OA13157A - Alpha substituted carboxylic as PPAR modulators. - Google Patents

Alpha substituted carboxylic as PPAR modulators. Download PDF

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OA13157A
OA13157A OA1200500283A OA1200500283A OA13157A OA 13157 A OA13157 A OA 13157A OA 1200500283 A OA1200500283 A OA 1200500283A OA 1200500283 A OA1200500283 A OA 1200500283A OA 13157 A OA13157 A OA 13157A
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OAPI
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methyl
oxazol
phenyl
ethoxy
cr11r12
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OA1200500283A
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Simon Bailey
Paul Stuart Humphries
Donald James Skalitzky
Wei-Guo Su
Luke Raymond Zehnder
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Pfizer
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Abstract

Alpha substituted carboxylic acids of formula (I): wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R", R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR alpha/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.

Description

ï 3 7 5 7 -1 - *
Pfizer Inc.
ALPHA SUBSTITUTEP CARBOXYLIC ACIDS ÀS PPAR MODULATORS
Backqround of The Invention
This invention relates to alpha substituted carboxylic acids that modulate 5 the activities of peroxisome proliferator-activated receptor (PPAR), preferably twoor more of PPAR-a, PPAR-δ, or PPAR-γ, enabling them to be useful in modulationof blood glucose and the increase of insulin sensitivity in mammals. This inventionalso relates to treatment of PPAR related disorders, such as diabètes,dyslipidemia, obesity and inflammatory disorders. 10 Peroxisome proliferators are a structurally diverse group of compounds which, when administered to rodents, elicit dramatic increases in the size andnumber of hepatic and rénal peroxisomes, as well as concomitant increases in thecapacity of peroxisomes to metabolize fatty acids via increased expression of theenzymes required for the β-oxidation cycle. Chemicals included in this group are 15 the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers(Reddy and Lalwani, Crû. Rev. Toxicol., 12:1-58 (1983)). Peroxisome proliférationcan also be elicited by dietary or physiological factors such as a high-fat diet andcold acclimatization. lnsight into the mechanism whereby peroxisome proliferators exert their 20 pléïotropie effects was provided by the identification of a member of the nudearhormone receptor superfamily activated by these Chemicals (Isseman and Green,Nature, 347-645-650 (1990)). This receptor, termed PPAR-α, was subsequentlyshown to be activated by a variety of medium and long-chain fatty acids and tostimulate expression of the genes encoding rat acyl-CoA oxidase and hydratase- 25 dehydrogenase (enzymes required for peroxisomal β-oxidation), as well às rabbitcytochrome P450 4A6, a fatty acid Q-hydroxylase. PPAR-α activâtes transcription by binding to DNA sequence éléments,termed peroxisome proliferator response éléments (PPRE), as a heterodimer withthe retinoid X receptor. The retinoid X receptor is activated by 9-cis retinoic acid 30 (see Kliewer, et al., Nature, 358:771-774 (1992), Gearing, et al., Proc. Natl. Acad.Sci. USA, 90:1440-1444 (1993), Keller, étal., Proc. Natl. Acad. Sci. USA, 90:2160-2164 (1993), Heyman, et al., Cell, 68:397-405 (1992), and Levin, et al., Nature,355:359-361 (1992)). Since the PPAR-a-RXR complex can be activated byperoxisome proliferators and/or 9-cis retinoic acid, the retinoid and fatty acid 35 signaling pathways are seen to converge in modulating lipid metabolism.
Since the discovery of PPAR-α, additional isoforms of PPAR hâve been identified, e.g., PPAR-δ, or PPAR-γ, which are spatially dHTerentîally expressed.Each PPAR receptor shows a different pattern of tissue expression, and .13157 : -2- differences in activation by structurally diverse compounds. PPAR-γ, for instance,is expressed most abundantiy in adipose tissue and at lower tevels in skeletalmuscle, heart, liver, intestine, kidney, vascular endothélial and smooth muscle cellsas well as macrophages. Two isoforms of PPAR^y exist, identified as y, and y2,respectively. PPAR-ymediates adipocyte signalling, lipid storage, and fatmetabolism. Evidence gathered to date support the conclusion that PPAR-γ is theprimary, and perhaps the only, molecular target mediating the insulin sensitizingaction of one class of antidiabetic agents, the thiazolidine 2,4 diones.
In a monotherapeutic or combination therapy context, new and establishedoral antidiabetic agents are still considered to hâve non-uniform and even limitedeffectiveness. The effectiveness of oral antidiabetic thérapies may be limited, inpart, because of poor or limited glycémie control, or poor patient compliance due tounacceptable side effects. These side effects include edema, weight gain, or evenmore serious complications. For instance, hypoglycémie is observed in somepatients taking sulfonylureas. Metfomnin, a substituted biguanide, can causediarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in somecases, hepatoxicity, hâve been linked to the administration of some thiazolidine 2,4dione antidiabetic agents. Combination therapy using two or more of the aboveagents is common, but generally only leads to incrémental improvements inglycémie control.
As a resuit, there is a need for antidiabetic agents that display combinedPPAR-α and PPAR-γ activation which should lead to the discovery of efficaciousglucose and triglycéride lowering drugs that hâve great potential in the treatment oftype 2 diabètes and the metabolic syndrome (i.e., impaired glucose tolérance,insulin resistancem hyoertriglyceridemia and/or obesity).
Summarv of The Invention
The présent invention provides novel compounds of Formula (I):
or a pharmaceutically acceptable sait or solvaté thereof, wherein:
Ring Q is (C6-C10)aryI or (4-10)-membered heterocyclyl; R1 is H, halo, (C,-Ce)alkyl, (CrCe)alkoxy, CN, CF3, -O-CF3, -O-SO2-(CrCe)alkyl, -O-SO2-(CR11R12),(C6-C,D)aryl, -(CR'1R'2)t(C3-C,o)cycloalkyl-(CR’1R12)t, -(CR1’R12)t(C3-C10)cycloalkyl-(CR11R’2)rO-, -(CR1'Rl2),(Cs-Cio)aryl-(CR11R<2)i, -(CR”R12),(C6-Cw)aryl-(CR1’R12)1-O-, 13157; -3- -(CR11R12),-(4-10)-membered heterocyclyl-(CR11R12),, or -(CR11R12),-(4-10)-membered heterocyclyl-(CR11R12),-O-; wherein the ring carbon atoms of R1 areoptionally substituted by 1 to 3 R13 groupe; and the ring nitrogen atoms of R’ areoptionally substituted by 1 to 3 (CrCe)alkyl; 5 R2 is H, (C1-Ca)alkyi, -(CR11R12)r(C3-C,o)cycloalkyl, -<CR”R,2)t- (C6-C10)aryl, or -(CR11R12),(4-lO)-membered heterocyclyl; and wherein the carbonatoms of R2 are optionally substituted by 1 to 3 R13 groups; and the ring nitrogenatoms of R2 are optionally substituted by 1 to 3 (CrC8)alkyl; R3 is selected from the group consisting of: r*-} r\ B) C) D)
-R
10 mi -R4—Y-Y". -R4-
Yis -(C=O)- or -SOr!Y" is NR10or-O-; pis0,1, or2; each q, r, and t are independently 0,1,2, 3,4, or 5; 15 each n is independently 0,1,2, 3, or 4; each k is independently 1,2, or 3;each m and s are independently 0,1,2, or 3;each j is 0,1, or 2;
Each R4 is -<CRnR12)„-, -(CR1lR12)n-S-(CR1'R12)n-, -(CRuR'2)n-NR10-,-(CRnR12)n-NR10-(CR11R12)n-O-, -(CRnR12)n-O-(CR11R12)k-NR10-, -(CR1lR,2)n-O-(CR11R12)n-, -(CR11R12)n-O-(CR11R1VO-(CR1’R’2)n-, -(CR11R,2)„-CR11=CR12-(CR11R12)n-, or -CH=CH-(CRnR12)-O-(CH2)n-; 20 13157? -4-
Each R5is a bond or -(CR11R’2)m-Z-(CR'1R12)s; wherein Z is -CR11R12-, -0-,-NR10a-, or-S(O)r;
Each R® is -(C=O)-OH, -(C=0)-OM\ -(C=O)-(CrC9)alkyl,-(C=O)-O-(CrC8)alkyl, -(C=O)-NR10R11, -(C=O)-NR10-SO2-R11, -SO2-NH-R10,'NH-SO2-R10, -(C=O)-NH-CbN, or R® has a formula:
Each R7 and R® is independently H, (CrC8)alkyl, (CrC9)alkoxy,-(CR11R12),(C3-C10)cycloalkyl, -(CR11R12),(Cs-Cl0)aryl, -(CR11R12)t(C6-C10)aryl-O-,-(CR11R12)t(4-10)-membered heterocyclyl or -(CR11R12)t(4-10)-memberedheterocyclyl-O-;
Or R7 and R® may optionally be taken together with the carbon to whichthey are attached to form a (C3-C)O)cycloalkyl or a (3-10)-membered heterocyclyl;
Each of Ar1, Ar2, Ar3, and Ar4 represents (CE-C10)aryl or (5-10)-memberedheterocyclyl; wherein the ring carbon atoms of each of Ar1, Ar2, Ar3, and Ar4 areoptionally substituted by 1 to 3 R13 groups;
Ring A represents a 3, 4, 5, 6 or 7-membered ring optionally containing 1to 4 heteroatoms which may be the same or different and which are selected from -N(R10b)-, O, and S(O)j, wherein j is 0,1, or 2, with the proviso that the ring does notcontain two adjacent O or S(O)j atoms, and wherein the carbon atoms of the ring Amoiety are optionally substituted by 1 to 3 R13 groups; R® is (CrCa)alkyl, -{CR11R12),(C6-C10)aryl or -(CRuR12),(4-10)-memberedheterocyclyl, wherein t is independently 0, 1,2, 3,4, or 5, wherein said R9 groupsare substituted with 1 to 3 groups independently selected ffom -{CR11R12)qNR10R11,-(CR11R12)qNR10(C,-Cê)alkanoyl, -(CR11R12)qO(CR11R12)rR10, and -(CR11R12)qR10; andwherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups areoptionally substituted with 1 to 3 R13 groups; R9® and R10 are independently H or (C,-Ce)alkyl; R11 and R12 are independently H, (CrC8)alkyl, hydroxy, or (CvCeJalkoxy; R10a is selected from H, (CrC8)alkyl, -(C=O)-R14, -SO2NR15R16, or-S(O)j(CrC6)aikyl;
Each R13 and R13a are independently selected from the group consisting ofhalo, cyano, nitro, trifiuoromethoxy, trifluoromethyl, azido, hydroxy, (CrC6)alkoxy,{C5-C10)alkyl, (CrC6)alkenyt, (CjrQalkynyl, -O-(CR11R,2jk-O-(CR11R12)n-. -(C=O)- 13157; -5- 10 15 20 25 R14, -(C=O)-O-R15, -O-(C=O)-R15, -NR15(C=O)-R16, -NR1S(C=O)-O-R16, -(C=O)-NR15R16, -NR15R16, -NR1SOR16, -SO2NR15R16, -SiO^CrCelalkyl, -O-SO2-R14, -NR15-SO2-R16, R15-(CR11R12)t(C6-C,0 aryl), -(CR11R12),(4-10)-membered heterocyclyl, -(CR11R12)q(C=O)(CR11R12)t(C6-C10)aryl, -(CR11R12)q(C=O)(CR11R12),(4-10)-membered heterocyclyl, -(CR11 R12),O(CR’1 Rl2)q(Ce-C10)aryl, -(CR11 R12),O(CR11 R12)q(4-10)-memberedheterocyclyl, -(CR11R12)qSO2(CR11R12)l(C6-C10)aryl, and -(CR11R12)qSO2(CR11R12)t(4-10)-nnembered heterocyclyl; 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R13 and R13a groups are optionallysubstituted with an oxo (=0) moiety, and the alkyl, alkenyl, alkynyl, aryl andheterocyclic moieties of the foregoing R13 and R138 groups are optionally substitutedwith 1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, -OR15, -(C=O)-R15, -(C=O)-O-R1S,-O-(C=O)-R15, -NR15(C=O)-R16, -(C=O)-NR15R16, -NR15R16, -NR15OR1s, (C,-C6)alkyi, (CrCgJalkenyl, (C2-C6)alkynyl, -(CR11R12)t(Cs-C10)aryl, and-(CR11R12),(4-10)-membered heterocyclyl; each R14, R15, and R16 is independently selected from H, (Ci-C6)alkyi,-(CR11R12)i(C6-Cio)aryl, and -(CR11R12),(4-10)-membered heterocyclyl; 1 or 2 ringcarbon atoms of the heterocyclic group are optionally substituted with an oxo (=0)moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R14, R1S andR16 groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, -NR11R12, trifluoromethyl, trifluoromethoxy, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, and (CrC6) alkoxy; R17 is H, (CrCe)alkyl, -O-(CrC8)alkyl, halo, CN, OH, CF3, or-0-CF3;and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halo,SO or S02 group or to a N, 0 or S atom optionally bears on said group asubstituent selected from hydroxy, halo, (CrC^alkyl, (CrC4)alkoxy, -NH2, -NH(CrC8)alkyl, and -N((Ci-C8)alkyl)2.
In one embodiment, the inventiorr relates to compounds of the Formuta Iwherein R3 is A)
-R -Ar· -Ar2- r?/ R8.
In another embodiment, the invention relates to compounds of the FormulaI wherein R3 is 30 13157 ? -6 —
Within this embodiment, preferred -R4-Y-Y\ are-(CR11R12)r-O-(CR11R,2)n-(C=0)-NR,°-or — (CR11Rt2)n-NR10-(C=O)-O-.
In anolher embodiment, the invention relates to compounds of tbe Formula5 I wherein R3 is
ln another embodiment, the invention relates to compounds of the Formula
10
In another embodiment, the invention relates to compounds of the Formula 1 wherein ring Q is selected from the group consisting of
In another embodiment, the invention relates to compounds of the FormulaI wherein R1 is H, halo, (CrC8)alkyl, (CrC^alkoxy, CF3, -O-CF3, -0-S02-(CrC8)alkyl, -O-SO2-(CR11R12),(Ce-C10)aryl, or -(CR11R12),(Ce-C10)aryl-O-, wherein thering carbon atoms of R1 are optionally substituted by 1 to 3 R13 groups.
In another embodiment, the invention relates to compounds of the Formula I wherein R2 is H, phenyl,
15 13157 : -7-
In another embodiment, the invention relates to compounds of the Formula
O-SO2-(Ci-C8)alkyl 0-(Cg-Cio)®yt O-SO2-(C6-C10)aryl
10 1 315 7 .1 •8-
N=N V-N N-R3 5 and —f
In another embodiment, the invention relates to compounds of the FormulaI wherein R4 is -CHrO-, -CH2-O-CH2-, -CHrCH2-O-, -CH=CH-CH2-O-, or-CHz-CHrCHî-O-, 10 In another embodiment, the invention relates to compounds of the Formula I wherein R4 is -(CH2)n-; wherein n is independently 0,1, 2, or 3.
In another embodiment, the invention relates to compounds of the FormulaI wherein R5 is a bond or -(CR11R12)m-Z-(CR11R1z)s; wherein Z is -O-, -NR10a-, or-S(O)j-; wherein each m and s are independently 0,1,2, or 3; and wherein j is 0,1, 15 or 2.
In another embodiment, the invention relates to compounds of the FormulaI wherein R5 is a bond, -O-, -CH2-, -C(CH3)H-, -C(OH)H-, or -C(O-(CrCe)alkyl)H-.
In another embodiment, the invention relates to compounds of the FormulaI wherein R®is -(C=O)-OH. 20 In another embodiment, the invention relates to compounds of the Formula I wherein R6 is -(0=0)-01^, wherein M+ is selected from the group consisting ofCa++, Li*. Na* and K*.
In another embodiment, the invention relates to compounds of the FormulaI wherein each R7 and R8 is independently H, (CrC8)alkyl, or (CrC8)alkoxy. 13157 ; -9- ln another embodiment, the invention relates to compounds of the FormulaI wherein each R7 and R® are taken together with the carbon to which they areattached to form a (3-7)-membered heterocyclyl.
In another embodiment, the invention relates to compounds having a 5 formula:
Within this embodiment, the invention relates to compounds wherein said-Ar’-Ar2- is selected from the group consisting of:
wherein the ring carbon atoms of each of Ar1 and Ar2 are optionally15 substituted by 1 to 3 R13 groups selected from the group consisting of halo, (Cr C8)alkyl, and (CrC8)alkoxy.
Preferably, said -Ap-Ai2- is selected from the group consisting of:
20 Within this embodiment, spécifie compounds of the présent invention are selected from the group consisting of 13157 ? -10- 2-Meth yl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 ’-biphenyl-3-yl}oxy)propanoic acid; 2-Wlethyl-2-[(3'-{{4-(trifluoromethyl)benzyl]oxy}-1l1‘-biphenyl-3-yl)oxy]propanoic acid; 2-Methyl-2-[(3’-{2-[1 -(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1 ·-biphenyl-3-yl)oxy]propanoic acid; 1 -({3’-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 '-biphenyl-3-yl}oxy)cyclobutanecarboxylic acid; 2-({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 '-biphenyl-3-yl)oxy)butanoic acid; 2-(3-{6-{2-(5-Methyl-2-phenyl-1,3-oxazoI-4-yl)ethoxyJpyridin-2-yl}phenoxy)butanoic acid; 1 -(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxylpyridin-2-yl}phenoxy)cyclobutanecarboxylic acid; 2-Methyl-2-(3-{6-[2-(5-methy!-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)propanQic acid; 2-Methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyrazin-2-yl}phenoxy)propanoic acid; and and pharmaceutically acceptable salts thereof.
Wrthin this embodiment, a spécifie compound of the présent invention is 1-({3'-t2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 -biphenyl-3-yl}oxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 '-biphenyl-3-yl}oxy)butanoicacid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-(3-{6’[2-(5-Methyl-2-phenyl-1l3-oxazol-4-yl)ethoxy]pyrÎdin-2-yl}phenoxy)butanoicacid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 1-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)cyclobutanecarboxyiic acid or the pharmaceutically acceptable saltsthereof.
Within this embodiment, a spécifie compound of the présent invention is 1 -{(3'-{[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-ylîmethoxy}biphenyl-3-yl)oxy]cyciobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 1-({3'-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]biphenyl-3-yl}oxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. 13 13 7 1 -11-
Within this embodiment, a spécifie compound of the présent invention is 1-[(3'-{[5-(4-methoxyphenyl)-1,2l4-oxadÎazol-3-yl]methoxy}biphenyl-3-yl)oxy]cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-5 [(3‘-{2-[2-(3-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}biphenyl-3-yl)oxy]-2- methylpropanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methyi-2-({3'-[{5-metbyl-2-phenyl-l,3-oxazol-4-yl)methoxy]biphenyl-3-yl}oxy)propanoic acid or the pharmaceutically acceptable salts thereof. 10 Within this embodiment, a spécifie compound of the présent invention is 2- ethoxy-3-i3-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]biphenyl-3-yl}propanoicacid or the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to compounds having a formula:
wherein Y is -(C=O)- or -SO-r, Y" is NR10, and p is 1.
Preferably, each of R11 and R12 are independently H.
Preferably, A? is phenyl.
Within this embodiment, spécifie compounds of the présent invention are20 selected fforn the group consisting of 1- (3-{{({2-[3- (Trifhjoromethyl)phenyllethoxy}carbonyl)amino]methyl}phenoxy)cyclobutanecarboxylic acid; 2- (3-Q({2-[3- 25 (Trifluoromethyl)phenyl}ethoxy}carbonyl)amino]methyl}phenoxy)butanoicacid;2-Methyl-2-(3-{[({2-[3- (trifluoromethyl)phenyl]ethoxy}carbonyl5amino]methyl}phenoxy)propanoic acid; 2-Methyl-2-{3-l({[2-(5-methyl-2-phenyl-1,3-oxazol-4-30 yl)ethoxy]carbonyl}amino)methyl] phenoxyjpropanoic acid; 1315 7; -12- 2-Methyl-2-(3-{[({[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]oxy}carbonyl)aminojmethyl}phenoxy)propanoic acid; 2-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}butanoic acid; 1-{3-[({[2-(5-Methyl-2-phenyî-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy} cyclobutanecarboxylic acid; 1- {3-[({[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxylcarbonyl}amino)methyl]phenoxy} cyclobutanecarboxylic acid; 2- {3-[({[3-{5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]phenoxyjbutanoic acid; 2-Methyl-2-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]phenoxyjpropanoic acid; and pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-Methyl-2-{3-[({I2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]carbonyl}amino)methyl]phenoxy}propanoic acid or the pharmaceuticallyacceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4- yl)methoxy]carbonyl}amino)methyl]phenoxy}propanoic acid or the pharmaceuticallyacceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methyl-2-{4-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4- yl)propoxy]carbonyl}amino)methyl]phenoxy}propanoic acid or the pharmaceuticallyacceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyI}amino)methylJphenoxy}-2-methylpropanoic acid or thepharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]carbonyl}amino)methyl]phenoxy}butanoic acid or the pharmaceuticallyacceptable salts thereof. 13157 -13- 10 15 20
Within this embodiment, a spécifie compound of the présent invention is 2-{3-l(ü(5-mettiyk2-phenyl-1,3-oxazol-4- yl)methoxy]carbonyl}amino)methyr|phenoxy}butanoic acid or the pharmaceuticallyacceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 1-{3-[({[2-(5-Methyl-2-phenyH,3-oxazol-4- yl)ethoxy]carbonyl}amino)methyl]phenoxy}cyclobutanecarboxylic acid or thepharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl)amino}carbonyl)oxy]methyi}phenoxy)propanoic acid or thepharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-ethoxy-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4- yl)propoxy]carbortyl}amino)metbyl]phenyl}propanoic acid or the pharmaceuticallyacceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-ethoxy-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]carbony!}amino)methyl]phenyl}propanoic acid or the pharmaceuticallyacceptable salts thereof.
In another embodiment, the invention relates to compounds having a formula:
In another embodiment, ring A is selected ffom the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In another embodiment, ring A is selected from the group consisting of 25 13157 .1 - 14-
wherein — is an optional double bond.
In another embodiment, ring A is selected from the group consisting of 5
wherein — is an optional double bond.
In another embodiment, ring A is selected from the group consisting of 21 O :and
-NR wa. wherein — is an optional double bond.
Within this embodiment, Ar4 is phenyl, naphthyl, pyridinyl, pyrimidinyl, orpyrazinyl.
Within this embodiment, spécifie compounds of the présent invention areselected from the group consisting of
10 15 13157 -15- 1 -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclohexanecarboxylic acid; 1-{4-[2-(5-methyl-2-phenyl-1,3-oxazoi-4-yl)ethoxy]benzyl}cyclopentanecarboxylicacid; 5 1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4- yl)propoxy]banzyl}cyclopentanecarboxylic acid; 4-{4-t(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}tetrahydro-2H-pyran-4-cart>oxylic acid; 4-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydro-2H-10 pyran-4-carboxylic acid; 1-{4-f2-(4’-methoxy-1,1'-biphenyf-4-yi)ethoxyJbenzyl}cyclobutanecarboxyiic acid; 1-{4-(2-(4‘-fluoro-1)r-biphenyl-4-yl)ethoxyJbenzyl}cyclobutanecarboxyiic acid; 15 1-{4’t2-(2'-methoxy-1,r-biphenyl-4-y!)ethoxy]benzyl}cyciobutanecarboxylic acid; 1-(4-{2-[3'-(trifluoromethoxy)-1,r-biphenyl-4- yl)ethoxy}benzyl)cydobutanecarboxylicacid; 1 -(4-{2-[4-(6-methoxypyridin-3-20 yl)phenyl]ethoxy}benzyl)cyclobutanecarboxylic acid; 1-(4-{2-[4'-(methylsulfonyl)-1, r-biphenyl-4-yi]ethoxy}benzyl)cydobutanecarboxylicacid; 1 -(4-{2-{4-{2,3-dihydro-1 -benzofuran-6-yl)phenyl]ethoxy}benzyl)cyclobutanecarboxyiicacid; 25 1 -[4-(2-{4'-[(methylsulfonyl)amino]-1,1 '-biphenyl-4- yl}ethoxy)benzyl}cyciobutanecarboxylic acid; 1-{4-[3-(5-methyl-2-phenyl-1,3-oxazdl-4-yl)propoxy]benzyl}cyclobutanecarboxylicacid; 1-{4-K5-methyl-2-phenyl-1,3-oxazol-4-30 yl)methpxy]benzyl}cyclobutanecarboxyiic acid; 1 -{3-[2-(5-iïiethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid; 1 -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyt}cyclobutanecarboxylic acid; 35 1-{4-[(2,5-diphenyl-1,3-oxazol-4-yl)methoxylbenzyl}cyclobutanecarboxylic acid; 1-{4-[3-(2,5-diphenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyciobutanecarboxylic acid; 13157 ί -16- l-{4-[(2,5-diphenyl-1,3-oxazol-4-yl)methoxy]phenoxy}cyclobutanecarboxylic acid; 1 -{4-[3-(2,5-diphenyl-1,3-oxazol-4-yl)propoxy]phenoxy}cyclobutanecarboxylic acid; 1 -{4-{2-[2-(1 ,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenoxy)cyclobutanecarboxylic acid; 1 -{4-l2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenoxy}cyclobutanecarboxylic acid; ' 1 -{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phénoxy}cyclobutanecarboxylic acid; 1 -{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}cyclobutanecarboxylic acid; 1 -({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cydobutanecarboxylicacid; 1-(hydroxy{6-[2-(5-methyt-2-phenyl-1,3-oxazol-4-yi)ethoxy]pyridin-3-yl}methyl)cyclobutanecarboxylic acid; 1- ({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclopentanecarboxylic acid; 1 -({6-t2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxylpyridin-3-yl}methyl)cyclohexanecarboxylicadd; 2- ({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid; 2-({5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}methyl)tetrahydrofuran-2-carboxylic acid; and the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 1-{4-{3-(5-methyl-2-phenyl-1,3-oxazoM-y))propoxy]benzyl}cyclobutanecarboxylicacid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 1-{4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxyiic acidor the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-{{6-|2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-y!}methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptablesalts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2({5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2- 13157 -17- yl}methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptablesalts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxylpyridin-3-yl}methyl)tetrahydro-2/+ 5 pyran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2- [(6-{2-[2-{3-chlorophenyl)-5-methy!-1,3-oxazol-4-yl]ethoxy}pyridin-3-yi)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptablesalts thereof. 10 Within this embodiment, a spécifie compound of the présent invention is 2- [<6-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-yI)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptablesalts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2- 15 {5-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethaxy]-pyrazin-2-ylmethyl}-tetrahydro-furan-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydrofuran-2-cart>oxylicacid or the pharmaceutically acceptable salts thereof. 20 Within this embodiment, a spécifie compound of the présent invention is 2- {6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-2-ylmethyI}-tetrahydro-furan-2-carboxyiic acid or the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to compounds having a
Within this embodiment, preferably the invention relates to compoundshaving a formula: 13157 ; -18-
Within this embodiment, preferably the invention relates to compoundshaving a formula:
Within this embodiment, preferably R9is methyl, ethyl, or benzyl. Preferably R17is H.
Within this embodiment, a spécifie compound of the présent invention is 2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yI}propanoicacid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methoxy-3-(6-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)propanoic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-methoxy-3-{6-[2-(4-phenoxyphenyl)ethoxylpyridin-3-yl}propanoic acid or thepharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-ethoxy-3-[6-(2-{4-[(phenylsulfonyi)oxy]phenyi}ethoxy)pyridin-3-yl]propanoic acid orthe pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-Ethoxy-3-{5-[2-(5-methyI-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic acidor the pharmaceutically acceptable salts thereof.
Within this embodiment, a spécifie compound of the présent invention is 2-Methoxy-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazat-4-yl)-propoxy]-pyridin-3-yl}-propionic acid or the pharmaceutically acceptable salts thereof. 13157 ? -19- 10 15 20 25 30
Wrthin this embodiment, a spécifie compound of the présent invention is 2-Methoxy-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic acid or the pharmaceutically acceptable salts thereof.
Wrthin this embodiment, a spécifie compound of the présent invention is 3-(6-{2-|2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-yl)-2-methoxy-2-methyl-propionic acid or the pharmaceutically acceptable salts thereof.
Wrthin this embodiment, a spécifie compound of the présent invention is 2-Methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyl oxazol-4-yl)-ethoxy]-pyridin-3-yl}-propionic acid or the pharmaceutically acceptable salts thereof.
Wittiin this embodiment, a spécifie compound of the présent invention is 2-Methoxy-3-(6-{2-[2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-yl)-2-methyl-propionic acid or the pharmaceutically acceptable salts thereof.
The présent invention also provides a method of treating non-insulindépendent diabètes mellitus in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound of Formula (I). Inone embodiment, said mammal has an impaired glucose tolérance.
The présent invention also provides a method of treating polycystic ovariansyndrome in a mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating obesity in amammal comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of Formula (I).
The présent invention also provides a method of reducing body weight inan obese mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating hyperglycemia ina mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating hyperlipidemia ina mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (1).
The présent invention also provides a method of treatingbyperchoiesteremia in a mammal comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating atherosclerosis ina mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (1). 35 13157 . -20-
The présent invention also provides a method of treatinghypertriglyceridemia in a mammal comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating hyperinsulinemiain a mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (l).
The présent invention also provides a method of treating a patient sufferingfrom abnormal insulin and/or evidence of glucose disorders associated withcirculating glucocorticoids, growth hormone, catecholamines, glucagon, orparathyroid hormone, comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula (I).
The présent invention also provides a method of treating insulin résistancesyndrome in humans comprising administering to a patient in need of treatment atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of treating PPAR-relateddisorders in humans comprising administering to a patient in need of treatment atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of modulating PPAR activityin a mammal, comprising administering to a mammal a therapeutically effectiveamount of a compound of Formula (I).
The présent invention also provides a method of lowering blood glucose ina mammal, comprising administering to a mammal an amount of a compound ofFormula (I) effective to lower blood glucose levels.
The présent invention also provides a method of modulating fat celldifférentiation in a mammal, comprising administering to a mammal atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of modulating processesmediated by PPAR in a mammal, comprising administering to a mammal atherapeutically effective amount of a compound of Formula (I).
The présent invention also provides a method of increasing insulinsensitivity in mammals, comprising administering to a mammal a therapeuticallyeffective amount of a compound of Formula (l).
The présent invention also provides a method of treating metabolicsyndromes selected from the group consisting of galactosemia, maple syrup urinedisease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria,isovaieric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency. 10 15 20 25 30 1 3 15 7 .1 -21-
The présent invention also provides a composition comprising at least onemodulator of PPAR of Formula (I) and a pharmaceutically acceptable carrierthereof. Exemptary pharmaceutically acceptable carriers include carriers suitablefor oral, intravenous, subcutaneous, intramuscular, Intracutaneous, and the likeadministration. Administration in the form of creams, lotions, tablets, dispersiblepowders, granules, syrups, élixirs, stérile aqueous or non-aqueous solutions,suspensions or émulsions, and the like, is contemplated.
The PPAR agonists of the présent invention may be administered incombination with other agents such as α-glucosidase inhibitors, aldose reductaseinhibitors, biguanide préparations, statin base compounds, squalene synthesisinhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors. in the above description, an α-glucosidase inhibitor is a médicamenthaving action in inhibiting a digestive enzyme such as amylase, maltase, a-dextrinase or sucrase, thereby retarding the digestion of starch or sucrose.Examples of α-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)variolamine (common name: voglibose) and miglitol.
In the above description, an aldose reductase inhibitor is a médicamentwhich inhibits a rate-limiting enzyme of the first step of the poiyoi pathway, therebyinhibiting diabetic complications. Examples include tolrestat, epalrestat, 2,7-difluoro-spiro(9H-fluoren-9,4’-imidazo)idine)-2',5'-dione (common name: imirestat),3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinozolineacetic acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2,5'-dioxo-spiroi4H-1-benzopyran-4,4'-imidazolidine]- 2-carboxamide (SNK-860), zopolrestat,sorbinil and 1-{(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209).
In the above description, a biguanide préparation is a médicament havingeffects in anaérobie glycolysis promotion, insulta action reinforcement at theperiphery, intestinal glucose absorption inhibition, hepatic gluconeogenesisinhibition and fatty-acid oxidation inhibition and examples include phenformin,metformin and buformin.
In the above description, a statin base compound is a médicament whichinhibits hydroxymethylglutaryl CoA (HMG-CoA) reductase, thereby lowering theblood cholestérol level and examples include pravastatin and the sodium saitthereof, simvastatin, lovastatin, atorvastatta and fluvastatin. in the above description, a squalene synthesis inhibitor is a médicamentfor inhibiting squalene synthesis, thereby lowering the blood cholestérol level andexamples include monopotassium (S)-a‘[bis(2,2-dimethyl-1- 35 13157 -22- oxopropoxy)methoxy}phosphinyl-3-phenoxybenzene-butanesulfonate (BMS-188494).
In the above description, a fibrate base compound is a médicament forinhibiting synthesis and sécrétion of triglycérides in the liver and activatinglipoprotein lipase, thereby lowering the triglycéride level in the blood. Examplesinclude bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate,clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate,simfibrate and theofibrate.
In the above description, a LDL catabolism promoter is a médicament forincreasing LDL (low-density lipoprotein) receptors, thereby lowering the bloodcholestérol level and examples include compounds described in Japanese PatentApplication Kokai Hei 7-316144 or salts thereof, more specifically, N-[2-[4-bis(4-fluorophenyl)methyl-1 -piperazinyl]ethyl]-7,7-diphenyl-2,4,6- heptatrienoic amide.
The above-described statin base compounds, squalene synthesisinhibitors, fibrate base compounds and LDL catabolism promoters can be replacedwith another Chemical effective for lowering the blood cholestérol or triglycéridelevel. Examples of such a médicament include nicotinic acid dérivativepréparations such as nicomol and niceritrol; antioxidants such as probucol; and ionexchange resin préparations such as cholestyramine.
In the above description, an angiotensin-converting enzyme inhibitor is amédicament for inhibiting angiotensin-converting enzyme, thereby lowering theblood pressure and at the same time, partially lowering the blood sugar level of apatient suffering from diabètes. Examples include captopril, enalapril, alaceprii,delapril, ramipril, lisinopril, imidapril, benazepril, ceronaprill cilazapril, enalaprilat,fosinopril, moveltipril, perindopril, quinapril, spirapril, temocapril and trandolapril.
For the préparation of oral liquids, suitable carriers include émulsions,solutions, suspensions, syrups, and the like, optionally containing additives such aswetting agents, emulsifying and suspending agents, sweetening, flavoring andperfuming agents, and the like.
For the préparation of fluids for parentéral administration, suitable carriersinclude stérile aqueous or non-aqueous solutions, suspensions, or émulsions.Examples of non-aqueous solvents or vehicles are propylene glycol, polyethyleneglycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organicesters such as ethyl oleate. Such dosage forms may also contain adjuvants suchas preserving, wetting, emulsifying, and dispersing agents. They may be sterilized,for example, by filtration through a bacteria-retaining filter, by incorporatingsterilizing agents into the compositions, by irradiating the compositions, or by
13157J -23- heating the compositions. They can also be manufacturée! in the form of stérilewater, or some other stérile injectable medium immediately before use. Définitions
For purposes of the présent invention, as described and claimed herein, 5 the following terms are defined as follows:
The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicale having straight or branched moieties. 10 The term "alkenyi", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as definedabove and including E and Z isomers of said alkenyi moiety.
The term "alkynyl", as used herein, unless otherwise indicated, includes alkylmoieties having at least one carbon-carbon triple bond wherein alkyl is as defined 15 above.
The term "alkoxy", as used herein, unless otherwise indicated, includes 0-alkyl groups wherein alkyl is as defined above.
The term “Me” means methyl, “Et” means ethyl, and “Ac” means acetyl.
The term “cycloalkyl”, as used herein, unless otherwise indicated refers to a 20 non-aromatic, saturated or partially saturated, monocyclic or fused, spiro orunfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkylsinclude monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Illustrative
The term "aryT, as used herein, unless otherwise indicated, includes an 30 organic radical derived from an aromatic hydroçarbon by removal of one hydrogen,such as phenyl or naphthyl. 13157 „ -24-
The term "4-10 membered heterocyclic", as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groups containing one tofour heteroatoms each selected from O, S and N, wherein each heterocyclic grouphas from 4-10 atoms in its ring system, and with frie proviso that the ring of saidgroup does not contain two adjacent O or S atoms. Non-aromatic heterocyclicgroups include groups having only 4 atoms in their ring System, but aromaticheterocyclic groups must hâve at least 5 atoms in their ring system. The heterocyclicgroups include benzo-fused ring Systems. An example of a 4 memberedheterocyclic group is azetidinyl (derived from a2etidine). An example of a 5membered heterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morphoiino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, d'rthiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicycloI3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl. 3H-indolyl and quinolizinyl. Examples of aromaticheterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyt, isothiazolyl,pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyi, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, bertzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listed above, maybe C-attached or N-attached where such is possible. For instance, a group derivedfrom pyrrole may be pyrrol-1-yf (N-attached) or pyrrol-3-yl (C-attached). Further, agroup derived from imidazoie may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-10 membered heterocyclic may be optionally substituted on anyring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An exampie of aheterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4-10 memberedheterocyclic are derived from, but not limited to, the following:
H
H ’ H 13157 ; -25-
H ' H
5 Unless otherwise indicated, the term “oxo” refers to =0.
The term "-Ar’-Ar2-”, as used herein, unless otherwise indicated include two rings without any limitation of the order of attachments to R4 and R5. For exampie, if-Ar’-Ar2- is defined as
; then the -Ar’-Ar2- groups can be
The phrase “pharmaceutically acceptable salt(s)", as used herein, unless15 otherwise indicated, includes salts of acidic or basic groups which may be présent in 13157 -26- the compounds of formula (I). The compounds of formula (!) that are basic in natureare capable of forming a wide variety of salts with various inorganic and organicacids. The acids that may be used to préparé pharmaceutically acceptable acidaddition salts of such basic compounds of formula (I) are those that form non-toxicacid addition salts, Le., salts containing pharmacologically acceptable anions, suchas the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorànate, hydrabamine,hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate,oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phospate/diphosphate, polygalacturonate, salicylate, stéarate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
In the compounds of formula (1), where terms such as (CR” R12), or(CR”R12)t are used, R” and R12 may vary with each itération of q or t above 1. Forinstance, where q or t is 2 the terms (CR”R12)q or (CRnR12)t may equal -CH2CH2-,or -CH(CH3)C(CH2CH3)(CH2CH2CH3)-i or any number of similar moieties fallingwithin the scope of the définitions of R” and R12. Further, as noted above, anysubstituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) groupwhich is not attached to a halogeno, SO or SO2 group or to a N, O or S atomoptionally bears on said group a substituent selected from hydroxy, CrC4 alkoxyand amines.
