg/day. Preferably, the therapeutically effective amount is in the range of about 1 mg to about 500 mg/day.

Now, the present invention will be further described by the following examples, which are considered to be illustrative only and not to limit the scope of the present invention.

Example

The following examples are for the purpose of illustration and are not intended to limit the invention in any way.

General method: Melting points were obtained on a Thomas-Hoover apparatus and were uncorrected. Optical rotation was measured with a Perkin-Elmer model 241 polarimeter. 1H-NMR spectra were recorded with a Varian XL-200, Mercury-300 or Unityplus 400 MHz spectrometer. Tetramethylsilane (TMS) was used as internal standard. Electron impact (El, 70ev) and fast atom bombardment (FAB) mass spectra were obtained on a VG Autospec or VG 70E-HF mass spectrometer. The silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh flash chromatography silica gel; the column was run under 0-5 psi head nitrogen to aid flow. Thin-layer chromatography was run on silica gel-coated glass thin-layer plates supplied by E. Merck (E. Merck #1.05719) and either by exposure to I _vapor , or by phosphomolybdic acid in aqueous ethanol ( PMA) spray, or after exposure to Cl ₂ , with 4,4′-tetramethyldiaminobis The phenylmethane reagent spray was inspected by observing under 254nm UV light in the observation box.

Adopt Rainin HPLC to carry out reverse-phase high-pressure liquid chromatography (RP-HPLC), described RaininHPLC adopts 41.4 * 300mm, 8 μ M, Dynamax ^TM C-18 column, flow rate is 49mL/min, and described C-18 column is in 35- Acetonitrile:water (each containing 0.75% TFA), typically a gradient of 5 to 95% acetonitrile was used over 40 min. HPLC conditions are typically described in format (5-95-35-214); this refers to a linear gradient of 5% to 95% acetonitrile in water over 35 min while monitoring the effluent with a UV detector at 214nM wavelength.

Preparative supercritical fluid chromatography (SFC) was performed on a Berger MultiGram II supercritical fluid chromatography system (model SD-1 ) from Mettler-Toledo AutoChemBerger Instruments, Newark, DE, USA. The system included an automated liquid injection system with a DAICELAD chiral column, a 5 mL loop for injection and a thermal control module (TCM) for controlling the column temperature. Chromatographic conditions: SFC separation was performed at a temperature of 30 °C, a flow rate of 70 mL/min and a _CO2 pressure of 100 bar. A Knauer variable wavelength UV detector (supplied by Mettler-Toledo) with a high pressure flow cell was used for SFC detection. Detection in SFC was performed by measuring UV absorbance at 220 nm.

Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, diethyl ether, and methanol were Fisher or Baker reagent grade and were used without additional purification unless noted, acetonitrile was Fisher or Baker HPLC grade and used as received.

Definitions as used herein include:

DGAT is diacylglycerol:acyl-CoA O-acyltransferase,

THF is tetrahydrofuran,

DMF is N,N-dimethylformamide,

DMA is N,N-dimethylacetamide,

DMSO is dimethylsulfoxide,

DCM is dichloromethane,

DME is dimethoxyethane,

MeOH is methanol,

EtOH is ethanol,

NaOH is sodium hydroxide,

NBS is N-bromosuccinimide,

TFA is 1,1,1-trifluoroacetic acid,

HOBT is 1-hydroxybenzotriazole,

PyBroP is bromotripyrrolidinophosphonium hexafluorophosphate,

EDCI is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,

DIPEA is diisopropylethylamine,

The brine is a saturated aqueous sodium chloride solution,

DAG is 1,2-dioleoyl-sn-glycerol,

TLC is thin layer chromatography,

RP HPLC is reversed-phase high performance liquid chromatography,

APCI-MS is atmospheric pressure chemical ionization mass spectrometry,

ES-MS is electrospray mass spectrometry,

LCMS is liquid chromatography mass spectrometry,

RT is room temperature or ambient temperature.

Silica gel chromatography on Biotage columns refers to the use of flash chromatography systems supplied by the Biotage Division of the Dyax Corporation using prepacked 40g (40s columns), 90g (40m columns) or 800g (75m columns) ). Elution was performed with a hexane-ethyl acetate mixture under 10-15 psi nitrogen pressure.

Part I: Intermediates

Preparation of 6-morpholin-4-yl-pyridin-3-ylamine

A mixture of 2-chloro-5-nitro-pyridine (5 g, 31 mmol), morpholine (13 mL, 155 mmol), and triethylamine (10 mL) in dichloromethane (30 mL) was stirred at room temperature for 3 hours. After the reaction, the mixture was mixed with water, and the two layers were separated. The aqueous layer was extracted _twice with _CH2Cl2 . The organic layers were collected, combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 4-(5-nitro-pyridin-2-yl)-morpholine (6.48 gm, 100%) as a yellow solid. LCMS calcd. for C9H11N3O3 (m/e) 209, found 210 (M+H).

A solution of 4-(5-nitro-pyridin-2-yl)-morpholine (1.5 g, 7.18 mmol) in ethyl acetate (20 mL) in the presence of 10% palladium on carbon (0.75 g) was prepared at Shake at room temperature for 3 hours under 50 psi of hydrogen. After the reaction, the reaction mixture was filtered through a plug of celite, and the filter pad was washed with ethyl acetate. The organic layer was collected, concentrated and dried to afford 6-morpholin-4-yl-pyridin-3-ylamine (1.11 g, crude) as a reddish solid which was directly used in the next step reaction without further purification . LCMS calcd. for C9H14N3O (m/e) 179, found 180 (M+H).

Preparation of 2-morpholin-4-yl-pyrimidin-5-ylamine

2-Morpholin-4-yl was prepared from 2-chloro-5-nitro-pyrimidine and morpholine using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above -pyrimidin-5-ylamine. LCMS calcd. for C8H12N4O (m/e) 180, found 181 (M+H).

Preparation of 6-thiomorpholin-4-yl-pyridin-3-ylamine

6-Thiomorpholine was prepared from 2-chloro-5-nitro-pyridine and thiomorpholine using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above -4-yl-pyridin-3-ylamine. LCMS calcd. for C9H13N3S (m/e) 195, found 196 (M+H).

Preparation of N-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from 2-chloro-5-nitro-pyridine and N-methyl-N-pyrrolidin-3 -Yl-Acetamide Preparation of N-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide. LCMS calcd. for C12H18N4O (m/e) 234, found 235 (M+H).

Preparation of 2-(5-amino-pyridin-2-ylamino)-ethanol

2-(5- Amino-pyridin-2-ylamino)-ethanol. LCMS calcd. for C7H11N3O (m/e) 153, found 154 (M+H).

Preparation of 2-(2-methoxy-ethyl)-pyridine-2,5-diamine

Using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, 2 was prepared from 2-chloro-5-nitro-pyridine and 2-methoxy-ethylamine. -(2-Methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd. for C8H13N3O (m/e) 167, found 168 (M+H).

Preparation of N ² -(2-methoxy-ethyl)-N ² -methyl-pyridine-2,5-diamine

Using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, from 2-chloro-5-nitro-pyridine and (2-methoxy-ethyl)- Methyl-amine Preparation of ^N2- (2-methoxy-ethyl) ^-N2 -methyl-pyridine-2,5-diamine. LCMS calcd. for C9H15N3O (m/e) 181, found 182 (M+H).

Preparation of 6-(2-methoxy-ethoxy)-pyridin-3-ylamine

6-( 2-methoxy-ethoxy)-pyridin-3-ylamine. LCMS calcd. for C8H12N2O2 (m/e) 168, found 169 (M+H).

Preparation of 2-[(5-amino-pyridin-2-yl)-methyl-amino]-ethanol

2-[ (5-Amino-pyridin-2-yl)-methyl-amino]-ethanol. LCMS calcd. for C8H13N3O (m/e) 167, found 168 (M+H).

Preparation of N ² -(3-methoxy-propyl)-N ² -methyl-pyridine-2,5-diamine

Using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, from 2-chloro-5-nitro-pyridine and (3-methoxy-propyl)- Methyl-amine Preparation of ^N2- (3-methoxy-propyl) ^-N2 -methyl-pyridine-2,5-diamine. LCMS calcd. for C10H17N3O (m/e) 195, found 196 (M+H).

Preparation of N ² -(3-methoxy-propyl)-pyridine-2,5-diamine

N was prepared from 2-chloro-5-nitro-pyridine and 3-methoxy-propylamine using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above. ^2- (3-Methoxy-propyl)-pyridine-2,5-diamine. LCMS calcd. for C9H15N3O (m/e) 181, found 182 (M+H).

Preparation of N ² -ethyl-N ² -(2-methoxy-ethyl)-pyridine-2,5-diamine

Using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, even 2-chloro-5-nitro-pyridine and ethyl-(2-methoxy-ethyl N ² -Ethyl-N ² -(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd. for C10H17N3O (m/e) 195, found 196 (M+H).

Preparation of N ² -butyl-N ² -methyl-pyridine-2,5-diamine

^N2- Butyl-N ² -methyl-pyridine-2,5-diamine. LCMS calcd. for C10H17N3 (m/e) 179, found 180 (M+H).

Preparation of N ² -methyl-N ² -propyl-pyridine-2,5-diamine

^N2- Methyl-N ² -propyl-pyridine-2,5-diamine. LCMS calcd. for C9H15N3 (m/e) 165, found 166 (M+H).

Preparation of N ² -ethyl-N ² -methyl-pyridine-2,5-diamine

^N2- Ethyl-N ² -methyl-pyridine-2,5-diamine. LCMS calcd. for C8H13N3 (m/e) 151, found 152 (M+H).

Preparation of N ² -ethyl-pyridine-2,5-diamine

^N2 -ethyl- Pyridine-2,5-diamine. LCMS calcd. for C7H11N3 (m/e) 137, found 138 (M+H).

Preparation of N ² , N ² -diethyl-pyridine-2,5-diamine

Using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, ^N2 , ^N2 was prepared from 2-chloro-5-nitro-pyridine and diethyl-amine - Diethyl-pyridine-2,5-diamine. LCMS calcd. for C9H15N3 (m/e) 165, found 166 (M+H).

Preparation of N ² -isopropyl-N ² -methyl-pyridine-2,5-diamine

Using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, ^N2 was prepared from 2-chloro-5-nitro-pyridine and isopropyl-methyl-amine -Isopropyl-N ² -methyl-pyridine-2,5-diamine. LCMS calcd. for C9H15N3 (m/e) 165, found 166 (M+H).

Preparation of N ² ,N ² -dimethyl-pyridine-2,5-diamine

A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol) in DMF (2 mL) was added dropwise to a suspension of NaH (151 mg, 6.31 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 hour, then heated to 55 °C overnight. The reaction mixture was then poured into ice water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to afford dimethyl-(5-nitro-pyridin-2-yl)-amine as a yellow solid. LCMS calcd. for C7H11N3 (m/e) 137, found 138 (M+H).

A solution of dimethyl-(5-nitro-pyridin-2-yl)-amine (100 mg, 0.47 mmol) and 10% palladium on carbon (0.05 g) in methanol (5 mL) was shaken at room temperature under a hydrogen atmosphere of 50 psi 3 hours. The reaction mixture was then filtered through a plug of celite and the filter pad was washed with ethyl acetate. The organic phase was collected, concentrated and dried to afford N ² ,N ² -dimethyl-pyridine-2,5-diamine (90 mg crude) as a reddish oil which was used directly in the next step without further purification step.

Preparation of N ² -cyclopentyl-pyridine-2,5-diamine

To a 20 mL vial containing cyclopentylamine (300 mg, 3.53 mmol) was added DMF (5 mL), 2-chloro-5-nitro-pyridine (559 mg, 3.53 mmol), and TEA (0.98 mL). The vessel was flushed with argon, sealed, and heated by microwave at 200° C. for 5 minutes (Personal Chemistry, Emrys Optimizer). The reaction mixture was concentrated, diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give cyclopentyl-(5-nitro-pyridin-2-yl)-amine. LCMS calcd. for _C10H13N3O2 (m/e) 207, found ₂₀₈ (M+H _{) .} The intermediate nitropyridyl compound was transferred to a PARR vessel with MeOH (5 mL), the vessel was pressurized with 55 psi of _H2 and shaken for 2.5 hours. The mixture was then filtered through a bed of celite, concentrated from _{CH2Cl2 to} dryness twice. The purple-black material was used immediately for amide coupling (LCMS calcd. for _C10H15N3 (m/e) ₁₇₇ , found 178 ( _M +H).

Preparation of N ² -cyclohexyl-pyridine-2,5-diamine

N2-cyclohexyl-pyridine-2 was prepared from 2-chloro-5-nitro-pyridine and cyclohexylamine ^using a method similar to that used to prepare cyclopentyl-pyridine-2,5-diamine above, 5-diamine. LCMS calcd. for _C11H17N3 (m _/ e) ₁₉₁ , found 192 (M+H).

Preparation of N ² -cyclopropyl-pyridine-2,5-diamine

Preparation of N2-cyclopropyl-pyridine-2 from 2-chloro-5-nitro-pyridine and cyclopropylamine using a method similar to that used for the preparation of cyclopentyl-pyridine- ^2,5 -diamine , 5-diamine. (LCMS calcd. for _C8H11N3 (m/e) 149 _, found ₁₅₀ (M+H).

Preparation of N ² -cyclopropyl-N ² -methyl-pyridine-2,5-diamine

The intermediate cyclopropyl-(5-nitro-pyridin-2-yl)-amine from the above step was methylated with methyl iodide. To a 2 mL microwave tube was added cyclopropyl-(5-nitro-pyridin-2-yl)-amine (146 mg, 0.812 mmol), DMF (2 mL), potassium carbonate (224 mg, 1.62 mmol), and MeI (56 μl, 0.893 mmol). Using Personal Chemistry, Emrys Optimizer, the mixture was heated by microwave at 200°C for two 10 min increments. This was followed by another portion of MeI (56 μL, 0.893 mmol), microwaved at 200° C. for 10 minutes, then conventionally heated at 70° C. for 15 hours. At the end of this period, a third portion of MeI (56 μL, 0.893 mmol) was added and the mixture was heated again by microwave at 200° C. for 10 minutes. The reaction mixture was then concentrated to dryness, suspended in ethyl acetate (100 mL), washed twice with water (100 mL), and once with brine. The aqueous layers were combined and extracted once with ethyl acetate (50 mL). The combined organic layers were washed once with brine (100 mL), concentrated, supported on silica gel, and purified by flash chromatography using an Analogix system, 12 g Silicycle silica gel column, using increasing concentrations of ethyl acetate in hexane (20 mL/ min, with 0% balance, 0 to 5min: 0%; 5 to 25min: 0 to 30%; 25-45min: 30%). Appropriate fractions were collected and dried to obtain 90 mg of cyclopropyl-methyl-(5-nitro-pyridin-2-yl)-amine as a yellow solid (57% yield). LCMS calcd. _{for C9H11N3O2} (m/e) 193, found ₁₉₄ (M+H) _. This intermediate nitropyridyl compound is then reduced, as described above for the preparation of cyclopentyl-pyridine-2,5-diamine, to afford ^N2 -cyclopropyl- ^N2 -picoline-2,5-diamine amine. LCMS calcd. for _C9H13N3 (m/e) 163, found ₁₆₄ (M ₊ H).

Preparation of N ² -cyclobutyl-N ² -methyl-pyridine-2,5-diamine

Using a method similar to that used to prepare cyclopentyl-(5-nitro-pyridin-2-yl)-amine above, cyclobutyl was prepared from 2-chloro-5-nitro-pyridine and cyclobutylamine -(5-Nitro-pyridin-2-yl)-amine. LCMS calcd. for C9H11N3O2 (m/e) 193, found 194 (M+H). This intermediate nitropyridyl group is then methylated and reduced to N using methods similar to those described in the synthesis of ^N2 -cyclopropyl- ^N2 -picoline-2,5-diamine above ² -Cyclobutyl-N ² -picoline-2,5-diamine. LCMS calcd. for _C10H15N3 (m _/ e) 177, found ₁₇₈ (M+H).

Preparation of N ² -cyclopropyl-N ² -methyl-pyrimidine-2,5-diamine

Using a method similar to that used to prepare ^N2 -cyclopropyl- ^N2 -picoline-2,5-diamine above, from 2-chloro-5-nitro-pyrimidine, cyclopropylamine and formazan Preparation of N ² -cyclopropyl-N ² -methylpyrimidine-2,5-diamine from base iodide. LCMS calcd. for _C8H12N4 (m _/ e) 164, found 165 (M+H) _.

Preparation of N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from 2-chloro-5-nitro-pyrimidine and (2-methoxy-ethyl)- Methyl-amine Preparation of N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd. for C8H14N4O (m/e) 182, found 183 (M+H).

Preparation of 6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine

From 2-chloro-5-nitro-pyridine and (R)-2-methoxymethyl - Pyrrolidine Preparation of 6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd. for C11H17N3O (m/e) 207, found 208 (M+H).

Preparation of [(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from 2-chloro-5-nitro-pyridine and (S)-1-pyrrolidin-2- Preparation of [(S)-1-(5-Amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol. LCMS calcd. for C10H15N3O (m/e) 193, found 194 (M+H).

Preparation of 1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol

1-(5 -amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd. for C9H13N3O (m/e) 179, found 180 (M+H).

Preparation of 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-3-ol

Using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, the 5'-amino -3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-3-ol. LCMS calcd. for C10H15N3O (m/e) 193, found 194 (M+H).

Preparation of 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-4-ol

Using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, the 5'-amino -3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-4-ol. LCMS calcd. for C10H15N3O (m/e) 193, found 194 (M+H).

Preparation of (S)-2-(5-amino-pyrimidin-2-ylamino)-propan-1-ol

Prepared from 2-chloro-5-nitro-pyrimidine and 2-amino-propan-1-ol using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above ( S)-2-(5-Amino-pyrimidin-2-ylamino)-propan-1-ol. LCMS calcd. for C7H12N4O (m/e) 168, found 169 (M+H).

Preparation of (S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol

Prepared from 2-chloro-5-nitro-pyridine and (S)-pyrrolidin-3-ol using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above 1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd. for C9H13N3O (m/e) 179, found 180 (M+H).

Preparation of 2-(5-amino-pyridin-2-ylamino)-2-methyl-propan-1-ol

Using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above, from 2-chloro-5-nitro-pyridine and 2-amino-2-methyl-propan- 1-Alcohol Preparation of 2-(5-amino-pyridin-2-ylamino)-2-methyl-propan-1-ol. LCMS calcd. for C9H15N3O (m/e) 181, found 182 (M+H).

Preparation of [(5-amino-pyridin-2-yl)-methyl-amino]-acetic acid methyl ester

Prepared from 2-chloro-5-nitro-pyridine and methylamino-acetic acid methyl ester using a method similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above [(5 -amino-pyridin-2-yl)-methyl-amino]-acetic acid methyl ester (heat reaction to 100° C. in DMF). LCMS calcd. for C9H13N3O2 (m/e) 195, found 196 (M+H).

