AU2008253118A1 - Diacylglycerol acyltransferase inhibitors - Google Patents

Diacylglycerol acyltransferase inhibitors Download PDF

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AU2008253118A1
AU2008253118A1 AU2008253118A AU2008253118A AU2008253118A1 AU 2008253118 A1 AU2008253118 A1 AU 2008253118A1 AU 2008253118 A AU2008253118 A AU 2008253118A AU 2008253118 A AU2008253118 A AU 2008253118A AU 2008253118 A1 AU2008253118 A1 AU 2008253118A1
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phenyl
carbonyl
trifluoromethyl
amino
oxazole
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AU2008253118A
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AU2008253118B2 (en
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David Robert Bolin
Adrian Wai-Hing Cheung
Fariborz Firooznia
Matthew Michael Hamilton
Lee Apostle Mcdermott
Yimin Qian
Jenny Tan
Weiya Yun
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Madrigal Pharmaceuticals Inc
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VIA Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 2008/141976 PCT/EP2008/055843 -1 DIACYLGLYCEROL ACYLTRANSFERASE INHIBITORS The invention relates to inhibitors of diacylglycerol acyltransferase. The inhibitors are useful for the treatment of diseases such as obesity, type II diabetes mellitus, 5 dyslipidemia and metabolic syndrome. Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major 10 functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270). Diacylglycerol 0-acyltransferase, also known as diglyceride acyltransferase or DGAT, is 15 a key enzyme in triglyceride synthesis. DGAT catalyzes the final and rate-limiting step in triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates. Thus, DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, 395-400). 20 DGAT has a specificity 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). DGAT activity levels increase in fat cells as they differentiate in vitro and recent evidence suggests that DGAT may be regulated in adipose tissue post-transcriptionally 25 (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 primarily expressed in the endoplasmic reticulum (see Colman, Methods in Enzymology (1992) 209, 98-104). In hepatocytes, DGAT activity has been shown to be expressed on both the WO 2008/141976 PCT/EP2008/055843 -2 cytosolic and luminal surfaces of the endoplasmic reticular 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, the regulation of triglyceride synthesis and partitioning, between retention as cytosolic droplets and secretion, is of primary 5 importance in 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 have been cloned and are designated DGAT1 and DGAT2 (see 10 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 substrates, there is no homology between DGAT1 and DGAT2. Both enzymes are widely expressed however some differences do exist in the relative 15 abundance of expression in various tissues. The gene encoding mouse DGAT1 has been used to create DGAT knock-out. 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 20 90). This would suggest that multiple catalytic mechanisms contribute to triglyceride synthesis, such as DGAT2. An alternative pathway has also been shown to form triglycerides from two diacylglycerols by the action of diacylglycerol transacylase (see Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210). 25 Dgat-/- mice are resistant to diet-induced obesity and remain lean. When fed a high fat diet, Dgat-/- mice maintain weights comparable to mice fed a diet with regular fat content. Dgat-/- mice have lower tissue triglyceride levels. The resistance to weight gain seen in the knockout mice, which have a slightly higher food intake, is due to an increased energy expenditure and increased sensitivity to insulin and leptin (see Smith et 30 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). Dgat-/- mice have reduced rates of triglyceride absorption, improved triglyceride metabolism, and improved glucose metabolism, with lower 35 glucose and insulin levels following a glucose load, in comparison to wild-type mice (see WO 2008/141976 PCT/EP2008/055843 -3 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 imbalances in triglyceride metabolism, both absorption as well as de novo 5 synthesis, have been implicated in the pathogenesis of a variety of disease risks. These include 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 10 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 decrease the synthesis of triglycerides from diacylglycerol by inhibiting or lowering the activity of the DGAT enzyme would be of value as therapeutic 15 agents for the treatment diseases associated with abnormal metabolism of triglycerides. Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack, et al, EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al, W02004047755), 20 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 25 Miyata, et al, JP 2004067635), aryl alkyl acid derivatives (see Smith et al, W02004100881 and US20040224997), furan and thiophene derivatives (see W02004022551), pyrrolo[1,2b]pyridazine derivatives (see Fox et al, W02005103907), and substituted sulfonamides (see Budd Haeberlein and Buckett, W020050442500). 30 Also known to be inhibitors of DGAT 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 (see Noriko et al, (Journal of Antibiotics (1999) 52, 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, 942-7), isochromophilone, 35 prenylflavonoids (see Chung et al, Planta Medica (2004) 70, 258-260), polyacetylenes WO 2008/141976 PCT/EP2008/055843 -4 (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 (see Ko, et al, Planta 5 Medica (2002) 68, 1131-1133). Also known to be modulators of DGAT activity are antisense oligonucleotides (see Monia and Graham, US20040185559). A need exits in the art, however, for additional DGAT inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, type II diabetes 10 mellitus and metabolic syndrome. Further, a need exists in the art for DGAT inhibitors having IC 50 values less than about 1 tiM. The present invention relates to DGAT inhibitors. In particular, the invention provides compounds of the formula (I): 15 R 1 -R 2 Q 3--R R 6 R5 C - N -X - R7 - Y- R 8 -C - Re H 11 o 0 (I), wherein:
R
1 is tert-butyl; phenyl optionally substituted with one to four substituents independently 20 selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and
-O-CF
3 ;
R
2 is C or N; 25 R 3 is C, N, O or S;
R
4 is C or N;
R
5 is C, N, O or S;
R
6 is halogen, lower alkyl, haloloweralkyl or alkoxy;
R
7 is N optionally substituted with lower alkyl; 30 0; or absent; WO 2008/141976 PCT/EP2008/055843 -5
R
8 is C optionally substituted with lower alkyl; N optionally substituted with lower alkyl; 0; or absent; 5 R 9 is lower alkyl; alkoxy; hydroxyl; amine; lower alkyl amine; 10 haloloweralkyl; lower alkoxy; lower alkenyloxy; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, 15 -C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl; 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -S0 2 -loweralkyl, -C(O)OH, -C(0)0-lower alkyl and -C(0)0-lower alkyl phenyl; 20 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, -C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl; 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, 25 -C(O)OH, -C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl;
-(CH
2 )nC(O)OH;
-CH
2 C(lower alkyl) 2 C(O)OH;
-CH
2 (cycloalkyl)C(0)OH; -(cycloalkyl)C(O)OH; 30 -CH 2
C(CH
3
)
3 ;
-(CH
2 )n-cycloalkyl; cycloalkenyl; bicycloalkenyl-C(0)OH;
-(CH
2 )n-O-alkyl; 35 -0-C(=C)-lower alkyl; WO 2008/141976 PCT/EP2008/055843 -6
-O-(CH
2 )n-phenyl;
-NSO
2 -loweralkyl;
-NSO
2 -cycloalkyl;
-NSO
2 -aryl; 5 -N-lower alkyl; -N-cycloalkyl optionally substituted with -C(O)OH; -N-heterocycloalkyl; -N-aryl;
-N-(CH
2 )n-aryl; 10 -N-heteroaryl optionally substituted with alkyl; -N-CH(lower alkyl)C(O)OH; -N-(cycloalkyl)C(O)OH; -N-CH(lower alkyl)C(O)O-lower alkyl; or phenyl-C(O)OH; 15 X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; Y is phenyl optionally substituted with one to four substituents independently 20 selected from lower alkyl, halogen and cyano; heteroaryl; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four 25 substituents independently selected from lower alkyl, halogen and cyano; or
-N(CH
2 )n 1 )N-; and n is 1, 2 or 3; or pharmaceutically acceptable salts thereof 30 In another embodiment of the present invention, provided is 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.
WO 2008/141976 PCT/EP2008/055843 -7 In a further embodiment of the present invention, provided is 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 5 As used herein, the term "alkyl" means, for example, a branched or unbranched, cyclic (i.e., "cycloalkyl") or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C 3 to C 1 2 , more preferably C 4 to Cio, more preferably C 4 to C 7 . Where 10 acyclic, the alkyl group is preferably C1 to CIO, more preferably C1 to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. It will be appreciated therefore that the term "alkyl" as used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), 15 substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl. In a preferred embodiment, the "cycloalkyl" moieties can optionally be substituted with 20 one, two, three or four substituents, wherein each substituent is independently, for example, hydroxy, alkyl, alkoxy, halogen or amino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, 25 optionally substituted cyclohexylene, optionally substituted cycloheptyl, optionally substituted adamantyl and the like or those which are specifically exemplified herein. The term "heterocycloalkyl" denotes a cyclic alkyl ring, wherein one, two or three of the carbon ring atoms is replaced by a heteroatom such as N, 0 or S. Examples of 30 heterocycloalkyl groups include, but are not limited to, morpholyl, thiomorpholyl, piperazyl, piperidyl, tetrahydrofuryl, pyrrolidyl, oxazolyl, 1H-pyrazolyl, 1H-tetrazolyl and the like. The heterocycloalkyl groups may be unsubstituted or substituted. As used herein, the term "lower alkyl" means, for example, a branched or unbranched, 35 cyclic (e.g., "cycloloweralkyl") or acyclic, saturated or unsaturated hydrocarbyl radical WO 2008/141976 PCT/EP2008/055843 -8 wherein said cyclic lower alkyl group is C 3 , C 4 , C 5 , C 6 or C 7 , and wherein said acyclic lower alkyl group is C1, 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 tertiary-butyl). It will be appreciated therefore that the term "lower alkyl" as used herein includes, for example, 5 lower alkyl (branched or unbranched) and cycloloweralkyl. As used herein, the term "aryl" means a carbocyclic aromatic group. Examples of aryl groups are phenyl, naphthyl and the like. A particularly preferred exemples of aryl is phenyl. 10 The term "heteroaryl", alone or in combination with other groups, means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, 0, and S, the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl 15 group. The heteroaryl group described above may be substituted independently with one, two, or three substituents, preferably one or two substituents such as, for example, halogen, hydroxy, C 1
-
6 alkyl, halo C 1
-
6 alkyl, C 1
-
6 alkoxy, C 1
-
6 alkyl sulfonyl, C 1
-
6 alkyl sulfinyl, C 1
-
6 alkylthio, amino, amino C 1
-
6 alkyl, mono- or di-substituted amino-C 1 -6 alkyl, nitro, cyano, oxo, acyl, carbamoyl, mono- or di-substituted amino, aminocarbonyl, 20 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 carboxyl C 1
-
6 alkoxy, preferably halogen, hydroxy, C 1
-
6 alkyl, halo C 1
-
6 alkyl, C 1
-
6 alkoxy, C 1
-
6 alkyl sulfonyl, C 1
-
6 alkyl 25 sulfinyl, 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, carboxyl, C 1
_
6 alkoxy carbonyl and cyano. Examples of heteroaryl are pyridyl, pyrimidyl, thiophenyl and tetrazolyl. 30 Preferred examples of 5- or 6-membered heteroaryl are pyridyl, pyrimidyl, thiophenyl, oxadiazolyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl and 1H-tetrazolyl. Preferred examples of 5- or 6-membered heterocycloalkyl are tetrahydrofuryl, pyrrolidyl, 35 piperidyl and piperazyl.
WO 2008/141976 PCT/EP2008/055843 -9 The alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substituents present, preferably 1 substituent. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, 5 arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, 10 alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), acids (e.g. 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), carbamates (e.g. alkoxycarbonylamino, 15 arloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (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), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides 20 and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, 25 pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, 30 pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, carbolinyl, pyrimidyl and tetrazolyl). The lower alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substitutents present, 35 preferably 1 substituent.
WO 2008/141976 PCT/EP2008/055843 - 10 As used herein, the term "alkoxy" means, for example, alkyl-O- and "alkoyl" means, for example, alkyl-CO-. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups. 5 As used herein, the term "halogen" means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical. 10 As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, 15 glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids, and most preferred is hydrochloric acid. Acceptable base salts 20 include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts. The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a 25 consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates. The compounds of formula I can contain several asymmetric centers and can be present 30 in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention the asymmetric carbon 35 atom can be of the "R" or "S" configuration.
WO 2008/141976 PCT/EP2008/055843 - 11 As used herein, the term "optionally substituted with one to four substituents" defines a group which has one to four substituents, preferably one to three, more preferably one to two, and even more preferably one. 5 Preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four 10 substituents independently selected from halogen, lower alkyl, alkoxy and
-O-CF
3 ; and wherein both R 7 and R 8 are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R 3 is C, N or S and R 5 is C, 0 or S. 15 Also preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four 20 substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; and wherein both R 7 and R 8 are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R 3 is C, N or S and R 5 is C, 0 or S. 25 Also preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four 30 substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
R
2 is C;
R
3 is 0;
R
4 is C; 35 R 5 is N; WO 2008/141976 PCT/EP2008/055843 - 12 and wherein both R 7 and R 8 are not absent. Also preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently 5 selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
R
2 is C; 10 R 3 is 0;
R
4 is C;
R
5 is N; and wherein both R 7 and R 8 are absent. 15 Preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 20 -0-CF 3 . Further preferred are compounds of formula (I) wherein R 1 is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 . 25 Preferred are compounds of formula (I) wherein R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 . 30 Preferred are compounds of formula (I) wherein R 1 is phenyl optionally substituted with halogen. Further preferred are compounds of formula (I) wherein R 1 is phenyl, fluorophenyl, chlorophenyl, bromophenyl, thiophenyl, pyridyl, trifluoromethoxyphenyl or tert-butyl. 35 WO 2008/141976 PCT/EP2008/055843 - 13 Preferred are compounds of formula (I) wherein R 1 is pyridyl optionally substituted with halogen. Most preferred are compounds of formula (I) wherein R 1 is phenyl. 5 Preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and X is 5- or 6-membered aryl optionally substituted with one to four substituents 10 independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein X is 5- or 6-membered aryl, preferably phenyl, optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 15 Preferred are compounds of formula (I) wherein X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 20 Preferred are compounds of formula (I) wherein X is phenyl, pyridyl or pyrimidyl and most preferred phenyl or pyridyl. Preferred are compounds of formula (I) wherein: Y is cycloloweralkyl optionally substituted with one to four substituents 25 independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein Y is phenyl, pyridyl, piperazyl, 30 piperidyl, pyrrolidyl or cyclopentyl, and most preferred phenyl, piperidyl or piperazyl. Preferred are compounds of formula (I) whereinY is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 35 Preferred are compounds of formula (I) wherein X and Y are unsubstituted.
WO 2008/141976 PCT/EP2008/055843 - 14 Preferred are compounds of formula (I) wherein:
R
1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and X is 5- or 6-membered optionally substituted with one to four substituents 5 independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein:
R
1 is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 10 -O-CF 3 ; and X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein: 15 R 1 is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and
-O-CF
3 ; and X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 20 Preferred are compounds of formula (I) wherein:
R
1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and Y is phenyl optionally substituted with one to four substituents independently 25 selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein:
R
1 is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 30 -O-CF 3 ; and Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein: WO 2008/141976 PCT/EP2008/055843 - 15 R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein:
R
1 is 5- or 6-membered heteroaryl optionally substituted with one to four 10 substituents independently selected from halogen, lower alkyl, alkoxy and
-O-CF
3 ; and Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four 15 substituents independently selected from lower alkyl, halogen and cyano. Preferred are compounds of formula (I) wherein: X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and 20 Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; heteroaryl; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; 25 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
-N(CH
2 )n)N. Preferred are compounds of formula (I) wherein: 30 X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; heteroaryl; WO 2008/141976 PCT/EP2008/055843 - 16 cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5 -N(CH 2 )n)N. Preferred are compounds of formula (I) wherein: X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 10 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 15 Preferred are compounds of formula (I) wherein: X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and 20 Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 25 Preferred are compounds of formula (I) wherein R 2 is N. Preferred are compounds of formula (I) wherein R 3 is N. Preferred are compounds of formula (I) wherein R 4 is N. Preferred are compounds of formula (I) wherein R 5 is N. Preferred are compounds of formula (I) wherein R 2 and R 3 are N. 30 Preferred are compounds of formula (I) wherein R 3 and R 4 are N. Preferred are compounds of formula (I) wherein R 2 , R 3 and R 5 are N. Preferred are compounds of formula (I) wherein one of R 3 or R 5 is N and the other is S. Also preferred are compounds of formula (I) wherein R 2 is N, R 3 is N, R4 is C and R 5 is 35 C.
WO 2008/141976 PCT/EP2008/055843 - 17 Also preferred are compounds of formula (I) wherein R 2 is N, R 3 is C, R4 is C and R 5 is S. Also preferred are compounds of formula (I) wherein R 2 is N, R 3 is N, R4 is C and R 5 is N. 5 Further preferred are compounds of formula (I) wherein R 2 is C, R 3 is 0, R4 is C and R 5 is N. Preferred are compounds of formula (I) wherein R 6 is halogen, trifluoromethyl, 10 trifluoroethyl, methyl, ethyl, propyl, methoxymethyl or methoxyethyl. Most preferred are compounds of formula (I) wherein R6 is trifluoromethyl. Preferred are compounds of formula (I) wherein R 7 is N optionally substituted with lower 15 alkyl. Preferred are compounds of formula (I) wherein R 8 is N optionally substituted with lower alkyl. 20 Preferred are compounds of formula (I) wherein:
R
9 is lower alkyl; alkoxy; hydroxyl; lower alkyl amine; 25 cycloloweralkyl optionally substituted with one to four substituents independently selected from loweralkyl, hydroxy, halogen, -C(O)OH, -C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl; 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, 30 -S0 2 -loweralkyl, -C(O)OH, -C(0)0-lower alkyl and -C(0)0-lower alkyl phenyl;
-(CH
2 )nC(O)OH;
-CH
2 C(lower alkyl) 2 C(O)OH;
-CH
2 (cycloalkyl)C(O)OH; 35 -(cycloalkyl)C(O)OH; WO 2008/141976 PCT/EP2008/055843 - 18 -NSO 2 -loweralkyl; -N-lower alkyl; -N-cycloalkyl optionally substituted with -C(O)OH; -N-CH(lower alkyl)C(O)OH; or 5 -N-(cycloalkyl)C(O)OH. Preferred are compounds of formula (I) wherein n is 1. Preferred are compounds of formula (I) wherein R 9 is hydroxyl, tert-butyl, carboxy-ethyl, 10 2,2-dimethyl-2-carboxy-ethyl, 2-cyclopentyl-2-carboxy-ethyl, 2-cyclohexyl-2 carboxyethyl, cyclopropyl, cyclopentenyl, tetrahydrofuryl, methoxy, ethoxy, isobutyloxy, methoxymethyl, trifluoromethyl, isopropyloxy, methyl, ethyl, propyl, butyl, 2,2 dimethyl-propyl, 2,2-dimethyl-propyloxy, 3,3-dimethyl-propyl, 4-methyl-pentanol, methyl-cyclopentyl, carboxy-cyclohexyl, methoxycarbonyl-cyclohexyl, carboxy 15 cyclopentyl, ethoxycarbonyl-cyclopentyl, methoxycarbonyl-cyclopentyl, N,N dimethylamino, tert.butoxy, benzyloxy, amino, butyl-amino, tert-butyl-amino, isopropenyloxy, propyl-amino, cyclohexyl-amino, cyclopentyl-amino, benzyl-amino, methyl-amino, isopropyl-amino, methyl-pyridyl-amino, N-ethyl-N-methyl-amino, -NH S0 2
-C(CH
3
)
3 , -NH-S0 2
-C
2
H
5 , -NH-S0 2
-CH
3 , 1H-tetrazolyl, 1H-tetrazolyl-methyl, 20 oxadiazolyl, carboxy-pyrrolidyl, carboxy-piperidyl, methoxycarbonyl-pyrrolidyl, methyl (2,4-dioxo-thiazolidyl), methane-sulfonyl-pyrrolidyl, dimethyl-sulfamoyl-pyrrolidyl, carboxy-adamantyl, hydroxy-isoxasolyl, cyclopentyl-methyl, 3-carboxy-2,2-dimethyl propyl, 2,2-diethyl-methoxycarbonyl-ethyl, 2-carboxy-1,2,2-trimethyl-cyclopentyl, carboxy-cyclobutyl, ethoxycarbonyl-methyl, methoxycarbonyl-methyl, carboxy-N 25 pyrolidyl, 2,2,2-trifluoro-ethyl, methyl-isoxazo lyl-amino, methoxycarbonyl-cyclopentyl amino, dihydroxy-cyclopentyl, methoxycarbonyl-isopropyl-methyl-amino, carboxy isopropy-methyl-amino, carboxy-piperidyl, N-((carboxy-cyclopropyl)-methyl)-amino, N ((carboxy-cyclobutyl)- methyl)-amino, N-((carboxy-cyclopentyl)-methyl)-amino, N ((carboxy-tert-butyl)-methyl)-amino, N-((carboxy-isobutyl)-methyl)-amino, N 30 benzyloxycarbonyl-pyrrolidyl, N-ethoxycarbonyl-pyrrolidyl, carboxy-methyl-piperidyl, carboxy-ethyl-piperidyl, carboxy-propyl-piperidyl, carboxy-oxazolyl-ethyl, N methanesulfonyl-pyrrolidyl or N-dimethylsulfamoyl-pyrrolidyl.
WO 2008/141976 PCT/EP2008/055843 - 19 Most preferred are compounds of formula (I) wherein R 9 is 2,2-dimethyl-2-carboxy ethyl, carboxy-cyclohexyl, carboxy-cyclopentyl, cyclopropyl or tert-butyl-sulfonyl amino. 5 Preferred examples of compounds of formula (I) are: (S)-3- {5-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2 ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester; (S)-3- {4-[(1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenylamino} pyrrolidine-1-carboxylic acid ethyl ester; 10 (S)-3- {5-[(1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-pyridin-2 ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester; (S)-3- {5-[(4-Methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin-2-ylamino } pyrrolidine-1-carboxylic acid ethyl ester; (S)-3- {5-[(4-Methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin-2-ylamino } 15 pyrrolidine-1-carboxylic acid tert-butyl ester; 4- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenyl} piperidine- 1 -carboxylic acid propylamide; 4- {4-[(5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-phenyl} -piperidine-1 carboxylic acid propylamide; 20 2-Pyridin-2-yl-4-trifluoromethyl-oxazole-5-carboxylic acid [6-(4-isobutylcarbamoyl phenyl)-pyridin-3-yl]-amide; 4-[4-(4- { [1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino} phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid; 4-(5 - { [1-(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -pyridin 25 2-yl)-benzoic acid; 1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(1 cyclopentanecarbonyl-piperidin-4-yl)-phenyl]-amide; 3 -Chloro-4-(5 - { [1-(4-fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4carbonyl] -amino} pyridin-2-yl)-benzoic acid; 30 trans-4- [4-(4- { [1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino} phenyl)-piperidine-1-carbonyl]-benzoic acid; pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(1 cyclopropanecarbonyl-piperidin-4-yl)-phenyl]-amide; 4'- { [1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazole-4-carbonyl] -amino } -biphenyl-4 35 carboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 20 (1R,2R)-2- {4'-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4 ylcarbamoyl} -cyclopentanecarboxylic acid; (IS,2S)-2- {4'-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4 ylcarbamoyl} -cyclopentanecarboxylic acid; 5 (S)-3-(5- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -pyrimidin-2-yloxy)-pyrrolidine- 1 -carboxylic acid ethyl ester; (S)-3- {5 -[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy} pyrrolidine-1-carboxylic acid ethyl ester; (S)-3-(4- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] 10 amino } -phenylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-isobutyryl-pyrrolidin-3 ylamino)-pyridin-3-yl]-amide; 2,2-Dimethyl-3- {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-yl}-propionic acid; 15 (S)-3-(5-{[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -pyridin-2-ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester; (S)-3- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino} pyrrolidine-1-carboxylic acid ethyl ester; (S)-3-(5- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] 20 amino } -pyrimidin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester; 2,2-Dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazin- 1 -yl)-butyric acid; trans-4-(4- {4- [(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; 25 (1R,2R)-2-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-cyclopentanecarboxylic acid; trans-4-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-cyclohexanecarboxylic acid; cis-4-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 30 piperidine-1-carbonyl)-cyclohexanecarboxylic acid; (IS,2S)-2- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4 carbonyl} -cyclopentanecarboxylic acid; (1R,2R)-2-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclopentanecarboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 21 cis-4-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; (1R,3S)-3-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; 5 2,2-Dimethyl-4-oxo-4- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-yl} -butyric acid; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-cyclopropylcarbamoyl phenyl)-pyridin-3-yl]-amide; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-methyl-propane-2 10 sulfonylaminocarbonyl)-piperidin- 1-yl]-phenyl} -amide; (S)-3- {4-[(1-Phenyl-3-trifluoromethyl- 1H-pyrazole-4-carbonyl)-amino]-phenoxy} pyrrolidine-1-carboxylic acid ethyl ester; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{4-[4-(1H-tetrazol-5-yl) cyclohexanecarbonyl]-piperazin- 1-yl} -phenyl)-amide; 15 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[4-(1H-tetrazol-5-yl) cyclohexanecarbonyl]-piperidin-4-yl} -phenyl)-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[4-(5-oxo-4,5-dihydro 1,2,4]oxadiazo 1-3 -yl)-cyclohexanecarbonyl] -piperidin-4-yl} -phenyl)-amide; 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H 20 1,2']bipyridinyl-4-carboxylic acid amide; [1 -(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperidine 1 -carbonyl)-piperidin-4-yl] -acetic acid; 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1 carbonyl)-piperidine-4-carboxylic acid; 25 1-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1 carbonyl)-pyrrolidine-3-carboxylic acid; 3-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine 1-carbonyl)-piperidin-4-yl]-propionic acid; 4-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine 30 1-carbonyl)-piperidin-4-yl]-butyric acid; (R)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yloxy} pyrrolidine-1-carboxylic acid ethyl ester; 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carbonyl)-piperidine-4-carboxylic acid ethyl ester; WO 2008/141976 PCT/EP2008/055843 - 22 1 -(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperidine-4 carbonyl)-piperidine-4-carboxylic acid; 1-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carbonyl)-piperidine-3-carboxylic acid ethyl ester; 5 1-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carbonyl)-piperidine-3-carboxylic acid; 2,2-dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-piperidin-1-yl)-butyric acid; 2,2-dimethyl-4-oxo-4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 10 amino] -phenoxy} -pyrrolidin- 1 -yl)-butyric acid; 4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} pyrrolidine-1-carbonyl)-trans-cyclohexanecarboxylic acid; 1-[2-oxo-2-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidin-1-yl)-ethyl]-cyclopentanecarboxylic acid; 15 2,2-dimethyl-4-(4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-amino]-phenyl} piperidin-1-yl)-4-oxo-butyric acid; (1R,2R)-2-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid; 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 20 carbonyl)-pyrrolidine-3-carboxylic acid methyl ester; hydrochloride; (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester; hydrochloride; (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid; 25 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carbonyl)-piperidine-2-carboxylic acid; hydrochloride; (iS,2S)-2-(4-{4-[(2-tert-butyl-5-methyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine 1-carbonyl)-cyclopentanecarboxylic acid; hydrochloride; 4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} 30 pyrrolidine-1-carbonyl)-cis-cyclohexanecarboxylic acid; 2-phenyl-thiazole-4-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl] piperazin-1-yl}-phenyl)-amide; hydrochloride; (iS,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 23 trans-4-(4- {3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carbonyl)-cyclohexanecarboxylic acid; trans-2- [methyl-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid; 5 (1R,2R)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid; (iS,2S)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid; (iS,2S)-2-(methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 10 tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamoyl)-cyclopentanecarboxylic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1-methanesulfonyl pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1-dimethylsulfamoyl pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 15 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1-methanesulfonyl pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1-dimethylsulfamoyl pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} 20 benzoyl)-cyclopentanecarboxylic acid methyl ester; 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} benzoyl)-cyclopentanecarboxylic acid; 3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy} piperidine-1-carboxylic acid ethyl ester; 25 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-propyl-1-methyl-ureido) piperidin-1-yl]-phenyl}-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(3 -ethyl-i -methyl-ureido) piperidin-1-yl]-phenyl}-amide; 2,2,N-trimethyl-N-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 30 phenyl} -piperidin-4-yl)-succinamic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-1H-tetrazol-5-yl-acetyl) piperazin-1-yl]-phenyl}-amide; 3-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1 carbonyl)-adamantane-1-carboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 24 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-acetyl) piperidin-4-yl]-phenyl}-amide; 1-methyl-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-cyclohexanecarboxylic acid; 5 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[2-(2,4-dioxo-thiazolidin-5 yl)-acetyl]-piperidin-4-yl}-phenyl)-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[3-(3-hydroxy-isoxazol-5 yl)-propionyl]-piperidin-4-yl}-phenyl)-amide; 2,2-dimethyl-4-oxo-4-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 phenoxy}-piperidin-1-yl)-butyric acid; 2,2-dimethyl-5-oxo-5-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-piperidin-1-yl)-pentanoic acid; and 3,3-dimethyl-5-oxo-5-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-piperidin-1-yl)-pentanoic acid. 15 Particularly preferred examples of compounds of formula (I) are: 2,2-Dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazin- 1 -yl)-butyric acid; 4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperazine- 1 20 carbonyl)-cyclohexanecarboxylic acid; (1R,2R)-2-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-cyclopentanecarboxylic acid; 4-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1 carbonyl)-cyclohexanecarboxylic acid; 25 4-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1 carbonyl)-cyclohexanecarboxylic acid; (IS,2S)-2- {4'-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4 carbonyl} -cyclopentanecarboxylic acid (or enantiomer); (1R,2R)-2-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 30 piperazine-1-carbonyl)-cyclopentanecarboxylic acid; 4-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperazine- 1 carbonyl)-cyclohexanecarboxylic acid; (1R,3S)-3-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 25 2,2-Dimethyl-4-oxo-4- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-yl} -butyric acid; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-cyclopropylcarbamoyl phenyl)-pyridin-3-yl]-amide; and 5 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-methyl-propane-2 sulfonylaminocarbonyl)-piperidin-1-yl]-phenyl}-amide. The invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt 10 thereof and a pharmaceutically acceptable carrier. The invention also relates to a method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof 15 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. Further, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and 20 materials are now described. Compounds of the present invention can be prepared beginning with commercially available starting materials and utilizing general synthetic techniques and procedures known to those skilled in the art. Outlined below are reaction schemes suitable for 25 preparing such compounds. Further exemplification is found in the specific examples listed below. Scheme 1 WO 2008/141976 PCT/EP2008/055843 - 26 Nr 0 N I CH O N-N N "' 0 iii v R ( C H O) ii O v 0 0 SN H 2 )n X Hal N
(RH
2 )M ' vi R2 0 Viii -Y R X Y N N / N NO' N / N N (CH O X I XII 02 Vii ix o.1 +10 x ~,-Y Hal N COOk (CH2)(CH/)r N N-- / YCOR -x '(CHn Nn \>-i O x T COO 0R' -x (CH2)n In Scheme 1, compound i (X and Y can be CH or N, Hal can be F, Cl, Br or I) can be 5 treated with various cyclic amines (ii, iv, vi, viii, x, xii) in the presence of base and WO 2008/141976 PCT/EP2008/055843 - 27 through nucleophilic aromatic substitution gave the corresponding nitro adduct (iii, v, vii, ix, xi, xiii). The resulting nitro compounds can be reduced to the corresponding amines by catalytic hydrogenation. Each arrow in Scheme 1 represents two individual reactions. 5 For the formation of compound iii, the cyclic amine can be 3-amino-pyrrolidine-1 carboxylic acid tert-butyl ester (compound ii, n=1) or 4-amino-piperidine-1-carboxylic acid tert-butyl ester (compound ii, n=2) and the exocyclic nitrogen can be alkylated or non-alkylated (compound ii, R=H or lower alkyl group). The configuration of 3-amino pyrrolidine can be (R) or (S)-stereoisomer. 10 When the cyclic amine is piperazine-1-carboxylic acid tert-butyl ester (compound iv), substitution and subsequent reduction will generate compound v. Alternatively, the cyclic amine can be pyrrolidin-3-yl-carbamic acid tert-butyl ester 15 (compound vi, n=1) or piperidin-4-yl-carbamic acid tert-butyl ester (compound vi, n=2) and the carbamate nitrogen can be alkylated or non-alkylated (compound vi, R=H or lower alkyl group). The stereochemistry of pyrrolidin-3-yl-carbamic acid tert-butyl ester can be (R) or (S)-configuration. 20 Additionally, the cyclic amine can also be a 4-substituted piperidine derivative as in compound viii for the preparation of compound ix (m=O or 1, R' can be methyl or ethyl). Applying the same methodology, compounds xi and xiii (n=1 or 2, R' can be methyl or ethyl) can be prepared by reacting compound i with the ester of amino-cycloalkyl 25 carboxylic acid (compound x) or the ester of pyrrolidine-3-carboxylic acid (compound xii, n=1). Scheme 2 WO 2008/141976 PCT/EP2008/055843 - 28 N O B - N N N X Hal xiv xv In Scheme 2, the cross-coupling of aryl halide (compound i, Hal can be Cl, Br or I) with a pinacol borate (compound xiv) can be accomplished through a palladium catalyzed 5 reaction according to known procedure (Tetrahedron Letters, 2000, 41, 3705). The pinacol borate (compound xiv) can be prepared from 4-trifluoromethylsulfonyloxy-3,6 dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as described in the literature (Synthesis, 1991, 11, 993). The nitro group and the olefin in the coupling product can both be hydrogenated to generate compound xv. 10 Scheme 3 N R R Aryl- ZO + Ay /l' N 0- ArylI i 0 xvi xvii xviii In Scheme 3, amide formation of an aryl-substituted five membered ring heterocyclic 15 carboxylic acid (compound xvi, where Z1 can be carbon or nitrogen, X 1 and Y 1 can be oxygen, nitrogen, or sulfur, R can be halogen, lower alkyl, fluorine substituted alkyl or alkoxy group) with an aryl amine xvii can be carried out by using general amide coupling methods such as acid chloride, mixed anhydride or coupling reagents. It is understood that a variety of coupling reagents such as EDCI, PyBroP* and many others can be 20 applied.
