WO2006082010A1 - Inhibitors of diacylglycerol acyltransferase (dgat) - Google Patents

Inhibitors of diacylglycerol acyltransferase (dgat) Download PDF

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WO2006082010A1
WO2006082010A1 PCT/EP2006/000786 EP2006000786W WO2006082010A1 WO 2006082010 A1 WO2006082010 A1 WO 2006082010A1 EP 2006000786 W EP2006000786 W EP 2006000786W WO 2006082010 A1 WO2006082010 A1 WO 2006082010A1
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hydrazide
isopropyl
acetyl
biphenyl
yloxy
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PCT/EP2006/000786
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French (fr)
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David Robert Bolin
Christophe Michoud
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F.Hoffmann-La Roche Ag
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Priority to EP06706491A priority Critical patent/EP1848687A1/en
Priority to CA002596639A priority patent/CA2596639A1/en
Priority to AU2006210056A priority patent/AU2006210056A1/en
Priority to KR1020077018042A priority patent/KR100883694B1/en
Priority to MX2007009210A priority patent/MX2007009210A/en
Priority to BRPI0607861-3A priority patent/BRPI0607861A2/en
Priority to JP2007553522A priority patent/JP2008529983A/en
Publication of WO2006082010A1 publication Critical patent/WO2006082010A1/en

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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • 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
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
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    • C07C2601/14—The ring being saturated

Abstract

Provided herein are compounds of the formula (I), as well as pharmaceutically acceptable salts thereof, wherein R1, R2, R2´, R3, R4, R5 and X are as defined in the specification and claims. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

Description

Case 22252
INHIBΠΌRS OF DIACYLGLYCEROL ACYLTRANSFERASE (OGAT")
■ The invention relates to inhibitors of diacylglycerol acyltransferase. The inhibitors include, for example, phenoxy- and thiophenoxyacetamide derivatives and are useful for the treatment of diseases such as obesity, type II diabetes mellitus and metabolic syndrome. All documents cited or relied upon below are expressly incorporated herein by reference. The invention relates to inhibitors of diacylglycerol acyltransferase of formula (I)
Figure imgf000002_0001
wherein:
X is O or S;
R1 is hydrogen, halogen, (d-C6)alkyl or cyano;
R2, R2' are independently of each other H or halogen;
R3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, NH(CH2)nCH(CH3)2, or -O(CH2)nOCH3, unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (Ci-C6) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring;
R4 is branched or unbranched (C2-C6) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (Ci-C6) alkyl, (Ci-C6) alkoxy, -O(CH)(CH3)2, -CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, -NO2, -(CH2)-Aryl and
CS / 05.12.05 0
-C(O)-O-CH3, or unsubstituted or substituted 5-10 membered carboxylic ring; R5 is (C1-C6) alkyl or -CH(CH3)2; n is O, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
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 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 O-acyltransferase, also known as diglyceride acyltransferase or DGAT, is 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).
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 (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 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 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 were cloned and designated DGATl and DGAT2 (see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, 13018-13023,
Lardizabal et al, Journal of Biological Chemistry (2001) 276, 38862-38869 and Cases et al, Journal of Biological Chemistry (2001) 276, 38870-38876). Although both enzymes utilize the same substrates, there is no homology between DGATl and DGAT2. Further, although both enzymes are widely expressed, differences exist in the relative abundance of DGATl and DGAT2 expression in various tissues.
The gene encoding mouse DGATl has been used to create DGAT knock-out mice. These mice, although unable to express a functional DGAT enzyme (Dgat-/- mice), are viable and continue to synthesize triglycerides (see Smith et al, Nature Genetics (2000) 25, 87-90). This would suggest that multiple catalytic mechanisms 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).
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 also 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 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 glucose and insulin levels following a glucose load, in comparison to wild-type mice (see Buhman et al, Journal of Biological Chemistry (2002) 277, 25474-25479 and Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192). „ .
Disorders or imbalances in triglyceride metabolism, both absorption as well as de novo synthesis, are implicated in the pathogenesis of a variety of diseases. These diseases include, for example, obesity, insulin resistance syndrome, type π diabetes, metabolic syndrome (syndrome X) and coronary heart disease (see Kahn, Nature Genetics (2000) 25, 6-7; Yanovski and Yanovski, New England Journal of Medicine (2002) 346, 591-602; Lewis et al, Endocrine Reviews (2002) 23, 201; Brazil, Nature Reviews Drug Discovery (2002) 1, 408; Malloy and Kane, Advances in Internal Medicine (2001) 47, 111; Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270; Yu and Ginsberg, Annals of Medicine (2004) 36, 252-261); and S.R. Smith, Current Drug Targets CNS Neurol Disord. 2004 Oct;3(5):431-9). ' " J
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 agents for the treatment of 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, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, 1340-1346), substituted benzyl- phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, 1433-1437, Goto, et al, Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Uceda, et al, Thirteenth International Symposium on Athersclerosis (2003), abstract 2P-0401, and Miyata, et al, JP 2004067635) and substituted aryl alkyl acid (see Smith et al, US20040224997A1).
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, prenylflavonoids (see Chung et al, Planta Medica (2004) 70, 258-260), polyacetylenes (see Lee et al, Planta Medica (2004) 70, 197-200), cochlioquinones (see Lee et al, Journal of Antibiotics (2003) 56, 967- 969), tanshinones (see Ko et al, Archives of Pharmaceutical Research (2002) 25, 446-448), gemfibrozil (see Zhu et al, Atherosclerosis (2002) 164, 221-228), and substituted quinolones (see Ko, et al, Planta Medica (2002) 68, 1131-1133).
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 mellitus and metabolic syndrome. Further, a need exists in the art for DGAT inhibitors having IC50 values less than about 1 μM.
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 materials are now described.
As used herein, the term "alkyl" means, for example, a branched or unbranched, cyclic 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 C3 to C12, more preferably C5 to C10, more preferably C5 to C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, 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), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl. (C1-C6) alkyl preferably is branched or unbranched, unsubstituted and not cyclic.
As used herein, the term "lower alkyl" means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical wherein said cyclic lower alkyl group is C5, C6 or C7, and wherein said acyclic lower alkyl group is C1, C2, C3 or C4, and is preferably selected from methyl, ethyl, propyl (n-propyl or r
- 6 - isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). It will be appreciated therefore that the term "lower alkyl" as used herein includes lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower alkynyl (branched or unbranched), cycloloweralkyl, cycloloweralkenyl and cycloloweralkynyl. Branched or unbranced, unsubstituted and acyclic lower alkyl are preferred.
As used herein, the term "aryl" means, for example, a substituted or unsubstituted carbocyclic aromatic group, such as phenyl or naphthyl, or a substituted or unsubstituted heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, imidazolyl, triazolyl, pyrimidinyl pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolyl, quinazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl. Substituted or unsubstituted phenyl or napthyl groups are preferred, with phenyl groups being more preferred.
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, 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, aryloxy alkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, 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, 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 asthiols, thioethers, sulfoxides 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, 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, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
The lower alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substitutents present, preferably 1 substituent.
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.
As used herein, the term "halogen" means, for example, a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical.
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, 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. - -
Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
g _
In detail, the present invention relates to compounds of formula (I)
Figure imgf000010_0001
wherein:
X is O or S;
R1 is hydrogen, halogen, (C1-C6)alkyl or cyano; R2, R2' are independently of each other H or halogen; R3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, NH(CH2)nCH(CH3)2, or -O(CH2)nOCH3, unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with
(Ci-C6) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring; R4 is branched or unbranched (C2-C6) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2,
-CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, -NO2, -(CH2)-Aryl and
-C(O)-O-CH3, or unsubstituted or substituted 5-10 membered carboxylic ring; R5 is (C1-C6) alkyl or -CH(CH3)2; n is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
Compounds of formula (I) are individually preferred and physiologically acceptable salts thereof are individually preferred, with the compounds of formula (I) being particularly preferred. The compounds of formula (I) can have one or more asymmetric C atoms and can therefore exist as an enantiomeric mixture, mixture of stereoisomers or as optically pure compounds.
Preferred compounds of formula (I) are those, wherein X is O or S; R1 is hydrogen, halogen, (Ci-C6)alkyl or cyano; R2, R2' are independently of each other H or halogen;
R3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, NH(CH2)nCH(CH3)2, or -O(CH2)nOCH3, unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C1-C6) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring; R4 is branched or unbranched (C2-C6) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -0(CH)(CHs)2, -CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, -NO2, -(CH2)-Aryl, or unsubstituted or substituted 5-10 membered carboxylic ring; R5 is (C1-C6) alkyl or -CH(CH3)2; n is O, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, R3 is:
Figure imgf000012_0001
Figure imgf000012_0002
wherein Y is O or S.
Preferably, X is O. Other preferred compounds are those, wherein X is S.
A preferred embodiment of the present invention is related to compounds as defined above, wherein R4 is substituted phenyl which is phenyl mono.-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, and -NO2.
Preferably, R1 is halogen. More preferably, R1 is fluorine. It is also preferred that R2 and R2' are hydrogen.
Other preferred compounds of formula (I) as defined above are those, wherein R3 is
Figure imgf000012_0003
Figure imgf000012_0004
wherein Y is O or S. Preferably, R3 is phenyl.
Another preferred embodiment of the present invention refers to compounds of formula (I) as defined above, wherein R4 is (C1-C6) alkyl, cyclopentyl, benzyl, unsubstituted phenyl or phenyl which is mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -CF3, -OCF3, - SCH3, -SO2CH3, -NO2 and -C(O)-O-CH3. Preferabl, R4 is unsubstituted phenyl or phenyl which is mono- or di-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (Ci-C6) alkoxy, -O(CH)(CH3)2, -OCF3, -SCH3, -NO2 and -C(O)-O-CH3. More preferably, R4 is phenyl, 4-methoxy-phenyl, 4-chloro-phenyl, 3- methoxy-phenyl, 3-fluoro-phenyl, 3-chloro-phenyl, 3-isopropyl-phenyl, 2-methylsylfanyl- phenyl, 2-nitro-phenyl, 2-isopropoxy-phenyl, 2-ethyl-phenyl, 2-propoxy-phenyl, 2- methoxycarbonyl-phenyl, 2,3-dimethyl-phenyl, 2-trifluoromethoxy-phenyl or 2-efhoxy- phenyl.
Further preferred compounds are those wherein R5 is -CH(CH3)2- Other preferred compounds are those wherein n is 0, 1 or 2.