Preparation of 2-[(5-amino-pyridin-2-yl)-methyl-amino]-N,N-dimethyl-acetamide

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from 2-chloro-5-nitro-pyridine and N,N-dimethyl-2-methanol 2-[(5-Amino-pyridin-2-yl)-methyl-amino]-N,N-dimethyl-acetamide was prepared from dimethylamino-acetamide. red oil. LCMS calcd. for C10H16N4O (m/e) 208, found 209 (M+H).

Preparation of 5-morpholin-4-yl-thiazol-2-ylamine

5-Morpholin-4-yl was prepared from 5-bromo-2-nitro-thiazole and morpholine using a procedure similar to that used to prepare 6-morpholin-4-yl-pyridin-3-ylamine above - Thiazol-2-ylamine. LCMS calcd. for C7H11N3OS (m/e) 185, found 186 (M+H).

Preparation of N ⁵ -(2-methoxy-ethyl)-N ⁵ -methyl-thiazole-2,5-diamine

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from 5-bromo-2-nitro-thiazole and (2-methoxy-ethyl)- Methyl-amine Preparation of ^N5- (2-methoxy-ethyl) ^-N5 -methyl-thiazole-2,5-diamine. LCMS calcd. for C7H13N3OS (m/e) 187, found 188 (M+H).

Preparation of N-(5-amino-pyridin-2-yl)-N-methyl-acetamide

A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine (2M in THF, 15 mL, 30 mmol) in dichloromethane (40 mL) was heated at 50 degrees overnight. After cooling to room temperature, the reaction mixture was concentrated to afford methyl-(5-nitro-pyridin-2-yl)-amine, which was used in the following step without purification. Acetic anhydride (9.3 mL, 98.5 mmol) was added to methyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24 mL, 197 mmol), and a catalytic amount of 4-bis A solution of methylamino-pyridine (DMAP) in dichloromethane (40 mL). The obtained mixture was heated at 90°C overnight. After the reaction was complete, the solvent was removed, and then ethyl acetate was added. The ethyl acetate solution was extracted three times with water. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50% ethyl acetate in hexanes for 20 min) afforded N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide.

The hydrogenation of N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide in methanol was performed overnight at room temperature under a pressure of 50 psi in the presence of a catalytic amount of palladium on carbon. After the reaction, the reaction mixture was filtered through a plug of celite. Collect and concentrate the filtrate. Flash chromatography (50 g diol column) afforded N-(5-amino-pyridin-2-yl)-N-methyl-acetamide. LCMS calcd. for C8H11N3O (m/e) 165, found 166 (M+H).

Preparation of N-(5-amino-pyridin-2-yl)-N-methyl-propionamide

Using a method similar to that used to prepare N-(5-amino-pyridin-2-yl)-N-methyl-acetamide above, from methyl-(5-nitro-pyridin-2-yl)- Preparation of N-(5-amino-pyridin-2-yl)-N-methyl-propionamide from amine and propionic anhydride. LCMS calcd. for C9H13N3O (m/e) 179, found 180 (M+H).

Preparation of cyclopropanecarboxylic acid (5-amino-pyridin-2-yl)-methyl-amide

Using a method similar to that used to prepare N-(5-amino-pyridin-2-yl)-N-methyl-acetamide above, from methyl-(5-nitro-pyridin-2-yl)- Preparation of cyclopropanecarboxylic acid (5-amino-pyridin-2-yl)-methyl-amide from amine and cyclopropanecarbonyl chloride. The crude product after reduction of the nitro group was used directly in the next step without further purification.

Preparation of N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide

Using a method similar to that used to prepare N-(5-amino-pyridin-2-yl)-N-methyl-acetamide above, from methyl-(5-nitro-pyridin-2-yl)- Amine and methoxy-acetyl chloride to prepare N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide. LCMS calcd. for C9H13N3O2 (m/e) 195, found 196 (M+H).

Preparation of (S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol

Using a method similar to that used to prepare the above 6-morpholin-4-yl-pyridin-3-ylamine, from (S)-2-(5-nitro-pyridin-2-ylamino)-propan- (S)-2-(5-Amino-pyridin-2-ylamino)-propan-1-ol was prepared from 1-alcohol (commercially available from TCI-EP). LCMS calcd. for C8H13N3O (m/e) 167, found 168 (M+H).

Preparation of 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine

To a solution of 1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-ol (120 mg, 0.57 mmol) in 5 mL of DMF was added 10 equivalents of sodium hydride (228 mg, 5.7 mmol, 60%, in mineral oil). The mixture was stirred at 23° C. for 15 minutes, followed by the addition of 10 equivalents of iodomethane (355 uL, 5.7 mmol). The reaction was stirred continuously for 2 hours, then extracted with ethyl acetate and water. The organic phase was dried and the solvent was evaporated. The residue was purified on a flash column using EtOAc/hexanes to afford 2-(3-methoxy-pyrrolidin-1-yl)-5-nitro-pyridine. LRMS calcd for C10H13N3O3 (m/e) 223, found 224 (M+H).

The nitro compound was dissolved in 10 mL of EtOAc and treated with 100 mg of 10% palladium on carbon. The reaction was shaken overnight under 50 psi of _H2 . The reaction was filtered through a pad of celite and the filtrate was concentrated to afford 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine which was used directly in the next step without further purification. LRMS calcd. for C10H15N3O (m/e) 193, found 194 (M+H).

Preparation of 3-methoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-ylamine

Using a method similar to that used to prepare 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine above, from 5'-nitro-3,4,5,6- Preparation of 3-methoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-3-ol and methyl iodide 5'-ylamine. LCMS calcd. for C11H17N3O (m/e) 207, found 208 (M+H).

Preparation of N ² -((S)-2-methoxy-1-methyl-ethyl)-N ² -methyl-pyridine-2,5-diamine

Using a method similar to that used to prepare the above 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine, from (S)-2-(5-amino-pyridine-2 Preparation of N ² -((S)-2-methoxy-1-methyl-ethyl)-N ² -methyl-pyridine-2,5-diamine from -ylamino)-propan-1-ol and iodomethane . LCMS calcd. for C10H17N3O (m/e) 195, found 196 (M+H).

Preparation of N ² -(2-cyclopropylmethoxy-ethyl)-N ² -methyl-pyridine-2,5-diamine

Using a procedure similar to that used to prepare 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine above, from 2-[methyl-(5-nitro-pyridine- Preparation of N2-( ² -cyclopropylmethoxy-ethyl)-N2-methyl-pyridine-2,5-diamine from ² -yl)-amino]-ethanol and bromomethyl-cyclopropane. LCMS calcd. for C12H19N3O (m/e) 221, found 222 (M+H).

Preparation of (S)-2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine

(S)-3-aminotetrahydrofuran was prepared as the tosylate salt following the procedure described in the literature (Journal of the Chemical Society, Chemical Communication 6, 474-475, 1987). (L)-Methionine is protected as N-trityl-(L)-methionine and formic acid is reduced to alcohol. The N-tritylmethioninol obtained is methylated to form a sulfonium salt, which cyclizes to form (S)-N-trityl-3-aminotetrahydrofuran. Final deprotection with p-toluenesulfonic acid in methanol afforded (S)-3-aminotetrahydrofuran tosylate as a white solid.

Potassium carbonate (340 mg, 2 , 46mmol) and triethylamine (0.17mL, 1.22mmol). The mixture was heated at 65°C overnight and the solvent was evaporated. The residue was dissolved in ether and extracted with brine. The solvent was evaporated and the oily residue was purified by flash column chromatography using ethyl acetate and hexanes (10% to 40% ethyl acetate) to give (S)-2-(N-tetrahydrofuran)amino-5-nitro- Pyridine as a yellowish oil (180 mg, 73%). [α] _D = +9.76 (0.675, CHCl ₃ ). LCMS calcd. for C9H11N3O3 m/e 209.2, found 210.1 (M+H). The nitro compound (170 mg, 0.81 mmol) was hydrogenated in methanol with a catalytic amount of 5% palladium on carbon (35 mg) at 40 psi for 2 hours. The mixture was filtered and the solvent was evaporated to give the desired compound as an oil (139 mg). MS calcd for C9H13N3O m/e 179.2, found 180.0 (M+H).

Preparation of 2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine

Using the same procedure as described for the preparation of (S)-2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine by using 2-chloro-5-nitro-pyridine and racemic 3 - Aminotetrahydrofuran To prepare this compound, racemic 3-aminotetrahydrofuran is synthesized by Curtius rearrangement of tetrahydrofuran-3-carboxylic acid. LCMS calcd. for C9H13N3O m/e 179.2, found 180.0 (M+H).

Preparation of 2-N-(tetrahydropyran-4-yl)-2,5-diaminopyridine

This compound was prepared using the same method as above by using 4-aminotetrahydropyran and 2-chloro-5-nitro-pyridine. LCMS calcd. for C10H15N3O m/e 193.2, found 194.1 (ES, M+H).

Preparation of (R)-2-N-(1-phenylethyl)-2,5-diaminopyridine

Using the same method as above, this compound was prepared by using (R)-(α)-methylbenzylamine and 2-chloro-5-nitropyridine to obtain (R)-2-N-(1-phenyl ethyl)-2-amino-5-nitro-pyridine. LCMS calcd. for C13H13N3O2 m/e 243.2, found 244.1 (ES, M+H). The nitro compound is reduced under the above hydrogenation conditions to obtain (R)-2-N-(1-phenylethyl)-2,5-diaminopyridine.

Preparation of N-(2-methoxy-1-methylethyl)-2,5-diaminopyridine

Using the same method as above, this compound was prepared by using 2-methoxy-1-methylethylamine and 2-chloro-5-nitro-pyridine to obtain N-(2-methoxy-1-methyl (ethylethyl)-2-amino-5-nitro-pyridine. LCMS calcd. for C9H13N3O3 m/e 211.22, found 210.2 (AP, MH). This nitro compound was hydrogenated under the same conditions as above to obtain N ² -(2-methoxy-1-methylethyl)-2,5-diaminopyridine.

Preparation of N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

To a solution of 2-chloro-5-nitro-pyrimidine (638 mg, 4 mmol) in THF (15 mL) cooled to 0 °C was added 3-hydroxypyrrolidine (392 mg, 4.5 mmol) and triethylamine (1.2 mL). The mixture was stirred overnight at room temperature. The solid was filtered off and the solution was concentrated. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was washed with dilute aqueous citric acid. After evaporation of the solvent, the residue was treated with ether and the yellow solid was filtered to give N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol (570 mg). LCMS calcd. for C8H10N4O3 m/e 210.19, found 211.0 (ES, M+H). Hydrogenation of the nitro compound as above affords N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of (R)-N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

This compound was prepared using the same method as above using (R)-3-hydroxypyrrolidine and 2-chloro-5-nitropyrimidine to give (R)-N-(5-nitro-pyrimidin-2-yl) -pyrrolidin-3-ol. LCMS calcd. for C8H10N4O3 m/e 210.19, found 211.0 (ES, M+H). Hydrogenation of the nitro compound as above affords (R)-N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of (S)-N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

This compound was prepared using the same method as above using (S)-3-hydroxypyrrolidine and 2-chloro-5-nitro-pyrimidine to give (S)-N-(5-nitropyrimidin-2-yl) -pyrrolidin-3-ol. LCMS calcd. for C8H10N4O3 m/e 210.19, found 211 (ES, M+H). Hydrogenation of the nitro compound as above affords (S)-N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine

2-Chloro-5-nitro-pyridine (317 mg, 2 mmol) and 3,3-difluoroazetidine hydrochloride (259 mg, 2 mmol) were mixed in 8 mL of THF. Diisopropylethylamine (1.4 mL) was added and the mixture was heated in the microwave at 120°C for 20 minutes. After cooling to room temperature, the solid was filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was evaporated and the solid material was triturated with methanol. The obtained solid was filtered to obtain 5-nitro-2-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd. for C8H7F2N3O2 m/e 215.16, found 216.1 (ES, M+H). Hydrogenation of the nitro compound as above provides 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine.

Preparation of N ² -methyl-N ² -(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine

2-Chloro-5-nitro-pyridine (500mg, 3.15mmol), 2,2,2-trifluoro-ethylamine (940mg, 9.45mmol) and N,N-diisopropyl A mixture of ethylamine (1.64 mL, 9.45 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) was heated by microwave at 200 °C for 10 min. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (Isco 120g column, 40% ethyl acetate/hexanes) to afford (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro -Ethyl)-amine (300 mg, 43%) as a yellow solid. LCMS calcd. for C7H6F3N3O2 (m/e) 221, found 222 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

(5-Nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (230 mg, 1.04 mmol), cesium carbonate (730 mg, 2.07 mmol) and iodomethane (0.59 mL , 4.18 mmol) in DMF (4 mL) was heated at 50° C. for 3 hours in a sealed tube. The reaction mixture was evaporated to dryness and the crude was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (270 mg, crude) , as a brown solid, which was directly used in the next step reaction without further purification. LCMS calcd. for C8H8F3N3O2 (m/e) 235, found 236 (M+H).

A solution of methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (80 mg, 0.34 mmol) in ethanol (10 mL) was dissolved in 10% Shake at room temperature under hydrogen at 50 psi pressure in the presence of palladium on carbon (10 mg) for 2 hours. After the reaction was complete, the reaction mixture was filtered through a plug of celite, and the filter pad was washed with ethanol. The organic layers were combined and concentrated to afford ^N2 -methyl- ^N2- (2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine (70 mg, crude) as a brown oil, It was used directly in the next step without further purification. LCMS calcd. for C8H10F3N3 (m/e) 205, found 206 (M+H).

Preparation of N-methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine

Using a procedure similar to that used to prepare ^N2 -methyl- ^N2- (2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine above, from 2-chloro-5- Preparation of N-methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine from nitro-pyrimidine and 2,2,2-trifluoro-ethylamine. LCMS calcd. for C7H9F3N4 (m/e) 206, found 207 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Preparation of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid

Lithium bis(trimethylsilyl)amide (1M in THF, 6 mL, 6 mmol) was added to (dibenzylidene-amino)-acetic acid benzyl ester (1.97 g, 6 mmol). The reaction mixture was stirred at this temperature for about 1 hour. Isobutyryl chloride (0.641 mL, 6 mmol) in tetrahydrofuran (5 mL) was then slowly added to the above mixture. The reaction mixture was allowed to warm to room temperature for an additional 2 hours. After the above reaction was completed, the reaction mixture was quenched with dilute hydrochloric acid (2M) and stirred at room temperature for 1 hour. After removal of tetrahydrofuran, the aqueous solution was extracted twice with ethyl acetate. The collected organic layers were extracted with dilute hydrochloric acid (2M). The combined aqueous solutions were concentrated in vacuo to obtain 2-amino-4-methyl-3-oxo-pentanoic acid benzyl ester chloride which was used in the next step without further purification. Benzoyl chloride (3 mL) was slowly added to 2-amino-4-methyl-3-oxo-pentanoic acid benzyl chloride (1.63 g, 6 mmol) and anhydrous pyridine (20 mL) in dichloromethane ( 60mL). The reaction mixture was stirred at room temperature for 1 hour after which time the solvent was removed and water was added. The obtained mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with brine, dried over sodium sulfate, concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-40% ethyl acetate in hexane, 20 min) afforded benzyl 2-benzoylamino-4-methyl-3-oxo-pentanoate Ester (1.08 g, 53%) as a pale yellow solid. LCMS calcd. for C20H21NO4 (m/e) 339, found 340 (M+H).

2-Benzoylamino-4-methyl-3-oxo-pentanoic acid benzyl ester (1.08g, 3mmol), triphenylphosphine (2.01g, 8mmol), and iodine (1.62g, 6.37mmol) in The mixture in tetrahydrofuran (60 mL) was cooled to -78°C, followed by the addition of triethylamine (1.7 mL). The resulting solution was stirred at -78°C for about 10 minutes and then allowed to warm to room temperature. The reaction was continued for about 1 hour at room temperature. After the reaction, the solvent was removed and dichloromethane was added. The resulting solution was washed sequentially with saturated sodium bicarbonate, citric acid (0.5M), and brine, dried over sodium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-40% ethyl acetate in hexane, 20 min) afforded benzyl 5-isopropyl-2-phenyl-oxazole-4-carboxylate (0.84 g, 82%), as a pale yellow solid. LCMS calcd. for C20H19NO3 (m/e) 321, found 322 (M+H).

A solution of benzyl 5-isopropyl-2-phenyl-oxazole-4-carboxylate (830 mg, 2.59 mmol) in a mixture of THF, methanol and water (3:1:1, 10 mL) was oxygenated with hydrogen Lithium monohydride (258 mg, 6.5 mmol) was treated at room temperature for 1 hour. After the reaction was complete, the solvent was removed. To the residue, water and dichloromethane were added to form a white precipitate. After filtering off the solids, the filtrate was collected and the phases were separated. The pH of the aqueous layer was adjusted to 1-2 with dilute hydrochloric acid (1N). The aqueous layer was then extracted three times with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane, 20 min) afforded 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (247 mg, 41% ), as a white solid. LCMS calcd. for C13H13NO3 (m/e) 231, found 232 (M+H).

Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, propionyl chloride and benzoic acid Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid from acid chloride. LCMS calcd. for C12H11NO3 (m/e) 217, found 218 (M+H).

Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, butyryl chloride and benzoic acid Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid from acid chloride. LCMS calcd. for C13H13NO3 (m/e) 231, found 232 (M+H).

Preparation of 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid

Using a method similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, butyryl chloride and 2- Chloro-benzoyl chloride to prepare 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid. LCMS calcd. for C13H12ClNO3 (m/e) 265, found 266 (M+H).

Preparation of 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid

Using a method similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, butyryl chloride and 2- Preparation of 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid from bromo-benzoyl chloride. LCMS calcd. for C13H12BrNO3 (m/e) 310, found 311 (M+H).

Preparation of 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid

Using a method similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, butyryl chloride and 2- Preparation of 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid from methyl-benzoyl chloride. LCMS calcd. for C14H15NO3 (m/e) 245, found 246 (M+H).

Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above, from (benzylidene-amino)-benzyl acetate, butyryl chloride and cyclohexane Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid from alkylcarbonyl chloride. LCMS calcd. for C13H19NO3 (m/e) 237, found 238 (M+H).

Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid

Phenylboronic acid (729mg, 5.98mmol), ethyl 2-chloro-oxazole-4-carboxylate (according to Org.Lett.2002,4(17),2905 and J.Med.Chem.1971,14,1075 (1.0 g, 5.70 mmol), Pd[PPh ₃ ] ₄ (329 mg, 0.285 mmol), and a mixture of sodium carbonate (2M, 2 mL) in ethylene glycol dimethyl ether (10 mL) at 90 degrees Heat overnight. After cooling the reaction, the solvent was removed to obtain a crude residue. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-45% ethyl acetate in hexanes, 35 min) afforded ethyl 2-phenyl-oxazole-4-carboxylate (1.03 g, 83%) as Colorless oil. LCMS calcd. for C12H11NO3 (m/e) 217, found 218 (M+H).