WO 2008/141976 PCT/EP2008/055843 - 29 The chemical structure of compound xvii is meant to encompass those represented by compounds iii, v, vii and xv with the different cyclic amines being represented by spacer Q. The nitrogen that links spacer Q and the tert-butyloxycarbonyl group can be part of the ring (e.g. compound v) or outside of the ring (e.g. compound vii). The tert 5 butyloxycarbonyl group in the coupling product can be cleaved under acidic condition to generate the corresponding amine xviii. In addition, heterocyclic carboxylic acid xvi can also be coupled with amine ix, xi and xiii under the same amide formation conditions. The esters of the amide coupling product 10 can further be hydrolyzed to generate the corresponding carboxylic acids. Scheme 4 R Ar''Z -- /NQ R' ' 0 // Q R Ary- if 0 Ax R'COCI or R'COOH l Ary Aryl\ Aryl
Z--
X 1 1 R R X' R 0 N 0 N 0 N R'NCOCI R'OCOCI | X Y or R'NCO X Y Q O, Q N R' IY - 0- 0 O xx xviii xx' //-E 0 or E xxii xxiii0 R Y ~ N AryZ 1 - Q E xxiv WO 2008/141976 PCT/EP2008/055843 - 30 The key intermediate xviii in Scheme 3 can be functionalized to form various amides, carbamates and ureas. As shown in Scheme 4, compound xviii can be treated with acyl chloride or carboxylic acid to form amide xix (R' can be cyclic or acyclic alkyl group). 5 For the formation of urea xx, compound xviii can be treated with isocyanate or alkylaminocarbonyl chloride. Finally, the reaction of xviii with alkoxycarbonyl chloride will generate carbamate xxi. To prepare amides with terminal carboxylic acids, xviii can be treated with anhydride 10 xxiii (E can be cyclic or acyclic alkyl group) to form carboxylic acid xxiv. In case when xxiii is not readily available, the direct coupling of xviii with dicarboxylic acid xxii using coupling reagents can also lead to xxiv. Alternatively, the dicarboxylic acid in xxii can be transformed to a mono-ester mono 15 carboxylic acid which can be coupled with xviii, and the cleavage of the resulting ester will generate compound xxiv. For compound xxii, when spacer E is cyclic, the dicarboxylic acid can be in cis or trans conformation. For cases where spacer E has stereogenic centers, single enantiomers of 20 compound xxiv can be prepared through chiral separation. Scheme 5 R /Y1 N_ AryI-Z / N AryI-Z l. OO + I*x 1 N Ay 1 COOH N Hal A O N xvi xxv xxvi X Hal B(OR")2 R' A xxvii R W Ary--Z N x 1 1 O v: R ' xxviii A W WO 2008/141976 PCT/EP2008/055843 - 31 Compounds with the structure xxviii, where a biarylamine is linked to a heterocyclic carboxylic acid through an amide linkage, can be prepared by using Suzuki coupling reactions. In Scheme 5, 5-amino-2-halogen substituted aromatic compound xxv (Hal=Cl, 5 Br or I, X and Y can be CH or N) can be coupled with aryl substituted heterocyclic carboxylic acid xvi using general amide coupling conditions as described above to generate compound xxvi. Suzuki coupling of xxvi with aryl boronic acid derivative xxvii (A can be CH or N, R'=H, halogen or simple alkyl, R"=H or alkyl, the boronic acid ester can also be cyclic such as pinocolate, W can be amide, carbamate, urea, ester or 10 carboxylic acid) will generate compound xxviii. Scheme 6 B(OR")2 N Hal A R W A W xxv xxvii R XXiX Aryl--Z 1 (j ' COOH xvi R Aryl-Z/ N xxviii A W 15 An alternative route to prepare compound xxviii is shown in Scheme 6. Compound xxv can be coupled with aryl boronic acid derivative xxvii first to form a biarylamine derivative xxix under Suzuki coupling conditions. The resulting biarylamine can then be reacted with heterocyclic carboxylic acid xvi under amide formation conditions to form 20 compound xxviii.
WO 2008/141976 PCT/EP2008/055843 - 32 Scheme 7 0 0 I -(CH,)n 0 0 N 0 O X Hal xxx 0 (CH 2 )n xxxi R AyArylZ O HO R RV /rl z.Y 1 lY 1 .
1 Arh 1 N Y 0 AryI-Z 1 0 (CH )n R 0 (CHN0 2~ ~ (CH2)n2) XXXIIIXXXII 5 Shown in Scheme 7 is a general method to prepare claimed compounds with an ether linkage. The hydroxyl substituted heterocycle xxx (n=1l or 2) can be reacted with aryl halide i in the presence of sodium hydride or 4-dimethylaminopyridie to generate an aryl ether xxxi. The nitro group in xxxi can be reduced and the resulting amine can be 10 coupled with heterocyclic carboxylic acid xvi to generate compound xxxii. The tert butyloxycarbonyl group in xxxii can be cleaved under acidic condition and the resulting amine can be functionalized to generate compound xxxiii, where R represents alkyl, alkoxy, cycloalkyl, and alkyllcycloalkyl with carboxylic acid. 15 In the practice of the method of the present invention, an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination. The compounds or compositions can thus be administered orally (e.g., buccal cavity), 20 sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. The 25 therapeutic composition can also be in the form of an oil emulsion or dispersion in WO 2008/141976 PCT/EP2008/055843 - 33 conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration. Useful pharmaceutical carriers for the preparation of the compositions hereof, can be 5 solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or 10 synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an 15 aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing 20 agents, 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. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient. 25 The invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following reactions: (a) the reaction of a compound according to formula
-R
2 R3 OH (Ia) 30 in the presence of of a compound according to formula WO 2008/141976 PCT/EP2008/055843 - 34 NO 2 - X - R7 - Y- R 8 -C - R 11 O (Ila); (b) the reaction of a compound according to formula
-
R
2 C OH (Ib) in the presence of a compound according to formula 5
NH
2 - X - R7 - Y- R 8 -C - R O (Ilb); (c) the reaction of a compound according to formula R5 C R 1
-R
2 Q0 Rs CN H -X-Hal (Ic) in the presence of a compound according to formula
B(OR)
2
-Y-R
8 -C-Re || 10 0 (I1c); wherein R 1 to R 9 , X and Y are as defined above, wherein Hal represents F, Cl, Br or I, and wherein R represents hydrogen, alkyl or cycloalkyl. The invention also relates to a compound of formula (I) for use as therapeutically active 15 substance. The invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 20 WO 2008/141976 PCT/EP2008/055843 - 35 The invention also relates to the use of a compound of formula (I) for the preparation of medicaments for the treatment or prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes. 5 The invention also relates to compounds of formula (I) for use as medicaments for the treatment and prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes. The invention also relates to a compound according of formula (I), when manufactured 10 according to a process according to the invention. The invention also relates to a method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a 15 patient in need thereof The dose of a compound of the present invention depends on a number of factors, such as, for example, the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the 20 attending physician or veterinarian. Such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein, and in the claims, as a "therapeutically effective amount". For example, the dose of a compound of the present invention is typically in the range of about 1 to about 1000 mg per day. Preferably, the therapeutically effective amount is in an amount of from about 1 mg to 25 about 500 mg per day. A compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: 30 WO 2008/141976 PCT/EP2008/055843 - 36 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg 5 Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg 10 A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg 15 Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg 20 The invention will now be further described in the Examples below, which are intended as an illustration only and do not limit the scope of the invention. 25 PART I: PREPARATION OF PREFERRED INTERMEDIATES Amines Preparation of (5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester o / 0 N N 30 N To a mixture of 2-chloro-5-nitropyridine (476 mg, 3.0 mmol) and 4-piperidine acetic acid methyl ester (471 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added diisopropylethylamine (1.0 mL, 5.74 mmol). The mixture was heated in a microwave at WO 2008/141976 PCT/EP2008/055843 - 37 120 C for 30 minutes. The mixture was evaporated to dryness and extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give (5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-acetic 5 acid methyl ester as a yellow solid. The NMR spectrum obtained on the sample is compatible with its structure. To a solution of (5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester (279 mg, 1 mmol) from above in a mixture of tetrahydrofuran (10 mL) and 10 methanol (50 mL) was added 10% palladium on carbon (50 mg). The mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated to give (5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester that was used in the next step without further purification. 15 Preparation of 2-(5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-2-methyl propionic acid ethyl ester N N O N o To a solution of diisopropylamine (7.64 mL, 54.5 mmol) in dry tetrahydrofuran (5 mL) at -78 0 C was added n-butyl lithium (2.5 M, 20 mL, 50.0 mmol). The mixture was stirred at 20 -65 0 C for 30 minutes. Then ethyl isobutyrate (6.09 mL, 45.6 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at -60 0 C for 45 minutes. To this solution was added 1-benzylpiperidone (6.15 g, 32.5 mmol) in 5 mL of tetrahydrofuran. The mixture was allowed to warm up to room temperature and stirred overnight. The mixture was quenched with ammonium chloride solution (30 mL) and extracted with ether (100 mL). 25 The organic layer was first washed with brine and then dried over sodium sulfate. Solvents were evaporated and the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2 methyl-propionic acid ethyl ester (5.87 g) as an oily material. The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C18H27NO3 30 (m/e) 305.43, obsd 306.2 (M+H). 2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester (3.24 g, 10.6 mmol) from above was dissolved in chloroform (13 mL) containing N,N- WO 2008/141976 PCT/EP2008/055843 - 38 dimethylformamide (34 tL). To this solution was added thionyl chloride (1.56 mL). The mixture was refluxed overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium hydroxide (IN) solution. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvents, the residue was 5 purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2 (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester (1.17 g) as an oily material. The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C18H25NO2 (m/e) 287.4, obsd 288.2 (M+H). 10 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester from above (1.15 g, 4.0 mmol) was dissolved in 50 mL of ethanol and 10% palladium on carbon (600 mg) was added. The mixture was hydrogenated at 50 psi for 20 hrs. The mixture was filtered and solvents were evaporated to give 2-methyl-2-piperidin-4-yl propionic acid ethyl ester (760 mg) as an oil. The NMR spectrum obtained on the sample 15 is compatible with its structure. LRMS calcd for C11H21NO2 (m/e) 199.29, obsd 200.1 (M+H). The above 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester (606 mg, 3.82 mmol) was mixed with 2-chloro-5-nitropyridine (760 mg, 3.82 mmol) in 10 mL of tetrahydrofuran. 20 To this solution was added diisopropylethylamine (1.33 mL). The mixture was heated in a microwave at 140 0 C for 30 minutes. Solvents were evaporated and the residue was extracted with methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro 25 2H-[1,2']bipyridinyl-4-yl)-propionic acid ethyl ester as a solid (1.13 g, 92%). The NMR spectrum obtained on the sample is compatible with its structure. With a method similar to that used for the preparation of (5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester above, 2-(5'-amino-3,4,5,6-tetrahydro 30 2H-[1,2']bipyridinyl-4-yl)-2-methyl-propionic acid ethyl ester was prepared from the hydrogenation of 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl) propionic acid ethyl ester. This compound was used in the next step without further purification.
WO 2008/141976 PCT/EP2008/055843 - 39 Preparation of 2-(5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-2-methyl propionic acid N N 0 \ No To a solution of 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl) 5 propionic acid ethyl ester (321 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and methanol (6 mL) was added sodium hydroxide solution (IN, 2 mL). The mixture was heated in a microwave at 140 0 C for 1.5 hr. The mixture was evaporated and the residue was dissolved in hot methanol and water. The clear solution was then acidified with IN hydrochloric acid (2.5 mL). The resulting pale yellow precipitate was filtered and dried 10 to give 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-propionic acid (210 mg). LC-MS calcd. for C14H19N304 (m/e) 293.1, obsd 294.1. With a method similar to that used for the preparation of (5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester above, 2-(5'-amino-3,4,5,6-tetrahydro 15 2H-[1,2']bipyridinyl-4-yl)-2-methyl-propionic acid was prepared from the hydrogenation of 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-propionic acid. This compound was used in the next step without further purification. Preparation of 3-(5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-2,2 20 dimethyl-propionic acid N N 0 0 To a solution of 3-(N-Boc-piperidine-4-yl)-propionic acid (4.0 g, 15.6 mmol) in ether (100 mL) was added a solution of diazomethane in ether (0.2 M, 100 ml) in portions until the solution became lightly yellow. The mixture was stirred at room temperature for 1 hr 25 and the solvents were evaporated to give 3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (4.2 g) as an oil. 3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (2.0 g, 7.38 mmol) from above was dissolved in tetrahydrofuran (50 mL). The solution was cooled to -78 0 C and sodium 30 bis(trimethylsilyl)amide (1.0 M, 9.0 mL) was added. The mixture was stirred at -78 0 C for 1 hr and methyl iodide (1.2 mL, 19.5 mmol) was added. The mixture was warmed to WO 2008/141976 PCT/EP2008/055843 - 40 room temperature and stirred for 2 hrs. The mixture was extracted with ether and washed with dilute hydrochloric acid. The organic layer was dried, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as an oil (789 5 mg). 2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (789 mg, 2.77 mmol) from above was dissolved in dry tetrahydrofuran (2 mL) and cooled to -78 0 C. To this solution was added lithium diisopropylamide (5.5 mmol, prepared from 10 diisopropylamine and n-butyl lithium). The mixture was stirred at -78 0 C for 1 hr and methyl iodide (0.7 mL, 11.24 mmol) was added. The mixture was stirred at -78 0 C for 2 hrs until complete consumption of the starting material. The mixture was treated with hydrochloric acid (IN, 10 mL) and extracted with ether. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvents, the residue 15 was purified using flash chromatography (eluting with hexanes and ethyl acetate) to give 2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as a colorless oil that slowly turned into a solid (598 mg). 2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (598 mg) from 20 above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The mixture was partitioned between ether and sodium hydroxide solution (IN). The organic layer was washed with brine and dried. Evaporation of solvents gave 2,2-dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (370 mg) as an oil. 25 2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140 0 C for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic 30 layer was washed with brine and dried. Solvents were evaporated and the residue was triturated with ether to give 2,2-dimethyl-3-(5'-nitro-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-yl)-propionic acid methyl ester (199 mg) as a crystalline material. The NMR spectrum obtained on the sample is compatible with its structure.
WO 2008/141976 PCT/EP2008/055843 - 41 2,2-Dimethyl-3 -(5'-nitro-3,4,5,6-tetrahydro-2H-[ 1,2']bipyridinyl-4-yl)-propionic acid methyl ester (199 mg, 0.62 mmol) from above was dissolved in tetrahydrofuran (2 mL). Then methanol (4 mL) and sodium hydroxide solution (IN, 2 mL) were added. The mixture was stirred and refluxed for 8 hrs. Solvents were evaporated and the residue was 5 dissolved in hot methanol. The solution was cooled to room temperature and hydrochloric acid (IN, 2 mL) was added. The resulting mixture was cooled in an ice bath and the solid was filtered and washed with water. The solid was dried in air to give 2,2 dimethyl-3-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-propionic acid (181.5 mg). The NMR spectrum obtained on the sample is compatible with its structure. LC-MS 10 calcd for C15H21N304 (m/e) 307.34, obsd 308.1 (M+H). With a method similar to that used for the preparation of (5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester above, 3-(5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl)-2,2-dimethyl-propionic acid was prepared from the 15 hydrogenation of 2,2-dimethyl-3-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl) propionic acid. This compound was used in the next step without further purification. Preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester N, 20 N N A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(-)-3-amino-pyrrolidine-1 carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate (14.5 g, 0.105 mol) in acetonitrile (50 mL) was heated at reflux for 24 h. The reaction was monitored by LCMS and additional (S)-(-)-3-amino-pyrrolidine- 1 -carboxylic acid tert-butyl ester was 25 added until the reaction was driven to completion. The reaction mixture was then filtered and concentrated to give (S)-3 -(5 -nitro-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N404 (m/e) 308, obsd 307.1(M-H). 30 A mixture of (S)-3 -(5 -nitro-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester (500 mg, 1.67 mmol), 10 % palladium on carbon (80 mg) in methanol (10 mL) was hydrogenated at 50 psi in a Parr Shaker at room temperature for 2 h. The reaction mixture was then filtered through a plug of celite and the filtration pad was washed with WO 2008/141976 PCT/EP2008/055843 - 42 ethyl acetate. The organic layers were collected and concentrated to give (S)-3-(5-amino pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (490 mg, crude) as a light red solid, which was directly used in the next step without further purification. 5 Preparation of (R)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester N N N With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-3 -(5 -nitro-pyridin-2 10 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-5 nitro-pyridine and (R)-(-)-3-amino-pyrrolidine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C14H20N404 (m/e) 308.3, obsd 309 (M+H). This material was a mixture of product and starting material (6:1 ratio) and was used in the next step without further purification. 15 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-3 -(5 -amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by the hydrogenation of (R)-3 -(5 -nitro-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert 20 butyl ester. This material was used in the next step without further purification. Preparation of [(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert butyl ester N N N N \ 0 25 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)- 1-(5 -nitro-pyridin-2 yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared from 2-chloro-5-nitro pyridine and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS calcd for C14H20N404 (m/e) 308.34, obsd 309 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 43 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)- 1-(5-amino-pyridin-2 yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of 5 (S)- 1-(5 -nitro-pyridin-2-yl)-pyrro lidin-3 -yl] -carbamic acid tert-butyl ester. This material was directly used in the next step without further purification. Preparation of [(R)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert butyl ester N N N QOX 10 0 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)- 1 -(5 -nitro-pyridin-2 yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared from 2-chloro-5 -nitro pyridine and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS calcd for 15 C14H20N404 (m/e) 308.34, obsd 309 (M+H). This material was a mixture of product and starting material (10:1 ratio) and was used in the next step without further purification. With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 20 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-1-(5-amino-pyridin-2 yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of (R)-1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification. 25 Preparation of racemic [1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester NN QOx N 0 WO 2008/141976 PCT/EP2008/055843 - 44 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic [1-(5-nitro pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from 2 chloro-5 -nitro-pyridine and racemic 3-(N-tert-butoxycarbonyl-N 5 methylamino)pyrrolidine. LCMS called for C15H22N404 (m/e) 322.37, obsd 323.1 (M+H). With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic [1-(5-amino 10 pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared by the hydrogenation of racemic [1 -(5 -nitro-pyridin-2-yl)-pyrrolidin-3 -yl] -methyl-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification. 15 Preparation of racemic 1-(5-amino-pyridin-2-yl)-pyrrolidine-3-carboxylic acid methyl ester N N N -0 o\ With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic 1-(5 -nitro-pyridin 20 2-yl)-pyrrolidine-3-carboxylic acid methyl ester was prepared from 2-chloro-5-nitro pyridine and racemic Pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C11H15N304 (m/e) 251.3, obsd 252 (M+H). With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 25 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic 1-(5-amino pyridin-2-yl)-pyrrolidine-3-carboxylic acid methyl ester was prepared by the hydrogenation of racemic 1-(5 -nitro-pyridin-2-yl)-pyrrolidine-3 -carboxylic acid methyl ester. This material was directly used in the next step without further purification. 30 Preparation of (1S,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 45 N N o.' 0- With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (iS,3S)-3-(5-nitro-pyridin 2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared from 2-chloro-5 5 nitro-pyridine and (iS,3S)-3-amniocyclopentanecarboxylic acid methyl ester hydrochloride salt. LCMS calcd for C12H15N304 (m/e) 265.3, obsd 266 (M+H). This material was a mixture of product and starting material (76:24 ratio) and was used in the next step without further purification. 10 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (IS,3 S)-3 -(5-amino pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by the hydrogenation of (IS ,3 S)-3-(5 -nitro-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester. This material was directly used in the next step without further purification. 15 Preparation of (1R,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic acid ethyl ester Nr N N With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 20 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1 R,3 S)-3-(5 -nitro-pyridin 2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared from 2-chloro-5 nitro-pyridine and (1R,3S)-3-amniocyclopentanecarboxylic acid methyl ester hydrochloride salt. LCMS calcd for C12H15N304 (m/e) 265.3, obsd 266 (M+H). 25 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1 R,3 S)-3 -(5-amino pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by the hydrogenation of (1R,3S)-3-(5-nitro-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester. This material was directly used in the next step without further purification. 30 WO 2008/141976 PCT/EP2008/055843 - 46 Preparation of 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester N N 0 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 5 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 5'-nitro-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester was prepared from 2-chloro-5 -nitro pyridine and piperidine-4-carboxylic acid ethyl ester. LCMS called for C13H17N304 (m/e) 279.3, obsd 280 (M+H). 10 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 5'-amino-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester was prepared by the hydrogenation of 5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester. This material was directly used in the next step without further purification. 15 Preparation of (S)-3-(5-amino-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester N N 0 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 20 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3-(5-nitro-pyrimidin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-5 nitro-pyrimidine and (S)-3 -amino-pyrrolidine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C13H19N504 (m/e) 309.3, obsd 310 (M+H). 25 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3 -(5 -amino-pyrimidin 2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by the hydrogenation of (S)-3 -(5 -nitro-pyrimidin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert butyl ester. This material was directly used in the next step without further purification.
WO 2008/141976 PCT/EP2008/055843 - 47 Preparation of 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester N N N NyO 5 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 4-(5-nitro-pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-nitro-pyridine and piperazine-1-carboxylic acid tert-butyl ester. LCMS called for C14H20N404 (m/e) 308.3, obsd 309 (M+H). This material was a mixture of product and starting material (5:2 10 ratio) and was used in the next step without further purification. With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 4-(5 -amino-pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester was prepared by the hydrogenation of 4-(5 15 nitro-pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester. This material was directly used in the next step without further purification. Preparation of (S)-3-(4-amino-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester 20 0 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2 ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester above, (S)-3-(4-nitro phenylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 1-fluoro 4-nitrobenzene and (S)-3 -amino-pyrro lidine- 1 -carboxylic acid tert-butyl ester. LCMS 25 calcd for C15H21N304 (m/e) 307.4, obsd 306.2 (M-H). (S)-3-(4-nitro-phenylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester was deprotected with trifluoroacetic acid according to known procedures. After concentration, the amine trifluoroacetate salt was treated with ethyl chloroformate (1 equiv.) and WO 2008/141976 PCT/EP2008/055843 - 48 triethylamine (3 equiv.) in methylene chloride to afford (S)-3-(4-nitro-phenylamino) pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C13H17N304 (m/e) 279.3, obsd 280.1 (M+H). 5 With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3-(4-amino phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester was prepared by the hydrogenation of (S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester. This material was directly used in the next step without further purification. 10 Preparation of [4-(4-amino-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester N N N4O With a method similar to that used for the preparation of (S)-3-(4-amino-phenylamino) pyrrolidine-1-carboxylic acid ethyl ester, [4-(4-amino-phenylamino)-cyclohexyl] 15 carbamic acid tert-butyl ester was prepared from (4-amino-cyclohexyl)-carbamic acid tert-butyl ester and 1-fluoro-4-nitro-benzene. LCMS calcd for C17H27N302 m/e 305.2, obsd 306 (M+H). Preparation of (S)-3-[(5-amino-pyridin-2-yl)-methyl-amino]-pyrrolidine-1 20 carboxylic acid tert-butyl ester N N To a solution of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert butyl ester described previously (300 mg, 0.97 mmol) in tetrahydrofuran cooled at 0 0 C was added sodium hydride (47 mg, 1.95 mmol) gradually. The mixture was stirred at 25 room temperature for 15 min followed by the addition of methyl iodide (166 mg, 1.17 mmol). The reaction mixture was stirred for 2 h and then extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-3 -[(5 -nitro-pyridin-2-yl)-methyl-amino] -pyrrolidine- 1 carboxylic acid tert-butyl ester (295 mg, crude) as a yellow solid, which was directly WO 2008/141976 PCT/EP2008/055843 - 49 used in the next step without further purification. LCMS called for C15H22N404 (m/e) 322, obsd 323 (M+H). With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 5 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3 - [(5-amino-pyridin-2 yl)-methyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by the hydrogenation of (S)-3 -[(5 -nitro-pyridin-2-yl)-methyl-amino] -pyrrolidine- 1 -carboxylic acid tert-butyl ester. This material was directly used in the next step without further purification. 10 Preparation of 4-(2-cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 00 N A solution of 2-fluoro-5-nitrobenzonitrile (500 mg, 3.0 mmol) in ethanol (35 mL) was 15 treated with potassium carbonate (420 mg, 3.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (560 mg, 3.0 mmol). The reaction mixture was stirred at 80 0 C for 1 h, then cooled and partitioned between ethyl acetate and water. The organic layer was then collected, dried over sodium sulfate, filtered and evaporated to a yellow residue. Purification using flash chromatography yielded 4-(2-cyano-4-nitro-phenyl)-piperazine 20 1-carboxylic acid tert-butyl ester (590 mg, 59% yield) as a bright yellow solid. HRMS calcd for C16H20N404 (M+Na) 355.1377, obsd 355.1376. Preparation of 4-(5-amino-pyridin-2-ylamino)-piperidine-l-carboxylic acid tert butyl ester 0 25 N N A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1 carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in N,N dimethylformamide (30 mL) was stirred at 90 0 C for 14 h. The reaction mixture was then partitioned between water and ethyl acetate, and the two layers were separated. The WO 2008/141976 PCT/EP2008/055843 - 50 aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give 7.15 g (90 %) 4-(5-nitro-pyridin-2 ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS calcd for 5 C15H22N404 (m/e) 322, obsd 323 (M+H). With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 4-(5 -amino-pyridin-2 ylamino)-piperidine- 1 -carboxylic acid tert-butyl ester was prepared by the hydrogenation 10 of 4-(5 -nitro-pyridin-2-ylamino)-piperidine- 1 -carboxylic acid tert-butyl ester. This material was directly used in the next step without further purification. Preparation of (5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-methyl carbamic acid tert-butyl ester N N N N 15 A mixture of 2-bromo-5-nitro-pyridine (4.74 g, 23.3 mmol), methyl-piperidin-4-yl carbamic acid tert-butyl ester (5 g, 23.3 mmol), and triethylamine (5 mL) in N,N dimethylformamide (30 mL) was stirred at 90 0 C for 14 h. Upon completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The 20 aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from methanol and water to give methyl (5'-nitro-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-yl)-carbamic acid tert-butyl ester (6.7 g, 85.5%) as brown crystals. LCMS calcd for C16H24N404 (m/e) 336, obsd 337 (M+H). 25 A solution of methyl (5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-carbamic acid tert-butyl ester (1.4 g, 4.2 mmol) in ethyl acetate (5 mL) in the presence of 10% palladium on carbon (0.15 g) was shaken under 40 psi of hydrogen at room temperature for 2 h. The reaction mixture was filtered through a plug of celite and the filtration pad 30 was washed with ethyl acetate. The combined washings were concentrated and dried to give 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-methyl-carbamic acid tert- WO 2008/141976 PCT/EP2008/055843 - 51 butyl ester (1.25 g, 98%) as a brown solid. This material was used in the next step without further purification. Preparation of (S)-3-(5-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylic acid tert 5 butyl ester 0_ OO N N A solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.67 mmol) in anhydrous tetrahydrofuran (10 mL) was added to sodium hydride (60% in mineral oil, 215 mg, 5.34 mmol) gradually, and the resulting mixture was stirred at room 10 temperature for 1 h. 2-Chloro-5-nitropyridine (425 mg, 2.68 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h, then quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to afford (S)-3-(5 -nitro-pyridin-2-yloxy)-pyrro lidine- 1 -carboxylic acid tert-butyl ester as a brown oil (800 mg, 98% yield). The NMR spectrum obtained on the 15 sample is compatible with its structure. Preparation of (S)-3-(4-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester 0.,. + N 00 0 0 20 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester, (S)-3-(4-nitro-phenoxy)-pyrrolidine-1 carboxylic acid tert-butyl ester was prepared from (S)-3-hydroxy-pyrrolidine-1 carboxylic acid tert-butyl ester and 1-fluoro-4-nitrobenzene. The NMR spectrum 25 obtained on the sample is compatible with its structure. Preparation of (S)-3-(5-nitro-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid tert butyl ester WO 2008/141976 PCT/EP2008/055843 - 52 N 0 0 0 With a method similar to that used for the preparation of (S)-3-(5-nitro-pyridin-2-yloxy) pyrrolidine- 1 -carboxylic acid tert-butyl ester, (S)-3 -(5 -nitro-pyrimidin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from (S)-3-hydroxy 5 pyrrolidine-1-carboxylic acid tert-butyl ester and 2-fluoro-5-nitropyrimidine. The NMR spectrum obtained on the sample is compatible with its structure. Preparation of (2-amino-ethyl) methyl carbamic acid ethyl ester trifluoroacetate salt N N 10 0 To a solution of N-tert-butoxycarbonyl-2-methylamino-ethylamine hydrochloride salt (1 g, 4.7 mmol) in methylene chloride (30 mL) was added triethylamine (1.63 mL), followed by ethyl chloroformate (450 tL, 4.7 mmol). The reaction mixture was allowed 15 to stir at room temperature overnight. After solvent removal, the residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The resulting material was treated with trifluoroacetic acid without further purification. The reaction mixture was stirred at room temperature for 1 h and concentrated to yield (2-amino ethyl) methyl carbamic acid ethyl ester trifluoroacetate salt which was carried on to the 20 next step without further purification. Preparation of racemic trans-2-(4'-amino-biphenyl-4-carbonyl) cyclopentanecarboxylic acid 0 0 N O0 \ / 0 25 A mixture of 4-aminophenylboronic acid hydrochloride (0.21 g, 1.2 mmol), trans-2-(4 bromo-benzoyl)-cyclopentanecarboxylic acid (0.30 g, 1 mmol), tetrakis(triphenylphosphine) palladium (0) (10 mg), 2 M aqueous sodium carbonate solution (0.5 mL), ethanol (2 mL), and ethylene glycol dimethyl ether (3 mL) was heated WO 2008/141976 PCT/EP2008/055843 - 53 under microwave condition to 160 0 C for 30 min. The crude reaction mixture was adsorbed onto silica gel and flash chromatography (eluting with ethyl acetate and hexanes) yielded 0.2 g of trans-2-(4'-amino-biphenyl-4-carbonyl) cyclopentanecarboxylic acid as a brown solid. LCMS calcd for C19H19NO3 (m/e) 309, 5 obsd 310 (M+H). Preparation of trans-2-(4'-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid
-
0 V o
N
With a method similar to that used for the preparation of trans-2-(4'-amino-biphenyl-4 10 carbonyl)-cyclopentanecarboxylic acid, trans-2-(4'-amino-biphenyl-4-carbonyl) cyclohexanecarboxylic acid was prepared from 4-aminophenylboronic acid hydrochloride and trans-2-(4-bromo-benzoyl)-cyclohexanecarboxylic acid. LCMS calcd for C20H21NO3 (m/e) 323, obsd 324 (M+H). 15 Preparation of 4-(5-amino-pyridin-2-yl)-N-isobutyl-benzamide N N - N 0 With a method similar to that used for the preparation of trans-2-(4'-amino-biphenyl-4 carbonyl)-cyclopentanecarboxylic acid, 4-(5 -amino-pyridin-2-yl)-N-isobutyl-benzamide was prepared from 5-amino-2-bromopyridine and 4 20 (isobutylaminocarbonyl)benzeneboronic acid. LCMS calcd for C16H19N30 (m/e) 269, obsd 270 (M+H). Acids Preparation of rac-trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester 0
--
25
O
WO 2008/141976 PCT/EP2008/055843 - 54 A solution of trans-DL-cyclopentane-1,2-dicarboxylic acid (316 mg, 2 mmol) in 25 mL ethanol was saturated with hydrogen chloride gas by bubbling for 5 minutes. The mixture was heated under reflux overnight, cooled and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, 5 filtered and evaporated to dryness under vacuum to give rac-trans-cyclopentane-1,2 dicarboxylic acid diethyl ester (393 mg) that was used in the next step without further purification. To a solution of rac-trans-cyclopentane-1,2-dicarboxylic acid diethyl ester (393 mg, 1.84 10 mmol) was added a solution of lithium hydroxide (75.5 mg, 1.8 mmol) in water (7 mL). The reaction mixture was stirred at room temperature for 30 minutes and then heated to 55 0 C for 1 hr. The reaction mixture was cooled and evaporated under reduced pressure. The residue was dissolved in 25 mL water and washed with diethyl ether (2 x 5 mL). The pH of the aqueous layer was adjusted to pH 5 with IN hydrochloric acid and extracted 15 with methylene chloride (2 x 5 mL) and ethyl acetate (5 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give rac-trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester (95 mg) that was used without further purification. 20 Preparation of 2,2-diethyl-succinic acid 1-methyl ester 0 0 With a method similar to that used for the preparation of rac-trans-cyclopentane-1,2 dicarboxylic acid monoethyl ester, 2,2-diethyl-succinic acid 1-methyl ester was prepared from 2,2-diethyl-succinic acid. This material was used in the next step without further 25 purification. Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid / F
-