The term “treating'’, as used herein, uniess otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of such disorder orcondition. The term "treatmenf, as used herein, uniess otherwise indicated, refers tothe act of treating as “treating" is defined immediately above.
The term “modulate” or “modulating”, as used herein, refers to the ability ofa modulator for a member of the steroid/thyroid superfamily to either directly (bybinding to the receptor as a ligand) or indirectly (as a precursor for a ligand or aninducer which promûtes production of ligand from a precursor) induce expressionof gene(s) maintained under hormone expression control, or to repress expressionof gene(s) maintained under such control.
The term "obesity” or “obese”, as used herein, refers generally toindividuels who are at least about 20-30% over the average weight for hts/her âge,sex and height. Technically, "obese" is defined, for maies, as individuals whosebody mass index is greater than 27.8 kg/m, and for femaies, as individuals whose 13157 4 -27- body mass index is greater than 27.3 kg/m2. Those of skill in the art readilyrecognize that the invention method is not limited to those who fall within the abovecriteria. Indeed, the method of the invention can also be advantageously practicedby individuais who fall outside of these traditional criteria, for example, by those 5 who may be prone to obesity.
The term “Inflammatory disorders", as used herein, refers to disorders suchas rbeumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis,chondrocaicinosis, goût, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, fibromyalgia, and cachexia. 10 The phrase “therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceuticai agent that will elicit the biologicai or medicalresponse of a tissue, System, animal, or human that is being sought by aresearcher, veterinarian, medical doctor or other.
The phrase "amount... effective to lower blood glucose levels," as used 15 herein, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls inthe range of about 10 nM up to 2 μΜ; with concentrations in the range of about 100nM up to 500 nM being preferred. As noted previously, since the activity of differentcompounds which fall within die définition of Formula (I) as set forth above may 20 vary considerably, and since individual subjects may présent a wide variation inseverity of symptoms, it is up to the practitioner to détermine a subject's responseto treatment and vary the dosages accordingly.
The phrase “insulin résistance", as used herein, refers to the reducedsensitivity to the actions of insulin in the whole body or individual tissues, such as 25 skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulinrésistance occurs in many individuais with or without diabètes mellitus.
The phrase “insulin résistance syndrome”, as used herein, refers to thecluster of manifestations that include insulin résistance, hyperinsulinemia, noninsulin dépendent diabètes mellitus (NIDDM), arterial hypertension, central 30 (viscéral) obesity, and dyslipidemia.
The phrase "in combination with”, as used herein, means that the alphasubstituted carboxylic acids compound of Formula (I) may be administered shortlybefore, shortly after, concurrently, or any combination of before, after, orconcurrently, with such other agents as described in the previous paragraphs. 35 Thus, the alpha substituted carboxylic acids compound of Formula (I) and the otheragents may be administered simultaneousiy as either as a single composition or astwo separate compositions or sequentially as two separate compositions. 13157? -28-
Certain compounds of formula (I) may hâve asymmetric centers andtherefore exist in different enantiomeric forms. Ali optical isomers and stereoisomersof the compounds of formula (I), and mixtures thereof, are considered to be withinthe scope of the invention. With respect to the compounds of formula (I), theinvention includes the use of a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, or mixtures thereof. The compounds of formula (I) mayalso exist as tautomers. This invention relates to the use of ali such tautomers andmixtures thereof.
Certain functional groupe contained within the compounds of the présentinvention can be substituted for bioisosteric groups, that is, groupe which hâve similarspatial or electronic requirements to the parent group, but exhiblt differing orimproved physicochemical or other properties. Suitable examples are well known tothose of skill in the art, and include, but are not limited to moieties described in Patini,étal., Chem. Rev, 1996,96,3147-3176 and référencés cited therein.
The subject invention also includes isotopically-labelled compounds, whichare identical to those recited in Formula (I), but for the fact that one or more atomsare replaced by an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ZH, 3H, 13C,14C, 1SN, 18O, 17O, 31P, 32P, 35S, 18F, and æCI, respectively. Compounds of theprésent invention, prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention. Certainisotopically-labelled compounds of the présent invention, for example those intowhich radioactive isotopes such as 3H and 14C are incorporated, are useful in drugand/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e.,14C, isotopes are particulariy preferred for their ease of préparation anddetectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H,can afford certain therapeutic advantages resulting from greater metabolic stability,for exampte increased in vivo half-life or reduced dosage requirements and, hence,may be preferred in some circumstances. Isotopically labelled compounds ofFormula (I) of this invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in the Examples andPréparations below, by substituting a readily available isotopically labelled reagentfor a non-isotopically labelled reagent.
This invention also encompasses pharmaceutical compositions containingand methods of treating bacterial infections through administering prodrugs of 13157 -29- compounds of the formula 1, Compounds of formula 1 having free amino, amido,hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide Chain of two or more(e.g., two, three or four) amino acid residues is covalently joined through an amide or 5 ester bond to a free amino, hydroxy or carboxylic acid group of compounds offormula 1. The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols and alsoincludes 4-hydroxyprotine, hydroxylysine, demosine, isodemosine, 3-methylhistidine,norvalin. beta-alanine, gamma-aminobutyric acid, citrulline homocystéine, 10 homoserine, omithine and méthionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxyl groups can be derivatized as amides oralkyl esters. Free hydroxy groups may be derivatized using groups including but notlimited to hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outiined in Advanced Drug Delivery Reviews, 15 1996, 19,115. Carbamate prodrugs of hydroxy and amino groups are aiso included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethy! etherswherein the acyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acid functionaiities, or where 20 the acyl group is an amino acid ester as described above, are also encompassed.Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. Free aminescan also be derivatized as amides, sulfonamides or phosphonamides. Ali of theseprodrug moieties may incorporate groups including but not limited to ether, amineand carboxylic acid functionaiities. 25 Other aspects, advantages, and preferred features of the invention will become apparent from the detailed description below.
Detailed Description And Preferred Embodiments of The InventionThe following réaction Scheme illustrâtes the préparation of the compounds of the présent invention. Unless otherwise indicated, R - R17, Q, Y, 30 Ar1-Ar4, and Ring A, in the reaction scheme and discussion that follow are as definedabove. 13157 ? -30-
Scheme 1
5
13157 ;
Scheme 2
Lv3
V'OH
Vllia ’r
Ai?
Lv
V
Lv4 XO2RIXa xr8
R5 CO2R
Vlla R7 R8 X. co2r
Ilia 5 13157 : -32-
lla 131577 -33-
R5is -(CR11R12)m-Z-(CR11R12)s; wherein Z is -O-, -NR10a-, or -S(O)r; whereinm and s are independently 0,1,2, or 3; and wherein j is 0,1, or 2 5 13157 ?* -34- 10 Y'
Scheme 5
'V
R" R
Vllb 12
Ar, -r5h
Ar3-R3
,COOR 12 lllb R1'
R5 is -(CR11R12)m-Z-(CR11R12)s; wherein Z is -O-, -NR10a-, or -S(O)r; wherein each m and s are independentiy 0,1.2, or 3; and wherein j is 0,1, or 21 ) 13157 : -35-
Scheme 6
R5ls -(CR’,R’I)„-2-(CR’’R1îfc wharein 2 (a -CHr;whareln each m and s are Independently 0,1, 2 or 3. 10
Scheme 7 13157 ? -36-
Rs is -(CR11R12)m-2-(CR11R12)9; wherein 2 is -CH2-;wherein each m and s are independently 0,1,2, or 3. 13157 " -37-
Scheme SPO—Ar4—Lv9Xlllc O. Il
PO—Ar4—C-H
Xilc
Lv® COOR nie
PO-Ar4-R®. ,COOR
Xc
R5 is -(CR11R12)ffl-2-{CR11R12)s; wherein 2 is -CH2-;wherein each m and s are indépendante 0,1,2, or 3. 13157 .1 -38-
Scheme 9 PO—Ar4—Lv9Xtllc
PO-Ar4-RSOH XVc PO-Ar4-RsLv10
X,VC Lv5 COOR
Hic
PO-Ar4-R5 .COOR
Xc (A) R5 is -(CR11R12)m-Z-(CR11R12)s; wherein Z is -CH2-;wherein each m and s are independently 0,1, 2, or 3. 13157 ; -39-
Scheme 10
PO-Ar4-OH
PO-Ar4-R? .COOR
Xlc
HO-Ar4-R® ,COOR
R5 is -(CR11 R12)m-Z-(CR11R12)S; wherein Z is -O-, -NR10a-, or -S(O)r;wherein each m and s are independently 0,1,2, or 3; and wherein j is 0,1, or 2. 13157 ; -40 —
Scheme 11
5 10 13157 ? -41 -
Scheme 12
5 1 3 157 . -42-
Scheme 13
13157 .1 -43-
Referring to Scheme 1 above, the compound of formula la may be preparedby hydrolysis of compounds lia, wherein the group CO2R is a hydrolyzable estergroup such as methyl ester (CO2-CK3) or ethyl ester (CO2-CH2CH3), by alkali métalhydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, 5 aqueous methanol or combinations thereof) at a température between 0 and 100degrees or by heating in a microwave synthesizer. Compounds of formula lia maybe prepared by a coupling reaction of compound IVa, wherein Lv1 is Cl, Br, I, ortriflate, and an organometallic compound Ilia, wherein Met = boronic acid or ester,stannane etc, and the group CO2R is as described above, mediated by a 10 palladium(O) or other transition métal catalyst. Compound IVa can be obtained by1 alkylation of compound Va, wherein Lv1 is as described above, with compound Via, wherein Lv2 is Cl. Br, I, or triflate.
Referring to Scheme 2 above, the compound of formula Ilia, which is used inScheme 1, may be obtained from compounds Vlla, wherein Lv3 is Cl, Br, I, or 15 triflate, by pailadium(O) mediated coupling reactions with a reagent such aspinacolatodiborane. Compounds Vlla, wherein Lv3 is as described above, can beobtained by alkylation of compounds Villa, wherein Lv3 is as described above, withcompound IXa, wherein Lv4 is Cl, Br, I, or triflate.
Referring to Scheme 3 above, esters lia, which is used in Scheme 1, 20 wherein the group CO2R is as described above, may also be prepared by alkylationof compound Xa, wherein the group CO2R is as described above, with compoundVia, wherein Lv2 is as described above in the description of Scheme 1.Compounds Xa may be obtained from compound Xla, wherein the group CO2R is _ as described above, by reacting compound Xla with a deprotecting agent, such as _ 25 with hydrogen gas over a métal catalyst (e.g. palladium on carbon) in a suitable solvent (e.g. THF, methanol, éthanol) at a température between 0 degrees Celcius and 100 degrees Celcius.
Compounds Xla are commercially available or can be made by thoseskilled in the art. 30 Referring to Scheme 4 above, compounds of formula Ib; wherein R5 is - (CR11R12)m-Z-(CR11R12)6; wherein Z is -O-, -NH10a-, or -S(O),-; wherein each mand s are independentiy 0, 1,2, or 3; and wherein j is 0, 1, or 2; may be preparedby hydrolysis of compounds (Ib, wherein Rs is as described in the compounds offormula Ib and the group CO2R is as described above, by an alkali métal hydroxide 35 (e.g. Na OH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinations thereof) at a température 0 degrees Celcius and 100degrees Celcius. Compounds of formula llb, wherein R5 is as described in thecompounds of formula Ib, may be prepared by reaction of compounds lllb, wherein 1315*7 3 -44- R5 is as described in the compounds of formula llb and the group CO2R is asdescribed above, with an activated acylating agent such as Vlb in a suitablesolvent (e.g. THF, acetonitrile, dioxane, toluene) at a température between 0degrees Celcius and 100 degrees Celcius. Compounds IVb may be obtained fromcompound Vb by reacting compound Vb with compound Vlb, wherein Lv6 is aleaving group. Suitable compound Vlb includes Ν,Ν’-carbonyl diimidazole.
Compounds Vb and Vlb are commercially available or can be made bythose skilled in the art.
Referring to Scheme 5 above, compounds of formula lllb, which is used inScheme 4, wherein Rs is as described in the description of Scheme 4 and thegroup CO2R is as described above, may be prepared by reacting compound Vllbwherein R5 is as described in the previous paragraph, with an appropriateelectrophile of formula Lv6-C(R7R8)-COOR, wherein Lv6 is a leaving group such ashalo, in the presence of a base (e.g. césium carbonate, potassium carbonate) in asuitable solvent (e.g. THF, DMF, acetonitrile, or DMSO) at a température between0 degrees Celcius and 100 degrees Celcius. Suitable electrophiles of formula Lv6-C(R7R8)-COOR include methyl 2-bromo-2-methyl propanoate. Compounds Vllb arecommercially available or can be made by those skilled in the art.
Compounds of formula Ib, llb, Mb, and Vllb; wherein R5 is -(CR11R12)m-Z-(CR11R12)e; wherein Z is -CH2-, and wherein each m and s are as described above;can be prepared by methods knôwn to those skilled in the art
Referring to Scheme 6 above, compounds of formula le, wherein R5 is -(CRuR12)m-Z-(CR11R12)s; wherein Z is -CHr, may be prepared by hydrolysis ofcompounds Ile, wherein the group CO2R is as described above, by alkali métalhydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF,aqueous methanol or combinations thereof) at a température between 0 degreesCelcius and 100 degrees Celcius or by heating in a microwave synthesizer.Compounds Ile may be prepared by alkylation of compound Mc, wherein Lv5 is aleaving group, with compound IVc (when Lv7 is iodide, bromide, chloride or otherleaving group). Various methods can be used to effect this reaction, such asdeprotonation of compound lllc (Lv5 = H) with a base e.g. sodiumbis(trimethylsilyl)amide. Compounds IVc may be prepared from compounds Vc byreaction with a halogénation agent or halogénation System e.g. oxalyl chloride anddimethyl formamide or from another halide (e.g. reaction of compound IVc, Lv7 = Clwith sodium iodide). Compounds Vc may be prepared from compounds Vie byreacting compounds Ville with a reducing agent, such as sodium borohydride.Compounds Vie may be obtained from compound Vile (Lv8 = Br or other halogen) 13157 : -45- by metal-halogen exchange (e.g. with butyllithium) followed by reaction withdimethyl formamide.
Altematively, referring to Scheme 7 above, compounds of formula Ile,wherein R5 is -(CR11R1z)n,-2-(CR11R12)8; wherein Z is -CH2-, may be prepared bythe reductive deoxygenation of compound Ville using a silane and an acid source,typically triethylsilane and trifluoroacetic acid. Compounds Ville may be obtainedby addition of compound (lie to compound Vie. Various methods can be used toeffect this reaction, such as deprotonation of lllc (Lvs = K) with a base e.g. lithiumdiisopropylamide, or Reformatsky type activation of lllc (Lvs = Br) with a métal ormétal sait (e.g. chromium(ll) chloride). Compounds Vie may be obtained fromcompound Vile (Lv8 = Br or other halo) by metal-halogen exchange (e.g. withbutyllithium) followed by reaction with dimethyl formamide.
Altematively, referring to Scheme 8 above, compound Ile, wherein Rs is-(CR11R12)m-Z-(CR11R12)a; wherein Z is -CHr, may be obtained by reaction ofcompounds IXe with suitable coupling partners of formula Via. These reactionsmay be effected using electrophiles Via (e.g. Lv2 = halides, sulphonate esters) inthe presence of a base (e.g. césium carbonate) or with alcohols (Lv2 = OH) underMitsunobu-type conditions (e.g. triphenyl phosphine and diethylazodicarboxyfate).Compounds IXe can be prepared by deprotection of protected compounds Xc.Suitable protecting groups can include allyl, benzyl etc. Deprotection of Xc (P =allyl) can be achieved by exposure to a soluble transition métal (e.g.tetrakis(triphenylphosphine)palladium(0)) in the presence of a base e.g.morpholine. intermediates Xc-Xlllc may be prepared by the methods described inScheme 6.
Altematively, referring to Scheme 9 above, compound Xc can be preparedby reacting compound XIVc (e.g. Lv10 = halides, sulphonate esters) with compoundlllc, wherein Lv5 is as described above. Compound XIVc can be prepared byreacting compound XVc with (C=O)CI2 in a polar aprotic solvents such asdimethyiformamide. Compound XVc can be prepared by reacting compound Xllcwith a reducing agent, such as sodium borohydride. Compounds Xlllc may beprepared by the method described in Scheme 6.
Altematively, referring to Scheme 10 above, the compound of formula le,wherein R5 is -(CR11R12)m-Z-(CRnR12)8; wherein Z is -O-, -NR10a-, or -S(O)r;wherein each m and s are independently 0,1,2, or 3; and wherein j is 0,1, or 2;may be prepared by hydrolysis of compounds Ile by aikali métal hydroxides (e.g.NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol orcombinations thereof) at a température between 0 degrees Celcius and 100 13157 -46- degrees Celcius or by heating in a microwave synthesizer. Compounds of formulaIle may be obtained by reaction of compounds IXe with suitable coupling partners.These reactions may be effected using electrophiles (e.g. Via; Lv2 = halides,sulphonate esters) in the presence of a base (e.g. césium carbonate, potassiumcarbonate or potassium f-butoxide) or with alcohols (Via; Lv2 = OH) underMitsunobu-type conditions (e.g. triphenyl phosphine and diethylazodicarboxytate).Compounds IXe may be prepared by deprotection of compounds Xlc wherein P isa protecting group. Suitable P protecting groups can include allyl, benzyl etc.Deprotection of Xlc (P = allyî) can be achieved by exposure to a soluble transitionmétal (e.g. tetrakis(triphenylphosphine)palladium(0» in the presence of a base e.g.morpholine or by réduction (Xlc; P = benzyl) with hydrogen gas over a métalcatalyst (e.g. palladium on carbon) in a suitable solvent (e.g. THF, methanol,éthanol) at a température between 0 degrees Celcius and 100 degrees Celcius.Compounds Xlc can be obtained by alkylation of compounds XIVc with compoundHic (Lvs= Cl, Br, I, triflate, as described above).
Referring to Scheme 11 above, in certain cases alkylation of an enolateanion of compound lllc with a benzylhalide having a formula XVIc affordscompounds XVc. Compounds XVc can be converted into compounds le by e.g.palladium mediated coupling réaction in a solvent known by those skilled in the art(e.g., March, Advanced organic Chemistry, Fourth Edition).
Referring to Scheme 12 above, compounds of formula Id may be preparedby hydrolysis of compounds lld by alkali métal hydroxides (e.g. NaOH, UOH, KOH)in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinationsthereof) at a température between 0 degrees Celcius and 100 degrees Celcius.Compounds of formula lld may be prepared by reaction of compounds llld with anappropriate hydrogénation agent such as hydrogen gas over a métal catalyst (e.g.,palladium on carbon) in a suitable solvent (e.g. THF, methanol, éthanol) at atempérature between 0 degrees Celcius and 100 degrees Celcius. Compounds offormula llld may be prepared by reaction of compounds IVd with an appropriatetriphenyl phosphine reagent having a formula: (C6Hs)3P+-CH(OR9)(COOR) Cr in aWittig reaction. Suitable triphenyl phosphine reagents include 1,2-diethoxy-2-oxoethyl)(triphenyl) phosphonium chloride. Compounds of formula IVd may beprepared by reaction of compounds Vd as described in Scheme 9. Compounds offormula Vd may be prepared by reaction of compounds Vld and Vlld as describedin Scheme 9.
Altematively, compounds of formula lld may be prepared by the methodsof Scheme 13. Referring to Scheme 13, alkylation of enolate anion of methyl 2-methoxy propanoate with a benzyl halide IXd affords compounds Vllld. C' 13157 . -47-
Compounds Vllld car» be elaborated to compounds lld by e.g. palladium mediatedcoupling reaction. Compounds lld may also be prepared from compounds Xd.Compounds Xd can be prepared from compounds Xlld by a sequence of reactionssuch as (i) palladium mediated coupling reaction to form compounds Xld, and (ii)réduction of the ester to alcohol, and (iii) halide formation to form compounds lld.
Any of the above compounds of formula I and any of the compounds in theschemes 1-13 above can be converted into another analogous compound bystandard Chemical manipulations. These Chemical manipulations are known to thoseskilled in the art and include a) removal of a protecting group by methods outlined inT. W. Greene and P.G.M. Wuts, “Protective Groupe in Organic Synthesis”, SecondEdition, John Wiley and Sons, New York, 1991; b) displacement of a leaving group(halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or alcohol toform a secondary or tertiary amine, thioether or ether, respectively; c) treatment ofphenyl (or substituted phenyl) carbamates with primary of secondary amines to formthe corresponding ureas as in Thavonekham, B et. al. Synthesis (1997), 10, p1189;d) réduction of propargyl or homopropargyl alcohols or N-BOC protected primaryamines to the corresponding E-ailylic or E-homoallyiic dérivatives by treatment withsodium bis(2-methoxyethoxy)aluminum hydride (Red-AI) as in Denmark, S. E.;Jones, T. K. J. Org. Chem. (1982) 47, 4595-4597 or van Benthem, R. A. T. M.;Michels, J. J.; Speckamp, W. N. Synlett (1994), 368-370; e) réduction of alkynes tothe corresponding Z-alkene dérivatives by treatment hydrogen gas and a Pd catalystas in Tomassy, B. et. al. Synth, Commun. (1998), 28, p1201 f) treatment of primaryand secondary amines with an isocyanate, acid chloride (or other activatedcarboxylic acid dérivative), alkyl/aryl chloroformate or sulfonyl chloride to provide thecorresponding urea, amide, carbamate or sulfonamide; g) reductive amination of aprimary or secondary amine using R’CH(O); and h) treatment of alcohols with anisocyanate, acid chloride (or other activated carboxylic acid dérivative), alkyl/arylchloroformate or sulfonyl chloride to provide the corresponding carbamate, ester,carbonate or sulfonic acid ester.
The compounds of the présent invention may hâve asymmetric carbonatoms. Diasteromeric mixtures can be separated into their individual diastereomerson the basis of their physical Chemical différences by methods known to those skilledin the art, for example, by chromatography or fractional crystallization. Enantiomèrecan be separated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g., alcohol),separating the diastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers; or by chromatographieséparation using chiral stationary or mobile phase. Ail such isomers, including 1315*7 ? -48- diastereomeric mixtures and pure enantiomers are considered as part of theinvention.
The compounds of formulas (I) thaï are basic in nature are capable offorming a wide variety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable for administration toanimais, it is often désirable in practice to initially isolate the compound of formula (I)from the réaction mixture as a pharmaceutically unacceptable sait and then simplyconvert the iatter back to the free base compound by treatment with an alkalinereagent and subsequentiy convert the Iatter free base to a pharmaceuticallyacceptable acid addition sait. The acid addition salts of the base compounds of thisinvention are readily prepared by treating the base compound with a substantiallyéquivalent amount of the chosen minerai or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or éthanol. Upon carefuiévaporation of the solvent, the desired solid sait is readily obtained. The desired acidsait can also be precipitated from a solution of the free base in an organic solvent byadding to the solution an appropriate minerai or organic acid.
Those compounds of formula (I) that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations. Examples ofsuch salts include the alkalî métal or alkaline-earth métal salts and particularly, thesodium and potassium salts. These salts are ail prepared by conventionaltechniques. The Chemical bases which are used as reagents to préparé thepharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I). Such non-toxic base saltsinclude those derived from such pharmacologically acceptable cations as sodium,potassium calcium and magnésium, etc. These salts can easily be prepared bytreating the corresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferabiy under reduced pressure. Altematively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compounds and thedesired alkali métal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometric quantities ofreagents are preferabiy employed in order to ensure completeness of réaction andmaximum yields of the desired final product.
The compounds of the présent invention are modulators of PPAR, preferabiyPPAR y and a. The compounds of the présent invention can modulate processesmediated by PPAR-γ, which refers to biological, physiological, endocrinological,and other bodily processes which are mediated by receptor or receptorcombinations which are responsive to the PPAR agonists described herein (e.g.,
13157 ; -49-
diabetes, hyperlipidemia, obesity, impaired glucose tolérance, hypertension, fattyliver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts andcoronary artery diseases and the like), arteriosclerosis, pregnancy diabètes,poiycystic ovary syndrome, cardiovascular diseases (e.g. ischémie heart disease 5 and the like), cell injury (e.g. brain injury induced by strokes and the like) inducedby atherosclerosis or ischémie heart disease, goût, inflammatory diseases (e.g.arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acné,sunbum, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmunediseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation 10 of such processes can be accomplished in vitro or in vivo. In vivo modulation canbe carrifed out in a wide range of subjects, such as, for example, humans, rodents,sheep, pigs, cows, and the like.
The compounds of the présent invention may also be useful in the treatmentof other metabolic syndromes associated with impaired glucose utilization and 15 insulin résistance include major late-stage complications of NIDDM, such asdiabetic artgiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy,and diabetic ocular complications such as retinopathy, cataract formation andglaucoma, and many other conditions linked to NIDDM, including dyslipidemiaglucocorticoid induced insulin résistance, dyslipidemia, polycysitic ovarian 20 syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia,hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief définitions oftheseconditions are available in any medical dictionary, for instance, Stedman’s MedicalDictionary (Xth Ed.).
The in vitro activity of the compounds of formula (I) may be determined by 25 the following procedure.
Scintillatian Proximitv Assav (SPA) assavs
In the SPA assay, 3H labeled darglitazone (for PPAR-y) or GW2331 (forPPAR-α) is bound to the PPAR protein captured on SPA polylysine beads andgenerates radioactive count signal that can be detected by TopCounts (Packard). 30 The PPAR-bound 3H labeled ligand can be displaced by an unlabeled compound.The Ki of the compound can be then determined by the extent of displacement atvarious compound concentrations.
Reagents: SPA polylysine beads, which can be purchased from Amersham 35 Bioscience. 3H labeled Darglitazone for PPAR-γ. 3K labeled GW2331 for PPAR-a. PPAR proteins. 13157 -50-
Buffer - PBS, 10% glycerol, 14 mM beta-mercaptoethanol.
The compounds of the présent invention that were tested ail hâve Kis in at least one of the above SPA assays of between 0.3 nWl to 30 μΜ. Certain preferredgroups of compounds possess differential selectivity toward the various PPARs. 5 One group of preferred compounds possesses sélective activity towards PPAR-aover PPAR-y. Another preferred group of compounds possesses sélective activitytowards towards PPAR-γ over PPAR-α. Another preferred group of compoundspossesses sélective activity towards both PPAR-α and PPAR-γ over PPAR-δ.Another preferred group of compounds possesses sélective activity towards PPAR- 10 δ over both PPAR-α and PPAR-γ.
The alpha substituted carboxylic acids compounds of Formula (I) may be provided in suitable topical, oral and parentéral pharmaceutical formulations for usein the treatment of PPAR mediated diseases. The compounds of the présentinvention may be administered orally as tablets or capsules, as oily or aqueous 15 suspensions, lozenges, troches, powders, granules, émulsions, syrups or elixars.The compositions for oral use may include one or more agents for flavoring,sweetening, coloring and preserving in order to produce pharmaceutically élégantand palatabte préparations. Tablets may contain pharmaceutically acceptableexcipients as an aid in the manufacture of such tablets. As is conventional in the art 20 these tablets may be coated with a pharmaceutically acceptable enteric coating,such as glyceryl monostearate or glyceryl distearate, to delay disintegration andabsorption in the gastrointestinal tract to provide a sustained action over a longerperiod.
Formulations for oral use may be in the form of hard gelatin capsules 25 wherein the active ingrédient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. They may also be in the form ofsoft gelatin capsules wherein the active ingrédient is mixed with water or an oilmedium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain active ingrédients in admixture with 30 excipients suitable for the manufacture of an aqueous suspension. Such excipientsmay be a suspending agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia; a dispersing or wetting agent that may be anaturally occuring phosphatide such as lecithin, a condensation product of ethylene 35 oxide and a long Chain fatty acid, for example polyoxyethylene stéarate, acondensation product of ethylene oxide and a long chain aliphatic alcohol such asheptadecaethylenoxycetanol, a condensation product of ethylene oxide and apartial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol
13157 ? -51 -
monooieate or a fatty acid hexito! anhydrides such as polyoxyethylene sorbitanmonooleate.
The pharmaceutical compositions may be in the form of a stérile injectableaqueous or oleagenous suspension. This suspension may be formulated according 5 to know methods using those suitable dispersing or wetting agents and suspendingagents that hâve been mentioned above. The stérile injectable préparation mayalso be formulated as a suspension in a non toxic perenterally-acceptable diluentor solvent, for example as a solution in 1,3-butanediol. Among the accetablevehicles and solvents that may be employed are water, Ringers solution and 10 isotonie sodium chloride solution. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition fatty acids such asoleic acid find use in the préparation of injectables.
The alpha substituted carboxylic acids compounds of Formula (I) may alsobe administered in the form of suppositories for rectal administration of the drug. 15 These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about room température but liquid at rectaltempérature and will therefore melt in the rectum to release the drug. Suchmaterials include cocoa butter and other glycerides.
For topical use préparations, for example, creams, ointments, jellies 20 solutions, or suspensions, containing the compounds of the présent invention areemployed.
The alpha substituted carboxylic acids compounds of Formula (I) may alsobe administered in the form of liposome delivery Systems such as small uniiamellarvesicles, large uniiamellar vesicles and multimellar vesicles. Liposomes can be 25 formed from a variety of phospholipides, such as cholestérol, stearylamine orphosphatidylcholines.
Dosage levels of the compounds of the présent invention are of the orderof about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferreddosage rate is between about 30 mg/kg body weight to about 100 mg/kg body 30 weight. It will be understood, however, that the spécifie dose level for any particularpatient will dépend upon a number of factors including the activity of the particularcompound being administered, the âge, body weight, general health, sex, diet, timeof administration, route of administration, rate of excrétion, drug combination andthe severity of the particular disease undergoing therapy. To enhance the 35 therapeutic activity of the présent compounds they may be administeredconcomitantly with other orally active antidiabetic compounds such as thesulfonylureas, for example, tolbutamide and the like. 13157 . -52-
Wlethods of preparing various pharmaceutical compositions with a spécifieamount of active compound are known, or wi.lt be apparent, to those skilled in this art.For examples, see Reminqton's Pharmaceutical Sciences, Mack PublishingCompany, Easter, Pa., 15th Edition (1975). 5 The examples and préparations provided below further illustrate and exemplify the compounds of the présent invention and methods of preparing suchcompounds. It is to be understood that the scope of the présent invention is notlimited in any way by the scope of the following examples and préparations. In thefollowing examples molécules with a single chiral center, unless otherwise noted, 10 exist as a racemic mixture. Those molécules with two or more chiral centers,unless otherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to those skilled inthe art.
Where HPLC chromatography is referred to in the préparations and 15 examples below, the general conditions used, unless otherwise indicated, are asfollows. The column used is a ZORBAX™ RXC18 column (manufactured byHewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samplesare run on a Hewlett Packard- 1100 systemA gradient solvent method is usedrunning 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent 20 acetonitrile over10 minutes. The system then proceeds on a wash cycle with 100percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3minutes. The flow rate over this period is a constant 3 ml / minute.
In the following examples and préparations, "Et” means ethyl, “AC” meansacetyl, “Me” means methyl, “ETOAC” or "ETOAc" means ethyl acetate, “THF” means 25 tetrahydrofuran, and “Bu” means butyl.
Chiral supercritical fluid chromatography (SFC) conditions.
Single enantiomers of certain racemic compounds were obtained by SFCusing a chiralpak AD-H column at 140 bar and 2.5 mL/min, chiralpak AS-H columnat 140 bar and 2.5 mL/min, chiralpak OJ-H column at 140 bar and 2.5 mL/min. 30 Throughout the following sections, compounds of the general formula below were prepared by procedures analogous to those described in Heterocycles,2001,55(4), 689-703.
OH 13157 . -53-
Example A-1 2-Methyl-2-{{3'-f2-(5-methy|-2-phenyl-1.3-oxazol-4-yl)ethoxv)-1, T-biphenyl-3- yl)oxv)propanoic acid
To a solution of methyl 2-methyl-2-({3'-[2-(5-methyi-2-phenyl-1,3-oxa2ol-4-yi)ethoxy]-1,T-biphenyl-3-yl}oxy)propanoate (0.89 g, 1.76 mmol) in methanol (20mL) was-added water (2.6 mL) and potassium carbonate (0.73 g, 2.0 equiv). Themixture was then heated at reflux for 5 hours and allowed to cool to ambient 10 température. The solution was poured into water, acidified to pH 2 with 1Nhydrochloric acid and extracted with ethyl acetate (3x30 mL). The combinedorganics were washed with saturated aqueous sodium chloride, dried (anhydroussodium sulfate), fiitered and concentrated to dryness to give the title compound asa white crystalline solid (0.6 g, 70%). 15 Elemental Analysis: Calcd for C28H27NO5 C 73.51, H 5.95, N 3.0B. FoundrC 73.26,H 6.08, N 3.06. LRMS: 458 (M+H)+. 1H NMR (CDCI3,400 MHz): 7.97 (2H, dd, J= 3.0, 6.6 Hz), 7.43 (2H, d, J = 2.8 Hz),7.41 (1H, s), 7.31 (2H, t, J = 8.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.17 (1H, d, J =7.6 20 Hz), 7.12 (1H, bs), 6.93 (1H, dd, J = 1.4, 8.2 Hz), 6.87 (1H, dd, J =2.0, 8.1 Hz),4.29 (2H, t, J = 7.7 Hz), 3.07 (2H, t, J = 7.7 Hz), 2.40 (3H, s), 1.63 (6H, s).
Example A-2 2-Methvl-2-I(3'-fi4-(trifiuoromethvl)benzvnoxv)-1.r-biphenvl-3-vl)oxy)propanoic acid
Following the procedure described in Example A-1, starting from methyl 2-methyl·2-[(3'-{(4-(trifluoromethyl)benzyl]oxy}-1,T-biphenyl-3-yl)oxy]propanoate, the titlecompound was produced. LRMS: 431 (M+H)*. 30 Ί Π i C *î 1315/ . -54-
Example Α-3 2-Methvl-2-f(3,-f2-H-(6-methvlpvridazin-3-vl)piperidin-4-vl1ethoxv)-1,1,-biphenvl-3- vDoxvIpropanoic acid
Following the procedure described in Example A-1, starting from methyl 2-methyl-2-[(3’-{2-[1 -(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1 '-biphenyl-3-yl)oxy]propanoate, the title compound was produced as a pale yellow crystallinesolid. LRMS: 477 (M+H)+. 1H NMR (CDCI3, 400 MHz): 7.27 (2H, q, J- 8.1 Hz), 7.20-7.18 (2H, m), 7.12 (1H,bd, J = 7.8 Hz), 7.08-7.06 (2H, m), 6.94-6.93 (1H, m), 6.91-6.90 (1H, m), 6.84 (1H,dd, J= 2.0, 7.8 Hz), 4.25 (2H, bd, J = 13.1 Hz), 4.04 (2H, t. J= 6.1 Hz), 2.88 (2H, t,J = 13.4 Hz), 2.48 (3H, s), 1.80-1.70 (5H, m), 1.65 (6H, s), 1.33-1.27 (2H, m).
Example A-4 1 -(f3'-i2-(5-Methyl-2-phenyl-1,3-oxazol-4-vl)ethoxv)-1,1 '-biphenyl-3- yl)oxv)cvclobutanecarboxylic acid
To a solution of ethyl 1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl}oxy)cyclobutanecarboxylate (0.138 g, 0.278 mmol) in tetrahydrofuran(3 mL) and methanol (1 mL) was added 2M aqueous lithium hydroxide (0.28 mL).The resulting mixture was stirred at ambient température for 16 hours. Water (5mL) and diethyl ether (10 mL) were added and the resulting solution stirred for 10min. The ethereal tayer was removed and the aqueous layer acidified to pH 2 with1N hydrochloric acid at 0 °C and stirred for 20 min. The white precipitate wascollected by filtration and washed with tce-cold water. After drying at 40 °C underhigh vacuum the title compound was afforded as a white crystalline solid (0.091 g,70%).
Elemental Analysis: Calcd for C29H27NO5.O.15UCI C 73.18, H 5.72, N 2.94.Found:C 73.08, H 5.67, N 2.93. LRMS: 471 (M+Hf. ’H NMR (CDCI3, 400 MHz): 8.03-8.00 (2H, m), 7.43 (3H, t, J = 3.3 Hz), 7.30 (2H, t,J = 7.8 Hz), 7.16 (2H, d, J = 6.8 Hz), 7.09 (1H, t, J = 2.3 Hz), 6.91-6.85 (3H, m), 13157 . -55- 4.27 (2H, t, J = 7.8 Hz), 3.06 (3H, t, J = 8.1 Hz), 2.83-2.76 (2H, m), 2.53-2.46 (2H,m), 2.40 (3H, s), 2.06-1.97 (2H, m).
Examples A-5 to A-28 5 Examples A-5 to A-28 were prepared using procedures analogous to thosedescribed for Example A-4.