A mixture of ethyl 2-phenyl-oxazole-4-carboxylate (217 mg, 1 mmol), 1-chloro-pyrrolidine-2,5-dione (400 mg, 3 mmol) and two drops of sulfuric acid in chloroform (10 mL) Heat overnight at 90 degrees. After the reaction was complete, the solvent was evaporated. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, combined, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-40% ethyl acetate in hexane, 30 min) afforded ethyl 5-chloro-2-phenyl-oxazole-4-carboxylate (95 mg, 37% ), as a white solid. LCMS calcd. for C12H10ClNO3 (m/e) 251, found 252 (M+H).

To a solution of ethyl 5-chloro-2-phenyl-oxazole-4-carboxylate (92mg, 0.37mmol) in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 5mL) was added with lithium hydroxide- The hydride (44 mg, 1.1 mmol) was treated at room temperature for 2 hours. After completing the reaction, the solvent was evaporated. Water was added to the residue and the pH of the aqueous layer was adjusted to ~1-2 by the addition of dilute hydrochloric acid (1N). The white precipitate was collected by centrifugation to obtain 5-chloro-2-phenyl-oxazole-4-carboxylic acid (73 mg, 88%). LCMS calcd. for C10H6ClNO3 (m/e) 223, found 224 (M+H).

Preparation of 5-bromo-2-phenyl-oxazole-4-carboxylic acid

From 2-phenyl-oxazole-4-carboxylic acid ethyl ester, 1-bromo-pyrrolidine-2 , 5-Diketone Preparation of 5-bromo-2-phenyl-oxazole-4-carboxylic acid. LCMS calcd. for C10H6BrNO3 (m/e) 268, found 269 (M+H).

Preparation of 4-phenyl-thiazole-2-carboxylic acid

Ethyl 4-phenyl-thiazole-2-carboxylate (1.0 g, 4.28 mmol) commercially available from Pharma Core in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 10 mL) was oxidized with hydrogen Lithium monohydride (514 mg, 12.8 mmol) was treated at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated. Water was added to the residue and the pH of the resulting solution was adjusted to ~1-2 by the addition of dilute hydrochloric acid (1 N). The white precipitate was collected by centrifugation and further washed with water to obtain 4-phenyl-thiazole-2-carboxylic acid (473 mg, 54%). LCMS calcd for C10H7NO2S (m/e) 205, found 206 (M+H).

Preparation of (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid

From (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid methyl ester: (methyl -{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid. LCMS calcd. for C19H15F3N4O4 (m/e) 420, found 421 (M+H).

Preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

This compound was prepared according to the methods described in Iht. J. Peptide Protein Res. 1989, 33, 353, and J. Chem. Soc., Chem. Commun. 1995, 2335. 2-Amino-butyric acid (3.87 g, 37.5 mmol) was suspended in 90 mL of dichloromethane and treated with chloro-trimethyl-silane (9.6 mL, 75 mmol). The mixture was refluxed for 1 hour and cooled in an ice bath. Diisopropylethylamine (11.3 mL, 65 mmol) and 2-chloro-benzoyl chloride (4.3 mL, 35.6 mmol) were added. The solution was stirred with cooling for 20 minutes, then allowed to warm to room temperature for 1.5 hours. The mixture was concentrated then partitioned between diethyl ether and dilute NaHCO ₃ solution. The phases were separated. The aqueous layer was extracted with ether, and the ether layer was backwashed with water. The combined aqueous layers were acidified to pH 2 with 1N HCl and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered and concentrated to afford 2-(2-chloro-benzoylamino)-butyric acid as an off-white solid (7.0 g, 77% yield), which was used without further Purified and used directly in the next step. LCMS calcd. for C11H12ClNO3 (m/e) 241, found 242 (M+H).

To a stirred slurry of 2-(2-chloro-benzoylamino)-butyric acid (2.84 g, 11.8 mmol) in 60 mL of anhydrous tetrahydrofuran was added oxalyl chloride (10.1 mL, 118 mmol). The mixture was stirred overnight at 50°C, then the solvent was evaporated in vacuo. The oily residue was treated with toluene and traces of oxalyl chloride were removed by evaporation. The residue was then cooled in an ice bath and triethylamine (3.4 mL, 23.6 mmol) was added followed by 1-hydroxy-pyrrolidine-2,5-dione. The reaction mixture was stirred overnight at 50 °C, after which time the solvent was removed in vacuo. The residue was then purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 5-60% ethyl acetate in hexane, 25 min) to afford 2-(2-chloro-phenyl)-4-ethyl- Oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (997 mg, 25% yield) as a pale yellow solid. LCMS calcd. for C16H13ClN2O5 (m/e) 348, found 349 (M+H).

Preparation of 2,5-dioxo-pyrrolidin-1-yl 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylate

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidine-1- from DL-norvaline and 2-chloro-benzoyl chloride base ester. LCMS calcd. for C17H15ClN2O5 (m/e) 362, found 363 (M+H).

Preparation of 4-methyl-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 4-methyl-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-alanine and benzoyl chloride. LCMS calcd. for C15H12N2O5 (m/e) 300, found 301 (M+H).

Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-alanine and 2-methyl-benzoyl chloride. LCMS calcd. for C16H14N2O5 (m/e) 314, found 315 (M+H).

Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-norvaline and 2-methyl-benzoyl chloride. LCMS calcd. for C18H18N2O5 (m/e) 342, found 343 (M+H).

Preparation of 4-(2-methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 4-(2-methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-methionine and benzoyl chloride . LCMS calcd. for C17H16N2O5S (m/e) 360, found 361 (M+H).

Preparation of 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from DL-norvaline and 2-bromo-benzoyl chloride to prepare 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidine-1- base ester. LCMS calcd. for C17H15BrN2O5 (m/e) 407, found 408 (M+H).

Preparation of 2,5-dioxo-pyrrolidin-1-yl 2-cyclohexyl-4-propyl-oxazole-5-carboxylate

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-norvaline and cyclohexanecarbonyl chloride. LCMS calcd. for C17H22N2O5 (m/e) 334, found 335 (M+H).

Preparation of 2,5-dioxo-pyrrolidin-1-yl 2-phenyl-4-propyl-oxazole-5-carboxylate

Using a method similar to that used for the preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester above, from Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester from DL-norvaline and benzoyl chloride. LCMS calcd. for C17H16N2O5 (m/e) 328, found 329 (M+H).

Preparation of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid:

Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexanes to afford (2-chloro-benzoylamino)-acetic acid methyl ester as a pale yellow solid. LCMS calcd. for C10H10ClNO3 (m/e) 227, found 228 (M+H).

To a solution of the above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until the pH of the solution was adjusted to pH 2-3. The mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, dried over MgSO ₄ , filtered and concentrated to dryness to obtain (2-chloro-benzoylamino)-acetic acid as a solid. To a -20°C solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone was added excess trifluoroacetic anhydride. The mixture was warmed to room temperature and stirred overnight. Solvent was removed in vacuo. The residue was poured into 400 mL of water and stirred for 20 minutes. The solid was filtered off, washed with 2 x 100 mL of water, and dried under vacuum to obtain 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butanoic acid as red solid. The red solid was suspended in 80 mL of methanol and heated to reflux for 30 minutes. The solvent was removed and the mixture was purified by flash chromatography with ethyl acetate/hexanes to afford 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butane Acid methyl ester, as light yellow solid. Suspend the methyl ester in 100 g of phosphorus oxychloride and stir overnight at 80°C. The reaction mixture was concentrated to remove excess _POCl3 . The remaining oil was diluted with toluene and poured into an ice-water mixture. The layers were separated, and the organic layer was washed with water and dilute sodium bicarbonate, then concentrated to dryness. The solid was dissolved in 30 mL of methanol, treated with 2.5 equivalents of lithium hydroxide in 30 mL of water, and stirred for 30 minutes. Methanol was removed in vacuo and the mixture was diluted with water. The pH of the solution was adjusted to about 3 with 12M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to obtain 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a pale yellow solid. LCMS calcd. for C11H5ClF3NO3 (m/e) 291, found 292 (M+H).

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above, from 2-bromo-benzoyl chloride, amino-acetic acid methyl ester and trifluoroacetic anhydride to prepare 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid. LCMS calcd. for C11H5BrF3NO3 (m/e) 336, found 337 (M+H).

Preparation of 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above, 2-ethyl-benzoyl chloride, amino-acetic acid methyl Esters and trifluoroacetic anhydride to prepare 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid. LCMS calcd. for C13H10F3NO3 (m/e) 285, found 286 (M+H).

Preparation of 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above, from 2-trifluoromethoxy-benzoyl chloride, amino - Preparation of 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid from methyl acetate and trifluoroacetic anhydride. LCMS calcd. for C12H5F6NO4 (m/e) 341, found 342 (M+H).

Preparation of 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

Using a procedure similar to that used to prepare 2-(2-chloro-phenyl)-5-trifluoromethyloxazole-4-carboxylic acid above, from 2-methoxy-benzoyl chloride, amino-acetic acid methyl Esters and trifluoroacetic anhydride to prepare 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid. LCMS calcd. for C12H8F3NO4 (m/e) 287, found 288 (M+H).

Preparation of 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid

Using a procedure similar to that used for the preparation of 2-(2-chloro-phenyl)-5-trifluoromethyloxazole-4-carboxylic acid above, from cyclohexanecarbonyl chloride, methyl amino-acetate and trifluoro Preparation of 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid from acetic anhydride. LCMS calcd. for C11H12F3NO3 (m/e) 263, found 264 (M+H).

Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid

2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was prepared according to the method described in Bioorg.Med.Chem.Lett.2003, 13 , 1517. A solution of ethyl 2-chloro-4,4,4-trifluoro-3-oxo-butyrate (436 mg, 2 mmol) and benzamide (484 mg, 4 mmol) in ethanol (6 mL) in a sealed tube Heat at 120 degrees for 30 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane, 25 min) to obtain 4-hydroxy-2-phenyl-4 - Ethyl trifluoromethyl-4,5-dihydro-oxazole-5-carboxylate as an off-white solid (229 mg, 38% yield). LCMS calcd. for C13H12F3NO4 (m/e) 303, found 304 (M+H). The ester was dehydrated by heating with 2 mL of phosphorus oxychloride at 80 degrees overnight. The reaction mixture was cooled and concentrated. The obtained residue was mixed with THF and concentrated again to remove remaining _POCl3 . The oily residue was quenched with water, extracted with DCM (2X). The organic layer was concentrated. The crude product was purified by flash chromatography (silica gel 60, 230-400 mesh, 0-50% ethyl acetate in hexane, 25 min) to give 2-phenyl-4-trifluoromethyl-oxazole-5- Ethyl formate as an off-white solid (160 mg, 75% yield). The ester was hydrolyzed by stirring with lithium hydroxide monohydrate in a 3:1:1 THF:MeOH:water mixture (3 mL) at RT for 4 h. The reaction was concentrated and water was added. The pH of the solution was adjusted to ~1-2 with 1N HCl. The white precipitate was collected by centrifugation and washed with water. After drying in vacuo, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid (141 mg, 98% yield) was obtained as a white solid. LCMS calcd. for C11H6F3NO3 (m/e) 257, found 258 (M+H).

Preparation of 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid

Using a procedure similar to that used to prepare 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid above, from 2-chloro-4,4,4-trifluoro-3-oxo-butane Preparation of 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid from ethyl ester and 2-methoxy-benzamide. LCMS calcd. for C12H8F3NO4 (m/e) 287, found 288 (M+H).

Preparation of 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid

Using a procedure similar to that used to prepare 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid above, from 2-chloro-4,4,4-trifluoro-3-oxo-butane Preparation of 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoro from ethyl acetate, 2-hydroxy-benzamide and 1-bromo-2-methoxy-ethane Methyl-oxazole-5-carboxylic acid. LCMS calcd. for C14H12F3NO5 (m/e) 331, found 332 (M+H).

Preparation of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid

A solution of methyl cyclohexyl acetate (1.56 g, 10 mmol) in 25 mL of anhydrous diethyl ether was stirred at -78°C under argon. DIBAL (1M in hexanes, 11 mL, 11 mmol) was added dropwise over 45 minutes and the reaction mixture was stirred for an additional 1 hour. A solution of sodium potassium tartrate tetrahydrate (6 g, 12.2 mmol) in 25 mL of water was added and the mixture was stirred at room temperature overnight. After dilution with ether, the organic layer was washed with 0.5N HCl, saturated sodium bicarbonate and saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to afford cyclohexyl-acetaldehyde (1.17 g, 93%).

A solution of the above cyclohexyl-acetaldehyde (1.04 g, 8.25 mmol) and ethyl acetoacetate (0.873 mL, 6.85 mmol) in 300 mL of ethanol was stirred in an ice bath while piperidine (7.3 uL , 73umol). The mixture was stirred in an ice bath for 5 hours and placed in a refrigerator for 16 hours. The reaction mixture was diluted with 50 mL of ether and extracted with saturated sodium chloride (3 x 30 mL, containing 2 drops of AcOH). The brine layer was back extracted with ether (2 x 40 mL). The combined ether layers were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated to give ethyl 2-acetyl-4-cyclohexyl-but-2-enoate (1.79 g).

A solution of ethyl 2-acetyl-4-cyclohexyl-but-2-enoate (1.79 g, 7.52 mmol) in 40 mL of _CCl4 was added to a slurry of NBS (1.338 g, 7.52 mmol) in 40 mL _{of CCl4} . The mixture was refluxed under argon for 12 hours, stirred at room temperature for 68 hours, then cooled in an ice bath. The precipitated solid was filtered off and the filtrate was evaporated to an oil, which was purified by short-circuit distillation (165-185 °C, 1 mm Hg) to obtain ethyl 5-cyclohexyl-2-methyl-furan-3-carboxylate (1.36 g, 77% ).

A solution of ethyl 5-cyclohexyl-2-methyl-furan-3-carboxylate (143 mg, 0.605 mmol) and 2N sodium hydroxide (1.5 mL, 3.0 mmol) in 3 mL of ethanol and 1.5 mL of water was heated to reflux for 1 hour . The reaction mixture _was cooled, the pH was adjusted to 1 with 1N HCl, and extracted with _CH2Cl2 (5 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (96 mg, 76%).

Preparation of 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid

5-Cyclohexyl-2-ethyl-furan-3-carboxylic acid (49 mg) was prepared as a powder similarly to the above method except that ethyl 3-oxopentanoate was used instead of ethyl acetoacetate.

Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (1.25g, 6.0mmol), copper(I) iodide (0.342g, 1.8mmol) and potassium carbonate (0.58g, 4.2mmol) were dissolved in The mixture in toluene (6 mL) was purged with argon in a round bottom flask. Iodobenzene (0.81 mL, 7.2 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (0.58 mL, 3.6 mmol) were then added to the reaction mixture. The slurry was heated at 110 °C in an oil bath under Ar for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a layer of celite. After washing the celite with ethyl acetate, the filtrates were combined and concentrated to give a crude material which was purified by silica gel chromatography (Isco 120g column, 0 to 30% ethyl acetate/hexane) to give 1-phenyl- 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.40 g, 82%) as an off-white solid. The NMR spectrum obtained on the sample was consistent with its structure.

A mixture of ethyl 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate (160 mg, 0.56 mmol) and 1N aqueous sodium hydroxide solution (2.3 mL, 2.3 mmol) in methanol (10 mL) Stir overnight at room temperature. The reaction mixture was acidified to pH~2 with 1N aqueous hydrochloric acid and concentrated to afford 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an off-white solid which was used without further purification. LCMS calcd. for C11H7F3N2O2 (m/e) 256, found 257 (M+H).

Preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid

Sodium hydride (60% in mineral oil in, 110mg, 2.75mmol). The mixture was stirred at 0°C for 10 minutes, then at room temperature for 40 minutes. After recooling the reaction mixture to 0°C, 2,2,2-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (500 mg, 2.39 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. The reaction was carefully quenched with ice water and neutralized with 1N aqueous hydrochloric acid. The mixture was extracted with dichloromethane, and the organic layer was dried over sodium sulfate. Filtration and concentration gave a crude material which was purified by silica gel chromatography (Isco 120g column, 11% ethyl acetate/hexanes) to give 5-phenyl-2-(2,2,2-trifluoro-ethyl )-2H-Pyrazole-3-carboxylic acid ethyl ester (360 mg, 52%) as a white solid. The NMR spectrum obtained on the sample was consistent with its structure.

5-Phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360mg, 1.21mmol) and 1N aqueous sodium hydroxide solution (3.6mL, 3.6mmol ) in methanol (10 mL) was stirred overnight at room temperature. The reaction mixture was acidified to pH~2 with 1N aqueous hydrochloric acid and concentrated to afford 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white solid, It was directly used in the next step reaction without further purification. LCMS calcd. for C12H9F3N2O2 (m/e) 270, found 271 (M+H).

Preparation of N-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine

A mixture of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.797 mmol) and N-methyl-N-(2-methoxy)ethylamine (2.0 mL, 18.6 mmol) was placed in an oil bath Heat at 75°C for 10 minutes. The reaction mixture was evaporated to dryness and the residue was triturated with anhydrous ether (50 mL) to obtain methyl 5-[N-methyl-N-(2-methoxyethyl)]aminopyrazine-2-carboxylate as a solid Ester hydrochloride (1.55 g, 100%). LCMS calcd. for C10H15N3O3 (m/e) 225, found 226.1 (M+H).

The above solid (1.55 g) was dissolved in methanol (20 mL) and (1 N) aqueous sodium hydroxide solution (12 mL) was added. The mixture was stirred at 45°C for 60 minutes. The reaction mixture was evaporated to dryness to obtain a yellow waxy solid (ca. 3.0 g) as sodium 5-[N-methyl-N-(2-methoxyethyl)]aminopyrazine-2-carboxylate. LCMS calcd. for C9H13N3O3 (m/e) 211, found 212.1 (M+H).

The above crude sodium salt was suspended in DMF (25 mL), and diphenylphosphoryl azide (2.0 mL, 9.3 mmol) was added. The mixture was stirred at room temperature for 18 hours to obtain a clear solution. The solvent was evaporated in vacuo and the residue was extracted with ethyl acetate (75 mL) and water (50 mL). The aqueous layer was further extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to give amber crystals (1.83g). The crystalline material was dissolved in toluene (20 mL) and benzyl alcohol was added. The mixture was stirred at 95°C for 60 minutes. The obtained solution was cooled to room temperature, and the solution was concentrated to two-thirds volume to prevent the appearance of crystalline material. The solid was filtered and washed with toluene and then ether to give white crystals as benzyl 5-[N-(2-methoxyethyl)-N-methylamino]pyrazine-2-carbamate ( 705 mg, 39%). LCMS calcd. for C16H20N4O3 (m/e) 316, found 317.2 (M+H).

The above benzyl carbamate (316 mg, 1.0 mmol) was suspended in a mixture of methanol (25 mL) and THF (5 mL) containing 5% palladium on carbon (60 mg). The solution was placed under a hydrogen atmosphere (hydrogen balloon) for 1 hour. The mixture was filtered through a thin layer of celite and the solution was evaporated to give a green oil which was N-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine (180 mg, 100% ). LCMS calcd. for C8H14N4O (m/e) 182, found 183.1 (M+H).