Preferred compounds of formula (J) as defined above are those selected from the group consisting of
Benzoic acid N'-[2-(5,4'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(2'-chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N' - [2-(5-fluoro-2' -methyl-biphenyl-2-yloxy)-acetyl] -N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-methoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(5,2'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, Benzoic acid N' -[2-(4' -chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N' - [2-(5-fluoro-3 ' -methoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N' -[2-(5,3 ' -difluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-isopropyl-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- - - hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N' - [2-(5-fluoro-2' -isopropoxy-biphenyl-2-yloxy)-acetyl] -N' -isopropyl- hydrazide, Benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(2',3'-dimethyl-5-fluoro -biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-methanesulfonyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5,2',4'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5, 4'-difluoro-4'-methyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-ethyl-5-methyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(2'-ethyl-4,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(2'-ethyl-3,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5-cyano-2'-ethyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(5-fluoro-2'-ethyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide, Benzoic acid N'-[2-(5-methyl-2'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide,
Benzoic acid N'-[2-(4,5-difluoro-2'-txifluoroniethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide, Benzoic acid N'-[2-(3,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide,
Tetrahydro-pyran-4-carboxylic-acid-N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2- yloxy)-acetyl] -N' -isopropyl-hydrazide, 3-methyl-furan-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N'-isopropyl-hydrazide,
Furan-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]~N'- isopropyl-hydrazide,
Furan-3-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide,
Cyclohexanecarboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N' -isopropyl-hydrazide,
4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N' -isopropyl hydrazide, Thiophene-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl] -N' -isopropyl hydrazide,
Tetrahydro-thiopyran-4-carboxylic acid N'-[2-(5-fluoro-2' -tiifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N' -isopropyl hydrazide,
Thiophene-3-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N' -isopropyl hydrazide,
Thiophene-3-carboxylic acid N' -[2-(5-fluoro-2' -ethyl-biphenyl-2-yloxy)-acetyl]-N' - isopropyl hydrazide,
Benzoic acid N'-[2-(2-cyclopentyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N' -[2-(2-sec-butyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(2-propyl-phenoxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(2~benzyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(3'-fluoro-biphenyl-2-ylsulfanyl)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(2',3'-dimethyl-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(3'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(4'-fluoro-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(3'-trifluoromethyl-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide, B enzoic acid N' - [2-(2! -fluoro-biphenyl-2-ylsulf anyl)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(4'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide, and 4-(Isobutylamino)-benzoic acidN'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl] -N' -isopropyl hydrazide, and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) as defined above are those selected from the group consisting of Benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(4'-chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N' - [2-(5-fluoro-2 ' -isopropoxy-biphenyl-2-yloxy)-acetyl] -N' -isopropyl- hydrazide, Benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N' -[2-(5-fluoro-2' -propoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, Benzoic acid N' -[2-(2',3 ' -dimethyl-5-fluoro -biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N' -[2-(5-fluoro-2' -trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, and Benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, and pharmaceutically acceptable salts thereof.
A preferred embodiment of the present invention refers to the compound benzoic acid N'- [2-(5-fluoro-2' -methoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5,2'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-isopropoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl- hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biρhenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide. Another preferred embodiment of the present invention refers to the compound benzoic acid N' - [2-(2' -ethyl-3 ,5-difluoro-biphenyl-2-yloxy)-acetyl] -N' -isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-methyl-2'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(4,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(3,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
Another preferred embodiment of the present invention refers to the compound cyclohexanecarboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N'-isopropyl-hydrazide.
Another preferred embodiment of the present invention refers to the compound thiophene- 2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide.
It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Another embodiment of the present invention refers to a process for the manufacture of compounds of formula (I) as defined above, which process comprises reacting a compound of formula (H)
Figure imgf000019_0001
with a compound of formula (IH)
Figure imgf000019_0002
wherein R1, R2, R2', R3, R4, Rs and X are as defined above.
The present invention also relates to compounds of formula (I) as defined above, when prepared by a process as described above.
The compounds of formula (I), (II) and (IH) can be prepared by methods known in the art
1 O 1^ A. *ϊ or as described below or in analogy thereto. Unless otherwise indicated, R , R , R , R , R and X are as described above.
^
As described above, the novel compounds of the present invention have been found to inhibit liver diacylglycerol acyltransferase activity. The compounds of the present invention can therefore be used in the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type It diabetes mellitus and metabolic syndrome.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
The invention likewise embraces compounds as described above for use as therapeutic active substances, especially as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome.
In another preferred embodiment, the invention relates to a method for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome, which method comprises administering a therapeutically effective amount of a compound as defined above to a human being or animal. Preferred is amethod as defined above, wherein said therapeutically effective amount of said compound is in an amount of from about 10 mg to about 1000 mg per day.
The invention also embraces the use of compounds as defined above for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome.
The invention also relates to the use of compounds as described above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type π diabetes mellitus and metabolic syndrome. Such medicaments comprise a compound as described above.
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 preferred reaction schemes suitable for preparing such compounds. Further exemplification is found in the specific Examples detailed below.
As shown in Scheme 1 :
Scheme 1
Figure imgf000022_0001
hydroxy-substituted beήzoate esters i can be alkylated with 2-bromoethyl methyl ether by heating in the presence of potassium carbonate to give the alkoxy-ether substituted benzoate esters ii, where R1' is lower alkyl.
As shown in Scheme 2:
Scheme 2
Figure imgf000022_0002
tetrahydro-2H-thiopyran-4-one ϋi can be treated with tosylmethylisocyanide and potassium t-butoxide in t-butyl alcohol (6.61 g, 33.8 mmol) in an appropriate solvent to yield the nitrile iv. Nitrile iv can be treated with hydrogen chloride gas in a lower alkyl alcohol solution to yield ester v, where R1' is lower alkyl.
Additionally, as shown in Scheme 3, Scheme 3
Figure imgf000023_0001
vi VII VlU
esters vi, where Ri' is lower alkyl and R2' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl can be treated with hydrazine monohydrate in an appropriate solvent with heating to yield hydrazide vii. Hydrazide vii can be dissolved in acetone, heated and then concentrated to dryness. The residue can be dissolved in and treated with triethylsilane, with warming, to yield alkyl hydrazide viii, where R2' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl.
As shown in Scheme 4:
Scheme 4
Figure imgf000023_0002
IX
a substituted bromo-benzene ix, where X is O or S and R3' is H, halogen, cyano or lower alkyl, in an appropriate solvent can be treated with triethylamine and t-butyl bromoacetate. The intermediate can then be treated with a solution of hydrochloric acid in an appropriate to yield to yield x, where R3' is H, halogen, cyano or lower alkyl.
As shown in Scheme 5: Scheme 5
Figure imgf000024_0001
Xl XII
a substituted phenol xi, where R3' is H, halogen, cyano or lower alkyl and R4' is H, lower alkyl, cycloalkyl, arylalkyl, can be alkylated with t-butyl bromoacetate and potassium carbonate in an appropriate solvent. The resultant material can be treated with hydrochloric acid in an appropriate solvent to yield the aryloxy acetic acid xii.
According to Scheme 6:
Scheme 6
Figure imgf000024_0002
a substituted-bromo-phenol xiii, where R3' is H, halogen, cyano or lower alkyl, can be alkylated with t-butyl bromoacetate and potassium carbonate in an appropriate solvent with heating to yield t-butyl ester xiv. Using standard palladium catalyzed "cross coupling" procedures, xiv can be heated with a commercially available substituted arylboronic acid in the presence of a base, typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene, with a catalytic amount of palladium, typically Pd[PPh3]4, to yield xv, where R5' is H, halogen, lower alkyl, nitro, alkoxy, thioalkoxy, haloalkoxy, lower alkyl carboxylate, or alkyl sulfonyl. As shown is Scheme 7:
Scheme 7
Figure imgf000025_0001
viii XVI
Figure imgf000025_0002
xvii
a substituted acetic acid x, where X is O or S and R3' is H, halogen, cyano or lower alkyl from Scheme 4 can be used to acylate a hydrazide viii from Scheme 3, where R2' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond forming conditions, as practiced by those skilled in the art, may be used. Typically, x and viii, in an appropriate solvent, may be treated with a base, such as triethyl amine, and PyBroP or ECDI and HOBT to yield acyl hydrazide xvi. Using standard palladium catalyzed "cross coupling" procedures, the arylbromide xvi can be heated with a commercially available substituted arylboronic acid in the presence of a base, typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene, with a catalytic amount of palladium, typically Pd[PPh3]4, to yield xvii, where R5' is H, halogen, lower alkyl, nitro, alkoxy, thioalkoxy, haloalkoxy, lower alkyl carboxylate, or alkyl sulfonyl.
Further, as shown in Scheme 8: Scheme 8
Figure imgf000026_0001
XlI viii XVlIl
a substituted phenoxy-acetic acid xii, from Scheme 5, where R3' is H, halogen, cyano or lower alkyl and R4' is H, lower alkyl, cycloalkyl, arylalkyl, can be used to acylate a hydrazide viii from Scheme 3, where R2' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl. Various standard amide bond forming conditions, as practiced by those skilled in the art, may be used. Typically, x and viii, in an appropriate solvent, may be treated with a base, such as triethyl amine, and PyBroP or ECDI and HOBT to yield acyl hydrazide xviii.
.,
- ZD -
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), 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 therapeutic composition can also be in the form of an oil emulsion or dispersion in 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 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 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 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 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.
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 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 an "effective amount". For example, the dose of a compound of the present invention is typically in the range of about 10 to about 1000 mg per day.
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.
EXAMPLES
General Methods: Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. Optical rotations were determined with a Perkin-Elmer model 241 polarimeter. IH-NMR spectra were recorded with Varian XL-200, Mercury-300 or Unityplus 400 MHz spectrometers, using tetramethylsilane (TMS) as internal standard. Electron impact (El, 70 ev) and fast atom bombardment (FAB) mass spectra were taken on VG Autospec or VG 70E-HF mass spectrometers. Silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh silica gel for flash chromatography; columns were run under a 0-5 psi head of nitrogen to assist flow. Thin layer chromatograms were run on glass thin layer plates coated with silica gel as supplied by E. Merck (E. Merck # 1.05719) and were visualized by viewing under 254 nm UV light in a view box, by exposure to 12 vapor, or by spraying with either phosphomolybdic acid (PMA) in aqueous ethanol, or after exposure to Cl2, with a 4,4'- tetramethyldiaminodiphenylmethane reagent prepared according to E. Von Arx, M. Faupel and M Brugger, J. Chromatography, 1976, 220, 224-228.
Reversed phase high pressure liquid chromatography (RP-HPLC) was carried out using a Rainin HPLC employing a 41.4 x 300 mm, 8 uM, Dynamax™ C-18 column at a flow of 49 mIVmin employing a gradient of acetonitrile:water (each containing 0.75% TFA) typically from 5 to 95% acetonitrile over 35-40 min. HPLC conditions are typically described in the format (5-95-35-214); this refers to a linear gradient of from 5% to 95% acetonitrile in water over 35 min while monitoring the effluent with a UV detector at a wavelength of 214 nM.
Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fisher or Baker reagent grade and were used without additional purification except as noted, acetonitrile was Fisher or Baker HPLC grade and was used as is.
Definitions as used herein include:
DGAT is diacylglycerol:acyl CoA 0-acyltransferase,
THF is tetrahydrofuran, DMF is N,N-dimemylformamide,
DMA is N,N-dimethylacetamide,
DMSO is dimethylsulfoxide,
DCM is dichloromethane, DME is dimethoxyethane,
MeOH is methanol,
EtOH is ethanol,
NaOH is sodium hydroxide,
TFA is 1,1,1-trifluoroacetatic acid, HOBT is 1-hydroxybenzotriazole,
PyBroP is bromotripyrrolidinophosphonium hexafluorophosphate,
EDCI is l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,
DIPEA is diisopropylethylamme, brine is saturated aqueous sodium chloride solution, DAG is 1,2-dioleoyl-sn-glycerol,
TLC is thin layer chromatography,
RP HPLC is reversed phase high performance liquid chromatography,
APCI-MS is atmospheric pressure chemical ionization mass spectrometry,
ES-MS is electrospray mass spectrometry, RT is room or ambient temperature.