F 0 0 WO 2008/141976 PCT/EP2008/055843 - 55 A mixture of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans 5 N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at 1 10 C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0 -> 30% ethyl acetate/hexanes) to give 1 10 phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.91 g, 85%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 15 g, 4.4 mmol) and IN aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH ~1 with IN aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3 20 trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C 1H7F3N202 (m/e) 256, obsd 255 (M-H). Preparation of 1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid FQ _ r F F F N N F - F 0 25 0 With a method similar to that used for the preparation of 1-phenyl-3-trifluoromethyl-1H pyrazole-4-carboxylic acid above, 1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carboxylic acid was prepared from 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester and 1-fluoro-4-iodobenzene. LCMS calcd for C 1H6F4N202 (m/e) 274, obsd 30 273 (M-H). Preparation of 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid WO 2008/141976 PCT/EP2008/055843 - 56 CI F N "N F F - F 0 0 With a method similar to that used for the preparation of 1-phenyl-3-trifluoromethyl-1H pyrazole-4-carboxylic acid above, 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carboxylic acid was prepared from 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 5 ethyl ester and 1-chloro-2-iodobenzene. LCMS called for C1H6ClF3N202 (m/e) 290, obsd 289 (M-H). Preparation of 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid N N F - F 0 0 10 With a method similar to that used for the preparation of 1-phenyl-3-trifluoromethyl-1H pyrazole-4-carboxylic acid above, 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4 carboxylic acid was prepared from 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester and 2-bromopyridine. LCMS calcd for C10H6F3N302 (m/e) 257, obsd 258 (M+H). 15 Preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid F FF N 0 0 To a mixture of 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 2.31 mmol) in N,N-dimethylformamide (30 mL) at 0 0 C was added sodium hydride (60% in mineral 20 oil, 110 mg, 2.75 mmol). The mixture was stirred at 0 0 C for 10 minutes and stirred at room temperature for 40 minutes. After the reaction mixture was re-cooled to 0 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 up to room temperature and stirred overnight. The reaction was quenched carefully with ice water and neutralized with IN aqueous WO 2008/141976 PCT/EP2008/055843 - 57 hydrochloric acid. The mixture was extracted with methylene chloride and the organic layer was dried over sodium sulfate. Filtration and concentration gave a crude which was purified by silica gel chromatography (Isco 120 g column, 10% ethyl acetate/hexanes) to give 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 5 mg, 52%) as a white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 1.21 mmol) and IN aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) in 10 methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH ~ 2 with IN aqueous hydrochloric acid and concentrated to give 5 phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C12H9F3N202 (m/e) 270, obsd 271 (M+H). 15 Preparation of 5-phenyl-2-propyl-2H-pyrazole-3-carboxylic acid / \' N N 0 0 With a method similar to that used for the preparation of 5-phenyl-2-(2,2,2-trifluoro ethyl)-2H-pyrazole-3-carboxylic acid above, 5-phenyl-2-propyl-2H-pyrazole-3 20 carboxylic acid was prepared from 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester and 1-iodopropane. LCMS calcd for C13H14N202 (m/e) 230, obsd 229 (M-H). Preparation of 2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carboxylic acid / N 0 0 0 25 With a method similar to that used for the preparation of 5-phenyl-2-(2,2,2-trifluoro ethyl)-2H-pyrazole-3-carboxylic acid above, 2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole 3-carboxylic acid was prepared from 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 58 and 1-iodo-2-methoxy-ethane. LCMS called for C13H14N203 (m/e) 246, obsd 245 (M H). Preparation of 2-propyl-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid / \N SN 0 5 0 With a method similar to that used for the preparation of 5-phenyl-2-(2,2,2-trifluoro ethyl)-2H-pyrazole-3-carboxylic acid above, 2-propyl-5-thiophen-2-yl-2H-pyrazole-3 carboxylic acid was prepared from 5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester and 1-iodo-propane. LCMS called for Cl 1H12N202S (m/e) 236, obsd 235 (M-H). 10 Advanced Intermediates Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1 yl-pyridin-3-yl)-amide; hydrochloride F F N IF -NN N N 0 C N N 15 4-(5 -Amino-pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester described above was mixed with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3.0 mmol) and bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0 mmol) in N,N-dimethylformamide (20 mL) and methylene chloride (5 mL) containing triethylamine (0.85 mL). The mixture was stirred at room temperature overnight and the 20 solvents were evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and solvent was evaporated. The residue was triturated with ethyl acetate and the solid was filtered to give 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.09 g). LC-MS calcd for C25H26F3N504 (m/e) 517.5, obsd 518.1 25 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} -piperazine 1-carboxylic acid tert-butyl ester (300 mg, 0.58 mmol) from above was suspended in WO 2008/141976 PCT/EP2008/055843 - 59 methylene chloride (5 mL) and methanol (5 mL). To this mixture was added hydrogen chloride in ether (4N, 3 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with dry ether and then filtered to give a hydrochloride salt of 2-phenyl-5 5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (274 mg). LC-MS calcd C20H18F3N502 (m/e) 417.39, obsd 418.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1 10 yl-pyrimidin-5-yl)-amide; hydrochloride F F S N N N CI N To a solution of 4-(5-nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-piperazine) in tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon 15 (240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-amino pyrimidin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester. To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3 20 mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0 mmol) and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The residue was treated with benzene (5 mL) and the solvents were again evaporated. The oily residue was dried in vacuum and then dissolved in methylene chloride (10 mL). The solution was cooled in an ice bath. To this 25 solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL). The mixture was stirred at 0 0 C for 10 minutes and room temperature for 2 hrs. After concentration, the residue was partitioned between methylene chloride and water. The organic layer was washed with aqueous citric acid solution and dried over sodium 30 sulfate. The solvents were evaporated and the residue was dried in vacuum. The resulting material was triturated with ethyl acetate and the precipitate was filtered to give 4- {5-[(2- WO 2008/141976 PCT/EP2008/055843 - 60 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl} -piperazine- 1 carboxylic acid tert-butyl ester (1.38 g). LC-MS called for C24H25F3N604 (m/e) 518.5, obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 5 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide above, hydrochloride salt of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl pyrimidin-5-yl)-amide was prepared from 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 10 carbonyl)-amino] -pyrimidin-2-yl} -piperazine- 1 -carboxylic acid tert-butyl ester. LC-MS calcd for the free base C19H17F3N602 (m/e) 418.39, obsd 419.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4 15 yl-phenyl)-amide F F o F N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2 phenyl-5-trifluoromethyloxazole-4-carboxylic acid and 4-(4-aminophenyl)-piperidine-1 carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is compatible with its structure. 25 4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperidine-1 carboxylic acid tert-butyl ester (245 mg, 0.475 mmol) from above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature and the solvents were evaporated. The residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The organic layer was washed 30 with brine and dried over sodium sulfate. Evaporation of solvents gave 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (183 mg) as a WO 2008/141976 PCT/EP2008/055843 - 61 white solid. LC-MS called for C22H20F3N302 (m/e) 415.41, obsd 416.0. The NMR spectrum obtained on the sample is compatible with its structure. Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 5 (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide F F ON F N 0 N N 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (prepared according to known procedures Synthesis, 1991, 11, 993) was reacted with bis(pinacolato)diboron to generate N-tert-butoxycarbonyl- 1,2,3,6 10 tetrahydropyridine-4-boronic acid pinacol ester according to literature procedures (Tetrahedron Letters, 2000, 41, 3705). To a mixture of 2-bromo-5-nitropyridine (0.5 g, 2.46 mmol) and N-tert-butoxycarbonyl 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.913 g, 2.95 mmol) in toluene 15 (4 mL) and ethanol (1.0 mL) was added potassium carbonate solution (2M, 2 mL) and PdCl 2 dppf (180 mg, 0.246 mmol). The mixture was degassed with argon and heated to 100 0 C in a microwave for 40 minutes with stirring. The solvents were evaporated and the residue was extracted with ethyl acetate. After evaporation of the solvents, the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 20 5 -nitro-3',6'-dihydro-2'H- [2,4']bipyridinyl- '-carboxylic acid tert-butyl ester as a solid (400 mg). The NMR spectrum obtained on the sample is compatible with its structure. 5 -nitro-3',6'-dihydro-2'H- [2,4']bipyridinyl- '-carboxylic acid tert-butyl ester (400 mg) from above was dissolved in methanol (50 mL) and tetrahydrofuran (10 mL). To this 25 mixture was added 10% palladium on carbon (100 mg). The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered and the solvents were evaporated to give 5 amino-3',4',5',6'-tetrahydro-2'H- [2,4']bipyridinyl- '-carboxylic acid tert-butyl ester as a white solid (363 mg). The NMR spectrum obtained on the sample is compatible with its structure. 30 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic WO 2008/141976 PCT/EP2008/055843 - 62 acid tert-butyl ester above, 5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-l'-carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid and 5 -amino-3',4',5',6' tetrahydro-2'H-[2,4']bipyridinyl-l'-carboxylic acid tert-butyl ester. The NMR spectrum 5 obtained on the sample is compatible with its structure. 5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3',4',5',6'-tetrahydro-2'H [2,4']bipyridinyl-l'-carboxylic acid tert-butyl ester (535 mg) from above was dissolved in a mixture of methylene chloride (35 mL) and trifluoroacetic acid (9 mL). The mixture 10 was stirred at room temperature for 2 hrs. The solvents were evaporated and the residues were partitioned between methylene chloride and dilute sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of solvents gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1',2',3',4',5',6' hexahydro-[2,4']bipyridinyl-5-yl)-amide (360 mg) as a solid. LC-MS calcd for 15 C21H19F3N402 (m/e) 416.1, obsd 417.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1 yl-phenyl)-amide F F oN F o N N 20 N A solution of di-tert-butyldicarbonate (5.79 g, 26.5 mmol) in 20 mL dioxane was added dropwise to a solution of 1-(4-nitro-phenyl)-piperazine (5 g, 24.1 mmol) in 150 mL dioxane and stirred at room temperature for 1 hr. The reaction mixture was diluted with 250 mL ethyl acetate, washed with water, dried over sodium sulfate and filtered. The 25 organic filtrate was evaporated under reduced pressure to yield 7.9 g of 4-(4-nitro phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the next step without further purification. A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3 g, 9.76 30 mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl acetate was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2 hrs. The reaction mixture was filtered through a plug of Celite and evaporated under reduced WO 2008/141976 PCT/EP2008/055843 - 63 pressure to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the in the next step without further purification. 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.5 g, 9.76 mmol), 4-(4-amino 5 phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.65 g, 10.34 mmol), and triethylamine (4.1 mL, 29.3 mmol) were dissolved in 50 mL of 1-methyl-2 pyrrolidinone. To this solution was added (benzotriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 4.51 g, 10.34 mmol) in one portion. The mixture was stirred at room temperature overnight and then diluted 10 with 250 mL of ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (2 x 50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by chromatography over a silica gel plug (eluting with ethyl acetate/methylene chloride) to yield 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid tert 15 butyl ester as an amorphous solid. ES-MS calcd for C26H27F3N404 (m/e) 516.52, obsd 517 (M+H). With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide above, 20 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carboxylic acid tert-butyl ester. LC-MS calcd. for C2 1 Hi 9F3N402 (m/e) 416.1, obsd 417.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-cyano-4 piperazin-1-yl-phenyl)-amide F F tF N N N N N 4-(2-Cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (587 mg, 1.77 30 mmol) was dissolved in methanol (50 mL) and to this solution was added ammonium chloride (945 mg, 17.66 mmol) and zinc (1155 mg, 17.66 mmol). The mixture was WO 2008/141976 PCT/EP2008/055843 - 64 magnetically stirred for 3 hr and the mixture was filtered through a pad of celite. The solids were rinsed with methanol and the combined filtrate was concentrated to a yellow solid. This crude intermediate was dissolved in ethyl acetate (400 mL) and the resulting solution was washed with water (400 mL) and brine (200 mL). The organic layer was 5 collected, dried over sodium sulfate, and concentrated to give 4-(4-amino-2-cyano phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the next step without further purification. Crude 4-(4-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester from 10 above was dissolved in methylene chloride (10 mL) and to the resulting solution was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg), triethylamine (247 tL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 337 mg). The reaction mixture was stirred at room temperature for 3 hr. Another portion of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. 15 The reaction mixture was stirred at 50'C for 3 hr and at room temperature for 3.5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded 4- {2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 25 % 20 yield) as a yellow solid. LCMS calcd for C27H26F3N504 (m/e) 541, obsd 542 (M+H). With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-cyano-4-piperazin-1-yl 25 phenyl)-amide was prepared from 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C22H18F3N502 (m/e) 441, obsd 442 (M+H). Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin 30 4-ylamino)-pyridin-3-yl]-amide trifluoroacetate salt O F F F F 0 F 0 F N N
N
WO 2008/141976 PCT/EP2008/055843 - 65 A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.67 g, 2.6 mmol), 4-(5 -amino-pyridin-2-ylamino)-piperidine- 1 -carboxylic acid tert-butyl ester (0.76 g, 2.6 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop, 1.45 g, 3.1 mmol), and diisopropylethylamine (0.9 mL, 5.2 mmol) in anhydrous dichloromethane 5 (15 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, eluted with ethyl acetate and hexane) to give 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.78 g, 56 %) as a white solid. LCMS calcd for C26H28F3N504 (m/e) 531, obsd 532 10 (M+H). With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin 15 3-yl]-amide trifluoroacetate salt was prepared from 4-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester. LCMS calcd for C21H20F3N502 (m/e) 431, obsd 432 (M+H). Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 20 methylamino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate salt F F N F F N N N A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.91 g, 3.54 mmol), 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl 25 ester (1.25 g, 4 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop, 1.86 g, 4 mmol), and diisopropylethylamine (0.8 mL, 4.6 mmol) in anhydrous dichloromethane (15 mL) was stirred at room temperature overnight. After concentration, the crude was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a solid. 30 The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 WO 2008/141976 PCT/EP2008/055843 - 66 mesh, 0%-100% ethyl acetate in hexane) to give methyl-{5'-[(2-phenyl-trifluoromethyl oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid tert-butyl ester in quantitative yield (1.9 g) as an off-white solid. LCMS calcd for C27H30F3N504 (m/e) 545, obsd 546 (M+H). 5 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate salt was prepared from 10 methyl-{5'-[(2-phenyl-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro 2H- [1,2']bipyridinyl-4-yl} -carbamic acid tert-butyl ester. Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo pyridin-3-yl)-amide F F 0 F N N 0 15 N Br A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.0 g, 11.7 mmol), 6-bromo-pyridin-3-ylamine (2.0 g, 11.7 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (2.4 g, 17.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g, 17.5 mmol) in anhydrous dichloromethane (100 mL) was stirred at room 20 temperature overnight. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. Recrystallization of the crude solid from ethyl acetate/hexane/methanol gave 4.04 g of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin 3-yl)-amide. The mother liquor was purified by flash chromatography (Merck silica gel 25 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give an additional 200 mg of 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide (4.24 g in total, 88 %) as a light brown solid. LCMS calcd for C16H9BrF3N302 (m/e) 412, obsd 413 (M+H). 30 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo phenyl)-amide WO 2008/141976 PCT/EP2008/055843 -67 F F o F /\ 3 I N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide above, 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl)-amide was prepared from 2 5 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-iodo-phenylamine. LCMS called for C17H10F3IN202 (m/e) 458, obsd 459 (M+H). Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-bromo-3 fluoro-phenyl)-amide F F o F - N N Br 10 F With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide above, 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-bromo-3-fluoro-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-bromo-3 15 fluoro-phenylamine. LCMS calcd for C17H9BrF4N202 (m/e) 429, obsd 430 (M+H). Preparation of 2,2-dimethyl-4-oxo-4-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-yl}-butyric acid methyl ester FE o F N NI 00 0~~ 0 20 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide, 2,2-dimethyl-4-oxo-4-{4'-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-yl}-butyric acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-(4'-amino-biphenyl-4-yl)-2,2-dimethyl-4-oxo-butyric acid methyl ester (prepared WO 2008/141976 PCT/EP2008/055843 -68 according to the procedure described in US 20040224997). LCMS calcd for C30H25F3N205 (m/e) 550, obsd 551 (M+H). Preparation of 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 5 (4-piperidin-4-yl-phenyl)-amide;hydrochloride F F F CI N- NO C i N -6 HOI To 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid described above (320 mg, 1.10 mmol) in methylene chloride (10 mL) was added 10 bromotrispyrrolidinophosphonium hexafluorophosphate (770 mg, 1.65 mmol). The reaction was stirred for 10 minutes and then 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (320 mg, 1.10 mmol) followed by diisopropylethylamine (0.60 mL, 3.30 mmol) were added. The reaction was stirred at room temperature overnight. The crude mixture was diluted in methanol (100 mL), loaded onto silica gel and purified 15 using Isco chromatography (eluting with ethyl acetate and hexanes) to give 4-(4-{[1-(2 chloro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl)-piperidine- 1 carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is compatible with its structure. 20 4-(4- { [1-(2-chloro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl) piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.73 mmol) from above was dissolved in dioxane (10 mL). To this reaction mixture was bubbled in HCl gas for 1 minute. Reaction was stirred at room temperature for 2 hours. The solvents were evaporated to give 400 mg of 1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 25 carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride salt. The NMR spectrum obtained on this sample is compatible with its structure. Preparation of 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carboxylic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 69 F F N NIN O With a method similar to that used for the preparation of 4-{4-[(1-(2-chloro-phenyl-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carboxylic acid tert butyl ester, 4- {4-[(1 -pyridin-2-yl-3-trifluoromethyl- 1 H-pyrazole-4-carbonyl] 5 amino}-phenyl)-piperidine-1-carboxylic acid tert butyl ester was prepared from 1 pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-carboxylic acid and 4-(4-amino-phenyl) piperidine-1-carboxylic acid tert butyl ester. The NMR spectrum obtained on the sample is compatible with its structure. 10 Preparation of 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4 piperidin-4-yl-phenyl)-amide ; hydrochloride F F N- FN-N N N N0 U": HCI With a similar method to that used for the preparation of 1-(2-chloro-phenyl)-3-trifluoro methyl-iH-pyrazole-4-carboxylic acid (4-piperidine-4-yl-phenyl)-amide hydrochloride, 15 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidine-4-yl phenyl)-amide hydrochloride was prepared from 4- {4-[(1-pyridin-2-yl-3-trifluoromethyl 1H-pyrazole-4-carbonyl)-amino]-phenyl)-piperidine-1-carboxylic acid tert-butyl ester. Preparation of 4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl)-amino] 20 phenyl}-piperazine-1-carboxylic acid tert-butyl ester F F O F N N N -0 \ 0 With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl)-piperidine- 1 -carboxylic acid tert-butyl ester, 4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl)-amino]-phenyl} 25 piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-phenyl-2- WO 2008/141976 PCT/EP2008/055843 - 70 trifluoromethyl-furan-3-carboxylic acid and 4-[4-amino-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. HRMS m/z called. for C27H29F3N304 [M+H]: 516.2105; found 516.2105. 5 Preparation of (1R,2R)-2-(4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester F F FNO ON N 0 O
-
With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl)-piperidine- 1 -carboxylic acid 10 tert-butyl ester, (1R,2R)-2-(4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester was prepared from 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (4-piperazin-1-yl-phenyl) amide and (1R,2R)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester. The product was isolated as a white solid (225 mg, 61 % yield). HRMS m/z calcd. for 15 C36H35F3N305 [M+H]*: 646.2524; found: 646.2524. Preparation of (4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenylamino}-cyclohexyl)-carbamic acid tert-butyl ester 'F F 0 F o N N N 20 With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl)-piperidine- 1 -carboxylic acid tert-butyl ester, (4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenylamino}-cyclohexyl)-carbamic acid tert-butyl ester was prepared from [4-(4 amino-phenylamino)-cyclohexyl] -carbamic acid tert-butyl ester and 2-phenyl-5 25 trifluoromethyl-oxazole-4-carboxylic acid. HRMS m/z calcd. for C28H32F3N404 [M+H]*: 545.2370; found: 545.2370.
WO 2008/141976 PCT/EP2008/055843 - 71 Preparation of rac-trans-2-(4'-nitro-biphenyl-4-ylcarbamoyl) cyclopentanecarboxylic acid 0 1 ON 0 0 0
%N
With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-phenyl)-3 5 trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino } -phenyl)-piperidine- 1 -carboxylic acid tert-butyl ester, rac-trans-2-(4'-nitro-biphenyl-4-ylcarbamoyl)-cyclopentanecarboxylic acid was prepared from 4'-nitro-biphenyl-4-ylamine and rac-trans-cyclopentane-1,2 dicarboxylic acid. LCMS called for C19H18N205 (m/e) 354, obsd 355 (M+H). 10 Preparation of rac-trans-2-[(4'-amino-biphenyl-4-yl)-methyl-carbamoyl] cyclopentanecarboxylic acid N N 0 To a solution of rac-trans-2-(4'-nitro-biphenyl-4-ylcarbamoyl)-cyclopentanecarboxylic acid (3.54 g, 10 mmol) in DMF cooled at 0 0 C was added sodium hydride (0.48 g, 12 15 mmol) gradually. The mixture was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.7 mL). The reaction mixture was stirred for 2 h. The reaction was then mixed with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer dried over sodium sulfate, filtered and concentrated to give rac-trans-2-[methyl-(4'-nitro-biphenyl-4-yl)-carbamoyl] 20 cyclopentanecarboxylic acid as a yellow solid. With a method similar to that used above, trans-2-[(4'-amino-biphenyl-4-yl)-methyl-carbamoyl]-cyclopentanecarboxylic acid was prepared by the hydrogenation of trans-2-[methyl-(4'-nitro-biphenyl-4-yl)-carbamoyl] cyclopentanecarboxylic acid. This material was directly used in the next step without further purification. LCMS calcd for C20H22N203 (m/e) 338, obsd 339 (M+H). 25 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1 yl-pyrimidin-5-yl)-amide hydrochloride salt WO 2008/141976 PCT/EP2008/055843 - 72 F F O F /\ N O N 0 N N CI N To a solution of 4-(5-nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-piperazine) in tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon 5 (240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-amino pyrimidin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester. To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3 10 mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0 mmol) and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The residue was treated with benzene (5 mL) and the solvents were again evaporated. The oily residue was dried in vacuum and then dissolved in methylene chloride (10 mL). The solution was cooled in an ice bath. To this 15 solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL). The mixture was stirred at 0 0 C for 10 minutes and room temperature for 2 hrs. After concentration, the residue was partitioned between methylene chloride and water. The organic layer was washed with aqueous citric acid solution and dried over sodium 20 sulfate. The solvents were evaporated and the residue was dried in vacuum. The resulting material was triturated with ethyl acetate and the precipitate was filtered to give 4- {5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1 carboxylic acid tert-butyl ester (1.38 g). LC-MS calcd for C24H25F3N604 (m/e) 518.5, obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with its 25 structure. 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl} piperazine-1-carboxylic acid tert-butyl ester from above was suspended in methylene chloride and methanol. To this mixture was added hydrogen chloride in ether (4N, 3 30 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with WO 2008/141976 PCT/EP2008/055843 - 73 dry ether and then filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide hydrochloride salt. LC-MS calcd for C19H17F3N602 (m/e) 418.39, obsd 419.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4 methylamino-piperidin-1-yl)-pyrimidin-5-yl]-amide hydrochloride salt F F O F N N N HCI 0-N N aN I With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 10 oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide above, 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -yl)-pyrimidin 5-yl]-amide hydrochloride salt was prepared from 2-phenyl-5-trifluoromethyloxazole-4 carboxylic acid, 2-chloro-5-nitropyrimidine and methyl-piperidin-4-yl-carbamic acid tert-butyl ester. LCMS calcd for C21H21F3N602 (m/e) 446, obsd 447 (M+H). 15 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4-amino piperidin-1-yl)-pyrimidin-5-yl]-amide hydrochloride salt F F o F / \N N N HCI N N aN With a method similar to that used for the preparation of hydrochloride salt of 2-phenyl 20 5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4-amino-piperidin-1 yl)-pyrimidin-5-yl]-amide hydrochloride salt was prepared from 2-phenyl-5 trifluoromethyloxazole-4-carboxylic acid, 2-chloro-5-nitropyrimidine and piperidin-4-yl carbamic acid tert-butyl ester. LCMS calcd for C20H19F3N602 (m/e) 432, obsd 433 25 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 74 PART II: PREPARATION OF PREFERRED COMPOUNDS 5 Example 1 Preparation of 4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazin-1-yl)-butyric acid F O F F N -O N O 0 N O N O 0 0 10 A solution of dioxane (10 mL) that was saturated with hydrogen chloride gas was added to 4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1 carboxylic acid tert-butyl ester (300 mg, 0.581 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then the volatiles were evaporated under reduced pressure. The residue was triturated with diethyl ether to yield 2-phenyl-5 15 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride as a white powder (226 mg). 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (100 mg, 0.204 mmol), triethylamine (57.5 tL, 0.408 mmol) and succinic 20 anhydride (22.4 mg, 0.224 mmol) in 5 mL toluene and 3 mL dimethylsulfoxide were stirred at room temperature. After 3 hrs, an additional 5.5 mg of succinic anhydride was added and stirred for an additional 1 hr. The reaction mixture was diluted with 50 mL ethyl acetate, washed with 500 mL water, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was dissolved in acetonitrile and water 25 and lyophilized to yield 4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazin-1-yl)-butyric acid as an amorphous, light yellow solid (83 mg, 78%). ES-MS calcd for C25H23F3N405 (m/e) 516.48, obsd 517 (M+H). Example 2 30 Preparation of 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazin-1-yl)-butyric acid WO 2008/141976 PCT/EP2008/055843 - 75 F O F - N N N 0 N 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 2,2-dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 phenyl}-piperazin-1-yl)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and dimethylsuccinic anhydride. ES-MS calcd for C27H27F3N405 (m/e) 544.53, obsd 545.1 (M+H). 10 Example 3 Preparation of 1-[2-oxo-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazin-1-yl)-ethyl] -cyclopentanecarboxylic acid F o F '\ FN N NN O o N 0 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 1-[2-oxo-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazin-1-yl)-ethyl]-cyclopentanecarboxylic acid was prepared from 2-Phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and 2-oxa-spiro[4.4]nonane-1,3-dione. ES-MS calcd for C29H29F3N405 20 (m/e) 570.57, obsd 571 (M+H). Example 4 Preparation of 1-[2-oxo-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazin-1-yl)-ethyl] -cyclohexanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 76 F 0 F N N 0 N C~y 0 06 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 1-[2-oxo-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 5 piperazin-1-yl)-ethyl]-cyclohexanecarboxylic acid was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and 2-oxa-spiro[4.5]decane-1,3-dione. ES-MS calcd for C30H31F3N405 (m/e) 584.60, obsd 585.1 (M+H). 10 Example 5 Preparation of 2,2-dimethyl-4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-butyric acid F 0 F NN N NO N N 0 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 2,2-dimethyl-4-oxo-4-(4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazin-1-yl)-butyric acid was prepared from 2-Phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin- 1 -yl-pyridin-3 -yl)-amide hydrochloride and dimethylsuccinic anhydride. ES-MS calcd for C26H26F3N505 (m/e) 20 545.2, obsd 546.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 6 Preparation of 4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -pyridin-2-yl}-piperazin-1-yl)-butyric acid WO 2008/141976 PCT/EP2008/055843 - 77 F 0 F Nil Nn 0 N N 0 N OI 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} 5 piperazin-1-yl)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride and succinic anhydride. ES-MS calcd for C24H22F3N505 (m/e) 517.2, obsd 518.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 7 Preparation of 2,2-dimethyl-4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyrimidin-2-yl}-piperazin-1-yl)-butyric acid F F FN N N o N N N O 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 2,2-dimethyl-4-oxo-4-(4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yl}-piperazin-1-yl)-butyric acid was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide and 2,2-dimethylsuccinic anhydride. ES-MS calcd for C25H25F3N605 (m/e) 546.2, obsd 20 547.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 8 Preparation of 4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -pyrimidin-2-yl}-piperazin-1-yl)-butyric acid WO 2008/141976 PCT/EP2008/055843 - 78 F FF N N N O N N 0 N 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 4-oxo-4-(4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2 5 yl}-piperazin-1-yl)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole 4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide and succinic anhydride. ES MS called for C23H21F3N605 (m/e) 518.2, obsd 519.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 9 Preparation of 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-1-yl)-butyric acid F o F N N o N 0 With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid above, 2,2-Dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-1-yl)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 2,2-dimethylsuccinic anhydride. ES-MS calcd for C28H28F3N305 (m/e) 543.2, obsd 544.0 (M+H). The NMR 20 spectrum obtained on the sample is compatible with its structure. Example 10 Preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 79 F O F F Na N 0 N N 00 To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl phenyl)-amide hydrochloride (212 mg, 0.435 mmol), racemic trans-cyclopentane-1,2 dicarboxylic acid monoethyl ester (81 mg, 0.435 mmol) and triethylamine (305 tL, 2.17 5 mmol) in 5 mL 1-methyl-2-pyrrolidinone was added (benzotriazol-1 yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (BOP, 202 mg, 0.456 mmol) in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated under 10 reduced pressure. The residue was purified by flash chromatography (eluted with ethyl acetate/hexane) to yield rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid ethyl ester as an amorphous solid (236 mg, 93%). ES-MS calcd for C30H31F3N405 (m/e) 584.60, obsd 585 (M+H). 15 Example 11 Preparation of 2,2-diethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazin-1-yl)-butyric acid methyl ester F o F SF N N N 0 N 0 0 20 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2,2-diethyl-4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid methyl ester was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 25 piperazin-1-yl-phenyl)-amide hydrochloride and 2,2-diethyl-succinic acid 1-methyl ester. ES-MS calcd for C30H33F3N405 (m/e) 586.61, obsd 587 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 80 Example 12 Preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester F r N N O N O 5 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid 10 methyl ester was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride and cis-cyclohexane-1,4-dicarboxylic acid monomethyl ester. ES-MS calcd for C30H31F3N405 (m/e) 584.60, obsd 585.1 (M+H). 15 Example 13 Preparation of 2,2-diethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazin-1-yl)-butyric acid F F N 0 NN N 0 N O 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2,2-diethyl-4-oxo-4-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl phenyl)-amide hydrochloride and 2,2-diethylsuccinic acid. ES-MS calcd for 25 C29H31F3N405 (m/e) 572.58, obsd 573 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 81 Example 14 Preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid F / F NF N - Nj0 0 5 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1 10 yl-phenyl)-amide hydrochloride and trans-1,4-cyclohexanedicarboxylic acid. ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571 (M+H). Example 15 Preparation of rac-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester F o F NN NO 0 N N0 0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, rac-3-(4-{4-[(2-phenyl-5-trifluoromethyl 20 oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 piperazin- 1 -yl-phenyl)-amide hydrochloride and racemic cis-cyclohexane-1,3 dicarboxylic acid monomethyl ester. ES-MS calcd for C30H31F3N405 (m/e) 584.57, obsd 585.1 (M+H). 25 Example 16 WO 2008/141976 PCT/EP2008/055843 - 82 Preparation of (1R,3S)-1,2,2-trimethyl-3-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F N F F N N 0 0 N0 0 5 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, (1R,3S)-1,2,2-trimethyl-3-(4-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-l-carbonyl) cyclopentanecarboxylic acid was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4 1o carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride and d-camphoric acid. ES-MS calcd for C31H33F3N405 (m/e) 598.62, obsd 599.2 (M+H). Example 17 Preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F - N N 0 o N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperidine- 1 -carbonyl) cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic 1,2-trans-cyclopetane dicarboxylic acid. ES-MS calcd for C29H28F3N305 (m/e) 555.2, obsd 556.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Example 18 WO 2008/141976 PCT/EP2008/055843 - 83 Preparation of (1R,2R)-2-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid F 0N F F
-
N 0 0 The racemic mixture of 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -phenyl} -piperidine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was separated under supercritical fluid chromatography (SFC) conditions (chiral OJ column, 25% methanol in liquid carbon dioxide, flow rate 70 mL/min, pressure 100 bar at 30 0 C). The earlier eluting fraction provided (1R,2R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic 10 acid [a]D- 24
.
2 (4.5 mg/mL in ethyl acetate). HRMS calcd for C29H28F3N305 (M+H)* 556.2054, obsd 556.2052. The NMR spectrum obtained on the sample is compatible with its structure. Example 19 15 Preparation of (1S,2S)-2-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F - N N N 00 The racemic mixture of 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperidine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was 20 separated under supercritical fluid chromatography (SFC) conditions (chiral OJ column, 25% methanol in liquid carbon dioxide, flow rate 70 mL/min, pressure 100 bar at 30 C ). The later eluting fraction provided (iS,2S)-2-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid. [a]D=+ 2 5.
3 (3.2 mg/mL in ethyl acetate). LC-MS calcd for C29H28F3N305 (m/e) 25 555.2, obsd 556.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
WO 2008/141976 PCT/EP2008/055843 - 84 Example 20 Preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid F 0 IF 0 N N 0 0 N 0 5 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid 10 was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4 yl-phenyl)-amide and 1,4-trans-cyclohexane dicarboxylic acid. HRMS calcd for C30H30F3N305 (M+H)* 570.2211 obsd 570.2210 Example 21 15 Preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclobutanecarboxylic acid F N F 0 <N F 0i 0 N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) 20 cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperidine- 1 -carbonyl) cyclobutanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic 1,2-trans-cyclobutane dicarboxylic acid. LC-MS calcd for C28H26F3N305 (m/e) 541.2, obsd 542.3 (M+H). 25 Example 22 Preparation of rac-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 85 F 0 F Nl N N N r N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl) cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic 1,2-trans cyclopentane dicarboxylic acid. LC-MS calcd for C27H26F3N505 (m/e) 557.2, obsd 558.1 (M+H). 10 Example 23 Preparation of (1S,2S)-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid] F 0 F N N N N 0~ 0 15 The racemic mixture of 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was separated under supercritical fluid chromatography (SFC) conditions as described earlier. The earlier eluting fraction provided (1S,2S)-2-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl) 20 cyclopentanecarboxylic acid. [a]D=+ 2 1.8 (4.3 mg/mL in ethyl acetate). LC-MS calcd for C27H26F3N505 (m/e) 557.2, obsd 558.1 (M+H). Example 24 Preparation of (1R,2R)-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 86 F 0 F N N N 0 0 0 The racemic mixture of 2-(4-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was separated under supercritical fluid chromatography (SFC) conditions as described 5 earlier. The later eluting fraction provided (1R,2R)-2-(4-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino] -pyridin-2-yl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid. [a]D=- 2 1
.
6 (4.2 mg/mL in ethyl acetate). LC-MS calcd for C27H26F3N505 (m/e) 557.2, obsd 558.1 (M+H). 10 Example 25 Preparation of rac-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F - NN o A N 0 / 0
'
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carbonyl) cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide and racemic 1,2-trans 20 cyclopentane dicarboxylic acid. LC-MS calcd for C26H25F3N605 (m/e) 558.2, obsd 559.1 (M+H). Example 26 Preparation of (1R,2R)-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -pyrimidin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 87 F N F o N 0 N . 0 0 The racemic mixture of 2-(4-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-yl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was separated under supercritical fluid chromatography (SFC) conditions as described 5 earlier. The earlier eluting fraction provided (1R,2R)-2-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl} -piperazine-1-carbonyl) cyclopentanecarboxylic acid. [a]D=- 1 9
.
3 (4.2 mg/mL in ethyl acetate). LC-MS calcd for C26H25F3N605 (m/e) 558.2, obsd 559.1 (M+H). 10 Example 27 Preparation of (1S,2S)-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F o F Ni N 0 0 The racemic mixture of 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -pyrimidin-2-yl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid from above was separated under supercritical fluid chromatography (SFC) conditions as described earlier. The later eluting fraction provided (IS,2S)-2-(4- {5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carbonyl)-cyclopentane carboxylic acid. [U]D=+20.