Preparation of N-(tetrahydropyran-4-yl)pyrazine-2,5-diamine

4-aminotetrahydropyran (500mg, 4.94mmol) and methyl 2-chloropyrazine-5-carboxylate (770mg, 4.46mmol) were dissolved in N,N-diisopropylethylamine (1.0mL, 5.7 mmol) in DMF (5 mL) was stirred at 55°C for 17 hours. The reaction mixture was concentrated and the residue was partitioned between diethyl ether (25 mL) and hydrochloric acid (1N, 25 mL). The aqueous layer was further extracted with diethyl ether (25 mL). The obtained aqueous layer was first treated with sodium chloride (10 g) and then extracted with dichloromethane (3 x 50 mL). The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the solvent gave an oil which slowly crystallized as methyl 2-(N-tetrahydropyran-4-yl)-aminopyrazine-5-carboxylate (900 mg, 85%). MS calcd for C11H15N3O3 (m/e) 237, found 238.1 (M+H).

The above methyl ester (877 mg, 3.7 mmol) was dissolved in methanol (10 mL), treated with solid sodium hydroxide (300 mg, 7.5 mmol) and water (0.6 mL). The solution was stirred at 50°C for 60 minutes. The reaction mixture was evaporated to dryness, the residue was dissolved twice in toluene (2 x 25 mL) and evaporated to give a solid as the sodium salt. The salt was suspended in DMF (15 mL), and diphenylphosphoryl azide (1.1 mL, 5.11 mol) was added. The mixture was stirred at room temperature overnight to obtain a clear solution. The solvent was evaporated and the residue was partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated to obtain an oil (900 mg). The oil was treated with benzyl alcohol (0.8 mL, 7.7 mmol) and heated at 95 °C with stirring for 45 minutes. The solid obtained was dissolved in a minimal amount of dichloromethane and loaded onto a Biotage flash column, eluting with a gradient of ethyl acetate (25% to 100%) in hexane. The desired fractions were concentrated to obtain yellowish crystals as benzyl 5-(N-tetrahydropyran-4-yl)aminopyrazine-2-carbamate (605 mg, 49.7%). MS calcd for C17H20N4O3 (m/e) 328, found 329.3 (M+H).

The above methyl carbamate (200 mg, 0.609 mol) was suspended in methanol (10 mL) and THF (4 mL) containing 10% palladium on carbon (40 mg). The mixture was placed under a hydrogen atmosphere (hydrogen balloon) at room temperature for 90 minutes. The mixture was filtered through a thin layer of celite. The filtrate was evaporated to dryness to obtain a yellow solid as 5-(N-tetrahydropyran-4-yl)pyrazine-2,5-diamine (120 mg, 100%). MS calcd for C9H14N4O (m/e) 194, found 195.1 (M+H).

Preparation of N ² -[cis-3-(tert-butyl-dimethyl-silyloxy)-cyclopentyl]-pyridine-2,5-diamine

To a 20 mL vial containing cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (580 mg, 2.69 mmol) prepared according to reference (see Chen, et al. US 2004/0204427 A1) DMF (10 mL), 2-chloro-5-nitro-pyridine (428 mg, 2.69 mmol), and TEA (1.5 mL) were added. The vessel was flushed with Ar, sealed, heated to 75 °C for 4.5 hours, cooled to room temperature and allowed to stir over weekend (60 hr). The reaction mixture was heated again at 75 °C for an additional 6 hours, then allowed to cool to RT overnight (18 hr). The reaction mixture was concentrated and redissolved in DMF (10 mL). 2eq of _K2CO3 ( _744mg ) was added and heated at 70°C for 1 hour. The reaction mixture was concentrated, loaded onto silica gel and purified by flash chromatography using Analogix using an 80 g Redisep silica gel column at 60 mL/min with increasing concentrations of _Et20 in hexane (0-5 min: 0%, 5-25 min : 0-20%, 25-40min: 30%, 40-65min: 30-100%). Appropriate fractions were collected and dried to obtain a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H), calcd for C16H27N3O3Si (m/e) 337, 50-100% ACN in _H2O /HCOOH , C18, APCI). The nitropyridyl compound and MeOH (10 mL) were transferred to a PARR vessel, Pd/C (10%) was added, and the vessel was pressurized with 54 psi of _H2 . After 3 hours, the reaction mixture was filtered through a bed of celite and concentrated to dryness twice from DCM. The purple-black material was used immediately for amide coupling (LCMS 2.94 min, 308 (M+H), calcd for C16H27N3O3Si (m/e)307, 10-100% CAN in _H2O /HCOOH 0.3%, C18, APCI).

Preparation of N ² -[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine

Using a procedure similar to that used to prepare ^N2- [cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine above, prepared by following 2-Chloro-5-nitro-pyridine and trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl prepared by reference (see Chen, et al. US2004/0204427 A1) to prepare ^N2 -[trans-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine. (LCMS 3.15 min, 308 (M+H), calcd for C16H27N3O3Si (m/e) 307, 0-100% ACN in _H2O /HCOOH 0.3%, Echelon C18, ESI).

Preparation of N ² -[(1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5 diamine

Using a method similar to that used to prepare ^N2- [cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine, from trans- Preparation of N ² -[(1S,3S)-3 from (1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine and 2-chloro-5-nitro-pyridine -(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine. LCMS calcd. for C16H29N3OSi (m/e) 307, found 308 (M+H).

Preparation of N ² -[trans-(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-(5-nitro-pyridin-2-yl)-amine

Using a method similar to that used to prepare ^N2- [cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine, from trans- Preparation of N ² -[(1R,3R)-3 from (1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine and 2-chloro-5-nitro-pyridine -(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine. LCMS calcd. for C16H29N3OSi (m/e) 307, found 308 (M+H).

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl Amino]-pyridin-3-yl}-amide

Using a procedure similar to that used to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide above, from 2-phenyl Base-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -[(1S,3S)-3-(tert-butyl-dimethyl-silyloxy)-cyclopentyl]-pyridine- 2,5-diamine (by reducing N ² -[trans-(1S,3S) ^-3- (tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-(5-nitro-pyridin-2-yl)-amine in situ preparation) to prepare 2-phenyl-5-trifluoromethyl -Oxazole-4-carboxylic acid {6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide. Red solid.LCMSC calcd. _{for 27H33F3N4O3Si} (m/e) 546, _{found 547} (M ₊ H).

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1R,3R)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl Amino]-pyridin-3-yl}-amide

Using a method similar to that used to prepare the above 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-(tert-butyl-dimethyl-silyloxy Base)-cyclopentylamino]-pyridin-3-yl}-amide method, by 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -[(1R, 3R )-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine (according to the method similar to that used for the preparation of N ² -cyclopentyl-pyridine-2 , the method of the 5-diamine method, by reducing N ² -[trans-(1R,3R)-3-(tert-butyl-dimethyl-silyloxy)-cyclopentyl]-(5-nitro base-pyridin-2-yl)-amine in situ preparation) to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1R,3R)-[3-(tert-butyl -Dimethyl-silyloxy)-cyclopentylamino]-pyridin-3 _- yl}-amide. LCMS calcd _{. for C27H33F3N4O3Si} (m/e) 546, found ₅₄₇ (M+H).

Preparation of 1-(6-nitropyridin-3-yl)-pyrrolidin-3-ol

A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL) was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and (S)-3-hydroxypyrrolidinol (350mg, 4.04mmol) treatment. The mixture was heated in a sealed tube at 85°C for 21.5 hours _, then cooled and partitioned between _CH2Cl2 and water. The organic layer was dried over _Na2SO4 , filtered and concentrated, and the residue was chromatographed on _a silica gel column using a gradient of 40-100% EtOAc in hexanes to 0-30% THF in EtOAc to obtain the product, As a yellow solid (200 mg, 47% yield). HRMS m _/ z _calcd for _C9H11N3O3 [M+H] ⁺ : _210.0873 ; found: 210.0873.

Preparation of 5-(3-(S)-methoxy-pyrrolidin-1-yl)-2-nitro-pyridine

A solution of 5-(3-(S)-hydroxypyrrolidinol)-2-nitropyridine (200 mg, 0.96 mmol) in anhydrous THF was washed with MeI (178 μL, 2.88 mmol) and then 60% in mineral oil NaH (57 mg, 1.44 mmol) was treated at room temperature. After stirring at room temperature overnight, the reaction mixture was partitioned between EtOAc and water. _The organic layer was dried over _Na2SO4 , filtered and concentrated. Precipitation from _CH2Cl2 using excess hexane afforded the product as a yellow solid ( ₁₇₀ mg, 80% yield). HRMS m/z calcd for C ₁₀ H ₁₁ N ₃ O ₃ [M+Na] ⁺ : 246.0849; found: 246.0849.

Preparation of (2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine

A solution of 2-nitro-5-bromopyridine (500 mg, 3.15 mmol) in EtOH (15 mL) was treated with methoxyethyl-N-methylamine (1.12 g, 12.6 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol) was treated. The resulting mixture was then heated in a sealed tube at 90 °C for 4 days, then cooled and partitioned between EtOAc and water. _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was chromatographed on silica gel with a gradient of 40-100% EtOAc in hexanes to afford the product as a dark yellow oil that slowly crystallized upon standing (270 mg, 41% yield). _HRMS m _/ z calcd for _C9H13N3O3 [M+Na] ⁺ : 234.0849; _found : 234.0850.

Preparation of 1-(5-nitro-pyridin-2-yl)-azetidin-3-ol

2-Bromo-5-nitropyridine (406 mg, 2 mmol), 3-hydroxyazetidine hydrochloride (199 mg, 2 mmol), and finely divided potassium carbonate (828 mg, 6 mmol) were heated in 20 mL of anhydrous DMF to 80°C for 5 hours. The mixture was diluted with EtOAc, extracted with _H2O and dried over _MgSO4 . The EtOAc layer was filtered, evaporated to dryness and used without further purification. ES-MS calcd. for C8H9N3O3 (m/e) 195.18, found 196.2 (M+H).

Preparation of (2-ethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (197 mg, 1 mmol) in THF (5 mL) and DMF (2 mL) was mixed with 60 % NaH (48mg, 1.2mmol) was stirred for 1 hour. The mixture was cooled, and ethyl iodide (120 uL, 1.5 mmol) was added thereto. The reaction was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with _H2O and dried over _MgSO4 . The EtOAc layer was filtered, evaporated to dryness and used without further purification. Yield: 155 mg. ES-MS calculated for C10H15N3O3 (m/e) 225.25, found 225.1 (M+H).

Preparation of 2-(3-methoxy-azetidin-1-yl)-5-nitro-pyridine

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol), 125 mg of crude product were obtained, which was used without further purification. ES-MS calcd. for C9H11N3O3 (m/e) 209.21, found 210 (M+H).

Preparation of sec-butyl-(5-nitro-pyridin-2-yl)-amine

2-Bromo-5-nitropyridine (341 mg, 1.68 mmol), (S)-(+)-sec-butylamine (123 mg, 1.68 mmol), and finely divided potassium carbonate (707 mg, 5.1 mmol) were dissolved in 15 mL of anhydrous Heat to 80°C in DMF for 3.5 hours. The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . The EtOAc layer was filtered, evaporated to dryness, and purified by flash chromatography to give 233 mg. ES-MS calcd. for C9H13N3O2 (m/e) 195.22, found 196.1 (M+H).

Preparation of 2-(3-ethoxy-azetidin-1-yl)-5-nitro-pyridine

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was used in 60% NaH (60 mg, 1.5 mmol) in oil and ethyl as above Treatment with iodine (400 uL, 5 mmol) afforded 62 mg of product after purification by flash chromatography. ES-MS calcd for C10H13N3O3 (m/e) 223.23, found 224.1 (M+H).

Preparation of (2-cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (98.5 mg, 0.5 mmol) in THF (10 mL) and DMF (2 mL) was mixed with 60% NaH (32mg, 0.8mmol) was stirred for 1 hour. The mixture was cooled, and bromomethylcyclopropane (0.685 mg, 5 mmol) was added thereto. The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 82 mg. ES-MS calculated for C12H17N3O3 (m/e) 251.29, found 252.1 (M+H).

Preparation of (2-ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (198 mg, 1 mmol) in THF (15 mL) and DMF (3 mL) was mixed with 60 % NaH (60 mg, 1.75 mmol) was stirred for 1 hour. The mixture was cooled, and ethyl iodide was added thereto. The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 75 mg. ES-MS calcd. for C9H14N4O3 (m/e) 226.24, found 227 (M+H).

Preparation of [1-(5-nitro-pyridin-2-yl)-azetidin-3-yloxy]-tert-butyl acetate

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (176 mg, 0.9 mmol) was used as above with 60% NaH in oil (108 mg, 2.7 mmol) and tert-butyl bromoacetate Treatment with the ester (199.7 uL, 1.35 mmol) afforded 210 mg of a yellow solid. ES-MS calcd for C14H19N3O5 (m/e) 309.32, found 310.2 (M+H).

Preparation of [1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-tert-butyl acetate

1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-ol (340 mg, 1.62 mmol) was used as above in 60% NaH (130 mg, 3.25 mmol) and tert-butyl bromoacetate (1.2 mL, 8.13 mmol) to obtain 280 mg of a yellow solid after flash chromatography. ES-MS calcd for C15H21N3O5 (m/e) 323.35, found 324.1 (M+H).

Preparation of {2-[methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-acetic acid tert-butyl ester

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (350 mg, 1.77 mmol) in THF (15 mL) and DMF (2 mL) was mixed with 60% NaH (142 mg, 4.44 mmol) was stirred. The mixture was cooled, and tert-butyl bromoacetate (1.31 mL, 8.88 mmol) was added thereto. The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with _H2O and dried over _MgSO4 . The EtOAc layer was filtered and evaporated to dryness to give 262 mg after flash chromatography. ES-MS calcd for C14H21N3O5 (m/e) 311.34, found 312 (M+H).

Preparation of methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine

2-Chloro-5-nitropyridine (158 mg, 1 mmol), N-methylisoamylamine (101 mg, 1 mmol), and finely divided potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL of anhydrous DMF for 3.5 hours . The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . The EtOAc layer was filtered and evaporated to dryness to obtain 220mg. ES-MS calcd for C11H17N3O2 (m/e) 223.28, found 224.1 (M+H).

Preparation of 3-[methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile

2-Chloro-5-nitropyridine (158 mg, 1 mmol), 3-methylamino-propionitrile (84 mg, 1 mmol), and finely divided potassium carbonate (414 mg, 3 mmol) were heated to 80° C. in 10 mL of anhydrous DMF for 3.5 Hour. The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . The EtOAc layer was filtered and evaporated to dryness. ES-MS calcd. for C9H10N4O2 (m/e) 206.21, found 207.1 (M+H).

Preparation of bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine

2-Chloro-5-nitropyridine (158 mg, 1 mmol), 2-aminonorbornane hydrochloride (147 mg, 1 mmol), and finely divided potassium carbonate (419 mg, 3 mmol) were heated to 80 °C in 10 mL of anhydrous DMF 3.5 hours. The mixture was diluted with EtOAc, extracted with _H2O , dried over _MgSO4 . EtOAc was filtered and evaporated to dryness to obtain 220 mg. ES-MS calcd. for C12H15N3O2 (m/e) 233.21, found 234.1 (M+H).

Part II: Examples of preferred embodiments

Example 1

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.58g, 6.14mmol), 6-morpholin-4-yl-pyridin-3-ylamine (1.0g, 5.58mmol), N-hydroxybenzotriazole (1.27g, 8.37mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.6g, 8.37mmol) in anhydrous The mixture in dichloromethane (20 mL) was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated. The obtained mixture was mixed with water and extracted twice with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over sodium sulfate, and concentrated to obtain a solid. The crude was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexanes) to afford 2-phenyl-5-trifluoromethyl-oxazole-4 -Formic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (1.15 g, 50%) as an off-white solid. LCMS calcd. for C20H17F3N4O3 (m/e) 418, found 419 (M+H).

Example 2

Preparation of 2-phenyl-thiazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

2-Phenyl-thiazole-4-carboxylic acid (6 -morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C19H18N4O2S (m/e) 366, found 367 (M+H).

Example 3

Preparation of 4-phenyl-thiazole-2-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

4-Phenyl-thiazole-2-carboxylic acid (6 -morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C19H18N4O2S (m/e) 366, found 367 (M+H).

Example 4

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-pyrimidin-5-yl)-amide

Preparation of 2-phenyl from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-pyrimidin-5-ylamine using a procedure similar to that of Example 1 above -5-Trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-pyrimidin-5-yl)-amide. LCMS calcd. for C19H16F3N5O3 (m/e) 419, found 420 (M+H).

Example 5

Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 1 above, from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and 6-morpholin-4-yl-pyridine-3- Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide from base amine. LCMS calcd. for C19H20N6O2 (m/e) 364, found 365 (M+H).

Example 6

Preparation of 5-bromo-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a procedure similar to that of Example 1 above, 5-bromo-2-benzene was prepared from 5-bromo-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine Ethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C19H17BrN4O3 (m/e) 429, found 430 (M+H).

Example 7

Preparation of 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 1 above, from 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid and methyl-(6-morpholin-4-yl-pyridin-3-yl)-amine Preparation of 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C21H18F3N3O3 (m/e) 417, found 418 (M+H).

Example 8

Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a procedure analogous to Example 1 above, 5-chloro-2-phenyl-oxazole-4-carboxylic acid and methyl-(6-morpholin-4-yl-pyridin-3-yl)-amine were prepared from 5 -Chloro-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C19H17C1N4O3 (m/e) 384, found 385 (M+H).

Example 9

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 1 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- from pyridine-2,5-diamine 3-yl}-amide. LCMS calcd. for C20H19F3N4O3 (m/e) 420, found 421 (M+H).

Example 10

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

Using a method similar to Example 1 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine-5- from 2,5-diamine base}-amide. LCMS calcd. for C19H18F3N5O3 (m/e) 421, found 422 (M+H).

Example 11

Preparation of (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid methyl ester

Using a procedure similar to that of Example 1 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and [(5-amino-pyridin-2-yl)-methyl-amino]-acetic acid Methyl ester Preparation of (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid methyl ester. LCMS calcd. for C20H17F3N4O4 (m/e) 434, found 435 (M+H).

Example 12

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide

Using a method similar to Example 1 above, from (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl from amino)-acetic acid and methylamine ]-amide. LCMS calcd. for C20H18F3N5O3 (m/e) 433, found 434 (M+H).

Example 13

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(dimethylcarbamoylmethyl-methyl-amino)-pyrdin-3-yl]-amide

Using a method similar to Example 16, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-[(5-amino-pyridin-2-yl)-methyl-amino]- N,N-Dimethyl-acetamide to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(dimethylcarbamoylmethyl-methyl-amino)-pyridine- 3-yl]-amide. LCMS calcd. for C21H20F3N5O3 (m/e) 447.42, found 448.16 (M+H).

Example 14

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide

Using a procedure similar to that of Example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-thiomorpholin-4-yl-pyridin-3-ylamine were prepared from 2- Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C20H17F3N4O2S (m/e) 434, found 435 (M+H).

Example 15

Preparation of 4-methyl-2-phenyl-thiazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a procedure similar to that of Example 1 above, 4-methyl-2- Phenyl-thiazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C20H20N4O2S (m/e) 380, found 381 (M+H).