Ex.# Structure ’hnmr MS (m/z)(LR or HR) Analysis A-5 . CH. Yy 0 fl (CDCIa, 400 MHz) 7.95 (2H, dd,J =2.9,6.7 Hz), 7.38-7.35 (3H,m), 7.29-7.22 (2H, m), 7.13-7.10(3H, m), 7.07(1 H, t, J =2.3 Hz),6.91-6.88 (1H, m), 6.81 (1H, dd,J =1.8, 8.3 Hz), 4.57 (1 H, t, J =6.2 Hz). 4.23 (2H,t. 7 = 7.7 Hz),3.05-2.92 (2H, m), 2.34 (3H. s),2.03-1.96 (2H, m), 1.06 (3H, t, J= 7.5 Hz). for LR458 (M+H)4 Calcd forC28H27NO50.41H20 C 72.34, H6.03, N 3.01.Found:C 72.33, H6.01, N 2.95. A-6 <CHî 0 ΊΪΗ, (DMSO-d6,400 MHz) 7.91 (2H,dd, J= 1.8,7.6 Hz), 7.73(1 H, t,7 = 7.8 Hz), 7.52-7.44 (6H, m),7.25 (1H, t, J =8.0 Hz), 6.83(1H, dd, J =2.0, 8.1 Hz), 6.72(1H, d, J =8.1 Hz), 4.61 (2H, t,7=6.7 Hz), 4.11 (1H, 1,7=6.3Hz), 2.98 (2H,t, J = 6.7 Hz),2.32 (3H, s), 1.84-1.69 (2H, m),0.95 (3H, t, J =7.3 Hz). for LR459 (M+H)4 Calcd for^7H25LiN2O5.2.32H2O C 64.82, H6.17, N 5.60.FoundrC 64.83, H5.B9, N 5.52. A-7 (CDCI3,400 MHz) 8.02-8.00(2H, m), 7.65-7.64 (1H, m), 7.61(1H, m), 7.45-7.42 (3H, m),7.40-7.30 (3H, m), 7.05 (1H,ddd, J= 1.0, 2.5, 7.8 Hz), 6.65(1H, d, J =8.1 Hz), 4.74-4.69(2H, m). 3.10-3.07 (2H, m),2.83-2.76 (2H, m), 2.47-2.38(2H, m), 2.40 (3H, s). 2.09-1.95(2H,m). forLR471 (M+H)4 Calcd forC2bH26N2Os 0.09 LiCl C 70.89, H5.52, N 5.90.Found:C 70.94, H5.65, N 5.93. A-8 fbv’· _ .. ___^O^N._AfcJ*s,sXxOH Xo 0 CH, (CDCI3,400 MHz) 8.11 (1H, dd,J =1.5, 2.5 Hz), 8.00-7.97 (2H,m), 7.62 (1 H, t, 7= 7.6 Hz),7.46-7.41 (4H, m), 7.35 (1H, d,7 = 7.3 Hz), 7.31 (1H, t,7=7.8Hz), 7.00 (1H. ddd, J =1.0, 2.8,8.1 Hz), 6.65(1 H, d, J =8.3Hz), 4.74-4.69 (2H, m). 3.16-3.12 (2H, m), 2.41 (3H, S), 1.63(6H, s). for LR459 (M+H)4 A-9 r^î^V4· (CDCI3i 400 MHz) 8.63 (1H, bs)8.13(1H,bs), 8.06 (1H, dd, 7 =1.3, 2.5 Hz), 7.99-7.96 (2H, m),7.52 (1H, d, J =7.8 Hz), 7.46-7.42 (3H, m), 7.35 (1H, t, J =7.8 Hz), 7.04(1 H, dd, J =2.3,8.1 Hz), 4.72-4.68 (2H, m), for LR460 (M+H)4 Calcd forC26H2sN3O50.47H2O C 66.73, H5.59, N 8.98.FoundrC 66.69, H5.48, N 8.96. 1 3157 . -56- 3.16-3.12 (2H, m), 2.43 (3H, s),1.63 (6H, s). A-10 xLOj^y1*1 -'"cA* o Ή NMR (400 MHz, CDCfe) 1.91-2.02 (m, 2 H), 2.24 - 2.31 (m, 3 H), 2.38 - 2.49 (m, 2 H), 2.75 (td, 2 H), 2.86 (t, 2 H), 4.04 (t, 2 H), 6.58 (dd, 1 H), 6.75 -6.86 (m, 3 H), 7.04 (d,.1 H),7.16-7.22 (m, 2 H), 7.30 - 7.38(m, 3 H), 7.90 (dd, 2 H). LRMS(m/z): 470(M+H)\ A-11 JL. /*\ ,O. .Xï*. >-Ls JL JL -OH 0 Ή NMR (400 MHz, CDCI3) : 1.83-2.05(m, 2H), 2.51 (s, 3H). 2.50-2.2.58(m, 2H), 2.75-2.83(m, 2H), 5.02(s, 2H), 6.52(m, 1H), 6.96-7. 56(m,9H),7.73-7.86(m, 2H). A-12 cA /\ ^0\. -'-K >L. JL JL -CH "Z· γ '«γ'' ο Ύ L-J ° ’H NMR (400 MHz, CDCI3) : 1.97-2.07 (m, 2H), 2.13-2.23 (m, 2 H), 2.29 (s, 3 H), 2.45 - 2.54 (m, 2 H), 2.70 - 2.81 (m, 4H), 4.21 (q, 2 H), 6.63-6.65 (m, 1 H), 7.07 - 7.18 (m, 2 H) 7.24 -7.34 (m, 4 H) 7.37 - 7.45 (m. 4H) 7.98 (dd, 2 H). LRMS(m/z): 484.5(M+H)*. A-13 jri o> “ H M e II X^J o ’H NMR (400 MHz, CDCI3) : 1.61 (s, 6 H), 2.35 (s, 3 H), 2.78- 2.89 (m, 4 H), 4.23 - 4.31 (m, 2H), 6.77 (d,2H), 7.15 (d, 4 H),7.36 - 7.45 (m, 4 H), 7.97 (dd, 2H). LRMS(m/z): 473.5(M-t-Hf A-14 LK o -o. z>s xLs. JL JL Tfi 0 H XjÿJ O Ή NMR (400 MHz, CDCI3) : 1.99-2.11 (m, 2 H), 2.51 (dq,2H), 2.77 - 2.85 (m, 2 H), 5.25 (s.2 H), 6.65-6.72 (m, 2 H), 6.94-6.99 (m, 2 H), 7.15-7.22 (m, 2H), 7.35 (t, 2 H), 7.42 - 7.51 (m,2 H), 7.60 (dd, 4 H) LRMS(m/z): 443.0(M+H)+. A-15 Λ». Λ JL SL χΌ« V^° î ’H NMR (400 MHz, CDCI3) : 1.98-2.08 (m, 2 H), 2.45 - 2.55(m, 2 H), 2.74 - 2.83 (m, 2 H),5.18 (s, 2 H), 6.91 -6.98 (m, 1H) 7.13-7.21 (m, 2 H) 7.26-7.37 (m, 5 H), 7.56 - 7.63 (m, 2H), 7.69 (d, 2 H). LRMS(m/z): 423(M+Hf. A-16 ’H NMR (400 MHz, CDCI3) : 1.96-2.07 (m,2H),2.48-2.51(m,2H), 2.73-2.82 (m, 2H), 4.31 - 4.40 (m, 4 H), 6.63(dd, 1 H), 6.92 - 7.00 (m, 5 H),7.13-7.21 (m, 3 H), 7.25 - 7.36(m, 4 H) LRMS(m/z): 423(M+H)\ 13157 . -57- A-17 Ή NMR (400 MHz, CDCI3) :1.96 - 2.07 (m, 2 H), 2.44 - 2.55(m, 2 H), 2.74 - 2.82 (m, 2 H),3.89 (s, 1 H), 5.25 - 5.31 (s, 2 H), 6.63-6.65 (m, 1 H), 7.00-7.10 (m, 4 H), 7.17 (t, 2 H), 7.23-7.31 (m,4H), 8.12 (d, 2 H). LRMS(m/z): 473.5(M+H)+. A-18 i /X-^Û σ” tr c s Ή NMR (400 MHz, CDCI3) : 2.02-2.14 (m,2H) 2.44-2.54(m, 5H) 2.75-2.86 (m, 2 H)5.26 (s, 2 H) 6.95-7.05 (m, 1H) 7.16-7.23 (m, 2H) 7.25- 7.36 (m, 6 H) 7.46 (t, 2H) 8.02, (d,2H). . LRMS(m/z): 456.5(M+H)+. A-19 XÎ Xe* u^° s 'H NMR (400 MHz, CDCI3) : 1.96-2.07 (m,2H), 2.44-2.54 (m, 5 H), 2.74 - 2.82 (m, 2 H),5.25 (s, 2 H), 6.96 - 7.04 (m, 1H), 7.16 (d, 2 H), 7.22-7.28 (m,2 H), 7.32 (td, 4 H), 7.42-7.49(m, 2 H), 7.99 - 8.05 (m, 2 H) LRMS(m/z): 456.1(M+Hf. A-20 Ck_/^ "V “'•e/X CVxJLTXo “ ’H NMR (400 MHz, CDCi3) : 1.97 - 2.07 (m, 2 H), 2.52 (s, 3H), 2.64 - 2.65 (m, 2 H), 2.74 -2.82 (m, 2 H), 4.89 (s, 2H),6.68-6.70 (m, 1H), 6.83-6.85 (m,2H), 7.24 - 7.30 (m, 3 H) 7.41 -7.47 (m, 3 H), 7.58-7,62(m, 2H),7.66-7.68(m, 2H). LRMS(m/z): 456.2(M+Hf A-21 CHX y=s n'"s^x*'·F o'O'-Q^'w ’H NMR (400 MHz, CDCI3) 1.56 -1.65 (m, 6 H), 2.43 (s, 3H), 3.09 (t, 2 H), 4.33 (t, 2 H),6.86-6.96 (m,2H), 7.11-7.19(m, 2 H), 7.20 - 7.26 (m,4H),7.32 (t, 2 H), 7.41 (td, 1 H), 7.70(ddd, 1 H) 7.81 (d, 1 H). LRMS(zn/z): 476(M+Hf. A-22 bvc r ΓΊ ? 'ο·^χγ<!:γο^ς·οΗ Ή NMR (400 MHz, CDCI3)1.64 (s, 6 H), 2.41 (s, 3 H), 3.06(t, 2 H), 4.31 (t, 2H), 6.88 (dd, 3H), 7.04-7.13 (m, 1 H), 7.14 -7.23 (m, 2 H), 7.23 - 7.34 (m, 3H), 7.52 (dd, 2 H). LRMS(m/zy. 494(M+Hf. A-23 U " JL. >C ja* •y' o >r L^ ° Ή NMR (400 MHz, CDCI3) : 1.71 (s, 6 H), 2.10-2.22 (m, 2 H), 2.35 (s, 3 H), 2.67 - 2.77 (m,2 H), 3.99-4.09 (m,2H),6.67-6.69(m, 2H), 7.04 - 7.13 (m, 2H) 7.20 - 7.32 (m, 4 H) 7.37 -7.44 (m, 2 H) 7.92 - 8.02 (m,3H). LRMS(zn/z): 472.5(M+Hf A-24 rC_ Xr^°V Ή NMR (400 MHz, CDCI3) :1.76 (s, 6 H), 2.49 (S, 3 H),5.16(s,2H), 7.07 - 7.19 (m, 2H), 7.23 (t, 1 H), 7.32 (td, 4 H),7.36 - 7.47 (m, 4 H), 7.98 (dd, 2ÈÜ LRMS(m/zy. 444.£(M+H)+ 13157 ; -58- A-25 Ο0Ω XX _ o a ’H NMR (400 MHz, CDCI3)1.58 (s, 6 H), 3.35 (t, 2 H), 3.99(s, 3 H), 4.40 (t, 2 H), 6.80 (d, 1H), 6.81 (dd, 1 H), 7.00 (d, 1 H),7.11 -7.20 (m, 3 H), 7.25 (m, 2H), 7.33 - 7.38 (m, 3 H), 7.92 -8.00 (m,2H). LRMS(m/z): 458(M+H)+. A-26 fY-N-V jQ o î Ή NMR (400 MHz, CDCI3) 1.56 (s, 6 H), 2.31 (s, 3 H), 3.11(t, 2 H), 4.25 (t, 2 H), 6.81 (m, 2H), 6.96 (s, 1 H), 7.06 (m, 2 H),7.20 (m, 4 H), 7.30 (t, 2 H), 7.82(d, 2 H). LRMS(m/z)·. 458 (M+Hf. A-27 Π ° Qpo'— ’H NMR (400 MHz, CDCI3) 1.62 (s, 6 H), 2.07-2.15 (m, 2 H), 3.60-3.71 (m, 2 H), 4.13 (q, 2 H), 4.53 (s, 2 H), 6.83-6.93 (m, 2 H), 7.01 - 7.09 (m, 1 H), 7.12 (d, 1 H), 7.14-7.20 (m, 1H), 7.30 (ddd, 8 H). LRMS(m/z): 421(M+H)\ A-28 ’H NMR (400 MHz, CDCI3) : 1.18 (t. 3 H), 2.43 (s, 3 H), 2.96 - 3.08 (m, 4 H), 3.32-3.35(m,2H), 3.62-3.65(m, 1 H), 4.24-4.33 (m, 2 H), 7.07-7.19 (m, 2H), 7.23 (t, 1 H), 7.32 (td, 4 H),7.36 - 7.47 (m, 4 H), 7.98 (dd, 2ΗΣ LRMS(m/z): 472.5(M+Hf.
Preparations of Startinq Materials for Examples A-1 to A-28 (Préparations a-1 to a- 111 5 Préparation a-1
Methyl 2-(3-iodophenoxv)-2-methylpropanoate
O
To a solution of 3-iodophenol (1.08 g, 4.9 mmol) in W,A/-dimethylformamide (10 mL)was added methyl 2-bromo-2-methyl-propionate (0.76 mL, 1.2 equiv) and césium 10 carbonate (3.45 g, 2 equiv). The resulting mixture was heated at 90 °C for 24 hours and then allowed to cool to ambient température. Water was introduced andthe mixture extracted with diethyl ether (3x20 mL). The combined organics werewashed with water and saturated aqueous sodium chloride, dried (anhydroussodium sulfate), filtered and concentrated. The residue was purified by silica gel 15 chromatography using 0-30% ethyl acetate in hexanes to provide the title compound (0.83 g, 53%). 1 3 157 . -59- LRMS: 321 (M+H)+. 1H NMR (CDCI3, 400 MHz): 7.22 (1H, dt, *7=1.3, 7.8 Hz), 7.12 (1H, dd, J = 1.6,2.4 Hz), 6.84 (1H, t, J = 8.1 Hz), 6.66 (1H, ddd, J = 0.8, 2.5, 8.3 Hz), 3.66 (3H, s),1.47 (6H, s). 5 Préparation a-2
Methvl 2-(3-iodophenoxv)butanoate ,OMe
Following the procedure described in Préparation a-1, using ethyl 2-bromopropionate in place of methyl 2-bromo-2-methyl-propionate at ambient 10 température, the title compound was obtained in 93% yield. LRMS: 321 (M+H)+. ’H NMR (CDCI3, 400 MHz): 7.30 (1H, ddd. J= 1.0,1.5, 7.8 Hz), 7.24 (1H, dd, J =1.6, 2.4 Hz). 6.97 <1 H. dd, J = 7.8, 8.3 Hz), 6.82 (1H, ddd, J= 1.0, 2.5, 8.6 Hz),4.53 (1H, dd, J = 5.8, 6.6 Hz), 3.75 (3H, s), 2.00-1.93 (2H, m), 1.05 (3H, t, J = 7.5 15 Hz).
Préparation a-3
Ethyl 1 -(3-bromophenoxv)cvclobutanecarboxvlate OEt
Following the procedure described in Préparation a-1, using 3-bromophenol and20 ethyl 1-bromocyc!obutanecarboxylate as starting materials and heating in a solution of acetonitrile, the title compound was obtained in 56% yield. LRMS: 300 (M+Hf.
Préparation a-4 4-r2-(3-lodophenoxv)ethvn-5-methvl-2-phenyl-1.3-oxazole
Following the procedure described in Préparation a-1, starting from 3-iodophenoland 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethyl-4-methylbenzenesulfonate atambient température, the title compound was produced in 77% yield as a colorlessoit. 30 LRMS: 406 (M+Hf. 1 3 15*1 .1 -60- 1H NMR (CDCIa, 400 MHz): 7.87 (2H, dd, J = 1.9, 7.7 Hz), 7.34-7.29 (3H, m), 7.15-7.13 (2H, m), 6.86 (1 H, t, J = 8.1 Hz), 6.76-6.73 (1 H, m), 4.10 (2H, t, J = 6.6 Hz),2.85 (2H, t, J = 6.6 Hz), 2.26 (3H, s).
Préparation a-5 2-Bromo-6-f2-(5-methvl-2-phenyl-1,3-oxazol-4-vl)ethoxy)pyridine
To a solution of 2-(5-methyI-2-phenyl-1,3-oxazol-4-yl)-ethanol (1.04 g, 5.1 mmol)and 2,6-dibromopyridine (1.21 g, 5.1 mmol) in anhydrous dioxane (20 mL) at 0 °Cwas added sodium hydride (60% in oil, 0.368 g, 3 equiv). The resulting mixturewas stirred at ambient température for 16 hours. The mixture was poured into ice-cold water and extracted with ethyl acetate (3x50 mL). The combined organicswere washed with saturated aqueous sodium bicarbonate and saturated aqueoussodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Theresidue was purified by silica gel chromatography using 0-50% ethyl acetate inhexanes to afford the title compound as a white crystalline solid (1.19 g, 65%).LRMS: 359 (M+Hf. 1H NMR (CDCIs, 400 MHz): 7.97 (2H, dd, J = 1.8, 7.8 Hz), 7.44-7.35 (4H, m), 7.03(1H, d, J = 7.3 Hz), 6.65 (1H, d, J = 8.1 Hz), 4.55 (2H, t, J = 6.8 Hz), 2.97 (2H, t, J =6.8 Hz), 2.34 (3H, s).
Préparation a-6 2-Chloro-6-f2-(5-methyl-2-phenvl-1,3-oxazol-4-vl)ethoxvlpyrazine
Following the procedure described in Préparation a-5, starting from 2-(5-methyl-2-pheny[-1,3-oxazol-4-yl)-ethanol and 2,6 dichloropyrazine, the title compound wasobtained in 64% yield. LRMS: 316 (M+Hf. ’H NMR (CDCIa, 400 MHz): 8.11 (2H, d, J= 10.4 Hz), 7.97 (2H, dd, J= 1.9, 7.7Hz), 7.44-7.39 (3H, m), 4.60 (2H, t, J - 6.7 Hz), 2.99 (2H, t, J = 6.7 Hz), 2.35 (3H,s)·
Préparation a-7
Methyl 2-f3-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yi)phenoxv)butanoate 13157 t -βί- ο.
oB
OMe
O
To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Préparation a-2)(1.49 g, 4.65 mmol) in dimethylsulfoxide (40 mL) was added potassium acetate(1.37 g, 3 equiv), bis(pinacolato)diboron (1.3 g, 1.1 equiv) and a solution of [1,1’-bis(diphenylphosphino)-ferrocene]dichloropalladium (il) complex (0.152 g, 0.04equiv) in dichloromethane. The resulting mixture was heated at 80 °C for 16 hoursand allowed to cool to ambient température. Water was introduced and the mixtureextracted with diethyl ether (3x30 mL). The combined organics were washed with5% aqueous sodium bicarbonate (2x50 mL) and saturated aqueous sodiumchloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residuewas purified by silica gel chromatography using 0-25% ethyl acetate in hexanes toprovide the title compound (0.92 g, 62%) LRMS: 321 (M+H)+. 1H NMR (CDCI3,400 MHz): 7.40 (1H, d, J = 7.3 Hz), 7.32 (1 H, d, J =2.8 Hz), 7.28(1H, d, J= 8.1 Hz), 6.97 (1H. ddd, J = 1.0, 2.8, 8.1 Hz), 4.64 (1H, t, J = 6.3 Hz),3.73 (3H, s), 2.01-1.94 (2H, m), 1.32 (12H, s). 1.06 (3H, t, J= 7.5 Hz).
Préparation a-8
Methyl 2-methvt-2-r3-(4,4,5,5-tetramethvl-1,3.2-dioxaborolan-2- vDphenoxvlpropanoate OMe
Foilowing the procedure described in Préparation a-7, using methyl 2-(3-iodophenoxy)-2-methylpropanoate (Préparation 1) as starting material, the titlecompound was produced in 75% yield. LRMS: 321 (M+Hf. 1H NMR (CDCIj, 400 MHz): 7.42 (1H, d, J = 7.1 Hz), 7.29 (1H, d, J = 2.8 Hz), 7.22(1H, t, J= 7.8 Hz), 6.90 (1 H, ddd, J = 0.8, 2.8, 8.1 Hz), 3.75 (3H, s), 1.56 (6H, s),1.30 (12H, s).
Préparation a-9
Ethyl 1-f3-(4.4.5,5-tetramethvl-1,3.2-dioxaborolan-2- vQphenoxvlcvclobutanecarboxvlate 13157 . -62-
,o-ch2-ch3
Foliowing the procedure described in Préparation a-7, using ethyl 1-(3-bromophenoxy)cyclobutanecarboxylate (Préparation 3) as starting matériel, the titlecompound was produced in 80% yield. LRMS: 347 (M+H)’.
Préparation a-10
Methvl 2-([3'-(benzyloxv)-1,r-biphenvl-3-vlloxy}-2-methvlpropanoate
To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Préparation a-1)(1.14 g, 3.56 mmol) in benzene (20 mL) was added 3-benzyloxyphenylboronic acid(0.89 g, 1.1 equiv), 2M aqueous sodium carbonate (3.56 mL) andtetrakis(triphenylphosphine) palladium (0) (0.2 g, 0.05 equiv). The resulting mixture heated at reflux for 2 hoursand allowed to cool to ambient température. Water was added and the mixtureextracted with diethyl ether (3x20 mL). The combined organics were washed with5% aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried(anhydrous sodium sulfate) and concentrated. The residue was purified by silicagel chromatography using 0-15% ethyl acetate in hexanes to give the titlecompound as a coioriess oil (1.08 g, 81%). LRMS: 377 (M+H)’. 1H NMR (CDCIa, 400 MHz): 7.47-7.45 (2H, m), 7.39 (2H, t, J= 7.3 Hz), 7.33 (2H, t, J =7.8 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.21 (1H, ddd, J = 1.0, 1.5, 8.1 Hz), 7.17 (1H, dd, J = 1.8, 2.3 Hz), 7.14 (1H, dm,.J= 7.6 Hz), 7.08 (1H, dd, J = 1.8. 2.3 Hz), 6.96(1H, ddd, J = 0.8, 2.5, 8.3 Hz), 6.79 (1H, ddd, J = 1.0, 2.5, 8.1 Hz), 5.11 (2H, s),3.78 (3H, s), 1.62 (6H, s).
Préparation a-11
Methvl 2-methvl-2-(f3'-f2-(5-methvl-2-phenvl-2f7-1.2.3-triazol-4-vhethoxv1biphenyl- 3-yl)oxv)propanoate 13157 -63-
2-(5-Methÿl-2-phenyl-2H-1,2,3-triazol-4-yl)ethanol (51 mg, 0.25 mmol), methyl 2-[(3‘-hydroxybiphenyl-3-yl)oxy)-2-methylpropanoate (86 mg, 0.30 mmol), and Ph3P 5 (98 mg, 0.375 mmol) were dissolved in anhydrous THF (1 mL) and followed by the dropwise addition of dièthyl azodicarboxylate (65 mg, 0.375 mmol) in anhydrousTHF (1 mL) at room température via a syringe. The resulting reaction solution wasstirred at room température for 18 hours and concentrated. Purification by silicagel column with 20 - 40% EtOAc in hèxane afforded 69 mg (59%) of light yellow oil. 10 1H NMR (400 MHz, CDGI3) 1.55 (s, 6 H), 2.31 (s, 3 H), 3.10 (t, 2 H), 3.68 (s, 3 H),4.25 (t, 2 H), 6.70 (m, 1 H), 6.82 (m. 1 H), 7.00 (s, 1 H), 7.05 (d, 1 H), 7.20 (m, 4H), 7.32 (t, 2 H), 7.90 (d. 2 H) LRMS (m/z): 472 (M+H)4.
1 3 157 ; -64-
Example B-1 1-(341((2-(3- (Trifluoromethvl)phenvnethoxv)carbonvl)amino1methvl)phenoxv)cyclobutane carboxylic acid
O O s
To a solution of elhyl 1-(3-{[({2-[3-(trifluoromethyl)phenyl]ethoxy}carbonyl)amino}methyl}phenoxy)cyclobutanecarboxylate (0.150 g, 0.32 mmol) in tetrahydrofuran (3mL) and methanol (0.6 mL) at 0 °C was added 2M aqueous lithium hydroxide (0.32mL, 2 equiv). The resulting mixture was stirred at ambient température for 24 10 hours. Water (10 mL) was added and the mixture was extracted with diethyl ether(1x15 mL. discarded). The aqueous phase was adjusted to pH 2 with 1Nhydrochloric acid and extracted with ethyl acetate (3x20 mL). The combinedorganics were washed with saturated aqueous sodium chloride, dried (anhydroussodium sulfate), filtered and concentrated to dryness to produce the title compound 15 (85%). LRMS: 436 (M+H)+. 1H NMR (CDCI3i 400 MHz): 7.62 (1H, d, J = 7.8 Hz), 7.46 (1H, t. J = 7.3 Hz), 7.36(1H, d, J = 7.3 Hz), 7.31 (1H, dd. J = 6.1, 7.6 Hz), 7.18 (1H, t, J = 8.0 Hz), 6.84(1H, d, J= 7.6 Hz), 6.65 (1H, s), 6.56 (1H, d, J = 7.8 Hz), 4.32-4.27 (4H, m), 3.11 20 (2H, t, J = 6.8 Hz), 2.79-2.72 (2H, m), 2.49-2.41 (2H, m), 2.09-1.93 (2H, m).
Examples B-2 to B-29
Examples B-2 to B-29 were prepared bv procedures analoqous to that used for
Example B-1.
Example # Structure 1H NMR MS (m/z) (LR or HR) B-2 « η r W O O (CDCI3, 400 MHz) 7.62 (1H,d, J= 7.8 Hz), 7.46(1 H, t, J =7.3 Hz), 7.36(1 H, d, J =7.6Hz). 7.31 (1H,t, J =7.6 Hz),7.22 (1H, t, J =7.8 Hz), 6.88(1H, d, J= 7.3 Hz), 6.83 (1H,S), 6.78 (1H, dd, J= 1.9, 8.2Hz), 4.60 (1H, t, J =5.8 Hz),4.36-4.29 (4H, m), 3.11 (2H, t,J= 6.8 Hz), 2.03-1.97 (2H,m), 1.08 (3H, t, J =7.5 Hz). ForLR 426 (M+H)+ 13157 . -65- B-3 *1^ ο o (CDCfe, 400 MHz) 7.62 (1H, d, J =7.8 Hz), 7.46(1 H. t, J = 7.5 Hz), 7.36(1 H, d, J =7.6Hz), 7.31 (1H, t, J =7.6 Hz),7.21 (1H,t, J = 7.6 Hz), 6.94(1H,d, J =7.3 Hz), 6.86 (1H,S), 6.81 (1H,d, J = 7.8 Hz),4.36-4.29 (4H, m), 3.11 (2H, t, J =7.0 Hz), 1.58 (6H, s). forLR 426 (M+Hf B-4 ’H NMR (400 MHz, CDCI3) : 1.69 (s, 6 H), 4.34 (d, 2 H). 5.05-5.17 (m, 1 H), 5.23 (s,2 H), 6.71 (dd, 1 H), 6.78 (s, 1H), 6.90 (d, 1 H), 7.18-7.23(m, 1 H), 7.26-7.33 (m, 1 H). 7.69 (d, 1 H), 7.89 (d, 1 H), 8.73 (s, 1 H). LRMS (zn/z): 426.4(M+H)+. B-5 O^jÇ'Y^V (CDCI3, 400 MHz) 7.98-7.92(2H, m), 7.44-7.38 (3H, m),7.15 (1H, t, J = 7.7 Hz), 6.87(1H. s), 6.84-6.79 (2H, m), 4.33-4.28 (4H, m), 2.89 (2H, t,J = 6.8 Hz), 2.32 (3H, s), 1.60(6H, s). for LR 439 (M+H)* B-6 '®>l ‘H NMR (400 MHz, CDCt3) : 1.58 (d, 6 H), 2.46 (s, 3 H),4.32 (d, 2 H), 5.06 (s, 2 H),6.70-6.72(m, 1H), 6.89-6.91 (m, 1H). 7.23 - 7.28 (m, 2H), 7.39-7.48 (m, 2 H), 7.96-8.05 (m, 2H). LRMS (m/z): 423.5(M+H)+ B-7 ’H NMR (400 MHz, CDCI3) : 1.63 (m, 6 H), 1t95-2.01(m, 2H), 2.34 (s, 3 H), 2.56-2.58(m,2H), 4.11-4.13(m, 2H),4.32-4.35(d, 2H), 4.89-4.92(b,1 H), 6.82-6.83(m, 2H), 7.21 -7.27 (m, 3 H) 7.36-7.44 (m, 2 H), 7.93-7.96(m, 2H). LRMS (m/z): 453.5(M+H)\ B-8 'H NMR (400 MHz, CDCI3) : 1.59 (s, 6 H), 2.47 (s, 3 H),4.24-4.32 (m, 2 H), 4.99-5.09 (m, 3 H), 6.73 - 6.80 (m,2 H), 7.15 (d, 2 H), 7.21 -7.27 (m, 1 H), 7.37 - 7.46 (m,2H), 7.96-8.04 (m, 2 H). LRMS (m/z): 425.5(M+H)+ B-9 σ^^ά-γ Ή NMR (400 MHz, CDCI3) : 1.64 (m, 6 H), 2.35 (s, 3 H),2.82 (t, 2 H), 4.28-4.38 (m, 4H), 6.55 (d, 2 H), 7.17-7.28(m,2H), 7.36 - 7.45 (m,2H) 7.92-8.00 (m,2H) LRMS (m/z): 457.5(M+Hf. 13157 -66- B-10 ηΗ NMR (400 MHz. CDCI3) :1.67 (s, 6 H), 4.33 (d, 2 H),5.03-5.14 (m, 3 H). 6.69 (dd.1 H), 6.78 (s, 1 H), 6.92 (dd, 2H). 7.01 (d, 3 H), 7.06-7.14(m, 2 H), 7.18 (t, 1 H), 7.25-7.36 (m, 3 H). LRMS (m/z): 435.5(M+H)+. B-11 xr-My/- ΊΗ NMR (400 MHz, CDCI3j : 1.05-1.16 (m. 3 H), 2.02- 2.04(m, 2H), 4.11 -4.13 (m, 1H), 4.48-4.58 (m, 2 H), 4.95-5.96(m, 1H), 5.11 (s. 2 H),5.21(s, 2H), 6.75 (d, 1 H),6.83-6.93 (m, 2 H), 7.10-7.21 (m, 1 H), 7.30-7.41 (m,6 H), 8.44 (s, 2 H). LRMS (m/z): 451(M+Hf B-12 O 0 (CDCIs, 400 MHz) 8.06-8.00(1H, m), 8.01 (1H, d, J = 7.6Hz), 7.47-7.42 (1H, m), 7.43(1H, d, J=7.8Hz), 7.19(1 H,t, J =7.8 Hz), 6.87 (1H,d, J =7.1 Hz), 6.68 (1H, s), 6.57(1H, dd, J = 2.3, 8.1 Hz), 5.17(2H, s), 4.32 (2H, d, J =6.1Hz), 2.80-2.75 (2H. m), 2.65(3H, s), 2.49-2.41 (2H, m),2.03-1.97 (2H, m). for LR 426 (M+H)·* B-13 ’H NMR (400 MHz, CDCI3) 0.85-0.95 (m, 3 H), 1.82 (s,2 H), 2.13 (s, 3 H), 2.62-2.73 (m, 2 H), 3.85 (d, 1 H), 3.91 (S, 1 H), 4.30-4.41 (m,2 H), 4.99 (s, 1 H), 6.58 (d, 1H), 6.66 (s, 2 H), 6.94-7.06(m, 2 H), 7.22 (s, 3 H), 7.70 -7.81 (m, 2 H). LRMS (m/z): 439(M+Hf. B-14 Ck'°Z '^o' 'H NMR (400 MHz, CDCi3) : 1.93-2.01 (m, 2 H), 2.46 (s,3 H), 4.34 (d, 2 H), 4.56-4.57(m, 1H), 5.06 (s, 3 H),6.74-6.76(m, 1H), 6.82-6.84(m, 1 H), 6.89-6.91 (m, 1 H), 7.19-7.28 (m, 2 H), 7.41-7.46 (m, 2H), 7.98-8.04 (m, 2 H) LRMS (m/z): 425.5(M+Hf B-15 forLR 451 (M+Hf -67- B-16 0 o <CDCI3, 400 MHz) 7.96-7.94(2H, m), 7.42-7:40 (3H. m), 7.19 (1 H, t, J =7.7 Hz). 6.79(2H,d, J = 7.6 Hz), 6.60 (1 H.s), 4.32 (1H,d, J = 6.1 Hz), 4.20 (2H, s), 2.81-2.75 (2H,m). 2.62-2.59 (1H, m), 2.49-2.41 (3H, m), 2.32-2.28 (2H, m), 2.08 (3H, s), 2.00-1.92(3H, m). for LR 465 (M+H)+ B-17 ’H NMR (400 MHz, CDCI3) : 1.94 - 2.05 (m,2H), 2.38-2.48 (m, 5 H), 2.68 - 2.76 (m.2 H), 4.31 (d, 2 H), 5.06 (s, 3H), 6.52-6.53(m, 1H), 6.65-6.67(m, 1H), 6.83-6.85(m,1H),7.16-7.17(m, 1H),7.41 -7.46 (m, 3 H) ,7.99-8.03 (m,2 H). LRMS (m/z): 411.4(M+H)+ B-18 O 0 for LR 453 (M+H)‘ B-19 0 0 forLR 453 (M+H)+ B-20 Ctû<Xx«jClov oHo J ’H NMR (400 MHz, CDCfe) 1.51 (s, 6 H), 4.02 (d, 2 H), 5.12 (s, 1 H), 6.72-6.80 (m, 2 H), 6.89-6.96 (m. 2 H),6.96 - 7.02 (m, 2 H), 7.09 (t, 1H), 7.29 (s, 2 H), 7.31 - 7.39(m,2H), 7.64-7.73 (m, 2 H). LRMS (m/z): 442(M+H)+. B-21 Ή NMR (400 MHz, CDCI3) : 1.62 (s, 6 H), 2.30 (s, 3 H),2.69-2.71 (m, 2H), 3.49-3.58(m, 2 H), 5.05 (s, 2 H), 5.36- 5.38(m, 1H), 6.73-6.75(m,1H), 6.97-6.99(m, 1 H), 7.19-7.28 (m,3H), 7.38-7.48 (m,1 H), 7.96-7.98 (m, 2H) LRMS (m/z):439.5(M+H)\ B-22 ’H NMR (400 MHz, CDCI3) : 1.19 - 1.26 (m, 3 H), 2.46 (s, 3 H), 2.93 - 3.02 (m, 2 H),3.26-3.29 (m, 2H), 3.99-4.01(m, 1H), 4.36 (d, 2 H), 5.06 (s, 3 H), 7.15 (m, 3 H),7.40-7.47 (m,3H), 7.98- LRMS (m/z): 439.5 (M+Hf. 1 3 157 ; -68- 8.04 (m, 2 H). B-23 J 'H NMR (400 MHz, CDCI3) : 1.21-1.27 (m, 3 H), 1.97-2.06 (m, 2 H), 2.34 (s, 3 H),2.57 (t, 2 H), 2.95 - 3.03 (m, 2H). 3.34-3.59(m, 2H),4.11 -4.20 (m, 4 H), 4.35 (d, 2 H),4.96-4.98(m, 1H), 7.11 -7.18(m, 3 H), 7.21-7.27 (m, 3 H),7.37-7.45 (m, 2H), 7.93-7.99 (m, 2 H). LRMS (m/z): 467.5(M+H)+ B-24 cr''' [j (T ··, Y NMR (400 MHz..CDCI3) : 1.26-1.28 (m, 3 H), 2.35 (s, 3 H), 2.86-2.88(m, 2H),2.95-3.06 (m, 1 H), 3.47-3.52(m,2H), 4.18-4.20 (m, 2 H),4.29 - 4.40 (m. 4 H), 4.96-4.99(m, 1H), 7.10-7.18 (m, 2H), 7.19-7.28 (m, 3 H), 7.35- 7.46 (m, 2 H), 7.92-7.99(m, 2 H). LRMS (m/z): 453.5(M+Hf. B-25 θΑ^^°γιι'"^^'ο'^Υ“ Ή NMR (400 MHz, CDCI3) : 1.07 (t, 3 H), 1.94-2.05 (m, 3H), 2.17 (s, 3 H), 2.57 (t, 2 H),4.15 (t, 1 H), 4.17(d, 2H), 4.33(d, 2 H), 4.58(m, 1H), 6.83(m,1H),6.89(m, 1H), 6.95(m,1H), 7.21 - 7.27 (m, 3 H),7.37 - 7.44 (m, 2 H), 7.94-7.99 (m, 1 H). LRMS (m/ï): 453.5(M+Hf B-26 1H NMR (400 MHz, CDCI3) :1.65 (s, 6 H), 2.88 (d, 2 H),3.46 (s, 2 H), 5.03 (d, 3 H),6.73 (s, 1 H), 6.83 (d, 1 H),6.89-7.00 (m, 1 H), 7.19-7.31 (m, 3 H), 7.55 (t, 2 H) LRMS (m/z): 426.4(M+Hf. B-27 ΎΜ^Ο^°γ"'^'°Α'°κ Ο 0 ICI3) : 1.07 (t, 3H), 1.98 (dq, 2 3 (S, 2 H), 4.57-4 59(m, 1H), (s, 2 H), 6.83(m, 1H),6.89(m,(t, 1 H), 7.48 (d, 2 H). 8.06 (d,2 H). LRMS (m/z): 426.5(M+Hf. B-28 cmY^-Y ’H NMR (400 MHz, CDCI3) : 1.21 (m, 3 H), 1.57 (s, 6 H),2.63-2.84 (m, 2H), 4.22 (d, 2H), 4.83-4.85(b, 1H), 5.23-5.25(m, 1H), 6.84-6.87(m,3H),7.13(dt,2H)7.18 7.23(m, 4 H). LRMS (m/z): 372.4(M+Hf.