6 (4.4 mg/mL in ethyl acetate). LC-MS calcd for 20 C26H25F3N605 (m/e) 558.2, obsd 559.1 (M+H). Example 28 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carbonyl}-cyclohexanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 88 F o F I NT, N13 N N -r 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl 5 oxazole-4-carbonyl)-amino]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-l'-carbonyl} cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide and 1,4-trans cyclohexane dicarboxylic acid. LC-MS calcd for C29H29F3N405 (m/e) 570.2, obsd 571.4 (M+H). 10 Example 29 Preparation of 4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid F o F NN 0 N 1 4 N 0 0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino] -pyridin-2-yl} -piperazine- 1 -carbonyl) cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 20 carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and 1,4-trans-cyclohexane dicarboxylic acid. LC-MS calcd for C28H28F3N505 (m/e) 571.2, obsd 572.2 (M+H). Example 30 Preparation of rac-2-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 25 3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carbonyl}-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 89 F oN F F N N 0 0 /-o With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl l'-carbonyl} -cyclopentanecarboxylic acid was prepared from 2-phenyl-5 -trifluoromethyl oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide and 1,2-trans-cyclopentane dicarboxylic acid. LC-MS calcd for C28H27F3N405 (m/e) 556.2, obsd 557.3 (M+H). 10 Example 31 Preparation of racemic 2-(4-{5-[(5-phenyl-2-propyl-2H-pyrazole-3-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid \ N N N O oN N NQ 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(5-phenyl-2-propyl-2H pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-piperazine-1 carbonyl)cyclopentanecarboxylic acid was prepared from 5-phenyl-2-propyl-2H 20 pyrazole-3-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic trans cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H34N604 (m/e) 530, obsd 531 (M+H). Example 32 WO 2008/141976 PCT/EP2008/055843 -90 Preparation of racemic 2-(4-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4 carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid / F N N F -F N 0 N N NQ With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-(4-{5-[(1-phenyl-3-trifluoromethyl-1H pyrazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl) cyclopentanecarboxylic acid was prepared from 1 -phenyl-3 -trifluoromethyl- 1 H-pyrazo le 4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic trans-Cyclopentane 10 1,2-dicarboxylic acid. LCMS calcd for C27H27F3N604 (m/e) 556, obsd 557 (M+H). Example 33 Preparation of racemic 2-(4-{4-[(5-phenyl-2-propyl-2H-pyrazole-3-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid NN N NQ 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(5-phenyl-2-propyl-2H pyrazole-3-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic 20 acid was prepared from 5-phenyl-2-propyl-2H-pyrazole-3-carboxylic acid (4-piperazin 1-yl-phenyl)-amide and racemic trans-cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C30H35N504 (m/e) 529, obsd 530 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 91 Example 34 Preparation of racemic 2-(4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid N FF F
-
N F F N o onN N N>Q 5 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(1-phenyl-3 trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl) cyclopentanecarboxylic acid was prepared from 1 -phenyl-3 -trifluoromethyl- 1 H-pyrazo le 10 4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide and racemic trans-cyclopentane-1,2 dicarboxylic acid. LCMS calcd for C28H28F3N504 (m/e) 555, obsd 556 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 35 15 Preparation of racemic 2-(4-{5-[(5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid k N N N N N With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) 20 cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {5-[(5-Methyl-2-phenyl-2H [1,2,3]triazo le-4-carbonyl)-amino] -pyridin-2-yl} -piperazine- 1 -carbonyl)cyclopentane carboxylic acid was prepared from 5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic WO 2008/141976 PCT/EP2008/055843 -92 acid (6-piperazin- 1 -yl-pyridin-3-yl)-amide and racemic trans-cyclopentane- 1,2 dicarboxylic acid. LCMS called for C26H29N704 (m/e) 503, obsd 504 (M+H). Example 36 5 Preparation of racemic 2-[4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H pyrazole-4-carbonyl]-amino}-pyridin-2-yl)-piperazine-1-carbonyl] cyclopentanecarboxylic acid F NN F N F N 0 N N 0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-[4-(5-{[1-(4-fluoro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -pyridin-2-yl)-piperazine- 1 -carbonyl] cyclopentanecarboxylic acid was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic trans 15 cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C27H26F4N604 (m/e) 574, obsd 575 (M+H). Example 37 Preparation of racemic 2-[4-(5-{[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3 20 carbonyl]-amino}-pyridin-2-yl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid N 0 N N N N
O
WO 2008/141976 PCT/EP2008/055843 - 93 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-[4-(5-{[2-(2-methoxy-ethyl)-5 phenyl-2H-pyrazo le-3 -carbonyl] -amino } -pyridin-2-yl)-piperazine- 1 -carbonyl] 5 cyclopentanecarboxylic acid was prepared from 2-(2-methoxy-ethyl)-5-phenyl-2H pyrazole-3-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic trans cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H34N605 (m/e) 546, obsd 547 (M+H). 10 Example 38 Preparation of racemic 2-(4-{5-[(2-propyl-5-thiophen-2-yl-2H-pyrazole-3-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid N // N N 0 N N 0 o j 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(2-propyl-5-thiophen-2 yl-2H-pyrazole-3-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl) cyclopentanecarboxylic acid was prepared from 2-propyl-5-thiophen-2-yl-2H-pyrazole 3-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and racemic trans-cyclopentane 20 1,2-dicarboxylic acid. LCMS calcd for C27H32N604S (m/e) 536, obsd 537 (M+H). Example 39 Preparation of racemic 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 94 O F 0 FF N N o N N With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide and racemic trans cyclopentane-1,2-dicarboxylic acid methyl ester. LCMS called for C29H29F3N405 (m/e) 570, obsd 571 (M+H). The NMR spectrum obtained on the sample is compatible with its 10 structure. Example 40 Preparation of rac-2-(4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid NN F F F N N o0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(1-phenyl-3 trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl) 20 cyclopentanecarboxylic acid was prepared from 1 -phenyl-3 -trifluoromethyl- 1 H-pyrazo le 4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic trans-cyclopentane-1,2 dicarboxylic acid. LCMS calcd for C29H29F3N404 (m/e) 554, obsd 555 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 95 Example 41 Preparation of 4-(4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid N/ N F F F
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N F' -F N 0 N O 5 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(1-phenyl-3-trifluoromethyl-1H pyrazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic 10 acid was prepared from 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4 piperidin-4-yl-phenyl)-amide and trans-1,4-cyclohexanedicarboxylic acid. LCMS calcd for C30H31F3N404 (m/e) 568, obsd 569 (M+H). Example 42 15 Preparation of racemic 2-[4-(4-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H pyrazole-4-carbonyl]-amino}-phenyl)-piperidine-1-carbonyl] cyclopentanecarboxylic acid F / F NC F -- N 'N N oo 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-[4-(4-{[1-(4-fluoro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] cyclopentanecarboxylic acid was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic trans- WO 2008/141976 PCT/EP2008/055843 - 96 cyclopentane-1,2-dicarboxylic acid. LCMS called for C29H28F4N404 (m/e) 572, obsd 573 (M+H). Example 43 5 Preparation of 4-[4-(4-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid F N/N FFF N F -F N o0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) 10 cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(4-fluoro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] cyclohexanecarboxylic acid was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cis-cyclohexane-1,4 dicarboxylic acid. LCMS calcd for C30H30F4N404 (m/e) 586, obsd 585 (M-H). 15 Example 44 Preparation of 4-[4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid F N F - F N O 00 20 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] cyclohexanecarboxylic acid was prepared from 1-(2-chloro-phenyl)-3-trifluoromethyl- WO 2008/141976 PCT/EP2008/055843 - 97 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cis-cyclohexane-1,4 dicarboxylic acid. LCMS called for C30H30ClF3N404 (m/e) 603, obsd 602 (M-H). The NMR spectrum obtained on the sample is compatible with its structure. 5 Example 45 Preparation of 4-[4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid N F F N N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] cyclohexanecarboxylic acid was prepared from 1-(2-chloro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and trans-cyclohexane 15 1,4-dicarboxylic acid. LCMS calcd for C30H30ClF3N404 (m/e) 603, obsd 602 (M-H). The NMR spectrum obtained on the sample is compatible with its structure. Example 46 Preparation of racemic 2-[4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H 20 pyrazole-4-carbonyl]-amino}-phenyl)-piperidine-1-carbonyl] cyclopentanecarboxylic acid N F F N1 N o \ N 0 WO 2008/141976 PCT/EP2008/055843 - 98 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-[4-(4-{[1-(2-chloro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] 5 cyclopentanecarboxylic acid was prepared from 1-(2-chloro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic trans cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H28ClF3N404 (m/e) 589, obsd 588 (M-H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 47 Preparation of 4-[4-(4-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid FN N' FFF FF N F N 0 N Q 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(4-fluoro-phenyl)-3 trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] cyclohexanecarboxylic acid was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl 1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and trans-cyclohexane 20 1,4-dicarboxylic acid. LCMS calcd for C30H30F4N404 (m/e) 586, obsd 585 (M-H). Example 48 Preparation of (1R,2R)-2-((S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carbonyl) 25 cyclopentanecarboxylic acid F 0 0 F \ N F O N 0 0 WO 2008/141976 PCT/EP2008/055843 - 99 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, (1R,2R)-2-((S)-3-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1 5 carbonyl)-cyclopentanecarboxylic acid was prepared from (S)-2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(pyrrolidin-3-ylamino)-pyridin-3-yl]-amide and racemic trans-cyclopentane-1,2-dicarboxylic acid. The mixture of diasteriomers were then separated by chiral SFC to give (1R,2R)-2-((S)-3-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carbonyl) 10 cyclopentanecarboxylic acid. LCMS calcd for C27H26F3N505 (m/e) 557.53, obsd 558.53 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 49 15 Preparation of (1S,2S)-2-((S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carbonyl) cyclopentanecarboxylic acid F 0 0 F \ / N F N 0 N 0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, (iS,2S)-2-((S)-3-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1 carbonyl)-cyclopentanecarboxylic acid was prepared from (S)-2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(pyrrolidin-3-ylamino)-pyridin-3-yl]-amide 25 and racemic trans-cyclopentane-1,2-dicarboxylic acid. The mixture of diasteriomers were then separated by chiral SFC to give (iS,2S)-2-((S)-3-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carbonyl) cyclopentanecarboxylic acid. LCMS calcd for C27H26F3N505 (m/e) 557.53, obsd 558.53 (M+H). The NMR spectrum obtained on the sample is compatible with its 30 structure. Example 50 WO 2008/141976 PCT/EP2008/055843 - 100 Preparation of 4-((S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acid F 0 F 0 _< I FN 0 NN NN 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-((S)-3-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carbonyl) cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide and trans 1o cyclohexane-1,4-dicarboxylic acid. LCMS calcd for C28H28F3N505 (m/e) 571.55, obsd 572.21 (M+H). Example 51 Preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 15 phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid F S 0 F 0 N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(2-phenyl-5-trifluoromethyl 20 oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4 yl-phenyl)-amide and cis-cyclohexane-1,4-dicarboxylic acid. LCMS calcd for C30H30F3N305 (m/e) 569.58, obsd 570.22 (M+H). 25 Example 52 Preparation of rac-2-(4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 101 F F F 0 0_\4
-
.,0 N N N N // o o N With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{2-cyano-4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (3-cyano-4-piperazin-1-yl-phenyl)-amide and racemic trans cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H26F3N505 (m/e) 581, obsd. 582 (M+H). 10 Example 53 Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1 (tetrahydro-furan-2-carbonyl)-piperidin-4-yl]-phenyl}-amide F o F NN j 0 N 0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid {4-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yl]-phenyl} amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 20 piperidin-4-yl-phenyl)-amide and racemic tetrahydrofuran-2-carboxylic acid. LC-MS calcd for C27H26F3N304 (m/e) 513.2, obsd 514.4 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 54 25 Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1 (tetrahydro-furan-3-carbonyl)-piperidin-4-yl]-phenyl}-amide WO 2008/141976 PCT/EP2008/055843 - 102 F o F O NN 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, racemic 2-phenyl-5-trifluoromethyl 5 oxazole-4-carboxylic acid {4-[1-(tetrahydro-furan-3-carbonyl)-piperidin-4-yl]-phenyl} amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 piperidin-4-yl-phenyl)-amide and racemic tetrahydrofuran-3-carboxylic acid. LC-MS calcd for C27H26F3N304 (m/e) 513.2, obsd 514.4 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 55 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4 (cyclopent-3-enecarbonyl)-piperazin- 1 -yl]-pyridin-3-yl}-amide F 0 F
-
Nj Nn 0 N N 0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {6-[4-(cyclopent-3-enecarbonyl)-piperazin-1-yl]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1 20 yl-pyridin-3-yl)-amide and 3-cyclopentene carboxylic acid. LC-MS calcd for C26H24F3N503 (m/e) 511.2, obsd 512.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 56 25 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1 (cyclopent-3-enecarbonyl)-piperidin-4-yl]-phenyl}-amide WO 2008/141976 PCT/EP2008/055843 - 103 F 0 FF / J \ N) F - N N N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4 5 carboxylic acid {4-[1-(cyclopent-3-enecarbonyl)-piperidin-4-yl]-phenyl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl phenyl)-amide and 3-cyclopentene carboxylic acid. LC-MS calcd for C28H26F3N303 (m/e) 509.2, obsd 510.2 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 57 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1' cyclopropanecarbonyl-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide F o F N N oN 0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (1'-cyclopropanecarbonyl-l',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5 yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 20 (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide and cyclopropane carboxylic acid. LC-MS calcd for C25H23F3N403 (m/e) 484.2, obsd 485.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 58 25 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4 cyclopropanecarbonyl-piperazin-1-yl)-phenyl]-amide WO 2008/141976 PCT/EP2008/055843 - 104 F o F F N, 0 N N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid ethyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4 5 carboxylic acid [4-(4-cyclopropanecarbonyl-piperazin-1-yl)-phenyl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl) amide and cyclopropane carboxylic acid. LC-MS calcd for C25H23F3N403 (m/e) 484.2, obsd 485.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 59 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester F F o F NN N N N N 0 0 15 4-(5-Amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was mixed with 2 phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3.0 mmol) and bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0 mmol) in N,N dimethylformamide (20 mL) and methylene chloride (5 mL) containing triethylamine (0.85 mL). The mixture was stirred at room temperature overnight and the solvents were 20 evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate and the solid was filtered to give 4-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino] -pyridin-2-yl} -piperazine- 1 -carboxylic acid tert-butyl ester (1.09 g). LC-MS calcd for C25H26F3N504 (m/e) 517.5, obsd 518.1 (M+H). The NMR 25 spectrum obtained on the sample is compatible with its structure. Example 60 WO 2008/141976 PCT/EP2008/055843 - 105 Preparation of (1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-4- yl)-acetic acid ethyl ester F F o N F - N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-4-yl)-acetic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid and [1-(4-aminophenyl)-piperidine-4-yl] acetic acid ethyl ester. LC-MS calcd for C26H26F3N304 (m/e) 501.2, obsd 502.1 10 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 61 Preparation of {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H- [1,2'] bipyridinyl-4-yl}-acetic acid methyl ester F F oN FN \ \ N, N 0 15 K With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl} -acetic acid methyl ester was prepared from 20 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl)-acetic acid methyl ester. LC-MS calcd for C24H23F3N404 (m/e) 488.2, obsd 489.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Example 62 Preparation of 2-Methyl-2-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4-yl}-propionic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 106 F 0 F N N 00 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-methyl-2-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -propionic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5'-amino 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-2-methyl-propionic acid ethyl ester. LC-MS calcd for C27H29F3N404 (m/e) 530.2, obsd 531.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 63 Preparation of 4-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester N F F N 0 N N 15 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1 phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4-(5 -amino-pyridin-2-yl) 20 piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C25H27F3N603 (m/e) 516, obsd 517 (M+H). Example 64 Preparation of 4-(5-{[5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carbonyl] 25 amino}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 107 N F FF F N 0 N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-(5- { [5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3 5 carbonyl] -amino } -pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester was prepared from 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid and 4-(5 amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C26H29F3N603 (m/e) 530, obsd 531 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 65 Preparation of 4-{5-[(5-phenyl-2-propyl-2H-pyrazole-3-carbonyl)-amino]-pyridin-2 yl}-piperazine-1-carboxylic acid tert-butyl ester S N-_ N N N 15 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4- {5-[(5-phenyl-2-propyl-2H-pyrazole-3-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-phenyl 2-propyl-2H-pyrazole-3-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1 20 carboxylic acid tert-butyl ester. LCMS calcd for C27H34N603 (m/e) 490, obsd 491 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 66 WO 2008/141976 PCT/EP2008/055843 - 108 Preparation of 4-{5-[(5-methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester N N NJ N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(5-methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl) amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5 methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and 4-(5 -amino-pyridin-2 yl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C25H31N704 (m/e) 10 493, obsd 494 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 67 Preparation of 4-(5-{[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbonyl] 15 amino}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester N N-N N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-(5-{[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbonyl] 20 amino}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2 (2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carboxylic acid and 4-(5 -amino-pyridin-2 yl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C27H34N604 (m/e) 506, obsd 507 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
WO 2008/141976 PCT/EP2008/055843 - 109 Example 68 Preparation of 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester F N F F F F N 0 N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl] -amino } -pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester was 10 prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C25H26F4N603 (m/e) 534, obsd 535 (M+H). Example 69 15 Preparation of 4-{5-[(2-propyl-5-thiophen-2-yl-2H-pyrazole-3-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester / \ N~ Q_ N S / N--\ N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 20 tert-butyl ester above, 4-{5-[(2-propyl-5-thiophen-2-yl-2H-pyrazole-3-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-propyl-5 thiophen-2-yl-2H-pyrazole-3-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1- WO 2008/141976 PCT/EP2008/055843 - 110 carboxylic acid tert-butyl ester. LCMS called for C25H32N603S (m/e) 496, obsd 497 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 70 5 Preparation of 4-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] pyridin-2-yl}-benzoic acid N' F F F N 0 N 0 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 10 tert-butyl ester above, 4-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-pyridin-2-yl}-benzoic acid was prepared from 1-phenyl-3-trifluoromethyl-1H pyrazole-4-carboxylic acid and 4-(5-amino-pyridin-2-yl)-benzoic acid methyl ester followed by basic hydrolysis of the methyl ester. LCMS calcd for C23H15F3N403 (m/e) 452, obsd 453 (M+H). The NMR spectrum obtained on the sample is compatible with its 15 structure. Example 71 Preparation of 4'-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonyl] amino}-biphenyl-4-carboxylic acid F / N F F N~ NZ F -F N 2 0 200 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4'-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4- WO 2008/141976 PCT/EP2008/055843 - 111 carbonyl] -amino } -biphenyl-4-carboxylic acid was prepared from 1-(4-fluoro-phenyl)-3 trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4'-amino-biphenyl-4-carboxylic acid methyl ester followed by basic hydrolysis of the methyl ester. LCMS calcd for C24H15F4N303 (m/e) 469, obsd 470 (M+H). 5 Example 72 Preparation of 4-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin 2-yl}-benzoic acid N N N S 0 o K N - 0 0 10 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] pyridin-2-yl}-benzoic acid was prepared from 4-methyl-2-pyridin-2-yl-thiazole-5 carboxylic acid and 4-(5-amino-pyridin-2-yl)-benzoic acid methyl ester followed by 15 basic hydrolysis of the methyl ester. LCMS calcd for C22H16N403S (m/e) 416, obsd 417 (M+H). Example 73 Preparation of 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 20 carbonyl]-amino}-pyridin-2-yl)-benzoic acid F N~ FFF NC F -F N o N 0 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 25 carbonyl] -amino } -pyridin-2-yl)-benzoic acid was prepared from 1-(4-fluoro-phenyl)-3- WO 2008/141976 PCT/EP2008/055843 - 112 trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-benzoic acid methyl ester followed by basic hydrolysis of the methyl ester. LCMS calcd for C23H14F4N403 (m/e) 470, obsd 471 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 5 Example 74 Preparation of 4-{5-[(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester N ,N F F r N F F 0 N N 10 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1 phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4-(5 -amino-pyridin-2-yl) 15 piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C25H27F3N603 (m/e) 516, obsd 517 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 75 20 Preparation of 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carboxylic acid tert-butyl ester N F F N F N
N
WO 2008/141976 PCT/EP2008/055843 - 113 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-phenyl} -piperidine- 1 -carboxylic acid tert-butyl ester was prepared from 1 5 pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 4-(4-amino-phenyl) piperidine-1-carboxylic acid tert-butyl ester. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 76 Preparation of 2-methyl-2-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4-yl}-propionic acid F F 0 F N < 'NN N N
O
With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-methyl-2-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -propionic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5'-amino-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-yl)-2-methyl-propionic acid. LC-MS calcd for 20 C25H25F3N404 (m/e) calcd 502.2, obsd 503.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 77 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 25 pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester F F Nn~ 0 N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)- WO 2008/141976 PCT/EP2008/055843 - 114 amino]-pyridin-2-ylamino} -pyrrolidine- 1 -carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3 -(5 -amino-pyridin 2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS called for C25H26F3N504 (m/e) 517.6, obsd 518.2 (M+H). 5 Example 78 Preparation of (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester F 0 " 0 FF N N 10 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5- { [2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl oxazole-4-carbonyl] -amino } -pyrimidin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert butyl ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 15 4-carboxylic acid and (S)-3 -(5-amino-pyrimidin-2-ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester. LCMS calcd for C23H20F6N605 (m/e) 574.4, obsd 575.2 (M+H). Example 79 Preparation of (S)-3-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] 20 pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester - N N S N O With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] 25 pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 4 methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid and (S)-3 -(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS calcd for C24H28N603S (m/e) 480.6, obsd 481.2 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 115 Example 80 Preparation of 4-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin 2-yl}-piperazine-1-carboxylic acid tert-butyl ester N s N N NNO 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] pyridin-2-yl} -piperazine- 1 -carboxylic acid tert-butyl ester was prepared from 4-methyl 2-pyridin-2-yl-thiazole-5-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1 10 carboxylic acid tert-butyl ester. LCMS calcd for C24H28N603S (m/e) 480.6, obsd 481.2 (M+H). Example 81 Preparation of 4-{5-[(2-pyridin-3-yl-thiazole-4-carbonyl)-amino]-pyridin-2-yl} 15 piperazine-1-carboxylic acid tert-butyl ester
-
S N N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(2-pyridin-3-yl-thiazole-4-carbonyl)-amino]-pyridin-2-yl} 20 piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-pyridin-3-yl-thiazole 4-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C23H26N603S (m/e) 466.6, obsd 467.2 (M+H). Example 82 25 Preparation of 4-{5-[(4-methyl-2-pyridin-3-yl-thiazole-5-carbonyl)-amino]-pyridin 2-yl}-piperazine-1-carboxylic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 116 - N N 0 N N 00 N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-{5-[(4-methyl-2-pyridin-3-yl-thiazole-5-carbonyl)-amino] 5 pyridin-2-yl} -piperazine- 1 -carboxylic acid tert-butyl ester was prepared from 4-methyl 2-pyridin-3-yl-thiazole-5-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-piperazine- 1 carboxylic acid tert-butyl ester. LCMS called for C24H28N603S (m/e) 480.6, obsd 481.2 (M+H). 10 Example 83 Preparation of (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester F F_ F F 0
-
0 F F N N O 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5- { [2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl oxazole-4-carbonyl] -amino } -pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4 carboxylic acid and (S)-3 -(5-amino-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid 20 tert-butyl ester. LCMS calcd for C26H25F6N505 (m/e) 601.5, obsd 601.9 (M+H). To a flask containing (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl oxazole-4-carbonyl] -amino } -pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester (150 mg, 0.249 mmol) was added trifluoroacetic acid (5 mL). When all the starting 25 material was consumed, as indicated by TLC, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane (10 mL) and then cooled to 0 0 C. Ethyl chloroformate (24 tL, 0.249 mmol) and triethylamine (75.5 mg, 0.747 mmol) were WO 2008/141976 PCT/EP2008/055843 - 117 added dropwise, and the reaction mixture was stirred for 2 h at room temperature and then concentrated. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution with 0%-100% ethyl acetate in hexane) to give (S)-3-(5- { [2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] 5 amino }-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (61 mg, 42.7% yield) as a light yellow solid. LCMS for C24H21F6N505 calculated (m/e) 573.46, found 574.15 (M+H). Example 84 10 Preparation of (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenylamino}-pyrrolidine-1-carboxylic acid ethyl ester F 0 F IF 00 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 15 tert-butyl ester above, (S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-phenylamino} -pyrrolidine- 1 -carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-phenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is compatible with its structure. 20 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3-{4-[(2-Phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic acid 25 ethyl ester was from (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester and ethyl chloroformate. LCMS calcd for C24H23F3N404 (m/e) 488.47, obsd 489.17 (M+H). Example 85 30 Preparation of (R)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 118 F - 0 F \ I F N N o N,. N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (R)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino]-pyridin-2-ylamino} -pyrrolidine- 1 -carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)-3 -(5 -amino-pyridin 2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS calcd for C25H26F3N504 (m/e) 517.6, obsd 518.2 (M+H). 10 Example 86 Preparation of (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester F 0 F \ I F N N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-yl} -pyrrolidin-3 -yl)-carbamic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)-1-(5-amino pyrimidin-2-ylamino)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS calcd for 20 C24H25F3N604 (m/e) 518.5, obsd 519.2 (M+H). Example 87 Preparation of (S)-3-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 119 F 0 F -- < I F N N Q< With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(methyl- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-pyridin-2-yl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-[(5 amino-pyridin-2-yl)-methyl-amino] -pyrro lidine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C26H28F3N504 (m/e) 531.5, obsd 532.2 (M+H). 10 Example 88 Preparation of (S)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester F 0 0 F F \N 0N o N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl} -pyrro lidin-3 -yl)-carbamic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)- [1 -(5-amino-pyridin-2-yl) pyrrolidin-3-yl]-carbamic acid tert-butyl ester. LCMS calcd for C25H26F3N504 (m/e) 20 517.6, obsd 518.2 (M+H). Example 89 Preparation of (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester WO 2008/141976 PCT/EP2008/055843 - 120 F Q 0 F "F o N N N Q0 N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)- [1 -(5 -amino-pyridin-2-yl) pyrrolidin-3-yl]-carbamic acid tert-butyl ester. LCMS calcd for C25H26F3N504 (m/e) 517.6, obsd 518.2 (M+H). 10 Example 90 Preparation of rac-methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester F 0 F \ I F \ / N N N N / 0 N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, racemic methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic [1-(5 amino-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester. LCMS calcd 20 for C26H28F3N504 (m/e) 531.5, obsd 532.2 (M+H). Example 91 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(R)-3 (acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide WO 2008/141976 PCT/EP2008/055843 - 121 F - 0 F F N NN / N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(R)-3 5 (acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic N-[1 -(5 -amino-pyridin 2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide followed by chiral SFC. LCMS called for C23H22F3N503 (m/e) 473.45, obsd 474.17 (M+H). [U] D= -15.2 10 Example 92 Preparation of rac-1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-pyrrolidine-3-carboxylic acid methyl ester F 0 F F N N N N N 0 0 \ With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, racemic 1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-pyridin-2-yl}-pyrrolidine-3-carboxylic acid methyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic 1-(5 -amino-pyridin-2 yl)-pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C22H19F3N404 (m/e) 20 460.4, obsd 461.1 (M+H). Example 93 Preparation of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 122 F Q 0 F ~ F N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5'-amino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester. LCMS calcd for C24H23F3N404 (m/e) 488.46, obsd 489.17 (M+H). 10 Example 94 Preparation of (1S,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino}-cyclopentanecarboxylic acid methyl ester F 0 F F o N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (iS,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino } -cyclopentanecarboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (IS ,3 S)-3 -(5 -amino-pyridin-2 ylamino)-cyclopentanecarboxylic acid methyl ester. LCMS calcd for C23H21F3N404 20 (m/e) 474.44, obsd 475.16 (M+H). Example 95 Preparation of (1R,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino}-cyclopentanecarboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 123 F 0 F _( I F \N /0 N 00 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (1R,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -pyridin-2-ylamino } -cyclopentanecarboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (1 R,3 S)-3 -(5 -amino-pyridin-2 ylamino)-cyclopentanecarboxylic acid ethyl ester. LCMS calcd for C24H23F3N404 (m/e) 488.46, obsd 489.17 (M+H). 10 Example 96 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester F Q 0 F F OI _y N_ 07( O 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-ylamino } -pyrrolidine- 1 -carboxylic acid tert-butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(5-amino pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS calcd for 20 C24H25F3N604 (m/e) 518.49, obsd 519.2 (M+H). Example 97 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((1S,3R)-3 dimethylcarbamoyl-cyclopentylamino)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 124 F S 0 F -< I FN
NNN
0 nI N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((iS,3R) 5 3-dimethylcarbamoyl-cyclopentylamino)-pyridin-3-yl]-amide was prepared from (1R,3S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 ylamino}-cyclopentanecarboxylic acid and dimethylamine hydrochloride. LCMS calcd for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H). 10 Example 98 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((1S,3S)-3 dimethylcarbamoyl-cyclopentylamino)-pyridin-3-yl]-amide F QO F EN
NN
0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((1S,3S) 3-dimethylcarbamoyl-cyclopentylamino)-pyridin-3-yl]-amide was prepared from (1S,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 ylamino}-cyclopentanecarboxylic acid and dimethylamine hydrochloride. LCMS calcd 20 for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H). Example 99 Preparation of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid dimethylamide WO 2008/141976 PCT/EP2008/055843 - 125 F 0__ 0 FF \F N N N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid dimethylamide was prepared from 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-carboxylic acid and dimethylamine hydrochloride. LCMS calcd for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H). 10 Example 100 Preparation of racemic trans- 2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid FE 0 F - N N o N. To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.25 g, 1 mmol) 15 and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.47 g, 1 mmol) in methylene chloride was added racemic trans-2-(4'-amino-biphenyl-4-carbonyl) cyclopentanecarboxylic acid (0.20 g, 0.78 mmol) and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated and the residue was re-dissolved in DMSO and acetonitrile. HPLC reverse 20 phase purification with acetonitrile and water afforded 44 mg of racemic trans-2-{4'-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid as a white solid. LCMS calcd for C30H23F3N205 (m/e) 548, obsd 549 (M+H). 25 Example 101 WO 2008/141976 PCT/EP2008/055843 - 126 Preparation of (1R,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl}-cyclopentanecarboxylic acid (or enantiomer) F F 0 F 0 N NN Racemic trans-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 5 4-carbonyl}-cyclopentanecarboxylic acid from above was separated by chiral SFC to afford (1R,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 4-carbonyl} -cyclopentanecarboxylic acid (or enantiomer). [a]D: -36.70 in CHC1 3 . Example 102 10 Preparation of (1S,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl}-cyclopentanecarboxylic acid (or enantiomer) F F 0 F N N' 00 0 0 Racemic trans-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 4-carbonyl}-cyclopentanecarboxylic acid from above was separated by chiral SFC to 15 afford (iS,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 4-carbonyl} -cyclopentanecarboxylic acid (or enantiomer). [a]D: +37.60 in CHC1 3 . Example 103 Preparation of (1R,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino] -biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer) WO 2008/141976 PCT/EP2008/055843 - 127 F F 0 F /\ N \- N N 0 0 With a method similar to that used for the preparation of racemic trans-2-{4'-[(2-phenyl 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, racemic 2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole 5 4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4' amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product obtained was separated by chiral SFC to afford (1R,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} -cyclohexanecarboxylic acid (or 10 enantiomer). [a]D: +25.40 in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd 563 (M+H). Example 104 Preparation of (1S,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer) FF 0 F - N N \---o N 00 With a method similar to that used for the preparation of racemic trans-2-{4'-[(2-phenyl 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, racemuc 2- {4'- [(2-phenyl-5 -trifluoromethyl-oxazo le 20 4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4' amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product obtained was separated by chiral SFC to afford (1S,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} -cyclohexanecarboxylic acid (or WO 2008/141976 PCT/EP2008/055843 - 128 enantiomer). [M]D: -230 in DMSO. LCMS called for C31H25F3N205 (m/e) 562, obsd 563 (M+H). Example 105 5 Preparation of (1R,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer) F F 0 F I N oNN 00 o o With a method similar to that used for the preparation of racemic trans-2-{4'-[(2-phenyl 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} 10 cyclopentanecarboxylic acid above, racemic 2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic cis-2-(4'-amino biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product was separated by chiral SFC to afford (1R,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [a]D: +11.70 in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd 563 (M+H). Example 106 Preparation of (1S,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino] -biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer) F F 0 F /\ N \- N N 0 N With a method similar to that used for the preparation of racemic trans-2-{4'-[(2-phenyl 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, racemic 2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole- WO 2008/141976 PCT/EP2008/055843 - 129 4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and cis-2-(4'-amino biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product was separated by chiral SFC to afford (iS,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -biphenyl-4-carbonyl} -cyclohexanecarboxylic acid (or enantiomer). [a]D: -23.80 in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd 563 (M+H). Example 107 Preparation of 2,2-dimethyl-3-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 10 amino] -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4-yl}-propionic acid F F F N N N N O 0 To a suspension of 2,2-dimethyl-3-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl) propionic acid (153.5 mg, 0.5 mmol) in methanol (30 mL) and tetrahydrofuran (5 mL) was added 10% of palladium on carbon (30 mg). The mixture was hydrogenated at 50 psi 15 for 2 hrs. The mixture was filtered and the solvents were evaporated. The resulting aminopyridine derivative was reacted with 2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl chloride (prepared from the corresponding carboxylic acid (128.5 mg, 0.5 mmol), oxalyl chloride and catalytic amount of N,N-dimethylformamide) at room temperature. After concentration, the residue was partitioned between methylene chloride 20 and water. The organic layer was washed with aqueous citric acid solution and dried over sodium sulfate. The solvents were evaporated and the residue was dried in vacuum. The crude product was triturated with methanol (4 mL) and the solid was filtered to give 2,2 dimethyl-3- {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-yl}-propionic acid (87 mg). LC-MS calcd. For 25 C26H27F3N404 (m/e) 516.1984, obsd 517.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 108 Preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 30 amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 130 F 0 \, F 0 N N o 0/ To a solution of racemic 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid ethyl ester (100 mg, 0.171 mmol) in 10 mL ethanol was added a solution of lithium hydroxide (14 mg, 0.342 5 mmol) in 5 mL water. The reaction mixture was stirred at room temperature for 4 hrs and then heated to 50 0 C for 1 hr. The reaction mixture was cooled, diluted with water, and washed with diethyl ether. The pH of the aqueous layer was adjusted to pH 5 with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by 10 flash chromatography (eluted with ethyl acetate/methylene chloride) to yield rac-2-(4- {4 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperazine- 1 carbonyl)-cyclopentanecarboxylic acid (27 mg, 28%). ES-MS calcd for C28H27F3N405 (m/e) 556.54, obsd 557.1 (M+H). 15 Example 109 Preparation of (1R,2R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F N 00 0 The racemic mixture of 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino] -phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid described above was purified by chiral supercritical fluid chromatography (first eluting peak) to yield (1R,2R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclopentanecarboxylic acid as an off-white solid. ES-MS calcd for C28H27F3N405 (m/e) 556.54, obsd 557 (M+H); [a]D -16.70. 25 Example 110 WO 2008/141976 PCT/EP2008/055843 - 131 Preparation of (1S,2S)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F