Silica gel chromatography on Biotage columns refers to use of a flash chromatography system supplied by the Biotage Division of the Dyax Corporation employing prepacked 4Og (40s columns), 9Og (40m columns) or 80Og (75m columns). Elution is carried out with hexane-ethyl acetate mixtures under 10-15 psi nitrogen pressure.
PART I: PREFERRED INTERMEDIATES
Preparation of benzoic acid N'-isopropyl-hydrazide
Figure imgf000030_0001
A solution of benzoylhydrazine (10 g, 73.45 mmol) in hexane (200 ml) was treated with acetone (54 mL, 734.5 mmol) and refluxed overnight. The precipitate was collected by suction filtration to afford a white solid which was treated with TFA (200 ml) and triethylsilane (24 mL, 149.24 mmol) at 6O0C overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and IN NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the product as a white solid (9.31 g, 71%).
Preparation of tetrahydro-pyran-4-carboxylic acid N'-isopropyl-hydrazide
Figure imgf000031_0001
A solution of methyl tetrahydro-2H-pyran-4 (250 mg, 1.73 mmol) and hydrazine monohydrate (1.8 ml, 34.68 mmol) in MeOH (3 ml) was heated to 1200C for 20 minutes in a microwave oven. The mixture was concentrated to dryness and the residue was triturated with hexanes. The resulting hydrazide 1 was collected by suction filtration and air dried (235 mg). This material was dissolved in acetone (3ml) and heated to 600C for 20 min. The solution was concentrated to dryness. The residue was dissolved in TFA (10 ml) and treated with triethylsilane (0.65 ml, 4.10 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was saturated with brine and extracted with DCM. The combined organics were dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (198 mg, 53%).
Preparation of cvclohexane carboxylic acid N'-isopropyl-hydrazide
Figure imgf000031_0002
A solution of methyl-cyclohexane carboxylate (20 g, 140.65 mmol) and hydrazine monohydrate (35 ml, 703.25 mmol) in MeOH (100 ml) was refluxed overnight. The mixture was concentrated to dryness and the residue was partitioned between saturated aqueous sodium bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated (14.35 g, 75%). A portion of the resulting hydrazide 1 (2.6 g, 18.28 mmol) was dissolved in acetone (100 ml) and the solution was refluxed overnight. The solution was concentrated to dryness. The residue was dissolved in TFA (30 ml) and treated with triethylsilane (5.83 ml, 36.56 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between IN NaOH and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (2.O g, 61%).
Preparation of thiophene-2-carboxyIic acid N'-isopropyl-hydrazide
Figure imgf000032_0001
A solution of ethyl-2-thiophene carboxylate (2 g, 12.8 mmol) and hydrazine monohydrate
(6.2 ml, 128 mmol) in EtOH (10 ml) was refluxed overnight. The mixture was concentrated to dryness to afford intermediate 1 as an off white solid (1.81 g). A portion of this material (500 mg) was dissolved in acetone (5 ml) and the solution was heated to 500C overnight. The solution was concentrated to dryness. The residue was dissolved in TFA (5 ml) and treated with triethylsilane (1.1 ml, 6.74 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (516 mg, 80%).
Preparation of furan-2-carboxyIic acid N'-isopropyl-hydrazide
Figure imgf000032_0002
A solution of ethyl-2-furoate (2 g, 14.3 mmol) and hydrazine monohydrate (6.9 ml, 143 mmol) in EtOH (10 ml) was refluxed overnight. The mixture was concentrated to dryness to afford intermediate 1 (1.65 g). A portion of this material (500 mg) was dissolved in acetone (5 ml) and the solution was heated to 500C overnight. The solution was concentrated to dryness. The residue was dissolved in TFA (5 ml) and treated with triethylsilane (1.30 ml, 8.18 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (511 mg, 74%).
Preparation of thiophene-3-carboxyIic acid N'-isopropyI-hvdrazide
Figure imgf000033_0001
A solution of ethyl-3-thiophene carboxylate (2 g, 12.8 mmol) and hydrazine monohydrate (6.2 ml, 128 mmol) in EtOH (10 ml) was refluxed overnight. The mixture was concentrated to dryness to afford intermediate 1 (1.86 g, 100%). A portion of this material (500 mg) was dissolved in acetone (5 ml) and the solution was heated to 600C overnight: The solution was concentrated to dryness. The residue was dissolved in TFA (5 ml) and treated with triethylsilane (1.16 ml, 7.24 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (484 mg, 75%).
Preparation of furan-3-carboxylic acid N'-isopropyl-hydrazide
Figure imgf000033_0002
A solution of ethyl-3-fαroate (2 g, 14.3 mmol) and hydrazine monohydrate (6.9 ml, 143 mmol) in EtOH (10 ml) was refluxed overnight. The mixture was concentrated to dryness to afford intermediate 1 (1.52 g). A portion of this material (500 mg) was dissolved in acetone (5 ml) and the solution was heated to 600C overnight. The solution was concentrated to dryness. The residue was dissolved in TFA (5 ml) and treated with triethylsilane (1.25 ml, 7.82 mmol) at 600C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the product as a solid (406 mg, 62%).
Preparation of 3-methyl-furan-2-carboxyIic acid N'-isopropyl-hydrazide
Figure imgf000034_0001
A solution of methyl-3-methyl-2-furoate (250 mg, 1.78 mmol) and hydrazine monohydrate (1.8 ml, 34.68 mmol) in MeOH (3 ml) was heated to 1200C for 20 minutes in a microwave oven. The mixture was concentrated to dryness and the residue was triturated with hexanes. The resulting hydrazide 1 was collected by suction filtration and air dried (242 mg). This material was dissolved in acetone (3ml) and stirred at rt overnight. The solution was concentrated to dryness. The residue was dissolved in TFA (3 ml) and treated with triethylsilane (0.58 ml, 3.6 mmol) at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and DCM. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford the product as oil (268 mg, 82%).
Preparation of 4-(2-methoxy-ethoxy)-benzoic acid-N'-isopropyl hydrazide
Figure imgf000034_0002
Figure imgf000034_0003
A DMF (20 ml) solution of methyl-p-hydroxybenzoate (1.0 g, 6.57 mmol), potassium carbonate (9.08 g, 65.72 mmol) and 2-bromoethyl methyl ether (6.17 ml, 65.72 mmol) was heated to 1500C for 20 minutes in a microwave oven. The reaction mixture was filtered through celite, and partitioned between 1 N NaOH and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford intermediate 1 as pale yellow oil (1.28 g, 93%). A solution of ester 1 (1.0 g, 4.76 mmol) and hydrazine monohydrate (4.61 ml, 95.12 mmol) in MeOH (8 ml) was heated to 1600C for 20 minutes in a microwave oven. The reaction mixture was concentrated under reduced pressure to afford hydrazide 2 as a yellow solid (790 mg, 79%). A solution of hydrazide 2 (200 mg, 0.95 mmol) in acetone (4 ml) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to afford intermediate 3 as brown oil (240 mg, 100%). Compound 3 (240mg, 0.95 mmol) was then treated with Et3SiH (0.35 ml, 2.1 mmol) in TFA (5 ml) at 600C overnight. The reaction mixture was concentrated and the residue was partitioned between DCM and IN NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the product as oil (170 mg, 62%).
Preparation of 2-(2-methoxy-ethoxy)-benzoic acid-N'-isopropyl hydrazide
Figure imgf000035_0001
Figure imgf000035_0003
Figure imgf000035_0002
A DMF (20 ml) solution of methyl o-hydroxybenzoate (1.0 g, 6.57 mmol), potassium carbonate (9.08 g, 65.72 mmol) and 2-bromoethyl methyl ether (6.17 ml, 65.72 mmol) was heated to 1500C for 20 minutes in a microwave oven. The reaction mixture was filtered through celite, and partitioned between 1 N NaOH and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford intermediate 1 as brown oil (807 mg, 58%). A solution of ester 1 (0.8 g, 3.8 mmol) and hydrazine monohydrate (4.0 ml, 76.0 mmol) in MeOH (8 ml) was heated to 1600C for 20 minutes in a microwave oven. The reaction mixture was concentrated under reduced pressure to afford hydrazide 2 as oil (840 mg, 88%). A solution of hydrazide 2 (840 mg,
3.99 mmol) in acetone (10 ml) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to afford intermediate 3 as brown oil (1.1 g, 100%). This crude material was then treated with Et3SiH (1.5 ml, 9.25mmol) in TFA (25 ml) at 600C overnight. The reaction mixture was concentrated and the residue was partitioned between DCM and IN NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the product as oil (460 mg, 40%).
Preparation of tetrahvdro-thiopγran-4-carboxyIic acid N'-isopropyl-hydrazide
Figure imgf000036_0001
A cold (ice water bath) solution of tetrahydro-2H-thiopyran-4-one (3.57 g, 30.7 mmol) and tosylmethylisocyanide (6.61 g, 33.8 mmol) in DME (125 ml) was treated with a suspension of potassium t-butoxide (6.93 g, 61.8 mmoles) in t-butyl alcohol (100 ml). The reaction mixture was stirred at room temperature for 3 hours, and then diluted with ether (250 ml). The mixture was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by short path distillation under high vacuum to give nitrile 1 as colorless oil (1.98 g, 50.7%). A solution of nitrile 1 (1.0 g, 7.9 mmoles) in ethanol (15 ml) was cooled in an ice bath. Hydrogen chloride gas was bubbled into the solution until saturation. The reaction mixture was then stirred at room temperature for 2 hours. Water (5 ml) was added and stirring was continued at room temperature for 2.5 hours, at 60° C for 4 hours, and finely at room temperature for 12 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to afford ester 2 (539 mg, 40%). A solution of ester 2 (539 mg, 3.1 mmoles) and hydrazine monohydrate (3 ml, 61.9 mmoles) in MeOH (1 ml) was heated in a microwave oven at 160° C for 10 min. Concentration of the reaction mixture under reduced pressure afforded hydrazide 3 (481 mg, 97%). A solution of 3 (481 mg, 3 mmoles) in acetone (2 ml) was heated in a microwave oven at 120° C for 20 min.. The acetone was removed under vacuum and the residue was dissolved in TFA (8 ml) and treated with triethylsilane (0.874 ml, 5.47 mmol) at 60° C for 18 hours. The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product (302 mg, 55%).
Preparation of 4-nitro-benzoic acid N'-isopropyl-hydrazide
Figure imgf000037_0001
A solution of 4-nitrobenzoylhydrazine (2.5 g, 13.8 mmol) in hexane (50 ml) was treated with acetone (20.3 mL, 276 mmol) and refluxed overnight. The reaction mixture was cooled and the precipitate was collected by suction filtration, washed with hexanes and dried under vacuum to afford 2.9 g (13.12 mmol, 95%) of a white solid. This material was treated with TFA (19.5 ml) and triethylsilane (4.19 mL, 26.24 mmol) at 50-550C for 2 hours and then at RT overnight. The reaction mixture was diluted with 250 ml of IN HCl and extracted with hexanes (2 x 100 ml). The aqueous layer was cooled in an ice bath and the pH was adjusted to 12.5 by the addition of NaOH pellets. This mixture was extracted with ethyl acetate (3 x 250 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 5% ethyl acetate/hexanes and poured through a silica gel plug. The silica gel was eluted with 35% ethyl acetate/hexanes and the filtrates were evaporated to afford the product as a white solid (3 g, 100%).