13157 -69-
Ή NMR (400 MHz, CDCI3) : 1.78 (s, 6 H), 2.66 (s, 3H), 4.34 (d, 2 H), 4.85-4.87(b, 1H), 5.05-5.06(s, 2H), 6.53- LRMS (m/z): 426.56.54(m, 1H). 6.67-6.69(m, (M+H)+. 1H),6.83-6.85(m, 1 H), 7.13(dt, 1 H) 7.18-7.23 (m, 2 H), 7.95-7.97(m, 2H),
Préparations of startinq materials for Examples B-1 to B-29 (Préparations b-1 to b- 20}
Préparation b-1
Methvl 2-(3-cvanophenoxv)-2-methylpropanoate NC/ OMe
To a solution of 3-cyanophenol (5 mmoi) in acetonitrile (20 mL) or any polar,aprotic solvent such as dimethyl sulfoxide, W,/V-dimethylformamide, etc) was addedmethyl 2-bromo-2-methyl-propanoate (1.2 equiv) and césium carbonate (2 equiv). 10 The resulting was mixture heated at 60 °C fot 6 hours and then cooled to ambienttempérature. Water (20 mL) was introduced and the mixture extracted with ethylacetate (3x20 mL). The combined organics were washed with saturated aqueoussodium bicarbonate and saturated aqueous sodium chloride, dried (anhydroussodium sulfate), filtered, and evaporated to dryness to provide the title compound 15 in75%yield. LRMS: 220 (M+H)*. 1H NMR (CDCIa, 400 MHz): 7.30 (1H, t, J = 8.0 Hz), 7.23 (1H, dt, J = 1.3, 7.6 Hz),7.05 (1H, dd, J = 1.3, 2.3 Hz), 7.01 (1H, ddd, J = 2.3, 2.8, 8.3 Hz), 373 (3H, s),1.57 (6H, s). 20 Préparations b-2 to b-3
Préparations b-2 to b-3 were prepared usinq procedures analoqous to those described for préparation b-1
Préparation # Structure 1H NMR MS (m/z) (LR or HR) 2 O (CDCb, 400 MHz) 7.33 (1 H, dd, J =7.6, 8.8 Hz), 7.22(1 H, dt, J= 1.3,7.6 Hz), 7.09-7.06 (2H, m), 4.56(1H, dd, J~ 5.6, 6.6 Hz), 3.73 (3H,s), 2.01-1.93 (2H, m), 1.03 (3H, t, J= 7.5 Hz). For LR 220 (M+H)* 13157 · -70 — 3 O (CDCIa, 400 MHz) 7.31 (1 H, dd, J =7.6, 9.1 Hz), 7.22(1 H, dt, J =1.0,7.8 Hz), 6.91-6.88 (2H, m), 4.20(2H, q, J= 7.2 Hz), 2.78-2.71 (2H,m), 2.48-2.40 (2H, m), 2.08-1.96(2H, m), 1.18 (3H, t, J =7.2 Hz). For LR 246 (M+Hf
Préparation b-4
Methyl 2-f3-(aminomethvl)phenoxv1-2-methvlpropanoate
5 To a solution of methyl 2-(3-cyanophenoxy)-2-methylpropanoate (Préparation b-1) (4 mmol) in methanol (20 mL) was added 10% palladium on carbon (20% byweight). The resulting mixture was stirred under an atmosphère of hydrogen for 24hours and filtered through Celite. The filtrate was concentrated and the residuetaken up in ethyl acetate and washed with 1N hydrochloric acid (2x20 mL). The 10 combined aqueous washes were adjusted to pH >10 with 4N aqueous sodiumhydroxide and extracted with dichloromethane (3x20 mL). The combined organicextracts were washed with saturated aqueous sodium chloride, dried (potassiumcarbonate), filtered and concentrated to dryness to provide the title compound in65% yield. 15 LRMS: 224 (M+H)+.
Préparations b-5 to b-6
Préparations b-5 to b-6 were prepared usinq procedures analoqous to those described for préparation b-4 l
Préparation # Structure 1H NMR MS (m/z) (LR or HR) b-5 A A O (CDCI3l 400 MHz) 7.22 (1H, t, J =7.8 Hz), 6.91 (1H. d, J =7.6 Hz),6.86 (1 H, S), 6.72 (1 H, dd, J = 2.5,8.1 Hz), 4.58 (1 H, t, J = 6.2 Hz),3.82 (2H, s), 3.74 (3H, s), 2.01-1.94(2H. m), 1.06 (3H, t, J =7.6 Hz). ForLR 224 (M+Hf b-6 H2N O for LR 250 (M+H)+ -71-
Preparation b-7 2-(5-Methyl-2-phenvl-1.3-oxazoi-4-vriethyi 1 H-imidazole-1 -carboxylate
5 To a solution of 2-(5-methyl-2-phenyi-1,3-oxazol-4-yl)-ethanol (1.015 g, 5 mmol) intoluene (25 mL) was added potassium carbonate (1.38 g, 2 equiv) and N,N’~carbonyldiimidazole (0.97 g, 1.2 equiv). The resulting mixture was stirred atambient température for 24 hours before water (20 mL) was introduced. Extractionwith ethyl acetate and washing the combined organic extracts with saturated 10 aqueous sodium chloride, drying (anhydrous sodium sulfate), filtration, andconcentration to dryness afforded the title compound (100%). LRMS: 298 (M-t-H)+. 1H NMR (CDCIj, 400 MHz): 8.10 (1H, s), 7.97-7.93 (2H, m), 7.44-7.39 (5H, m),4.68 (2H, t, J = 6.7 Hz), 2.98 (2H, t, J- 6.7 Hz), 2.34 (3H, s).
Préparations b-8 to b-10 20 Préparations b-8 to b-10 were prepared usinq procedures analoqous to those described for préparation b-7
Prep# Structure ’H NMR MS (m/z) (LR or HR) b-8 o (CDCI3, 400 MHz) 8.10 (1H, s), 7.68 (1H,d, J = 7.6 Hz), 7.52 (1H, t, J= 7.6 Hz),7.40 (1H, s), 7.38 (1H, s), 7.24 (1H, t, J =7.3 Hz). 7.17-7.13 (1H, m), 4.63 (2H, t, J= 6.8 Hz), 3.29 (2H, t, J =6.8 Hz). ForLR 285 (M+H)* b-9 O-N " -Vu n O (CDCIj, 400 MHz) 8.49 (1H, bs), 8.13(2H. d, J= 8.3 Hz), 7.57 (1H, s), 7.54(2H, s), 7.26-7.24 (1H, m), 5.52 (2H, s), 2.66 (3H, s). for LR 285 (M+H)+ b-10 l· for LR312(M+H)+ 13157 -72-
O
Préparation b-11
Methvl 2-methyl-2-<3-ff(f2-(5-methvl-2-phenvl-1,3-oxazol-4- vl)ethoxv1carbonvl)amino)methyn phenoxvlpropanoate
10 15
To a solution of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl 1W-imidazole-1-carboxyfate (Préparation 7) (0.48 g, 1.6 mmol) in tetrahydrofuran (3 mL) was addedmethyl 2-[3-{aminomethyl)phenoxy]-2-nnethylpropanoate (Préparation b-4) (0.39 g,1.1 equiv). The resulting mixture was heated at reflux for 16 hours and then cooledto ambient température. Concentration and purification by silica gelchromatography using 0-50% ethyl acetate in hexanes gave the title compound(0.39 g. 53%). LRMS: 453 (M+H)+. 1H NMR (CDCIj, 400 MHz): 7.96 (2H, dd, J= 1.9,7.7 Hz), 7.44-7.38 (3H, m), 7.16(1 H, t, J = 8.0 Hz), 6.89 (1 H, d, J = 7.3 Hz), 6.77 (1 H, s), 6.67 (1 H, dd, J = 2.3, 8.3Hz), 4.36 (2H, t, J = 6.7 Hz), 4.30 (2H, d, J = 5.8 Hz), 3.75 (3H, s), 2.83 (2H, t, J =6.7 Hz), 2.32 (3H, s), 1.57 (6H, s). 20 Préparations b-12 to b-20
Préparations b-12 to b-20 were prepared using procedures analoqous to those used for Préparation b-11
Préparation # Structure 1H NMR MS (zn/z)(LR or HR) b-12 Ο Ο forLR 440 (M+Hf 13157 : -73- t>-13 0 &amp; (CDCIa, 400 MHz) 7.63 (1H, d, J = 7.8Hz), 7.47 (1 H, t, J= 7.5 Hz), 7.38 (1 H, d, J= 6.3 Hz), 7.34-7.28 (1 H, m), 7.18 (1 H,dd, J=7.6, 8.1 Hz), 6.89 (1H, d, J = 7.3Hz), 6.77 (1H, s), 6.69 (1H, dd, J = 2.3,8.3 Hz), 4.33-4.30 (4H, m), 3.75 (3H, s),3.13 (2H, t, J =7.0 Hz), 1.58 (6H, s). for LR 440 (M+Hf b-14 0 0 (CDCIa, 400 MHz) 7.99 (2H, d, J= 8.1Hz), 7.41 (2H, m), 7.11 (1H,t, J = 8.1 Hz),6.79 (1 H, d, J = 7.6 Hz), 6.60 (1 H, S), 6.46 (1H, dd, J= 2.3, 8.1 Hz), 5.12 (2H. s),4.27 (2H,d, J =6.1 Hz), 4.12 (2H, q, J =7.1 Hz), 2.71-2.60 (2H, m), 2.59 (3H, s),2.42-2.32 (2H, m), 1.98-1.88 (2H, m), 1.09(3H,t, J =7.1 Hz). For LR 440 (M+Hf b-15 (XX^Ÿ'^'Ç" forLR 453 (M+Hf b-16 (CDCIa, 400 MHz) 7.96 (2H, dd, J = 1.9,7.7 Hz), 7.44-7.36 (3H, m), 7.18-7.13 (1H,m), 6.85 (1H, d, J = 7.6 Hz), 6.66 (1H, s),6.50 (1H, dt, J = 1.3, 8.1 Hz), 4.35 (2H, t, J = 7.1 Hz), 4.29 (2H, d, J = 6.1 Hz), 4.11(2H, q, J = 7.1 Hz). 2.83 (2H, t, J = 6.8 Hz), 2.77-2.69 (2H, m), 2.48-2..38 (2H,m),2.32(3H, s), 2.01-1.94 (2H, m), 1.16(3H, t, J-7.2 Hz). For LR 479 (M+H)+ b-17 θ^ιΧΧ-θγΜΟ-ο^θθ 0 0 (CDCIa, 400 MHz) 7.96 (2H, dd, J = 1.8, 7.8 Hz), 7.43-7.38 (3H, m), 7.17 (1H, t, J = 7.8 Hz), 6.85 (1H, d, J = 7.6 Hz), 6.66 (1H, s), 6.50 (1H, dd, J = 2.3, 8.1 Hz), 4.30 (2H, d, J = 5.8 Hz), 4.19 (2H, q, J =7.3 Hz), 4.18-4.08 (2H, t, J = 7.5 Hz),2.77-2.69 (2H, m), 2.56 (2H, t, J = 7.5 Hz), 2.48-2.39 (2H, m), 2.30 (3H, s), 2.02-1.94(4H, m), 1.16 (3H,t, J = 7.1 Hz). For LR 493 (M+H)+ b-18 Û^vJOuÇ- O 0 (CDCIa, 400 MHz) 7.96 (2H, dd, J = 1.8, 7.8 HZ), 7.43-7.38 (3H, m), 7.22 (1H, t, J =8.1 Hz), 6.89 (1H, d. J= 7.8 Hz), 6.82(1H, s), 6.74 (1H, dd, J- 2.2, 8.2 Hz), 4.56 (1H, t. J =6.2 Hz), 4.32 (2H, d, J = 5.8 Hz), 4.14 (2H, t, J = 6.3 Hz), 3.74 (3H,s), 2.56 (2H, t, J = 7.3 Hz), 2.30 (3H, s), 2.03-1.93 (4H, m), 1.06 (3H, t, J = 7.3 Hz) For LR 467 (M+H'f b-19 O 0 (CDCIa, 400 MHz) 7.96 (2H, dd, J= 1.8, 7.8 Hz), 7.43-7.38 (3H, m), 7.18 (1H, t, J = 8.0 Hz), 6.90(1 H, d, J= 7.6 Hz), 6.78 (1H, s), 6.68 (1H, dd, J = 2.2, 8.0 Hz), 4.31 (2H,d, J=6.1 Hz), 4.13 (2H, t, J = 6.1 Hz), 3.75 (3H, s), 2.56 (2H, t, J = 7.3 Hz), 2.30 (3H, s), 2.00 (2H, t, J = 7.1 Hz),1.58 (6H, s). for LR 467 (M+H)+
1 3 1 5774J b-20 0 O (CDCI3,400 MHz) 7.63 (1H, d, J= 7.8Hz), 7.47 (1 H, t. J = 7.6 Hz), 7.38 (1 H, d, J= 7.6 Hz), 7.32 (1H, t, J = 7.7 Hz), 7.16(1H, t, J= 8.0 Hz), 6.83 (1H, d, J= 7.3Hz), 6.65 (1 H, s), 6.51 (1 H, dd, J = 2.3,8.1 Hz), 4.33-4.29 (4H, m), 4.18 (2H, q, J= 7.1 Hz), 3.13 (2H, t, J= 7.0 Hz), 2.76-2.69 (2H, m), 2.47-2.39 (2H, m), 2.01-1.94(2H, m), 1.16 (3H,t, J = 7.1 Hz). For LR412(M+Hf
Préparation of imidazole b-21c 5 To a solution of the alcohol b-21b (1 mmol) in toluene (5 ml) were added N, N"-carbonyldiimidazole (1.05 mmol) and potassium carbonate (1 mmol). The resultingsolution heated at reflux for 3 hr. After cooling to room température, water (20 ml)was added and the mixture extracted with ethyl acetate (3x20 ml). The combinedextracts were washed with brine, dried over sodium sulfate and concentrated in 10 vacuo to provide the acyl imidazole b-21c in quatitative yield.
Préparation of alcohol b-21 b
To a solution of 3-hydroxybenzyl alcohol b-21a (1 mmol) and césium carbonate (1mmol) in acetonitrile (10 ml) was added metbyl 2-bromo-2-methyl propionate (2mmol). The mixture was heated under reflux for 6 hours. After cooling to room 15 température, water (50 ml) was introduced and the mixture extracted with ethylacetate (3x20 ml). Combined organics were washed with brine, dried over sodiumsulfate and evaporated in vacuo. Siiica gel chromatography (SGC) using 10-30%ethyl acetate-hexane gave alcohol b-21b. Yields ranged between 40-85%. 13157 ; -75-
NK2 b-21c
b-Zlg COOMe
Préparation of methvi ester b-21q
Following the procedures described in b-11, methyl ester b-21g was prepared byreacting compound b-21f with compound b-21c in yields ranging from 60 to 90%.Préparation of amine b-21f A solution of the azide b-21e (2 mmol) in ethyl acetate (20 ml) and palladium oncarbon (10% by weight, 50 mg) was treated with hydrogen gas at roomtempérature for 4 hours. Removal of palladium by filtration through a pad of Celiteand concentration produced the amine b-21f in quantitative yield.
Préparation of azideb-21e
To a solution of the tosylate b-21d (1 mmol) in DMF (5 ml) was added sodiumazide (3 mmol). The resulting mixture stirred at room température for 14 hoursbefore water (50 ml) was added. Extraction with ethyl acetate (3x20 ml), washing ofthe combined organics with water, saturated sodium bicarbonate and brine, dryingover sodium sulfate and concentration gave rise to the azide b-21e in 85% yield.
Example C-1 1-f4-f2-(5-methvl-2-phenvl-1,3-oxazol-4-vl)ethoxv1benzvl)cyclohexanecarboxylic acid ΌΗ 0 13157 . -76- 10 15
Triethylsilane (1.03 g, 8.86 mmol) was added to a solution of methyl 1-(hydroxyl{4-(2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]phenyl}methyl)cyclohexanecarboxylate (0.797 g. 1.77 mmol) indichloromethane (5 mL) and trifluoroacetic acid (1 mL) at room température. Theresulting mixture was stirred for 1 hourthen evaporated in vacuo and azeotropedwith heptane. The residue was dissolved in tetrahydrofuran (3 mL) and water (3mL) and lithium hydroxide monohydrate (0.223 g, 5.31 mmol) was added. Theresulting mixture was stirred at room température for 18 hours, acidified to pH 2with 4N hydrochloric acid and extracted with ethyl acetate. The organic phase wasdried (anhydrous magnésium sulfate), filtered and evaporated to afford the titlecompound (0.332 g, 45%).
Elemental Analysis: Calcd for CæHïgNCL C 74.44, H 6.97, N 3.34. Found:C 74.22, H 6.89, N 3.34. LRMS: 420 (M+Hf. 1H NMR (DMSO-d6, 400 MHz): 7.90 (2H, dd. J= 1.8, 7.8 Hz), 7.51-7.46 (3H, m),6.98 (2H, d, J= 8.6 Hz), 6.80 (2H, d, J= 8.6 Hz), 4.16 (2H, t, J = 6.6 Hz), 2.90 (2H,t. J = 6.6 Hz), 2.64 (2H, s), 2.34 (3H, s), 1.85 (2H, d, J = 12.6 Hz), 1.53-1.46 (3H,m), 1.29-1.11 (5H, m).
Examples C-2 to C-5
Examples C-2 to C-5 were prepared by procedures analoqous to those used for
Example C-1 with the exception that the final hydrolysis step was carried out bv dissolving the crude residue in dimethvl sulfoxide (75 mq/mL) and 6N sodium hydroxide (1 mL) and heatinq at 150 °Cfor 10 minutes in a microwave svnthesizer. 20 13157 -77-
Ex# Structure 1H NMR MS (m/z)(LR or HR) Analysis C-2 (DMSO-ds, 400 MHz) 7.90(2H, dd, J= 1.9, 7.7 Hz), 7.51-7.44 (3H.m), 7.04 (2H, d, J =8.6 Hz), 6.80 (2H, d, J = 8.6Hz), 4.15 (2H,t, J =6.7 Hz),2.90 (2H,t, J =6.6 Hz), 2.79(2H, s), 2.34 (3H, s), 2.05-2.00 (2H, m), 1.75-1.60 (6H, m). for LR406 (M+H)+ Calcd for C25H27NLC 74.05, H 6.71, N 3.45. Found: C 73.3H 6.69, N 3.36. C-3 O (DMSO-dB, 400 MHz) 7.89(2H, dd, J =1.8, 7.8 Hz), 7.51-7.46 (3H, m), 7.04 (2H, d, J =8.6 Hz), 6.81 (2H,d, J =8.6Hz), 3.93 (2H, t, J = 6.2 Hz),2.79 (2H, s), 2.60 (2H, t, J = 7.3 Hz), 2.27 (3H, s), 2.04- 1.97 (2H, m), 1.92-1.85 (2H,m), 1.61-1.46 (6H,m). for LR420 (M+H)+ Calcd forC26H29NO4 C74.44, H 6.97, N3.34. Found: C74.30, H 6.95, N3.26. C-4 0 (DMSO-de, 400 MHz) 7.94- 7.92 (2H, m), 7.54-7.48 (3H,m), 7.04 (2H, d, J =8.6 Hz), 6.92 (2H,d, J = 8.6 Hz), 4.95(2H, s), 3.75-3.70 (2H, m),3.28 (2H, dd, J= 10.0,11.2 Hz), 2.73 (2H, s), 2.43 (3H, S),1.81 (2H,d, J =13.1 Hz). 1.49-1.42 (2H, m). for LR 408(M+H)+ Calcd for^HæNOsC70.75, H 6.18, N3.44. Found: C70.60, H 6.33, N3.31. C-5 (DMSO-de, 400 MHz) 7.90(2H, dd, J =1.9,7.7 Hz), 7.51-7.44 (3H,m), 6.99 (2H,d, J =8.6 Hz), 6.81 (2H,d, J=8.6Hz), 4.16 (2H, t, J =6.6 Hz),3.74-3.69 (2H, m), 3.27 (2H, t,J= 10.6 Hz), 2.90 (2H, t, J =6.4 Hz), 2.71 (2H, s), 2.34 (3H,S), 1.79 (2H, d, J= 13.1 HZ),1.47-1.39 (2H,m). forLR122 (M+H)* Calcd forCz5H27NO5 C71.24, H 6.46, N3.32. Found: C71.01, H 6.47, N3.32.
Example C-6 1-f4-f2-f4'-methoxv-1,r-biphenvl-4-vl)ethoxvlbenzvOcvclobutanecarboxylic acid
5 To a solution of ethyl 1-{4-[2-(4'-methoxy-1,T-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylate (Préparation 14) (0.3921 mmol, 1 equiv.) in acetonitrile (2mL) was added 1N aqueous sodium hydroxide (7.2 mL, 8 equiv.). The resultingmixture was subjected to microwave heating (100 °C) in a Personal ChemistrySmith Synthesizer for 40 minutes. Following cooling of the reaction mixture, 1M 13157 ; -78- aqueous hydrochloric acid was added until pH 1 was achieved. The mixture wasextracted with ethyl acetate (3x50 mL). The combined organic extracts were thenwashed with saturated aqueous sodium chloride (100 mL), dried (anhydrousmagnésium sulfate), Filtered and concentrated in vacuo to afford the crude product. 5 The residue was purified by trituration from diethyl ether to afford the titlecompound as a white crystalline solid (0.1321 g, 81%).
Elemental Analysis: Calcd for C27H2eO4 C 77.86, H 6.78. Found:C 77.65, H 6.85.LRMS (m/z): 416 (M)'. 1H NMR (Acetone-d6, 300 MHz): 7.53 (2H, d, J = 6.1 Hz), 7.66 (2H, d, J = 5.1 Hz), 10 7.46 (2H, d. J = 8.5 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.7 Hz), 6.85 (2H, d, J = 8.5 Hz), 4.20 (1H, t, J = 6.1 Hz), 3.86 (3H, s), 3.10 (2H, t, J = 7.0 Hz),3.00 (2H, s), 2.40-2.30 (2H, m), 2.07-1.98 (2H, m), 1.92-1.80 (2H, m).
Examples C-7 to C-93
Examples C-7 to C-93 were preoared by procedures analooous to those used for 15 Example C-6 or by stirrinq a solution of the ester with sodium or lithium hvdroxide in aqueous methanol, aqueous éthanol, aqueous tetrahydrofuran or mixtures
thereof at températures between 20 °C and 75°C,
Ex# Structure ’H NMR MS (m/z)(LRorHR) Analysis C-7 (Acetone-d6, 300 MHz) 7.48 (2H, d, J = 8.9Hz), 7.58 (2H, d, J= 8.7 Hz), 7.41 (2H, d. J= 8.5 Hz), 7.13 (2H, t, J = 8.9 Hz), 7.07 (2H,d, J= 8.7 Hz), 6.78 (2H, d, 8.7 Hz), 4.14(2H, t, J= 7.0 Hz), 3.03 (2H, t, 7.0 Hz),2.97 (2H, s), 2.40-2.30 (2H, m), 2.01-1.92(2H, m), 1.85-1.72 (2H,m). forLR404 (M)* Calcd forC26H25FO3C77.21, H6.23.Found: C77.13, H6.28. C-8 rt”’’"· î (Acetone-d5, 300 MHz) 7.58 (2H, d, J = 8.3Hz), 7.41 (2H, d, J= 8.3 Hz), 7.34 (1H, t, J =7.9 Hz), 7.21-7.15 (2H, m), 7.12 (2H, d, J~8.7 Hz), 6.90 (1H, ddd, J = 0.94, 2.64, 8.3Hz), 6.83 (2H, d, J = 8.7 Hz), 4.19 (2H, t, J =6.9 Hz), 3.85 (3H, s), 3.09 (2H. t, J- 6.8Hz), 3.02 (2H, S), 2.39-2.30 (2H, m), 2.07-1.98 (2H, m), 1.89-1.81 (2H, m) forLR416 (M)' Calcd forC27H2BO4C 77.86,H 6.78.Found: C77.67, H6.67. C-9 Jkp (Acetone-d6, 300 MHz) 7.69 (1H, dt, J = 0.9,8.3 Hz), 7.65 (2H, d, J = 8.3 Hz), 7.58 (2H, t,J= 8.1 Hz), 7.47 (2H, d, J = 8.3 Hz), 7.31(1H, dt, J = 1.1,8.1 Hz), 7.13 (2H, d, J= 8.7Hz), 6.83 (2H, d, J= 8.7 Hz), 4.21 (2H, t, J =6.8 Hz), 3.12,(2H, t, J = 6.8 Hz), 3.03 (2H,s), 2.40-2.30 (2H, m), 2.08-1.98 (2H, m),1.92-1.79 (2H,m) forLR470 (M)' Calcd forC27H25F3O4C68.93, H5.36.Found: C69.04, H5.47. 13157 . -79- C-10 (Acetone-dg, 300 MHz) 8.42 (1H, d, J = 2.6Hz), 7.93 (1 H, dd, J= 2.6, 8.7 Hz), 7.57 (2H,d, J= 8.3 Hz), 7.44 (2H, d, J= 8.3 Hz), 7.13(2H, d, J= 8.9 Hz), 6.84 (2H, d, J -8.7 Hz),6.85-6.81 (1H, m), 4.20 (2H, t, J = 6.8 Hz),3.91 (3H, s), 3.10 (2H, t, J = 7.0 Hz), 3.03(2H, s), 2.40-2.30 (2H, m), 2.07-1.99 (2H,m), 1.90-1.82 (2H,m). forLR417 (M)' Calcd forC26H27NO4C74.80, H6.52, H3.35.Found: C74.67, H6.46, N3.31. C-11 CHj (Acetone-dg, 300 MHz) 8.01 (2H, d, J= 8.5Hz), 7.92 (2H, d, J= 8,5 Hz), 7.70 (2H, d, J= 8.5 Hz), 7.50 (2H, d, J-8.1 Hz), 7.13 (2H,d, J = 8.7 Hz), 6.84 (2H, d, J= 8.7 Hz), 4.22<2H, t, J = 6.8 Hz), 3.15 (3H, s), 3.13 (2H, t,J = 6.8 Hz), 3.03 (2H, s), 2.40-2.30 (2H, m),2.07-1.98 (2H, m), 1.92-1.79 (2H, m). for LR482 (M)’ Calcd for C27H2gO5 SC 69.80, H6.07.Found: C69.41, H6.12. C-12 (Acetone-dg, 300 MHz) 7.53-7.48 (1 H, m), 7.52 (2H, d, J= 8.3 Hz), 7.38-7.34 (1Ή, m),7.37 (2H, d, J= 8.3 Hz), 7.13 (2H, d, J = 8.7Hz), 6.83 (2H, d, J= 8.7 Hz), 6.78 (1H, d, J~ 8.3 Hz), 4.57 (2H, t, J= 8.7 Hz), 4.18 (2H,t, J = 6.8 Hz), 3.25 (2H, t, J = 8.7 Hz), 3.08(2H, t, J =7.0 Hz), 3.03 (2H, s), 2.40-2.30(2H. m), 2.07-1.99 (2H, m), 1.92-1.79 (2H,m). for LR428 (M)' Calcd forC2SH28O.4C 78.48,H 6.59.Found: C78.30, H6.62. C-13 CKjO H (Acetone-dg, 300 MHz) 7.65 (2H, d, J = 8.7Hz), 7.59 (2H, d, J = 8.1 Hz), 7.42 (4H, dd, J= 1.5, 8.1 Hz), 7.13 (2H, d, J= 8.5 Hz), 6.84(2H, d, J = 8.9 Hz), 4.20 (2H, t, J = 6.8 Hz),3.10 (2H, t, J = 6.8 Hz), 3.03 (2H, s), 3.01(3H, s), 2.40-2.30 (2H, m), 2.07-1.99 (2H,m), 1.92-1.81 (2H, m). forLR479 (M)' Calcd forC27H2SNOgSC67.62, H6.09, N2.92.Found: C67.36. H6.11, N2.85.· C-14 ’H NMR (400 MHz, CDCIg) 2.29 (s, 3 H),2.39 (m, 2 H), 2.75 (m, 2 H), 3.00 (q, 2 H),3.30 (d, 2 H), 6.00 (td, 1 H), 6.25 (d, 1 H),6.56 (d, 2 H), 7.08 (d, 2 H), 7.35 (m, 3 H),7.90 (m, 2 H). LRMS (m/z): 390 (M+H)+. C-15 O-COû^" 1H NMR (400 MHz, CDCI3) 1.77 1.89 (m, 2 H), 1.93 2.05 (m, 2 H), 2.27 (s, 3 H), 2.40 2.51 (m, 6 H), 2.71 2.80 (m, 2 H), 6.63 (d, 2H), 6.97 (d, 2 H). 7.40 (dd, 3 H), 7.92 (m, 2H). LRMS (m/z): 392 (M+H)+. 13157 ; -80- C-16 (DMSO-cfe, 400 MHz) 12.13 (1 H, s), 7.86 (2H, m), 7.49-7.40 (3H, m), 7.01 (2H, d, J =8.8Hz) 6.78 (2H, t, J = 8.6Hz), 3.90 (2H, t, J= 6.3Hz), 2.89 (2H, s), 2.56 (2H, t, J =7.3Hz), 2.24 (3H, s), 2.24-2.15 (2H, m) 2.00-1.67 (6H,m). Calcd forC2SH23NO 406.2013. Found: 406.2002. Calcd forC25H27NO4C74.05, H6.71, N3.45.Found: C73.75, H6.64, N3.44. C-17 O~ ° CH, (DMSO-cfe, 400 MHz) 12.04 (1H,s), 7.79(2H. m), 7.40-7.34 (3H, m), 6.95 (2H, d, J =8.6Hz), 6.78 (2H, t, J= 8.6Hz), 4.80 (2H, s),2.80 (2H, s), 2.28 (3H, s), 2.12-2.06 (2H, m) 1.83-1.57 (4H, m). Calcd forC23H24NO 4 378.1700. Found: 378.1692. Calcd forC23H23NO4C73.19, H6.14, N3.71.Found: C73.15, H6.26, N3.75. C-18 O '''='^û'CX (CDCIs, 400 MHz) 8.00-7.97 (2H, m), 7.49-7.40 (3H, m), 7.17 (1H, t, J = 7.8Hz), 7.03(1H, s), 6.78 (2H, t, J = 7.1Hz), 4.24 (2H, t, J = 8.1Hz), 3.14 (2H, s). 2.90 (2H, t, J =7.8Hz), 2.51-2.40 (2H, m), 2.36 (3H, s),2.07-1.83 (4H, m). Calcd forc24h26no 4 392.1857. Found: 392.1859. Calcd forC24H25NO40.2H2OC 72.96, H6.48, N3.55.Found:C72.66, H6.65, N3.47. C-19 (XCM· O (DMSO-de, 400 MHz) 7.90 (2H, dd, J= 1.9,7.7 Hz), 7.51-7.44 (3H, m), 7.05 (2H, d, J =8.6 Hz), 6.81 (2H, d, J= 8.6 Hz), 4.15 (2H, t,J = 6.7 Hz), 2.92 (2H, s), 2.90 (2H, t, J = 6.8Hz), 2.34 (3H, S), 2.25-2.18 (2H, m), 1.95-1.88 (2H, m), 1.86-1.71 (2H, m). for LR392(M+H)* Calcd forC24H25NO4C73.64. H6.44, N3.58.Found: C73.49, H6.46, N3.54. C-20 ' 4-/ U OH ’H NMR (DMSO-d6,400 MHz) : 7.83 (2H,d, J = 9.1 Hz), 7.06-7.02 (4H, m), 6.82 (2H,d, J = 8.6 Hz), 4.17 (2H, t, J = 6.3 Hz), 3.80(3H, s), 3.10 (2H, t, J = 6.3 Hz), 2.92 (2H, s),2.25-2.17 (2H, m), 2.08 (3H, s), 1.95-1.69(4H, m). Calcd forC25H2BNO 422.1962. Found: 422.1961 C-21 c/\ Qn ^~OH 0 (DMSO-d6, 400 MHz) 7.25-7.24 (1H, m),7.19-7.17 (2H, m), 7.00-6.97 (2H, m), 6.76-6.75 (1H, m), 6.72-6.70 (2H, m), 4.10 (2H, t,J = 6.5 Hz), 2.90 (6H, s), 2.85 (2H, t, J = 6.5Hz), 2.25 (3H, s), 2.24-2.21 (2H, m), 1.95- 1.92 (2H, m), 1.78-1.74 (2H, m). HR Calcdfor C26H3oN2 O4 (M+H)‘ 435.2279 Found 13157 . -81- 435.2270.For LR435(M+Hf C-22 a' % y-ûH O (CDCI3, 400 MHz) 8.13-8.11 (1H, m), 7.77-7.75 (1H, m), 7.66-7.62 (1H. m), 7.49-7.45(1H. m). 7.09-7.07 (2H, m), 6.81-6.79 (2H,m). 4.23 (2H, t, J= 6.3 Hz), 3.03 (2H, s),2.99 (2H. t, J = 6.3 Hz), 2.46-2.38 (2H, m),2.40 (3H. s), 2.09-2.02 (2H, m), 1.90-1.86(2H, m). HR Calcdfor C25H24N- 2Ο4 (M+Hf 417.1809. Found 417.1813. ForLR 418 (M+Hf C-23 X O (DMSO-d6, 400 MHz) 12.04 (1H, s), 7.89-7.84 (4H, m), 6.96-6.94 (2H, m), 6.72-6.70(2H, m), 4.06 (2H, t, 6.5 Hz), 3.06-3.05(1H, m), 2.82-2.80 (4H, m), 2.26 (3H, s),2.15-2.08 (2H, m), 1.83-1.79 (2H, m), 1.69-1.65 (2H,m). HR Calcdfor C25H26N- ïOs (M+Hf 435.1915. Found 435.1922. ForLR 435 (M+Hf C-24 % /'0H (CDCI3l 300 MHz) 7.84-7.76 {2H, m), 7.66-7.61 (1H, m). 7.09-7.06 (2H, m), 6.80-6.77(2H, m), 4.19 (2H, t, J = 6.5 Hz), 3.03 (2H,s), 2.96 (2H, t, J ~ 6.4 Hz), 2.47-2.40 (2H,m), 2.37 (3H, s), 2.10-2.01 (2H, m), 1.95-1.81 (2H, m). HR Calcdfor C25H23N- O4F4 (M+Hf 478.1636. Found 478.1624. ForLR 478 (M+Hf C-25 O (CDCI3, 300 MHz) 8.06-8.05 (1H, d), 7.80-7.77 (1H, m), 7.50-7.47 (1H, d), 7.09-7.06(2H, m), 6.80-6.77 (2H. m), 4.19 (2H, t, J =6.5 Hz), 3.03 (2H, s), 2.94 (2H, t, J = 6.5Hz), 2.44-2.38 (2H, m), 2.35 (3H, s), 2.08-2.01 (2H, m), 1.92-1.84 (2H, m). HR Calcdfor C24H23N- O4CI2 (M+Hf 460.1077. Found460.1089.For LR461 (M+Hf 13157 . -82- C-26 Γί w V O (COCI3, 300 MHz) 7.87-7.85 (2H,m), 7.24-7.21 (2H, m), 7.09-7.07 (2H, m), 6.81-6.78(2H, m), 4.20-4.17 (2H, m), 3.04 (2H, s),2.98-2.94 (2H, m), 2.48-2.41 (2H, m), 2.38(3H, s), 2.35 (3H, s). 2.10-2.02 (2H, m),1.90-1.83 (2H,m). HR Calcdfor C25H27N- 0. (M+Hf 406.2013. Found 406.2014 ForLR 406 (M+Hf C-27 Γί ν>ά--= X-ÔM 0 {CDCI3. 300 MHz) 7.91-7.88 (2H, m). 7.40-7.37 (2H, m), 7.09-7.06 (2H, m). 6.80-6.77(2H, m), 4.18 (2H. t, J = 6.5 Hz), 3.03 (2H,s), 2.95 (2H, t, J =6.5 Hz), 2.44-2.41 (2H,m), 2.35 (3H, s), 2.08-2.01 (2H, m), 1.90-1.87 (2H,m). HR Calcdfor C24H24N- O„CI (M+Hf 426.1467. Found ¢26.1471. ForLR 426 (M+H)* C-28 % ^~0M O (CDCIa, 300 MHz) 7.92-7.89 (2H, m), 7.10-7.07 (2H, m), 6.95-6.92 (2H, m), 6.80-6.77(2H, m), 4.17 (2H, t, J =6.5 Hz), 3.85 (3H,s), 3.04 (2H, s), 2.95 (2H, t, J =6.5 Hz),2.48-2.38 (2H, m), 2.34 (3H, s), 2.10-2.02(2H, m), 1.94-1.83 (2H, m). HR Calcdfor C25H27N* Os (M+Hf 422.1962. Found422.1948.For LR423(M+Hf C-29 ?% )*OH 0 (CDCI3, 300 MHz) 7.57-7.55 (1H, m), 7.51-7.49 (1H, m), 7.35-7.30 (1H, m), 7.10-7.07(2H, m), 6.97-6.93 (1H, m), 6.81-6.78 (2H,m), 4.19 (2H, t, J = 6.5 Hz), 3.87 (3H,s),3.04 (2H, s), 2.96 (2H, t, J = 6.5 Hz), 2.48-2.38 (2H, m), 2.36 (3H, s), 2.11-2.02 (2H,m), 1,94-1.85 (2H,m). HR Calcdfor C25H27N- o5 (M+H)+ 422.1962. Found 422.1947. ForLR 422 (M+H)+ C-30 ? Qç )~Ol· 0 (CDCI3,400 MHZ) 8.23 (1H, s), 8.15-8.13(1H, m), 7.64-7.63 (1H, m), 7.54-7.50 (1H,m). 