-
Nj Na 0 N N '' o 0 The racemic mixture of 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid described above was purified by chiral supercritical fluid chromatography (second eluting peak) to yield (S,S)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclopentanecarboxylic acid as an off-white solid. ES-MS calcd for C28H27F3N405 (m/e) 556.54, obsd 557 (M+H); [a]D +16.70. 10 Example 111 Preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid F o F -NN - N Noj 0 N 0 0 15 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 20 phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester and lithium hydroxide. ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.2 (M+H). Example 112 Preparation of (1R,3S)-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 132 F 0 F F N 0 N N 0 0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, racemic 3-(4-{4-[(2-phenyl-5-trifluoromethyl 5 oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester and lithium hydroxide. The crude racemate was purified by chiral supercritical fluid chromatography to yield (1R,3S)-3-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid as an off-white solid (first eluting peak). ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.1 (M+H). Example 113 Preparation of (1S,3R)-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid F o F I F N N o N .. N .. O NW o 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, racemic 3-(4-{4-[(2-phenyl-5-trifluoromethyl 20 oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester and lithium hydroxide. The crude racemate was purified by chiral supercritical fluid chromatography (second eluting peak) to yield (iS,3R)-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 25 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid as an off white solid. ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.1 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 133 Example 114 Preparation of (1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidin-4-yl)-acetic acid F F o FN - N o N 0 5 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, (1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-acetic acid was prepared from (1-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-4-yl)-acetic 10 acid ethyl ester and lithium hydroxide. LC-MS called for C24H22F3N304 (m/e) 473.2, obsd 474.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 115 15 Preparation of {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H- [1,2'] bipyridinyl-4-yl}-acetic acid F F oN FN - N O N O With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) 20 cyclopentanecarboxylic acid above, {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl} -acetic acid was prepared from {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-4-yl}-acetic acid ethyl ester and lithium hydroxide. LC-MS calcd for C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The NMR spectrum obtained on 25 the sample is compatible with its structure. Example 116 WO 2008/141976 PCT/EP2008/055843 - 134 Preparation of rac-2-[(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-amino] -cyclopentanecarboxylic acid F 0 F N N o 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, racemic 2-[(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-amino] cyclopentanecarboxylic acid was prepared from racemic 2-[(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl)-amino] 10 cyclopentanecarboxylic acid methyl ester and lithium hydroxide. LC-MS called for C28H28F3N505 (m/e) 571.6, obsd 572 (M+H). Example 117 Preparation of rac-1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 15 amino] -phenyl}-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid F 0 F F NN N N N No O With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, racemic 1-(4-{4-[(2-phenyl-5-trifluoromethyl 20 oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid was prepared from racemic 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid methyl ester and lithium hydroxide. LC-MS calcd for C27H26F3N505 (m/e) 557.5, obsd 558.1 (M+H). 25 Example 118 WO 2008/141976 PCT/EP2008/055843 - 135 Preparation of (1S,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino}-cyclopentanecarboxylic acid F - 0 F F N N N 0 N"O 1O 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, (iS,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-pyridin-2-ylamino}-cyclopentanecarboxylic acid was prepared from (IS,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 ylamino}-cyclopentanecarboxylic acid methyl ester and lithium hydroxide. LCMS called 10 for C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H). Example 119 Preparation of (1R,3S)-3-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino}-cyclopentanecarboxylic acid F 0 F F N N 0 , N5: " 15 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, (1R,3S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-pyridin-2-ylamino}-cyclopentanecarboxylic acid was prepared from 20 (1R,3S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 ylamino}-cyclopentanecarboxylic acid methyl ester and lithium hydroxide. LCMS calcd for C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H). Example 120 25 Preparation of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid WO 2008/141976 PCT/EP2008/055843 - 136 F - 0 F N N I N N 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-carboxylic acid was prepared from 5' [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-carboxylic acid methyl ester and lithium hydroxide. LCMS called for C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H). 10 Example 121 Preparation of 2,2-dimethyl-4-oxo-4-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-yl}-butyric acid F F 0 F N N 0 0 With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclopentanecarboxylic acid above, 2,2-dimethyl-4-oxo-4- {4'-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-yl}-butyric acid was prepared from 2,2-dimethyl-4-oxo-4- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-biphenyl-4-yl}-butyric acid methyl ester and lithium hydroxide. LCMS calcd for 20 C29H23F3N205 (m/e) 536, obsd 537 (M+H). Example 122 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-acetyl piperazin-1-yl)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 137 F F 0 F N - N Ij0 N 0 To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1 yl-pyridin-3-yl)-amide hydrochloride salt (65 mg, 0.13 mmol) in methylene chloride (5 mL) was added triethylamine (0.15 mL). The mixture was cooled in an ice bath and 5 acetyl chloride (12 tL) was added. The mixture was stirred at room temperature for 30 minutes and partitioned between methylene chloride and brine. The organic layer was dried over sodium sulfate and the solvents were evaporated. The residue was first dried in vacuum and then triturated with methanol (3 mL) to give 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide (21 mg) as a 1o solid. LC-MS calcd for C22H20F3N503 (m/e) 459.2, obsd 460.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 123 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 15 isobutyryl-piperazin-1-yl)-pyridin-3-yl]-amide F F 0 IF N -N N N N 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-isobutyryl-piperazin- 1 -yl) 20 pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and isobutyryl chloride. LC-MS calcd for C24H24F3N503 (m/e) 487.2, obsd. 488.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Example 124 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 138 F F 0 F - N O N N N 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-cyclopropanecarbonyl 5 piperazin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and cyclopropanecarbonyl chloride. LC-MS calcd for C24H22F3N503 (m/e) 485.2, obsd 486.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 125 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 propionyl-piperazin-1-yl)-pyridin-3-yl]-amide F F 0 IF N -N N N 0 15 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-propionyl-piperazin- 1-yl) pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and propionyl chloride. 20 LC-MS called for C23H22F3N503 (m/e) 473.2, obsd 474.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 126 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(2,2 25 dimethyl-propionyl)-piperazin-1-yl]-pyridin-3-yl}-amide WO 2008/141976 PCT/EP2008/055843 - 139 F F 0 F - N jj0 N N N 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(2,2-dimethyl-propionyl) 5 piperazin-1-yl]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and pivaloyl chloride. LC-MS calcd for C25H26F3N503 (m/e) 501.2, obsd 502.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 127 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(1 cyclopropanecarbonyl-piperidin-4-yl)-phenyl]-amide F F 0 IF N N N 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 15 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(1 -cyclopropanecarbonyl piperidin-4-yl)-phenyl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cyclopropanecarbonyl chloride. LC MS calcd for C26H24F3N303 (m/e) 483.2, obsd 484.3 (M+H). The NMR spectrum 20 obtained on the sample is compatible with its structure. Example 128 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1 isobutyryl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 140 F - 0 F N NN Nl 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-isobutyryl-pyrrolidin-3 5 ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide and isobutyryl chloride. LCMS calcd for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H). Example 129 10 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1 methanesulfonyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide F - 0 F F N N N 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 15 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)- 1 -methanesulfonyl pyrrolidin-3-ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin-3-yl] amide and methane sulfonyl chloride. LCMS calcd for C21H20F3N504S (m/e) 495.5, obsd 496.1 (M+H). 20 Example 130 Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3 (isobutyryl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide WO 2008/141976 PCT/EP2008/055843 - 141 F - 0 F F \N 0N N N Q0 /N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, racemic 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(isobutyryl-methyl 5 amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methylamino-pyrrolidin-1-yl)-pyridin-3 yl]-amide and isobutyryl chloride. LCMS calcd for C25H26F3N503 (m/e) 501.51, obsd 502.21 (M+H). 10 Example 131 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6 (1-cyclopropanecarbonyl-piperidin-4-ylamino)-pyridin-3-yl]-amide F F O F - Nj Nn- N 0O N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 15 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 -cyclopropanecarbonyl piperidin-4-ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and cyclopropanecarbonyl chloride. LCMS calcd for C25H24F3N503 (m/e) 499, obsd 20 500 (M+H). Example 132 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 phenylacetyl-piperidin-4-ylamino)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 142 FE F F 0 "I N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 -cyclopropanecarbonyl 5 piperidin-4-ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and phenyl-acetyl chloride. LCMS calcd for C29H26F3N503 (m/e) 549, obsd 550 (M+H). 10 Example 133 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(2,2,2 trifluoro-acetyl)-piperidin-4-ylamino]-pyridin-3-yl}-amide FF 0 F 0 /\ "~ N F N N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 15 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(2,2,2-trifluoro-acetyl) piperidin-4-ylamino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and trifluoroacetic anhydride. LCMS calcd for C23H19F6N503 (m/e) 20 527, obsd 528 (M+H). Example 134 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(3,3 dimethyl-butyryl)-piperidin-4-ylamino]-pyridin-3-yl}-amide FF 10 IF 0
-
"Nj N z 25 N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2- WO 2008/141976 PCT/EP2008/055843 - 143 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6- [1-(3,3 -dimethyl-butyryl) piperidin-4-ylamino]-pyridin-3-yl} -amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and 3,3-dimethyl-butyryl chloride. LCMS calcd for C27H30F3N503 5 (m/e) 529, obsd 530 (M+H). Example 135 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-butyryl piperidin-4-ylamino)-pyridin-3-yl]-amide F F 0 F 0 S N N 10 N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-butyryl-piperidin-4-ylamino) pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic 15 acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and butyryl chloride. LCMS calcd for C25H26F3N503 (m/e) 501, obsd 502 (M+H). Example 136 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 20 isobutyryl-piperidin-4-ylamino)-pyridin-3-yl]-amide F F 0 F N N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 -isobutyryl-piperidin-4 25 ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and isobutyryl chloride. LCMS calcd for C25H26F3N503 (m/e) 501, obsd 502 (M+H). Example 137 WO 2008/141976 PCT/EP2008/055843 - 144 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 propionyl-piperidin-4-ylamino)-pyridin-3-yl]-amide F F 0 F 0 /\ HN N a N N N NN With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 5 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 -propionyl-piperidin-4 ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and propionyl chloride. LCMS calcd for C24H24F3N503 (m/e) 487, obsd 488 (M+H). 10 Example 138 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 pentanoyl-piperidin-4-ylamino)-pyridin-3-yl]-amide F F 0 F 0 - N NN Na 0 N N 15 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1 -pentanoyl-piperidin-4 ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and 20 pentanoyl chloride. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H). Example 139 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(2 cyclopentyl-acetyl)-piperidin-4-ylamino]-pyridin-3-yl}-amide F F 0 IF 0 / O N N 25 N 25 N N WO 2008/141976 PCT/EP2008/055843 - 145 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(2-cyclopentyl-acetyl) piperidin-4-ylamino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5 5 trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and cyclopentyl-acetyl chloride. LCMS calcd for C28H30F3N503 (m/e) 541, obsd 542 (M+H). Example 140 10 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(3 methyl-butyryl)-piperidin-4-ylamino]-pyridin-3-yl}-amide F F 0 F 0 - N NN 0 N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 15 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(3-methyl-butyryl)-piperidin 4-ylamino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole 4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide trifluoroacetate and 3 methyl-butyryl chloride. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H). 20 Example 141 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(4 methyl-pentanoyl)-piperidin-4-ylamino]-pyridin-3-yl}-amide F F 0 F 0 - N N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 25 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[1-(4-methyl-pentanoyl) piperidin-4-ylamino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl]-amide WO 2008/141976 PCT/EP2008/055843 - 146 trifluoroacetate and 4-methyl-pentanoyl chloride. LCMS called for C27H30F3N503 (m/e) 529, obsd 530 (M+H). Example 142 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl pentanoyl-amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F o F N n o N N 0 N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 10 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-pentanoyl-amino) 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and pentanoyl chloride. LCMS calcd for C27H30F3N503 (m/e) 529, obsd 530 (M+H). 15 Example 143 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(2 cyclopentyl-acetyl)-methyl-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl} amide F F o F N n N N 0 20 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(2-cyclopentyl-acetyl)-methyl amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 25 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro- WO 2008/141976 PCT/EP2008/055843 - 147 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and cyclopentylacetyl chloride. LCMS called for C29H32F3N503 (m/e) 555, obsd 556 (M+H). Example 144 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4 (cyclopropanecarbonyl-methyl-amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5' yl]-amide F F O F NN 0 N O With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl Io oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(cyclopropanecarbonyl-methyl amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and cyclopropanecarbonyl chloride. LCMS 15 calcd for C26H26F3N503 (m/e) 513, obsd 514 (M+H). Example 145 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl propionyl-amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F O F N N N N 0 N 20 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-propionyl-amino) 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl-5 25 trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H- WO 2008/141976 PCT/EP2008/055843 - 148 [1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and propionyl chloride. LCMS called for C25H26F3N503 (m/e) 501, obsd 502 (M+H). Example 146 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(3,3 dimethyl-butyryl)-methyl-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl} amide F F o F N N N O N N 0 N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl Io oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(3,3-dimethyl-butyryl)-methyl amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and tert-butylacetyl chloride. LCMS 15 calcd for C28H32F3N503 (m/e) 543, obsd 544 (M+H). Example 147 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(isobutyryl methyl-amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F o F - N N N 0 NN O 20 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(isobutyryl-methyl-amino) 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl-5 25 trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H- WO 2008/141976 PCT/EP2008/055843 - 149 [1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and isobutyryl chloride. LCMS called for C26H28F3N503 (m/e) 515, obsd 516 (M+H). Example 148 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(3 methyl-butyryl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl}-amide F F o F N N N N 0 NAIL With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 10 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(3-methyl-butyryl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and isovaleryl chloride. LCMS called for C27H30F3N503 (m/e) 529, obsd 530 (M+H). 15 Example 149 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(butyryl methyl-amino)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F o F N n N N 0 N 20 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(butyryl-methyl-amino)-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H 25 [1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and butyryl chloride. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 150 Example 150 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl (3,3,3-trifluoro-propionyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl} 5 amide F F OF -0 F N N 0 F aN F With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(3,3,3-trifluoro 10 propionyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and 3,3,3-trifluoropropionyl chloride. LCMS called for C25H23F6N503 (m/e) 555, obsd 556 (M+H). 15 Example 151 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(4 methyl-pentanoyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl}-amide F F 0 F -Nn 0 N N 0 NN With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 20 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(4-methyl-pentanoyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and 4-methyl-pentanoyl chloride. 25 LCMS calcd for C28H32F3N503 (m/e) 543, obsd 544 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 151 Example 152 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(2 methoxy-acetyl)-methyl-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl} amide F F O F N N N 0 N 5 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[(2-methoxy-acetyl)-methyl amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 10 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and methoxyacetyl chloride. LCMS calcd for C25H26F3N504 (m/e) 517, obsd 518 (M+H). Example 153 15 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl (2,2,2-trifluoro-acetyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl}-amide F F o F N N N 0 F I F F With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 20 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-(2,2,2-trifluoro-acetyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-5'-yl} -amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro 2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and trifluoroacetic anhydride. LCMS calcd for C24H21F6N503 (m/e) 541, obsd 542 (M+H). 25 Example 154 WO 2008/141976 PCT/EP2008/055843 - 152 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester F F 0 F - N F N N N O To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1 5 yl-pyridin-3-yl)-amide hydrochloride salt (50 mg, 0.102 mmol) in methylene chloride (6 mL) was added triethylamine (0.1 mL). The clear solution was cooled in an ice bath and isopropylchloroformate (IM in toluene, 0.2 mL) was added. The mixture was stirred at 0 0 C for 30 minutes and at room temperature for 1 hr. The solvents were evaporated and the residue was triturated with methanol. The precipitate was filtered and dried to give 4 10 {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1 carboxylic acid isopropyl ester (32.4 mg). LC-MS calcd for C24H24F3N504 (m/e) 503.2, obsd 503.8 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 15 Example 155 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester F F - NN N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and ethyl chloroformate. LC-MS calcd for C23H22F3N504 (m/e) 25 489.2, obsd 490.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
WO 2008/141976 PCT/EP2008/055843 - 153 Example 156 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid methyl ester F F 0 F - N jj0 N N 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid methyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide 10 hydrochloride salt and methyl chloroformate. LC-MS calcd for C22H20F3N504 (m/e) 475.1, obsd 476.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 157 15 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid propyl ester F F 0 F /N - N N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 20 isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid propyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and propyl chloroformate. LC-MS calcd for C24H24F3N504 (m/e) 503.2, obsd 504.0 (M+H). The NMR spectrum obtained on the sample is compatible with 25 its structure. Example 158 WO 2008/141976 PCT/EP2008/055843 - 154 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid isobutyl ester F F _ IF N jj0 N N N O With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid isobutyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt and isobutyl chloroformate. LC-MS calcd for C25H26F3N504 (m/e) io 517.2, obsd 518.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 159 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 15 pyrimidin-2-yl}-piperazine-1-carboxylic acid methyl ester F F N N o N O0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 20 pyrimidin-2-yl}-piperazine-1-carboxylic acid methyl ester was prepared from 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide and methyl chloroformate. LC-MS calcd for C21H19F3N604 (m/e) 476.1, obsd 477.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Example 160 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 155 F F F O N 0 O N O With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 phenyl}-piperidine-1-carboxylic acid methyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and methyl chloroformate. LC-MS called for C24H22F3N304 (m/e) 473.2, obsd 474.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 161 Preparation of 5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid methyl ester F F o F N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-l'-carboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro [2,4']bipyridinyl-5-yl)-amide and methyl chloroformate. LC-MS calcd for 20 C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 162 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 25 phenyl}-piperazine-1-carboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 156 FEF 0 F FN N NN N o0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 phenyl}-piperazine-1-carboxylic acid methyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide and methyl chloroformate. LC-MS called for C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 163 Preparation of 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-pyridin-2-yl)-piperazine-1-carboxylic acid ethyl ester F /N F F F N F F N 0 N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl] -amino } -pyridin-2-yl)-piperazine- 1 -carboxylic acid ethyl ester was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (6-piperazin 1-yl-pyridin-3-yl)-amide and ethyl chloroformate. LCMS calcd for C23H22F4N603 20 (m/e) 506, obsd 507 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 164 Preparation of 4-{5-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] 25 pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 157 0--c N N" N N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] 5 pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester was prepared from 5-methyl-2 phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and ethyl chloroformate. LCMS called for C22H25N703 (m/e) 435, obsd 436 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 165 Preparation of 4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] phenyl}-piperidine-1-carboxylic acid methyl ester N F F F N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-phenyl} -piperidine- 1 -carboxylic acid methyl ester was prepared from 1-phenyl 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and methyl chloroformate. LCMS calcd for C24H23F3N403 (m/e) 472, obsd 473 (M+H). 20 The NMR spectrum obtained on the sample is compatible with its structure. Example 166 WO 2008/141976 PCT/EP2008/055843 - 158 Preparation of 4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] phenyl}-piperidine-1-carboxylic acid ethyl ester N FF F
-
N F F N 0 N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-phenyl} -piperidine- 1 -carboxylic acid ethyl ester was prepared from 1-phenyl-3 trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and ethyl chloroformate. LCMS called for C25H25F3N403 (m/e) 486, obsd 487 (M+H). The NMR 10 spectrum obtained on the sample is compatible with its structure. Example 167 Preparation of 4-(5-{[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbonyl] amino}-pyridin-2-yl)-piperazine-1-carboxylic acid ethyl ester /\ N~ N ND 15 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-(5-{[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbonyl] amino}-pyridin-2-yl)-piperazine-1-carboxylic acid ethyl ester was prepared from 2-(2 20 methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl) amide and ethyl chloroformate. LCMS calcd for C25H30N604 (m/e) 478, obsd 479
(M+H).
WO 2008/141976 PCT/EP2008/055843 - 159 Example 168 Preparation of 4-{5-[(5-methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl) amino] -pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester No N N 0 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(5-methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl) amino]-pyridin-2-yl}-piperazine-1-carboxylic acid ethyl ester was prepared from 5 methoxymethyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-piperazin-1-yl-pyridin 1o 3-yl)-amide and ethyl chloroformate. LCMS called for C23H27N704 (m/e) 465, obsd 466 (M+H). Example 169 Preparation of 4-{4-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] 15 phenyl}-piperidine-1-carboxylic acid ethyl ester N N N' N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] 20 phenyl}-piperidine-1-carboxylic acid ethyl ester was prepared from 5-methyl-2-phenyl 2H-[1,2,3]triazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and ethyl chloroformate. LCMS calcd for C24H27N503 (m/e) 433, obsd 434 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
WO 2008/141976 PCT/EP2008/055843 - 160 Example 170 Preparation of 4-{4-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] phenyl}-piperidine-1-carboxylic acid methyl ester N N N N 0 N -0 0 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino] phenyl} -piperidine- 1 -carboxylic acid methyl ester was prepared from 5 -methyl-2-phenyl 2H-[1,2,3]triazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and methyl 1o chloroformate. LCMS called for C23H25N503 (m/e) 419, obsd 420 (M+H). (37660-298 2) Example 171 Preparation of 4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 15 carbonyl]-amino}-phenyl)-piperidine-1-carboxylic acid ethyl ester N F F - N N N oo With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-(4-{[1-(2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 20 carbonyl]-amino}-phenyl)-piperidine-1-carboxylic acid ethyl ester was prepared from 1 (2-chloro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl phenyl)-amide and ethyl chloroformate. LCMS calcd for C25H24ClF3N403 (m/e) 520, obsd 521 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 161 Example 172 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester F - 0 F F N NN 0 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3-ylamino) 10 pyridin-3-yl]-amide and ethyl chloroformate. LCMS called for C23H22F3N504 (m/e) 489.45, obsd 490.17 (M+H). Example 173 Preparation of (R)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 15 pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester F 0 F N F N 00 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (R)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-pyrrolidin-3-ylamino) pyridin-3-yl]-amide and ethyl chloroformate. LCMS calcd for C23H22F3N504 (m/e) 489.45, obsd 490.17 (M+H). 25 Example 174 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 162 F F OEN 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino]-pyridin-2-ylamino} -pyrrolidine- 1 -carboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3 ylamino)-pyridin-3-yl]-amide and methyl chloroformate. LCMS called for C22 H20 F3 N5 04 (m/e) 475.43, obsd 476.15 (M+H). 10 Example 175 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid isopropyl ester F G 0 F \ / N F N o N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid isopropyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3 ylamino)-pyridin-3-yl]-amide and isopropyl chloroformate. LCMS calcd for 20 C24H24F3N504 (m/e) 503.48, obsd 504.19 (M+H). Example 176 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid benzyl ester WO 2008/141976 PCT/EP2008/055843 - 163 F 0 F \\ I0 o NN With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -pyridin-2-ylamino } -pyrrolidine- 1 -carboxylic acid benzyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3-ylamino) pyridin-3-yl]-amide and benzyl chloroformate. LCMS called for C28H24F3N504 (m/e) 551.52, obsd 552.18 (M+H). 10 Example 177 Preparation of (S)-3-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-amino)-pyrrolidine-1-carboxylic acid ethyl ester F 0 F N O F o N 0 -/ With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3-(methyl- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-amino)-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-methyl pyrrolidin-3-yl-amino)-pyridin-3-yl]-amide and ethyl chloroformate. LCMS called for 20 C24H24F3N504 (m/e) 503.48, obsd 504.19 (M+H). Example 178 Preparation of rac-methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 164 F - 0 F F o N NN 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, racemic methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid methyl ester was prepared from racemic 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methylamino -pyrrolidin-1-yl)-pyridin-3-yl]-amide and methyl chloroformate. LCMS called for C23H22F3N504 (m/e) 489.45, obsd 490.17 (M+H). 10 Example 179 Preparation of (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid methyl ester F - 0 F F N N N__ 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (R)-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid methyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-3 -amino-pyrrolidin- 1-yl) pyridin-3-yl]-amide and methyl chloroformate. LCMS calcd for C22H20F3N504 (m/e) 20 475.43, obsd 476.15 (M+H). Example 180 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester WO 2008/141976 PCT/EP2008/055843 - 165 F 0 F F \~ /N >- 0 N "' N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino]-pyrimidin-2-ylamino} -pyrrolidine- 1 -carboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-pyrrolidin-3 ylamino)-pyrimidin-5-yl]-amide and methyl chloroformate. LCMS called for C21H19F3N604 (m/e) 476.41, obsd 477.15 (M+H). 10 Example 181 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester F - 0 F F / N N 0 0 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-pyrimidin-2-ylamino} -pyrrolidine- 1 -carboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-pyrrolidin-3 ylamino)-pyrimidin-5-yl]-amide and ethyl chloroformate. LCMS calcd for 20 C22H21F3N604 (m/e) 490.44, obsd 491.16 (M+H). Example 182 Preparation of (S)-3-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester S N N 0 I_ C N 0/ 25 N0 250 WO 2008/141976 PCT/EP2008/055843 - 166 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, (S)-3-{5-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 4 5 methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin 3-yl]-amide and ethyl chloroformate. LCMS called for C22H24N603S (m/e) 452.54, obsd 453.17 (M+H). Example 183 10 Preparation of 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carboxylic acid ethyl ester F F F 0 0 0-\ N N N N-K H \ \,/ 0 N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 15 isopropyl ester above, 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-phenyl} -piperazine- 1 -carboxylic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (3-cyano-4-piperazin-1-yl-phenyl)-amide and ethyl chloroformate. LCMS for C25H22F3N504 (m/e) calc. 513, obsd 514 (M+H). 20 Example 184 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid butyl ester F F0 F N - N/ N4 N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 25 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid butyl ester was prepared from 2-phenyl-5- WO 2008/141976 PCT/EP2008/055843 - 167 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide and butyl chloroformate. LCMS called for C26H27F3N404 (m/e) 516, obsd. 517 (M+H). Example 185 5 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid isobutyl ester F F 0 F 0 0 N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 10 isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid isobutyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and isobutyl chloroformate. LCMS calcd for C26H28F3N504 (m/e) 531, obsd 532 (M+H). 15 Example 186 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid methyl ester F F 0 F0 N N N N 00 N N N C 20 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid methyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 25 yl]-amide trifluoroacetate and methyl chloroformate. LCMS calcd for C23H22F3N504 (m/e) 489, obsd 490 (M+H). Example 187 WO 2008/141976 PCT/EP2008/055843 - 168 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid ethyl ester F F 0 F - \N N N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino } -piperidine- 1 -carboxylic acid ethyl ester was prepared from 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-yl] amide trifluoroacetate and ethyl chloroformate. LCMS called for C24H24F3N504 (m/e) 10 503, obsd 504 (M+H). Example 188 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester F F 0 F 0 0i 15 N N NO With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino } -piperidine- 1 -carboxylic acid 2,2-dimethyl-propyl ester was prepared 20 from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino) pyridin-3-yl]-amide trifluoroacetate and 2,2-dimethylpropyl chloroformate. LCMS calcd for C27H30F3N504 (m/e) 545, obsd 546 (M+H). Example 189 25 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid isopropyl ester WO 2008/141976 PCT/EP2008/055843 - 169 F F 0 F - \N N N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 pyridin-2-ylamino}-piperidine-1-carboxylic acid isopropyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and isopropyl chloroformate. LCMS called for C25H26F3N504 (m/e) 517, obsd 518 (M+H). 10 Example 190 Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid methyl ester F F 0 F N N N 0 NO With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -carbamic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and methyl 20 chloroformate. LCMS calcd for C24H24F3N504 (m/e) 503, obsd 504 (M+H). Example 191 Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 170 F F O F N N N N 0 N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -carbamic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and ethyl chloroformate. LCMS called for C25H26F3N504 (m/e) 517, obsd 518 (M+H). 10 Example 192 Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid isobutyl ester F F 0 F N) Nn 0 N N 0 N 'O With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -carbamic acid isobutyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and isobutyl 20 chloroformate. LCMS calcd for C27H30F3N504 (m/e) 545, obsd 546 (M+H). Example 193 Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid 2,2-dimethyl-propyl 25 ester WO 2008/141976 PCT/EP2008/055843 - 171 FF 0 F NN -Nn 0 N N 0 N'J O With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -carbamic acid 2,2-dimethyl-propyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 methylamino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and 2,2-dimethylpropyl chloroformate. LCMS called for C28H32F3N504 (m/e) 559, obsd 560 (M+H). 10 Example 194 Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamic acid isopropenyl ester F F o F N NN N N N0O 15 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl} -carbamic acid isopropenyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 20 methylamino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and isopropenyl chloroformate. LCMS calcd for C26H26F3N504 (m/e) 529, obsd 530 (M+H). Example 195 25 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid propylamide WO 2008/141976 PCT/EP2008/055843 - 172 F 0 F F N 0 NN 0 To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl phenyl)-amide hydrochloride (100 mg, 0.204 mmol) and triethylamine (57 tL, 0.408 mmol) in 5 mL THF at 0 0 C was added n-propylisocyanate (21.6 mg, 0.255 mmol). The 5 ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to yield 4-{4-[(2-phenyl-5-trifluoromethyl 10 oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid propylamide (83 mg, 81%). ES-MS calcd for C25H26F3N503 (m/e) 501.51, obsd 502.1 (M+H). Example 196 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 15 phenyl}-piperazine-1-carboxylic acid isopropylamide F o F F N N N N With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 20 phenyl}-piperazine-1-carboxylic acid isopropylamide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and isopropylisocyanate. LC-MS calcd for C25H26F3N503 (m/e) 501.5, obsd 502.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 25 Example 197 WO 2008/141976 PCT/EP2008/055843 - 173 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid propylamide F F F NN N N N N 0 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid propylamide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride and propylisocyanate. LC-MS calcd for C24H25F3N603 (m/e) 502.2, io obsd 503.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 198 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-tert 15 butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide F - 0 F 0 N F N N "CN o N N 0 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-tert 20 butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin-3-yl] amide and tert-butyl isocyanate. LCMS calcd for C25H27F3N603 (m/e) 516.52, obsd 517.2 (M+H). 25 Example 199 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino pyridin-2-ylamino}-piperidine-1-carboxylic acid butylamide WO 2008/141976 PCT/EP2008/055843 - 174 F F 0 F N NI N Na With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino 5 pyridin-2-ylamino}-piperidine-1-carboxylic acid butylamide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and butyl isocyanate. LCMS called for C26H29F3N603 (m/e) 530, obsd 531 (M+H). 10 Example 200 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid cyclohexylamide F F 0 F 0 Na 0 N NJ: With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid cyclohexylamide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and cyclohexyl isocyanate. LCMS calcd for C28H31F3N603 20 (m/e) 556, obsd 557 (M+H). Example 201 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid benzylamide F F 0 F 0 N NN 25 N N WO 2008/141976 PCT/EP2008/055843 - 175 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid benzylamide was prepared from 2 5 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and benzyl isocyanate. LCMS called for C29H27F3N603 (m/e) 564, obsd 565 (M+H). Example 202 10 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid methylamide F F O F Nn IN\ N N 0 N N C With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid 15 propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-piperidine-1-carboxylic acid methylamide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3 yl]-amide trifluoroacetate and methyl isocyanate. LCMS calcd for C23H23F3N603 (m/e) 488, obsd 489 (M+H). 20 Example 203 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3 isopropyl-1-methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F 0 F N N 0 N N 0 N N 25 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3 isopropyl-1-methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was WO 2008/141976 PCT/EP2008/055843 - 176 prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and isopropyl isocyanate. LCMS called for C26H29F3N603 (m/e) 530, obsd 531 (M+H). 5 Example 204 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-butyl-1 methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide F F O F N N 0 N N 0 N N With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-butyl-1 methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide trifluoroacetate and butyl isocyanate. LCMS 15 calcd for C27H31F3N603 (m/e) 544, obsd 545 (M+H). Example 205 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-piperazine-1-carboxylic acid dimethylamide F o F N F F N - N 0 N N 20 0 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl} -piperazine- 1 -carboxylic acid dimethylamide was prepared from 2-phenyl 25 5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin- 1 -yl-pyridin-3 -yl)-amide hydrochloride and N,N-dimethylcarbamoyl chloride. LC-MS calcd for C23H23F3N603 WO 2008/141976 PCT/EP2008/055843 - 177 (m/e) 488.2, obsd 489.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 206 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1 dimethylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide F OO F ON
N