Preparation of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester
Figure imgf000037_0002
A solution of 2-bromo-4-fluorophenol (2.15 g, 11.25 mmol) in DMF (60 ml) was treated with potassium carbonate (7.77 g, 96.25 mmol) and t-butyl bromoacetate (1.99 ml, 13.5 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5%-10% ethyl acetate/hexanes gradient to give the product as colorless oil (2.86 g, 83%).
Preparation of (2'-ethγl-5-fluoro-biphenvI-2-vIoχy)-acetic acid
Figure imgf000038_0001
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (2.00 g, 6.55 mmol) in DME (16 ml)/ 2M Na2CO3 (11.46 ml, 22.93 mmol) was treated with 2-ethylphenylboronic acid (1.96 g, 13.10 mmol), and Pd[PPh3J4 (757 mg, 0.655 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel. column with a 5-20% .ethyl acetate/hexanes gradient to afford 1.25 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (10 ml) and stirred at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (1.08 g, 60%).
Preparation of (5-fluoro-2'-trifluoromethoxy-biphenyI-2-yIoxy)-acetic acid
Figure imgf000038_0002
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (5.1 g, 16.71 mmol) in DME (60 ml)/ 2M Na2CO3 (29.25 ml, 58.50 mmol) was treated with 2- trifluoromethoxyphenylboronic acid (5.16 g, 25.08 mmol), and Pd[PPh3J4 (3.87 g, 3.33 mmol) in a microwave oven at 15O0C for 15 min. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with IN NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 8-10% ethyl acetate/hexanes gradient to afford 4.65 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (40 ml) and stirred at 6O0C for 2 h and then at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (4.17 g, 24%). Preparation of (2-bromo-4-fluoro-phenoxv)-acetic acid
Figure imgf000039_0001
A solution of 2-bromo-4-fluorophenol (5.00 g, 26.18 mmol) in DMF (130 ml) was treated with potassium carbonate (18.45 g, 130.9 mmol) and t-butyl bromoacetate (4.64 ml, 31.41 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5%-10% ethyl acetate/hexanes gradient to afford the (t-butyl ester). This product was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, triturated with hexane, and filtered under suction to afford the product as a white solid (4.78 g, 74%).
Preparation of (2-bromo-phenvIsulfanyl)-acetic acid
Figure imgf000039_0002
A solution of 2-bromo-benzenethiol (2.0 g, 10.6 mmol) in THDF (20 ml) was treated with triethylamine (3.54 ml, 25.4 mmol) and t-butyl bromoacetate (1.64 ml, 11.1 mmol) at rt for 2 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the t-butyl ester. This material was treated with 4 N HCl in dioxane (20 ml) at room temperature for 18 hours. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to afford the product as a white solid (2.65 g, 100%).
Preparation of (2-cycIopentvl-phenoxy)-acetic acid
Figure imgf000040_0001
A mixture of 2-cyclopentylphenol (1.00 g, 6.164 mmol) and t-butyl bromoacetate (1.09 ml, 7.39 mmol) in DMF (30 ml) was treated with potassium carbonate (4.25 g, 30.82 mmol) and stirred at 6O0C for 5 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid. This material was treated with 4 N HCl in dioxane (10 ml) at room temperature for 72 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.26 g, 93%).
Preparation of (2-sec-butyl-phenoxy)-acetic acid
Figure imgf000040_0002
A mixture of 2-sec-butyl-phenol (1.00 g, 6.66 mmol) and t-butyl bromoacetate (1.18 ml, 7.98 mmol) in DMF (35 ml) was treated with potassium carbonate (4.60 g, 33.28 mmol) and stirred at 6O0C for 5 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid. This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.46 g, 100%).
Preparation of (2-propγI-phenoxy)-acetic acid
Figure imgf000041_0001
A mixture of 2-propyl-ρhenol (1.00 g, 9.89 mmol) and t-butyl bromoacetate (1.5 ml, 10.1 mmol) in DMF (35 ml) was treated with potassium carbonate (5.07 g, 36.7 mmol) and stirred at 6O0C for 5 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid. This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 72 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.63 g, 85%).
Preparation of (2-benzyI-phenoxy)-acetic acid
Figure imgf000041_0002
A mixture of 2-benzyl-phenol (1.00 g, 5.43 mmol) and t-butyl bromoacetate (0.962 ml, 6.52 mmol) in DMF (30 ml) was treated with potassium carbonate (3.75 g, 27.15 mmol) and stirred at 6O0C for 5 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid'. This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.15 g, 97%).
Preparation of benzoic acid NM2-(2-bromo-4-fluoro-phenoxy)-acetyri-N'-isopropyl- hvdrazide
Figure imgf000042_0001
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (2.00 g, 8.03 mmol) and benzoic acid N'-isopropyl-hydrazide (1.72 g, 9.63 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (3.5 mL, 20.07 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 5.62 g, 12.04 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (2.29 g, 70%).
Preparation of benzoic acid N'-r2-(2-bromo-phenvIsuIfanyl)-acetvn-N'-isopropyl- hydrazide
Figure imgf000042_0002
A solution of (2-bromo-phenylsulfanyl)-acetic acid (694 mg, 2.81 mmol) and benzoic acid N'-isopropyl-hydrazide (500 mg, 2.81 mmol) in DMF (10 mL) was treated with triethylamine (1.17 ml, 8.43 mmol), HOBT (455 mg, 3.37 mmol) and EDCI (645 mg, 3.37 mmol) at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was successively washed with IN HCl, aqueous saturated sodium bicarbonate, and brine, then dried over sodium sulfate, filtered and concentrated. Pure product was obtained by crystallization from ethyl acetate (611 mg, 54%).
Preparation of cyclohexanecarboxylic acid N'-r2-(2-bromo-4-fluoro-phenoxy)-acetvH- N'-isopropyl-hydrazide
Figure imgf000042_0003
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (249 mg, 1.0 mmol) and cyclohexane carboxylic acid N'-isopropyl-hydrazide (221 mg, 1.2 mmol) in DMF (10 ml) was treated with diisopropylethyl amine (0.44 mL, 2.5 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 700 mg, 1.5 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated IN NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (310 mg, 75%).
Preparation of 4-(2-methoxy-ethoxy)-benzoic acid N'-r2-(2-bronio-4-fluoro-phenoxy)- acetyli-N'-isopropyl-hydrazide
Figure imgf000043_0001
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (164 mg, 0.66 mmol) and 4-(2- methoxy-ethoxy)-benzoic acid-N'-isopropyl hydrazide (200 mg, 0.79 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.29 mL, 1.65 mmol) and PyBroP (462mg,
0.99 mmol) at room temperature overnight. The reaction mixture was partitioned between
IN HCl and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexanes gradient to afford the product as a solid (202 mg, 63%).
Preparation of thiophene-2-carboxyIic acid N>-r2-(2-bromo-4-fluoro-phenoxy)- acetyli-N'-isopropyl-hydrazide
Figure imgf000043_0002
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (220 mg, 0.91 mmol) and thiophene-
2-carboxylic acid N'-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-50% ethyl acetate/hexanes gradient to afford the product as a solid (263 mg, 70%).
Preparation of thiophene-3-carboxyIic acid N'-r2-(2-bromo-4-fluoro-phenoxγ)- acetyli-N'-isopropyl-hydrazide
Figure imgf000044_0001
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (226 mg, 0.91 rnmol) and thiophene- 3-carboxylic acid N'-isopropyl-hydrazide (200 mg, 1.09 rnmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 rnmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (251 mg, 66%).
Preparation of tetrahydro-thiopyran-4-carboxyIic acid N'-r2-(2-bromo-4-fluoro- phenoxy)-acetyIl-N'-isopropyl-hydrazide
Figure imgf000044_0002
A solution of tetrahydro-thiopyran-4-carboxylic acid N'-isopropyl-hydrazide_(300 mg, 1.48 mmol) and (2-bromo-4-fluoro-phenoxy)-acetic acid (369 mg, 1.48 mmol) in DMF (6 ml) was treated at rt with HOBT (240 mg, 1.78 mmol), EDCI (341 mg, 1.78 mmol), and triethylamine (0.620 ml, 4.45 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between IN HCl solution and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by RP HPLC to afford the product as a solid (116 mg, 18.1%). Preparation of f2-bromo-4-methyl-phenoxy)-acetic acid
Figure imgf000045_0001
A solution of 3-bromo-4-methylphenol (1.00 g, 5.35 mmol) in DMF (25 mL) was treated with potassium carbonate (3.69 g, 23.9 mmol) and t-butyl bromoacetate (0.95 ml, 5.74 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/hexanes gradient to give a white solid (t-butyl-ester). This product was treated with 4 N HCl in dioxane (10 ml) at room temperature for 12 hours. The reaction mixture was concentrated, triturated with hexane, and filtered under suction to afford the product as a white solid (0.88g, 3.34 mmol, 63%).
Preparation of benzoic acid N'-r2-(2-bromo-4-methyl-phenoxy)-acetvn-N'-isopropyI- hydrazide
Figure imgf000045_0002
A solution of (2-bromo-4-methyl-phenoxy)-acetic acid (879 mg, 3.34 mmol) and benzoic acid N'-isopropyl-hydrazide (714 mg, 4.00 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.45 ml, 8.35 mmol) and PyBroP (2.33 g, 5.01 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (463 mg, 34%).
Preparation of (2-bromo-4,5-difluoro-phenoxv)-acetic acid - -
Figure imgf000046_0001
A solution of 2-bromo-4,5-difluorophenol (1.00 g, 4.78 mmol) in DMF (25 mL) was treated with potassium carbonate (3.3 g, 23.9 mmol) and t-butyl bromoacetate (0.85ml,
5.736 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/ hexanes gradient to give a white solid (t-butyl-ester). This product was treated with 4 N HCl in dioxane (10 ml) at room temperature for 12 hours. The reaction mixture was concentrated, triturated with hexane, and filtered under suction to afford the product as a white solid (985, 72%).
Preparation of benzoic acid N'-r2-(2-bromo-4,5-difluoro-phenoxy)-acetvn-N'- isopropyl-hydrazide
Figure imgf000046_0002
A solution of (2-bromo-4,5-difluoro-phenoxy)-acetic acid (985 mg, 3.68 mmol) and benzoic acid N'-isopropyl-hydrazide (787 mg, 4.416 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.6 mL, 9.2 mmol) and PyBroP (2.57 g, 5.52 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (832 mg, 34%).