7.07-7.05 (2H. m), 6.99-6.96 (1H, m),6.77-6.75 (2H, m), 6.70-6.68 <1H, m), 4.19(2H, t, J = 6.5 Hz), HR Calcdfor CæH^N- O4F3 (M+Hf 460.1730. Found460.1728.For LR460(M+H/ -83- C-31 y-oH 0 (CDCIj, 300 MHz) 7.96 (1H, s), 7.86-7.83(1H, m), 7.36-7.33 (2H, m), 7.09-7.06 (2H,m), 6.79-6.76 (2H, m), 4.18 (2H, t, J= 6.5Hz), 3.03 (2H, s), 2.95 (2H, t, J =6.5 Hz),2.47-2.38 (2H, m), 2.35 (3H, s), 2.08-2.01(2H, m), 1.91-1.84 (2H, m). HR Calcdfor C24H24N- O4CI (M+H)4 426.1467. Found 426.1465. ForLR 426 (M+H)4 C-32 O y~0H O (CDCI3, 400 MHz) 7.81 1H, s), 7.77-7.75 (1H, m), 7.33-7.29 (1H, m), 7.22-7.20 (1H,»n), 7.09-7.07 (2H, m), 6.81-6.78 (2H, m).4.19 (2H, t, J =6.5 Hz), 3.04 (2H, s), 2.96(2H, t, J = 6.5 Hz), 2.44-2.42 (2H, m), 2.39(3H, s), 2.35 (3H, s), 2.08-2.03 (2H, m),1.89-1.87 (2H,m). HR Calcdfor C25H27N- 0, (M+H)4 406.2013. Found 406.2026. ForLR 407 (M+H)4 C-33 .^cA-v y*0H 0 (CDCIs, 400 MHz) 8.08-8.06 (2H, d), 7.68-7.66 (2H, d), 7.09-7.07 (2H, m), 6.80-6.78(2H, m), 4.91 (2h, t, J =6.5 Hz). 3.03 (2H,s), 2.97 (2H, t, J= 6.5 Hz), 2.46-2.38 (2H,m), 2.37 (3H, s), 2.09-2.02 (2H, m), 1.92-1.82 (2H, m). HR Calcdfor C25H24N- O4F3 (M+H)4 460.1730. Found460.1723.For LR461(M+H)4 034 01¾. OH (DMSO-d6, 300 MHz) 12.19 (1H, s), 8.12-8.11 (2H, m), 7.82-7.79 (2H, m), 7.59-7.44(6H, m), 7.13-6.98 (4H, m), 5.17 (2H, s),2.97 (2H, s), 2.30-2.21 (2H, m), 2.01-1.73(4H, m). Calcd forCjeHîeNO4 440.1857. Found: 440.1846. 035 ,p OH (CDCI3, 300 MHz) 8.09-8.07 (2H, m), 7.68-7.66 (2H, m), 7.46-7.26 (6H, m), 7.10-6.78(4H, m), 4.01 (2H. t, J = 5.8 Hz), 3.04-3.00(4H, m), 2.49-2.39 (2H, m), 2.30-2.21 (2H,m), 2.11-2.02 (2H, m), 1.94-1.81 (2H, m). Calcd forC30H30NO4 468.2107. Found: 468.2165. 036 O o=F OH (DMS0-d6, 300 MHz) 12.92 (1H. s), 8.12-8.09 (2H, m), 7.82-7.79 (2H, m), 7.60-7.44(6H, m), 7.02-6.99 (2H, m), 6.64-6.60 (2H,m). 5.13 (2H, s), 2.68-2.59 (2H, m), 2.37-2.26 (2H, m), 1.95-1.84 (2H, m). Calcd forC27H24NO5 442.1649 Found: 442.1639 13157 -84- · C-37 OH (CDCI3, 300 MHz) 8.10-8.06 (2H, m), 7.69-7.66 (2H, m), 7.46-7.32 (6H, m), 6.79-6.66(4H, m), 3.91 (2H. t, J = 6.0 Hz), 2.98 (2H, t,J= 7.3 Hz), 2.80-2.71 (2H, m), 2.50-2.40(2H, m), 2.24-2.15 (2H, m), 2.06-1.93 (2H,m). Calcd for^gHîaNO 470.1962. Found: 470.1952. Calcd forC29H27NO5C74.18, H 5.80, N2.98. Found: C73.07, H 6.81, N2.43. C-38 ιΓΛ 0 OH (CDCI3. 300 MHz) 8.09-8.07 (2H, m), 7.68-7.66 (2H, m), 7.46-7.26 (6H, m), 7.10-6.78(4H, m), 4.01 (2H, t, J = 5.8 Hz), 3.04-3.00(4H, m), 2.49-2.39 (2H, m), 2.30-2.21 (2H,m), 2.11-2.02 (2H, m), 1.94-1.81 (2H, m) HR Calcdfor C30H29NO4 (M+H)*468.2107. Found468.2165.For LR468(M+H)* C-39 (CDCI3,400 MHz) 8.03 (2H, d, J = 8.3 Hz),7.66 (2H, d, J~ 8.3 Hz), 7.65-7.60 (2H, m),7.49-7.32 (3H, m), 6.74-6.63 (4H, m), 4.03<2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.6 Hz),2.81-2.70 (2H, m), 2.49-2.35 (2H, m), 2.38(3H, s), 2.10-1.90 (2H,m). Calcd forC29H28NO 470.1962, Found: 470.1948. Calcd forC29H27No5 C 74.18,H 5.80, N2.98.Found: C74.07, H5.83, N2.89. C-40 <ΗχΧσ°^“ (CDCI3. 400 MHz) 8.00-7.93 (2H, m), 7.46-7.40 (3H, m), 6.73-6.62 (4H, m), 4.02 (2H, t,J = 6.6Hz), 2.94 (2H, t, J = 6.6Hz), 2.80-2.69(2H, m), 2.47-2.33 (2H, m), 2.36 (3H, s),2.10-1.88 (2H, m). Calcd forC23H24NO 5 394.1649 Found: 394.1639 Calcd forC23H23NO5C70.21, H5.89, N3.56.Found: C69.87, H6.05, N3.47. C-41 O CHj (CDCI3, 400 MHz) 8.01-7.94 (2H, m), 7.47-7.39 (3H, m), 6.82-6.65 (4H, m), 3.87 (2H, d,J= 6.0Hz), 2.82-2.71 (2H, m). 2.67-2.60(2H, m), 2.50-2.38 (2H, m), 2.29 (3H, s),2.10-1.90 (4H, m). forLR 408 (M+Hf Calcd forC24H25NO5C70.74, H 6.18, N3,44. Found: C70.52, H 6.19, N3.41. 13157 . -85- C-42 (CDCIa, 400 MHz) 8.04-7.97 (2H, m), 7.47-7.40 (3H, m), 6.86-6.63 (4H, m), 4.90 (2H,s), 2.78-2.70 (2H, m), 2.47-2.35 (2H, m),2.41 (3H, s),,2.10-1.90(2H, m). for LR380(M+H)+ Calcd forC22H21NOsC69.64, H5.58, N6.69.Found: C69.49, H5.68, N3.62. C-43 OCW 0 (MeOH-d4,400 MHz) 7.87-7.84 (3H, m),7.46 (1H, dd, J = 2.3, 8.6 Hz), 7.39-7.35(3H, m),6.57 (1H, d, J= 8.6 Hz), 4.38 (2H,t, J =6.7 Hz), 2.88 (4H, m), 2.25 (3H, s),2.29-2.20 (2H. m), 1.88-1.81 (2H, m), 1.75-1.68 (2H, m). Calcd forC23H24N2O4 393.1809. Found: 393.1815. C-44 OH 0 (DMSO-de, 300 MHz) 8.02 (1H, d, J = 2.1Hz), 7.91-7.88 (2H, m), 7.60 (1H, dd, J =2.3, 8.5 Hz), 7.52-7.47 (3H, m), 6.72 (1H, d,J= 8.7 Hz), 5.66 (1H, bs), 4.73 (1H, s), 4.45(2H, t, J = 6.8 Hz), 2.90 (2H, t, J = 6.7 Hz),2.40-2.16 (2H, m), 2.30 (3H, s). 2.14-2.02(2H, m), 1.75-1.63 (1H. m), 1.56-1.42 (1H.m). forLR408 (M)' Calcd forC23H24N2OsC67.63, H5.92, N6.86.Found:C67.51, H6.08, N6.75. C-45 oJo <XUQ#" (Methyl sulfoxide-d6,400 MHz): 8.02 (1H, d,J = 2.1 Hz), 7.91-7.88 (2H, m), 7.60 (1H, dd,J = 2.3, 8.5 Hz), 7.52-7.47 (3H, m), 6.72(1H, d. J= 8.7 Hz), 4.68 (1H, s), 4.45 (2H, t,J= 6.8 Hz), 4.01 (2H, q, J= 7.1 Hz), 2.90(2H, t, J =6.7 Hz), 2.40-2.16 (2H, m), 2.30(3H, s), 2.14-2.02 (2H, m), 1.75-1.63 (1H,m), 1.56-1.42 (1H, m), 1.29 (3H, t, J = 7.2Hz) forLR 437 (M+H)+ C-46 (HW 0 (CDCIs, 400 MHz) 8.00-7.93 (3H, m), 7.42-7.37 (4H, m), 6.63 (1H, d, J = 8.5 Hz), 4.48(2H, 1. J = 6.6 Hz), 2.96 (2H. t, J = 6.7 Hz),2.86 (2H, s), 2.31 (3H, s), 2.10-2.02 (2H, m)1.66-1.50 (6H,m). forLR406 (M)' C-47 O-OÇ^Cl^- O (CDCb, 400 MHz) 7.97-7.93 (3H, m), 7.43-7.33 (4H, m), 6.63 (1H, d, J = 8.5 Hz), 4.48(2H. t, J = 6.8 Hz), 2.95 (2H. t, J = 6.8 Hz),2.73 (2H, s), 2.30 (3H, s), 2.01 (2H, d, J =12.6 Hz), 1.59-1.50 (3H, m), 1.40-1.15 (5H,m). forLR420 (M)’ 13157 . -86- C-48 ŒÎ'C°ÔXo„ (CDCla, 400 MHz) 7.99-7.94 (3H, m), 7.49 (1H, dd, J = 2.4, 8.6 Hz), 7.44-7.36 (3H, m),6.63 (1 H, d, J = 8.5 Hz), 4.50 (2H, t, J = 6.7Hz), 4.00-3.93 (1 H, m), 3.89-3.81 (1H, m),3.14 (1H, d, J = 14.1 Hz), 2.95 (2H, t, J= 6.7Hz), 2.85 (1H, d, J= 14.1 Hz), 2.31 (3H, s),1.99-1.73 (4H, m). for LR409 (M)* C-49 <KCW 0 (MeOH-d4, 300 MHz) 8.37 (1H, d, J= 2.6Hz), 8.07 (1H, dd, J= 2.6, 8.9 Hz), 7.93-7.90 (2H, m), 7.79 (1H, d, J = 8.9 Hz), 7.47-7.40 (3H, m), 4.41 (2H, t, J = 6.2 Hz), 3.92-3.86 (2H, m), 3.05 (2H, t, J = 6.2 Hz), 2.36(3H. s), 3.50 (1H, d, J= 14.3 Hz), 3.15 (ÎH.d, J= 14.3 Hz), 2.31-2.23 (1 H, m), 2.00-1.92(1H, m), 1.89-1.73 (2H,m). for LR408 (M)' Calcd forC23H25N2O5CI C62.09, H5.66, N6.30.Found. C61.96, H5.75, N6.18. C-50 0 jC^oh (MeOD, 400 MHz): 8.37 (1H, d, J = 2.6 Hz),8.07 (ΊΗ, dd, J = 2.6, 8.9 Hz), 7.93-7.90(2H, m), 7.79 (1H, d, J = 8.9 Hz), 7.47-7.40(2H, m), 4.41 (2H, t, J = 6.2 Hz), 3.92-3.86(2H, m), 3.50 (1 H, d, J = 14.3 Hz), 3.15(1 H,d, J= 14.3 Hz), 3.05 (2H, t, J= 6.2 Hz), 2.36(3H, s). 2.34 (3H, s), 2.31-2.23 (1H, m),2.00-1.92 (1H, m), 1.89-1.73 (2H, m) forLR 423 (M+H)+ C-51 iT\^_,sY iTV'xÎoh\=MA—oA^n <J (CDCla, 400 MHz): 8.03 (1H, d, J = 2.5 Hz),7.77-7.74 (2H, m), 7.36-7.31 (4H, m), 7.26(1H,d, J =8.6 Hz), 4.31 (2H. t, J =6.6 Hz),3.81-3.69 (2H, m), 3.11 (2H, f, J = 6.4 Hz),3.02(1 H, d, J = 13.9 Hz), 2.37 (3H. s), 2.36-2.34 (1H,m), 2.18-2.11 (1H, m), 1.94-1.87(1H, m), 1.78-1.68 (1H, m), 1.60-1.53 (1H,m) for LR425(M+H)+ C-52 ‘’^0C„XS^“ (CDCla, 400 MHz): 8.04 (1H, d, J =2.8 Hz), 7.85-7.83 (2H, m), 7.41-7.39 (2H, m), 7.33 (1H, dd, J = 8.6, 3.0 Hz), 7.27 (1H, d, J= 8.8Hz), 4.23 (2H, t, J= 6.3 Hz), 3.82-3.70 (2H,m), 3.17-3.15 (1H, m), 3.03 (1H, d, J= 14.2Hz), 2.91 (2H, t, J= 6.3 Hz), 2.29 (3H, s),2.19-2.12 (1H, m), 1.96-1.88 (1H, m), 1.78-1.71 (1H, m), 1.61-1.54(1 H, m) for LR443(M+Hf C-53 (MeOD, 400 MHz): 8.01 (1H. d, J= 1.5 Hz),7.80-7.77 (2H, m), 7,25-7.24 (2H, m), 6.93-6.91 (2H, m), 4.20 (2H, t, J = 6.3 Hz), 3.80-3.69 (2H, m), 3.75 (3H, s), 3.17-3.15 (1H,m), 3.01 (1H, d, J = 13.9 Hz), 2.88 (2H, t, J= 6.3 Hz), 2.26 (3H, s), 2.17-2.11 (1H, m),1.94-1.87 (1H, m), 1.75-1.66 (1H, m), 1.58-1.49 (1H,m) forLR 439 (M+H)* 13157 : -87- C-54 0 -0 (MeOD, 400 MHz): 8.01 (1H, d, J = 2.3 Hz),7.44-7.40 (2H, m), 7.30-7.22 (3H, m), 6.94-6.91 (1H, m), 4.21 (2H, t, J= 6.4 Hz), 3.80-3.67 (2H, m), 3.75 (3H. s), 3.21-3.17 (1H,m). 3.01 (1H, d, J = 13.9 Hz), 2.90 (2H, t, J= 6.4 Hz), 2.28 (3H, s). 2.17-2.11 (1H, m),1.94-1.87 (1H,m), 1.77-1.67 (1H, m), 1.60-1.50(1 H, m) for LR439(M+Hf C-55 (CDCI3i 300 MHz): 8.43 (1H, d, J= 2.6 Hz),7.97-7.93 (1H, m), 7.83-7.79 (1H, m), 7.60-7.52 (2H, m), 7.48-7.42 (3H, m), 4.14 (2H, t,J = 6.0 Hz), 4.06-3.99 (2H, m), 3.62(1 H, d,J- 13.9 Hz), 3.37 (1H, d, J= 13.9 Hz), 2.69(2H, t, J= 6.0 Hz), 2.32 (3H, s), 2.23-1.96(6H, m) for LR423(M+Hf C-56 (CDCI3i 300 MHz): 7.93-8.03 (3H, m), 7.83- 7.79 (1H, m), 7.37-7.54 (4H, m), 6.65 (1H,m). 4.50 (2H, t, J = 6.0 Hz), 3.75 (2H, m).2.95 (4H, m) 2.33 (3H, s) 2.12 (2H, m), 1.39-1.77 (5H, m) for LR423(M+Hf C-57 O^îC- OÇ)0H (MeOD, 400 MHz): 7.98 (1 H, d, J = 2.8 Hz), 7.86-7.84 (2H, m), 7.3S-7.36 (3H, m), 7.24(1H. d, J= 8.8, 2.8 Hz), 7.19 (1 H, d, J= 8.6Hz), 4.21 (2H, t, J = 6.6 Hz), 3.70-3.66 (1H,m), 3.60-3.53 (1H, m), 2.95 (2H, s), 2.90(2H, t, J= 6.4 Hz). 2.28 (3H, s). 2.07-2.01(1H, m), 1.61-1.58 (1H, m), 1.40-1.32 (4H,m) forLR 423 (M+Hf C-58 (DMSO-de, 400 MHz) 8.17 (2H, d, J = 8.3Hz), 7.99 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J= 8.3 Hz), 7.68 (2H, t, J = 8.3 Hz), 7.58 (1H,t, J- 8.3 Hz), 7.24-7.02 (4H, m), 4.36 (2H, t,J = 6.6 Hz), 3.11 (2H, s), 3.11-3.07 (2H, m),2.55 (3H, s), 2.44-2.37 (2H, m), 2.15-1.89(4H, m). Calcd forC3QH30NO 468.2170. Found: 468.2163. Calcd forC30H30NO4.O.2H2O C 76.47,H 6.29, N2.97.Found: C76.48, H6.30, N2.90. C-59 bC^ n-A. o Co 0H ’H NMR (DMSO-de, 400 MHz) : 8.04 (2H, d, J= 8.3 Hz), 7.95-7.93 (3H, m), 7.53 (1H,dd, J = 8.6 and 2.3 Hz), 6.69 (1H, d, J= 8.3Hz), 4.45 (2H, t, J = 6.6 Hz), 3.75 (2H, t, J =6.8 Hz), 3.01 (1H, d, J= 13.9 Hz), 2.93 (2H,t, J= 6.6 Hz), 2.82 (1H, d, J = 14.2 Hz), 2.33(3H, s), 2.13-2.07 (1H. m), 1.84-1.62 (3H,-01) Calcd forC23H24CI n2os443.1368. Found:443.1377 13157 . .- 88- C-60 —(1o-\ ^s=2 O > Ί y°jÇoH TH NMR (DMSO-de, 400 MHz) : 12.45 (ÎH,s), 7.95 (1H, d, J= 2.3 Hz). 7.83 (2H, d, J =8.8 Hz), 7.53 (1H, dd, J= 8.6 and 2.3 Hz),7.03 (2H, d, J = 8.8 Hz), 6.69 (1H, d, J - 8.3Hz), 4.42 (2H, t, J= 6.8 Hz), 3.80 (3H, s),3.75 (2H. t, J = 6.8 Hz), 3.01 (1H, d, J = 13.9Hz), 2.87 (2H, t, J =6.8 Hz), 2.82 (1H, d, J =14.2 Hz), 2.28 (3H, s), 2.14-2.07 (1H, m),1.83-1.63 (3H, m) Calcd forC24H27N2 o6 439.1864. Found:439.1874 C-61 «a-ZI Η'Γ° \ Ί P j?0H 'H NMR (DMSO-d6,400 MHz): 8.04 (2H, d, J= 8.3 Hz), 7.95-7.93 (3H, m), 7.53 (1H, dd,J = 8.6 and 2.3 Hz), 6.69 (1H, d, J = 8.3 Hz),4.45 (2H, t, J = 6.6 Hz), 3,75 (2H, t, J = 6.8Hz), 3.01 (1H, d, J = 13.9 Hz), 2.93 (2H, t, J= 6.6 Hz), 2.82 (1H, d, J = 14.2 Hz), 2.33(3H, s), 2.13-2.07 (1H, m), 1.84-1.62 (3H, Calcd forC24H24N3 O5 434.1711. Found:434.1705 C-62 a \ N^%, o-\ -°n NvjÿSk. 1 /°Γοπ Ή NMR (DMSO-de, 400 MHz) : 7.95(1 H,d, J = 2.0 Hz), 7.53 (1H, dd, J = 8.3 and 2.3Hz), 7.48 (1H, d, J = 7.8 Hz), 7.42-7.38 (2H,m), 7.04 (1 H, dd, J = 8.3 and 2.5 Hz), 6.69(1H, d, J = 8.3 Hz), 4.43 (2H, t, J = 6.6 Hz),3.81 (3H, s), 3.75 (2H, t, J = 6.8 Hz), 3.01(1H, d, J= 13.9 Hz), 2.90 (2H, t, J = 6.6 Hz),2.82 (1H, d, J = 13.9 Hz), 2.31 (3H, s). 2.13-2.07 (1H,m), 1.83-1.58 (3H, m) Calcd forC24H27N2 o6 439.1864. Found:439.1874 C-63 X-/) F Vas/ N.. Λ °\ 'Ί P Jo ’H NMR (DMSO-de, 400 MHz) : 12.51 (1H, s), 8.10 (2H, d, J= 8.1 Hz), 7.95 (1H, d, J =2.0 Hz), 7.85 (2H, d, J = 8.3 Hz), 7.53 (1H,dd, J = 8.3 and 2.3 Hz), 6.69 (1 H, d. J = 8.6Hz), 4.45 (2H, t,J= 6.8 Hz), 3.75 (2H, t, J =6.6 Hz), 3.01 (1H, d, J= 13.9 Hz), 2.93 (2H,t, J = 6.6 Hz), 2.82 (1H, d, J = 13.9 Hz), 2.34(3H, s), 2.13-2.06 (1H, m), 1.84-1.60 (3H,m) Calcd forC24H24F3N2O5477.1632.Found:477.1635 C-64 N.. n ° \ P Jo °K Ή NMR (CDCI3, 400 MHz) : 8.16 (1H, s), 7.88 (2H, d, J = 8.6 Hz), 7.81 (1H, d, J = 8.6Hz). 7.41 (2H, d, J = 8.6 Hz), 6.87 (1H, d, J= 8.8 Hz), 4.51 (2H, t, J = 6.1 Hz), 4.03-3.90(2H, m), 3.23 (1H, d, J= 14.2 Hz), 3.04 (2H,t, J = 6.1 Hz), 2.86 (1H, d, J = 14.2 Hz),2.42-2.35 (1H, m), 2.37 (3H, s), 2.0V1.87(3H, m) forLR 443 (M+H)+ C-65 < J 0 \ N^ÿssk Ί 0 T OH ’H NMR (DMSO-de, 400 MHz) : 7.95 (1H,d, J = 2.0 Hz), 7.73 (1H, s), 7.69 (1H, d, J =7.3 Hz), 7.51 (1H, dd, J= 8.6 and 2.3 Hz),7.37 (1 H, t, J = 7.8 Hz), 7.28 (1H, d, J = 7.1Hz), 6.69 (1H, d, 8.3 Hz), 4.43 (2H, t, J = 6.8Hz), 3.75 (2H, t, J = 6.6 Hz), 3.01 (1H, d, J =14.2 Hz), 2.89 (2H, t, J = 6.8 Hz), 2.82 (1H,d, J = 14.2 Hz), 2.36 (3H, s), 2.30 (3H, s),2.14-2.08 (1H, m), 1.84-1.60 (3H, m) Calcd forC24H27N2 o5 423.1915 Found: 423.1927 Calcd forC24H26N2Os0.4H20C 64.23H 6.01 N6.19.Found: C 64.16H 6.16 N6.01 13157 . -89- C-66 C>o 0H 1H NMR (DMSO-d5,400 MHz) : 7.95 (1H,d, J= 2.3 Hz), 7.79 {2H, d, J= 8.1 Hz), 7.53(1H, dd, J= 8.3 and 2.5 Hz), 7.29 (2H, d, J = 8.1 Hz), 6.68 (1H, d, 8.3 Hz), 4.43 (2H, t, J = 7.1 HZ), 3.75 (2H, t, J = 6.8 Hz), 3.01 (1 H, d, J = 13.9 Hz), 2.88 (2H, t, J = 6.8 Hz), 2.82(1H, d, J- 13.9 Hz), 2.34 (3H, s), 2.29 (3H, S). 2.14-2.07 (1H, m), 1.84-1.60 (3H. m) Calcd forC24H27>N2 o5 423.1915. Found: 423.1929. Calcd forC24H26N2050.9H20C 65.71 H 6.39 N6.39.Found: C 65.61 H 6.34 N6.20 C-67 <xc„W" ‘H NMR {MeOH-d4, 400 MHz): 8.28 (1 H, s) 7.76 (2 H, dt, >7.7, 0.2 Hz) 7.56 (1 H, d,>9.1 Hz) 7.34 - 7.39 (1 H, m) 7.14 - 7.20 (2H, m) 6.28 (1 H, d, >9.2 Hz) 4.12 (2 H, t,>8.0 Hz) 3.70 - 3.84 (2 H, m) 3.14 - 3.20 (1H, m) 3.00 - 3.06 (1 H, m) 2.75 (2 H, t, >8.0Hz) 2.34 - 2.44 (1 H, m) 2.26 - 2.31 (3 H, m)1.82-2.05 (3 H, m) LRMS: 426 (M+H)*. C-68 ’H NMR (MeOH-di, 400 MHz): 8.28 (1 H, s) 7.56 (1 H, d, >9.1 Hz) 6.28 (1 H, d, >9.2Hz) 4.12 (2 H, t, >8.0 Hz) 3.70 - 3.84 (2 H,m) 3.14 - 3.20 (1 H, m) 2.99 - 3.06 (1 H, m)2.58 (2 H, t, >8.0 Hz) 2.48 (3 H, s) 2.31 -2.44 (1 H, m) 2.18 {3 H, s) 1.81 - 2.05 (3 H,m) for LR364(M+H)+ C-69 0 ç», fVôA” O* 1H NMR (MeOH-d4, 400 MHz): 8.19 (1 H, s) 7.45 (2 H, dd, >9.0, 8.4 Hz) 7.33 (1 H, d,>7.7 Hz) 7.15 - 7.21 (1 H, m) 6.99 - 7.05 (1H, m) 6.24 (1 H, d, >9.2 Hz) 4.02 (2 H, t,>5.2 Hz) 3.70 - 3.84 (2 H, m) 3.42 (2 H, t,>5.2 Hz) 3.14 - 3.20 (1 H, m) 2.99 - 3.06 (1H, m) 2.93 (3 H, s) 2.34 - 2.43 (1 H, m) 1.82- 2.05 (3 H, m) forLR 398 (M+H)+ C-70 1H NMR (MeOH-d4, 400 MHz): 8.28 (1 H, s)7.56 (1 H, d. >9.1 Hz) 7.08-7.20 (4 H, m)6.28 (1 H, d, >9.2 Hz) 4.50 (2 H, t, >6.9Hz) 3.70 - 3.84 (2 H, m) 3.14 - 3.20 (1 H, m)3.00 - 3.05 (1 H, m) 2.90 (2 H, t, >6.9 Hz)2.32 - 2.43 (1 H, m) 2.28 (3 H, s) 1.81 - 2.05(3 H, m) for LR342(M+H)* C-71 'H NMR (MeOH-d4, 400 MHz): 8.28 (1 H, s)7.56 (1 H, d, >9.1 Hz) 7.09 - 7.15 (4 H, m)6.28 (1 H, d, >9.2 Hz) 4.57 (2 H, t, >6.5Hz) 3.70 -3.84 (2 H, m) 3.28 (2 H, t, >6.5Hz) 3.14 - 3.20 (1 H, m) 3.00 - 3.06 {1 H, m)2.34 - 2.44 (1 H, m) 2.27 - 2.31 (3 H, m)1.82-2.05 (3 H, m) for LR342(M+H)+ 13157 ; -90- C-72 1H NMR (CDCI3i 400 MHz): 8.2-8.6 (1H, brs), 8.10 (1 H. s) 7.58 (1 H, d, >9.1 Hz)6.85-7.25 (4 H, m) 6.70 (1 H. d, >9.2 Hz)3.80-4.05 (2H, m), 3.63 (2 H, t, >6.5 Hz)3.35 (3H, s), 2.85 (2 H, t, >6.5 Hz) 2.30(1H, m) 1.65-2.05 (3H, m) C-73 H.C\ CH. 0 ’ï 1H NMR (CDCI3,400 MHz): 7.98 (1H, s)7.48 (1 H, d, >9.1 Hz) 7.15-7.30 (4 H, m)6.65 (2 H, m) 4.37 (2 H, t, >6.5 Hz) 3.80-4.03 (2H, m). 2.80-3.20 (4H, m) 2.35 (3H,m) 1.70-2.05 (3H, m) 1.50 (9H, s) C-74 oOtf" (Acetone-ds, 300 MHz): 8.37 (1H, d, > 1.9Hz). 7.96 (2H, m). 7.56 (1H. dd. J= 7.9, 2.3Hz), 7.45 (3H, m), 7.14 (1H, d, J = 7.9 Hz).3.89 (2H, m), 3.05 (2H. m), 2.77 (2H, m),2.50 (2H, t, >7.4 HZ), 2.30 (3H, s) 2.16(2H, m), 1.88 (4H, m) for LR405 (M)’ C-75 0 o-x^' °û (MeOD, 400 MHz): 8.19 (1H, s), 7.82-7.80(2H, m), 7.61 (1H, dd, > 7.8,1.8 Hz), 7.35-7.33 (3H, m), 7.15 (1H, d, J = 8.1 Hz), 3.83-3.73 (2H, m). 3.09 (1 H, d, J = 13.9 Hz), 2.82(1H, d, > 13,9 Hz), 2.69 (2H, t, > 7.2 Hz),2.41 (2H, t, J = 6.7 Hz), 2.23-2.13 (1H, m),2.20 (3H, s). 1.88-1.79 (1H, m), 1.78-1.53 .(6H, m) for LR421 (M+H)+ C-76 (MeOD, 300 MHz): 8.34-8.32 (2H, bm),7.87-7.85 (2H, bm), 7.8-7.36 (3H, bm), 4.54(2H, bs), 3.83 (2H, bs), 3.06 (1H, d, J = 10.7 Hz), 2.93-2.89 (1H, bm), 2.80 (1H, d. > 10.7 Hz), 2.24 (3H, s), 1.92-1.77 (5H, m) forLR 410 (M+H)+ C-77 Cr\^iy&amp;" (Acetone-d6,400 MHz): 8.08 (1H, s), 7.95(2H, m), 7.46 (3H, m), 4.57 (2H, t, > 6.5Hz), 3.83 (2H, m), 3.10 (4H, m), 2.36 (3H,s), 2.20 (2H, d, J = 7.0 Hz), 1.75 (2H, m) forLR408 (M)' C-78 o\ Uk 0 Ço O" 1H NMR (DMSO-ds, 400 MHz) : 12.40 (1H,s), 7.90 (2H, dd, J = 7.8 and 1.8 Hz), 7.51-7.44 (3H, m), 7.10 (2H, d, > 8.3 Hz), 6.81(2H, d, >8.6), 4.16 (2H, t, J = 6.8 Hz),3.73 (2H, t, > 6.8 Hz), 2.99 (1H, d, J = 13.9Hz), 2.90 (2H, t, J = 6.6 Hz), 2.81 (1 H, d, J =13.9 Hz), 2.34 (3H, s), 2.11-2.04 (1H, m),1.82-1.57 (3H,m). Calcd forc24h26no5 408.1806 Found: 408.1797. Calcd forc24h25nO5C70.75 H6.18 N3.44.Found: C 70.53H 6.18 N3.31 13157 . -91 - C-79 ? "4 (DMSO-d6, 400 MHz) 7.25-7.24 (1H, m),7.19-7.17 (2H, m), 7.06-7.04 (2H, m), 6.76-6.75 (1H, m). 6.72-6.70 (2H. m). 4.11 (2H, t, J= 6.5 Hz), 3.77-3.71 (2H, m), 3.00-2.96 (1H, m), 2.89 (6H, s), 2.87-2.85 (2H, m), 2.84-2.76 (1H, m), 2.98 (3H, s), 2.12-2.10 (1H, m), 1.85-1.82 (1H, m), 1.71-1.56 (2H,m) HR Calcd forC26H30N2O5(M+Hf451.2228. Found451.2213.For LR 451(M+H)4 ÇT" v -o V-L-o VoH 0 C-80 O (DMSO-d6, 300 MHz) 12.40 (1H, s), 8.14-8.11 (2H, m), 8.03-8.04 (2H, m), 7.19-7.16(2H. m). 6.89-6.86 (2H, m), 4.24 (2H, t, J =6.5 Hz), 3.80 <2H, t, J = 6.6 Hz), 3.09-3.04(1H, m), 3.00 (2H, t, J = 6.4 Hz), 2.91-2.86(1H, m), 2.45 (3H, s), 2.19-2.13 (1H, m),1.88-1.67 (3H, m) HR Calcd forC25H24N2O5(M+H)4433.1758. Found433.1741.For LR 433(M+H)4 C-81 XV jfj^ 0 \ 0 (DMSO-de, 300 MHz) 8.10 (1H, s), 8.03- 7.96 (4H, m), 7.48 (1H, s), 7.15-7.12 (2H,m), 6.85-6.83 (2H, m), 4.20 (2H, t, J = 6.5Hz), 3.76 (2H, t, J = 6.5 Hz), 3.04-3.00 (1H,m), 2.95 (2H, t, J= 6.5 Hz), 2.86-2.82 (1H,m), 2.39 (3H, s), 2.12 (1H, m), 1.83-1.60(3H, m) For LR451(M+H)4 C-82 Vc ^~0H (CDCI3, 300 MHz) 7.85-7.77 (2H, m), 7.68-7.63 (1H, m), 7.15-7.12 {2H, m), 6.82-6.80(2H, m). 4.22 (2H, t, J = 6.5 Hz), 4.01-3.96(1H, m), 3.90-3.85 (1H, m), 3.19-3.14 (1H,m), 2.97 (2H, t, J = 6.5 Hz), 2.90-2.85 (1H.m), 2.39 (3H, s), 2.36-2.32 (1H, m), 2.06-1.96 (1H, m), 1.87-1.77 (2H, m). HR Calcd forC25H23NOsF4(M+H)4494.1585. Found494.1579.For LR 494(M+H)4 C-83 ?<JU N Λ '"ΤΌ ^~OH 0 (CDCI3, 400 MHz) 7.87-7.84 (2H, d), 7.23-7.21 (2H, d), 7.14-7.12 (2H, d), 6.82-6.80(2H, d), 4.19 (2H, t, J = 6.5 Hz), 4.01-3,94<1 H, m), 3.87-3.81 (1 H, m), 3.17-3.14 (1H,m), 2.95 (2H, t, J= 6.5 Hz), 2.90-2.87 (1H,m), 2.38 (3H, s), 2.35 (3H, s), 2.33-2.30 (1H,m), 2.03-1.95 (1H, m), 1.87-1.72 (2H, m). For LR 422(M+H)4 C-84 O / (CDCI3, 400 MHz) 7.92-7.90 (2H, m), 7.12-7.10 (2H, m), 6.94-6.92 (2H, m), 6.80-6.78(2H, m), 4,18 (2H, t, J = 6.5 Hz), 4.02-3.97(2H, m), 3.84 (3H, s), 3.17-3.13 (1H, m),2.95 (2H, t, J = 6.5 Hz), 2.90-2.86 (1H, m),2.35 (3H, s), 2.03-2.00 (2H, m), 1.87-1.81(2H, m). HR Calcd for C25H27NO6 (M+H)4 438.1911. Found438.1913.For LR438(M+H)4 C-85 çV /0 0 (CDCI3, 400 MHz) 7.57-7.55 (1H, m), 7.51-7.49 (1H, m), 7.35-7.30 (1H, m), 7.10-7.07(2H, m), 6.97-6.93 (1H, m), 6.81-6.78 (2H,m), 4.19 (2H, t, J = 6.5 Hz), 3.87 (3H, s),3.04 (2H, s), 2.96 (2H, t, J = 6.5 Hz), 2.48-2.38 (2H, m) 2.36 (2H, s), 2.11-2.02 (2H, m)1.94-1.85 (2H,m). 13157 . -92- C-8S 0 (CDCIs. 400 MHz) 7.97 (1 H, s). 7.86-7.84(1 H, m), 7.37-7.35 (2H, m), 7.15-7.12 (2H.m), 6.82-6.80 (2H, m), 4.20 (2H, 1, J = 6.5Hz), 3.99-3.95 <1H, m), 3.88-3.84 (1H, m),3.18-3.14 (1H, m), 2.96 (2H, t, J= 6.5 Hz),2.90-2.87 (1H, m), 2.37 (3H, s), 2.36-2.31(1H, m), 2.01-1.98 (1H, m), 1.88-1.73 (2H,EDI C-87 \~-Vo y-oH O CDCI3, 400 MHz) 8.24 (1H, s), 8.15-8.14 (1H, m), 7.66-7.64 (1H, m), 7.57-7.54 (1H,m). 7.15-7.13 (2H, m), 6.82-6.80 (2H, m),4.21 (2H, t, J = 6.5 Hz), 3.88-3.84 (2H, m),3.18-3.15 (1H, m), 2.97 (2H, t, J = 6.5 Hz),2.90-2.86 (1H, m), 2.39 (3H, s), 2.01-1.98(2H, m), 1.85-1.81 (2H, m). HR Calcd forC25H24NO5F3(M+H)*476.1680. Found476.1687.For LR 477(M+H)" C-88 y-oH 0 (CDCIs, 400 MHz) 7.91-7.89 (2H, m), 7.40-7.38 (2H, m), 7.14-7.13 (2H, m), 6.81-6.79(2H, m), 4.19 (2H, t, J = 6.5 Hz), 4.02-3.93(2H, m), 3.19-3.14 (1 H, m), 2.95 (2H, t, J =6.5 Hz), 2.90-2.87 (1H, m), 2.36 (3H, s),2.01-1.94 (2H, m), 1.87-1.81 (2H, m). HR Calcd forC2«tH24NO5CI(M+H)*442.01416. Found442.1413.For LR 443(M+H)" C-89 û (CDCI3,400 MHz) 7.81-7.75 (2H, m), 7.32-7.28 (1H, m), 7.22-7.20 1H, MO, 7.14-7.12(2H, m), 6.81-6.78 (2H, m), 4.19 (2H. t, J =6.5 Hz), 3.98-3.81 (2H, m), 3.17-3.10 (1H,m), 2.96 (2H, t. J= 6.5 Hz), 2.91-2.86 (1H.m), 2.38 (3H, s), 2.36 (3H. s), 2.00-1.69 (4H,m). HR Calcd for C25H27NO5 (M+H)" 422.1962. Found422.1948.For LR 422(M+H)" C-90 ' ' 0 (CDCI3, 300 MHz) 8.09-8.06 (2H, d), 7.69-7.66 (2H, d), 7.15-7.12 (2H, m), 6.82-6.79(2H, m), 4.21 (2H, t, J = 6.5 Hz), 4.00-3.81(2H, m), 3.18-3.14 (1H, m), 2.97 (2H, t, J =6.5 Hz), 2.91-2.86 (1H, m), 2.39 (3H, s),2.36-2.30 (1H, m), 2.04-1.72 (3H, m). HR Calcd forC25H24NO5F 3(M+H)"476.1680. Found476.1661.For LR 475(M+H)" C-91 (CDCI3,400 MHz): 7.99-7.97 (2H, m), 7.66(1H, d, J = 9.3 Hz), 7.62-7.59 (2H, m), 7.45-7.32 (4H, m), 7.11-7.08 (2H, m), 4.31 (2H, t,J =6.6 Hz), 3.97-3.82 (2H, m), 3.34 (1H, d,J= 13.9 Hz), 3.08-3.01 (3H, m,) 2.39-2.33(4H, m), 2.08-2.00 (1H, m), 1.87-1.67 (2H,m) for LR 458 (M+H)" 13157 . -93- C-92 (CDCIs, 400 MHz): 7.98 (2H, d, J = 5.8 Hz),7.68 (1H, d, J= 9.1 Hz), 7.62-7.60 (2H, m),7.42-7,33 (4H, m), 7.14(1 H, dd, J = 2.2, 8.8Hz), 7.07 (1H, s), 4.06-3.96 (3H, m), 3.87(1H, q, J = 7.5 Hz), 3.36 (1H, d, J = 13.9Hz), 3.08 (1H, d, J = 13.9 Hz), 2.73 (2H, t, J= 7.1 HZ), 2.43-2.35 (1H, m), 2.27 (3H, s),2.22-2.15 (2H, m), 2.10-2.01 (1H, m), 1.88-1.72 (2H,m) for LR 472 (M+H)+ C-93 (MeOD, 400 MHz): 7.93-7.90 (2H, m), 7.63- 7.56 (3H, m), 7.41-7.38 (3H, m), 7.31 (1H,dd, J = 2.5, 8.9 Hz), 5.01 (2H, s), 3.84-3.73(2H, m), 3.23-3.00 (2H, m), 2.39 (3H, s).2.23-2.16 (1H, m). 1.96-1.88 (1H, m), 1.76-1.57 (2H, m) for LR 444 (M+H)+
Alternative Préparations of the enantiomers of 2-({6-l2-(5-roethyl-2-phenvl-1.3- oxazol-4-vl)ethoxvlpvridin-3-yl)methyl)tetrahvdrofuran-2-carboxylic acid (Examples C-48a and C-48b) S Example C-48a
Enantiomer 1 of 2-((6-f2-(5-methvl-2-phenyl-1.3-oxazol-4-yl)ethoxy)pyridin-3- yl)methvl)tetrahvdrofuran-2-carboxylic acid
O
Lithium hydroxide monohydrate (993 mg, 21.1 mmol) was added to a solution of 10 (4S)-4-benzyl-3-{[2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yI)ethoxyjpyridin-3- yl}methyl)tetrahydrofuran-2-yl]carbonyl)-1,3-oxazolidin-2-one (600 mg, 1.06 mmol)in a mixture of tetrahydrofuran:methanol:water (1:1:1, 12 mL). The mixture wasstirred at 50°C for 4.5 hours, then cooled to ambient température and stirred for 2days. The volatile components were removed by évaporation and the residue was 15 difuted with water (5 mL) and extracted with 1:1 hexanes:ether. The aqueousphase was acidified to pH 5 and extracted with ethyl acetate. The organic phasewas washed with brine, dried over magnésium sulfate, filtered and evaporated. Theresidue was purified twice by flash column chromatography (95:4:1dichloromethane:methanol:ammonium hydroxide) to yield the title compound as a 20 colorless oil (72 mg) LRMS(m/z):4Q9 (M+H)+. 1H NMR (CDCIs, 300 MHz) 7.99-7.94 (3H, m), 7.49 (1H, dd, J = 2.4, 8.6 Hz), 7.44-7.36 (3H, m), 6.63 (TH, d, J = 8.5 Hz), 4.50 (2H, t, J = 6.7 Hz), 4.00-3.93 (1H, m), 13157 . -94- 3.89-3.81 (1H, m), 3.14 <1 H, d, J = 14.1 Hz), 2.95 (2H, t, J = 6.7 Hz). 2.85 (1H, d, J= 14.1 Hz), 2.31 (3H, s), 1.99-1.73 (4H, m).