With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid 10 propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1 dimethylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidin-3-ylamino) pyridin-3-yl]-amide and dimethyl carbamoyl chloride. LCMS calcd for C23H23F3N603 (m/e) 488.47, obsd 489.18 (M+H). 15 Example 207 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid (3-methyl-pyridin-2-yl)-amide F 0 FF N N 0 N N N 20 To a solution of 2-amino-3-picoline (26 tL, 0.204 mmol) and triethylamine (63 tL, 0.448 mmol) in 5 mL methylene chloride at -40'C was slowly added a 20% solution of phosgene in THF (118 tL, 0.224 mmol). The reaction mixture was stirred at -40'C for 1 hr and then a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 piperazin-1-yl-phenyl)-amide hydrochloride (100 mg, 0.204 mmol) and triethylamine (57 25 ptl, 0.408 mmol) in 8 ml of 1-methyl-2-pyrrolidinone was slowly added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and WO 2008/141976 PCT/EP2008/055843 - 178 washed with saturated sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (eluting with ethyl acetate/hexane) to yield 4-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic 5 acid (3-methyl-pyridin-2-yl)-amide (18 mg, 16%). ES-MS calcd for C28H25F3N603 (m/e) 550.6, obsd 551.1 (M+H). Example 208 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 phenyl}-piperazine-1-carboxylic acid ethylamide F O F \N F N N N N Y O With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid (3 methyl-pyridin-2-yl)-amide above, 4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 15 carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid ethylamide was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and ethylamine. LC-MS calcd for C24H24F3N503 (m/e) 487.5, obsd 488.1 (M+H). 20 Example 209 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid ethyl-methyl-amide F 0 F
-
N1 N N N 0 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 25 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid (3 methyl-pyridin-2-yl)-amide above, 4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4- WO 2008/141976 PCT/EP2008/055843 - 179 carbonyl)-amino]-phenyl} -piperazine- 1 -carboxylic acid ethyl-methyl-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl phenyl)-amide hydrochloride and N-ethylmethylamine. LC-MS calcd for C25H26F3N503 (m/e) 501.51, obsd 502.1 (M+H). 5 Example 210 Preparation of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carboxylic acid (5-methyl-isoxazol-3-yl)-amide F F F N N N O 00 10 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid (3 methyl-pyridin-2-yl)-amide above, 4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid (5-methyl-isoxazol-3-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1 15 yl-phenyl)-amide hydrochloride and 3-amino-5-methylisoxazole. LC-MS calcd for C26H23F3N604 (m/e) 540.4, obsd 541.1 (M+H). Example 211 Preparation of rac-2-[(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 20 amino] -phenyl}-piperazine-1-carbonyl)-amino] -cyclopentanecarboxylic acid methyl ester F OFO 0 F0 N N N With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid (3 25 methyl-pyridin-2-yl)-amide above, racemic 2-[(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-amino]- WO 2008/141976 PCT/EP2008/055843 - 180 cyclopentanecarboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride and racemic cis-2-aminocyclopentanecarboxylic acid methyl ester hydrochloride. LC-MS calcd for C29H30F3N505 (m/e) 585.6, obsd 586.1 (M+H). 5 Example 212 Preparation of rac-1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid methyl ester F 0 F \N F N O N 0 N 0 O/ 10 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid (3 methyl-pyridin-2-yl)-amide above, racemic 1-(4- {4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl} -piperazine- 1 -carbonyl)-pyrrolidine-3-carboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic 15 acid (4-piperazin-1-yl-phenyl)-amide hydrochloride and racemic pyrrolidine-3 carboxylic acid methyl ester hydrochloride. LC-MS calcd for C28H28F3N505 (m/e) 571.6, obsd 572.1 (M+H). Example 213 20 Preparation of 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-benzoic acid F F O F N N CI 0 N - 0 0 A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3 yl)-amide (600 mg, 1.46 mmol), (4-carboxy-2-chloro)benzeneboronic acid (437 mg, 2.18 25 mmol), tetrakis(triphenylphosphine)palladium(O) (84 mg, 0.07 mmol), and sodium carbonate (2M, 1.5 mL) in ethanol (10 mL) was microwaved at 160 0 C for 30 min. The WO 2008/141976 PCT/EP2008/055843 - 181 reaction was filtered and the precipitates were washed with ethanol. The combined filtrates were concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-25 % methanol in methylene chloride) to give 3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (506 5 mg, 71 %) as a light yellow solid. LCMS calcd for C23H13ClF3N304 (m/e) 487, obsd 488 (M+H). Example 214 Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 pyridin-2-yl}-benzoic acid F F 0 F NN 0 N N - 0 0 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid was 15 prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin 3-yl)-amide and 4-carboxyphenylboronic acid. LCMS calcd for C23H14F3N304 (m/e) 453, obsd 454 (M+H). Example 215 20 Preparation of 2-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-benzoic acid F F 0 F N N 0 c IN' 0 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-chloro 25 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic WO 2008/141976 PCT/EP2008/055843 - 182 acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo pyridin-3-yl)-amide and 4-carboxy-3-chlorophenylboronic acid. LCMS called for C23H13ClF3N304 (m/e) 487, obsd 488 (M+H). 5 Example 216 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide F F N N 01 N 0 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-isobutylcarbamoyl-phenyl)-pyridin-3 yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6 bromo-pyridin-3-yl)-amide and 4-(isobutylaminocarbonyl)benzeneboronic acid. LCMS calcd for C27H23F3N403 (m/e) 508, obsd 509 (M+H). 15 Example 217 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4' isobutylcarbamoyl-biphenyl-4-yl)-amide F F 0 1F N N N 0 20 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid (4'-isobutylcarbamoyl-biphenyl-4-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo phenyl)-amide and 4-(isobutylaminocarbonyl)benzeneboronic acid. LCMS calcd for 25 C28H24F3N303 (m/e) 507, obsd 508 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 183 Example 218 Preparation of 4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-carboxylic acid F F 0 F N o 0 5 0 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 4'-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl) 1o amide and 4-carboxyphenylboronic acid. LCMS calcd for C24H15F3N204 (m/e) 452, obsd 453 (M+H). Example 219 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 15 cyclopentylcarbamoyl-phenyl)-pyridin-3-yl]-amide F o F 0: F N N 0 N / With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-cyclopentylcarbamoyl-phenyl) 20 pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide and 4-(cyclopentylaminocarbonyl)benzeneboronic acid. LCMS calcd for C28H23F3N403 (m/e) 520, obsd 521 (M+H). Example 220 WO 2008/141976 PCT/EP2008/055843 - 184 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 cyclopropylcarbamoyl-phenyl)-pyridin-3-yl]-amide F F 0: F o N N /s N 0> With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-cyclopropylcarbamoyl-phenyl) pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide and 4-(N-cyclopropylaminocarbonyl)phenylboronic acid. LCMS calcd for C26H19F3N403 (m/e) 492, obsd 493 (M+H). 10 Example 221 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4' cyclopropylcarbamoyl-biphenyl-4-yl)-amide F kF '0 F 15 - N N NN 0 20 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-phenyl 5-trifluoromethyl-oxazole-4-carboxylic acid (4'-cyclopropylcarbamoyl-biphenyl-4-yl) amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo phenyl)-amide and 4-(N-cyclopropylaminocarbonyl) phenylboronic acid. LCMS calcd 25 for C27H20F3N303 (m/e) 491, obsd 492 (M+H). Example 222 Preparation of (R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid WO 2008/141976 PCT/EP2008/055843 - 185 F N I N ND 0o0 ,--O A mixture of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 yl}-benzoic acid (45 mg, 0.1 mmol), D-proline t-butyl ester hydrochloride (31 mg, 0.15 mmol), triethylamine (50 tL, 0.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (20 mg, 5 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give (R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 10 amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (51 mg, 84 %) as a white solid. (R)-1-(4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} benzoyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (37 mg) from above was treated 15 with 2 mL of trifluoroacetic acid and stirred at room temperature for one hour. The reaction was concentrated and the product was lyophilized to give 27 mg of (R)-1-(4-{5 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} -benzoyl) pyrrolidine-2-carboxylic acid as a white powder. LCMS calcd for C28H21F3N405 (m/e) 550, obsd 551 (M+H). 20 Example 223 Preparation of (S)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid FF o F N I N N 0 OT0 25 With a method similar to that used for the preparation of (R)-1-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2- WO 2008/141976 PCT/EP2008/055843 - 186 carboxylic acid above, (S)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl} -benzoyl)-pyrrolidine-2-carboxylic acid was prepared from 4-{5 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid and L-proline t-butyl ester. LCMS called for C28H21F3N405 (m/e) 550, obsd 551 (M+H). 5 Example 224 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-chloro-4 cyclopropylcarbamoyl-phenyl)-pyridin-3-yl]-amide FF 0 F /\:, 0 N - NN CI NN Io With a method similar to that used for the preparation of (R)-1-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2 carboxylic acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2 chloro-4-cyclopropylcarbamoyl-phenyl)-pyridin-3-yl]-amide was prepared from 4-{5 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid and 15 cyclopropylamine. LCMS calcd for C26H18ClF3N403 (m/e) 526, obsd 527 (M+H). Example 225 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-chloro-4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide FE I IF NNCI o N N 20 With a method similar to that used for the preparation of (R)-1-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2 carboxylic acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2 chloro-4-isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide was prepared from 3-chloro-4 25 {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid and isobutylamine. LCMS calcd for C27H22ClF3N403 (m/e) 542, obsd 543 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 187 Example 226 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-chloro-4 methanesulfonylaminocarbonyl-phenyl)-pyridin-3-yl]-amide FF 0 F - N N - CI 0 N N S, 5 0 0 According to the procedures described in Tetrahedron Lett. 1998, 39, 5891 and Org. Proc. Res. Dev. 2004, 8, 952, 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-benzoic acid (30 mg, 0.06 mmol), methanesulfonamide (7 mg, 0.07 mmol), 4-dimethylaminopyridine (2 mg, 0.02 mmol) and 1-ethyl-3-(3 10 dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.07 mmol) were suspended in 3 mL of dichloromethane and the mixture was refluxed for 3 h. The reaction mixture was cooled down to room temperature and filtered. The white precipitates were washed with ethyl acetate. The combined filtrate was stirred with 150 mg of Amberlyst-15 at room temperature for 2 h. The reaction was filtered to remove the resin, and the filtrate 15 was concentrated and purified by flash chromatography (eluting with ethyl acetate and hexanes) to afford 12 mg of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2 chloro-4-methanesulfonylaminocarbonyl-phenyl)-pyridin-3-yl]-amide as a light yellow solid. LCMS calcd for C24H16ClF3N405S (m/e) 564, obsd 565 (M+H). 20 Example 227 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[2-chloro-4 (methanesulfonyl-methyl-aminocarbonyl)-phenyl]-pyridin-3-yl}-amide FF F /\ I I~ N c 0 N NN S, O0 C '0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 25 oxazole-4-carboxylic acid [6-(2-chloro-4-methanesulfonylaminocarbonyl-phenyl) pyridin-3-yl]-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[2 chloro-4-(methanesulfonyl-methyl-aminocarbonyl)-phenyl]-pyridin-3-yl}-amide was WO 2008/141976 PCT/EP2008/055843 - 188 prepared from 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoic acid and N-methyl-methanesulfonamide. LCMS called for C25H18ClF3N405S (m/e) 578, obsd 579 (M+H). 5 Example 228 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-{2-chloro-4 (2-methyl-propane-2-sulfonylaminocarbonyl]-phenyl}-pyridin-3-yl)-amide FF '0 'F N CI O N N O 0 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 10 oxazole-4-carboxylic acid [6-(2-chloro-4-methanesulfonylaminocarbonyl-phenyl) pyridin-3-yl]-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-{2 chloro-4-(2-methyl-propane-2-sulfonylaminocarbonyl]-phenyl}-pyridin-3-yl)-amide was prepared from 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoic acid and 2-methyl-propane-2-sulfonic acid amide. LCMS calcd for 15 C27H22ClF3N405S (m/e) 606, obsd 607 (M+H). Example 229 Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(3,4 dihydroxy-cyclopentanecarbonyl)-piperazin-1-yl]-pyridin-3-yl}-amide F 0 F NN 20 N N 20 0 To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(cyclopent 3-enecarbonyl)-piperazin-1-yl]-pyridin-3-yl}-amide described previously (50 mg, 0.0978 mmol) in acetone (10 mL) was added two drops of osmium tetroxide in butanol (2.5% wt) and 4-methylmorpholine N-oxide (15 mg). The mixture was stirred at room 25 temperature for 1 hr and the solvents were evaporated. The residue was extracted with methylene chloride and water. The organic layer was washed with citric acid solution and dried over sodium sulfate. The solvents were evaporated and the residue was purified WO 2008/141976 PCT/EP2008/055843 - 189 using flash chromatography (eluting with methylene chloride and methanol) to give racemic 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(3,4-dihydroxy cyclopentanecarbonyl)-piperazin-1-yl]-pyridin-3-yl}-amide (25.7 mg) as a solid. LC-MS calcd for C26H26F3N505 (m/e) 545.2, obsd 546.1 (M+H). The NMR spectrum obtained 5 on the sample is compatible with its structure. Example 230 Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(3,4 10 dihydroxy-cyclopentanecarbonyl)-piperidin-4-yl]-phenyl}-amide F F 0 N 0 With a method similar to that used for the preparation of racemic 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid {6-[4-(3,4-dihydroxy-cyclopentanecarbonyl) piperazin-1-yl]-pyridin-3-yl}-amide above, racemic 2-phenyl-5-trifluoromethyl-oxazole 15 4-carboxylic acid {4-[1-(3,4-dihydroxy-cyclopentanecarbonyl)-piperidin-4-yl]-phenyl} amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1 (cyclopent-3-enecarbonyl)-piperidin-4-yl]-phenyl}-amide and osmium tetroxide. LC-MS calcd for C28H28F3N305 (m/e) 543.2, obsd 544.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 20 Example 231 Preparation of (S)-3-(5-{[2-(2-bromo-phenyl)-5-propyl-oxazole-4-carbonyl]-amino} pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester Br 0 N O N N 25 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5-{[2-(2-bromo-phenyl)-5-propyl-oxazole-4-carbonyl] amino }-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester was prepared from WO 2008/141976 PCT/EP2008/055843 - 190 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid and (S)-3 -(5 -amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester. HRMS called for C25H28BrN504 (M+H) 542.1398, obsd 542.1396. 5 Example 232 Preparation of (S)-3-(5-{[2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4 carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester F Br C0 F N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5-{[2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4 carbonyl] -amino } -pyridin-2-ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S) 3 -(5 -amino-pyridin-2-ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester. HRMS calcd 15 for C23H21BrF3N504 (M+H) 568.0802, obsd 568.0801. Example 233 Preparation of (S)-3-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester F N F -- N 20N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-{5-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester was prepared from 25 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and (S)-3 -(5-amino-pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester. HRMS calcd for C23H23F3N603 (M+H) 489.1857, obsd 489.1853. Example 234 WO 2008/141976 PCT/EP2008/055843 - 191 Preparation of (S)-3-{5-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester F N F F_ N N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-{5-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4 carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and (S)-3 (5 -amino-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester. HRMS calcd for 10 C22H22F3N703 (M+H) 490.1809, obsd 490.1807. Example 235 Preparation of (S)-3-(4-{[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-phenylamino)-pyrrolidine-1-carboxylic acid tert butyl ester F F__ F F 0 F
--
(\N 15 0 N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(4- { [2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl oxazole-4-carbonyl] -amino } -phenylamino)-pyrrolidine- 1 -carboxylic acid tert butyl ester 20 was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4 carboxylic acid and (S)-3-(4-amino-phenylamino)-pyrrolidine-1-carboxylic acid tert butyl ester. HRMS calcd for C27H26F6N405 (M+H) 601.188, obsd 601.1877. Example 236 25 Preparation of (S)-3-(4-{[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 192 0 FF F F F FF N C N N With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester above, (S)-3-(4-{[2-(2 5 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -phenylamino) pyrrolidine-1-carboxylic acid ethyl ester was prepared from 2-(2-trifluoromethoxy phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-phenylamino) pyrrolidine-1-carboxylic acid tert butyl ester, followed by deprotection with tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for 10 C25H22F6N405 (M+H) 573.1567, obsd 573.1565. Example 237 Preparation of (S)-3-{4-[ (1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenylamino}-pyrrolidine-1-carboxylic acid ethyl ester F N FF 15 0 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3-{4-[ (1-phenyl-3 trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic 20 acid ethyl ester was prepared from 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and (S)-3-(4-amino-phenylamino)-pyrrolidine-1-carboxylic acid tert butyl ester, followed by deprotection with tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for C24H24F3N503 (M+H) 488.1904, obsd 488.1904. 25 Example 238 Preparation of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 193 F O F - N N 0 N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 phenyl}-piperidine-4-carboxylic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid and 1-(4-amino-phenyl)-piperidine-4 carboxylic acid ethyl ester. HRMS calcd for C25H24F3N304 (M+H) 488.1792, obsd 488.1792. 10 Example 239 Preparation of 1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester F o F N F' N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid and 1-(5 -amino-pyrimidin-2-yl)-piperidine-4 carboxylic acid ethyl ester. HRMS calcd for C23H22F3N504 (M+H) 490.1697, obsd 20 490.1695. Example 240 Preparation of Methyl-[2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-amino)-ethyl]-carbamic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 194 F O F N F N n 0 N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, methyl-[2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-pyridin-2-yl}-amino)-ethyl]-carbamic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and {2- [(5 -amino-pyridin-2 yl)-methyl-amino]-ethyl} -methyl-carbamic acid ethyl ester. HRMS calcd for C23H24F3N504 (M+H) 492.1853, obsd 492.1855. 10 Example 241 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)amino] pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid tert butyl ester F 0 0 F \N F 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yloxy} -pyrrolidine-1-carboxylic acid tert butyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3 -(5 -amino-pyridin-2 yloxy)-pyrrolidine-1-carboxylic acid tert butyl ester. HRMS calcd for C25H25F3N405 20 (M+Na) 541.1669, obsd 541.1664. Example 242 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)amino] pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 195 F 0 0 F (\ IF N N N 0 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid tert butyl ester, by deprotection with tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for C23H21F3N405 (M+H) 491.1537, obsd 491.1537. 10 Example 243 Preparation of (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carboxylic acid tert butyl ester F 0 F 0 /\N IFN
CN
0 15 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert butyl ester was prepared from 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-phenoxy) 20 pyrrolidine-1-carboxylic acid tert butyl ester. HRMS calcd for C26H26F3N305 (M+Na) 540.1717, obsd 540.1716. Example 244 Preparation of (S)-3-(4-{[(2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl 25 oxazole-4-carbonyl]-amino}-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl ester WO 2008/141976 PCT/EP2008/055843 - 196 F 0
-
0 F C / N F N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(4-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl 5 oxazole-4-carbonyl]-amino} -phenoxy)-pyrrolidine- 1 -carboxylic acid tert butyl ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl ester. HRMS calcd for C27H25F6N306 (M+Na) 624.154, obsd 624.1539. 10 Example 245 Preparation of (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester F 0 0 F \ F N N N 0 15 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 20 carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert butyl ester, by deprotection with trifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for C24H22F3N305 (M+H) 490.1585, obsd 490.1585. Example 246 25 Preparation of (S)-3-(4-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 197 F FF F 0 0 F N N )aO 0 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester above, (S)-3-(4-{[(2-(2 5 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -phenoxy) pyrrolidine-1-carboxylic acid ethyl ester was prepared from (S)-3-(4-{[(2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -phenoxy) pyrrolidine-1-carboxylic acid tert butyl ester, by deprotection with trifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for C25H21F6N306 10 (M+Na) 596.1227, obsd 596.1223. Example 247 Preparation of (S)-3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid tert butyl 15 ester F F_ F F 0 0 F N O ONN O 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl 20 oxazole-4-carbonyl] -amino } -pyrimidin-2-yloxy)-pyrrolidine- 1 -carboxylic acid tert butyl ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxaxole-4 carboxylic acid and (S)-3 -(5 -amino-pyrimidin-2-yloxy)-pyrro lidine- 1 -carboxylic acid tert butyl ester. HRMS calcd for C25H23F6N506 (M+Na) 626.1445, obsd 626.1447. 25 Example 248 Preparation of (S)-3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole 4-carbonyl]-amino}-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 198 F F__kF F 0 0 F C 4N F NN 0 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester above, (S)-3-(5-{[(2-(2 5 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyrimidin-2 yloxy)-pyrrolidine-1-carboxylic acid ethyl ester was prepared from (S)-3-(5-{[(2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] amino } -pyrimidin-2 yloxy)-pyrrolidine-1-carboxylic acid tert butyl ester, by deprotection with tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for 10 C23H19F6N506 (M+Na) 576.1313, obsd 576.1314. Example 249 Preparation of (S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester F
-
0 F \ IF \N O N 15 0 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yloxy}-pyrrolidine-1 20 carboxylic acid ethyl ester was prepared from (S)-3-{5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyrimidin-2-yloxy}-pyrrolidine-1-carboxylic acid tert butyl ester, by deprotection with trifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS calcd for C22H20F3N505 (M+H) 492.149, obsd 492.149. 25 Example 250 WO 2008/141976 PCT/EP2008/055843 - 199 Preparation of (1R,2R)-2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenylamino}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid F 0 N F FN \- N3 N N OOH N 0 0 5 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenylamino } -pyrrolidine- 1 -carbonyl)-cyclopentanecarboxylic acid was prepared as a mixture of diastereomers. The diastereomeric mixture was purified by 10 chiral supercritical fluid chromatography (the first eluting peak) to yield (1R,2R)-2-((S) 3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino } pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid as a yellow oil. HRMS called for C28H27F3N405 (M+H) 557.2007, obsd 557.2004 15 Example 251 Preparation of (1S,2S)-2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenylamino}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid F 0 F F N -N OH N 0 0 20 From the above chiral supercritical fluid chromatography of racemic 2-((S)-3-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1 carbonyl)-cyclopentanecarboxylic acid, the second eluting peak was isolated to yield (IS,2S)-2-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenylamino}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid as a yellow oil. 25 HRMS calcd for C28H27F3N405 (M+H) 557.2007, obsd 557.2004. Example 252 Preparation of 4-((S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-ylamino}-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 200 F 0 F 0 \ / N F N N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 4-((S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino] -pyridin-2ylamino } -pyrro lidine- 1 -carbonyl)-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-pyrrolidine 3-yl-amino)-pyridin-3-yl]-amide and cis-cyclohexane-1,4-dicarboxylic acid. HRMS calcd for C28H28F3N505 (M+H) 572.2116, obsd 572.2113. 10 Example 253 Preparation of 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carboxylic acid ethyl ester F F N /\ N. F N 00 NO With a similar method to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino]-phenyl} -piperidine- 1 -carboxylic acid ethyl ester was prepared from 1-pyridin-2 yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride and ethyl chloroformate. LCMS calcd for C24H24F3N503(m/e) 487.18, 20 obsd 488 (M+H). Example 254 Preparation of 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carboxylic acid isopropyl ester 25 WO 2008/141976 PCT/EP2008/055843 -201 F F N F N N With a similar method to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) 5 amino]-phenyl} -piperidine- 1 -carboxylic acid isopropyl ester was prepared from 1 pyridin-2-yl-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl) amide hydrochloride and isopropyl chloroformate. LCMS calcd for C25H26F3N503 (m/e) 501.2, obsd 502 ( M+H). 10 Example 255 Preparation of 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4 (1-cyclopropanecarbonyl-piperidin-4-yl)-phenyl]-amide F F N F N -N o N 0 With a similar method to that used for the preparation of 2-phenyl-5-trifluoromethyl 15 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide from above, 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(1 cyclopropanecarbonyl-piperidin-4-yl)-phenyl]-amide was prepared from 1-pyridin-2-yl 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride and cyclopropanecarbonyl chloride. LCMS calcd for C25H24F3N502 20 (m/e) 483.2, obsd 484 (M+H). Example 256 Preparation of 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4 (1-cyclopentanecarbonyl-piperidin-4-yl)-phenyl]-amide WO 2008/141976 PCT/EP2008/055843 -202 F F FN OFF N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 5 [4-(1-cyclopentanecarbonyl-piperidin-4-yl)-phenyl]-amide was prepared from 1-pyridin 2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cyclopentanecarboxylic acid. LC-MS calcd for C27H28F3N502 (m/e) 511.2, obsd 512 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 257 Preparation of 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl}-piperidine-1-carboxylic acid propylamide F F N / N N With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenyl} -piperidine- 1 -carboxylic acid propylamide was prepared from 1-pyridin 2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and propylisocyanate. LC-MS calcd for C25H27F3N602 (m/e) 500.2, obsd 501 (M+H). 20 The NMR spectrum obtained on the sample is compatible with its structure. Example 258 Preparation of 4-{4-[(5-Methyl-2-phenyl-2H-[1,2,3]-triazole-4-carbonyl)-amino] phenyl}-piperidine-1-carboxylic acid propylamide WO 2008/141976 PCT/EP2008/055843 -203 N N N 00 With a method similar to that used for the preparation of 4-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carboxylic acid propylamide above, 4-{4-[(5-Methyl-2-phenyl-2H-[1,2,3]-triazole-4-carbonyl)-amino] 5 phenyl}-piperidine-1-carboxylic acid propylamide was prepared from 5-Methyl-2 phenyl-2H-[1,2,3]triazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and propylisocyanate. LCMS called for C25H30N602 (m/e) 446.24, obsd 447 (M+H). Example 259 10 Preparation of 4-[4-(4-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-phenyl)-piperidine-1-carbonyl]-benzoic acid F F F N 0 00 N O. 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid 15 tert-butyl ester above, 4-[4-(4-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl] -amino } -phenyl)-piperidine- 1 -carbonyl] -benzoic acid was prepared from 1-(4 fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl phenyl)-amide and terephthalic acid monomethyl ester, followed by basic hydrolysis. LC-MS calcd for C30H24F4N404 (m/e) 580.2, obsd 581 (M+H). The NMR spectrum 20 obtained on the sample is compatible with its structure. Example 260 Preparation of 3-chloro-4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4 carbonyl]-amino}-pyridin-2-yl)-benzoic acid WO 2008/141976 PCT/EP2008/055843 - 204 F F N F F N N CI ON 0 With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 3-chloro 4-(5 - { [1-(4-fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino } -pyridin 5 2-yl)-benzoic acid was prepared from 1-(4-fluoro-phenyl)-3-trifluoromethyl-1H pyrazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide and 2-chloro-4 carboxyphenylboronic acid. LCMS calcd for C23H13F4N403 (m/e) 504, obsd 505 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 261 Preparation of (1R,2R)-2-(4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid F F F N 0 With a similar procedure as above (1R,2R)-2-(4-{4-[(5-phenyl-2-trifluoromethyl-furan 15 3-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid was prepared from (1R,2R)-2-(4-{4-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester. The product was isolated as an off-white solid (183 mg, 99 % yield). HRMS m/z calcd. for C29H29F3N305 [M+H]*: 556.2054; found: 556.2054. 20 Example 262 Preparation of 2-fluoro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-benzoic acid WO 2008/141976 PCT/EP2008/055843 - 205 F F 0 F - N N 0 N N F With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid above, 2-fluoro 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic 5 acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo pyridin-3-yl)-amide and 4-carboxy-3-fluorophenylboronic acid. LCMS calcd for C23H13F4N304 (m/e) 471, obsd 472 (M+H). Example 263 10 Preparation of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester F F 0 F N N N CI NO N C N O-A A mixture of 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoic acid (50 mg, 0.1 mmol), (S)-2-amino-3-methyl-butyric acid methyl 15 ester (17 mg, 0.1 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (21 mg, 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. The solid 20 was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give 2-(3-chloro-4- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester (41 mg, 66 %) as a white solid. LCMS calcd for C29H24ClF3N405 (m/e) 600, obsd 601 (M+H). 25 WO 2008/141976 PCT/EP2008/055843 - 206 Example 264 Preparation of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid F F 0 F N N N CI N O N 0 5 A solution of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl} -benzoylamino)-3 -methyl-butyric acid methyl ester (30 mg, 0.05 mmol) in a mixture of tetrahydrofuran, methanol and water (3:1:1, 2 mL) was treated with lithium hydroxide monohydrate (6 mg, 0.15 mmol) at 50 0 C for an hour. The reaction mixture was concentrated, diluted with water and the pH was adjusted to 1~2 10 with dilute hydrochloric acid (IN). The white precipitate was collected by centrifugation, and then was dried under vacuum to give 2-(3-chloro-4- {5-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid (27 mg, 93%) as a white solid. LCMS calcd for C28H22ClF3N405 (m/e) 586, obsd 587 (M+H). 15 Example 265 Preparation of 1-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyridin-2-yl}-benzoyl)-piperidine-4-carboxylic acid F F 0 F - N N - CI 0 0 1 N 0 N N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 20 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, 1-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yl}-benzoyl)-piperidine-4-carboxylic acid was prepared from 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 yl}-benzoic acid and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for 25 C29H22ClF3N405 (m/e) 598, obsd 599 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 207 Example 266 Preparation of 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-carbonyl}-amino)-cyclopropanecarboxylic acid F F 0 F - N N NN 0 0 5 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl} -amino)-cyclopropanecarboxylic acid was prepared from 4' 10 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid and 1-amino-cyclopropanecarboxylic acid ethyl ester. LCMS calcd for C28H20F3N305 (m/e) 535, obsd 536 (M+H). Example 267 15 Preparation of 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-carbonyl}-amino)-cyclobutanecarboxylic acid F F o F N N N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 20 methyl-butyric acid above, 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl} -amino)-cyclobutanecarboxylic acid was prepared from 4' [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid and 1-amino-cyclobutanecarboxylic acid ethyl ester. LCMS calcd for C29H22F3N305 (m/e) 549, obsd 550 (M+H). 25 Example 268 WO 2008/141976 PCT/EP2008/055843 - 208 Preparation of 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] biphenyl-4-carbonyl}-amino)-cyclopentanecarboxylic acid F F o F / -\\N I~ N N N N 06 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 5 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, 1-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-carbonyl} -amino)-cyclopentanecarboxylic acid was prepared from 4' [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid and 1-amino-cyclopentanecarboxylic acid methyl ester. LCMS calcd for 10 C30H24F3N305 (m/e) 563, obsd 564 (M+H). Example 269 Preparation of (S)-3,3-dimethyl-2-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-butyric acid F F o F - N N N 0 15 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, (S)-3,3-dimethyl-2-({4'-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-butyric acid was prepared 20 from 4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid and (S)-2-Amino-3,3-dimethyl-butyric acid tert-butyl ester. LCMS calcd for C30H26F3N305 (m/e) 565, obsd 566 (M+H). Example 270 WO 2008/141976 PCT/EP2008/055843 -209 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-fluoro-4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide F F 0 F N N O F NN N N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 5 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3 fluoro-4-isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide was prepared from 2-fluoro-4 {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid and isobutylamine. LCMS called for C27H22F4N403 (m/e) 526, obsd 527 (M+H). 10 Example 271 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-chloro-4 methylcarbamoyl-phenyl)-pyridin-3-yl]-amide F F 0 F N N - CI N 0 N 0 15 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2 chloro-4-methylcarbamoyl-phenyl)-pyridin-3-yl]-amide was prepared from 3-chloro-4 {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid 20 and methylamine. LCMS calcd for C24H16ClF3N403 (m/e) 500, obsd 501 (M+H). Example 272 Preparation of (S)-3-methyl-2-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-butyric acid WO 2008/141976 PCT/EP2008/055843 - 210 F F 0 F - N N N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} -benzoylamino)-3 methyl-butyric acid above, (S)-3-methyl-2-({4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-butyric acid was prepared from 4'-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester. LCMS calcd for C29H24F3N305 (m/e) 551, obsd 552 (M+H). 10 Example 273 Preparation of racemic trans-2-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-[2,3']bipyridinyl-6'-ylcarbamoyl}-cyclopentanecarboxylic acid F F o F N 0 N N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 15 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, racemic trans-2-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-[2,3']bipyridinyl-6'-ylcarbamoyl}-cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin 3-yl)-amide, 2-tert-butyloxycarbonylaminopyridine-5-boronic acid pinacol ester and 20 racemic trans-cyclopentane-1,2-dicarboxylic acid monobenzyl ester. LCMS calcd for C28H22F3N505 (m/e) 565, obsd 566 (M+H). Example 274 Preparation of (1R,2R)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 25 amino] -biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid (or enantiomer) WO 2008/141976 PCT/EP2008/055843 -211 F F 0 F N 0 N 0 With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3 methyl-butyric acid above, racemic trans-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl)-amide, 4 (4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline and cyclopentane-1,2-dicarboxylic acid monobenzyl ester. The benzyl ester was then removed by hydrogenolysis. The racemic mixture was separated by chiral SFC to afford (1R,2R)-2-{4'-[(2-phenyl-5 10 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid (or enantiomer). LCMS calcd for C30H24F3N305 (m/e) 563, obsd 564 (M+H). Example 275 15 Preparation of (1S,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid (or enantiomer) F F o F N N 0 N 0 With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} 20 cyclopentanecarboxylic acid above, (iS,2S)-2-{4'-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid (or enantiomer) was obtained by chiral SFC separation. LCMS calcd for C30H24F3N305 (m/e) 563, obsd 564 (M+H). 25 Example 276 Preparation of racemic trans-2-(methyl-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-biphenyl-4-yl}-carbamoyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 212 F F 0 F N N 0 N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, racemic trans-2-(methyl-{4'-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-biphenyl-4-yl}-carbamoyl)-cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-[(4' amino-biphenyl-4-yl)-methyl-carbamoyl] -cyclopentanecarboxylic acid. LCMS calcd for C31H26F3N305 (m/e) 577, obsd 578 (M+H). 10 Example 277 Preparation of 2-pyridin-2-yl-4-trifluoromethyl-oxazole-5-carboxylic acid [6-(4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide F F N N F O N 0N N 0 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, 2-pyridin-2-yl-4-trifluoromethyl-oxazole-5-carboxylic acid [6-(4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide was prepared from 2-pyridin-2-yl-4 trifluoromethyl-oxazole-5-carboxylic acid and 4-(5 -amino-pyridin-2-yl)-N-isobutyl benzamide. LCMS calcd for C26H22F3N503 (m/e) 509, obsd 510 (M+H). 20 Example 278 Preparation of methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -pyrimidin-2-yl}-piperidin-4-yl)-carbamic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 213 F F O F N\ \ N N N-NN N With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester, methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 pyrimidin-2-yl}-piperidin-4-yl)-carbamic acid ethyl ester was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -yl)-pyrimidin 5-yl]-amide and ethyl chloroformate. LC-MS called for C24H25F3N604 (m/e) 518, obsd 519 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 279 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-{4-[methyl (2,2,2-trifluoro-acetyl)-amino]-piperidin-1-yl}-pyrimidin-5-yl)-amide F F 0 F N - N N 0 N NN 0 F F With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 15 oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide above, 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2- {4-[methyl-(2,2,2-trifluoro acetyl)-amino]-piperidin-1-yl}-pyrimidin-5-yl)-amide was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -yl)-pyrimidin 5-yl]-amide hydrochloride salt and trifluoroacetic anhydride. LCMS calcd for 20 C23H20F6N603 (m/e) 542, obsd 543 (M+H). Example 280 Preparation of (1R,2R)-2-[methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyrimidin-2-yl}-piperidin-4-yl)-carbamoyl] 25 cyclopentanecarboxylic acid (or enantiomer) WO 2008/141976 PCT/EP2008/055843 - 214 F F o F /\ ~ N N N N N~<N 0 With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, (1R,2R)-2-[methyl-(1-{5-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperidin-4-yl)-carbamoyl] cyclopentanecarboxylic acid (or enantiomer) was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -yl)-pyrimidin 5-yl]-amide hydrochloride salt and racemic trans-1,2-cyclopentanedicarboxylic acid, followed by chiral SFC. LCMS calcd for C28H29F3N605 (m/e) 586, obsd 587 (M+H). 10 Example 281 Preparation of (1S,2S)-2-[methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyrimidin-2-yl}-piperidin-4-yl)-carbamoyl] cyclopentanecarboxylic acid (or enantiomer) F F o F /\ ~ N N N N N 15 0 With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, (iS,2S)-2-[methyl-(1-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperidin-4-yl)-carbamoyl] 20 cyclopentanecarboxylic acid (or enantiomer) was prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -yl)-pyrimidin 5-yl]-amide hydrochloride salt and racemic trans-1,2-cyclopentanedicarboxylic acid, followed by chiral SFC. LCMS calcd for C28H29F3N605 (m/e) 586, obsd 587 (M+H). 25 Example 282 WO 2008/141976 PCT/EP2008/055843 - 215 Preparation of (R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester F F 0 F ):NN 0 N 0 With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-phenyl-5 5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, (R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 piperazin-1-yl-phenyl)-amide hydrochloride salt and (R)-pyrrolidine-1,2-dicarboxylic 10 acid 1-benzyl ester. LCMS calcd for C34H32F3N505 (m/e) 647, obsd 648 (M+H). Example 283 Preparation of (R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid ethyl ester F F 0 F NN 0 N 15 0 With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl} cyclopentanecarboxylic acid above, (R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid ethyl 20 ester was prepared by hydrogenolysis of (R)-2-(4-{4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester followed by reaction with ethyl chloroformate. LCMS calcd for C29H30F3N505 (m/e) 585, obsd 586 (M+H). 25 Example 284 WO 2008/141976 PCT/EP2008/055843 - 216 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 methanesulfonylaminocarbonyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl) amide F F F 0/ N N N 5 To a suspension of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid (39.4 mg, 0.085 mmol) in methylene chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4 dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCI (16.4 mg, 0.085 mmol) was added. The mixture was stirred at room temperature overnight. Solvents were evaporated 10 and the residue was purified by flash column chromatography using a linear gradient of ethyl acetate containing 1% acetic acid in hexanes (20% to 100% in 15 minutes) to give the desired compound as a pale yellow solid (16.5 mg). 'H-NMR is consistent with the desired structure. LRMS for C 23
H
22
F
3
N
5 0 5 S (m/e) calcd 537.13, obsd 538.1 (M+1). 15 Example 285 Preparation of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carboxylic acid methyl ester F F 0 F 0 0- N 0 0 To a solution of 4-fluoronitrobenzene (0.70g, 4.96 mmol) in THF (8 mL) was added 20 piperadine-4-carboxylic acid methyl ester (0.71g, 4.96 mmol) and diisopropylethylamine (0.66 g, 5.11 mmol). The mixture was heated in a microwave oven at 150 0 C for 1.5 hr. The resulting mixture was extracted with ethyl acetate and hydrochloric acid (0.2 N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a Biotage flash column 25 chromatography using ethyl acetate and hexanes (1:1 ratio) to give a yellow solid as 1-(4 nitrophenyl)-piperidine-4-carboxylic acid methyl ester (490 mg). 'H-NMR is consistent with the structure.