Preparation of (2-bromo-4,6-difluoro-phenoxy)-acetic acid
Figure imgf000046_0003
A solution of 2-bromo-4,6-difluorophenol (1.00 g, 4.78 mmol) in DMF (25 ml) was treated with potassium carbonate (3.3 g, 23.9 mmol) and t-butyl bromoacetate (0.85 ml, 5.74 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/ hexane gradient to afford a white solid (t-butyl ester). This product was treated with 4 N HCl in dioxane (10 ml) at room temperature for 12 hours. The reaction mixture was concentrated, triturated with hexane, and filtered under suction to afford a white solid (0.92 g, 72%).
Preparation of benzoic acid N'-r2-(2-bromo-4,6-difluoro-phenoxy)-acetyll-N'- isopropyl-hydrazide
Figure imgf000047_0001
A solution of (2-bromo-4,6-difluoro-phenoxy)-acetic acid (0.92 g, 3.45 mmol) and benzoic acid N'-isopropyl-hydrazide (738 mg, 4.14 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.5 ml, 8.625 mmol) and PyBroP (2.41 g, 5.175 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (478 mg, 1.12 mmol, 32%).
Preparation of (2-bromo-4-cvano-phenoxy)-acetic acid
Figure imgf000047_0002
A solution of 3-bromo-4-hydyroxybenzonitrile (1.00 g, 5.05 mmol) in DMF (25 ml) was treated with potassium carbonate (3.48 g, 25.25 mmol) and t-butyl bromoacetate (0.895 ml, 6.06 mmol) at 6O0C for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/hexanes gradient to a white solid
(t-butyl ester). The product was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, triturated with hexane, and filtered under suction to afford a white solid (1.1 g, 70%).
Preparation of benzoic acid N'-r2-(2-bromo-4-cγano-phenoxy)-acetyll-N'-isopropyI- hydrazide
Figure imgf000048_0001
A solution of (2-bromo-4-cyano-phenoxy)-acetic acid (910 mg, 3.5 mmol) and benzoic acid N'-isopropyl-hydrazide (749 mg, 4.2 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.52 mL, 8.75 mmol) and PyBroP (2.45 g, 5.25 mmol) at room
.temperature overnight. t The reaction mixture was partitioned between IN HCl. and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (410 mg, 0.9849 mmol, 28%).
PART II: PREPARATION OF PREFERRED COMPOUNDS
Example 1
Preparation of benzoic acid N'-[2-(5,4'-difluoro-biphenyl-2-yloxy)-acetyI]-N'- isopropyl-hydrazide
Figure imgf000048_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (215 uL, 0.427 mmol) was treated with 4-fmorobenzeneboronic acid (26 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, - - filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (42 mg, 81%). LC-MS m/e 425.28 (M+H+) ■
Example 2
Preparation of benzoic acid N'-[2-(2'-chIoro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000049_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]~N'-isopropyl- hydrazide (60 mg, 0.147 mmol) in DME (3 ml)/ 2M Na2CO3 (256 uL, 0.513 mmol) was treated with 3-chlorophenylboronic acid (34 mg, 0.219 mmol)and Pd[PPh3]4 (34 mg, 0.029 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/ hexanes gradient to afford the product as a white crystalline solid (52 mg, 80%). LC-MS m/e 441.24 (M-I-H+)
Example 3
Preparation of benzoic acid N'-[2-(5-fluoro-2'-methyl-biphenyl-2-yIoxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000049_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-tolylboronic acid (25 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.024 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (23 mg, 44%).
LC-MS m/e 421.31 (M+H1")
Example 4 Preparation of benzoic acid N'-[2-(5-fluoro-2'-methoxy-biphenyI-2-yloxy)-acetyl]-N'- isopropyl-hydrazide:
Figure imgf000050_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.024 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium- sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (39 mg, 73%). LC-MS m/e 437.29 (MH-H+)
Example 5
Preparation of benzoic acid N'-[2-(5,2'-difluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide:
Figure imgf000050_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 mL)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-fluorophenylboronic acid (26 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (30 mg, 58%). LC-MS m/e 425.28 (M+H^)
Example 6 Preparation of benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyI-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000051_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 mL)/ 2M Na2CO3 (0.215 ml, 0.427 rnmol) was treated 4-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 •mmol) for 12 hours at-90°G.--The reaction mixture was partitioned between water- and ethyl- acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/ hexanes to afford the product as a beige solid (47 mg, 88%). LC-MS m/e 437.31 (M+H*)
Example 7
Preparation of benzoic acid N'-[2-(4'-chIoro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000051_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with 4-chlorophenylboronic acid (29 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (15 mg, 0.034 mmol, 27%). LC-MS m/e 441.25 (M+Ε?)
Example 8 Preparation of benzoic acid N'-[2-(5-fluoro-3'-methoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000052_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with 3-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl , acetate. The organic layer was washed p with brine, dried over, .sodium, sulfate,,, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (44 mg, 83%). MS m/e 437.29 (M+H1")
Example 9
Preparation of benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide:
Figure imgf000052_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with 3-fluorobenezeneboronic acid (26 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried, over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with' 30% ethyl acetate/hexanes to afford the product as a white solid (35 mg,
68%). LC-MS m/e 425.28 (M+Ε?)
Example 10 ϊ Preparation of benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyI]-N'- isopropyl-hydrazide
Figure imgf000053_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]~N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with 3-chlorobenezeneboronic acid (29 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg,
0.0244 mmol) at 9O0C overnight. The reaction mixture was partitioned between water and
- ethyl acetate. The organic layer was washed with brine, dried over sodium, sulfate, filtered, - and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid (45 mg, 84%). LC- MS m/e 441.24 (M+H1")
Example 11
Preparation of benzoic acid N'-[2-(5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide
Figure imgf000053_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with phenylboronic acid (22 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (44 mg, 89%). MS m/e 407.22 (M+H1") Example 12
Preparation of benzoic acid N'-[2-(5-fluoro-3'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000054_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-isopropylbenzylboronic acid (30 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg,
0.0244 mmol) for 12 hours at 900C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid. (34 mg,
62%). MS m/e 449.30 (M+H1)
Example 13
Preparation of benzoic acid N'-[2-(5-fluoro-2'-methylsyIfanyl-biphenyI-2-yloxy)- acetyl]-N ' -isopropyl-hydrazide
Figure imgf000054_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methylthiophenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg,
0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid
(36 mg, 0.0795 mmol, 65%). MS m/e 453.19 (M+ϊt) Example 14
Preparation of benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000055_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0. 215 ml, 0.427 mmol) was treated with 2-nitrophenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes and then by RP HPLC to afford the product as a white solid (12 mg, 21%). MS m/e 452.Ϊ8" (M+H+)' ' ' "" " " ' '" ' ' "" '" " ; " '" ""
Example 15 Preparation of benzoic acid N'-[2-(5-fluoro-2'-isopropoxy-biphenyl-2-yloxy)-acetyl]-
N'-isopropyl-hydrazide
Figure imgf000055_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isoρropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-isopropoxylρhenylboronic acid (32 mg, 0.183 mmol) and Pd[PPh3J4 (27 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes then by RP HPLC to afford the product as a white solid (22 mg, 38%). MS m/e 465.27 (M+H+) Example 16
Preparation of benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yIoxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000056_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-ethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.024 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product (19 mg, 36%). MS m/e 435.44 (M-I-H+)
Example 17 Preparation of benzoic acid N'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000056_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-propoxyphenylboronic acid (33 mg, 0.183 mmol) and Pd[PPh3J4 (27 mg, 0.0244 mmol) for 12 hours at 900C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20- 30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (42 mg, 74%). MS m/e 407.23 (M+H+) Example 18
Preparation of benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biphenyl-2-yloxy)- acetyl] -N ' -isopropyl-hydrazide
Figure imgf000057_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methoxycarbonylphenyl boronic acid (33 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (8 mg, 14%). MS m/e 465.23 (MH-H+)
Example 19 Preparation of benzoic acid N'-[2-(2',3'-dimethyl-5-fluoro -biphenyl-2-yIoxy)-acetyl]-
N'-isopropyl-hydrazide
Figure imgf000057_0002
A solution of benzoic acid N' ~[2-(2-bromo-4-fluoro-phenoxy)-acetyl] -N' -isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2,3-dimethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (30 mg, 57%). MS m/e 435.30 (M+H+) Example 20
Preparation of benzoic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N' -isopropyl-hydrazide
Figure imgf000058_0001
5 A solution of benzoic acid N' -[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N' -isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (38 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium
10 sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a
■ " white solid (7 mg, 12%). MS m/e 491.19 (M+lT) " ■ ■ - ■ . .- , . ■ . . ■ ., - .- .. .
Example 21
15 Preparation of benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biphenyl-2-yIoxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000058_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N' -isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was 0 treated with 2-ethoxyphenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg, 0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate in hexanes gradient to afford the product as a white 5 solid (16 mg, 29%). MS m/e 451.23 (M+H+) Example 22
Preparation of benzoic acid N'-[2-(5-fluoro-2'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000059_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/ 2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-isopropylphenylboronic acid (30 mg, 0.183 mmol) and Pd[PPh3J4 (28 mg,
0.0244 mmol) for 12 hours at 9O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30—50% ethyl acetate/hexanes gradient to afford the product as a white,
• • ' crystalline solid (30 mg, 55%). MS m/e 449:25 (M+H*) ■ ■ .--.-
Example 23 Preparation of benzoic acid N'-[2-(5-fluoro-2'-methanesuIfonyl-biphenyI-2-yloxy)- acetyl]-N'-isopropyl-hydrazide
Figure imgf000059_0002
A solution of benzoic acid N'-[2-(5-fluoro-2'-methylsulfanyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide (30 mg, 0.066 mmol) in acetic acid (3 mL) was treated with 30% H2O2 (2 mL)) for 5.5 hours at 6O0C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturate sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white, crystalline solid (17 mg, 53%). MS m/e 485.28 (MH-EL+) Example 24
Preparation of benzoic acid N'-[2-(5,2',4'-trifluoro-biphenyI-2-yIoxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000060_0001
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.244 mmol) in DME (5 ml)/ 2M Na2CO3 (0.428 ml, 0.855 mmol) was treated with 2,4-difluorophenylboronic acid (77 mg, 0.489 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) at 9O0C overnight. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as solid (90 mg, 82%). MS m/e 443.38 (M+Ε?)