Example 16

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}- Amide

Using a method similar to Example 1 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-[1-(5-amino-pyridin-2-yl)-pyrrolidine- 3-yl]-N-methyl-acetamide to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(acetyl-methyl-amino)-pyrrolidine- 1-yl]-pyridin-3-yl}-amide. LCMS calcd. for C23H22F3N5O3 (m/e) 473, found 474 (M+H).

Example 17

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(R)-3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridine-3 -yl}-amide

2-Phenyl was prepared from the corresponding racemic compound as a light yellow solid by chiral supercritical fluid chromatography (Daicel AD column, 40% (1:1) EtOH/acetonitrile plus 20 mM ammonium acetate as modifier). -5-Trifluoromethyl-oxazole-4-carboxylic acid {6-[(R)-3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide . [α] _D = -15.2 (MeOH).

Example 18

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (260mg, 1mmol), N-(5-amino-pyridin-2-yl)-N-methyl-acetamide (165mg, 1mmol ), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (470 mg, 1 mmol), and triethylamine (202 mg, 2 mmol) in dry dichloromethane (5 mL) was stirred overnight at room temperature. After the reaction was complete, the solvent and excess triethylamine were removed by evaporation. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-40% ethyl acetate in hexane, 20 min) afforded 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6- (Acetyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. LCMS calcd. for C19H15F3N4O3 (m/e) 404, found 405 (M+H).

Example 19

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclopropanecarbonyl-methyl-amino)-pyridin-3-yl]-amide

Using a method similar to Example 16, 2-Phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid [6-(cyclopropanecarbonyl-methyl-amino)-pyridin-3-yl]-amide as a white solid. LCMS calcd. for C21H17F3N4O3 (m/e) 430, found 431 (M+H).

Example 20

Preparation of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Preparation of 5-isopropyl from 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine using a procedure similar to that of Example 16 above -2-Phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C22H24N4O3 (m/e) 392, found 393 (M+H).

Example 21

Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure analogous to Example 16 above, 5 was prepared from 5-chloro-2-phenyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-acetamide -Chloro-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C18H15ClN4O3 (m/e) 370, found 371 (M+H).

Example 22

Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

Prepared from 5-ethyl-2-phenyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-acetamide using a procedure similar to that of Example 16 above 5-Ethyl-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C20H20N4O3 (m/e) 364, found 365 (M+H).

Example 23

Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 16 above, 5-Ethyl-2 -Phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C21H22N4O3 (m/e) 378, found 379 (M+H).

Example 24

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-amide

Using a method similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-propane Amide Preparation 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C20H17F3N4O3 (m/e) 418, found 419 (M+H).

Example 25

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(3-methoxy-pyrrolidin-1-yl)-pyridine-3 -ylamine Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide. LCMS calcd. for C21H19F3N4O3 (m/e) 432, found 433 (M+H).

Example 26

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

2-Phenyl-5-trifluoromethyl-oxazole-4- Formic acid [6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide. [α] _D = +14.5, (MeOH).

Example 27

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5 '-yl)-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 3-methoxy-3,4,5,6-tetrahydro-2H-[ 1,2′]bipyridyl-5′-ylamine to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-methoxy-3,4,5,6-tetrahydro -2H-[1,2']bipyridyl-5'-yl)-amide. LCMS calcd. for C22H21F3N4O3 (m/e) 446, found 447 (M+H).

Example 28

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and ^N2 -methyl- ^N2 -propyl-pyridine-2,5-diamine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C20H19F3N4O2 (m/e) 404, found 405 (M+H).

Example 29

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(butyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and ^N2 -butyl- ^N2 -methyl-pyridine-2,5-diamine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(butyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C21H21F3N4O2 (m/e) 418, found 419 (M+H).

Example 30

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(3-methoxy-propyl)-N ² -methyl- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(3-methoxy-propyl)-methyl-amino]-pyridine- from pyridine-2,5-diamine 3-yl}-amide. LCMS calcd. for C21H21F3N4O3 (m/e) 434, found 435 (M+H).

Example 31

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-propylamino)-pyridin-3-yl]-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(3-methoxy-propyl)-pyridine-2,5- Diamine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-propylamino)-pyridin-3-yl]-amide. LCMS calcd. for C20H19F3N4O3 (m/e) 420, found 421 (M+H).

Example 32

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-thiazol-5-yl)-amide

Preparation of 2-phenyl from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-thiazol-5-ylamine using a procedure similar to that of Example 16 above -5-Trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-thiazol-5-yl)-amide. LCMS calcd. for C18H15F3N4O3S (m/e) 424, found 425 (M+H).

Example 33

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-thiazole- from thiazole-2,5-diamine 5-yl}-amide. LCMS calcd. for C18H17F3N4O3S (m/e) 426, found 427 (M+H).

Example 34

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]- Amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-((R)-2-methoxymethyl-pyrrolidine-1- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine )-pyridin-3-yl]-amide. LCMS calcd. for C22H21F3N4O3 (m/e) 446, found 447 (M+H).

Example 35

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -ethyl-N ² -(2-methoxy-ethyl)- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[ethyl-(2-methoxy-ethyl)-amino]-pyridine- from pyridine-2,5-diamine 3-yl}-amide. LCMS calcd. for C21H21F3N4O3 (m/e) 434, found 435 (M+H).

Example 36

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-pyridine-2,5- Diamine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide. LCMS calcd. for C19H17F3N4O3 (m/e) 406, found 407 (M+H).

Example 37

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(2-methoxy-ethoxy)-pyridin-3-ylamine Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide. LCMS calcd. for C19H16F3N3O4 (m/e) 407, found 408 (M+H).

Example 38

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and ^N2 -ethyl- ^N2 -methyl-pyridine-2,5-diamine Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C19H17F3N4O2 (m/e) 390, found 391 (M+H).

Example 39

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-ethylamino-pyridin-3-yl)-amide

Using a method similar to that of Example 16 above, ² -phenyl- 5-Trifluoromethyl-oxazole-4-carboxylic acid (6-ethylamino-pyridin-3-yl)-amide. LCMS calcd. for C18H15F3N4O2 (m/e) 376, found 377 (M+H).

Example 40

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-diethylamino-pyridin-3-yl)-amide

Using a procedure analogous to Example 16 above, 2 was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and ^N2 , ^N2 -diethyl-pyridine-2,5-diamine -Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-diethylamino-pyridin-3-yl)-amide. LCMS calcd. for C20H19F3N4O2 (m/e) 404, found 405 (M+H).

Example 41

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-dimethylamino-pyridin-3-yl)-amide

2-Benzene was prepared from 2-phenyl-trifluoromethyl-oxazole-4-carboxylic acid and ^N2 , ^N2 -dimethyl-pyridine-2,5-diamine using a method similar to that of Example 1 above. Ethyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-dimethylamino-pyridin-3-yl)-amide. LCMS calcd for C18H15F3N4O2 (m/e) 376.34 found 377.12 (M+H).

Example 42

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide

Using a method similar to Example 1 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -isopropyl-N ² -methyl-pyridine-2,5-di Amine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C20H19F3N4O2 (m/e) 404, found 405 (M+H).

Example 43

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide

A mixture of 2-phenyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid (454 mg, 1.77 mmol), CH ₂ Cl ₂ (5 mL), and a catalytic amount of DMF was stirred under Ar, on ice Cooled in a bath, oxalyl chloride (308 μL, 3.53 mmol) was added dropwise to the mixture over 5 minutes. The mixture was allowed to warm to room temperature immediately and after 1.5 hours the reaction was concentrated to dryness. Dichloromethane was added and the solution was evaporated again to dryness. The white-yellow solid was redissolved in 5 mL of _CH2Cl2 and added dropwise under Ar to cyclopentyl- _pyridine -2,5-diamine (448 mg, 2.53 mmol), catalytic amount of DMAP and triethylamine ( 602 μL, 4.33 mmol) in 5 _mL of _CH2Cl2 at 0°C. The reaction was allowed to warm to room temperature overnight, then concentrated and the residue was loaded onto silica gel and purified by flash chromatography using an Analogix system using a 40 g Redisep silica column with increasing concentrations of EtOAc in hexane (40 mL/min with 0 %, 0-5min: 0%, 5-25min: 0 to 30%, 25-40min: 30% balance). The product was triturated 6 times with hexane and 4 times with 10% diethyl ether hexane for a total of 20 mL to obtain the product 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino- Pyridin-3-yl)-amide as an off-white solid (315 mg, 50% yield). LCMS _calcd . _{for C21H19F3N4O2} (m _/ e) 416, found ₄₁₇ (M+H).

Example 44

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid

(6-Cyclohexylamino-pyridin-3-yl)-amide

Using a procedure similar to that used above for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide, from 2-phenyl Base-5-(trifluoromethyl)-oxazole-4-carboxylic acid and N ² -cyclohexyl-pyridine-2,5-diamine to prepare 2-phenyl-5-trifluoromethyl-oxazole-4- Formic acid (6-cyclohexylamino-pyridin-3-yl)-amide. The product was isolated as a white-pink solid after flash chromatography and recrystallization from diethyl ether as described above. LCMS _calcd . _{for C22H21F3N4O2} (m _/ e) ₄₃₀ , found 431 (M+H).

Example 45

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopropylamino-pyridin-3-yl)-amide

Using a procedure similar to that used above for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide, from 2-phenyl Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid from base-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -cyclopropyl-pyridine-2,5-diamine (6-Cyclopropylamino-pyridin-3-yl)-amide as a lilac solid. LCMS _calcd . for _C19H15F3N4O2 (m _/ e) ₃₈₈ , found ₃₈₉ (M+H).

Example 46

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino]-pyridin-3-yl]-amide

Using a procedure similar to that used above for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide, from 2-phenyl ^{2 -} phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. LCMS _calcd . for _C20H17F3N4O2 (m/e) ₄₀₂ , found ₄₀₃ (M ₊ H).

Example 47

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclobutyl-methyl-amino]-pyridin-3-yl]-amide

Using a procedure similar to that used above for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide, from 2-phenyl ² -Phenyl-5- ^{trifluoromethyl-} Oxazole-4-carboxylic acid [6-(cyclobutyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. (LCMS _calcd . _{for C21H19F3N4O2} (m _/ e) 416, found ₄₁₇ (M+H).

Example 48

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino]-pyrimidin-3-yl]-amide

Using a procedure similar to that used above for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-cyclopentylamino-pyridin-3-yl)-amide, from 2-phenyl ^{2 -} Phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyrimidin-3-yl]-amide as a white light yellow solid (calculated for LCMSC ₁₉ H ₁₆ F ₃ N ₅ O ₂ (m/ e) 403, experimental value 404 (M+H).

Example 49

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-2-methoxy- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-acetyl)-methyl-amino]-pyridine-3 from N-methyl-acetamide -base}-amide. LCMS calcd. for C20H17F3N4O4 (m/e) 434, found 435 (M+H).

Example 50

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]-pyridine -3-yl}-amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -((S)-2-methoxy-1-methyl-ethane Base)-N ² -methyl-pyridine-2,5-diamine for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[((S)-2-methoxy -1-methyl-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H21F3N4O3 (m/e) 434, found 435 (M+H).

Example 51

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(2-methoxy-1-methyl-ethylamino)pyridin-3-yl]amide hydrochloride

Using a procedure similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-1-methyl-ethyl)-2, Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(2-methoxy-1-methyl-ethylamino)pyridin-3-yl] from 5-diaminopyridine amide hydrochloride. The purified oily material from column chromatography was dissolved in ether and treated with gaseous hydrochloric acid in ether (3N) to give a white precipitate as the hydrochloride salt. LCMS calcd. neutral form C20H19F3N4O3 m/e 420.39, found 421.02 (ES, M+H).

Example 52

Preparation of (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(1-phenyl-ethylamino)pyridin-3-yl]amide

Using a method similar to that of Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)-2-N-(1-phenylethyl)-2,5 -Diaminopyridine Preparation of (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(1-phenyl-ethylamino)pyridin-3-yl]amide. LCMS calcd. for C24H19F3N4O2 m/e 452.4, found 453.2 (ES, M+H).

Example 53

Preparation of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 3-amino-6-(3,3-difluoroazetidine-1 -yl)pyridine to prepare 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide . LCMS calcd. for C19H13F5N4O2 m/e 424.33, found 425.0 (ES, M+H).

Example 54

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}- Amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -methyl-N ² -(2,2,2-trifluoro-ethane Base)-pyridine-2,5-diamine to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl) -amino]-pyridin-3-yl}-amide. LCMS calcd. for C19H14F6N4O2 (m/e) 444, found 445 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 55

Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]- Pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N ² -methyl-N ² -(2,2 , 2-trifluoro-ethyl)-pyridine-2,5-diamine to prepare 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[methyl -(2,2,2-Trifluoro-ethyl)-amino]-pyridin-3-yl}-amide. LCMS calcd. for C18H17F3N6O (m/e) 390, found 391 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 56

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}- Amide

Using a method similar to Example 16 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-methyl-N-(2,2,2-trifluoro-ethyl) -Pyrimidine-2,5-diamine to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[methyl-(2,2,2-trifluoro-ethyl)-amino ]-pyrimidin-5-yl}-amide. LCMS calcd. for C18H13F6N5O2 (m/e) 445, found 446 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 57

Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

Using a method similar to that of Example 16 above, from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N ² -cyclopropyl-N ² -methyl- Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridine- from pyridine-2,5-diamine 3-yl]-amide. LCMS calcd. for C19H20N6O (m/e) 348, found 349 (M+H).

Example 58

Preparation of 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a procedure similar to that of Example 16 above, from 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid (prepared by hydrolysis of the corresponding commercially available ethyl ester) and N ² -(2- Preparation of ² -methyl-5-phenyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy Base-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C20H23N5O2 (m/e) 365, found 366 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 59

Preparation of 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- 3-yl}-amide

Using a procedure analogous to Example 16 above, prepared from 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (prepared by hydrolysis of the corresponding commercially available ethyl ester ) and N ² -(2-methoxy-ethyl)-N ² -methyl-pyridine-2,5-diamine to prepare 5-(4-methoxy-phenyl)-2-methyl-2H -Pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H25N5O3 (m/e) 395, found 396 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 60

Preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino] -pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid and N ² -(2-methoxy -Ethyl)-N ² -methyl-pyridine-2,5-diamine for the preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid{ 6-[(2-Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H22F3N5O2 (m/e) 433, found 434 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 61

Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methanol Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino from base-pyridine-2,5-diamine ]-pyridin-3-yl}-amide. LCMS calcd. for C20H20F3N5O2 (m/e) 419, found 420 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 62

Preparation of 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3 -yl}-amide

Using a method similar to Example 16 above, from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N ² -(2-methoxy-ethyl) -N ² -methyl-pyridine-2,5-diamine to prepare 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[(2-methoxy Base-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C19H22N6O2 (m/e) 366, found 367 (M+H). The NMR spectrum obtained on the sample was consistent with its structure.

Example 63

Preparation of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3- base}-amide

Using a method similar to Example 16 above, from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)- Preparation of ^2- (2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy- Ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C20H18ClF3N4O3 (m/e) 454, found 455 (M+H).

Example 64

Preparation of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 16 above, from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-yl Amine Preparation of 2-(2-Chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C20H16ClF3N4O3 (m/e) 452, found 453 (M+H).

Example 65

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3- base}-amide

Using a method similar to Example 16 above, from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)- Preparation of ^2- (2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy- Ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C20H18BrF3N4O3 (m/e) 499, found 500 (M+H).

Example 66

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -ethyl-N ² -methyl-pyridine- Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl] from 2,5-diamine - amides. LCMS calcd. for C19H16BrF3N4O2 (m/e) 469, found 470 (M+H).

Example 67

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridine -3-yl}-amide

Using a method similar to Example 16 above, from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-cyclopropylmethoxy-ethyl Base)-N ² -methyl-pyridine-2,5-diamine to prepare 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-ring Propylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C23H22BrF3N4O3 (m/e) 539, found 540 (M+H).

Example 68

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine-5- base}-amide

Using a method similar to Example 16 above, from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)- Preparation of ^2- (2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy- Ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. LCMS calcd. for C19H17BrF3N5O3 (m/e) 500, found 501 (M+H).

Example 69

Preparation of 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine-3 -yl}-amide

Using a method similar to Example 16 above, from 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl) -N ² -methyl-pyridine-2,5-diamine to prepare 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy Base-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H23F3N4O3 (m/e) 448, found 449 (M+H).

Example 70

Preparation of 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl- Preparation of 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- from pyridine-2,5-diamine 3-yl}-amide. LCMS calcd. for C20H25F3N4O3 (m/e) 426, found 427 (M+H).

Example 71

Preparation of 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]- Pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy- Ethyl)-N ² -methyl-pyridine-2,5-diamine to prepare 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6- [(2-Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H18F6N4O4 (m/e) 504. found 505 (M+H).

Example 72

Preparation of 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]- Pyrimidin-5-yl}-amide

Using a procedure similar to that of Example 16 above, 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl Base)-N-methyl-pyrimidine-2,5-diamine to prepare 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[( 2-Methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. LCMS calcd. for C20H17F6N5O4 (m/e) 505. found 506 (M+H).

Example 73

Preparation of 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- 3-yl}-amide

Using a method similar to Example 16 above, from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl )-N ² -methyl-pyridine-2,5-diamine to prepare 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2- Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H21F3N4O4 (m/e) 504. found 505 (M+H).

Example 74

Preparation of 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine- 5-yl}-amide

Using a method similar to Example 16 above, from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl) -N-methyl-pyrimidine-2,5-diamine to prepare 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy base-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. LCMS calcd. for C20H20F3N5O4 (m/e) 451. found 452 (M+H).

Example 75

Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to that of Example 16 above, from 2-phenyl-5-propyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl-pyridine- Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} from 2,5-diamine - amides. LCMS calcd. for C22H26N4O3 (m/e) 394, found 395 (M+H).

Example 76

Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a procedure analogous to Example 16 above, 2-Phenyl-5 -Propyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C22H24N4O3 (m/e) 392, found 393 (M+H).

Example 77

Preparation of 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} -amide

Using a method similar to Example 16 above, from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -Methyl-pyridine-2,5-diamine to prepare 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)- Methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H25ClN4O3 (m/e) 428, found 429 (M+H).

Example 78

Preparation of 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} -amide

Using a method similar to Example 16 above, from 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -Methyl-pyridine-2,5-diamine to prepare 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)- Methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H25BrN4O3 (m/e) 473, found 474 (M+H).

Example 79

Preparation of 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 16 above, from 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -Methyl-pyridine-2,5-diamine to prepare 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino ]-pyridin-3-yl}-amide. LCMS calcd. for C23H28N4O3 (m/e) 408, found 409 (M+H).

Example 80

Preparation of 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 16 above, from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and ^N2 -ethyl- ^N2 -methyl-pyridine-2, 5-Diamine Preparation of 2-(2-Chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C21H23ClN4O2 (m/e) 398, found 399 (M+H).

Example 81

Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to that of Example 16 above, from 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl-pyridine- Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} from 2,5-diamine - amides. LCMS calcd. for C22H32N4O3 (m/e) 400, found 401 (M+H).