WO 2008/141976 PCT/EP2008/055843 - 217 The yellow solid prepared above (463 mg, 1.75 mmol) was dissolved into methanol (25 ml) and THF (5 mL). To this solution was added 10% palladium on carbon (100 mg) and the mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered and solvents were evaporated to give a purple residue. This material was dissolved in methylene 5 chloride (5 mL) containing triethyl amine (0.4 mL) and the solution was added to a methylene chloride solution of 2-phenyl-5-trifluoromethyloxazole-4-carbonyl chloride which was prepared from 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (450.7 mg, 1.753 mmol) and oxalyl chloride. The mixture was stirred at r.t for 3 hrs and solvents were evaporated. The residue was extracted with ethyl acetate and diluted hydrochloric 10 acid and solvents were evaporated. The resulting mixture was purified through a flash column chromatography using ethyl acetate and hexanes (1:1 ratio) to give a white solid as 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carboxylic acid methyl ester (650 mg). 'H-NMR is consistent with the structure. LC-MS indicated a single peak (Rf=3.85 min). LRMS for C 24
H
22
F
3
N
3 0 4 (m/e) calcd 473.16, obsd 15 474.3 (M+1). Example 286 1-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carboxylic acid F F F 0 N 20 0 The above 1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carboxylic acid methyl ester (470 mg, 1 mmol) was dissolved in a mixture of methanol (7 mL) and THF (2 mL). To this solution was added IN sodium hydroxide solution (3 mL). The mixture was stirred at room temperature for 4 hrs until all starting 25 material was consumed. Solvents were evaporated and the residue was diluted with water (8 mL). The solution was filtered and the filtrate was acidified with IN hydrochloric acid (3.5 mL). The yellow precipitate was filtered and dried in the air to give 1-{4-[(2-phenyl 5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperidine-4-carboxylic acid (395 mg). 'H-NMR is consistent with the desired structure. LC-MS indicated a single peak 30 (Rf=3.23 min). LRMS for C 23
H
20
F
3
N
3 0 4 (m/e) calcd 459.14, obsd 460.2 (M+1). Example 287 WO 2008/141976 PCT/EP2008/055843 - 218 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4 methanesulfonylaminocarbonyl-piperidin-1-yl)-phenyl]-amide F F N NN 0 0 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl 5 oxazole-4-carboxylic acid (4-methanesulfonylaminocarbonyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4 (4-methanesulfonylaminocarbonyl-piperidin-1-yl)-phenyl]-amide was prepared from 1 {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carboxylic acid and methanesulfonamide. LRMS for C 24
H
23
F
3
N
4 0 5 S (m/e) called 536.13, io obsd 537.1 (M+1). The 'H-NMR obtained on the sample is consistent with the desired structure. Example 288 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4 15 ethanesulfonylaminocarbonyl-piperidin-1-yl)-phenyl]-amide F F F 0 NN NS 0 0 With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-methanesulfonylaminocarbonyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4 20 (4-ethanesulfonylaminocarbonyl-piperidin-1-yl)-phenyl]-amide was prepared from 1-{4 [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4 carboxylic acid and ethanesulfonamide. LRMS for C 25
H
25
F
3
N
4 0 5 S (m/e) calcd 550.15, obsd 551.1 (M+H). The 1 H-NMR obtained on the sample is consistent with the desired structure. 25 Example 289 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2 methyl-propane-2-sulfonylaminocarbonyl)-piperidin-1-yl]-phenyl}-amide WO 2008/141976 PCT/EP2008/055843 - 219 F F 0 00 4N N N With a method similar to that used for the preparation of 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (4-methanesulfonylaminocarbonyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4 5 [4-(2-methyl-propane-2-sulfonylaminocarbonyl)-piperidin-1-yl]-phenyl}-amide was prepared from 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carboxylic acid and tert-butylsulfonamide. LRMS for C 27 H29F 3
N
4 0 5 S (m/e) called 578.18, obsd 579.2 (M+H). The 'H-NMR obtained on the sample is consistent with the desired structure. 10 Example 290 Preparation of (S)-3-{4-[(1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] -phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester F N F S F N 0 N 15 With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, (S)-3-{4-[(1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carboxylic acid t-butyl ester was prepared from 2-phenyl-5 trifluoromethyl-1H-pyrazole-4-carboxylic acid and (S)-3 -(5-amino-phenoxy) 20 pyrrolidine-1-carboxylic acid tert butyl ester. LRMS calcd for C26H28F3N503 (M-1) 516.56, obsd 515.1 With a method similar to that used for the preparation of (S)-3-(5-{[2-(2 trifluoromethoxy-phenyl)-5 -trifluoromethyl-oxazole-4-carbonyl] -amino } -pyridin-2 25 ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester, (S)-3- {4 -[(1 -Phenyl-3 trifluoromethyl- 1H-pyrazole-4-carbonyl)-amino]-phenoxy} -pyrrolidine- 1 -carboxylic acid ethyl ester was prepared from (S)-3-{4- [(1 -Phenyl-3-trifluoromethyl- 1H-pyrazole-4 carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid t-butyl ester, by deprotection WO 2008/141976 PCT/EP2008/055843 - 220 with tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS called for C24H23F3N404 (M+H) 489.1745, obsd 489.1744. Example 291 5 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{4-[4-(1H tetrazol-5-yl)-cyclohexanecarbonyl]-piperazin-1-yl}-phenyl)-amide F F F0 F0 N N N H HNsN N HN A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl phenyl)-amide (130 mg, 0.31 mmol), 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid 10 (61 mg, 0.31 mmol), DMAP (2 mg, .016 mmol), and 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for 2.5 days. The reaction was diluted in water (100 mL) and extracted with dichloromethane (2 x 100 mL) and ethyl acetate (1 x 100 mL), the organic layers combined, dried over sodium sulfate and purified by flash 15 chromatograph with increasing concentrations of methanol in dichloromethane (0 to 10 % over 20 min) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {4-[4 (1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperazin-1-yl}-phenyl)-amide (90 mg, 49 %) as a light yellow solid. LCMS calcd for C29H29F3N803 (m/e) 594, obsd 595(M+H). 20 Example 292 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(1H tetrazol-5-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl)-amide F F F 0 NN N H H'N, N,N With a procedure similar to example 1, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic 25 acid (4- { 1-[4-(1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperidin-4-yl} -phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4 yl-phenyl)-amide (212 mg, 0.51 mmol) and 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic WO 2008/141976 PCT/EP2008/055843 - 221 acid (100 mg, 0.51 mmol) as an off white solid (147 mg, 49 %). LCMS called for C30H30F3N703 (m/e) 593, obsd 594 (M+H). Example 293 5 Preparation 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(5-oxo 4,5-dihydro-1,2,4]oxadiazol-3-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl) amide F 0 F N N 0"' 0 With a procedure similar to example 1, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic Io acid (4- { 1-[4-(5-oxo-4,5-dihydro- 1,2,4]oxadiazol-3-yl)-cyclohexanecarbonyl]-piperidin 4-yl}-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid (4-piperidin-4-yl-phenyl)-amide (202 mg, 0.49 mmol) and 4-(5-Oxo-4,5 dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid (104 mg, 0.49 mmol) as an off white solid (13 mg, 4 %). LCMS calcd for C31H30F3N505 (m/e) 609, obsd 610 15 (M+H). Example 294 Preparation of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6 tetrahydro-2H-1,2']bipyridinyl-4-carboxylic acid amide F F F 0 0 S N N- c 20 N N A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.42 g, 12.6 mmol), 5'-amino-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid amide (which was the product from the catalytic hydrogenation of 5'-nitro-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-carboxylic acid amide: 2.93 g, 12.6 mmol, 200 mL EtOH/THF/EtOAc 25 mixture, 50 psi H 2 , 7 hr, with 300 mg of Pd/C 10 %), 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (2.89 g, 15.1 mmol) and DMAP (catalytic) in anhydrous DMF (25 mL) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 mL) and washed with aqueous ammonium WO 2008/141976 PCT/EP2008/055843 - 222 chloride (saturated, 200 mL), sodium bicarbonate (saturated, 200 mL with addition of brine to clear emulsion) and brine (100 mL). The aqueous ammonium chloride was extracted with ethyl acetate (200 mL) which was subsequently washed with brine (100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and 5 tritrated from boiling ethyl acetate to give 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-3,4,5,6-tetrahydro-2H-1,2']bipyridinyl-4-carboxylic acid amide (1.5 g, 26 %) as a light brown solid. LCMS calcd for C22H20F3N503 (m/e) 459, obsd 460 (M+H). 10 Example 295 Preparation of [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-piperidin-4-yl] -acetic acid F 0 FF N N N O 0 0 To a mixture of 4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 15 piperidine-1-carboxylic acid 4-nitro-phenyl ester (150 mg, 0.26 mmol) in 1-methyl pyrrolidin-2-one (10 mL) at room temperature was added piperidin-4-yl-acetic acid methyl ester (0.04 g, 0.25 mmol) followed by N,N-diisopropylethylamine (0.14 mL, 0.8 mmol). The mixture was stirred in a 90 0 C oil bath overnight. The mixture was blown to dryness and the crude was purified by flash chromatography (Merck silica gel 60, 230 20 400 mesh, gradient elution with 0%-60% ethyl acetate in hexane) to give [1-(4-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperidine-l-carbonyl) piperidin-4-yl]-acetic acid methyl ester (70 mg). LCMS calcd for C31H33F3N405 (m/e) 598, obsd 599 (M+H). To a mixture of [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 25 phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid methyl ester (70 mg, 0.117 mmol) in dioxane (3 mL) and water (3 mL) at room temperature was added lithium hydroxide (0.01 g, 0.24 mmol). The mixture was stirred at room temperature for about an hour. The mixture was acidified to pH of about 2 and then blown to dryness. Purification WO 2008/141976 PCT/EP2008/055843 - 223 by reversed-phase HPLC gave [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino] -phenyl} -piperidine- 1 -carbonyl)-piperidin-4-yl] -acetic acid. LCMS calcd for C30H31F3N405 (m/e) 584, obsd 585 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 5 Example 296 Preparation of 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-piperidine-4-carboxylic acid O F 0 F NN 0 O= 0 10 With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carboxylic acid 4-nitro-phenyl ester and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for C29H29F3N405 (m/e) 570, obsd 571 (M+H). The NMR 15 spectrum obtained on the sample is compatible with its structure. Example 297 Preparation of 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid WO 2008/141976 PCT/EP2008/055843 - 224 0FF 0 F N N 0 oO With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 5 piperidine-1-carboxylic acid 4-nitro-phenyl ester and pyrrolidine-3-carboxylic acid methyl ester. LCMS called for C28H27F3N405 (m/e) 556, obsd 557 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. Example 298 io Preparation of 3-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-propionic acid 0 F F N N N 0 0 With a procedure similar to above, 3-[1-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-propionic acid was 15 prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-propionic acid methyl ester. LCMS calcd for C31H33F3N405 (m/e) 598, obsd 599 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 20 Example 299 WO 2008/141976 PCT/EP2008/055843 - 225 Preparation of 4-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-butyric acid 0 F N F NN 0 N 0 D0 0 With a procedure similar to above, 4-[1-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 5 carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-butyric acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-butyric acid methyl ester. LCMS called for C32H35F3N405 (m/e) 612, obsd 613 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. 10 Example 300 Preparation of (R)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyrimidin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester F F - 0 F O N N N 01 N "t,0 15 This compound was prepared using the same method described in the preparation of (S) 3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yloxy} pyrrolidine-1-carboxylic acid ethyl ester. LC-MS showed a single peak with retention time of 4.09 min. LRMS calcd for C22H20F3N505 (M+H) 492.14, obsd 492.1 20 Example 301 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 226 F F F 0 NN N N 0N 0 To a solution of 1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carboxylic acid (229.5 mg, 0.5 mmol) in DMF (4 mL) was added piperidine-4-carboxylic acid ethyl ester (79 mg, 0.5 mmol), PyBrop (233.1 mg, 0.5 5 mmol) and triethylamine (0.1 mL). The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. After the evaporation of solvents, the residue was purified through flash column chromatography using ethyl acetate and hexanes. The desired fraction was evaporated and triturated with ether and petroleum ether (2:1) to give a yellow solid as 1-(1-{4-[(2-phenyl-5-trifluoromethyl 10 oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester. LC-MS showed a single peak with a retention time of 3.54 min. LRMS calcd for C31H33F3N405 (M+H) 599.24, obsd 599.3 Example 302 15 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-piperidine-4-carboxylic acid F F NN N N 0 e 0 This compound was prepared from the hydrolysis of the corresponding ethyl ester. LC MS showed a single peak with a retention time of 3.09 min. LRMS calcd for 20 C29H29F3N405 (M+H) 571.21, obsd 571.2 Example 303 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-piperidine-3-carboxylic acid ethyl ester WO 2008/141976 PCT/EP2008/055843 - 227 F F O F NN 0 This compound was prepared from 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid and piperidine-3-carboxylic acid ethyl ester using the same method describer in earlier example. LC-MS showed a single 5 peak with a retention time of 3.62 min. LRMS calcd for C31H33F3N405 (M+H) 599.24, obsd 599.2 Example 304 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 phenyl}-piperidine-4-carbonyl)-piperidine-3-carboxylic acid F F F N 0N 0 N N N 0 0 This compound was prepared from the hydrolysis of the corresponding ethyl ester. LC MS showed a single peak with a retention time of 3.12 min. LRMS calcd for C29H29F3N405 (M+H) 571.21, obsd 571.2 15 Example 305 Preparation of 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid F F 0 X0 F 0 N0 - <\' N N 0 0 JD0 20 To a solution of 4-fluoronitrobenzene (1.41g, 10 mmol) in THF (50 mL) was added N Boc-4-hydroxypiperidine (2.01g, 10 mmol) and sodium hydride (60% in mineral oil, 583mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1 carboxylic acid tert-butyl ester (2.5 1g, 78% yield) was obtained as a solid. This nitro 25 compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5- WO 2008/141976 PCT/EP2008/055843 - 228 trifluoromethyloxazole-4-carboxylic acid to give 4- {4-[(2-phenyl-5-trifluoromethyl oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC MS showed a single peak with a retention time of 4.08 min. LRMS called for C27H28F3N305 (M+1) 532.20, obsd 532.1 5 The above compound (1.89g, 3.56 mmol) was dissolved in methylene chloride (6 mL) and treated with gaseous hydrogen chloride in ether (3.8M, 10 mL). The mixture was stirred at room temperature for 4 hrs and then diluted with ether (20 mL). The white solid was filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin 10 4-yloxy)-phenyl]-amide hydrochloride. LC-MS showed a single peak with a retention time of 3.03 min. LRMS calcd for C22H20F3N303 (M+1) 432.15, obsd 432.1 The above hydrochloride salt (101 mg, 0.2 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.12 mL) was added followed by the addition of 2,2 15 dimethylsuccinic anhydride (38.4 mg, 0.3 mmol). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and IN hydrochloric acid. The organic layer was washed with brine and solvents were evaporated. The residue was triturated with ether and the white solid was filtered to give 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 20 carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid (97 mg). LC-MS showed a single peak with a retention time of 4.14 min. LRMS calcd for C28H28F3N306 (M+1) 560.19, obsd 560.4 Example 306 25 Preparation of 2,2-dimethyl-4-oxo-4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole 4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-butyric acid F F F N N 0 0-0 This compound was prepared using the same method as the preparation of 2,2-dimethyl 4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} 30 piperidin-1-yl)-butyric acid. LC-MS showed a single peak with a retention time of 4.02 min. LRMS calcd for C27H26F3N306 (M+1) 546.18, obsd 546.2 WO 2008/141976 PCT/EP2008/055843 - 229 Example 307 Preparation of 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carbonyl)-trans-cyclohexanecarboxylic acid F 0 a 0 F 0 .4' 00 5 0 This compound was prepared by the hydrogenation of the corresponding benzyl ester. The benzyl ester was synthesized by coupling 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid [4-((S)-pyrrolidin-3-yloxy)-phenyl]-amide with trans-1,4-cyclohexane dicarboxylic acid mono-benzyl ester through an acid chloride intermediate. After the 10 hydrogenation and evaporation of solvents, the residue was triturated with ether to give a white solid. LC-MS showed a single peak with a retention time of 3.75 min. LRMS calcd for C29H28F3N306 (M+1) 572.19, obsd 572.3 Example 308 15 Preparation of 1-[2-oxo-2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-ethyl]-cyclopentanecarboxylic acid F F 0 F CHN 'N O N :-~ 0 This compound was prepared with the same method described previously by treating the amine hydrochloride salt with an anhydride in the presence of triethylamine. LC-MS 20 showed a single peak with a retention time of 4.17 min. LRMS calcd for C29H28F3N306 (M+1) 572.19, obsd 572.4 Example 309 Preparation of 2,2-dimethyl-4-(4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl) 25 amino] -phenyl}-piperidin-1-yl)-4-oxo-butyric acid N 0 \ N 0 0
-
N 0 00 WO 2008/141976 PCT/EP2008/055843 - 230 This compound was prepared with the same method described in previous examples. LC MS showed a single peak with a retention time of 4.05 min. LRMS calcd for C28H31N305 (M+1) 490.23, obsd 490.5 5 Example 310 Preparation of (1R,2R)-2-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid 0 -0 N oF F F O N ON O.. 0 "0 N This compound was prepared through the hydrogenation of the corresponding benzyl 10 ester. The benzyl ester was synthesized through the coupling of 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid [4-((S)-pyrrolidin-3-yloxy)-phenyl]-amide with (IR, 2R)-2-benzyloxycarbonyl-cyclopantane carboxylic acid. LC-MS showed a single peak with a retention time of 3.93 min. LRMS calcd for C28H26F3N306 (M+1) 558.18, obsd 558.4 15 Example 311 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-pyrrolidine-3-carboxylic acid methyl ester; hydrochloride F F O F N N N N O 0 0 20 H-CI With a method similar to that used for the preparation of compounds in previous examples. LRMS calcd for C29H29F3N405 (M+H) 571.21, obsd 571.1 Example 312 25 Preparation of (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester; hydrochloride WO 2008/141976 PCT/EP2008/055843 - 231 F F F NN N -0 N 0 / 0 H-Cl With a method similar to that used for the preparation of compounds in previous examples. LRMS called for C29H29F3N405 (M+H) 571.21, obsd 571.1 5 Example 313 Preparation of (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid F F F N N N N 0 0 0 0 With a method similar to that used for the preparation of compounds in previous 10 examples. LRMS called for C28H27F3N405 (M+H) 557.19, obsd 557.2 Example 314 Preparation of 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperidine-4-carbonyl)-piperidine-2-carboxylic acid; hydrochloride F F 0 F N N 0o 0 - 0 15 H-CI With a method similar to that used for the preparation of compounds in previous examples. LRMS called for C29H29F3N405 (M+H) 571.21, obsd 571.2 Example 315 20 Preparation of (1S,2S)-2-(4-{4-[(2-tert-butyl-5-methyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid; hydrochloride WO 2008/141976 PCT/EP2008/055843 - 232 N N N / N 0o N H-CI With a method similar to that used for the preparation of compounds in previous examples. The 2-tert-butyl-5-methyl-oxazole-4-carboxylic acid was prepared from (L) threonine methyl ester according to known procedure in literature. LRMS calcd for 5 C26H34N405 (M+H) 483.25, obsd 483.2 Example 316 Preparation of 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidine-1-carbonyl)-cis-cyclohexanecarboxylic acid F F 0 0 0 - F 0 N 10 With a method similar to that used for the preparation of compounds in previous examples. LRMS calcd for C29H28F3N306 (M+H) 572.19, obsd 572.30 Example 317 15 Preparation of 2-phenyl-thiazole-4-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5 yl)-acetyl]-piperazin-1-yl}-phenyl)-amide; hydrochloride SN 0 0 N 0 0 H-CI With a method similar to that used for the preparation of compounds in previous examples. LRMS calcd for C25H23N504S2 (M+H) 522.12, obsd 522.2 20 Example 318 Preparation of (1S,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 233 F F O F Q- KN N OH O F N 0 A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-fluoro-4 piperazin-1-yl-phenyl)-amide (0.22 g, 0.5 mmol) prepared from 2-phenyl-5 trifluoromethyl-oxazole-4-carboxylic acid and 4-(4-amino-3-fluoro-phenyl)-piperazine 5 using a procedure similar to the one described above, (1S,2S)-cyclopentane-1,2 dicarboxylic acid monobenzyl ester (0.26 g, 0.5 mmol), N-hydroxybenzotriazole (0.1 g, 0.74 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.74 mmol), NN-diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous dichloromethane (4 mL) was stirred at room temperature for overnight. After the 10 reaction, solvent was evaporated. The resulted mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were collected, combined, washed with brine before dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by reverse phase HPLC (10%-80% acetonitrile in water) to gave (1S,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 15 phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester as a yellow solid. LCMS calcd for C35H32F4N405 (m/e) 664, obsd 665 (M+H) To the solution of (1S,2S)-2-(4- {3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl 20 ester in methanol, lithium hydroxide and water were added. The so formed mixture was stirred at 25 0 C overnight. Solvent was removed and the residue was resuspended in ethyl acetate and water. Citric acid was added to acidify the mixture. Organic layer was concentrated and the residue was purified on a reverse phase HPLC system to give (1S,2S)-2-(4- {3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 25 phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid as a white solid. LCMS calcd for C28H26F4N405 (m/e) 574, obsd 575 (M+H). Example 319 Preparation of trans-4-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4 30 carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid WO 2008/141976 PCT/EP2008/055843 - 234 F F O F O 0 With a procedure similar to the one described above, trans-4-(4- {3-fluoro-4-[(2-phenyl 5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) 5 cyclohexanecarboxylic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid (2-fluoro-4-piperazin-1-yl-phenyl)-amide and trans cyclohexane-1,4-dicarboxylic acid monomethyl ester. LC-MS calcd for C30H30F4N405 (m/e) 602, obsd 603 (M+H). 10 trans-4-(4- {3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carbonyl)-cyclohexanecarboxylic acid methyl ester was hydrolized using a procedure similar to the one described above to give trans-4-(4- {3-fluoro-4-[(2 phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperazine- 1 -carbonyl) cyclohexanecarboxylic acid as a white solid. LC-MS calcd for C29H28F4N405 (m/e) 15 588, obsd 589 (M+H). Example 320 Preparation of trans-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid F F O F /\ \ H N aN N N N O0 O 20 With a similar coupling procedure as described above, trans-2-[methyl-(1-{4-[(2-phenyl 5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperidin-4-yl)-carbamoyl] cyclopentanecarboxylic acid benzyl ester was prepared from 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid [4-(4-methylamino-piperidin-1-yl)-phenyl]-amide and WO 2008/141976 PCT/EP2008/055843 - 235 cyclopentane-trans-1,2-dicarboxylic acid monobenzyl ester. LCMS called for C37H37F3N405 (m/e) 674, obsd 675 (M+H). Trans-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 5 phenyl} -piperidin-4-yl)-carbamoyl] -cyclopentanecarboxylic acid benzyl ester was hydrolyzed with lithium hydroxide in methanol and water. The resulted crude mixture was concentrated and the residue was dissolved in ethyl acetate and water with citric acid as acidifying agent. The organic layer then was concentrated and purified by reverse phase HPLC. The mixture of isomers was obtained as a yellow solid. LCMS calcd for 1o C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H). Example 321 Preparation of (1R,2R)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid F F O F N N NOO0 OH 15 (1R,2R)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperidin-4-yl)-carbamoyl] -cyclopentanecarboxylic acid was obtained from SFC chiral purification of trans-2-[methyl-( 1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid 20 LCMS calcd for C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H). Example 322 Preparation of (1S,2S)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid F F O F /\ ~ H N N 0 0 OH N N 0 25 WO 2008/141976 PCT/EP2008/055843 - 236 (IS,2S)-2-[methyl-( 1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperidin-4-yl)-carbamoyl] -cyclopentanecarboxylic acid was obtained from SFC chiral purification of trans-2-[methyl-( 1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid 5 LCMS calcd for C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H). Example 323 Preparation of (1S,2S)-2-(methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-carbamoyl) 10 cyclopentanecarboxylic acid F F O F /\- X N - N \ -i ND 0N , 0"0 0 N N 0 N With a similar coupling procedure as described above, (1S,2S)-2-(methyl-{5'-[(2-phenyl 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4 yl}-carbamoyl)-cyclopentanecarboxylic acid benzyl ester was prepared from 2-phenyl-5 15 trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-5'-yl)-amide and (IS, 2S)-cyclopentane-dicarboxylic acid monobenzyl ester. LCMS calcd for C36H36F3N505 (m/e) 675, obsd 676 (M+H). With a similar procedure as described above, (1S,2S)-2-(methyl-{5'-[(2-phenyl-5 20 trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4 yl}-carbamoyl)-cyclopentanecarboxylic acid was prepared from (iS,2S)-2-(methyl- {5' [(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-4-yl}-carbamoyl)-cyclopentanecarboxylic acid benzyl ester. LCMS calcd for C29H30F3N505 (m/e) 585, obsd 586 (M+H). 25 Example 324 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1 methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide WO 2008/141976 PCT/EP2008/055843 - 237 F F O F N N N N 0 With a similar coupling procedure as described above, 2-phenyl-5-trifluoromethyl oxazole-4-carboxylic acid {4-[4-((R)-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl} amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 5 piperazin- 1 -yl-phenyl)-amide and (R)-pyrrolidine- 1,2-dicarboxylic acid 1 -tert-butyl ester. LCMS calcd for C26 H26 F3 N5 03 (m/e) 513, obsd 514 (M+H). With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4-[4-((R)-1-methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl] 10 phenyl} -amide was prepared from 2-phenyl-5 -trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide and methanesulfonyl chloride. LCMS calcd for C27 H28 F3 N5 05 S (m/e) 591, obsd 592 (M+H). Example 325 15 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1 dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide F F o F N N 0
N
o S N N . 0 With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4-[4-((R)-1-dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl] 20 phenyl} -amide was prepared from 2-phenyl-5 -trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide and dimethylsulfamoyl chloride. LCMS calcd for C28 H31 F3 N6 05 S (m/e) 620, obsd 621 (M+H). 25 Example 326 WO 2008/141976 PCT/EP2008/055843 - 238 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1 methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide F F O F N N N 0 With a similar coupling procedure as described above, 2-phenyl-5-trifluoromethyl 5 oxazole-4-carboxylic acid {4-[4-((S)-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl} amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4 piperazin- 1 -yl-phenyl)-amide and (S)-pyrrolidine- 1,2-dicarboxylic acid 1 -tert-butyl ester. LCMS calcd for C26 H26 F3 N5 03 (m/e) 513, obsd 514 (M+H). 10 With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4-[4-((S)-1-methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl] phenyl} -amide was prepared from 2-phenyl-5 -trifluoromethyl-oxazole-4-carboxylic acid {4- [4-((S)-pyrrolidine-2-carbonyl)-piperazin- 1-yl] -phenyl} -amide and methanesulfonyl chloride. LCMS calcd for C27 H28 F3 N5 05 S (m/e) 591, obsd 592 (M+H). 15 Example 327 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1 dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide F o F N N N N N 0 20 With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4-[4-((S)-1-dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl] phenyl} -amide was prepared from 2-phenyl-5 -trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide and dimethylsulfamoyl chloride. LCMS calcd for C28 H31 F3 N6 05 S (m/e) 620, obsd 621 25 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 239 Example 328 Preparation of 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoyl)-cyclopentanecarboxylic acid methyl ester F OF N N __ o F
N
5 O 2-(4- {5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} benzoyl)-cyclopentanecarboxylic acid methyl ester was prepared through a standard Suzuki coupling procedure by mixing 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide (prepared using a similar coupling procedure as 10 described above from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6 bromo-pyridin-3-ylamine.), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) benzoyl]-cyclopentanecarboxylic acid methyl ester, palladium tetrakis(triphenylphosphine) and aquous sodium bicarbonate solution in toluene and ethanol, and heating this mixture to 160 0 C under microwave condition for 20 min. 15 Aqueous workup followed by silica gel chromatography separation gave 2-(4- {5-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} -benzoyl) cyclopentanecarboxylic acid methyl ester as light yellow solid. LCMS calcd for C30 H24 F3 N3 05 (m/e) 563, obsd 564 (M+H). 20 Example 329 Preparation of 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yl}-benzoyl)-cyclopentanecarboxylic acid F O F N /\N With a similar hydrolysis procedure as described above, 2-(4- {5-[(2-Phenyl-5 25 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)- WO 2008/141976 PCT/EP2008/055843 - 240 cyclopentanecarboxylic acid was obtained by a hydrolysis of 2-(4-{5-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} -benzoyl) cyclopentanecarboxylic acid methyl ester with lithium hydroxide in THF, methanol and water. LCMS called for C29 H22 F3 N3 05 (m/e) 549, obsd 550 (M+H). 5 Example 330 Preparation of 3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] pyridin-2-yloxy}-piperidine-1-carboxylic acid ethyl ester F F o F O O " N N N N_ 0 f 10 With a similar procedure to that used for the preparation of 3-{4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester (example in the application), 3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-pyridin-2-yloxy}-piperidine-1-carboxylic acid ethyl ester was prepared from 5-ethyl-2-phenyl-oxazole-4-carboxylic acid, 2-chloro-5 -nitro-pyridine, 3-hydroxy 15 piperidine-1-carboxylic acid tert-butyl ester and ethyl chloroformate. LCMS calcd for C24H23F3N405 (m/e) 504, obsd 505 (M+H). Example 331 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3 20 propyl-1-methyl-ureido)-piperidin-1-yl]-phenyl}-amide FF 0 F /\ ~ H N N 0 1 N 0 | H With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4- [4-(3 -propyl- 1 -methyl-ureido)-piperidin- 1 -yl] -phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-methylamino 25 piperidin-1-yl)-phenyl]-amide and propylisocyanate. LCMS calcd for C27H30F3N503 (m/e) 529, obsd 530 (M+H).