Example 25 Preparation of benzoic acid N'-[2-(5, 4'-difluoro-4'-methyI-biphenyl-2-yIoxy)-acetyl]-
N'-isopropyl-hydrazide
Figure imgf000060_0002
A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.244 mmol) in DME (5 ml)/ 2M Na2CO3 (0.428 ml, 0.855 mmol) was treated with 4-fluoro-2-methylphenylboronic acid (75 mg, 0.489 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) at 9O0C overnight. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as solid (69 mg, 63%). MS m/e 439.41 (M+Εt) Example 26
Preparation of benzoic acid N'-[2-(2'-ethyl-5-methyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000061_0001
A solution of benzoic acid N'-[2-(2-bromo-4-methyl-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.247 mmol) in DME (3 ml)/ 2M Na2CO3 (0.435 ml, 0.8645 mmol) was treated with 2-ethylphenylboronic acid (74 mg, 0.493 mmol), Pd[PPh3]4 (29 mg, 0.0247 mmol in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (77 mg, 72%). MS m/e 431.34 (M+ET*" )
Example 27 Preparation of benzoic acid N'-[2-(2'-ethyl-4,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000061_0002
A solution of benzoic acid N'-[2-(2-bromo-4,5-difluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/ 2M Na2CO3 (0.435 ml, 0.864 mmol) was treated with 2-ethylphenylboronic acid (70 mg, 0.468 mmol) and Pd[PPh3]4 (27 mg, 0.0234 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate in hexanes gradient to afford the product as a white solid (77 mg, 73%). MS m/e 453.30(M+!^) Example 28
Preparation of benzoic acid N'"[2-(2'-ethyl-3,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000062_0001
A solution of benzoic acid N'-[2-(2-bromo-4,6-difluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/ 2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-ethylphenylboronic acid (71 mg, 0.468 mmol), and Pd[PPh3]4 (27 mg, 0.0234 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (70 mg, 66%). MS m/e 453.30 (M+H"1")
Example 29 Preparation of benzoic acid N'-[2-(5-cyano-2'-ethyl-biphenyI-2-yloxy)-acetyI]-N'- isopropyl-hydrazide
Figure imgf000062_0002
A solution of benzoic acid N'-[2~(2-bromo-4-cyano-phenoxy)-acetyl]-N'-isopropyl- hydrazide (200 mg, 0.480 mmol) in DME (3 ml)/ 2M Na2CO3 (0.840 ml, 1.68 mmol) was treated with 2-ethylphenylboronic acid (144 mg, 0.9608 mmol) and Pd[PPh3]4 (55 mg, 0.048 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid (177 mg, 84%). MS m/e 442.25 (M+H1") Example 30
Preparation of 4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(5-fluoro-2'-ethyl-biphenyl-2- y!oxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000063_0001
A solution of (2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (38 mg, 0.1395 mmol), and 4-(2-methoxy-ethoxy)-benzoic acid-N'-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.053 ml, 0.38 mmol), HOBT (20 mg, 0.152 mmol), and EDCI (29 mg, 0.152 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white -solid (5 mg, 7%). MS m/e 509.42 (M+H1") ■ •
Example 31 Preparation of benzoic acid N'-[2-(5-methyl-2'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide
Figure imgf000063_0002
A solution of benzoic acid N'-[2-(2-bromo-4-methyl-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.234 mmol) in DME (3 mL)/ 2M Na2CO3 (0.443 ml, 0.863 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (76 mg, 0.370 mmol) and Pd[PPh3]4 (57 mg, 0.049 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (89 mg, 74%). MS m/e 487.30 (MH-H+) Example 32
Preparation of benzoic acid N'-[2-(4,5-difluoro-2'-trifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000064_0001
A solution of benzoic acid N'-[2-(2-bromo-4,5-difluoro-phenoxy)-acetyl]-N'-isoproρyl- hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/ 2M Na2CO3 (0.443 ml, 0.863 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate in hexanes gradient to afford the product as a white, crystalline solid (81 mg, 68%). MS m/e 509.24 (TVLfH+)
Example 33 Preparation of benzoic acid N'-[2-(3,5-difluoro-2'-trifluoromethoxy-biphenyl-2- yIoxy)-acetyI]-N'-isopropyl hydrazide
Figure imgf000064_0002
A solution of benzoic acid N'-[2-(2-bromo-4,6~difluoro-phenoxy)-acetyl]-N'-isopropyl- hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/ 2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (70 mg, 59%). MS m/e 509.24 (M+H4") Example 34
Preparation of tetrahydro-pyran-4-carboxylic-acid-N'-[2-(5-fluoro-2'- trifluoromethoxy-biphenyl-2-yIoxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000065_0001
A solution of (5-fluoro-2'-txifluoromethoxy-biphenyl-2-yloxy)-acetic acid (280 mg, 0.85 mmol) and tetrahydro-pyran-4-carboxylic acid N'-isopropyl-hydrazide (1.2 eq. 190 mg, 1.02 romol) in DMF (3 ml) was treated with diisopropyl amine (0.370 ml, 2.12 mmol) and PyBroP (595 mg, 1.275 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (262 mg, 62%). MS m/e 499.23 (MH-H+)
Example 35
Preparation of 3-methyl-furan-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy- biphenyI-2-y!oxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000065_0002
A solution of (5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (211 mg, 0.64 mmol) and 3-methyl-furan-2-carboxylic acid N'-isopropyl-hydrazide (140 mg, 0.768 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.278 ml, 1.6 mmol) and
PyBroP (448 mg, 0.96 mmol) at room temperature overnight. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a
50-100% ethyl acetate in hexanes gradient to afford the product as a white solid (180 mg,
57%). MS m/e 495.19 (MH-H+) Example 36
Preparation of furan-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-
2-yloxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000066_0001
A solution of (5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (174 mg, 0.52 mmol) and furan-2-carboxylic acid N'-isopropyl-hydrazide (90 mg, 0.53 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.235 ml, 1.32 mmol) and PyBroP (370 mg, 0.79 mmol) at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a
" 30-80% ethyl acetate in hexanes gradient to' afford the product as a white- solid (110 mg,
44%). MS m/e 481.38 (M+ΪT1")
Example 37
Preparation of furan-3-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-
2-yloxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000066_0002
A solution of (5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (180 mg, 0.54 mmol) and furan-3-carboxylic acid N'-isopropyl-hydrazide (110 mg, 0.65 mmol) in DMF
(5 ml) was treated with diisopropyl amine (0.237 ml, 1.36 mmol) and PyBroP (381 mg,
0.82 mmol) at room temperature overnight. The reaction mixture was partitioned between
IN HCl and ethyl acetate. The organic layer was successively washed with aqueous saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a
30-50% ethyl acetate in hexanes gradient to afford the product as a solid (145 mg, 56%).
MS m/e 481.35 (M+H"*') ££
- 66 -
Example 38
Preparation of cyclohexanecarboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy- biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000067_0001
A solution of cyclohexanecarboxylic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'- isopropyl-hydrazide (310 mg, 0.75 mmol) in DME (3 ml)/ 2M Na2CO3 (1.3 ml, 2.62 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (231 mg, 1.12 mmol) and
Pd[PPh3]4 (172 mg, 0.15 mmol) in a microwave oven at 15O0C for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 30-80% ethyl acetate/hexanes gradient to afford the
' product as a solid (232 mg, 63%). MS m/e 497.53 (M+H+) '
Example 39 Preparation of 4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(5-fluoro-2'- trifluoromethoxy-biphenyI-2-yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000067_0002
A solution of 4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(2-bromo-4-fluoro-ρhenoxy)- acetyl]-N'-isoproρyl-hydrazide (202 mg, 0.42 mmol) in DME (5 ml) / 2M Na2CO3 (0.731 ml, 1.46 mmol) was with 2-trifluoromethoxyphenylboronic acid (129 mg, 0.63 mmol) and Pd[PPh3J4 (96.5 mg, 0.084 mmol) in a microwave oven at 150° C for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexane gradient to afford the product as a solid (129 mg, 55%). MS m/e 565.55CMh-H+) Example 40
Preparation of thiophene-2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy- biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000068_0001
' A solution of thiophene-2-carboxylic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'- isopropyl-hydrazide (263 mg, 0.63 mmol) in DME (5 ml) / 2M Na2CO3 (1.10 ml, 2.22 mmol) was with 2-trifluoromethoxyphenylboronic acid (196 mg, 0.95 mmol) and Pd[PPh3J4 (146 mg, 0.13 mmol) in a microwave oven at 150° C for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the pro.ductas a solid.(.176 mg, 56%). MS m/e 497.41 (Md-H+)
Example 41 Preparation of tetrahydro-thiopyran-4-carboxylic acid N'-[2-(5-fluoro-2'- trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000068_0002
A solution of tetrahydro-thiopyran-4-carboxylic acid N'-[2-(2-bromo-4-fluoro-phenoxy)- acetyl]-N'-isopropyl-hydrazide (116 mg, 0.27 mmol) in DME (2.5 ml) / 2M Na2CO3 (0.468 ml, 0.94 mmol) was treated with 2-trifluoromethoxyphenylboronic acid (83 mg, 0.40 mmol) and Pd[PPh3]4 (62 mg, 0.053 mmol) in a microwave oven at 150° C for 10 min. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (62.6 mg, 45%). MS m/e 515.48 (M+Ε?) Example 42
Preparation of thiophene-3-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy- biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000069_0001
A solution of thiophene-3-carboxylic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'- isopropyl-hydrazide (251 mg, 0.60 mmol) in DME (5 ml) / 2M Na2CO3 (1.05 ml, 2.12 mmol) was with 2-trifluoromethoxyphenylboronic acid (187 mg, 0.91 mmol) and Pd[PPh3]4 (140 mg, 0.12 mmol) in a microwave oven at 150° C for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (188 mg, 63%). MS m/e 497.41 (M+H4")
Example 43 Preparation of thiophene-3-carboxylic acid N'-[2-(5-fluoro-2'-ethyl-biphenyl-2- yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000069_0002
A solution of (2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (100 mg, 0.36 mmol), and tiophene-3-carboxylic acid-N'-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.152 ml, 1.09 mmol), HOBT (59 mg, 0.44 mmol), and EDCI (84 mg, 0.44 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between IN HCl and DCM. The organic layer was successively washed with IN NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (41mg, 26%). MS m/e 441.30 (M+Εt) Example 44
Preparation of benzoic acid N'-[2-(2-cyclopentyl-phenoxy)-acetyl]-N'-isopropyl- hydrazide
Figure imgf000070_0001
A solution of (2-cyclopenyl-phenoxy)-acetic acid (203 mg, 0.92 mniol), and benzoic acid N'-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between IN HCl and DCM. The organic layer was successively washed with IN NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the prόduct as a white solid (123 mg, 35%)". MS m/e 38133 (M+H"1") - ■
Example 45 Preparation of benzoic acid N'-[2-(2-sec-butyl-phenoxy)-acetyl]-N'-isopropyl- hydrazide
Figure imgf000070_0002
A solution of (2-sec-butyl-phenoxy)-acetic acid (193 mg, 0.93 mmol), and benzoic acid N'- isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between IN HCl and DCM. The organic layer was successively washed with IN NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (113 mg, 33%). MS m/e 369.32 (M+H1") Example 46 Preparation of benzoic acid N'-[2-(2-propyl-phenoxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000071_0001
A solution of (2-propyl-phenoxy) -acetic acid (180 nig, 0.93 mmol), and benzoic acid N'~ isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine
(0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for
12 hours at room temperature. The reaction mixture was partitioned between IN HCl and
DCM. The organic layer was successively washed with IN NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product as a white solid (80 mg, 25%). MS m/e 355.35 (MH-H+)
Example 47 Preparation of benzoic acid N'-[2-(2-benzyl-phenoxy)-acetyl]-N'-isopropyl-hydrazide
Figure imgf000071_0002