Example C-48b
Enantiomer 2 of 2-(f6-ï2-(5-methvl-2-phenyl-1,3-oxazol-4-vl)ethoxvlpyridin-3-5 yl)methyl)tetrahydrofuran-2-carboxvlic acid
Enantiomer 2 was prepared using a similar sequence of reactions to thosedescribed for enantiomer 1, excepf starting from (4R)-4-benzyl-1,3-oxazolidin-2-one.
Example C-94 10 1-f6-f2-(5-Methvl-2-phenvl-oxazol-4-vl)-ethoxvl-pyridin-3-vlmethvl)- cyclooropanecarboxylic acid
O
To a solution of 1-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}- 15 cyclopropanecarboxylic acid fert-butyl ester (0.2017 g, 0.4642 mmol) in anisole (1.2mL) was added trifiuoroacetic acid (1.2 mL). The resulting solution was stirred atambient température for 3 hours and then concentrated under reduced pressure.The crude residue was diluted with ethyl acetate (25 mL) and water (10 mL) andthen basified to pH 5-6 by the addition of saturated aqueous sodium bicarbonate. 20 The phases were separated and the aqueous layer extracted with ethyl acetate (3x 25 mL). The combined organic extracts were then dried (anhydrous magnésiumsulfate), filtered and concentrated in vacuo to afford the crude product. The pureacid (0.071 g, 40%) was obtained, by recrystallization from diethyl ether/ hexanes,as a white solid. 25 LRMS (m/z): 379 (M+Hf. 1H NMR (MeOD, 300 MHz): 7.89-7.83 (3H, m), 7.53 (1H, dd, J = 8.5, 1.9 Hz),7.37-7.35 (3H, m), 6.60 (1 H, d, J = 8.5 Hz), 4.39 (2H, t, J = 6.5 Hz), 2.87 (2H, t, J =6.4 Hz), 2.73 (2H, s), 2.23 (3H, s), 1.14-1.11 (2H, m), 0.77-0.74 (2H, m).
Example C-95 30 2-r2-(5-Methvl-2-phenyl-oxazol-4-vl)-ethoxvl-5-[2-(1H-tetrazol-5-vl)-tetrahvdro-furan-2-vlmethvll-pyridine
13157 . -95- A solution of 2-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}-tetrahydro-furan-2-carbonitrile (0.11 g, 0.27 mmol), sodium azide (0.04 g, 0.54mmol) and zinc bromide (0.03 g, 0.14 mmol) in water and isopropanol (1:2, 1.24 5 mL) was refluxed for 23 hours. After cooling to ambient température, the reactionwas quenched with 3N hydrochioric acid (0.14 mL) and ethyl acetate (2.8 mL), andthe mixture stirred until completely homogeneous. The aqueous phase wasextracted with ethyl acetate (3 x 50 mL) and the combined organic extracts washedwith water (30 mL), dried (anhydrous magnésium sulfate), filtered, and 10 concentrated in vacuo to give the crude product. The residue was recrystallizedwith diethyl ether/hexanes to afford the title compound (0.052 g, 44%) as a whitesoiid.
Etemental Analysis: Calcd C22H23N7O3 C 60.96, H 5.35, N 22.62. Found: C 63.50,H 5.62, N 18.80. 15 ’H NMR (CDCI3, 300 MHz): δ 7.93 (2H, m), 7.86 (1H, s), 7.40 (3H, m), 7.11 (1H, d,J= 1.7 Hz), 6.49 (1 H, d, J= 8.5 Hz), 4.42 (2H, t, J =6.6 Hz), 3.88 (2H, m), 3.12(2H, m), 2.92 (2H, t, J= 6.5 Hz), 2.62 (1H, m), 2.31 (3H, s), 2.23 (1H, m), 1.89 (2H,m). LRMS (m/z): 433 (M+H)*. 20 Préparations of starting materials for Examples C-1 to C-95 (Préparations c-1 to c- 130)
Préparation c-1 4-i2-(5-methyl-2-phenvl-1,3-oxazol-4-vl)ethoxv)benzaldehvde
25 To a solution of the 4-hydroxybenzaldehyde (5.05 g, 41.4 mmol), 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethan-1-ol (8.39 g, 41.4 mmol), and triphenylphosphine (10.9 g,41.4 mmol) in anhydrous tetrahydrofuran (165 mL), under an atmosphère ofnitrogen, was added diethyl azodicarboxylate (7.21 g, 41.4 mmol) dropwise. Theresulting solution was stirred at ambient température for 8 hours, then diluted with 30 water and extracted with ethyl acetate. The organic phase was dried (anhydrousmagnésium sulfate), filtered and evaporated in vacuo. This residue was thenpurified by flash column chromatography (hexanes to ethyl acetate) to yield the titlecompound as a white crystalline soiid (10.2 g, 80%). LRMS (m/z): 308 (M+H)*. 35 Préparation c-2
Methvl 1 -(hvdroxvf4-f2-(5-methvl-2-phenvl-1.3-oxazol-4-yl)ethoxvlphen vDmethvl) 13157 ; -96-
To a suspension of chromium(li) cbloride (1.00 g, 8.10 mmol) and lithium iodide(0.087 g, 0.648 mmol) in tetrahydrofuran (20 mL) was added 4-[2-(5-methyl-2-phenyi-1,3-oxazol-4-yl)ethoxy]benzaldehyde (Préparation 1) (1.00 g, 3.24 mmol)and methyl 1-bromocyclohexanoate (1.07 g, 4.85 mmol). The resulting mixturewas heated at 50 °C untii TLC analysis indicated the reaction was complété. Themixture was cooled to ambient température and satuarted aqueous sodiumchloride (15 mL) was added. The resulting mixture was stirred for 15 minutes, thenpartitioned between water and ethyl acetate. The organic phase was washed withwater and dried (anhydrous magnésium sulfate), filtered and evaporated. Theresidue was purified by flash column chromatography (hexanes to 50% ethylacetate/hexanes) to yield the title compound as a colorless oil (0.797 g, 55%).LRMS {m/z}: 450 (M+K)\
Préparation c-3
Ethyl 1-(hvdroxy(4-r2-(5-methyl-2-phenvl-1,3-oxazol-4- vl)ethoxv)phenyl)methvl)cvclobutane carboxvlate
OH O
Using anaiogous procedures to those described for Préparation c-2, the titlecompound was obtained as a colorless oil. LRMS (m/z): 436 (M+H)+.
Préparation c-4
Methyl 1-iï4-fallvlôxy)phenyflfhvdroxv)methvncyclopentanecarboxylate
OH O
To a solution of methyl cyclopentanoate (3.84 g, 30.0 mmol), in tetrahydrofuran (30mL) at -78 °C was added a solution of lithium diisopropyiamide (15.0 mL of a 2M intetrahydrofuran, 30.0 mmol) dropwise. The mixture was stirred for 2 hours andthen 4-allyloxy benzaidehyde (2.12 g, 13.1 mmol) was added. The mixture wasaliowed to warm to ambient température and stirred for 18 hours. The mixture wasdiluted with water and extracted with ethyl acetate. The organic phase was 13157 ; -97- washed with saturated aqueous sodium chloride and dried (anhydrous magnésiumsulfate), filtered and evaporated. The residue was purified by flash columnchromatography (hexanes to 50% ethyl acetate/hexanes) to yield the titlecompound as a colorless pii (3.67 g, 97%). LRMS (m/z): 273 (M-OHf.
Préparation c-5
Methyl 4-[|4-fbut-3-envloxv)phenvnfhvdroxv)methvlltetrahvdro-2H-pvran-4-
10
Using analogous procedures to those described for Préparation c-4, the titlecompound was obtained as a colorless oil. LRMS (m/z): 273 (M-OHf.
Préparation c-6
Ethyi 1 -if4-( ailyloxy) phe n vllthydroxylmethyllcvclobutanecarboxylate 15
20 25
Using analogous procedures to those described for Préparation c-4, the titlecompound was obtained as a colorless oil. LRMS (mfc): 289 (Mf. 1H NMR (CDCI3, 300 MHz) 7.22 (2H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.10-5.98 (1H, m), 5.39 (1H, ddd, J= 1.5, 3.2, 17.3 Hz). 5.27 (1H, ddd, J= 1.5, 2.8,10.4Hz), 4.85 (1H, d, J = 6.4 Hz), 4.51 (2H, dt, J= 1.5, 5.3 Hz), 4.13 (2H, dq, J= 0.9,7.2 Hz). 3.12 (1H, d, J = 6.6 Hz), 2.84-2.78 (1H, m), 2.64-2.58 (1H, m), 2.35-2.29(2H, m), 1.89-1.83 (1H, m), 1.72-1.66 (1H,m), 1.19 (3H, t, J = 7.0 Hz).
Préparation c-7
Methyl 1 -(4-hvdroxvbenzyl)cvclopentanecarboxvlate ho. r~\
O
Triethylsilane (10.0 mL, 63 mmol) was added to a solution of methyl 1-([4-(aiiyloxy)phenyl](hydroxy)methyl]cyclopentanecarboxylate (Préparation c-4) (3.66g, 12.6 mmol) in dichloromethane (30 mL) and trifluoroacetic acid (30 mL) at room 30 température. The resulting mixture was stirred for 1 hour then evaporated in vacuo 13157 . -98- and azeotroped with toluene. The residue was dissolved in tetrahydrofuran (32mL) and morpholine (3.62 mL, 41.6 mmol) andtetrakis(triphenylphosphine)palladium (0) (1.46 g, 1.26 mmol) was added. Theresulting mixture was stirred at room température for 18 hours, filtered throughCelite and evaporated to dryness. The residue was dissolved in ethyl acetate andwashed with 1N hydrochloric acid then saturated sodium bicarbonate solution. Theorganic phase was dried (anhydrous magnésium sulfate), filtered and evaporatedand the residue was purified by flash column chromatography (hexanes to ethylacetate) to yield the title compound as a white crystalline solid (1.75 g, 59%). LRMS (m/z): 233 (M)'.
Préparation c-8
Methyl 4-(4-hydroxvbenzvl)tetrahvdro-2H-pyran-4-carboxvlate
Using analogous procedures to those described for Préparation c-7. the titlecompound was obtained as a white crystalline solid. LRMS (m/z): 249 (M)'.
Préparation c-9
Ethyl 1 -(4-h ydroxvbenzvhcvclobutanecarboxvlate
O
Using analogous procedures to those described for Préparation c-7, the titlecompound was obtained as a white crystalline solid. LRMS (m/z): 234 (M)'. 1H NMR (CDCI3i 300 MHz) 6.97 (2H, d, J = 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz), 5.10(1H, bs), 4.10 (2H, q, J = 7.2 Hz), 3.00 (2H, s), 2.44-2.35 (2H, m), 2.07-1.99 (2H,m), 1.91-1.80 (2H, m), 1.20 (3H, t, J = 7.2 Hz).
Préparation c-10
Methyl 1-f4-i2-(5-methvl-2-phenyl-1.3-oxazol-4-yl)ethoxv1benzvl cvclopentanecarboxvlate
compound was obtained as a coioriess oil. 1 3157 ; -99- LRMS (m/z): 249 (Μ)'.
Preparation c-11
Methyl 1H4-|3-(5-methyl-2-phenvl-1,3-oxazol-4- vDpropoxylbenzvlïcvclopentanecarboxvlate
O
OMe 10 10
Using analogous procedures to those described for Préparation c-1-c-7, the titlecompound was obtained as a colorless oil. LRMS (m/z): 434 (IW+H)*.
Préparation c-12
Methyl 4-(4-f2-<5-methvi-2-phenyl-1,3-oxazol-4-vhethoxvlbenzvBtetrahvdro-2/-/- pyran-4-carboxvlate
15 15
Using analogous procedures to those described for Préparation c-l-c-7, the titlecompound was obtained as a colorless oil. LRMS (m/z): 436 (M+H)*.
Preparation c-13
Ethyl 1 -(4-T2-(4-bromophenv1)ethoxv1benzvl>cvclobutanecarboxylate 20 20
Using analogous procedures to those described for Préparation c-1-c-7, the titlecompound was obtained as a colorless oil. LRMS (m/z): 417 (M)+. 1H NMR (CDCIs, 300 MHz) 7.36 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz), 6.96
(2H, d. J = 8.7 Hz), 6.70 (2H, d. J = 8.7 Hz), 4.04 (2H, t, J = 6.8 Hz), 4.03 (2H, q, J = 7.2 Hz). 2.95 (2H, t, J = 6.8 Hz), 2.94 (2H. s), 2.37-2.27 <2H, m), 2.00-1.91 (2H,m), 1.84-1.73 (2H, m), 1.14 (3H, t, J = 7.2 Hz).
Préparations c-14 to c-35
Préparations c-14 to c-35 were prepared using analogous procedures to those used for Préparation c-1, 13157 . -100-
Prep # Structure 1HNMR MS (mÆ) (LR or HR) c-14 Ψ" '—o t b? For LR 463(M+H)4 oH_ c-15 ci' N t V (CDCb, 300 MHz) 8.14-8.11 (1H,m). 7.78-7.75 (1H, m), 7.67-7.S2(1H. m), 7.51-7.45 (1 H. m), 7.04-7.01 (2H. m), 6.80-6.78 (2H, m),4.23 (2H, t, J = 6.5), 4.13-4.06 (2H,q, J = 7.1 Hz), 3.00 (2H, t, J =3.3Hz), 2.42 (3H, s), 2.40-2.36 (2H,m), 2.05-2.00 (2H, m), 1.87-1.84(2H,.m), 1.21 (3H,t, J =7.1 Hz). For LR 446(M+H)4 c-16 ar rv (CDCb, 300 MHz) 8.07-8.04 (2H,m), 7.71-7.68 (2H, m), 7.03-7.01(2H, m), 6.78-6.75 <2H, m), 4.19(2H, t, J= 6.5 Hz), 4.13-4.06 (3H,m), 2.99 (2H, s), 2.96 (2H, t, J =S.5Hz), 2.39 (3H, s), 2.38-2.34 (2H,m), 2.02-1.99 (2H, m), 1,87-1.82(2H, m), 1.20 (3H,t, J = 6.9 Hz). For LR 445(M+H)4 o-17 UJ ri \_ Ό V (CDCb, 300 MHz) 8.08-8.05 (2H,m), 7.71-7.68 (2H, m), 7.16-7.13(2H, m), 6.80-6.77 (2H, m), 5.01-4.92 (2H, m),4.21 (2H, t, J = 6.5Hz), 3.92-3.85 (2H, m), 3.15-3.08(1H, m), 2.97 (2H,t, J = 6.4 Hz),2.95-2.88 (1H,m),2.40(3H, s),2.28-2.21 (1H, m), 2.04 (3H, s),1.91-1.86 (2H,m). For LR461(M+H)4 ο-1δ vC ' · ί Π-. N > "kv For LR 506(M+H)4 c-19 Cl ? V, Z \ N V “0 V 0 (CDCb, 300 MHz) 8.05-8.04 (1H,d), 7.79-7.75 (1 H, m), 7.47-7.44(1H, d), 7.03-7.00 (2H, m), 6.76-8.75 (2H, m), 4.18 (2H, t, J= 6.5Hz), 4.13-4.06 (2H, q, J = 7.1 Hz),3.00 (2H, s), 2.94 (2h, t, J =6.5 Hz), 2.49-2.36 (2H, m), 2.35 (3H,5),2.04-1.97 (2H, m), 1.87-1.81 For LR 489(M+H)4 13157 ; -101-
2H, m), 1.20 (3H,t, J = 74 Hz). c-20 jQ ÎV-, N X For LR 435(M+Hf T, O V_ c-21 JO >fcs. z”"1 ForLR 455(M+Hf K 0 V_ c-22 -JO N )~Û 0 For LR 450(M+Hf c-23 V 0 (CDCIa, 400 MHz) 7.57-7.56 (1H,m), 7.51-7.50 (1H, m), 7.34-7.30(1H, m), 7.03-7.01 (2H, m), 6.96-6.93 (1H, m), 6.80-6.77 {2H, m).4.20 (2H. t. J = 6.6 Hz), 4.12-4.07(2H, q, 7 = 7.0 Hz), 3.86 (3H, s),3.00 (2H, s), 2.95 (2H, t, J =6.5Hz), 2.42-2.37 (2H, m), 2.35 (3H,m), 2.05-1.98 (2H, m), 1.88-1.81(2H, m). For LR 450(M+Hf c-24 XJ ?"v. Jîs, Z^ V_o ForLR 450(M+Hf o °V 13157 . -102- c-25 For LR 488(M+Hf c-26 y~oz 0 For LR 466(M+Hf c-27 _ V-o 0 (CDCI3,400 MHz) 7.57-7.56 (1H,m), 7.51-7.50 (1 H, m), 7.34-7.30(1H, m), 7.03-7.01 (2H, m), 6.96-6.93 (1H, m), 6.80-6.77 (2H, m),4.20 (2H. t, J = 6.5 Hz), 4.12-4.07(2H, q, J =7.0 Hz), 3.86 (3H, s).3.00 (2H, s), 2.95 (2H, t, J =6.5Hz), 2.42-2.37 (2H, m), 2.35 (3H,s), 2.05-1.98 (2H, m), 1.86-1.81(2H, m) 1.20 (3H,t, J = 7.0 Hz). For LR 450(M+H)+ c-28 0 \_ (CDCI3, 400 MHz) 7.97(1 H, s), 7.86-7.83 (1H, s), 7.35-7.33 (2H,m), 7.03-7.01 (2H, m), 6.79-6.77(2H, m), 4.19 (2H, t, J= 6.5 Hz),4.12-4.07 (2H, q, J = 7.0 Hz), 3.00(2H, s), 2.95 (2H, t, J = 6.5 Hz),2.422.38 (2H. m). 2.35 (3H, s),2.05-1.99 (2H, m), 1.91-1.82 (2H,m), 1.20 (3H, t, J = 7.0 Hz) For LR 454(M+H)+ c-29 '--Vo o (COCI3,400 MHZ) 7.97 (1H, s),7.87-7.84 (1H, m), 7.36-7.35 (2H,m), 7.16-7.14 (2H, m), 6.81-6.78(2H, m), 4.21 (2H, t, J= 6.5 Hz),4.15-4.10 (q, J= 7.0 Hz), 3.91-3.87(2H, m), 3.14-3.10 (1H,m), 2.96(2H, t, J= 6.5 Hz), 2.93-2.90 (1H,m), 2.37 (3H, s), 2.26-2.12 (2H, m),1.89-1.76 (2H.m), 1.21 (3H, t, J =7.0 Hz). For LR 470(M+H)+ c-30 ? cTV. (CDCI3,400 MHz) 8.24 (1H, s), 8.16-8.14 (1H, m), 7.66-7.64 (1H,m), 7.57-7.53 (1H, m), 7.16-7.14(2H, m), 6.81-6.79 (2H, m), 4.22(2H, t, J = 6.5 HZ), 4,15-4.10 (2H,q, J =7.0 Hz), 3.93-3.86 (2H, m),3.14-3.11 (1 H, m),2.97 (2H, t, J =6.5 Hz), 2.93-2.90 (1H, m), 2.39(3H, s), 2.26-2.20 (2H, m), 1.91- For LR 504(M+H)+ 13157 . -103- 1.78 (2H, m), Ï.21 (3H, t, J = 7.0Hz). c-31 ' (CDCI3, 300 MHz) 7.81-7.75 (2H,m), 7.32-7.27 (1H, m), 7.21-7.19(1H. m), 7.03-7.00 (2H, m), 6.78-6.76 (2H, m),4.19(2H, I, J = 6.5Hz), 4.13-4.06 (2H, q, J= 7.1 Hz),3.00 (2H, S), 2.95 (2H, t, J = 5.5Hz), 2.43-2.40 (2H, m), 2.37 (3H,s), 2.35 (3H, s), 2.07-1.97 (2H. m),1.89-1.79 (2H, m), 1.19 (3H, t, J =7.1 Hz) For LR 434(M+Hf c-32 (CDCIa, 300 MHz) 8.09-8.06 (2H,m), 7.69-7.66 (2H, m), 7.04-7.01(2H, m), 6.80-6.77 (2H, m), 4.21(2H, t, J= 6.5 Hz), 4.15-4.06 (2H,m), 3.00 (2H, s), 2.96 (2H, t, J =6.5 Hz), 2.43-2.34 (5H, m), 2.01-1.97 (2H, m), 1.92-1.79 (2H,m),1.20 (3H, t, J = 7.1 Hz) For LR 488(M+H)+ c-33 For LR 470(M+H)+ c-34 Aç 7ά_ (CDCI3i 300 MHz) 7.81-7.75 (1H,m). 7.33-7.27 (2H, m), 7.22-7.19(1H, m), 7.16-7.13 (2H, m), 6.81-6.78 (2H, m), 4.20 (2H, t, J = 6.7Hz), 4.16-4.09 (2H, q, J= 7.1 Hz),3.94-3.82 (2H, m), 3.14-3.08 (1H,m), 2.98-2.94 (2Htt, J= 6.5 Hz),2.94-2.88 (1H, m), 2.38 (3H, s),2.36 (3H. s), 2.27-2.19 (1H, m),1.92-1.74 (2H. m), 1.68-1.62 (1H,m), 1.21 (3H, t, J = 7.1 Hz). For LR 450(M-i-H)+ c-35 \__ • % y~°, 0 \_ (CDCI3, 300 MHz) 8.09-8.07 (2H,m), 7.69-7.66 (2H, m), 7.16-7.14(2H, m), 6.81-6.78 (2H, m), 4.21(2H, t, J= 6.5 Hz), 4.16-4.09 (2H,q. J = 7.1 Hz), 3.95-3.83 (2H, m),3.15-3.10 (1H, m), 2.97 (2H, t, J =6.5 Hz), 2.94-2.89 (1H, m), 2.39(3H,s), 2.27-2.18 (1H, m), 1.92-1.61 (3H, m), 1.21 (3H,t, J = 7.1 m For LR 504(M+Hf 13157 . -104-
Preparation c-36
Ethyl 1H4-t2-(4'-mefooxv-1.T-biphenyl-4-yl)ethoxv)benzyl)cyclobutanecarboxvlate
5 To a solution of ethyl 1-(4-(2-(4- bromophenyl)ethoxy]benzyl}cyclobutanecarboxylate (Préparation c-13) (0.25 g,0.5990 mmol), tetrakis(triphenylphosphine)palladium(0) (0.1252 g, 0.6589 mmol),benzene (1.6 mL), and 2M aqueous sodium carbonate (0.8 mL), under anatmosphère of nitrogen, was added a solution of the boronic acid (0.8640 mmol, 10 1.1 equiv.) in éthanol (0.4 mL). The resulting mixture was degassed and then refluxed for 16 hours followed by cooling to ambient température. To fois was thenadded 30% aqueous hydrogen peroxide (0.04 mL) dropwise and the resultingsolution stirred at ambient température for 1 hour. The solution was then extractedwith efoyl acetate (3x100 mL) and the combined organic extracts washed with 15 saturated aqueous sodium chloride (100 mL), dried (anhydrous magnésiumsulfate), filtered and concentrated in vacuo to afford the crude product. Theresidue was purified by flash column chromatography (hexanes to 40% ethylacetate/hexanes) to yield the pure product as a colorless oil. LRMS (m/z): 462 (M+H2O)+. 20 1H NMR (CDCL 300 MHz) 7.51 (2H, d, J = 5.7 Hz), 7.49 (2H, d, J = 4.7 Hz), 7.32(2H, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.9 Hz), 6.80 (2H, d, J= 8.5 Hz), 4.15 (1 H, t, J = 7.2 Hz). 4.10 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 3.10 (2H,t, J =7.1 Hz), 3.01 (2H, s), 2.43-2.34 (2H, m), 2.07-1.98 (2H, m), 1.90-1.80 (2H,m), 1.20 (3H,t, J = 7.2 Hz). 25 Préparations c-37 to c-43
Préparations c-37 to c-43 were prepared usinq analoqous procedures to foose used for Préparation c-36
Preparatio n# Structure ’HNMR MS (m/z) (LR orHR) 13 157 . -105- c-37 (CDCIâl 300 MHz) 7.46 (2H, d, J = 8.9 Hz), 7.41(2H, d, J = 8.3 Hz), 7.27 <2H, d, J= 8.1 Hz),7.03 (2H, t, J = 8.9 Hz), 6.97 (2H, d, J = 8.5 Hz),6.73 (2H, d, J = 8,7 Hz), 4.09 (2H, t, J = 7.0 Hz),4.03 (2H, q, J = 7.0 Hz), 3.03 (2H, t, J ~ 7.0 Hz),2.94 (2H, s), 2.37-2.27 (2H, m), 2.00-1.91 (2H,m), 1.83-1.72 (2H, m), 1.13 (3H,t, J =7.1 Hz). for LR433(M+H)+ c-38 Af° ‘CH. O Ûo (CDCIj, 300 MHz) 7.48 (2H, d, J = 8.1 Hz), 7.34-7.29 (4H, m), 7.05 (2H, d, J = 8.7 Hz), 6.99 (2H,d, J = 8.5 Hz), 6.81 (2H, d, J = 8.7 Hz), 4.18(2H, t, J = 7.3 Hz), 4.11 (2H, q, J = 7.0 Hz), 3.81{3H, s), 3.12 (2H, t, J= 7.3 Hz), 3.02 (2H, s),2.44-2.35 (2H, m), 2.08-1.99 (2H, m), 1.91-1.80(2H, m), 1.21 (3H, t, J= 7.0 Hz). for LR467 (M+Naf c-39 (CDCb, 300 MHz) 7.53-7.49 (3H, m), 7.44 (2H,t, J = 7.9 Hz), 7.38 (2H, t, J= 7.9 Hz), 7.09 (1H,dm, J = 8.0 Hz), 7.04 (2H, d, J = 8.5 Hz), 6.80(2H, d, J = 8.5 Hz), 4.17 (2H, t, J = 7.0 Hz), 4.10(2H, q, J = 7.0 Hz), 3.12 (2H, l, J = 7.0 Hz), 3.01(2H, s), 2.44-2.35 (2H, m), 2.07-1.98 (2H, m),1.90-1.83 (2H,m), 1.21 (3H, t, J =7.2 Hz). for LR499(M+H)+ c-40 (CDCI3, 300 MHz) 8.36 (1H. s), 7.77 (1H, dd, J = 2.5 and 8.7 Hz), 7.46 (2H, d, J = 8.1 Hz), 7.35(2H, d, J= 8.1 Hz), 7.03 (2H, d, J= 8.3 Hz),6.81 {1 H, d, J = 8.3 Hz), 6.79 (2H, d, J= 8.3Hz), 4.16 (2H, t, J= 6.8 Hz), 4.09 (2H, q, J = 7.2 Hz), 3.97 (3H, s), 3.10 (2H,-t, J= 7.0 Hz), 3.00(2H, s), 2.43-2.33 (2H, m), 2.06-1.97 (2H, m),1.89-1.79 (2H. m), 1.20 (3H, t, J = 7.1 Hz). for LR446(M+Hf c-41 o<I<vo-œ/0^ (CDCI3, 300 MHz) 7.99 (2H, d, J= 8.1 Hz), 7.75(2H, d, J= 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz).7.40 (2H, d, J = 7.9 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.79 (2H, d,J = 8.5 Hz), 4.17 (2H, t, J = 6.8Hz), 4.09 (2H, q, J = 7.2 Hz), 3.13 (2H, t, J = 6.9Hz). 3.08 (3H, s), 3.00 (2H, s), 2.43-2.33 (2H,m), 2.06-1.97 (2H, m), 1.90-1.79 (2H, m), 1.20(3H, t, J = 7.2 Hz). for LR511 (M+Naf 13157. -106- c-42 (CDCfe, 300 MHz) 7.48 (2H, d, J = 8.3 Hz), 7.41(1H, $),7.34-7.31 (1H, m),7.31 (2H, d, J =8.3Hz), 7.04 (2H, d, J = 8.7 Hz), 6.85 (1H, d, J = 8.5 Hz), 6.80 (2H, d, J = 8.5 Hz), 4.61 (2H, t, J =8.7 Hz), 4.16 (2H, t, J = 7.2 Hz), 4.10 (2H, q, J =7.2 Hz). 3.27 (2H, t, J = 8.7 Hz), 3.10 (2H, t, J =7.0 Hz), 3.01 (2H, s), 2.44-2.35 (2H, m), 2.07-1.99 (2H, m), 1.91-1.83 (2H, m), 1.21 (3H,t, J =7.2 Hz). for LR 479 (M+Na)* c-43 NH-SOj-CHi (CDCIj, 300 MHz) 7.57 (2H, d, J= 8.5 Hz), 7.50(2H, d, J = 8.5 HZ), 7.35 (2H, d, J = 8.5 Hz),7.27 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.7 Hz), 6.79 (2H, d, J= 8.7 Hz), 6.37 (1H, bs), 4.16(2H, t, J= 7.0 Hz), 4.09 (2H, q, J= 7.0 Hz), 3.11(2H, d, J= 7.0 Hz), 3.04 (3H, s), 3.00 (2H, s),2.43-2.33 (2H, m), 2.06-1.97 (2H, m), 1.89-1.79(2H,m), 1.20 (3H, t, J =7.2 Hz). for LR508 (M)*
Preparation c-44
Methyl 4-(4-K5-methvl-2-phenvl-1.3-oxazol-4-vl)methoxv1benzvDtetrahvdro-2H- pyran-4-carboxylate 5 OMe A solution of methyl 4-(4-hydroxybenzyl)tetrahydro-2H-pyran-4-carboxylate(Préparation c-8) (0.500 g, 2.0 mmol), césium carbonate (1.96 g, 6.0 mmol) andchloride (0.458 g, 2.2 mmol) in acetonitrile was heated at 140 °C in a microwave 10 synthesizer for 10 minutes. The mixture was cooled, filtered and the filtrateevaporated. The residue purified by flash column chromatography (hexanes toethyl acetate) to yield the title compound as a white crystalline solid (0.827 g, 98%).LRMS (m/z): 422 (M+H)+.
Préparation c-45 15 5-Bromo-2-[2-(5-methvl-2-phenvl-1,3-oxazol-4-vl)ethoxvlpyridine
To a solution of 2,5-dibromo-pyridine (5 g, 21.1060 mmol) and 2-(5-methyl-2-phenyl-oxazot-4-yl)-ethanol (5.1472 g, 25.3271 mmol) in anhydrous tetrahydrofuran 1 3 157 -107- (85 mL), under an atmosphère of nitrogert, was added potassium terî-butoxide(2.8422 g, 25.3271 mmol). The resulting mixture was heated at reflux for 16 hoursand then allowed to cool to ambient température. The mixture was evaporate toabout 20 mL and partitioned between saturated aqueous ammonium chloride (50 5 rrrL) and ethyi acetate (50 mL). The layers were separated and the aqueous layerextracted with ethy! acetate (2x50 mL). The combined organic extracts were thenwashed with water (2x50 mL), saturated aqueous sodium chloride (50 mL), dried(anhydrous magnésium sulfate), filtered and concentrated in vacuo to afford thecrude product. The residue was purified by flash column chromatography 10 (hexanes to 20% ethyi acetate/hexanes) to yield a white crystalline solid (6.3 g,83%). LRM$ (m/z): 359 (Mf. 1H NMR (CDCb, 400 MHz) 8.17 (1H, d, J = 2.0 Hz), 7.96 (2H, dd, J = 2.0, 8.1 Hz),7.61 (1H, dd, 2.7, 8.7 Hz), 7.43-7.38 (3H, m), 6.62 (1H, d, J = 8.6 Hz), 4.52 (2H, 15 t, J = 6.8 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.32 (3H, s).
Préparations c-46 to c-47
Préparations c-46 to c-47 were prepared bv general procedure for Préparation c- 45.