WO 2008/141976 PCT/EP2008/055843 - 241 Example 332 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-ethyl 1-methyl-ureido)-piperidin-1-yl]-phenyl}-amide F - N N 0' N N 'kN_ | H 5 With a similar procedure as described above, 2-phenyl-5-trifluoromethyl-oxazole-4 carboxylic acid {4- [4-(3 -ethyl-i -methyl-ureido)-piperidin- 1-yl] -phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-methylamino piperidin-1-yl)-phenyl]-amide and ethylisocyanate. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H). 10 Example 333 Preparation of 2,2,N-trimethyl-N-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenyl}-piperidin-4-yl)-succinamic acid FF 0 F - N N NN 0 With a similar procedure as described above, 2,2,N-trimethyl-N-(1-{4-[(2-phenyl-5 15 trifluoromethyl-oxazole-4-carbonyl)-amino] -phenyl} -piperidin-4-yl)-succinamic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4 methylamino-piperidin- 1 -yl)-phenyl] -amide and 2,2-dimethyl-succinic acid. LCMS calcd for C29H31F3N405 (m/e) 572, obsd 573 (M+H). 20 Example 334 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-1H tetrazol-5-yl-acetyl)-piperazin-1-yl]-phenyl}-amide WO 2008/141976 PCT/EP2008/055843 - 242 F O F F N 0N N N NN O NN 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (53 mg, 0.117 mmol), (1H-tetrazol-5-yl)-acetic acid (15 mg, 0.117 mmol), and triethylamine (49 uL, 0.351 mmol) were dissolved in 1.5 mL of DMF and chilled in 5 an ice bath. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature for 30 minutes and then diluted with 30 ml
CH
2 Cl 2 . The organic phase was washed with IN citric acid (1 x 8 mL), water (3 x 8 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO 4 , filtered and evaporated to dryness under vacuum. The residue was crystallized from 10 acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-1 H tetrazol-5-yl-acetyl)-piperazin-1-yl]-phenyl}-amide as light yellow crystals (26 mg, 42%). ES-MS calcd for C24H21F3N803 (m/e) 526.48, obsd 527 (M+H). Example 335 15 Preparation of 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl}-piperazine-1-carbonyl)-adamantane-1-carboxylic acid F O F
-
N I F N oN N 0 0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (51.5 mg, 0.113 mmol), adamantane-1,3-dicarboxylic acid (51 mg, 0.227 20 mmol), and triethylamine (48 uL, 0.341 mmol) were dissolved in 1 mL of DMF. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature overnight. 4-N,N-dimethylamino-pyridine (5 mg) was added and the reaction was stirred for an additional 72 hours and then diluted with 30 ml ethyl acetate. The organic phase was washed with saturated ammonium chloride (1 x 5 mL), 2.5% WO 2008/141976 PCT/EP2008/055843 - 243 KHSO 4 (3 x 5 mL), water (2 x 5 mL) and saturated sodium chloride. The organic layer was dried over MgSO 4 , filtered, passed through a plug of silica gel and evaporated to dryness under vacuum to a light brown solid. The residue was purified by flash chromatography to yield 3-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) 5 amino]-phenyl} -piperazine- 1 -carbonyl)-adamantane- 1 -carboxylic acid as light yellow crystals (9.4 mg, 13%). ES-MS calcd for C33H33F3N405 (m/e) 622.65, obsd 623 (M+H). Example 336 10 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide F o F N F N o N N IN 0 N'N 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (50.7 mg, 0.122 mmol), (1H-tetrazol-5-yl)-acetic acid (15.6 mg, 0.122 mmol), 15 triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were reacted as above to give a clear oil. The crude product was crystallized from methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4 [1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide as off-white crystals (11 mg, 17%). ES-MS calcd for C25H22F3N703 (m/e) 525.49, obsd 526 (M+H). 20 Example 337 Preparation of 1-methyl-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid F o F N F N O N 0 0 N O 0 WO 2008/141976 PCT/EP2008/055843 - 244 Methyl-cyclohexane-1,4-dicarboxylic acid (34.1 mg, 0.183 mmol) in dry CH 2 Cl 2 (3 mL) was treated with phosgene (2M in CH 2 Cl 2 , 366 uL, 0.732 mmol) for 30 minutes. THF (0.5 mL) was added and stirred for an additional 30 minutes. The reaction was 5 evaporated and re-evaporated from toluene three times and re-dissolved in 5 mL CH 2 Cl 2 . 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (76.2 mg, 0.183 mmol) and triethylamine (77 uL, 0.549 mmol) in 3 mL of CH 2 Cl 2 were added dropwise over 15 minutes to the above solution. The mixture was stirred at room temperature for 90 minutes and then diluted with 10 mL CH 2 Cl 2 . Following work-up, the 10 crude residue was purified by flash chromatography to yield 1-methyl-4-(4-{4-[(2 phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -piperidine-l-carbonyl) cyclohexanecarboxylic acid as a white solid (26 mg, 24%). ES-MS calcd for C31H32F3N305 (m/e) 583.61, obsd 584 (M+H). 15 Example 338 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[2-(2,4 dioxo-thiazolidin-5-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide F O F S N FN NN Ij 0 0 N laoo sY 0 _ 0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide 20 (60.1 mg, 0.149 mmol), (2,4-dioxo-thiazolidin-5-yl)-acetic acid (26.2 mg, 0.149 mmol), triethylamine (63 uL, 0.448 mmol) and BOP (63.2 mg, 0.149 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2 phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[2-(2,4-dioxo-thiazolidin-5 yl)-acetyl]-piperidin-4-yl}-phenyl)-amide as a white solid (76.9 mg, 90%). ES-MS calcd 25 for C27H23F3N405S (m/e) 572.57, obsd 573 (M+H). Example 339 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[3-(3 hydroxy-isoxazol-5-yl)-propionyl]-piperidin-4-yl}-phenyl)-amide WO 2008/141976 PCT/EP2008/055843 - 245 F O F F N N 0
O
0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (46.8 mg, 0.112 mmol), 3-(3-hydroxy-isoxazol-5-yl)-propionic acid (17.7 mg, 0.112 mmol), triethylamine (47 uL, 0.337 mmol) and BOP (47.6 mg, 0.112 mmol) in 1 mL 5 DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[3-(3-hydroxy isoxazol-5-yl)-propionyl]-piperidin-4-yl}-phenyl)-amide as a white solid (15.5 mg, 25%). ES-MS calcd for C28H25F3N405 (m/e) 554.53, obsd 555 (M+H). 10 Example 340 Preparation of 2,2-dimethyl-4-oxo-4-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid F o F -HN N O o N 0- 0 0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl] 15 amide (52.3 mg, 0.121 mmol), 3,3-dimethyl-dihydro-furan-2,5-dione (17 mg, 0.133 mmol) and triethylamine (34 uL, 0.242 mmol) in 1 mL DMSO were stirred at room temperature for 30 minutes and then diluted with 30 ml ethyl acetate. The organic phase was washed with 2.5% KHSO 4 (5 mL) and saturated sodium chloride (2 x 5 mL), dried over MgSO 4 , filtered and evaporated to dryness under vacuum. The crude product was 20 purified by flash chromatography to yield 2,2-dimethyl-4-oxo-4-(3- {4-[(2-phenyl-5 trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid as a white solid (46.4 mg, 68%). ES-MS calcd for C28H28F3N306 (m/e) 559.55, obsd 560 (M+H). 25 Example 341 WO 2008/141976 PCT/EP2008/055843 - 246 Preparation of 2,2-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid F O F 0 N 0 0 0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl] 5 amide (44.1 mg, 0.102 mmol), 3,3-dimethyl-dihydro-pyran-2,6-dione (17.5 mg, 0.122 mmol) and triethylamine (28.5 uL, 0.204 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 2,2-dimethyl-5-oxo-5 (3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} -piperidin-1 yl)-pentanoic acid as a white solid (33 mg, 56%). ES-MS calcd for C29H30F3N306 10 (m/e) 573.57, obsd 574 (M+H). Example 342 Preparation of 3,3-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4 carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid F o F 0 Nr 1 5No N 0 15 0 0 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl] amide (46.2 mg, 0.107 mmol), 4,4-dimethyl-dihydro-pyran-2,6-dione (18.3 mg, 0.128 mmol) and triethylamine (30 uL, 0.214 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 3,3-dimethyl-5-oxo-5 20 (3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} -piperidin-1 yl)-pentanoic acid as a white solid (34 mg, 55%). ES-MS calcd for C29H30F3N306 (m/e) 573.57, obsd 574 (M+H). Example 343 25 DGAT Phospholipid FlashPlate Assay WO 2008/141976 PCT/EP2008/055843 - 247 Materials for the assay were: PL-FlashPlate: Phospholipid FlashPlates from PerkinElmer, catalog number SMP108; DAG (1,2-Dioleoyl-sn-glycerol) 10 mM suspended in water containing 0.10% Triton X-100; 14 C-Pal-CoA (palmitoyl coenzyme A, [palmitoyl-1- 14 C]) from PerkinElmer, catalog number NEC-555 with a specific activity of 55 mCi/mmol; 5 and DGAT pellet, with a protein concentration of 9.85 mg/ml. Aqueous buffers were prepared or purchased as follows: The coating buffer (CB) was purchased from PerkinElmer, catalog number SMP900A; the reaction buffer (RB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.01 % BSA in water; the washing buffer (WB) 10 is 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.05 % deoxycholic acid sodium salt in water; the dilution buffer (DB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM EDTA, 0.2 % Triton X-100 in water. 1,2-Dioleoyl-sn-glycerol (DAG, 10 mmoles) was diluted to 500 gM with coating buffer 15 (CB). The diluted DAG solution was then added to 384-well PL-FlashPlates at 60 gl per well, and incubated at room temperature for 2 days. The coated plates were then washed twice with washing buffer (WB) before use. Test compounds were serial diluted to 2000, 666.7, 222.2, 74.1, 24.7, 8.2, 2.7 and 0.9 gM in 100 % DMSO. Diluted compound were further diluted 10 fold with reaction buffer (RB). 14 C-Pal-CoA was diluted to 8.3 gM 20 with RB. The DGAT pellet was diluted to 0.13 mg protein/ml with dilution buffer (DB) immediately before it was added to the PL-FlashPlates to start the reaction. 20 gl of the RB-diluted compounds (or 10% DMSO in RB for Total and Blank), 15 gl of RB diluted 14C-Pal-CoA and 15 gl of DB diluted DGAT pellet (DB without DGAT for Blanks) were transferred to each well of the PL-FlashPlates. The reaction mixtures were 25 incubated at 37 0 C for 1 hour. The reactions were stopped by washing 3 times with WB. Plates were sealed with Top-seal and read on a Topcount instrument. Calculation of IC 50 _: The IC 50 values for each compound were generated using an Excel template. The Topcount rpm readings of Total and Blank were used as 0 % and 100 % 30 inhibition. The percent inhibition values of reactions in the presence of compounds were calculated, and plotted against compound concentrations. All data were fitted into a Dose Response One Site model (4 parameter logistic model) as the following: (A+((B-A)/( 1 +((x/C)AD)))), 35 WO 2008/141976 PCT/EP2008/055843 - 248 with A and B as the bottom and top of the curve (highest and lowest inhibition), respectively, and C as IC 50 and D as Hill Coefficient of the compound. The results are summarized in Table 1 below: Table 1 5 Compound in Activity in DGAT Phospholipid FlashPlate Assay (pM) Example 1 0.055 Example 2 0.034 Example 3 0.034 Example 4 0.193 Example 5 0.085 Example 6 0.082 Example 7 0.065 Example 8 0.123 Example 9 0.098 Example 10 0.103 Example 11 0.091 Example 12 0.081 Example 13 0.092 Example 14 0.150 Example 15 0.122 Example 16 0.167 Example 17 0.164 Example 18 0.083 Example 19 0.272 Example 20 0.057 Example 21 0.142 Example 22 0.185 Example 23 0.218 Example 24 0.065 Example 25 0.148 Example 26 0.094 Example 27 0.911 Example 28 0.128 Example 29 0.035 Example 30 0.147 Example 31 0.049 Example 32 0.080 Example 33 0.088 Example 34 0.059 Example 35 0.056 Example 36 0.145 Example 37 0.236 Example 38 0.202 Example 39 0.131 Example 40 0.083 Example 41 0.137 Example 42 0.122 WO 2008/141976 PCT/EP2008/055843 - 249 Example 43 0.036 Example 44 0.045 Example 45 0.120 Example 46 0.112 Example 47 0.094 Example 48 0.236 Example 49 0.336 Example 50 0.118 Example 51 0.111 Example 52 0.397 Example 53 0.124 Example 54 0.146 Example 55 0.090 Example 56 0.101 Example 57 0.128 Example 58 0.136 Example 59 0.070 Example 60 0.167 Example 61 0.091 Example 62 0.185 Example 63 0.044 Example 64 0.134 Example 65 0.072 Example 66 0.039 Example 67 0.107 Example 68 0.091 Example 69 0.102 Example 70 0.066 Example 71 0.179 Example 72 0.027 Example 73 0.041 Example 74 0.140 Example 75 0.332 Example 76 0.145 Example 77 0.077 Example 78 0.040 Example 79 0.094 Example 80 0.040 Example 81 0.153 Example 82 0.161 Example 83 0.090 Example 84 0.043 Example 85 0.178 Example 86 0.196 Example 87 0.107 Example 88 0.254 Example 89 0.135 Example 90 0.107 Example 91 0.162 Example 92 0.221 Example 93 0.013 Example 94 0.023 WO 2008/141976 PCT/EP2008/055843 - 250 Example 95 0.016 Example 96 0.053 Example 97 0.200 Example 98 0.189 Example 99 0.085 Example 100 0.070 Example 101 0.054 Example 102 0.071 Example 103 0.090 Example 104 0.186 Example 105 0.173 Example 106 0.057 Example 107 0.060 Example 108 0.039 Example 109 0.083 Example 110 0.205 Example 111 0.045 Example 112 0.046 Example 113 0.208 Example 114 0.286 Example 115 0.084 Example 116 0.277 Example 117 0.048 Example 118 0.235 Example 119 0.124 Example 120 0.198 Example 121 0.063 Example 122 0.135 Example 123 0.060 Example 124 0.059 Example 125 0.140 Example 126 0.116 Example 127 0.067 Example 128 0.109 Example 129 0.073 Example 130 0.042 Example 131 0.118 Example 132 0.167 Example 133 0.157 Example 134 0.100 Example 135 0.062 Example 136 0.123 Example 137 0.117 Example 138 0.114 Example 139 0.068 Example 140 0.198 Example 141 0.187 Example 142 0.099 Example 143 0.095 Example 144 0.068 Example 145 0.059 Example 146 0.098 WO 2008/141976 PCT/EP2008/055843 - 251 Example 147 0.076 Example 148 0.094 Example 149 0.061 Example 150 0.043 Example 151 0.205 Example 152 0.188 Example 153 0.042 Example 154 0.061 Example 155 0.041 Example 156 0.028 Example 157 0.027 Example 158 0.062 Example 159 0.071 Example 160 0.084 Example 161 0.113 Example 162 0.165 Example 163 0.036 Example 164 0.038 Example 165 0.127 Example 166 0.070 Example 167 0.290 Example 168 0.087 Example 169 0.388 Example 170 0.631 Example 171 0.129 Example 172 0.061 Example 173 0.154 Example 174 0.057 Example 175 0.047 Example 176 0.052 Example 177 0.066 Example 178 0.053 Example 179 0.068 Example 180 0.072 Example 181 0.047 Example 182 0.198 Example 183 0.488 Example 184 0.133 Example 185 0.091 Example 186 0.070 Example 187 0.060 Example 188 0.125 Example 189 0.092 Example 190 0.053 Example 191 0.050 Example 192 0.109 Example 193 0.201 Example 194 0.043 Example 195 0.060 Example 196 0.148 Example 197 0.023 Example 198 0.119 WO 2008/141976 PCT/EP2008/055843 - 252 Example 199 0.116 Example 200 0.098 Example 201 0.064 Example 202 0.111 Example 203 0.149 Example 204 0.169 Example 205 0.041 Example 206 0.174 Example 207 0.100 Example 208 0.089 Example 209 0.115 Example 210 0.100 Example 211 0.124 Example 212 0.042 Example 213 0.048 Example 214 0.140 Example 215 0.072 Example 216 0.043 Example 217 0.045 Example 218 0.075 Example 219 0.111 Example 220 0.063 Example 221 0.218 Example 222 0.198 Example 223 0.146 Example 224 0.054 Example 225 0.043 Example 226 0.056 Example 227 0.078 Example 228 0.164 Example 229 0.114 Example 230 0.245 Example 231 0.183 Example 232 0.033 Example 233 0.040 Example 234 0.090 Example 235 0.299 Example 236 0.094 Example 237 0.075 Example 238 0.109 Example 239 0.102 Example 240 0.180 Example 241 0.167 Example 242 0.099 Example 243 0.245 Example 244 0.194 Example 245 0.120 Example 246 0.155 Example 247 0.186 Example 248 0.167 Example 249 0.120 Example 250 0.186 WO 2008/141976 PCT/EP2008/055843 - 253 Example 251 0.275 Example 252 0.101 Example 253 0.075 Example 254 0.212 Example 255 0.158 Example 256 0.260 Example 257 0.127 Example 258 0.196 Example 259 0.246 Example 260 0.097 Example 261 0.033 Example 262 0.071 Example 263 0.166 Example 264 0.151 Example 265 0.118 Example 266 0.082 Example 267 0.096 Example 268 0.213 Example 269 0.350 Example 270 0.138 Example 271 0.076 Example 272 0.690 Example 273 0.092 Example 274 0.215 Example 275 0.111 Example 276 0.217 Example 277 0.094 Example 278 0.095 Example 279 0.103 Example 280 0.053 Example 281 0.062 Example 282 0.171 Example 283 0.229 Example 284 0.032 Example 285 0.157 Example 286 0.358 Example 287 0.124 Example 288 0.074 Example 289 0.112 Example 290 0.064 Example 291 0.245 Example 292 0.421 Example 293 0.267 Example 294 0.373 Example 295 0.070 Example 296 0.349 Example 297 0.246 Example 298 0.059 Example 299 0.125 Example 300 0.311 Example 301 0.285 Example 302 0.137 WO 2008/141976 PCT/EP2008/055843 - 254 Example 303 0.322 Example 304 0.113 Example 305 0.110 Example 306 0.039 Example 307 0.067 Example 308 0.066 Example 309 0.160 Example 310 0.160 Example 311 0.319 Example 312 0.248 Example 313 0.298 Example 314 0.119 Example 315 0.423 Example 316 0.136 Example 317 0.046 Example 318 0.107 Example 319 0.105 Example 320 0.127 Example 321 0.102 Example 322 0.169 Example 323 0.101 Example 324 0.438 Example 325 0.066 Example 326 0.418 Example 327 0.325 Example 328 0.097 Example 329 0.082 Example 330 0.378 Example 331 0.206 Example 332 0.228 Example 333 0.065 Example 334 0.170 Example 335 0.403 Example 336 0.282 Example 337 0.184 Example 338 0.091 Example 339 0.139 Example 340 0.309 Example 341 0.307 Example 342 0.201 It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. 5

Claims (21)

1. A compound of formula (I): R1-R R 1 -R 2 Q-3 - R 4 -' 6 R C - N -X - R7 Y- R 8 -C Re H 5 (I), wherein: R 1 is tert-butyl; phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 10 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; R 2 is C or N; R 3 is C, N, O or S; 15 R 4 is C or N; R 5 is C, N, O or S; R 6 is halogen, lower alkyl, haloloweralkyl or alkoxy; R 7 is N optionally substituted with lower alkyl; 0; or 20 absent; R 8 is C optionally substituted with lower alkyl; N optionally substituted with lower alkyl; 0; or absent; 25 R 9 is lower alkyl; alkoxy; hydroxyl; amine; lower alkyl amine; 30 haloloweralkyl; WO 2008/141976 PCT/EP2008/055843 - 256 lower alkoxy; lower alkenyloxy; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, 5 -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl;
5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -S0 2 -loweralkyl, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl phenyl; 10 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl; 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, 15 -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl; -(CH 2 )nC(O)OH; -CH 2 C(lower alkyl) 2 C(O)OH; -CH 2 (cycloalkyl)C(O)OH; -(cycloalkyl)C(O)OH; 20 -CH 2 C(CH 3 ) 3 ; -(CH 2 )n-cycloalkyl; cycloalkenyl; bicycloalkenyl-C(O)OH; -(CH 2 )n-O-alkyl; 25 -O-C(=C)-lower alkyl; -O-(CH 2 )n-phenyl; -NSO 2 -loweralkyl; -NSO 2 -cycloalkyl; -NSO 2 -aryl; 30 -N-lower alkyl; -N-cycloalkyl optionally substituted with -C(O)OH; -N-heterocycloalkyl; -N-aryl; -N-(CH 2 )n-aryl; 35 -N-heteroaryl optionally substituted with alkyl; WO 2008/141976 PCT/EP2008/055843 - 257 -N-CH(lower alkyl)C(O)OH; -N-(cycloalkyl)C(O)OH; -N-CH(lower alkyl)C(O)O-lower alkyl; or phenyl-C(O)OH; 5 X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; Y is phenyl optionally substituted with one to four substituents independently 10 selected from lower alkyl, halogen and cyano; heteroaryl; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; 5- or 6-membered heterocycloalkyl optionally substituted with one to four 15 substituents independently selected from lower alkyl, halogen and cyano; or -N(CH 2 )n 1 )N-; and n is 1, 2 or 3; or pharmaceutically acceptable salts thereof 20 2. A compound of formula (I) according to claim 1, wherein: R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 25 -O-CF 3 ; and wherein both R 7 and R 8 are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R 3 is C, N or S and R 5 is C, 0 or S. 30 3. A compound of formula (I) according to claim 1, wherein: R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 35 -0-CF 3 ; WO 2008/141976 PCT/EP2008/055843 - 258 and wherein both R 7 and R 8 are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R 3 is C, N or S and R 5 is C, 0 or S. 5 4. A compound of formula (I) according to claim 1, wherein: R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and 10 -0-CF 3 ; R 2 is C; R 3 is 0; R 4 is C; R 5 is N; 15 and wherein both R 7 and R 8 are not absent. 5. A compound of formula (I) according to claim 1, wherein: R 1 is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 20 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; R 2 is C; R 3 is 0; 25 R 4 is C; R 5 is N; and wherein both R 7 and R 8 are absent.
6. A compound according to any of claims 1 to 5, wherein R 1 is phenyl optionally 30 substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 .
7. A compound according to any of claims 1 to 6, wherein R 1 is phenyl optionally substituted with halogen. 35 WO 2008/141976 PCT/EP2008/055843 - 259 8. A compound according to any of claims 1 to 5, wherein R 1 is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 . 5 9. A compound according to any of claims 1 to 5 and 8, wherein R 1 is pyridyl optionally substituted with halogen.
10. A compound according to any of claims 1 to 9, wherein X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from 10 lower alkyl, halogen and cyano.
11. A compound according to any of claims 1 to 9, wherein X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano. 15
12. A compound according to any of claims 1 to 11, wherein X is phenyl, pyridyl, or pyrimidyl.
13. A compound according to any of claims 1 to 12, wherein Y is phenyl optionally 20 substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
14. A compound according to any of claims 1 to 12, wherein Y is cycloloweralkyl optionally substituted with one to four substituents 25 independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
15. A compound according to any of claims 1 to 14, wherein Y is phenyl, pyridyl, 30 piperazyl, piperidyl, pyrrolidyl or cyclopentyl.
16. A compound according to any of claims 1 to 15, wherein R is halogen, trifluoromethyl, trifluoroethyl, methyl, ethyl, propyl, methoxymethyl, or methoxyethyl. 35 WO 2008/141976 PCT/EP2008/055843 - 260 17. A compound according to any of claims 1 to 16, wherein R 7 is N optionally substituted with lower alkyl.
18. A compound according to any of claims I to 17, wherein R 8 is N optionally 5 substituted with lower alkyl.
19. A compound according to any of claims I to 18, wherein R 9 is lower alkyl; alkoxy; 10 hydroxyl; lower alkyl amine; cycloloweralkyl optionally substituted with one to four substituents independently selected from loweralkyl, hydroxy, halogen, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl; 15 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -S0 2 -loweralkyl, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl phenyl; -(CH 2 )nC(O)OH; 20 -CH 2 C(lower alkyl) 2 C(O)OH; -CH 2 (cycloalkyl)C(O)OH; -(cycloalkyl)C(O)OH; -NSO 2 -loweralkyl; -N-lower alkyl; 25 -N-cycloalkyl optionally substituted with -C(O)OH; -N-CH(lower alkyl)C(O)OH; or -N-(cycloalkyl)C(O)OH.
20. A compound according to any of claims 1 or 19, wherein n is 1. 30
21. A compound according to any of claims 1 to 20, selected from: (S)-3- {5-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] pyridin-2-ylamino } -pyrrolidine- 1 -carboxylic acid ethyl ester; (S)-3- {4-[(1 -Phenyl-3-trifluoromethyl- 1 H-pyrazole-4-carbonyl)-amino] 35 phenylamino}-pyrrolidine-1-carboxylic acid ethyl ester; WO 2008/141976 PCT/EP2008/055843 - 261 (S)-3- {5-[(1 -Phenyl-3-trifluoromethyl- 1H-pyrazole-4-carbonyl)-amino]-pyridin-2 ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester; (S)-3- {5-[(4-Methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin-2 ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester; 5 (S)-3- {5-[(4-Methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-amino]-pyridin-2 ylamino } -pyrro lidine- 1 -carboxylic acid tert-butyl ester; 4- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenyl} piperidine- 1 -carboxylic acid propylamide; 4- {4-[(5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-phenyl} 10 piperidine- 1 -carboxylic acid propylamide; 2-Pyridin-2-yl-4-trifluoromethyl-oxazole-5-carboxylic acid [6-(4 isobutylcarbamoyl-phenyl)-pyridin-3-yl]-amide; 4-[4-(4- { [1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino} phenyl)-piperidine-1-carbonyl]-cyclohexanecarboxylic acid; 15 4-(5 - { [1-(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino} pyridin-2-yl)-benzoic acid; 1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(1 cyclopentanecarbonyl-piperidin-4-yl)-phenyl]-amide; 3-Chloro-4-(5-{[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4carbonyl] 20 amino } -pyridin-2-yl)-benzoic acid; trans-4-[4-(4-{[1-(4-Fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonyl] amino } -phenyl)-piperidine- 1 -carbonyl] -benzoic acid; pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(1 cyclopropanecarbonyl-piperidin-4-yl)-phenyl]-amide; 25 4'- { [1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazole-4-carbonyl] -amino} biphenyl-4-carboxylic acid; (1R,2R)-2- {4'-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 4-ylcarbamoyl} -cyclopentanecarboxylic acid; (IS,2S)-2- {4'-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 30 4-ylcarbamoyl} -cyclopentanecarboxylic acid; (S)-3-(5- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -pyrimidin-2-yloxy)-pyrrolidine- 1 -carboxylic acid ethyl ester; (S)-3- {5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2 yloxy}-pyrrolidine-1-carboxylic acid ethyl ester; WO 2008/141976 PCT/EP2008/055843 - 262 (S)-3-(4- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -phenylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-isobutyryl pyrrolidin-3-ylamino)-pyridin-3-yl]-amide; 5 2,2-Dimethyl-3- {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl}-propionic acid; (S)-3-(5-{[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -pyridin-2-ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester; (S)-3- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino} 10 pyrrolidine-1-carboxylic acid ethyl ester; (S)-3-(5- { [2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl] amino } -pyrimidin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester; 2,2-Dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperazin- 1 -yl)-butyric acid; 15 trans-4-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; (1R,2R)-2-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperidine- 1 -carbonyl)-cyclopentanecarboxylic acid; trans-4-(4- {4- [(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} 20 piperidine-1-carbonyl)-cyclohexanecarboxylic acid; cis-4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} piperidine-1-carbonyl)-cyclohexanecarboxylic acid; (IS,2S)-2- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl 4-carbonyl} -cyclopentanecarboxylic acid; 25 (1R,2R)-2-(4- {4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid; cis-4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} piperazine-1-carbonyl)-cyclohexanecarboxylic acid; (1R,3S)-3-(4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 30 phenyl} -piperazine- 1 -carbonyl)-cyclohexanecarboxylic acid; 2,2-Dimethyl-4-oxo-4- {4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino]-biphenyl-4-yl} -butyric acid; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4 cyclopropylcarbamoyl-phenyl)-pyridin-3-yl]-amide; WO 2008/141976 PCT/EP2008/055843 - 263 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-methyl-propane-2 sulfonylaminocarbonyl)-piperidin-1-yl]-phenyl}-amide; (S)-3-{4-[(1-Phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino] phenoxy} -pyrro lidine- 1 -carboxylic acid ethyl ester; 5 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{4-[4-(1H-tetrazol-5-yl) cyclohexanecarbonyl] -piperazin- 1-yl} -phenyl)-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[4-(1H-tetrazol-5-yl) cyclohexanecarbonyl] -piperidin-4-yl} -phenyl)-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[4-(5-oxo-4,5-dihydro 10 1,2,4]oxadiazo 1-3 -yl)-cyclohexanecarbonyl] -piperidin-4-yl} -phenyl)-amide; 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H 1,2']bipyridinyl-4-carboxylic acid amide; [1 -(4- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} piperidine- 1 -carbonyl)-piperidin-4-yl] -acetic acid; 15 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-piperidine-4-carboxylic acid; 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid; 3-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 20 piperidine-1-carbonyl)-piperidin-4-yl]-propionic acid; 4-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-1-carbonyl)-piperidin-4-yl]-butyric acid; (R)-3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2 yloxy}-pyrrolidine-1-carboxylic acid ethyl ester; 25 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester; 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-piperidine-4-carboxylic acid; 1-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} 30 piperidine-4-carbonyl)-piperidine-3-carboxylic acid ethyl ester; 1-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-piperidine-3-carboxylic acid; 2,2-dimethyl-4-oxo-4-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenoxy} -piperidin- 1 -yl)-butyric acid; WO 2008/141976 PCT/EP2008/055843 - 264 2,2-dimethyl-4-oxo-4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenoxy} -pyrrolidin- 1 -yl)-butyric acid; 4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} pyrrolidine-1-carbonyl)-trans-cyclohexanecarboxylic acid; 5 1-[2-oxo-2-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenoxy}-pyrrolidin-1-yl)-ethyl]-cyclopentanecarboxylic acid; 2,2-dimethyl-4-(4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-amino]-phenyl} piperidin-1-yl)-4-oxo-butyric acid; (1R,2R)-2-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 10 phenoxy}-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid; 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-pyrrolidine-3-carboxylic acid methyl ester; hydrochloride; (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester; hydrochloride; 15 (S)-1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid; 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperidine-4-carbonyl)-piperidine-2-carboxylic acid; hydrochloride; (iS,2S)-2-(4-{4-[(2-tert-butyl-5-methyl-oxazole-4-carbonyl)-amino]-phenyl} 20 piperazine-1-carbonyl)-cyclopentanecarboxylic acid; hydrochloride; 4-((S)-3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy} pyrrolidine-1-carbonyl)-cis-cyclohexanecarboxylic acid; 2-phenyl-thiazole-4-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl] piperazin-1-yl}-phenyl)-amide; hydrochloride; 25 (iS,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid; trans-4-(4- {3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperazine- 1 -carbonyl)-cyclohexanecarboxylic acid; trans-2- [methyl-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] 30 phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid; (1R,2R)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperidin-4-yl)-carbamoyl] -cyclopentanecarboxylic acid; (iS,2S)-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenyl} -piperidin-4-yl)-carbamoyl] -cyclopentanecarboxylic acid; WO 2008/141976 PCT/EP2008/055843 - 265 (IS,2S)-2-(methyl- {5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl} -carbamoyl)-cyclopentanecarboxylic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1 5 methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((R)-1 dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1 methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 10 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-((S)-1 dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-phenyl}-amide; 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} benzoyl)-cyclopentanecarboxylic acid methyl ester; 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl} 15 benzoyl)-cyclopentanecarboxylic acid; 3- {5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy} piperidine-1-carboxylic acid ethyl ester; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-propyl-1-methyl ureido)-piperidin-1-yl]-phenyl}-amide; 20 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(3 -ethyl-I-methyl ureido)-piperidin-1-yl]-phenyl}-amide; 2,2,N-trimethyl-N-(1- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperidin-4-yl)-succinamic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-f1H-tetrazol-5-yl 25 acetyl)-piperazin-1-yl]-phenyl}-amide; 3-(4- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} piperazine- 1 -carbonyl)-adamantane- 1 -carboxylic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-11H-tetrazol-5-yl acetyl)-piperidin-4-yl]-phenyl}-amide; 30 1-methyl-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] phenyl} -piperidine- 1 -carbonyl)-cyclohexanecarboxylic acid; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[2-(2,4-dioxo thiazo lidin-5 -yl)-acetyl] -piperidin-4-yl} -phenyl)-amide; 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- { 1-[3-(3-hydroxy 35 isoxazo 1-5 -yl)-propionyl] -piperidin-4-yl} -phenyl)-amide; WO 2008/141976 PCT/EP2008/055843 - 266 2,2-dimethyl-4-oxo-4-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenoxy} -piperidin- 1 -yl)-butyric acid; 2,2-dimethyl-5-oxo-5-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenoxy} -piperidin- 1 -yl)-pentanoic acid; and 5 3,3-dimethyl-5-oxo-5-(3- {4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl) amino] -phenoxy} -piperidin- 1 -yl)-pentanoic acid.
22. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 21 comprising one of the following reactions 10 (a) the reaction of a compound according to formula - RC OH (Ia) in the presence of of a compound according to formula NO 2 - X - R7 - Y- R 8 -C - R O (Ila); 15 (b) the reaction of a compound according to formula - R 2 C OH (Ib) in the presence of a compound according to formula NH 2 - X - R7 - Y- R 8 -C - R 0 (Ilb); 20 (c) the reaction of a compound according to formula WO 2008/141976 PCT/EP2008/055843 - 267 R5 R R 1 R 2 0 Rs C NH -X-Hal (Ic) in the presence of a compound according to formula B(OR) 2 -Y-R 8 -C-Re 11 0 (I1c); wherein R 1 to R 9 , X and Y are as defined in any one of claims 1 to 20, wherein Hal 5 represents F, Cl, Br or I, and wherein R represents hydrogen, alkyl or cycloalkyl.
23. Compounds according to any one of claims 1 to 21 for use as therapeutically active substance. 10 24. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to any of claims 1 to 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
25. The use of a compound according to any one of claims 1 to 21 for the preparation 15 of medicaments for the treatment or prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic syndrome.
26. Compounds according to any one of claims 1 to 21 for use as medicaments for the treatment and prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic 20 syndrome.
27. A compound according to any one of claims I to 21, when manufactured according to a process of claim 22. 25 28. A method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, comprising the step of administering a therapeutically effective amount of a compound according to any of claims 1 to 21 to a patient in need thereof
29. The invention as hereinbefore described.
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