Example 82

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (311 mg, 1.21 mmol), 2-(5-amino-pyridin-2-ylamino)-ethanol (84 mg, 0.55 mmol), N -Hydroxybenzotriazole (185mg, 1.38mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (264mg, 1.38mmol) in dichloromethane (5mL ) and DMF (1 mL) was stirred at room temperature for 5 hours. The solvent was removed, and lithium hydroxide hydrate (excess) in a mixed solvent of methanol, tetrahydrofuran, and water (3:1:1, 5 mL) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed and water was added. The obtained mixture was extracted twice with ethyl acetate. The organic layer was collected, washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in dichloromethane, 30 min), followed by preparative HPLC (0-90% acetonitrile in water, 20 min), followed by lyophilization afforded 2-benzene Ethyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide as a pale yellow solid. LCMS calcd. for C18H15F3N4O3 (m/e) 392, found 393 (M+H).

Example 83

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a procedure similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-[(5-amino-pyridin-2-yl)-methyl-amino] - Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide from - ethanol. LCMS calcd. for C19H17F3N4O3 (m/e) 406, found 407 (M+H).

Example 84

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide. LCMS calcd. for C20H17F3N4O3 (m/e) 418, found 419 (M+H).

Example 85

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)-pyrimidin-5-yl]amide

Using a method similar to Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyrimidin-2-yl)-pyrrolidin-3-ol Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide. LCMS calcd. for C19H16F3N5O3 m/e 419.37, found 420.0 (ES, M+H).

Example 86

Preparation of (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide

Using a method similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)-N-(5-aminopyrimidin-2-yl)-pyrrolidine- 3-Alcohol Preparation of (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide. LCMS calcd. for C19H16F3N5O3 m/e 419.37, found 420.1 (ES, M+H).

Example 87

Preparation of (S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide

Using a method similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-N-(5-aminopyrimidin-2-yl)-pyrrolidine- 3-Alcohol Preparation of (S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide. LCMS calcd. for C19H16F3N5O3 m/e 419.37, found 420.1 (ES, M+H).

Example 88

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′- base)-amide

Using a procedure similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5'-amino-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridyl-3-alcohol to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-hydroxyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridyl-5'-yl)-amide. LCMS calcd. for C21H19F3N4O3 (m/e) 432, found 433 (M+H).

Example 89

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide

Using a method similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and [(S)-1-(5-amino-pyridin-2-yl)-pyrrole Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridine from alk-2-yl]-methanol -3-yl]-amide. LCMS calcd. for C21H19F3N4O3 (m/e) 432, found 433 (M+H).

Example 90

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′- base)-amide

Using a procedure similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5'-amino-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridyl-4-alcohol to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-hydroxyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridyl-5'-yl)-amide. LCMS calcd. for C21H19F3N4O3 (m/e) 432, found 433 (M+H).

Example 91

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyridin-2-ylamino)-propane Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl from -1-alcohol ]-amide. LCMS calcd. for C19H17F3N4O3 (m/e) 406, found 407 (M+H).

Example 92

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]-amide

Using a method similar to that of Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyrimidin-2-ylamino)-propane Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl from -1-alcohol ]-amide. LCMS calcd. for C18H16F3N5O3 (m/e) 407, found 408 (M+H).

Example 93

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide

Using a method similar to Example 43 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5-amino-pyridin-2-ylamino)-2-methyl- Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl from propan-1-ol ]-amide. LCMS calcd. for C20H19F3N4O3 (m/e) 420, found 421 (M+H).

Example 94

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl ]-amide

Using a procedure similar to that of Example 43 above, from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-1-(5-amino-pyridine-2 -yl)-pyrrolidin-3-ol for the preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-hydroxy-pyrrolidine- 1-yl)-pyridin-3-yl]-amide. LCMS calculated value C20H16BrF3N4O3m/e 497, experimental value 498.

Example 95

Preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

2-(2-Chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (174 mg, 0.5 mmol) and 6-morpholine- A mixture of 4-yl-pyridin-3-ylamine (90 mg, 0.5 mmol) in 5 mL of acetonitrile was stirred overnight at 85 °C. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in dichloromethane, 30 min) to give 2-(2-chloro-phenyl)-4- Ethyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (107 mg, 52% yield) as a pale yellow solid. LCMS calcd. for C21H21ClN4O3 (m/e) 412, found 413 (M+H).

Example 96

Preparation of 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 50 above, 2-(2-Chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6 -Morpholin-4-yl-pyridin-3-ylamine to prepare 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3 -yl)-amide. LCMS calcd. for C22H23ClN4O3 (m/e) 426, found 427 (M+H).

Example 97

Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to that of Example 50 above, from 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholine- 4-yl-pyridin-3-ylamine Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C21H22N4O3 (m/e) 378, found 379 (M+H).

Example 98

Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to that of Example 50 above, from 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholine- 4-yl-pyridin-3-ylamine Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide. LCMS calcd. for C23H26N4O3 (m/e) 406, found 407 (M+H).

Example 99

Preparation of 4-methyl-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to Example 50 above, 4-methyl-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholine-4- 4-Methyl-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from base-pyridin-3-ylamine. LCMS calcd. for C20H20N4O3 (m/e) 364, found 365 (M+H).

Example 100

Preparation of 4-(2-methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

4-(2-Methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester using a method similar to that of Example 50 above and 6-morpholin-4-yl-pyridin-3-ylamine to prepare 4-(2-methylthio-ethyl)-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl -pyridin-3-yl)-amide. LCMS calcd. for C22H24N4O3S (m/e) 424, found 425 (M+H).

Example 101

Preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} -amide

Using a procedure similar to that of Example 50 above, 2,5-dioxo-pyrrolidin-1-yl ester from 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylate and N Preparation of ^2- (2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid from 2-( ² -methoxy-ethyl)-N 2 -methyl-pyridine-2,5-diamine {6-[(2-Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H23ClN4O3 (m/e) 414, found 415 (M+H).

Example 102

Preparation of 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} -amide

Using a procedure similar to that of Example 50 above, 2,5-dioxo-pyrrolidin-1-yl ester from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylate and N Preparation of ^2- (2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid from 2-( ² -methoxy-ethyl)-N 2 -methyl-pyridine-2,5-diamine {6-[(2-Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H25ClN4O3 (m/e) 428, found 429 (M+H).

Example 103

Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a procedure similar to that of Example 50 above, 2,5-dioxo-pyrrolidin-1-yl 2-phenyl-4-propyl-oxazole-5-carboxylate and N ² -(2-methanol Oxy-ethyl)-N ² -methyl-pyridine-2,5-diamine for the preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl base)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H26N4O3 (m/e) 394, found 395 (M+H).

Example 104

Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a procedure similar to that of Example 50 above, from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N ² -(2-carboxylate Oxy-ethyl)-N ² -methyl-pyridine-2,5-diamine to prepare 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl base)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H32N4O3 (m/e) 400, found 401 (M+H).

Example 105

Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

Using a method similar to that of Example 50 above, from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholine-4- 2-Cyclohexyl-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from base-pyridin-3-ylamine. LCMS calcd. for C22H30N4O3 (m/e) 398, found 399 (M+H).

Example 106

Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

Using a method similar to that of Example 50 above, from 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N ² -ethyl-N ² -Methyl-pyridine-2,5-diamine to prepare 2-phenyl-4-propyl-oxazole-5-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]- amides. LCMS calcd. for C21H24N4O2 (m/e) 364, found 365 (M+H).

Example 107

Preparation of 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl} -amide

Using a method similar to Example 50 above, 2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N Preparation of ^2- (2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid from 2-( ² -methoxy-ethyl)-N 2 -methyl-pyridine-2,5-diamine {6-[(2-Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C22H25BrN4O3 (m/e) 473, found 474 (M+H).

Example 108

Preparation of 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl} -amide

Using a method similar to Example 50 above, 2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N -(2-Methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine to prepare 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {2 -[(2-Methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. LCMS calcd. for C21H24BrN5O3 (m/e) 474, found 475 (M+H).

Example 109

Preparation of 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

Using a method similar to Example 50 above, 2-(2-Bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N Preparation of ^2- ( ² -bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl -methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C22H23BrN4O2 (m/e) 455, found 456 (M+H).

Example 110

Preparation of 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 50 above, 2,5-dioxo-pyrrolidin-1-yl ester from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylate and N Preparation of ^2- ( ² -chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl -methyl-amino)-pyridin-3-yl]-amide. LCMS calcd. for C22H23ClN4O2 (m/e) 410, found 411 (M+H).

Example 111

Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 1 above, from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N ² -(2-methoxy-ethyl)-N ² -methyl- Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- from pyridine-2,5-diamine 3-yl}-amide. LCMS calcd. for C20H19F3N4O3 (m/e) 420, found 421 (M+H).

Example 112

Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

Using a method similar to Example 1 above, from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine- Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine-5- from 2,5-diamine base}-amide. LCMS calcd. for C19H18F3N5O3 (m/e) 421, found 422 (M+H).

Example 113

Preparation of 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridine- 3-yl}-amide

Using a method similar to Example 1 above, from 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid and N ² -(2-methoxy-ethyl )-N ² -methyl-pyridine-2,5-diamine to prepare 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2- Methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C21H21F3N4O4 (m/e) 450, found 451 (M+H).

Example 114

Preparation of 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidine- 5-yl}-amide

Using a method similar to Example 1 above, from 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid and N-(2-methoxy-ethyl) -N-methyl-pyrimidine-2,5-diamine to prepare 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy base-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. LCMS calcd. for C20H20F3N5O4 (m/e) 451, found 452 (M+H).

Example 115

Preparation of 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)- Methyl-amino]-pyridin-3-yl}-amide

Using a method similar to Example 1 above, 2-[2-(2-Methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid and N ² -( Preparation of 2-[2-( ² -methoxy-ethoxy)-phenyl]-4-trifluoro from 2-methoxy-ethyl)-N 2 -methyl-pyridine-2,5-diamine Methyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide. LCMS calcd. for C23H25F3N4O5 (m/e) 494, found 495 (M+H).

Example 116

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-oxo-1λ ⁴ -thiomorpholin-4-yl)-pyridin-3-yl]-amide:

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide (30 mg, 0.07 mmol) was dissolved in 3 mL of di In methyl chloride, cool to -78°C. 1 equivalent of 3-chloroperbenzoic acid (12 mg, 0.07 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-20% methanol in dichloromethane, 25 min) to give 2-phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid [6-(1-oxo- ^1λ4 -thiomorpholin-4-yl)-pyridin-3-yl]-amide as an off-white solid. LCMS calcd. for C20H17F3N4O3S (m/e) 450, found 451 (M+H).

Example 117

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1,1-dioxo- ^1λ6 -thiomorpholin-4-yl)-pyridin-3-yl] -amide

Using a procedure similar to that of Example 58 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide and 2-equivalents of 3-chloroperbenzoic acid to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1,1-dioxo-1λ ⁶ -thiomorpholine-4- base)-pyridin-3-yl]-amide. LCMS calcd. for C20H17F3N4O4S (m/e) 466, found 467 (M+H).

Example 118

Preparation of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

5-cyclohexyl-2-methyl-furan-3-carboxylic acid (83 mg, 0.365 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (83 mg, 0.4 mmol), and triethylamine ( 154uL, 1.09mmol) was dissolved in 5mL of DMF and frozen in an ice bath. To this solution was added BOP (169 mg, 0.383 mmol) in one portion. The mixture was stirred at room temperature for 1 hour, then diluted with 30 mL of ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2 x 10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over _MgSO4 , filtered and evaporated to dryness in vacuo. The crude product was purified by flash chromatography with ethyl acetate/hexanes to afford 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)- Amide, as a light gray powder (87 mg, 64%). ES-MS calcd. for C21H27N3O3 (m/e) 369.5, found 370.3 (M+H).

Example 119

Preparation of 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (26 mg, 0.116 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (20 mg, 0.116 mmol), and triethylamine ( 49uL, 0.348mmol) was dissolved in 4mL of DMF and frozen in an ice bath. To this solution was added BOP (53 mg, 0.121 mmol) in one portion. The mixture was stirred at room temperature for 1 hour, then diluted with 30 mL of ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2 x 10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over _MgSO4 , filtered and evaporated to dryness in vacuo. The crude product was purified by flash chromatography with ethyl acetate/hexanes to afford 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)- Amide, as a light gray powder (11.5 mg, 26%). ES-MS calcd. for C22H29N3O3 (m/e) 383.5, found 384 (M+H).

Example 120

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(N-2-methoxyethyl-N-methyl)aminopyrazine]-2-yl-amide

To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (285 mg, 1.1 mmol) in dichloromethane (10 mL) cooled in an ice bath was added oxalyl chloride (0.22 mL, 2.5 mmol ) and a drop of DMF. The mixture was stirred at 0°C for 5 minutes, then at room temperature for 30 minutes. The solvent was evaporated, the residue was treated with toluene (10 mL), and the solvent was further evaporated. The residue was dried in vacuo and dissolved in dichloromethane (10 mL). Cool the solution in an ice bath and wash with pyridine (0.24 mL, 2.97 mmol) and 5-(N-2-methoxyethyl-N-methyl)-pyrazine-2,5-diamine (180 mg, 1.0 mmol) in dichloromethane (10 mL). The ice bath was removed and the mixture was stirred at room temperature for 90 minutes. The mixture was then extracted with dichloromethane and water. The organic layer was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by Biotage flash column chromatography eluting with ethyl acetate and hexanes (gradient elution with 10% to 50% ethyl acetate in hexanes) to afford 2-phenyl-5-trifluoromethane Ethyl-oxazole-4-carboxylic acid [5-(N-2-methoxyethyl-N-methyl)aminopyrazine]-2-yl-amide as a yellow solid (205 mg, 48%). LCMS calcd. for C19H18F3N5O3 (m/e) 421.3, found 422.2 (M+H).

Example 121

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(N-tetrahydropyran-4-yl)aminopyrazine]-2-yl-amide

Using a method similar to that of Example 62 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(tetrahydropyran-4-yl)pyrazine-2,5-bis Amine Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(N-tetrahydropyran-4-yl)aminopyrazine]-2-yl-amide. LCMS calcd. for C20H18F3N5O3 (m/e) 433, found 434 (M+H).

Example 122

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(tetrahydropyran-4-yl-amino)pyridin-3-yl]amide

To a solution containing 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (134 mg, 0.52 mmol) and 2-(N-tetrahydropyran-4-yl)-2,5-diaminopyridine ( 101 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (0.15 mL, 1.0 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (243 mg, 0.52 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography using ethyl acetate and hexane (1/1 to 2/1 ratio) to obtain a fluffy solid (108mg). LCMS calcd. for C21H19F3N4O3 m/e 432.41, found 433.1 (ES, M+H).

Example 123

Preparation of (S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide

Using a method similar to Example 17 above, from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-N-(tetrahydrofuran-3-yl)-2,5- Diaminopyridine Preparation of (S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide. LCMS calcd. for C20H17F3N4O3 m/e 418.38, found 419.2 (AP, M+H).

Example 124

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide

Prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine using a procedure similar to that of Example 17 above 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide. LCMS calcd. for C20H17F3N4O3 m/e 418.38, found 419.13 (ES, M+H).

Example 125

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(cis-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide

A mixture of 5-methyl-2-phenyl-oxazole-4-carboxylic acid (371 mg, 1.44 mmol), DCM (5 mL), and DMF (cat.) was stirred under Ar, cooled in an ice bath, and added to the Oxalyl chloride (252 μL, 2.89 mmol) was added dropwise to the mixture over 5 minutes. The mixture was allowed to warm to room temperature immediately and after 1.5 h the reaction was concentrated to dryness and then dried again from DCM. The white-yellow solid was dissolved in 5 mL of DCM, and added dropwise under Ar under ice-bath cooling to N ² -[cis-3-(tert-butyl-dimethyl-silyloxy) in 5 mL DCM )-cyclopentyl]-pyridine-2,5-diamine (443.7 mg, 1.44 mmol), DMAP (cat.) and TEA (602 μL, 4.33 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was concentrated, loaded onto silica gel, and purified by flash chromatography using an Analogix system using a 40 g Redisep silica column with increasing concentrations of EtOAc in hexane (30 mL/min, equilibrated with 5%, 0-5 min: 5 %, 5-20min: 5 to 30%, 20-40min: 30%). Appropriate fractions were collected and dried to obtain a red solid, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[cis-3-(tert-butyl-dimethyl-silyloxy yl)-cyclopentylamino]-pyridin-3-yl}-amide, 456 mg, 72.9% (LCMS 3.91 min, 547 (M+H), calculated for C27H33F3N4O3S (m/e) 546, 10-100% ACN in _H2O /HCOOH 0.3%, C18, ESI). The protected alcohol was dissolved in ACN (10 mL) and 5% aqueous HF (1.3 mL) was slowly added dropwise. The reaction was stirred for 22 hours, concentrated and the liquid was extracted with DCM. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to dryness. The dried material was redissolved in DCM (14 mL) and TFA (6 mL) was slowly added dropwise. After 1.5 hours, the solution was concentrated to dryness, loaded onto silica gel, and purified by flash chromatography using a 12 g 12M Biotage silica gel column with increasing concentrations of EtOAc in hexane (250 mL increments of 5, 10, 30, 50 , 80, 100% and then 5% MeOH in EtOAc). Appropriate fractions were collected and dried to give a white/yellow solid 189 mg, 53% (LCMS 3.00 min, 433 (M+H), calculated for C21H19F3N4O3 (m/e) 432, 10-100% ACN in _H2O /HCOOH 0.3%, C18, APCI).

Example 126

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(trans-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide

Using a procedure similar to that of Example 64 above, from 2-phenyl-oxazole-4-carboxylic acid and N ² -[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl] - Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(trans-3-hydroxy-cyclopentylamino)-pyridin-3-yl] from -pyridine-2,5-diamine - amides. The product was light yellow, 880 mg, 89% yield, (LCMS 2.71 min, 433 (M+H), calcd. for C21H19F3N4O3 (m/e) 432, 10-100% ACN in _H2O /HCOOH 0.3%, C18 , APCI).

Example 127

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide

To the 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-(tert-butyl-dimethyl-silyloxy)-cyclopentyl Dichloromethane (0.7mL) and trifluoroacetic acid (0.3mL) were added to a flask of 1-amino]-pyridin-3-yl}-amide (8mg, 0.015mmol). When the starting material was consumed, as shown by TLC, the reaction The mixture was neutralized with triethylamine and concentrated to dryness. The residue was dissolved in a minimum amount of dichloromethane and hexane was added dropwise to precipitate the product. The pale pink solid was filtered and washed with hexane to obtain 2-phenyl -5-Trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide. LCMS C ₂₁ H ₁₉ F Calcd. _{for 3 N4O3} (m/e) 432, found 433 (M+H).