Prep# Structure ’H NMR MS (m/z) (LR or HR) c-46 \=/ N^o N Cl (CDCIs, 400 MHz): 7.97 (2H,dd, J =8.0, 7.6 Hz), 7.49 (1H,dd, J = 8.T, 7.6 Hz), 7.43-7.38(3H, m), 6.87(1 H, d, J =7.6Hz), 6.62 (1H, d, J =8.1 Hz),4.55 (2H, t, J = 7.0 Hz). 2.97(2H, t, J =7.0 Hz), 2.34 (3H, s) for LR 315 (M+Hf c-47 (CDCfe, 300 MHz): 8.51 (2H,s), 7.97-7.94 (2H, m), 7.45-7.38(3H, m),4.61 (2H,t, J = 6.9 HZ), 3.01 (2H, t, J=6.9H2),2.35 (3H, s) for LR 361 (M+H)’ 13157 -108-
Preparation c-48 6-12-(5-Methyl-2-phenvl-1.3-oxazol-4-yhethoxv1nicotinaldehyde
O
H
To a solution of butyliithium (27.4 mL of a 1.6M solution in hexanes, 43.8199 mmol)in anhydrous tetrahydrofuran (200 mL), under an atmosphère of nitrogen, wasadded a solution of 5-bromo-2-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Préparation c-45) (14.31 g, 39.8363 mmol) in anhydroustetrahydrofuran (170 mL) and anhydrous diethyl ether (170 mL) over a period of 45minutes. To this solution was then added anhydrous W,A/-dimethylformamide (5.7mL) dropwise and the mixture stirred at 0 ’C for 1 hour. The reaction wasquenched by addition of saturated aqueous ammonium chioride (250 mL) and thenethyl acetate (250 mL). The resulting layers were separated and the aqueous layerextracted with ethyl acetate (2x250 mL). The combined organic extracts werewashed with water (2x250 mL), saturated aqueous sodium chioride (250 mL), dried(anhydrous magnésium sulfate), filtered and concentrated in vacuo to afford thecrude product The residue was purified by flash column chromatography(hexanes to 50% ethyl acetate/hexanes) to yield a pale yellow crystalline solid(7.17 g, 58%). LRMS (m/z): 309 (M+H)+. . ’H NMR (CDCI3i 300 MHz) 9.93 (1H, s), 8.61 (1H, d, J = 2.3 Hz), 8.04 (1H, dd, J = 2.5, 8.7 Hz), 7.98-7.95 (2H, m), 7.43-7.39 (3H, m), 6.81 (1H, d, J = 8.7 Hz), 4.68(2H, t, J = 6.8 Hz), 3.00 (2H, t, J = 6.8 Hz), 2.34 (3H, s).
Préparation c-49
Ethyl 1 -(hydroxy{6-f2-(5-methvl-2-phenyl-1,3-oxazol-4-vl)ethoxvlpyridin-3- vRmethvhcvclobutanecarboxvlate oh o
To a solution of 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde(Préparation c-48) (0.65 g, 2.1081 mmol), chromium (II) chioride (1 g, 8.1367mmol), and lithium iodide (0.0784 g, 0.5859 mmol) in anhydrous tetrahdrofuran (15mL), under an atmosphère of nitrogen, was added a solution of 1-bromo-cyclobutanecarboxylic acid ethyl ester (0.79 mL, 4.8821 mmol) in anhydrous 13157 . -109 - tetrahydrofuran (5 mL) dropwise. The resulting mixture was stirred at 50 °C for 3hours and allowed to cool to ambient température. The solution was thenquenched by addition of water (50 mL) and the organic layer separated, which wasfurther washed with water (2x50 mL), saturated aqueous sodium chloride (50 mL),dried (anhydrous magnésium sulfate), filtered and concentrated in vacuo to affordthe crude product: The residue was purified by flash column chromatography (50%ethyl acetate/hexanes to ethyl acetate) to yield a yellow oil (0.3422 g, 37%). LRMS (m/z): 437 (M+Hf. 1H NMR (CDCI3, 400 MHz) 8.05 (1H, d, J = 2.3 Hz), 7.98-7.95 (2H, m), 7.56 (1H,dd, J = 2.5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (1H, d, J- 8.7 Hz), 4.85 (1H, d, J = 6.6 Hz), 4.54 (2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 3.31 (1H, bs), 2.96 (2H, t, J = 6.7 Hz), 2.46-2.30 (2H. m). 2.32 (3H, s), 2.21-2.12 (1H, m), 1.97-1.85 (1H, m),1.79-1.65 (2H, m), 1.21 (3H, L J = 7.2 Hz).
Préparation c-50 1-fEthoxv-(6-f2-f5-methvl-2-phenvt-oxazol-4-vl)-ethoxvl-pvridin-3-vl)-methvl)- cvclobutanecarboxylic acid ethyl ester
To a solution of 1-(hydroxy-(6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-yl)-methyl)-cyclobutanecarboxylic acid ethyl ester (0.1711 g, 0.3920 mmol) in dryacetonitrile (2 mL) was added silver(l) oxide (1.8168 g, 7.8396 mmol) andiodoethane (0.64 mL, 7.8396 mmol). The resulting mixture was stirred for 5 daysand concentrated under reduced pressure to afford the crude product andrecovered remaining starting matériel. The residue was purified by flash columnchromatography (hexanes to ethyl acetate) to yield the pure ester (0.0474 g, 26%)as a colorless oit. LRMS (m/z); 465 (M+H)+. 1H NMR (CDCI3, 400 MHz): 8.05 (1H, d, J = 2.3 Hz), 7.98-7.95 (2H, m), 7.56 (1H,dd, J- 2.5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (1H, d, J~ 8.7 Hz), 4.65 (1H, m), 4.54(2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 4.06 (2H, q, J = 7.1 Hz), 2.96 (2H, t, J = 6.7Hz), 2.46-2.30 (2H, m), 2.32 (3H, s), 2.21-2.12 (1H, m), 1.97-1.85 (1H, m), 1.79-1.65 (2H, m), 1.42 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.2 Hz).
Préparation c-51 13157 . -110- f6-i2-(5-rnethvl-2-phenvl-1.3-oxazol-4-vl)ethoxvlpyridin-3-vl)methanol
Sodium borohydride (0.480 g, 12.7 mmol) was added portionwise to a solution of 6-5 [2-(5-methyI-2-phenyl-1,3-oxazol-4-yl)ethoxy]riicotinaldëhyde (Préparation c-48) (1.30 g. 4.22 mmol) in methanol (40 mL) at ambient température. The mixture wasstirred for 30 minutes then evaporated. The residue was partitioned betweensaturated aqueous ammonium chloride and ethyï acetate. The organic phase waswashed with saturated aqueous sodium chloride and dried (anhydrous magnésium 10 sulfate), filtered and evaporated to give the title compound as a whitecrystailinesolid (1.24 g, 100%). LRMS (m/z): 311 (M+H)+. 1H NMR (CDCIs, 300 MHz) 8.11 (1 H, d, J = 2.6 Hz), 8.00-7.95 (2H, m), 7.60 (1H,dd, J= 2.5, 8.5 Hz), 7.45-7.38 (3H, m), 6.72 (1H, d, J= 8.5 Hz), 4.61 (2H, bs), 4.56 15 (2H, t, J= 6.8 Hz), 2.98 (2H, t, J= 6.8 Hz), 2.33 (3H, s).
Préparation c-52 f2-f2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy)-pvrimidin-5-vl}-methanol
A solution of 5-bromo-2-[2-(5-methyl-2-phenyl-oxazo!-4-yl)-ethoxy)-pyrimidine (1.0g, 2.7765 mmol), fert-butyl-dimethyl-tributylstannanylmethoxy-silane (1.8 g, 4.1648mmol), and tetrakîs(triphenylphosphine)palladium(0) (0.3209 g, 0.2777 mmol) in 25 1,4-dioxane (2.8 mL) was heated (by microwave irradiation) at 150 °C for 2 hours.
The resuiting solution was allowed to cool to ambient température and saturatedaqueous potassium fluoride (10 mL) was added followed by stirring for 30 minutes.This mixture was then extracted with ethyl acetate (3 x 25 mL) and the combinedorganic extracts dried (anhydrous magnésium sulfate), filtered and concentrated in 30 vacuo to afford the crude product as a yellow oil.
To a solution of the crude residue in dry tetrahydrofuran (24 mL) was addedtetrabutylammonium fluoride (3.1 mL of a 1.0M solution in tetrahydrofuran). Theresuiting mixture was stirred at ambient température for 16 hours and concentratedunder reduced pressure. The residue was purified by flash column 13157 . - 111 - chromatography (50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) toyieid the pure alcohol (0.6137 g, 71% for 2 steps) as a white solid. LRMS (m/ï): 312 (M+H)*
Préparation c-53 5 5-Benzvloxv-2-iTiethvl-Pvridine
To a solution of 5-hydroxy-2-methylpyridine (20 g, 183.2677 mmol) and sodiumhydroxide (8.0638 g, 201.5944 mmol) in acetone (400 mL) and water (120 mL) wasadded benzyl bromide (24 mL, 201.5944 mmol). The resulting mixture was 10 refluxed for 16 hours and allowed to cool to ambient température. The acetonewas removed in vacuo and the mixture extracted with ethyl acetate (3 x 150 mL).The combined organic extracts were washed with saturated aqueous sodiumchloride (200 mL), dried (anhydrous magnésium sulfate), filtered and concentratedin vacuo to afford the pure product (31.35 g, 86%) as an orange oil 15 LRMS (m/z): 200 (M+Hf. 1H NMR (CDCÎ3, 300 MHz): 8.25 (1H, d, J= 2.8 Hz), 7.43-7.31 (5H, m), 7.15 (1H,dd, J s 8.5, 2.8 Hz), 7.04 (1H, d, J= 8.5 Hz), 5.06 (2H, s), 2.47 (3H, s).
Préparation c-54 5-Benzvloxv-2-methvl-pyridine 1 -oxide 20
To a solution of 5-benzyloxy-2-methyl-pyridine (31.35 g, 157.34 mmol) in drychloroform (800 mL), at ambient température, was added 3-chloroperoxybenzoicacid (77% max.) (38.7888 g, 173.074 mmol). The resulting mixture was stirred for 25 2 hours and then quenched with a solution of sodium thiosulfate (36.0805 g, 286.5 mmol) in water (500 mL) and stirred for 15 minutes. The phases were separatedand the organic layer washed with water (500 mL), saturated sodium chloride (500mL), dried (anhydrous magnésium sulfate), filtered and concentrated in vacuo toafford the crude product. The residue was recrystallized from acetone/hexanes to 30 yieid the pure product (33.1597 g, 97%) as a white solid. LRMS (m/z): 216 (M+H)+.
'H NMR (CDÇI3i 300 MHz): 8.10-8.09 (1H, bm), 7.38-7.34 (5H, m), 7.10 (1H, d, J = 8.7 Hz), 6.87 (1H, dd, J = 8.7, 2.3 Hz), 5.04 (2H, s), 2.43 (3H, s). 13157 -112-
Preparation c-55 (5-Benzyloxv-pvridin-2-vi)-methanol
OH A solution of 5-benzyloxy-2-methyi-pyridine 1-oxide (0.92 g, 4.2741 mmoî) in aceticanhydride (6.5 mL) was heated at 100 °C for 30 minutes. After cooling to ambienttempérature, the reaction mixture was poured rnto ethyl acetate (50 mL), washedwith saturated aqueous sodium bicarbonate (50 mL), saturated aqueôus sodiumchloride (50 mL), dried (anhydrous magnésium sulfate), filtered, and concentratedin vacuo to afford the crude acetate.
To the crude residue in methanol (45 mL) was added potassium carbonate (2.1784g, 15.7719 mmol) and the solution allowed to stir at ambient température for 16hours. The reaction mixture was poured into water (50 mL) and the organicremoved under reduced pressure. The resulting residue was extracted with ethylacetate (3 x 50 mL) and the combined organic extracts dried (anhydrousmagnésium sulfate), filtered, and concentrated in vacuo to afford the crude product.The residue was purified by flash column chromatography (hexanes to 20%methanol/ethyl acetate) to yield the pure alcohol (0.5719 g, 62% fortwo steps) as awhite solid. LRMS (m/z): 216 (M+H)+. 1H NMR (CDCIs, 300 MHz): 8.31 (1H, d, J =2.8 Hz), 7.44-7.31 (5H, m), 7.27 (1H,dd, J =8.7. 2.8 Hz), 7.17 (1H, d, J =8.5 Hz), 5.11 (2H, s), 4.69 (2H, s).
Préparation c-56 2-Methyl-5-[2-( 5-meth vl-2-phenyl-oxazol-4-vD-ethoxyl-py ridine 1 -oxide
To a solution of 2-methyl-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine(6.7973 g, 23.0917 mmol) in dry chloroform (140 mL), at ambient température, wasadded 3-chloroperoxybenzoic acid (77% max.) (7.7629 g, 34.6376 mmol). Theresulting mixture was stirred for 2 hours and then quenched with a solution ofsodium thiosulfate (4.3621 g, 34.6376 mmol) in water (25 mL) and stirred for 15minutes. The phases were separated and the organic layer washed with water (50mL), saturated sodium chloride (50 mL), dried (anhydrous magnésium sulfate),filtered and concentrated in vacuo to afford the crude product. This pale yeliow oil(7.0689 g, 98%) was used without further purification. 13157 -113- LRMS (nVz): 311 (M+H)\ 1K NMR (CDCfe, 300 MHz): 8.06 (1H, d, J= 2.3 Hz), 7.96-7.93 (2H, m), 7.41-7.39(3H, m), 7.10 (1H, d, J = 8.9 Hz), 6.85 (1H, dd, J= 8.8, 2.4 Hz), 4.23 (2H, t, J = 6.6Hz), 2.95 (2H, t, J= 6.6 Hz), 2.43 (3H, s), 2.35 (3H, s).
Préparation c-57 i5-f2-(S-Methvl-2-phenvl-oxazol-4-yl1-ethoxv1-pyridin-2-vl)-methanol
A solution of 2-methyl-5-[2-(5-methyl-2-phenyi-oxazol-4-yi)-ethoxy]-pyridine 1-oxide(3.5979 g, 11.5181 mmol) in acetic anhydride (17.5 mL) was heated at 100 °C for30 minutes. After cooling to ambient température, the reaction mixture was pouredinto ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate(150 mL), saturated aqueous sodium chloride (150 mL), dried (anhydrousmagnésium sulfate), filtered, and concentrated in vacuo to afford the crude acetate.To the crude residue in methanol (120 mL) was added potassium carbonate(5.8705 g, 42.617 mmol) and the solution allowed to stir at ambient température for16 hours. The reaction mixture was poured into water (150 mL) and the organicremoved under reduced pressure. The resulting residue was extracted with ethylacetate (3 x 150 mL) and the combined organic extracts dried (anhydrousmagnésium sulfate), filtered, and concentrated in vacuo to afford the crude product.The residue was purifïed by flash column chromatography (ethyf acetate to 10%methanol/ethyl acetate) to yield the pure alcohol (1.52 g, 43% for two steps) as apale yellow low melting solid. LRMS (mfc): 311 (M+H)*. 1H NMR (CDCIj, 300 MHz): 8.22 (1H, d, J= 2.5 Hz), 7.97-7.94 (2H, m), 7.42-7.38(3H, m), 7.20 (1H, dd, J= 8.5, 2.6 Hz), 7.15 (1H, d, J = 8.7 Hz), 4.67 (2H, s), 4.28(2H, t, J= 6.7 Hz), 2.98 (2H, t, J= 6.7 Hz), 2.37 (3H, s).
Préparation c-58 5-fchloromethvn-2-f2-(5-methyl-2-phenvl-1,3-oxazol-4-vl)ethoxvlpvridine
Cl
Oxalyl chloride (0.30 mL, 3.44 mmol) was added to a solution of {6-[2-(5-methyl-2-phenyl-I.S-oxazoM-yOethoxylpyridin-S-ylJmethanol (Préparation 26) (0.97 g, 3.13mmol) in dichloromethane (30 mL) and /V,/V-dimethyl formamide (3 mL) at 0 °C.The mixture was warmed to ambient température and stirred for 1 hour thenevaporated. The residue was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The organic phase was washed with saturated 13157 . -114- aqueous sodium chloride and dried (anhydrous magnésium sulfate), filtered andevaporated to give the title compound as a white crystalline solid (1.01 g, 100%).LRMS (m/z): 329 (M+Hf. 1H NMR (CDCl3, 300 MHz) 8.12 (1H, d, J= 2.5 Hz), 7.98-7.95 (2H, m), 7.60 (1Ή,5 dd, J = 2.5, 8.5 Hz), 7.45-7.37 (3H, m). 6.72 (1H, d, J = 8.5 Hz), 4.57 (2H, t, J = 6.8
Hz), 4.53 (2H, s), 2.97 (2H, t, J= 6.8 Hz), 2.33 (3H, s).
Préparations c-59 to c-63
Préparations c-59 to c-63 were prepared bv general procedure for Préparation c-58
13157 . 110
Prep# Structure 1H NMR MS (m/z) (LR or HR) c-59 îmx ïyci forLR 330 (M+Hf c-60 fV'a Cf0^ for LR 234 (M+H)+ c-61 for LR 329 (M+Hf c-62 fKi /TCI \==/ Ν'λ^Ο N (CDCI3, 300 MHz):. 8.16 (2H, s), 7.97 (2H, d, J = 7.7 Hz), 7.40 (3H, s), 4.61 (4H, m), 2.99 (2H,t, J = 5.7 Hz), 2.35 (3H. s) for LR 330 (M+H)* c-63 (CDCI3,400 MHz):. 7.75-7.72 (3H,m), 7.50-7.33 (6H, m), 7.24-7.22 (2H, m), 5.18 (2H, s), 4.74 (2H, s) for LR 282 (M+H)+
Préparation c-64 5-(iodomethvl)-2-f2-(5-methvl-2-phenvl-1,3-oxazol-4-vl)ethoxvlpyridine
5 Sodium iodide (0.750 g) was added to a solution of 5-{chloromethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxylpyridine (Préparation 27) (0.690 g, 2.10mmol) in acetone (5 mL) and the mixture was heated at reflux for 30 minutes,cooled and evaporated. The residue was suspended in ethyl acetate and filteredthrough a pad of silica gel. The filtrate was evaporated to give the title compound 10 as a yellow crystalline solid that was used directly in subséquent reactions. LRMS (m/z): 421 (M+H)+. 13157 ; 116
Préparations c-65 to c-69
Préparations c-65 to c-69 were prepared bv general procedure for Préparation c-64
Prep # Structure 1H NMR MS (m/z) (LR or HR) c-65 \ / A Λ IL J for LR 422 (M+H)+ c-66 œ..CT' for LR 326 (M+H)+ c-67 for LR 421 (M+H)* c-68 for LR 422 (M+Hf c-69 œo-oœ' (CDCI3,400 MHz)·, 7.76-7.66 (3H, m). 7.49-7.32 (5H, m), 7.24-7.18 (2H,m), 5.18 (2H, s), 4.63 (2H, s) for LR 375 (M+Hf - j. I }
Préparation c-70 5 Ethyi 1 -«6-[2-(5-methvl-2-phen yH .3-oxazol-4-vl)ethoxv)pyridin-3- vl)methvl)cvclobutane carboxylate o
Sodium (bis)trimethylsilyl amide (3.0 mL of a 1M solution in tetrahydrofuran, 3.0mmol) was added dropwise to a solution of ethyi cyclobutanoate (0.41 mL, 3.0 10 mmol) in anhydrous tetrahydrofuran (5 mL) at -50 °C. The mixture was stirred for1 hour and then a solution of 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4- 5 1 3 157’/s 1 ε 1 10
15 20 25 30 yl)ethoxy]pyridine (Préparation 28) (0.271 g, 0.64 mmol) in anhydroustetrahydrofuran (4 mL) was added dropwise. The resulting mixture was stirred at -60 ®C for 1 hour then quenched with saturated aqueous ammonium chloride andwarmed to ambient température. The mixture was extracted with ethyl acetate andthe organic phase dried (anhydrous magnésium sulfate), filtered and evaporated toafford a 1:1 mixture of the title compound and dimer (0.160 g) which was useddirectiy in the subséquent step. LRMS (m/z): 421 (IVH-Hf.
Préparation c-71 ethyl 2-({6-f2-(5-methyl-2-phenyl-1,3-oxazol-4-vl)ethoxvlDvridin-3- vl)methyl)tetrahydrofuran-2-carboxvlate
O
Sodium (bis)trimethyisiiyl amide (3.18 mL of 1M solution in tetrahydrofuran, 3.18mmol) was added dropwise to a solution of ethyl 2-tetrahydrofuranoate (0.458 g,3.18 mmol) in anhydrous tetrahydrofuran (4 mL) at -50 °C. The mixture wasstirred for 45 minutes and then a solution of 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Préparation 28) (0.267 g, 0.64 mmol) inanhydrous tetrahydrofuran (2 mL) was added dropwise. The resulting mixture wasstirred at -50 °C for 1.5 hours then quenched with saturated aqueous ammoniumchloride and warmed to ambient température. The mixture was extracted withethyl acetate and the organic phase dried (anhydrous magnésium sulfate), filteredand evaporated. The residue was purified by flash column chromatography (25%to 35% ethyl acetate/hexanes) to yieid the title compound as a colorless oïl (0.250g, 90%). LRMS (m/z): 437 (M+H)\ 1H NMR (CDCI3, 300 MHz) 7.95 (3H, m), 7.51 (1H, dd, J = 2.5, 8.5 Hz), 7.43-7.36(3H, m), 6.61 (1H, d, J~ 8.5 Hz), 4.51 (2H, t, J = 6.8 Hz), 4.29-4.18 (1H, m), 413(2H, q, J = 7.2 Hz), 3.95-3.82 (2H, m), 3.10 (1H, d, J = UA Hz), 2.95 (2H, t, J =6.8Hz), 2.86 (1H, d, J = 14.1 Hz), 2.31 (3H, s), 2.25-2.20 (1H, m), 1.92-1.77 (2H, m),1.70-1.61 (1H, m). 1.21 (3H, t, J = 7.2 Hz).
Préparations c-72 to c-79
Préparations c-72 to c-79 were prepared-bv general procedure for Préparation c- 71.
Prep# Structure 'H nmr MS (m/z) (LR or 13157 118 HR) C-72 CDCI3, 300 MHz): 8.38 (2H, s), 7.97-7.94 (2H, τι). 7.44-7.38 (3H. m). 4.59 (2H. t, J= 7.0 Hz). 4.15 (2H. q, J= 7.0 Hz), 3.99-3.86 (2H, m), 3.13(1H, d, J- 14.3 Hz). 3.00 (1H, t, J= 6.9 Hz). 2.84 ,1H. d, J = 14.3 Hz), 2.35 (3H, s), 2.26-2.20 (1H,τι), 1.91-1.63 (4H, m), 1.23 (3H, t. J= 7.0 Hz) for LR 438 (M+Hf c-73 ;CDCI3, 300 MHz): 8.27 (1H, d, J= 2.3 Hz), 7.42-7.32 (5H, m), 7.20-7.13 (2H, m), 5.06 (2H, s), 4.13(2H, q, J= 13.9 Hz), 3.33 (1 H, d, J = 13.9 Hz), 3.14 (1 H, d, J= 13.9 Hz), 2.64-2.55 (1H, m), 2.27-2.20 (1 H, m), 1.89-1.63 (4H, m), 1.24 (3H, t, J = 13.9 Hz) for LR 342 (M+Hf c-74 JL-'N Pi (CDCIs, 300 MHz): 8.27 (1H, d, J= 2.6 Hz), 7.42-7.29 (5H, m), 7.16 (1H, dd, J = 8.7, 2.8 Hz), 7.14- 7.08 (1H, m), 5.06 (2H, s), 3.71 (3H, s), 3.30 (3H, s). 3.16 (2H, s), 1.40 (3H, s) for LR 316 (M+H)+ c-75 XY^°' Βγ'Ίμ / (CDCb, 400 MHz): 8.14 (1H, d, J= 2.3 Hz), 7.41(1 H, dd, J = 8.3, 2.5 Hz), 7.36 (1 H, dd, J = 8.3, 0.8Hz), 3.69 (3H, s), 3.27 (3H, s), 2.99 (1H, d, J~ 13.9 Hz), 2.87 (1H, d, J= 13.9 Hz), 1.33 (3H, s) for LR 289 (M+Hf c-76 (CDCb, 400 MHz): 8.17 (1H, d, J = 2.3 Hz), 7.96(2H, dd, J= 7.7, 1.9 Hz), 7.43-7.38 (3H, m), 7.12(1H, d, J = 8.1 Hz), 7.09 (1H, dd, J = 8.6, 2.8 Hz),4.24 (2H, t, J - 6.7 Hz), 4.15 (2H, q, J = 7.2 Hz), 3.88-3.84 (1H, m), 3.64 (1H, dt, J= 11.6, 3.3 Hz),3.07 (2H, s), 2.96 (2H, t, J- 6.6 Hz), 2.36 (3H, s),2.22-2.18 (1H, m), 1.52-1.36 (5H, m), 1.20 (3H, t, J = 7.1 Hz) forLR 451 (M+H)* c-77 (CDCb, 300 MHz); 8.09 (1H, s), 7.91-8.01 (3H, m)7.34-7.45 (3H, m), 4.48-4.64 (2H, m), 3.84-4.24(2H, m), 3.22 (1 H, d, J = 15.0 Hz), 3.11 (1 H, d, J-15.0 Hz), 2.91-3.03 (1H, m), 2.31-2.35 (1H, m), 1.65-2.30 (2H, m), 1.24 (3H, t, J = 6.6 Hz) for LR 438 (M+H)+ 13157 ’ 119
c-78 (CDCIa. 300 MHz): 7.96 (1 H, m), 7.92 (2H, d, J =2.1 Hz), 7.41 (4H, m), 6.63 (1H, d. J = 8.5 Hz), 4.52 (2H,t, J- 6.8 Hz), 3.70 (3H, s), 3.30 (3H, m),2.93 (4H. m), 2.33 (3H, s), 1.33 (3H, s) forLR 411 (M+Hf c-79 æXXJ-û (CDCI3, 400 MHz): 7.69 (1H, d, J = 9.3 Hz), 7.64- 7.62 (2H, m), 7.49-7.48 (2H, m), 7.42-7.32 (4H,m), 7.21-7.18 (2H, m), 5.17 (2H, s), 4.24-4.18 (2H,m). 3.96-3.86 (2H, m), 3.33 (1H, d, J= 13.6 Hz),3.13 (1H, d, J= 13.8 Hz), 2.32-2.20 (1H, m), 2.03-1.89 (3H,m), 1.19 (3H, t, J =7.1 Hz) for LR 391 (M+H)4
Préparation c-80 2-Bromo-5-ibromomethvDpyridine
Br
Br 10
15
Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridineclumped together and the mixture was heated to 160 degrees C. Within 5 minutesof stirring at > 150 degrees C the mixture was seen to go very dark in coior withgas évolution. The mixture was stirred at this same température for approximately2.5 hours at which point it was cooled to room température. The mixture wascooled further to 0 degrees C whereupon saturated sodium bicarbonate was addedvery cautiously (highly exothermicl). As foaming became less vigorous, ice wasadded to the mixture until foaming subsided. Solid sodium bicarbonate was thencarefully added to achieve a pH of ~ 8-9. The mixture was extracted with ethylacetate and the organic layer was washed with brine and dried over anhydrousmagnésium sulfate. Concentrated in vacuo to afford a dark solid. This matérielwas dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65iover a gradient of 0 - 100 % ethyl acetate in hexanes to afford the title compoundas a pale yellow solid (5.57 g, 44%). LRMS: 252 (M+H)+. 1H NMR (DMSO-de, 400 MHz); 8.39 (1H, s) 7.59 (1H, d, J = 8.5 Hz) 7.48 (1H, d, J= 8.5 Hz) 4.46 (2H, s)
Préparation c-81 ethyl 2-r(6-bromopvridin-3-vl)methyntetrahvdrofuran-2-carboxylate 20 13157 ; 120
Ο Το a solution of ethyl tetrahydrofuran-2-carboxylate (52.9 mmol, 9.10 g, 1.5 eq.)cooled to -78 degrees C in THF (90 mL) was added dropwise a solution of 2 Mlithium diisopropylamide (52.9 mmol, 1.5 eq.) in a mixture of 5 heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at thesame low température whereupon a solution of 2-bromo-5-(bromomethyl)pyridine(35.3 mmol, 8.85 g, 1.0 eq.) in THF was added dropwise. The reaction wasallowed to warm slowly to room température overnight. The reaction wasquenched with saturated ammonium chloride. The mixture was extracted with 10 ethyl acetate and the organic extract was washed with brine. The organic layerwas dried over anhydrous magnésium sulfate and concentrated in vacuo to yield ayellow oll. This crude product was purïfied on a Biotage Sp4 65i over a gradient of5% to 95 % ethyl acetate in hexanes to afford a golden oil (8.70 g, 78%). LRMS: 315 (M+Hf. 15 1H NMR (DMSO-de, 400 MHz): 8.21 (1 H, s) 7.40 - 7.49 (2 H, m) 3.94 (2 H, q,J=7.0 Hz) 3.71 - 3.85 (2 H, m) 3.05 - 3.11 (1 H, m) 2.91 - 2.97 (1 H, m) 2.38 - 2.47(1 H, m) 1.83 - 2.09 (3 H, m) 1.09 (3 H, t, J=7.0 Hz)
Préparation c-82 20 Cvclopropanecarboxvlic acid terf-butvl ester
O. ^.O
Concentrated sulfuric acid (3.45 mL, 62.7832 mmol) was added to a vigorouslystirred suspension of anhydrous magnésium sulfate (30.1987 g, 251.1326 mmol) indichloromethane (250 mL). The mixture was stirred for 15 minutes, after which 25 cyclopropanecarboxylic acid (5 mL, 62.7832 mmol) and 2-methyl-propan-2-of (30mL, 313.9158 mmol) were added. The mixture was stoppered tightly and stirred atambient température for 16 hours. The reaction mixture was then quenched withsaturated aqueous sodium bicarbonate (450 mL) and stirred until ali themagnésium sulfate had dissolved. The phases were separated and the organic 30 phase washed with water (100 mL), saturdated aqueous sodium chloride (100 mL),dried (anhydrous magnésium sulfate), fiftered and concentrated in vacuo to affordthe pure ester (6.3921 g, 59.0162 mmol) as a colorless liquid. 1H NMR (CDCIa, 300 MHz): 1.45 (9H, s), 0.93-0.86 (3H, m), 0.79-0.73 (2H, m). 13157 . 121
Préparation c-83 1-(6-[2-f5-iVlethvl-2-phenvl-oxazol-4-vl)-ethoxv1-pvridin-3-vlmethvl1- cyclopropanecarboxvlic acid ferf-butyl ester
10 15 20
To a solution of diisopropylamine (0.14 mL, 0.9518 mmol) in dry tetrahydrofuran(2.4 mL), at 0 °C under an atmosphère of nitrogen, was added butyllithium (0.38mL of a 2.5M solution in hexanes, 0.9518 mmol). The resulting solution was stirredfor 30 minutes and then cooled to -50 °C. To this was added a solution ofcyclopropanecarboxylic acid tert-fautyl ester (0.1269 g, 0.8924 mmol) in drytetrahydrofuran (1 mL) and stirring was continued for 2 hours. A solution of 5-iodomethyI-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine (0.25 g, 0.5949mmol) in dry tetrahydrofuran (1 mL) was then added dropwise and the solutionstirred for a further 3 hours. The reaction was quenched by the addition ofsaturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (3x 25 mL). The combined organic extracts were then dried (anhydrous magnésiumsulfate), filtered and concentrated in vacuo to afford the crude product andremaining starting iodide. The residue was purified by flash columnchromatography (hexanes to 60% ethyl acetate/hexanes) to yield the ester (0.0827g, 32%), partially contaminated with started iodide, as a pale yellow solid. LRMS (m/z): 435 (M+H)\
Préparation c-84 ethyl 2-((6-f2-(5-methyl-2-phenyl-1.3-thiazol-4-yl)ethoxv)pyridin-3- vt)methvl)tetrahvdrofuran-2-carboxylate o
25
To an argon-purged solution of the bromopyridine (0.636 mmol) in toluene (12 mL)was added palladium (II) acetate (11.4 mg, 0.0508 mmol) and racemic-2-(di-t-butylphosphino)-1,T-binaphthyl (25.4 mg, 0.0636 mmol). The activated complexwas allowed to form over approximately ten minutes, at which point césium 30 carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956 mmol) wereadded. The mixture was heated to 115 °C and stirred at this température for 12-18hours. The mixture was cooled to room température and filtered through a pad ofsilica. The filter pad was washed with 2-3 aliquots of ethyl acetate and thecombined organic filtrâtes were combined and concentrated in vacuo. The 13157 . resulting residue was either purified by flash chromatography, or used withoutfurther purification
Préparations c-85 to c-88
Préparations c-85to c-88 were prepared bv procedures analogous to those used 5 for Préparation c-84
Préparation # Structure ’K NMR WS (zn/z) (LR or HR) c-85 O X. jÛVt'0" Ν 1—' (DMSO-d6, 400'MHz) for LR 420 (M+H)* c-86 O i ίΎ^0Κ _CT LV ô-7 c-87 c-88
Préparation c-89 5-ffîert-butvl(diphenvl)silvl1oxv)-2-(iodomethvl)pyridine
10 To a solution of 2-bromomethyI-5-(te/i-butyl-diphenyt-silanyloxy)-pyridine (Schow,S. R.; Quinn DeJoy, S.; Wick, Μ. M.; Kerwar, S. S. J. Org. Chem. 1994, 59, 6850-6852) (1.2692 g, 2.9763 mmol) in acetone (15 mL) was added sodium iodide(0.8922 g, 5.9526 mmol) and the resulting heterogeneous mixture stirred for 3hours at ambient température. The reaction mixture was concentrated in vacuo 15 and the resulting residue diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was further washed with saturated aqueous sodiumbicarbonate (50 mL) and saturated aqueous sodium thiosulfate (50 mL). The 123 13157 . combirted aqueous layers were extracted with ethyl acetate (3x50 mL)and the combined organic extracts dried (anhydrous magnésium sulfate), filteredand concentrated in vacuo to afford the crude product. The residue was purified byflash column chromatography (hexanes to 20% ethyl acetate/hexanes) to yield apale yellow oil (0.72 g, 51%). This compound was unstable to concentration andthus was used immediately. LRMS (m/z): 474 (M+H)*.
Préparation c-90 ethyl tetrahvdrofuran-2-carboxylate 10
15 20
To a solution of tetrahydrofuran-2-carboxylic acid (20 g, 172.2356 mmol) inanhydrous éthanol (100 mL) was added concentrated sulfuric acid (0.46 mL). Theresulting mixture was stirred at reflux for 16 hours and then allowed to cool toambient température. To this was added water (100 mL) and extracted with diethylether (3x100 mL). The combined organic extracts were washed with saturatedaqueous sodium bicarbonate (2x50 mL), saturated aqueous sodium chloride (100mL), dried (anhydrous magnésium sulfate), filtered and concentrated in vacuo toafford the pure product as a colorless liquid (22.5964 g, 91%). LRMS (m/r)·. 145 (M+H)\ ’H NMR (CDCIa, 300 MHz) 4.38 (1H, dd, J= 4.9, 8.1 Hz), 4.14 (2H, q. J= 7.2 Hz),3.99-3.92 (1H, m), 3.88-3.81 (1H, m), 2.24-2.12 (1H, m). 2.00-1.79 (3H, m), 1.22(3H, t, J = 7.2 Hz).
Préparation c-91
Tetrahvdro-pvran-2-carfaoxvlic acid ethyl ester o 25
The above compound was prepared according to the procedure described inRychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3, 807-810.
Préparation c-92 ethyl 2-ff5-fffert-butvlfdiphenyl)silylloxy)pvridin-2-vl)methvHtetrahvdrofuran-2- carboxylate
30 124 13157 . Το a solution of ethyl tetrahydrofuran-2- carboxylate (Préparation 32) (1.0965 g,7.604 mmol) in anhydrous tetrahydrofuran (7 mL) at -50 °C, under an atmosphèreof nitrogen, was added sodium bis(trimethylsilyl)amide (7.6 mL of a 1.0M solutionin tetrahydrofuran, 7.604 mmol) dropwise. The réaction mixture was stirred for 1 5 hour and then a solution of 5-(ferf-butyl-diphenyl-silanyloxy)-2-iodomethyl-pyridine(Préparation 31) (0.72 g, 1.5208 mmol) in anhydrous tetrahydrofuran (7 mL) wasadded dropwise. The resulting solution was stirred at -50 °C for 2 hours and thenquenched with saturated aqueous ammonium chloride (25 mL). This was thenextracted with ethyl acetate (3x25 mL), dried (anhydrous magnésium sulfate), 10 filtered and concentrated in vacuo to afford the crude product. The residue waspurified by flash column chromatography (hexanes to 40% ethyl acetate/hexanes)to yield a colorîess oil (0.2438 g, 33%). LRMS (m/z): 490 (M+H)\ 1H NMR (CDCI3l 300 MHz) 8.07 (1H, d, J =2.5 Hz), 7.67-7.63 (4H, m), 7.41-7.31 15 (6H, m), 6.97 (1H, d, J = 8.5 Hz), 6.86 (1H, dd, J = 2.8, 8.5 Hz), 4.21 (2H, q, J =7.2
Hz), 4.09 (2H, q, J =7.2 Hz), 3.22 (1H, d, J = 13.9 Hz), 3.07 (1H, d, J = 13.9 Hz),2.53-2.44 (1H, m), 2.31-2.15 (1H, m), 1.82-1.72 (1H, m), 1.60-1.46 (1H, m), 1.25(3H,t, J =7.2 Hz), 1.09 (9H. s).
Préparation c-93 20 ethyl 2-[(5-hvdroxypvridin-2-vl)methvntetrahvdrofuran-2-carboxvlate
O
To a solution of ethyl 2-[(5-{[iert-butyl(diphenyl)silyl]oxy}pyridin-2-yl)methyl]tetrahydrofuran-2-carboxylate (Préparation c-92) (0.5118 g, 1.1677mmol) in anhydrous tetrahydrofuran (10 mL) was added tetrabutylammonium 25 fluoride (1.3 mL of a 1.0M solution in tetrahydrofuran) dropwise. The resultingmixture was stirred at ambient température for 1 hour and the volatiles removed invacuo.. The residue was purified by flash column chromatography (50% ethylacetate/hexanes to 10% methanol/ethyl acetate) to yield a colorîess oil (0.2321 g,79%). 30 LRMS (m/z): 252 (M+Hf. ’H NMR (CDCIs. 300 MHz) 8.10 (1H, d, J = 2.3 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.14(1H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 3.88 (2H, q, J = 7.8 Hz). 3.35(1H, d, J= 13.9 Hz), 3.12 (1H, d, J = 13.9 Hz), 2.30-2.21 (1H, m), 2.04-1.94 (1H,m), 1.89-1.76 (1H, m), 1.75-1.63 (1 H, m), 1.20 (3H, t, J = 7.2 Hz). 13157 : 125 10
Préparation c-93a
Alternative préparation of ethyl 2-f(5-hvdroxypyridin-2-vl)meth ylltetrahydrofuran-2- carboxylate
To a solution of 2-(5-benzyloxy-pyridin-2-ylmethyl)-tetrahydro-furan-2-carboxylicacid ethyl ester (0.6065 g, 1.7765 mmol) in dry éthanol (10 mL) was addedpalladium (0.0607 g, 10 wt. % on activated carbon). The resulting solution washeated at 45 ®C under an atmosphère of hydrogen for 16 hours. After cooling toambient température the solution was filtered through a 3" bed of Celite andwashed with éthanol (100 mL). The filtrate was then concentrated in vacuo toafford the crude product which was used without further purification. LRMS (m/z): 252 (M+H)4. 1H NMR (COCl3, 400 MHz): 8.10 (1H, d, J =2.3 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.14(1H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 3.88 (2H, q, J = 7.8 Hz), 3.35 (1H, d, J = 13.9 Hz), 3.12 (1H, d, J= 13.9 Hz), 2.30-2.21 (1H, m). 2.04-1.94 (1H,15 m), 1.89-1.76 (1H, m), 1.75-1.63 (1H, m), 1.20 (3H, t, J = 7.2 Hz).