A solution of (2-benzyl-phenoxy)-acetic acid (1.15 g, 4.74 mmol), and benzoic acid N'- isopropyl-hydrazide (704 mg, 3.95 mmol) in DMF (30 ml), was treated with diisopropyl ethyl amine (1.8 ml, 9.88 mmol), and PyBroP (2.76 g, 5.93 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between IN HCl and DCM. The organic layer was successively washed brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (950 mg, 60%). MS m/e 403.25 (MH-H+) Example 48
Preparation of benzoic acid N'-[2-(3'-fluoro-biphenyl-2-ylsuIfanyl)-acetyI]-N'- isopropyl-hydrazide
Figure imgf000072_0001
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml) / 2M Na2CO3 (0.645 ml, 1.29 mmol) was treated with 3-fluorophenylboronic acid (34.4 mg, 0.246 mmol) and Pd[PPh3J4 (70.2 mg, 0.061 mmol) for 65 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8.7 mg, 16.7 %). MS m/e 423.21 (M+H÷)
Example 49 Preparation of benzoic acid N'-[2-(2',3'-dimethyI-biphenyI-2-ylsulfanyl)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000072_0002
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml) / 2M Na2CO3 (0.645 ml, 1.29 mmoles) was treated with 2,3-dimethylphenylboronic acid (36.9 mg, 0.246 mmol) and Pd[PPh3J4 (70.2 mg, 0.061 mmol) for 65 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8.5 mg, 16.4 %). MS m/e 433.24 (M+H1") Example 50
Preparation of benzoic acid N'-[2-(3'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000073_0001
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml) / 2M Na2CO3 (0.430 ml, 0.86 mmoles) was treated with 3-methoxyphenylboronic acid (75 mg, 0.491 mmol) and Pd[PPh3]4 (29 mg, 0.025 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (58 mg, 55 %). MS m/e 435.22 (M+ϊt)
Example 51 Preparation of benzoic acid N'-[2-(4'-fluoro-biphenyl-2-yIsulfanyl)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000073_0002
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml) / 2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with 4-fluorophenylboronic acid (35 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (9.5 mg, 20 %). MS m/e 423.22 (M+H+) Example 52
Preparation of benzoic acid N'-[2-(3'-trifluoromethyl-biphenyl-2-ylsulfanyl)-acetyl]-
N'-isopropyl-hydrazide
Figure imgf000074_0001
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml) / 2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with 3-trifluoromethylphenylboronic acid (47 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8 mg, 14 %). MS m/e 473.16 (M+H*)
Example 53 Preparation of benzoic acid N'-[2-(2'-methoxy-biphenyl-2-ylsulfanyI)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000074_0002
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml) / 2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 2-methoxyphenylboronic acid (75 mg, 0.49 mmol) and Pd[PPh3J4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (59 mg, 54 %). MS m/e 435.23 (M+H+) Example 54
Preparation of benzoic acid N'-[2-(2'-fluoro-biphenyl-2-ylsuIfanyl)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000075_0001
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml) / 2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 2-fluorophenylboronic acid (69 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (72 mg, 68 %). MS m/e 423.22 (M+Εt)
Example 55
Preparation of benzoic acid N'-[2-(4'-methoxy-biphenyI-2-yIsuIfanyl)-acetyl]-N'- isopropyl-hydrazide
Figure imgf000075_0002
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml) / 2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 4-methoxyphenylboronic acid (75 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and
DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (78mg, 72 %). MS m/e 435.24 (M+H"1") Example 56
Preparation of benzoic acid N'-[2-(biphenyl-2-ylsulfanyl)-acetyI]-N'-isopropyl- hydrazide
Figure imgf000076_0001
A solution of benzoic acid N'-[2-(2-bromo-phenylsulfanyl)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml) / 2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with phenylboronic acid (30 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. Additional amounts of Pd[PPh3J4 (28 mg, 0.025 mmol) and 2M Na2CO3 (0.215 ml, 0.43 mmoles) were added and the mixture was stirred at 90° C for another night. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (7.2 mg, 15 %). MS m/e 405.26 (MH-H+)
Example 57
Preparation of 4-(isobutylamino)-benzoic acid N'-[2-(5-fluoro-2'-trifluoromethoxy- biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide
Figure imgf000076_0002
A solution of 4-nitro-benzoic acid N'-isopropyl-hydrazide (84 mg, 0.378 mmol), (5-fluoro- 2'-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (100 mg, 0.302 mmol), and DIPEA (0.329 ml, 1.89 mmol) in DMF (5 ml) was treated with PyBroP (176 mg, 0.378 mmol) and let stir at 25° C overnight. The reaction mixture was diluted with 70ml ethyl acetate and extracted with IN HCl (2 x 30 ml), saturated sodium bicarbonate (2 x 30 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated to a gum (150 mg). The crude material (75 mg, 0.14 mmol) dissolved in EtOH (5 ml) containing acetic acid (2 drops), concentrated HCl (20 μ\), isobutyraldehyde (152 μϊ, 1.68 mmol) and 10% palladium on carbon (10 mg) This mixture was hydrogenated at 20 psi at rt for 5 hours.
The reaction mixture was filtered through celite diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The crude product was triturated with 1% ethyl acetate/hexanes to give an off-white solid (31 mg, 39%). MS m/e 562CM+F1")
Example 58 DGAT Phospholipid FlashPlate Assay
Materials for the assay: PL-FlashPlate: Phospholipid FlashPlates from PerkinElmer, catalog number SMP108; DAG (1,2-Dioleoyl-sn-glycerol) 10 mM suspended in water containing 0.1% Triton X-100; 14C-PaI-CoA (palmitoyl coenzyme A, [palmitoyl-l-14C]) from PerkinElmer, catalog number NEC-555 with a specific activity of 55 mCi/mmol; and DGAT pellet (in house preparation), 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) was 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 μM with coating buffer (CB). The diluted DAG solution was then added to 384-well PL-FlashPlates at 60 μl 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 μM in 100 % DMSO. Diluted compound were further diluted 10 fold with reaction buffer (PvB). 14C-PaI-CoA was diluted to 8.3 μM 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 μ\ of the RB-diluted compounds (or 10% DMSO in RB for Total and Blank), 15 μ\ of RB diluted 14C-PaI-CoA and 15 μl of DB diluted DGAT pellet (DB without DGAT for Blanks) were transferred to each well of the PL-FlashPlates. The reaction mixtures were incubated at 370C 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 ICgn : The IC50 values for each compound were generated using an Excel template. The Topcount rpm readings of Total and Blank were used as 0 % and 100 % inhibition. The percent inhibition values of reactions in the presence of compounds were calculated, and plotted against compound concentrations. AU data were fitted into a Dose Response One Site model (4 parameter logistic model) as the following:
(A+((B-A)/(l+((x/C)ΛD))))
with A and B as the bottom and top of the curve (highest and lowest inhibition), respectively, and C as IC50 and D as Hill Coefficient of the compound. The compounds of the present invention preferably have IC50 values in the range of 1 nM to 10 μM. The results are summarized in Table 1 :
Table 1
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Example 59 DGAT CHOKl Cell Assay
Materials for the assay were: petroleum ether (J .T. Baker #9268-22); diethyl ether (Aldrich #30995-8); acetic acid; l,2-dioleoyl-3-ρalmitoyl-glycerol (Sigma D-1782); 14 C Palmitic Acid (56.0mCi/mmol PerkinElmer Life Sciences # NEC 075H); DMEM/F12 (Gibco # 11330-032); fetal bovine serum; L-Glutamine; G418/ml media; DMEM High Glucose (Gibco # 11995-065); BSA Fraction V Fatty Acid Free (Roche # 100 377); 20 x 20 cm silica gel 60 glass plates (EM Science Plates #5721/7).
CHOK1/DGAT cell culture medium was prepared with DMEM/F12 (Gibco # 11330- 032),10% FBS, 1% L-Glutamine, and 20ul G418/ml media. l,2-dioleoyl~3-ρalmitoyl- glycerol was prepared by dissolving lOmg into ImI chloroform and stored at -20° C in lOOμl aliquots. Test compounds were prepared as 10 mM stock solutions in DMSO and store at -20° C before use. Test dilutions were prepared by five fold serial dilutions over final concentrations.
CHOKl cells transfected with DGATl were diluted in 6 well plates at 2.5 x 105 cells per well and cultured overnight. Cells were then washed twice with PBS. Test compound solutions (lOμl/ 2ml media aliquots) in DMEM High Glucose with 0.01% BSA (fatty acid free) were added to cell culture plates at 800μl per well. 14C Palmitic acid (0.5μ,Ci, 5/xl) was added to each well. The plates were incubated for 1 hour at 37° C. After the incubation period, the plates were placed on ice, cells were scraped into media and transferred to microfuge tubes. 400 μl chloroform: methanol (2:1) was added to each tube. Each tube was briefly vortexed by hand, then mechanically vortexed for 10 minutes. Each tube was then centrifuged at 14,000 RPM for 10 minutes at 4° C and the bottom layer removed and transferred to a new microfuge tube.
Extracted samples were spotted onto TLC plates at 20 μl per lane. The TLC plates were eluted with a solvent mixture of petroleum ether, diethyl ether and acetic acid (80:20:1) and air dried. Trigylceride (TG) spots were visualized by placing in an iodine chamber for several minutes, lμl of 14C palmitic acid (diluted 1:10 in 100% EtOH) was spotted on the TG standard lane (at TG level) as a reference. The TLC plates were wrapped in plastic wrap and placed in a phosphorimager cassette for scanning.
Calculation of ECgn
The compunds of the present invention preferably have EC50 values in the range of 0.1 to 40 μM. The EC50 values for those compounds tested in this Example were generated using an Excel template, the results of which are shown in Table II:
Table II
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
* # *
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.
Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
Ingredients
Per tablet
Kernel:
Compound of formula (I) 10.0 mg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
Povidone K30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose 150.0 mg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. ad pH 5.0
Water for injection solutions ad 1.0 ml
The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.
Example D
Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
Capsule contents
Compound of formula (I) 5.0 mg
Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil 110.0 mg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 83 8.0 mg (dry matter)
Titan dioxide 0.4 mg '
Iron oxide yellow 1.1 mg
The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a conventional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

Claims

1. Compounds of formula (I):
Figure imgf000089_0001
wherein:
X is O or S; R1 is hydrogen, halogen, (C1-C6)alkyl or cyano;
R2, R2' are independently of each other H or halogen;
R3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, NH(CH2)nCH(CH3)2, or -O(CH2)nOCH3, unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C1-C6) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring; R4 is branched or unbranched (C2-C6) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, -NO2, -(CH2>Aryl and -C(O)-O-CH3, or unsubstituted or substituted 5-10 membered carboxylic ring;
R5 is (C1-C6) alkyl or -CH(CH3)2; n is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
2. Compounds according to claim 1, wherein X is O or S; R1 is hydrogen, halogen, (Ci-C^alkyl or cyano; 006/000786
- 89 -
R2, R2' are independently of each other H or halogen;
R3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, NH(CH2)nCH(CH3)2, or -O(CH2)nOCH3, unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C1-C6) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring; R4 is branched or unbranched (C2-C6) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -0(CH)(CHs)2, -CF3, -O(CH2)nCH3, -OCF3, -SCH3, -SO2CH3, -NO2, -(CH2)-Aryl, or unsubstituted or substituted 5-10 membered carboxylic ring; R5 is (C1-C6) alkyl or -CH(CH3)2; n is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
3. Compounds according to any of claims 1 - 2, wherein R3 is:
Figure imgf000090_0001
Figure imgf000090_0002
wherein Y is O or S.