Example 128

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1R,3R)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide

Using a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1S,3S)-[3-hydroxy-cyclopentylamino]-pyridine-3- Base}-amide method, by 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1R, 3R)-[3-(tert-butyl-dimethyl- Silyloxy)-cyclopentylamino]-pyridin-3-yl}-amide to prepare 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-((1R,3R)-[ 3-Hydroxy-cyclopentylamino]-pyridin-3 _- yl}-amide _. LCMS Calcd. for _C21H19F3N4O3 (m/e) ₄₃₂ , found 433 (M ₊ H).

Example 129

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5-(3-(S)-methoxy-pyrrolidinyl)-pyridin-2-yl]-amide

A solution of (170 mg, 0.76 mmol) 5-(3-(S)-methoxy-pyrrolidin-1-yl)-2-nitro-pyridine in EtOH (20 mL) was washed with 10% Pd/C ( 80mg, 0.08mmol) treatment. The obtained mixture was hydrogenated at atmospheric pressure for 1 hour, then filtered. The solid was washed three times with EtOH and the combined organic layers were evaporated to the corresponding crude aminopyridine. The product was dissolved in _CH2Cl2 (15 _mL ) without further characterization. The resulting solution was then treated with diisopropylethylamine (790 μL, 4.6 mmol) and a catalytic amount of DMAP.

A slurry of 220 mg (0.83 mmol) of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid in _CH2Cl2 (15 mL) was treated with 80 μL ( _0.92 mmol) of oxalyl chloride and a catalytic amount of DMF was handled at room temperature. After stirring for 10 minutes, the slurry disappeared. The solvent was evaporated to dryness under reduced pressure to obtain the corresponding acid chloride. This intermediate was dissolved in about 15 mL _{of CH2Cl2} without characterization and added to the solution containing the above crude aminopyridine product with vigorous stirring. The combined mixture was stirred for 30 minutes, then concentrated. The residue was chromatographed on a silica gel column using a 0-20% _Et2O gradient in toluene to afford the product as a yellow solid. (170 mg, 52% yield). HRMS m _/ z calcd for _C21H19F3N4O3 [M+H] ⁺ : _433.1482 ; _{found :} 433.1482.

Example 130

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide.

Using a procedure similar to that of Example 66 above, from (2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine and 2-phenyl-5-trifluoromethyl- Preparation of oxazole-4-carboxylic acid from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {5-[(2-methoxy-ethyl)-methyl-amino]-pyridine-2- base} amides. The product was isolated as a yellow solid (200 mg, 37% yield). HRMS m _/ z calcd for _C20H19F3N4O3 [M+H] ⁺ : _421.1482 ; _{found :} 433.1481.

Example 131

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxyazetidin-1-yl)-pyridin-3-yl]-amide

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (400 mg, 2 mmol) was treated with 10% Pd/C (40 mg) in EtOH (30 mL) and acetic acid ( 2 drops) for 2 ^3/4 _hours . The mixture was filtered through a plug of celite, evaporated, then co-evaporated with toluene. The residue was dissolved in DMF (15 mL). Half of this solution (7.5 mL, ~1 mmol) was removed. To this was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (257mg, 1mmol), _Et3N (422uL, 3mmol) and BOP (464mg.1.05mmol). The reaction was stirred at room temperature for 1 hour. Purification of the crude material by flash chromatography according to the work-up as above afforded 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxyazetidine Alk-1-yl)-pyridin-3-yl]-amide as an off-white solid (41 mg). ES-MS calcd for C19H15F3N4O3 (m/e) 404.35, found 405.1 (M+H).

Example 132

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-ethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

(2-Ethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (150 mg, 0.666 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethane Ethyl-oxazole-4-carboxylic acid (171 mg, 0.666 mmol), Et ₃ N (464 uL, 3.3 mmol) and BOP (309 mg.0.699 mmol) were reacted. Purification of the crude by flash chromatography according to the above work-up gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-ethoxy-ethyl)-methanol 1-amino]-pyridin-3-yl}-amide as a yellow solid (194 mg). ES-MS calcd. for C21H21F3N4O3 (m/e) 434.42, found 435.1 (M+H).

Example 133

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide

2-(3-Methoxy-azetidin-1-yl)-5-nitro-pyridine (120 mg, 0.5 mmol) was hydrogenated as above and combined with 2-phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid (141 mg, 0.55 mmol), Et ₃ N (352 uL, 2.5 mmol) and BOP (232 mg.0.525 mmol) were reacted. After working up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-azetidine -1-yl)-pyridin-3-yl]-amide as a light green solid (45 mg). ES-MS calcd for C20H17F3N4O3 (m/e) 418.38, found 419.1 (M+H).

Example 134

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-sec-butylamino-pyridin-3-yl)-amide

Sec-butyl-(5-nitro-pyridin-2-yl)-amine (97.5 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid ( 135mg, 0.525mmol), Et ₃ N (352uL, 2.5mmol) and BOP (232mg.0.525mmol) were reacted. After working up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-sec-butylamino-pyridin-3-yl) -amide as a lavender solid (83 mg). ES-MS calcd for C20H19F3N4O2 (m/e) 404.40, found 405.1 (M+H).

Example 135

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide

2-(3-Ethoxy-azetidin-1-yl)-5-nitro-pyridine (59mg, 0.264mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxane Azole-4-carboxylic acid (74mg, 0.29mmol), _Et3N (186uL, 1.32mmol) and BOP (122mg. 0.277mmol) were reacted. After work-up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-ethoxy-azetidine -1-yl)-pyridin-3-yl]-amide as a solid (79 mg). ES-MS calcd for C21H19F3N4O3 (m/e) 432.41, found 433.1 (M+H).

Example 136

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}- Amide

(2-Cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (82 mg, 0.326 mmol) was hydrogenated as above and reacted with 2-phenyl-5-tris Fluoromethyl-oxazole-4-carboxylic acid (92 mg, 0.359 mmol), Et ₃ N (229 uL, 1.63 mmol) and BOP (151 mg.0.326 mmol) were reacted. After working up as above, the crude was purified by flash chromatography to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl yl)-methyl-amino]-pyridin-3-yl}-amide as a solid (95 mg). ES-MS calcd. for C23H23F3N4O3 (m/e) 460.46, found 461.1 (M+H).

Example 137

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-ethoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

(2-Ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (150 mg, 0.663 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl - Oxazole-4-carboxylic acid (179mg, 0.696mmol), _Et3N (466uL, 3.3mmol) and BOP (308mg. 0.696mmol) were reacted. After working up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-ethoxy-ethyl)- Methyl-amino]-pyrimidin-5-yl}-amide as a yellow solid (6 mg). ES-MS calcd. for C20H20F3N5O3 (m/e) 435.41, found 436.1 (M+H).

Example 138

Preparation of (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy )-tert-butyl acetate

[1-(5-Nitro-pyridin-2-yl)-azetidin-3-yloxy]-acetic acid tert-butyl ester (210 mg, 0.679 mmol) was hydrogenated as above and reacted with 2-phenyl-5 - Trifluoromethyl-oxazole-4-carboxylic acid (183mg, 0.71mmol), DIPEA (355uL, 2.03mmol) and BOP (315mg.0.74mmol) were reacted. After work-up as above, the crude was purified by flash chromatography to obtain (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridine- 2-yl}-azetidin-3-yloxy)-tert-butyl acetate as a light brown solid (169 mg). ES-MS calcd. for C25H25F3N4O5 (m/e) 518.50, found 519.1 (M+H).

Example 139

Preparation of (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy )-acetic acid hydrochloride

(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy )-tert-butyl acetate (132 mg) was treated with 8 mL of 97% TFA/ _H2O for 1 hour at room temperature. The reaction mixture was evaporated from 1N HCl (2 x 0.5 mL) to afford (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridine-2 -(yl)-azetidin-3-yloxy)-acetic acid hydrochloride as an off-white solid (130 mg). ES-MS calculated for free base C21H17F3N4O5 (m/e) 462.39, found 463.0 (M+H).

Example 140

Preparation of (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid tert-butyl ester

[1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-acetic acid tert-butyl ester (280 mg, 0.866 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoro Methyl-oxazole-4-carboxylic acid (245mg, 0.953mmol), _Et3N (486uL, 3.46mmol) and BOP (402mg.0.909mmol) were reacted. After work-up as above, the crude was purified by flash chromatography to obtain (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridine- 2-yl}-pyrrolidin-3-yloxy)-tert-butyl acetate as a solid (170 mg). ES-MS calcd. for C26H27F3N4O5 (m/e) 532.52, found 533.1 (M+H).

Example 141

Preparation of (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-B Hydrochloride

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid The tert-butyl ester (140 mg) was treated with 5 mL of 97% TFA/ _H2O at room temperature for 1.5 hours. The reaction mixture was evaporated from 1N HCl (2 x 0.5 mL) to afford (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridine-2 -(yl)-azetidin-3-yloxy)-acetic acid hydrochloride as an off-white solid (110 mg). ES-MS calculated for free base C22H21F3N4O5 (m/e) 476.42, found 477.1 (M+H).

Example 142

Preparation of [2-(Methyl-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy] - tert-butyl acetate

{2-[Methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-acetic acid tert-butyl ester (218 mg, 0.7 mmol) was hydrogenated as above and reacted with 2-phenyl-5- Trifluoromethyl-oxazole-4-carboxylic acid (189mg, 0.735mmol), _Et3N (394uL, 2.8mmol) and BOP (325mg.0.735mmol) were reacted. After work-up as above, the crude was purified by flash chromatography to afford [2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino ]-pyridin-2-yl}-amino)-ethoxy]-tert-butyl acetate as a solid (110 mg). ES-MS calcd. for C25H27F3N4O5 (m/e) 520.51, found 521.1 (M+H).

Example 143

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl}-amide

Methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine (110 mg, 0.49 mmol) was hydrogenated as above and combined with 2-phenyl-5-trifluoromethyl- Oxazole-4-carboxylic acid (138mg, 0.54mmol), _Et3N (352uL, 2.5mmol) and BOP (227mg. 0.514mmol) were reacted. After working up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(3-methyl-butyl )-amino]-pyridin-3-yl}-amide as a lavender solid (16 mg). ES-MS calcd. for C22H23F3N4O2 (m/e) 432.51, found 433.2 (M+H).

Example 144

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide

3-[Methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile (103 mg, 0.5 mmol) was hydrogenated as above and combined with 2-phenyl-5-trifluoromethyl-oxazole- 4-Formic acid (108mg, 0.423mmol), _Et3N (297uL, 2.11mmol) and BOP (196mg. 0.444mmol) were reacted. After working up as above, the crude was purified by flash chromatography to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyano-ethyl)-methanol 1-amino]-pyridin-3-yl}-amide as a solid (61 mg). ES-MS calcd for C20H16F3N5O2 (m/e) 415.38, found 416.1 (M+H).

Example 145

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide

Bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine (102 mg, 0.4 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxa Azole-4-carboxylic acid (123 mg, 0.48 mmol), Et ₃ N (281 uL, 2 mmol) and BOP (194 mg.0.444 mmol) were reacted. After working up as above, the crude was purified by flash chromatography to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(bicyclo[2.2.1]hept-2-yl Amino)-pyridin-3-yl]-amide as a lavender solid (30 mg). ES-MS calcd for C23H21F3N4O2 (m/e) 442.44, found 443.2 (M+H).

Example 146

DGAT Phospholipid FlashPlate Analysis

Materials used for the assay: PL-FlashPlate: Phospholipid FlashPlates from PerkinElmer, Cat. No. SMP108; DAG (1,2-dioleoyl-sn-glycerol) 10 mM suspended in water containing 0.1% TritonX-100; ¹⁴ C-Pal-CoA (palmitoyl-CoA, [palmitoyl- ^1-14C ]), from PerkinElmer, catalog number NEC-555, specific activity 55 mCi/mmol; and DGAT pellets, protein concentration 9.85 mg/ml.

Prepare or purchase buffered aqueous solutions as follows: Coating Buffer (CB) was purchased from PerkinElmer, catalog number SMP900A; Reaction Buffer (RB) was 50 mM Tris-HCl in water, pH 7.5, 100 mM NaCl, 0.01% BSA; Wash Buffer (WB ) is 50mM Tris-HCl in water, pH 7.5, 100mM NaCl, 0.05% sodium deoxycholate; dilution buffer (DB) is 50mM Tris-HCl in water, pH 7.5, 100mM NaCl, 1mM EDTA, 0.2% Triton X- 100.

1,2-Dioleoyl-sn-glycerol (DAG, 10 mmol) was diluted to 500 μΜ with coating buffer (CB). Then, the diluted DAG solution was added to 384-well PL-FlashPlates at 60 μl/well and incubated at room temperature for 2 days. The coated plates were then washed twice with wash buffer (WB) before use. Test compounds were serially diluted to 2000, 666.7, 222.2, 74.1, 24.7, 8.2, 2.7 and 0.9 [mu]M in 100% DMSO. Diluted compounds were further diluted 10-fold with reaction buffer (RB). ¹⁴ C-Pal-CoA was diluted to 8.3 μM with RB. DGAT pellets were diluted with dilution buffer (DB) to 0.13 mg protein/ml immediately before adding to PL-FlashPlates to initiate the reaction. Transfer 20 μl RB-diluted compound (or 10% DMSO in RB for bulk and blank), 15 μl RB-diluted 14C-Pal-CoA and 15 μl DB-diluted DGAT pellet (DB without DGAT, for blank) to each well of PL-FlashPlates. The reaction mixture was incubated at 37°C for 1 hour. The reaction was stopped by washing 3 times with WB. Plates were Top-sealed and read on a Topcount instrument.

Calculation of IC50 _: An Excel template was used to generate _IC50 values for each compound. Population and blank Topcount rpm readings were used as 0% and 100% inhibition. Percent inhibition values for reactions in the presence of compound were calculated and plotted against compound concentration. All data were fitted in the following Dose Response One Site (Dose Response One Site) model (4 parameter logarithmic model) as follows

(A+((B-A)/(1+((x/C)^D)))),

where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and C is the _IC50 and D is the Hill coefficient of the compound. The results are summarized in Table 1 below:

Table 1

The compounds of the examples Activity in DGAT phospholipid FlashPlate assay (A=IC ₅₀ <0.75 μM, B=IC ₅₀ >0.75 μM) 1 A 2 B 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A 12 B

13 A 14 A 15 A 16 A 17 A 18 B 18 A 20 B twenty one B twenty two A twenty three A twenty four A 25 A 26 A 27 B 28 0.084μM 29 A 30 A 31 B 32 A 33 A 34 A 35 A 36 A 37 B 38 A 39 A 40 A

41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 B 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A

69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 B 89 B 90 A 91 A 92 A 93 A 94 0.131uM 95 A 96 A

97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 B 106 A 107 A 108 A 109 A 110 A 111 0.022μM 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 B 121 A 122 A 123 A 124 A

125 A 126 A 127 A 128 A 129 B 130 B 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 A 145 A

It is to be understood that the present invention is not limited to the particular embodiments of the invention described above and that variations of the particular embodiments may be made and still fall within the scope of the appended claims.

Example A

Film-coated tablets may be prepared in a conventional manner containing the following ingredients:

ingredients per tablet

nuclear:

Compound of formula (I) 10.0mg 200.0mg

Microcrystalline Cellulose 23.5mg 43.5mg

Anhydrous lactose 60.0mg 70.0mg

Polyvinylpyrrolidone K30 12.5mg 15.0mg

Sodium starch glycolate 12.5mg 17.0mg

Magnesium stearate 1.5mg 4.5mg

(nuclear weight) 120.0mg 350.0mg

film coating

Hydroxypropyl Methyl Cellulose 3.5mg 7.0mg

Macrogol 6000 0.8mg 1.6mg

Talc 1.3mg 2.6mg

Iron oxide (yellow) 0.8mg 1.6mg

Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved, blended with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were blended with sodium starch glycolate and magnesium stearate and compressed to obtain 120 or 350 mg of cores, respectively. The cores are coated with an aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

Ingredients Per Capsule

Compound of formula (I) 25.0mg

Lactose 150.0mg

Corn starch 20.0mg

Talc 5.0mg

The ingredients are sieved and mixed and filled into 2# capsules.

Example C

Injections can have the following composition:

Compound of formula (I) 3.0mg

Macrogol 400 150.0mg

Acetic acid qs to pH 5.0

Add water for injection to 1.0ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The remaining volume of water was added to bring the volume to 1.0 ml. An appropriate excess of this solution is used, filtered, filled into vials and sterilized.

Example D

Soft gelatin capsules may be prepared in conventional manner containing the following ingredients:

capsule contents

Compound of formula (I) 5.0mg

Yellow wax 8.0mg

Hydrogenated soybean oil 8.0mg

Partially hydrogenated vegetable oil 34.0mg

Soybean Oil 110.0mg

Capsule content weight 165.0mg

gelatin capsule

Gelatin 75.0mg

Glycerin 85 32.0mg

Karion 83 8.0mg (dry matter)

Titanium dioxide 0.4mg

Iron oxide yellow 1.1mg

The active ingredient is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of suitable size. Filled soft gelatin capsules are processed according to methods commonly used in the art.

Example E

Sachets containing the following ingredients may be prepared in conventional manner:

Compound of formula (I) 50.0mg

Lactose, fine powder 1015.0mg

Microcrystalline Cellulose (AVICEL PH 102) 1400.0mg

Sodium carboxymethylcellulose 14.0mg

Polyvinylpyrrolidone K30 10.0mg

Magnesium stearate 10.0mg

Flavoring Additives 1.0mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are blended with magnesium stearate and flavoring additives and filled into sachets.