4. Compounds according to claim 1, wherein X is O.
5. Compounds according to claim 1, wherein X is S. 86
- 90 -
6. Compounds according to claim 1, wherein R4 is substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -CF3, -O(CH2)nCH3, -OCF3, - SCH3, -SO2CH3, and -NO2.
7. Compounds according to any of claims 1 - 6, wherein R1 is halogen
8. Compounds according to any of claims 1 - 7, wherein R1 is fluorine.
9. Compounds according to any of claims 1 - 8, wherein R2 and R2' are hydrogen.
10. Compounds according to any of claims 1 - 9, wherein R3 is
Figure imgf000091_0001
Figure imgf000091_0002
wherein Y is O or S.
11. Compounds according to any of claims 1 - 10, wherein R3 is phenyl.
12. Compounds according to any of claims 1 - 11, wherein R4 is (Ci-C6) alkyl, cyclopentyl, benzyl, unsubstituted phenyl or phenyl which is mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -CF3, -OCF3, -SCH3, -SO2CH3, -NO2 and -C(O)-O-CH3.
13. Compounds according to any of claims 1 - 12, wherein R4 is unsubstituted phenyl or phenyl which is mono- or di-substituted with a group independently selected from the group consisting of halogen, (Ci-C6) alkyl, (C1-C6) alkoxy, -O(CH)(CH3)2, -OCF3, -SCH3,
-NO2 and -C(O)-O-CH3.
14. Compounds according to any of claims 1 - 13, wherein R4 is phenyl, 4-methoxy- phenyl, 4-chloro-phenyl, 3-methoxy-phenyl, 3-fluoro-phenyl, 3-chloro-ρhenyl, 3-isopropyl- phenyl, 2-methylsylfanyl-phenyl, 2-nitro-phenyl, 2-isopropoxy-phenyl, 2-ethyl-phenyl, 2- propoxy-phenyl, 2-methoxycarbonyl-phenyl, 2,3-dimethyl-phenyl, 2-trifluoromethoxy- phenyl or 2-ethoxy-phenyl.
15. Compounds according to any of claims 1 - 14, wherein R5 is -CH(CHs)2.
16. Compounds according to any of claims 1 - 15, wherein n is 0, 1 or 2.
17. Compounds according to any of claims 1 - 16, selected from the group consisting of Benzoic acid N'-[2-(5,4'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(2'-chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-methyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(5,2'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acidN'-[2-(4'-chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acidN'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N' - [2-(5 ,3 ' -difluoro-biphenyl-2-yloxy)-acetyl] -N' -isopropyl-hydrazide, Benzoic acidN'-[2-(5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acidN'-[2-(5-fluoro-3'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acidN'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N' -[2-(5-fluoro-2' -nitro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-isopropoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biρhenyl-2-yloxy)-acetyl]-N'-isoρroρyl- hydrazide,
Benzoic acid N'-[2-(2',3'-dimethyl-5-fluoro -biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N' -[2-(5-fluoro-2' -isopropyl-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, Benzoic acid N' -[2-(5-fluoro-2' -methanesulfonyl-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(5,2',4'-txifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(5, 4'-difluoro-4'-methyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(2'-ethyl-5-methyl-biρhenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(2'-ethyl-4,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-ethyl-3,5-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N'-[2-(5-cyano-2'-ethyl-biphenyl-2-yloxy)-acetyl]-N'-isoproρyl-hydrazide,
4-(2-methoxy-ethoxy)-benzoic acid N'-[2-(5-fl.uoro-2'-ethyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide,
Benzoic acid N'-[2-(5-methyl-2'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide, Benzoic acid N'-[2-(4,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide,
Benzoic acid N'-[2-(3,5-difluoro-2'-trifluoromethoxy-biρhenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide, Tetrahydro-pyran-4-caiboxylic-acid-N' - [2-(5-fluoro-2' -trifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N'-isopropyl-hydrazide,
3-methyl-furan-2-carboxylic acidN'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N' -isopropyl-hydrazide, Furan-2-carboxylic acid N'-[2-(5-fluoro-2'-txifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide,
Furan-3-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl-hydrazide,
Cyclohexanecarboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N'-isopropyl-hydrazide,
4-(2-methoxy-ethoxy)-benzoic acidN'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N' -isopropyl hydrazide,
Thiophene-2-carboxylic acid N' -[2-(5-fluoro-2'-trifluoromethoxy~biphenyl-2-yloxy)- acetyl]-N'-isopropyl hydrazide, Tetrahydro-thiopyran-4-carboxylic acid N'-[2-(5-fluoro-2'-txifluoromethoxy-biphenyl-2- yloxy)-acetyl]-N' -isopropyl hydrazide,
Thiophene-3-carboxylic acid N' -[2-(5-tluoro-2' -trifluoromethoxy-biphenyl-2-yloxy)- acetyl] -N' -isopropyl hydrazide,
Thiophene-3-carboxylic acid N'-[2-(5-fluoro-2'-ethyl-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide,
Benzoic acid N'-[2-(2-cyclopentyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(2-sec-butyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(2-propyl-phenoxy)-acetyl]-N'-isoρropyl-hydrazide,
Benzoic acid N'-[2-(2-benzyl-phenoxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(3'-fluoro-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N' -[2-(2' ,3 ' -dimethyl-biphenyl-2-ylsulfanyl)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(3'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N'-[2-(4'-fluoro-biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acid N' - [2-(3 ' -txifluoromethyl-biphenyl-2-ylsulf anyl)-acetyl] -N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-methoxy-biphenyl-2-ylsulfanyl)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(2'-fluoro-biphenyl-2-ylsulfanyl)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N' -[2-(4' -methoxy-biphenyl-2-ylsulf anyl)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid NI-[2-(biphenyl-2-ylsulfanyl)-acetyl]-N'-isopropyl-hydrazide, and
4-(Isobutylamino)-benzoic acid N' -[2-(5-fluoro-25 -trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N'-isopropyl hydrazide, and pharmaceutically acceptable salts thereof.
18. Compounds according to any of claims 1 - 17 selected from the group consisting of
Benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N' ~[2-(4' -chloro-5-fluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N' -[2-(5,3 ' -difluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(5,3'-difluoro-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide,
Benzoic acid N'-[2-(5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-3'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, Benzoic acid N'-[2-(5-fluoro-2'-isopropoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
Benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide,
Benzoic acidN'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide, Benzoic acid N' -[2-(2' -methoxycarbonyl-5-fluoro-biρhenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide,
Benzoic acid N'-[2-(2',3'-dimethyl-5-fluoro -biphenyl-2-yloxy)-acetyl] -N' -isopropyl- hydrazide,
Benzoic acid N' -[2-(5-fluoro-2' -trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl- hydrazide, and
Benzoic acid N'-[2-(2'-ethoxy-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide, and pharmaceutically acceptable salts thereof.
19. A process for the manufacture of compounds of formula (T) as defined in any of claims 1 - 18, which process comprises reacting a compound of formula (H)
Figure imgf000096_0001
with a compound of formula (IH)
Figure imgf000096_0002
wherein R1, R2, R2', R3, R4, R5 and X are as defined in any of claims 1- 18.
20. Compounds according to any of claims 1 - 18, when manufactured by a process according to claim 19.
21. Pharmaceutical compositions comprising a compound according to any of claims 1 18 and a pharmaceutically acceptable carrier and/or adjuvant.
22. Compounds according to any of claims 1 - 18 for use as therapeutic active substances.
23. Compounds according to any of claims 1 - 18 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors.
24. A method for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome, which method comprises administering a therapeutically effective amount of a compound according to any of claims 1 - 18 to a human being or animal.
25. The use of compounds according to any of claims 1 - 18 for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors.
26. The use of compounds according to any of claims 1 - 18 for the therapeutic and/or prophylactic treatment of obesity, type π diabetes mellitus and metabolic syndrome.
27. The use of compounds according to any of claims 1 - 18 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors.
28. The use of compounds according to any of claims 1 - 18 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome.
29. The invention as hereinbefore defined.
PCT/EP2006/000786 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (dgat) WO2006082010A1 (en)

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EP06706491A EP1848687A1 (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (dgat)
CA002596639A CA2596639A1 (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (dgat)
AU2006210056A AU2006210056A1 (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (DGAT)
KR1020077018042A KR100883694B1 (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferasedgat
MX2007009210A MX2007009210A (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (dgat).
BRPI0607861-3A BRPI0607861A2 (en) 2005-02-07 2006-01-30 compounds, process for their manufacture, pharmaceutical compositions containing them, method for the therapeutic and / or prophylactic treatment of diseases and use of the compounds
JP2007553522A JP2008529983A (en) 2005-02-07 2006-01-30 Inhibitors of diacylglycerol acyltransferase (DGAT)

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US65067105P 2005-02-07 2005-02-07
US60/650,671 2005-02-07

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AU (1) AU2006210056A1 (en)
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US7795283B2 (en) 2004-12-14 2010-09-14 Astrazeneca Ab Oxadiazole derivative as DGAT inhibitors
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US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8084478B2 (en) 2006-05-30 2011-12-27 Asstrazeneca Ab Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
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WO2014039412A1 (en) 2012-09-05 2014-03-13 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
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US7795283B2 (en) 2004-12-14 2010-09-14 Astrazeneca Ab Oxadiazole derivative as DGAT inhibitors
US8017603B2 (en) 2005-12-22 2011-09-13 Astrazeneca Ab Pyrimido [4,5-B]-oxazines for use as DGAT inhibitors
US7749997B2 (en) 2005-12-22 2010-07-06 Astrazeneca Ab Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors
EP2402319A1 (en) 2006-03-31 2012-01-04 Novartis AG DGAT Inhibitors
EP2301923A1 (en) 2006-03-31 2011-03-30 Novartis AG New compounds
WO2007126957A2 (en) 2006-03-31 2007-11-08 Novartis Ag New compounds
EP2418202A1 (en) 2006-03-31 2012-02-15 Novartis AG New compounds
EP2404905A1 (en) 2006-03-31 2012-01-11 Novartis AG New compounds
EP2402320A1 (en) 2006-03-31 2012-01-04 Novartis AG Anorectic agents
EP2402317A1 (en) 2006-03-31 2012-01-04 Novartis AG DGAT inhibitor
EP2402318A1 (en) 2006-03-31 2012-01-04 Novartis AG DGAT inhibitors
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8084478B2 (en) 2006-05-30 2011-12-27 Asstrazeneca Ab Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
WO2010111665A1 (en) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2014039412A1 (en) 2012-09-05 2014-03-13 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
US9499482B2 (en) 2012-09-05 2016-11-22 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
US9586900B2 (en) 2012-09-05 2017-03-07 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto

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KR100883694B1 (en) 2009-02-12
MX2007009210A (en) 2007-08-17
CN101115711A (en) 2008-01-30
US20060178532A1 (en) 2006-08-10
AU2006210056A1 (en) 2006-08-10
KR20070093448A (en) 2007-09-18
BRPI0607861A2 (en) 2009-10-20
US7317125B2 (en) 2008-01-08
CA2596639A1 (en) 2006-08-10
JP2008529983A (en) 2008-08-07
EP1848687A1 (en) 2007-10-31

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