Claims (30)

1. the compound of formula (I):

Wherein:

R ₁Be unsubstituted aryl, be selected from alkyl ,-aryl that the group of O-alkyl, halogenated alkoxy, methoxyl group-oxyethyl group and halogen replaces, heteroaryl, alkyl or cycloalkyl;

R ₂Be C or N;

R ₃Be C, N, S or O;

R ₄Be C, O, S or N;

R ₅Be C, N or S;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂The O-alkyl; hydroxyl-dimethyl ethyl amino; hydroxyl-methylethyl amino, ring heptan-2-base is amino, morpholino; thiomorpholine generation; oxo thiomorpholine generation, dioxo thiomorpholine generation, alkyl-formamyl-alkyl-amino; the difluoro azetidine; the oxyethyl group azetidine, azetidine-3-base ethoxyacetic acid uncle butyl ether, azetidine-3-base ethoxyacetic acid hydrochloride; or has 4-to a 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O; its group that is not substituted or is selected from down group replaces: amino, acid amides ,-N (CH ₃) C (O) CH ₃, cyclopropane carbonyl-methyl ,-OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃, OCH ₂C (O) OH ,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclo propyl methoxy-ethyl, ethoxyl methyl ,-CH ₂CH ₂CN, alkyl alcohol, acyl group, cycloalkyl, or have 1 to 3 4-to 6-unit ring that is selected from the heterocyclic atom of S, N and O, its group that is not substituted or is selected from down group replaces :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃,-OCH ₂C (O) OH and-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

2. according to the compound of claim 1, wherein:

R ₁Be unsubstituted aryl, be selected from the aryl of the group replacement of alkyl and halogen, heteroaryl, alkyl or cycloalkyl;

R ₂Be C or N;

R ₃Be C, N or O;

R ₄Be C, O, S or N;

R ₅Be C or S;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio, alkoxyl group, thio alkoxy, halogenated alkoxy or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂, the O-alkyl, morpholino, thiomorpholine generation, oxo thiomorpholine generation, dioxo thiomorpholine generation, or have 1 to 3 5-or 6-unit ring that is selected from the heterocyclic atom of S, N and O, it is not substituted or is selected from down group replacement of group: acid amides ,-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl alcohol, acyl group or have the 5-or the 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O, it is not substituted or is selected from down group replacement of group: acid amides ,-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

3. according to the compound of claim 1, wherein:

R ₁It is the aryl that unsubstituted aryl or the group that is selected from alkyl and halogen replace;

R ₂Be C;

R ₃Be N;

R ₄Be O;

R ₅Be C;

R ₆It is alkyl;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂The O-alkyl; hydroxyl-dimethyl ethyl amino; hydroxyl-methylethyl amino, ring heptan-2-base is amino, morpholino; thiomorpholine generation; oxo thiomorpholine generation, dioxo thiomorpholine generation, alkyl-formamyl-alkyl-amino; the difluoro azetidine; the oxyethyl group azetidine, azetidine-3-base ethoxyacetic acid uncle butyl ether, azetidine-3-base ethoxyacetic acid hydrochloride; or has 4-to a 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O; its group that is not substituted or is selected from down group replaces: amino, acid amides ,-N (CH ₃) C (O) CH ₃, cyclopropane carbonyl-methyl ,-OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃, OCH ₂C (O) OH ,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclo propyl methoxy-ethyl, ethoxyl methyl ,-CH ₂CH ₂CN, alkyl alcohol, acyl group, cycloalkyl, or have 1 to 3 4-to 6-unit ring that is selected from the heterocyclic atom of S, N and O, its group that is not substituted or is selected from down group replaces :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃,-OCH ₂C (O) OH and-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

4. according to the compound of claim 1, wherein:

R ₁It is the aryl that unsubstituted aryl or the group that is selected from alkyl and halogen replace;

R ₂Be C;

R ₃Be O;

R ₄Be N;

R ₅Be C;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂The O-alkyl; hydroxyl-dimethyl ethyl amino; hydroxyl-methylethyl amino, ring heptan-2-base is amino, morpholino; thiomorpholine generation; oxo thiomorpholine generation, dioxo thiomorpholine generation, alkyl-formamyl-alkyl-amino; the difluoro azetidine; the oxyethyl group azetidine, azetidine-3-base ethoxyacetic acid uncle butyl ether, azetidine-3-base ethoxyacetic acid hydrochloride; or has 4-to a 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O; its group that is not substituted or is selected from down group replaces: amino, acid amides ,-N (CH ₃) C (O) CH ₃, cyclopropane carbonyl-methyl ,-OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃, OCH ₂C (O) OH ,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclo propyl methoxy-ethyl, ethoxyl methyl ,-CH ₂CH ₂CN, alkyl alcohol, acyl group, cycloalkyl, or have 1 to 3 4-to 6-unit ring that is selected from the heterocyclic atom of S, N and O, its group that is not substituted or is selected from down group replaces :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃,-OCH ₂C (O) OH and-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

5. according to the compound of claim 1, wherein:

R ₁Be unsubstituted aryl, be selected from alkyl ,-aryl that the group of O-alkyl, halogenated alkoxy, methoxyl group-oxyethyl group and halogen replaces, heteroaryl, alkyl or cycloalkyl;

R ₂Be C or N;

R ₃Be C, N, S or O;

R ₄Be C, O, S or N;

R ₅Be C, N or S;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl alcohol, acyl group or have the 5-or the 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O, it is not substituted or is selected from down group replacement of group :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

6. according to the compound of claim 1, wherein:

R ₁Be unsubstituted aryl, be selected from alkyl ,-aryl that the group of O-alkyl, halogenated alkoxy, methoxyl group-oxyethyl group and halogen replaces, heteroaryl, alkyl or cycloalkyl;

R ₂Be C or N;

R ₃Be C, N, S or O;

R ₄Be C, O, S or N;

R ₅Be C, N or S;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂The O-alkyl; hydroxyl-dimethyl ethyl amino; hydroxyl-methylethyl amino, ring heptan-2-base is amino, morpholino; thiomorpholine generation; oxo thiomorpholine generation, dioxo thiomorpholine generation, alkyl-formamyl-alkyl-amino; the difluoro azetidine; the oxyethyl group azetidine, azetidine-3-base ethoxyacetic acid uncle butyl ether, azetidine-3-base ethoxyacetic acid hydrochloride; or has 4-to a 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O; its group that is not substituted or is selected from down group replaces: amino, acid amides ,-N (CH ₃) C (O) CH ₃, cyclopropane carbonyl-methyl ,-OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃, OCH ₂C (O) OH ,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclo propyl methoxy-ethyl, ethoxyl methyl ,-CH ₂CH ₂CN, alkyl alcohol, acyl group, cycloalkyl, or have 1 to 3 4-to 6-unit ring that is selected from the heterocyclic atom of S, N and O, its group that is not substituted or is selected from down group replaces :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃,-OCH ₂C (O) OH and-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

7. according to the compound of claim 1, wherein:

R ₁Be unsubstituted aryl, be selected from alkyl ,-aryl that the group of O-alkyl, halogenated alkoxy, methoxyl group-oxyethyl group and halogen replaces, heteroaryl, alkyl or cycloalkyl;

R ₂Be C or N;

R ₃Be C, N, S or O;

R ₄Be C, O, S or N;

R ₅Be C, N or S;

R ₆Be H, alkyl, halogen, haloalkyl, alkylthio or do not exist;

R ₇Be

At least R ₈Or R ₉One of be N; And

R ₁₀Be-NR ₁₁R ₁₂The O-alkyl; hydroxyl-dimethyl ethyl amino; hydroxyl-methylethyl amino, ring heptan-2-base is amino, morpholino; thiomorpholine generation; oxo thiomorpholine generation, dioxo thiomorpholine generation, alkyl-formamyl-alkyl-amino; the difluoro azetidine; the oxyethyl group azetidine, azetidine-3-base ethoxyacetic acid uncle butyl ether, azetidine-3-base ethoxyacetic acid hydrochloride; or has 4-to a 6-unit ring of 1 to 3 heterocyclic atom that is selected from S, N and O; its group that is not substituted or is selected from down group replaces: amino, acid amides ,-N (CH ₃) C (O) CH ₃, cyclopropane carbonyl-methyl ,-OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃, OCH ₂C (O) OH ,-CH ₂OH ,-CH ₂OCH ₃With-OH;

R ₁₁Be H, low alkyl group, alkyl oxide, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclo propyl methoxy-ethyl, ethoxyl methyl ,-CH ₂CH ₂CN, alkyl alcohol, acyl group, cycloalkyl, or have 1 to 3 4-to 6-unit ring that is selected from the heterocyclic atom of S, N and O, its group that is not substituted or is selected from down group replaces :-OCH ₃,-CH ₂OH ,-CH ₂OCH ₃,-OCH ₂C (O) OC (CH ₃) ₃,-OCH ₂C (O) OH and-OH;

R ₁₂Be H or low alkyl group;

Or its pharmaceutical salts.

8. according to the compound of claim 1, R wherein ₆Be-CF ₃

9. according to the compound of claim 1, R wherein ₁₀Be-N (CH ₃) (CH ₂) _nOCH ₃,-N (CH ₃) CH ₂C (O) OCH ₃,-N (CH ₃) CH ₂C (O) NHCH ₃,-N (CH ₃) C (O) CH ₃,-N (CH ₃) (CH ₂) _nCH ₃,-NH (CH ₂) _nCH ₃,-N (CH ₂CH ₃) (CH ₂) _nOCH ₃, diethylamino ,-N (CH ₃) C (O) CH ₂OCH ₃,-N (CH ₃) CH (CH ₃) CH ₂OCH ₃,-N (CH ₃) (CH ₂) _nO ,-N (CH ₂) _nO ,-NCH ₂(CH ₃) CH ₂O or-the N-tetrahydropyrans;

Wherein n is 1,2 or 3.

10. according to each compound of claim 1 to 9, it is selected from the group of being made up of following:

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-thiazole-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

4-phenyl-thiazole-2-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (2-morpholine-4-base-pyrimidine-5-yl)-acid amides,

5-methyl-2-phenyl-2H-[1,2,3] triazole-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

5-bromo-2-phenyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

5-phenyl-2-trifluoromethyl-furans-3-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

5-chloro-2-phenyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

(methyl-5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-amino)-methyl acetate,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(methyl-methylamino formyl radical methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(formyl-dimethylamino methyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-thiomorpholine-4-base-pyridin-3-yl)-acid amides,

4-methyl-2-phenyl-thiazole-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[3-(ethanoyl-methyl-amino)-tetramethyleneimine-1-yl]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(R)-3-(ethanoyl-methyl-amino)-tetramethyleneimine-1-yl]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(ethanoyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(cyclopropane carbonyl-methyl-amino)-pyridin-3-yl]-acid amides,

5-sec.-propyl-2-phenyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

5-chloro-2-phenyl-oxazoles-4-formic acid [6-(ethanoyl-methyl-amino)-pyridin-3-yl]-acid amides,

5-ethyl-2-phenyl-oxazoles-4-formic acid [6-(ethanoyl-methyl-amino)-pyridin-3-yl]-acid amides,

5-ethyl-2-phenyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-methoxyl group-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-3-methoxyl group-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazole-4-formic acid (3-methoxyl group-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(methyl-propyl group-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(butyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(3-methoxyl group-propyl group)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-methoxyl group-propyl group amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (2-morpholine-4-base-thiazole-5-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-thiazole-5-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((R)-2-methoxymethyl-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[ethyl-(2-methoxyl group-ethyl)-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(2-methoxyl group-ethylamino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(2-methoxyl group-oxyethyl group)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-ethylamino-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-diethylamino-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-dimethylamino-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-cyclopentyl amino-pyridine-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-cyclohexyl amino-pyridine-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-cyclopropyl amino-pyridine-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(cyclobutyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [2-(cyclopropyl-methyl-amino)-pyrimidine-5-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethanoyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[((S)-2-methoxyl group-1-methyl-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(2-methoxyl group-1-methyl-ethylamino)-pyridin-3-yl]-acid amides; Hydrochloride,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((R)-1-phenyl-ethylamino)-pyridin-3-yl]-acid amides,

2-phenyl-5-San Fu Jia Ji oxazole-4-formic acid-[6-(3,3-difluoro azetidine-1-yl) pyridin-3-yl] acid amides,

2-phenyl-5-trifluoromethyl-oxazole-4-formic acid 6-[methyl-(2,2,2-three fluoro-ethyls)-amino]-pyridin-3-yl }-acid amides,

5-methyl-2-phenyl-2H-[1,2,3] triazole-4-formic acid 6-[methyl-(2,2,2-three fluoro-ethyls)-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazole-4-formic acid 2-[methyl-(2,2,2-three fluoro-ethyls)-amino]-pyrimidine-5-yl }-acid amides,

5-methyl-2-phenyl-2H-[1,2,3] triazole-4-formic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-acid amides; Trifluoroacetate,

2-methyl-5-phenyl-2H-pyrazoles-3-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-methyl-5-phenyl-2H-pyrazoles-3-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

5-phenyl-2-(2,2,2-three fluoro-ethyls)-2H-pyrazoles-3-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

1-phenyl-3-Trifluoromethyl-1 H-pyrazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

5-methyl-2-phenyl-2H-[1,2,3] triazole-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-chloro-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole 4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-(2-bromo-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-bromo-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-(2-bromo-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-cyclo propyl methoxy-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-bromo-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-cyclohexyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-(2-methoxyl group-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-methoxyl group-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-phenyl-5-propyl group-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-propyl group-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-(2-chloro-phenyl)-5-propyl group-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-bromo-phenyl)-5-propyl group-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

5-propyl group-2-tolyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-chloro-phenyl)-5-propyl group-oxazoles-4-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-cyclohexyl-5-propyl group-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(2-hydroxyl-ethylamino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-hydroxyl-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-hydroxyl-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [2-(3-hydroxyl-tetramethyleneimine-1-yl)-pyrimidine-5-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [2-((R)-3-hydroxyl-tetramethyleneimine-1-yl)-pyrimidine-5-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [2-((S)-3-hydroxyl-tetramethyleneimine-1-yl)-pyrimidine-5-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazole-4-formic acid (3-hydroxyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-2-hydroxymethyl-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazole-4-formic acid (4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-2-hydroxyl-1-methyl-ethylamino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [2-((S)-2-hydroxyl-1-methyl-ethylamino)-pyrimidine-5-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(2-hydroxyl-1,1-dimethyl-ethylamino)-pyridin-3-yl]-acid amides,

2-(2-bromo-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-3-hydroxyl-tetramethyleneimine-1-yl)-pyridin-3-yl]-acid amides,

2-(2-chloro-phenyl)-5-ethyl-oxazoles-4-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-(2-chloro-phenyl)-4-propyl group-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

4-methyl-2-neighbour-tolyl-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

4-propyl group-2-neighbour-tolyl-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

4-methyl-2-phenyl-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

4-(2-methylthio group-ethyl)-2-phenyl-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-(2-chloro-phenyl)-4-ethyl-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-chloro-phenyl)-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-cyclohexyl-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-cyclohexyl-4-propyl group-oxazoles-5-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-4-propyl group-oxazoles-5-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-(2-bromo-phenyl)-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-bromo-phenyl)-4-propyl group-oxazoles-5-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-(2-bromo-phenyl)-4-propyl group-oxazoles-5-formic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-(2-chloro-phenyl)-4-propyl group-oxazoles-5-formic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-phenyl-4-trifluoromethyl-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-4-trifluoromethyl-oxazoles-5-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-(2-methoxyl group-phenyl)-4-trifluoromethyl-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-(2-methoxyl group-phenyl)-4-trifluoromethyl-oxazoles-5-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-[2-(2-methoxyl group-oxyethyl group)-phenyl]-4-trifluoromethyl-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(1-oxo-1 λ 4-thiomorpholine-4-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(1,1-dioxo-1 λ 6-thiomorpholine-4-yl)-pyridin-3-yl]-acid amides,

5-cyclohexyl-2-methyl-furans-3-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

5-cyclohexyl-2-ethyl-furans-3-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [the amino pyrazine of 5-(N-2-methoxy ethyl-N-methyl)]-2-base-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [the amino pyrazine of 5-(N-tetrahydropyran-4-base)]-2-base-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(S)-(tetrahydrochysene-furans-3-yl) amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(tetrahydrochysene-furans-3-base is amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(suitable-3-hydroxyl-cyclopentyl amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(anti--3-hydroxyl-cyclopentyl amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((1S, 3S)-3-hydroxyl-cyclopentyl amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((1R, 3R)-3-hydroxyl-cyclopentyl amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [5-(3-(S)-methoxyl group-pyrrolidyl)-pyridine-2-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 5-[(2-methoxyl group-ethyl)-methyl-amino]-pyridine-2-yl } acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-hydroxyl-azetidine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-oxyethyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-methoxyl group-azetidine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-second month in a season-butyl amino)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(3-oxyethyl group-azetidine-1-yl)-pyridin-3-yl]-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-cyclo propyl methoxy-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-oxyethyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

(1-{5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-azetidine-3-base oxygen base)-tert.-butyl acetate,

(1-{5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-azetidine-3-base oxygen base)-acetate; Hydrochloride,

(1-{5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-tetramethyleneimine-3-base oxygen base)-tert.-butyl acetate,

(1-{5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-tetramethyleneimine-3-base oxygen base)-acetate; Hydrochloride,

[2-(methyl-5-[(2-phenyl-5-trifluoromethyl-oxazoles-4-carbonyl)-amino]-pyridine-2-yl }-amino)-oxyethyl group]-tert.-butyl acetate,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-cyano group-ethyl)-methyl-amino]-pyridin-3-yl-acid amides and

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(dicyclo [2.2.1] heptan-2-base is amino)-pyridin-3-yl]-acid amides,

Or its pharmaceutical salts.

11. according to each compound of claim 1 to 10, it is selected from the group of being made up of following:

5-phenyl-2-trifluoromethyl-furans-3-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-thiomorpholine-4-base-pyridin-3-yl)-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides,

2-(2-chloro-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-2-hydroxyl-1-methyl-ethylamino)-pyridin-3-yl]-acid amides and

2-(2-chloro-phenyl)-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl }-acid amides,

Or its pharmaceutical salts.

12. according to the compound of claim 1, wherein said compound is 5-phenyl-2-trifluoromethyl-furans-3-formic acid (6-morpholine-4-base-pyridin-3-yl)-acid amides.

13. according to the compound of claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-acid amides.

14. according to the compound of claim 1, wherein said compound be 2-(2-chloro-phenyl)-4-propyl group-oxazoles-5-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl-acid amides.

15. according to the compound of claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid [6-((S)-2-hydroxyl-1-methyl-ethylamino)-pyridin-3-yl]-acid amides.

16. according to the compound of claim 1, wherein said compound be 2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl-acid amides.

17. according to the compound of claim 1, wherein said compound be 2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid 2-[(2-methoxyl group-ethyl)-methyl-amino]-pyrimidine-5-yl-acid amides.

18. according to the compound of claim 1, wherein said compound be 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazoles-4-formic acid 6-[(2-methoxyl group-ethyl)-methyl-amino]-pyridin-3-yl-acid amides.

19. according to the compound of claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazoles-4-formic acid (6-thiomorpholine-4-base-pyridin-3-yl)-acid amides.

20. one kind prepares according to each the method for compound of claim 1 to 19, this method comprises: with the compound of formula (II)

With formula R ⁷-NH ₂Compound reaction, R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷Each defines as claim 1 to 19.

21. by according to each compound of the claim 1 to 19 of the method for claim 20 preparation.

22. pharmaceutical composition, it comprises according to each compound and pharmaceutical carrier and/or assistant agent of claim 1 to 19.

23. according to each compound of claim 1 to 19, it is as therapeutic active substance.

24. according to each compound of claim 1 to 19, the treatment of diseases active substance that it is used for the treatment of and/or prevents to be regulated by diacylglycerol acyltransferase inhibitors.

25. one kind is used for the treatment of and/or the method for the disease that prophylactic treatment is regulated by diacylglycerol acyltransferase inhibitors; especially for the treatment of obesity for the treatment of and/or preventing property; the method of type ii diabetes and metabolism syndrome, this method comprise to human or animal's drug treatment significant quantity according to any one compound among the claim 1-19.

26. according to any one the application of compound in the disease that the treatment for the treatment of and/or preventing property is regulated by diacylglycerol acyltransferase inhibitors among the claim 1-19.

27. according to any one compound among the claim 1-19 in the treatment of obesity for the treatment of and/or preventing property, the application in type ii diabetes and the metabolism syndrome.

28. according among the claim 1-19 any one compound preparation be used for the treatment of and/or the medicine of the disease that prophylactic treatment is regulated by diacylglycerol acyltransferase inhibitors in application.

29. be used for the treatment of and/or the prophylactic treatment obesity application in the medicine of type ii diabetes and metabolism syndrome in preparation according to the compound of any one among the claim 1-19.

30. the present invention as defined above.