Préparations c-94 to c-95
Préparations c-94 to c-95 were prepared bv general procedure for Préparation c-93
Prep Structure ’hnmr MS (m/z) (LR or HR) C-94 O cA” ? (CDCls, 400 MHz): 8.24 (1H, bs), 7.37-7.30 (1H, bm),7.24-7.22 (1H, bm), 3.71 (3H, S), 3.28 (3H, s), 3.23-3.18 (2H, m), 1.40 (3H, s) forLR 226 (M+H)4 c-95 (CDCI3,400 MHz): 7.64 (1H, d, J = 8.6 Hz), 7.61 (1H,s), 7.53 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 1.7, 8.6Hz), 7.05-7.01 (2H, m), 5.32 (1H, s), 3.99-3.88 (2H, m), 3.34 (1H, d, J = 13.6 Hz), 3.11 (1H, d, J = 13.9Hz), 2.33-2.27 (1H, m). 2.00-1.93 (1H, m), 1.89-1.77(1H, m), 1.73-1.65 (1H, m), 1.19 (3H, t, J = 7.3 Hz) for LR 301 (M+H)4
Préparation c-96 20 ethyl 2-({5-f2-(5-methvl-2-phenvl-1.3-oxazol-4-vl)etfioxv1pyridin-2- vl)methv0tetrahvdrofuran-2-carboxylate
To a solution of ethyl 2-((5-hydroxypyridin-2-yl)methylîtetrahydrofuran-2-carboxylate (Préparation c-93) (0.2321 g, 0.9237 mmol), 2-(5-methyl-2-phenyI-
oxazol-4-yl)-ethanol (0.2065 g, 1.0161 mmol), and triphenylphosphine (0.3634g, 1.3656 mmol) in anhydrous tetrahydrofuran (10 mL), under an atmosphère ofnitrogen, was added a solution of diethyi azodicarboxylate (0.22 mL, 1.3856 mmol)in anhydrous tetrahydrofuran (1 mL) dropwise. The resulting solution was stirred at 5 ambient température for 16 hours and the volatiles removed in vacuo. This residuewas then purified by flash column chromatography (hexanes to 50% ethylacetate/hexanes) to yield a pale yellow oïl (0.2618 g, 65%). LRMS (mZz): 437 (M+Hf. 1H NMR (CDCb, 300 MHz) 8.20 (1H, d, J-2.8 Hz), 7.99 (1 H, d, J = 2.5 Hz), 7.96 10 (1H, d, J= 1.7 Hz), 7.70-7.64 (1H, m), 7.49-7.39 (2H, m), 7.19 (1H, d. J= 8.5 Hz), 7.11 (1 H, dd, J = 3.0, 8.5 Hz), 4.26 (2H, t, J = 6.6 Hz), 4.17 (2H, q, J = 7.2 Hz),3.95-3.81 (2H. m), 3.33 (1H, d, J= 13.8 Hz), 3.16 (1 H. d, J= 13.8 Hz), 2.98 (2H, t, J =6.6 Hz), 2.37 (3H, s), 2.34-2.22 (1H, m), 2.09-2.00 (1H, m), 1.87-1.76 (1H, m), 1.72-1.62 (1 H, m), 1.23 (3H, t, J = 7.2 Hz). 15 Préparations c-97 to c-112
Préparations c-97 to c-112 were prepared by general procedure for Préparation c- 96
Prepa ration # Structure 1H NMR MS (m/z) (LR or HR) c-97 (CDCI3, 300 MHz): 8.19 (1H, d, J = 2.8Hz), 7.97-7.93 (2H, m), 7.42-7.39 (3H,m), 7.18 (1H, d, J = 8.5 Hz), 7.10 (1H,dd, J = 8.5,2.8 Hz), 4.16 (2H, q, J = 7.2 Hz), 3.98 (2H, t, J = 6.0 Hz), 3.92-3.82 (2H, m), 3.33 (1H, d, J = 13.8 Hz),3.14 (ÏH, d, J = 13.9 Hz), 2.67 (2H, t, J= 6.0 Hz), 2.26 (3H, s), 2.19-2.10 (2H,m), 1.91-1.63 (4H, m), 1.22 (3H, t, J =7.2 Hz) for LR 451 (M+H/ c-98 (CDCb, 400 MHz): 8.20 (1H, dd, J =2.0,1.5 Hz), 7.95 (2H, dd, J = 7.7,1.9Hz), 7.43-7.36 (3H, m), 7.10 (2H, d, J =1.5 Hz), 4.25 (2H, t, J = 6.6 Hz), 4.23-4.13 (3H, m), 3.63-3.55 (1H, m), 3.37-3.27 (1H, m), 3.15-3.02 (2H, m), 2.97(2H, t, J= 6.7 Hz), 2.35 (3H, s), 1.21(3H, t, J= 7.2 Hz), 1.08 (3H, t, J = 7.1Hz) for LR 425 (M+H)+ c-99 S·*/ -λ I ITT (CDCb, 400 MHz): 8.19 (1H, dd, J=2.0,1.5 Hz), 7.08-7.07 (2H, m), 4.26-4.23 (3H, m), 4.16 (2H, q, J =7.0 Hz),3.63-3.56 (1H, m), 3.36-3.28 (1H, m),3.15-3.02 (4H, m), 2.58 (3H, s), 2.34(3H, s), 1.21 (3H, t, J = 7.1 Hz), 1.08(3H,t, J = 7.0 Hz) for LR ' 379 (M+H)+ 13157 ; 127 c-100 - îvA"' (CDCI3i 400 MHz): 8.22 (1H, dd, J = 2.4, 1.1 Hz), 7.86-7.83 (2H, m), 7.42-7.36 (3H, m), 7.11-7.10 (2H, m), 4.35(2H, t, J = 6.8 Hz), 4.24 (1 H, dd, J = 8.3, 5.1 Hz), 4.18 (2H, q, J = 7.1 Hz),3.63-3.56 (1H, m), 3.36-3.28 (1H, m),3.18 (2H, t, J = 6.8 Hz), 3.14 (1H, dd, J= 13.9, 5.1 Hz), 3.05 (1H, dd, J= 13.9,8.3 Hz), 2.45 <3H, s), 1.22 (3H, t, J = 7.1 HZ), 1.09 (3H, t, J =7.1 Hz) forLR 441 (M+H)* C-101 CDCI3, 400 MHz): 8.22 (1H, dd, J =2.0,1.5 Hz), 7.97-7.93 (2H, m), 7.43-7.37 (3H, m), 7.11-7.10 (2H, m), 4.25(1H, dd, J= 8.6, 5.1 Hz), 4.18 (2H, q, J= 7.2 Hz), 3.99 (2H, t, J = 6.2 Hz),3.64-3.56 (1H, m), 3.37-3.29 (1H, m),3.14 (1H, dd, J= 13.9, 5.1 Hz), 3.06(1H, dd, J= 13.9, 8.6 Hz), 2.68 (2H, t, J = 7.1 Hz), 2.26 (3H, s), 2.18-2.12(2H, m), 1.22 (3H, t, J= 7.1 Hz), 1.09(3H, t, J = 7.0 Hz) for LR 439 (M+H)* ¢-102 \ /~* A J! h z o v=/ n-<^o^n r (CDCI3, 400 MHz): 8.18 (1H, dd, J =2.3, 1.3 Hz), 7.96 (2H. dd, J = 7.6, 2.0Hz), 7.54-7.51 (3H, m), 7.10-7.08 (2H,m), 4.25 (2H, t, J = 6.7 Hz), 3.29 (3H,s), 3.15 (2H, s), 2.96 (2H, t, J = 6.7Hz), 2.36 (3H, s), 2.32 (3H, s), 1.38[3H, s) for LR 411 (M+H)* c-103 (CDCL 400 MHz): 8.20 (1H, t, J = 7.8Hz), 7.97-7.93 (2H, m), 7.44-7.38 (3H,m), 7.09 (2H, d, J = 7.8 Hz), 3.99 (2H,t, J= 6.1 Hz), 3.72 (3H, s). 3.30 (3H,s), 2.68 (2H, t, J= 7.1 Hz), 2.62 (2H, t,J = 6.7 Hz), 2.27 (3H, s), 2.18-2.12(2H,m), 1.40 (3H,s) for LR 425 (M+H)* c-104 f\-^Y fVX'0'^ forLR 451 (M+H)* 0-105 O^jCoJCrJ'0^' for LR 453 (M+H)* 13151 . 128 c-106 for LR 471 (M+H)* c-107 -- for LR 467 (M+H)+ C-108 Q for LR 467 (M+H)* c-109 (CDCIj, 300 MHz): 8.16 (1H, d, J= 2.6Hz), 7.97-7.94 (2H, m), 7.48-7,39 (3H,m), 7.10 (1H, dd, J= 8.7, 3.0 Hz), 7.02(1 H, d, J = 8.5 Hz), 4.25 (2H, t, J = 6.7Hz), 2.96 (2H, t, J = 6.7 Hz), 2.46 (3H,s), 2.36 (3H, s) for LR 295 (M+H)+ c-110 (CDCIs, 300 MHz); 8.16 (1H, d, J = 1.3Hz), 7.96 (3H, dd, J = 7.4, 1.7 Hz),7.41 (3H, dd, J = 5.3, 1.9 Hz), 4.58(2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.8Hz), 2.34 (3H, s) for LR 360 (M)’ c-111 (CDCI3, 400 MHz): 7.99-7.97 (2H, m),7.66 (1 H, d, J = 8.8 Hz), 7.62-7.59 (2H,m), 7.45-7.35 (4H, m). 7.12-7.08 (2H,m), 4.35 (2H, t, J = 6.8 Hz), 4.16-4.09(2H, m), 3.96-3.85 (2H, m), 3.32 (1Hd, J= 13.6 Hz), 3.11 (1H, d, J = 13.9Hz), 3.04 (2H, t, J- 6.8 Hz), 2.40 (3Hs). 2.31-2.24 (1H, m), 1.99-1.76 (1Hm), 1.69-1.60 (1H, m), 1.18 (3H, t, J =7.1 Hz) forLR 486 (M+H)+ 13157 ' 12a * c-112 (CDCl3, 400 MHz): 7.99-7.97 (2H, m),7.67 (1H, d, J= 8.8 Hz), 7.61-7.59 (2H,m), 7.45-7.35 (4H, m), 7.12 (1H, dd, J= 2.3, 8.8 Hz), 7.08-7.07 (1H, d. J - 2.3Hz), 4.16-4.06 (4H, m), 3.96-3.86 (2H,m),3.33(1H, d, J= 13.6 Hz), 3.11 (1H,d, J = 13.6 Hz), 2.74 (2H, t, J = 7.1Hz), 2.32-2.18 (6H, m), 1.99-1.91 (1H,m), 1.86-1.77 (1H, m), 1.69-1.61 (1H,m), 1.19 (3H,t,J = 7.1 Hz) for LR 500 (IM+Hf
Préparation c-113 3-(5-Methvl-2-phenvl-oxazol-4-yl)-propionaldehvde
O 5 To a solution of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propan-1-ol (1.0 g, 4.6026 mmol)in dichloromethane (20 mL) was added pyridinium chlorochromate (9.9213 g of~20 wt. % on SiO2, 9.2051 mmol). The resulting mixture was stirred under anatmosphère of nitrogen at ambient température for 16 hours and the volatilesremoved under reduced pressure. The residue was purified by flash column 10 chromatography (hexanes to ethyl acetate) to yield the pure aldéhyde (0.4752 g,48%) as a colorless oil. LRMS (m/z): 216 (M+H)+. ’H NMR (CDCI3i 300 MHz): 9.84 (1H, s), 7.96-7.93 (2H, m), 7.42-7.37 (3H, m),2.85 (2H, dd, J = 6.0, 0.9 Hz), 2.80 (2H, d, J = 6.0 Hz), 2.33 (3H, s). 15 Préparation c-114 4-But-3-envl-5-methvl-2-phenyl-oxazole
To a solution of methyl triphenylphosphonium iodide (1.7848 g, 4.4154 mmol) indry tetrahydrofuran (95 mL), under an atmosphère of nitrogen at 0 °C, was added 20 butyllithium (1.8 mL of a 2.5M solution in hexanes, 4.4154 mmol) dropwise. Thesuspension dissolved and the solution turned orange. After 10 minutes a solutionof 3-{5-methyl-2-phenyl-oxazol-4-yI)-propionaldehyde (0.4752 g, 2.2077 mmol) indry tetrahydrofuran (15 mL) was added dropwise and the solution allowed to warmto ambient température. After 16 hours, hexanes (200 mL) was added and the 25 precïpitate filtered off. The filtrate was then extracted with water (200 mL) and theorganic phase dried (anhydrous magnésium sulfate), filtered, and concentrated invacuo to afford the crude product. The residue was purified by flash column 13157 chromatography (hexanes to ethyl acetate) to yield the pure title compound(0.291 g, 62%) as a colorless oii. LRMS (m/zy. 214 (M+H)\ 1H NMR (CDCIs, 300 MHz); 7.99-7.96 (2H, m), 7.43-7.38 (3H. m), 5.93-5.79 (1H.m), 5.09-5.02 (1H, m), 5.00-4.95 (1H, m), 2.57 (2H, t. J = 7 A Hz). 2.42 (2H, t. J =7.4 Hz), 2.31 (3H, s).
Préparation c-115 2-f644-(5-Methyl-2-phenyl-oxazol-4-vl)-butvll-pvridin-3-vlmethy|)-tetrahvdro-furan- 2-carboxvlic acid ethyl ester
O
9-Borabicyclononane <5.5 mL of a 0.5M solution in tetrahydrofuran, 2.729 mmol)was added to a yellow solution of 4-but-3-enyl-5-methyl-2-phenyl-oxazole (0.291 g,1.3645 mmol) in dry tetrahydrofuran (1.3 mL). The mixture was stirred at ambienttempérature for 4 hours and then transferred to another flask containing 2-(6-bromo-pyridin-3-ylmethyl)-tetrahydro-furan-2-carboxylic acid ethyl ester (0.3297 g,1.0496 mmol), palladium dichloride b;s(diphenylphosphino)ferrocene (0.0857 g,0.1050 mmol). césium carbonate (0.9551 g, 2.9389 mmol), triphenylarsine (0.0322g, 0.1050 mmol) in /V,W-dimethylformamide (2.8 mL) and water (0.23 mL). Thedark red mixture was stirred for 16 hours at ambient température under a nitrogenatmosphère. After cooling to 0 °C, the reaction was quenched with 2M aqueoussodium acetate (5 mL) and 30% aqueous hydrogen peroxide (2 mL). The resultingsolution was stirred for 2 hours, diluted with water (25 mL), and extracted with ethylacetate (4 x 50 mL). The combined organic extracts were washed with water (25mL), dried (anhydrous magnésium sulfate), filtered, and concentrated in vacuo togive the crude product. The residue was purified by flash columrt chromatography(hexanes to ethyl acetate) to afford the title compound (0.2805 g, 60%) as paleyellow oil. LRMS (m/z): 449 (M+Hf. 1H NMR (CDCIa, 300 MHz); 8.34 (1H, d, J= 1.9 Hz), 7.95 (2H, dd, J= 7.7, 1.9 Hz),7.52 (1H, dd, J= 8.0, 2.2 Hz), 7.42-7.36 (3H, m), 7.04 (1H, d, J= 7.9 Hz), 4.13 (2H,q, J= 7.2 Hz), 3.96-3.84 (2H, m), 3.16 (1H, d, J= 13.9 Hz), 2.90 (1H, d, J= 13.9Hz), 2.77 (2H, t, J = 7.3 Hz), 2.50 (2H, t, J = 6.9 Hz), 2.31-2.19 (1H, m), 2.28 (3H,s), 1.92-1.64 (7H, m), 1.20 (3H. t, J = 7.2 Hz).
Préparation c-116 2-(6-f3-(5-methvl-2-phenyl-oxazol-4-yl)-propvn-pvridin-3-ylmethvlMetrahvdro-furan- 2-carboxylic acid ethyl ester 13157 . 131
9-Borabicyclononane (4.2 mL of a 0.5M solution in tetrahydrofuran, 2.07 mmol)was added to a yeltow solution of 4-allyl-5-methyl-2-phenyl-oxazole (0.21 g, 1.04mmol) in dry tetrahydrofuran (1 mL). The mixture was stirred at ambienttempérature for 4 hours and then transferred to another flask containing 2-(6-bromo-pyridin-3-ylmethyl)-tetrahydro-furan-2-carboxylic acid ethyl ester (0.25 g,O.BO mmol), palladium dichloride iws(diphenylphosphino)ferrocene (0.07 g, 0.1mmol), césium carbonate (0.72 g, 2.90 mmol), triphenylarsine (0.02 g, 0.1 mmol) inW,W-dimethylformarnidé:water (4:1, 2.63 mL). The dark red mixture was stirred for16 hours at ambient température under a nitrogen atmosphère. After cooling to 0°C, the reaction was quenched with 2M aqueous sodium acetate (4.7 mL) and 30%aqueous hydrogen peroxide (1.7 mL). The resulting solution was stirred for 2hours, diluted with water (20 mL), and extracted with ethyl acetate (4 x 50 mL).The combined organic extracts were washed with water (20 mL), dried (anhydrousmagnésium sulfate), filtered, and concentrated in vacuo to give the crude product.The residue was purifïed by flash coiumn chromatography (40% to 90% ethylacetate/hexanes) to aflord the title compound (0.20 g, 57%) as a colorless oil. LRMS (m/z): 435 (M+Hf. ’H NMR (Dimethyl sulfoxide-d6, 400 MHz): 8.35 (1H, s), 7.96 (2H, d, J= 7.9 Hz).7.55 (1H, d, J= 8.3 Hz), 7.39 (3H, t, 5.9 Hz), 7.09 (1H, d, J= 8.1 Hz), 3.91 (2H,m), 3.80 (2H, t, J = 10.9 Hz), 3.17 (1H, d, J= 14.0 Hz), 2.91 (1H, d, J = 13.94 Hz),2.81 (2H, t), 2.53 (2H, t, J = 7.3 Hz), 2.28 (3H, s), 2.09 (2H, d, J = 7.5 Hz), 1.87(4H, d,J= 10.9 Hz), 1.23 (3H,m).
Préparation c-117
Ethyl 1 -(4-f( 1 E)-3-(5-methyl-2-phenyl-1,3-oxazol-4-vl)prop-1-en-1 - yllphenoxylcyclobutanecarboxylate
O
A mixture of Pd(OAc)2 (12 mg, 0.05 mmol) and Ph3P (26 mg, 0.05 mmol) in toluene(2 mL) was stirred under nitrogen at room température for 1 hour and followed bythe addition of Et3N (2 mL) and a solution of 4-allyl-5-methyl-2-phenyl-1,3-oxazole (100 mg, 0.50 mmol) and ethyl 1-(4-iodophenoxy)cyclobutanecarboxylate (173 mg,0.50 mmol) in toluene (2 mL). The resulting reaction solution was heated at 80 °C 13157 ' under nitrogen for 17 hours and cooled to room température. After solventremoval, the residue was partitioned between EtOAc and brine. The separatedorganic layer was washed with brine, dried over Na2SO4, and concentrated to givethe crude product as brown oil. Purification by silica gel column with 20% EtOAc inhexane gave 85 mg (41 %) of yellow oil. 1H NMR (400 MHz, CDCI3) 1.19 (t, 3 H), 1.98 (m, 2 H), 2.38 (s, 3 H), 2.43 (m, 2 H),2.72 (m, 2 H), 3.41 (d, 2 H), 4.18 (q, 2 H), 6.20 (td, 1 H), 6.40 (d, 1 H), 6.60 (d, 2H), 7.25 (d. 2 H), 7.40 (d, 3 H), 8.00 (d, 2 H). LRMS (m/z): 418 (M+Hf.
Préparation c-118
Ethvl 1-f4-f3-(5-methvl-2-phenvl-1.3-oxazol-4-vl)propynphenoxv)cvclobutane- carboxvlate
Ethyl1-{4-[(1£)-3-(5-methyt-2-phenyl-1,3-oxazol-4-yl)prop-1-en-1- yl]phenoxy}cyclobutanecarboxylate (85 mg, 0.20 mmol) was dissolved in MeOH (5mL) and foliowed by the addition of 10% Pd/C (15 mg). The mixture was stinred atroom température for 16 hours with a balloon, full of hydrogen gas, attached to theflask. The mixture was filtered through a pad of Celite and the cake was rinsedwith MeOH. The filtrate was concentrated to give 85 mg (100%) of yellow oil. 1H NMR (400 MHz, CDCI3) 1.19 (t, 3 H), 1.92 - 2.02 (m, 4 H), 2.27 (s, 3 H), 2.39 -2.51 (m, 4 H), 2.60 (t, 2 H), 2.66 - 2.77 (m, 2 H), 4.19 (q, 2 H), 6.60 (d, 2 H), 7.05(d, 2 H), 7.36 - 7.47 (m, 3 H), 7.98 (dd, 2 H). LRMS (m/z): 420 (M+H)\
Préparation c-119 5-Bromo-pyrazin-2-vlamine H2N N’
To a solution of pyrazin-2-ylamine (2.0 g, 21.03 mmol) in dry dichloromethane (120mL) at 0 °C, was added W-bromosuccinimide (3.74 g, 21.03 mmol) slowly tomaintain the internai température below 0 °C. The mixture was stirred at the sametempérature for 24 hours, and then washed with saturated aqueous sodiumbicarbonate (30 mL) and water (30 mL). The combined aqueous extracts wereextracted with dichloromethane (3 x 100 mL). The combined organic extracts weredried (anhydrous magnésium sulfate), filtered, and concentrated in vacuo to affordthe crude product. The residue was purified by flash column chromatography (10%to 50% ethyl acetate/hexanes) to yield the title compound (2.57 g, 70%) as a yellowsolid. 13157 . 133 LRMS (m/2): 174 (M)'. ’H NMR (CDC13i 300 MHz): 8.08 (1H, d, J= 1.3 Hz), 7.76 (1H, d, J = 1.3 Hz).Préparation c-120 5-Bromo-pvrazin-2-ol lNXBr
HO N
10 15 20
Sodium nitrite (1.35 g, 19.53 mmol) was added portionwise to concentrated sulfuricacid (9.8 mL) at 0 °C. The mixture was heated at 50 °C until ail of the sodiumnitrite had dissolved and the mixture was again cooled to 0 °C. A solution of 5-bromo-pyrazin-2-ylamine (2.57 g, 14.68 mmol) in concentrated sulfuric acid (14.7mL) was added dropwise to the nitronium solution at 0 °C. The ice bath wasremoved, the mixture warmed to ambient température and stirred for 15 minutesbefore heating to 45 °C for seven minutes. After cooling to ambient température,the mixture was poured slowly with précaution into crushed ice water (100 mL).The aqueous phase was neutralized to pH 4 with 20% aqueous sodium hydroxidethen extracted with ethyl acetate (3 x 100 mL). The combined organic extractswere washed with water (50 mL), dried (anhydrous magnésium sulfate), filtered,and evaporated to afford the titie compound (1.88 g, 73%) as a yellow solid. 1H NMR (CDCIa, 300 MHz): 8.07 (1H, s), 7.62 (1H, d, J= 3.0 Hz).
Préparation c-121 2-ftert-Butvl-dimethvl-silanyloxvmethvl)-5-i2-(5-methvl-2-phenvl-oxazol-4-vl)- ethoxvl-pyrazine \=/ N'A^xo'Sr
To a solution of 2-bromo-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine(0.50 g, 1.39 mmol) and ferf-butyl-dimethyl-tributylstannanylmethoxy-silane (0.91 g, 25 2.09 mmol) in dry 1,4-dioxane (8 mL) was added tetrakistriphenyiphosphine(O) palladium (0.16 g, 0.14 mmol). The mixture was degassed three times and thenheated at 120 °C for 22 hours. After cooling to ambient température the mixturewas diluted with diethyl ether (10 mL) and then quenched with saturated aqueouspotassium fluoride (5 mL). The resulting mixture was stirred for 30 minutes and 30 then extracted with ethyl acetate (3 x 50 mL). The organic phase was washed withwater (30 mL), dried (anhydrous magnésium sulfate), filtered, and evaporated toafford the titie compound without any further purification. LRMS (m/z): 426 (M+H)+. 13157 . 134 1H NMR (CDCl3, 300 MHz): 8.20 (1H, s), 8.09 (1H, s), 7.97 (2H, d, J = 7.4 Hz),7.41 (3H, d, J = 5.3 Hz), 4.78 (2H, s), 4.58 (2H, d, J = 6.6 Hz), 2.98 (2H, s), 2.34(3H, s), 0.97 (2H, m), 0.14 (6H, m).
Préparation c-122 5 i5-r2-f5-Methvi-2-Dhenvl-oxazol-4-ylï-ethoxv1-pvrazin-2-v()-methanol n (T ύ oh
Tetrabutylammonium fluoride (2.8 mL of a 1M solution in tetrahydrofuran, 2.78mmol) was added dropwise to a solution of 2-(ferf-butyl-dimethyl-silanyloxymethyl)- 10 5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine (-1.39 mmol) in drytetrahydrofuran (20 mL). The mixture was stirred at ambient température for 16hours and then quenched with water (1 mL), and acidified to pH 5 with IM aqueousacetic acid solution. The organics were removed in vacuo and the aqueous phaseextracted with dichloromethane (3 x 50 mL). The combined organic extracts were 15 dried (anhydrous magnésium sulfate), filtered, and concentrated in vacuo to afford the title compound (0.0928 g, 21%).
LRMS (m/z): 312 (M+H)T 1H NMR (CDCI3, 300 MHz): 8.12 (2H, s), 8.05 (2H, d, J = 6.0 Hz). 7.40 (3H, d, J =6.0 Hz), 4.72 (2H, s), 4.59 (2H, t, J = 6.0 Hz), 2.99 (2H, t, J= 6.0 Hz), 2.33 (3H, s). 20 Préparation c-123 6-Benzyloxv-naphthalene-2-carboxylic acid benzvl ester
O "'O'
The above compound was prepared according to the procedure described in Inui,S.; Suzuki, T.; limura, N.; Iwane, H.; Nohira, H. Mol. Cryst. Liq. Cryst. Sci. Technol. 25 Sect. A. 1994, 239, 1-10.
Préparation c-124 (6-Benzyloxv-naphthalen-2-vl)-methanol
To a solution of 6-benzyloxy-naphthalene-2-carboxylic acid benzyl ester (7.09 g,30 19.24 mmol) in dry tetrahydrofuran (60 mL), under an atmosphère of nitrogen at 0 °C, was added diisobutylaluminum hydride (58 mL of a 1.0M solution intetrahydrofuran, 57.73 mmol). The resulting mixture was allowed to warm to 13157 . 135 ambient température and stirred for 16 hours. An solution of citric acid (19 g) inwater (40 mL) was added dropwise (CAUTION!: strong exotherm). The aqueouslayer was then extracted with ethyl acétate (3 x 50 mL) and the combined organicextracts washed with saturated aqueous sodium chloride (50 mL), dried(anhydrous magnésium sulfate), and concentrated in vacuo to afford the crudeproduct. The residue was purified by flash column chromatography (hexanes toethyl acetate) to yield the title compound (4.37 g, 86%) as a white solid. LRMS (m/z): 287 (M+Naf. 1H NMR (CDCIs, 400 MHz): 7.76-7.72 (3H, m), 7.50-7.33 (6H, m), 7.25-7.23 (2H,m), 5.18 (2H, s), 4.82 (2H, d, J= 6.1 Hz).
Préparation c-125 2-l6-(5-Methvl-2-phenvl-oxazol-4-vlmethoxv)-naphthalen-2-vlmethyll-tetrahvdro-
A heterogeneous mixture of 2-phenyl-4-(chloromethyl)-5-methyloxazole (0.133 g,0.639 mmol), 2-(6-hydroxy-naphthalen-2-ylmethyl)-tetrahydro-furan-2-carboxylicacid ethyl ester (0.192 g, 0.639 mmol), and césium carbonate (0.521 g, 1.59 mmol)in dry acetonitrile (2 mL) was heated (in a microwave) at 140 °C for 10 minutes. Asecond portion of 2-phenyl-4-(chloromethyl)-5-methyloxazole (0.5 eq.) was addedand the mixture heated at 200 °C for a further 20 minutes. The reaction mixturewas filtered through Celite and washed with acetonitrile (200 mL). The filtrate wasconcentrated in vacuo and the residue purified by flash column chromatography(hexanes to ethyl acetate) to yield the title compound (0.180 g, 60%) as a colorlessoil.
Préparation c-126 (4S)-4-benzvl-3-(tetrahvdrofuran-2-vlcarbonyl)-1.3-oxazolidin-2-one
n-Butyllithium (22.6 mL of a 2.5M solution in hexanes, 56.4 mmol) was addeddropwise to a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (10.0 g, 56.4 mmol) intetrahydrofuran (200 mL) at -78°C. The mixture was stirred for 30 minutes then asolution of tetrahydrofuran-2-carbonyl chloride (9.12 g, 67.7 mmol) intetrahydrofuran (25 mL) was added. The mixture was stirred at -78°C for 30 13157 ; 136 5 minutes, warmed to 0°C over 1 hour and quenched with saturated ammoniumchloride solution. The Mixture was extracted with ethyl acetate and the organicphase was washed with brine, dried over magnésium sulfate, filtered andevaporated. The residue was punfied by flash column chromatography (1:3 then1.2 ethyl acetate:hexanes) to yield the title compound as a ca. 1:1 mixture ofdiastereoisomers as a colorless oil (15.0 g, 97%).
Préparation c-127 f4S)-4-benzyl-3-ff2-({e-f2-(5-methvl-2-phenvl-1,3-oxazol-4-yl)ethoxy|pyridin-3- vl)methvntetrahydrofuran-2-vncarbonylM,3-oxazolidin-2-one 10
15 20 25
Sodium (bis)trimethylsilyl amide (3.57 mL of 1M solution in tetrahydrofuran, 3.57mmol) was added dropwise to a solution of (4S)-4-benzyl-3-(tetrahydrofuran-2-ylcarbonyl)-1,3-oxazolidin-2-one (0.983 g, 3.57 mmol) in anhydrous tetrahydrofuran(6 mL) at -50 °C. The mixture was stirred for 45 minutes and then a solution of 5-(iodomethyl)-2-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Préparation28) (0.500 g, 1.19 mmol) in anhydrous tetrahydrofuran (6 mL) was added dropwise.The resulting mixture was stirred at -50 °C for 1.5 hours then quenched withsaturated aqueous ammonium chloride and warmed to ambient température. Themixture was extracted with ethyl acetate and the organic phase dried (anhydrousmagnésium sulfate), filtered and evaporated. The residue was purified by flashcolumn chromatography (1:1 ethyl acetate.'hexanes) to yield the title compound asa single diastereoisomer as a colorless oil (0.617 g, 90%). LRMS (m/z): 568 (M+Hf. 1H NMR (CDCfe, 300 MHz) 8.01 (1H, s), 7.96 (2H, m), 7.61 (1H, dd, J= 2.5, 8.5Hz), 7.40 (3H, m), 7.28 (3H, m), 7.17 (1H, m), 6.64 (1H, d, J = 8.6 Hz), 4.55 (3H,m), 4.18 (2H, m), 3.90 (1H, m). 3.79 (1H, m), 3.27 (1H, d, J = 14 Hz), 3.20 (1H, m),3.13 (1H, d, J = 14 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.79 (1H, m), 2.32 (3H, s), 2.34(3H, m), 2.11 (1H, m), 1.73 (1H,m), 1.54 (1H, m)
Préparation c-128
Tetrahvdro-furan-2-carboxylic acid amide
O
To a solution of tetrahydro-furan-2-carboxylic acid (2.42 g, 20.82 mmol) inanhydrous tetrahydrofuran (120 mL), under an atmosphère of nitrogen at 0 °C, was 30
13157 . 137 5 10
15 added triethylamine (8.5 mL, 61.23 mmol) and ethyl chloroformate (2.4 mL,25.10 mmol). White précipitation formed after the addition of ethyl chloroformateand the resuiting mixture stirred for 45 minutes at 0 °C. Ammonia gas was bubbledinto the solution for 2 hours and the gas source removed. The reaction mixturewas then allowed to warm to ambient température and stirred for 16 hours. Thesolution was adjusted to pH 1 by addition of 1N hydrochloric acid, and thenextracted with ethyl acetate (3 x 50 mL). The combined organic extracts weredried (anhydrous magnésium sulfate), filtered, and concentrated in vacuo to givethe crude product. The residue was purified by flash column chromatography(hexanes to 10% ethyl acetate/hexanes) to afford the title compound (0.97 g, 41%)as a white solid. LRMS (mfc): 116 (M+H)*. 1H NMR (CDCfe, 300 MHz): 4.35 (1H, dd, J = 8.5, 5.8 Hz), 3.92 (2H, m), 2.18 (2H,m), 1.90 (2H, m).
Préparation c-129Tetrahydro-furan-2-carbonitrile
Trifluoroacetic anhydride (1.55 g, 7.38 mmol) was added slowly, with a rate of onedrop every 10 seconds, to an ice-cold solution (0 °C) of tetrahydro-furan-2- 20 carboxylic acid amide (0.77 g, 6.71 mmol) and pyridine (1.06 g, 13.42 mmol) inanhydrous 1,4-dioxane (10 mL). The addition of trifluoroacetic anhydride wasmonitored to keep the internai température below 5 °C and was completed after 20minutes. The resuiting mixture was allowed to warm to ambient température, andstirred for 3 hours. Chloroform (100 mL) was added to the mixture, and then 25 extracted with water (30 mL) and saturated aqueous sodium chloride (20 rnL). Theorganic extracts were dried (anhydrous magnésium sulfate), filtered, andconcentrated in vacuo to give the crude product. The residue was purified by flashcolumn chromatography (hexanes to 25% ethyl acetate/hexanes) to afford the titlecompound (0.51 g, 62%) as a colorless oil. 30 1H NMR (CDCb, 300 MHz): 4.70 (1H, m), 3.96 (2H, m), 2.24 (2H, m), 2.08 (2H,m).
Préparation c-130 2-(6-f2-(5-Methvl-2-phenvl-oxazol-4-vl1-ethoxv1-pvridin-3-vlmethvl)-tetrahvdro- furan-2-carbonitrile
35 13157 .
Sodium bis(trimethylsi!yl)amide (1.8 mL, 1.79 mmol) was added to a solution oftetrahydro-furan-2-carbonitriie (0.17 g, 1.79 mmol) in anhydrous tetrahydrofuran (6mL) under an atmosphère of nitrogen at -78 °C. The resulting yetlow solution wasstirred for 50 minutes, and then a solution of 5-iodomethyl-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine (0.25 g, 0.596 mmol) in anhydrous tetrahydrofuran (3mL) was added to the enolate solution. The mixture was stirred at -78 °C for 1.5hours, and quenched with saturated aqueous ammonium chloride (5 mL). Theaqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combinedorganic extracts washed with water (30 mL), dried (anhydrous magnésium sulfate),filtered, and concentrated in vacuo to give the crude product. The residue waspurified by flash coiumn chromatography (7% to 45% ethyl acetate/hexanes) toafford the title compound (0.11 g, 46%) as a white solid. LRMS (m/z): 390 (M+H)’. 1H NMR (CDCIs, 300 MHz); 8.03 (1H, d, J = 2.5 Hz), 7.96 (2H, m), 7.56 (1H, dd, J= 8.5, 2.5 Hz), 7.40 (3H, m), 6.68 (1H, d, J = 8.5 Hz). 4.54 (2H, m), 3.96 (2H, m),3.00 (4H, m), 2.33 (5H, d, J = 3.2 Hz), 1.92 (2H, m).
Example D-1 2-ethoxv-3-(6-r2-f5-methyl-2-phenvl-1.3-oxazol-4-yl)ethoxyipyridin-3-v,l)propanoic
Lithium hydroxide monohydrate (180 mg, 4.31 mmol) was added to a solution ofethyl 2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yi)ethoxy]pyrÎdin-3- yljpropanoate (183 mg, 0.431 mmol) in a mixture oftetrahydrofuran;methanoi:water (1:1:1, 6 mL). The mixture was stirred 18.hoursthen the volatile components were removed by évaporation. The aqueous phasewas acidified with 3M hydrochloric acid and extracted with ethyl acetate. Theorganic phase was washed with brine, dried over magnésium sulfate, filtered andevaporated. The residue was purified twice by flash coiumn chromatography (98:2dichloromethane:methanol) to yield the title compound as a colorless glass (31 mg)LRMS (m/z): 396 (Mf. 1H NMR (CDCI3, 300 MHz) 7.99 (3H, m), 7.50 (1H, m), 7.40 (3H, m), 6.65 (1H, m),4.50 (2H, t, J= 7 Hz), 4.01 (1H, m), 3.64 (1H, m), 3.42 (1H, m), 2.98 (4H, m), 2.34(3H, s), 1.16 (3H, t, J = 7 Hz).
Examples D-2 to D-45
Examples D-2 to D-45 were prepared by procedures analogous to those used forExample D-1 by stirring a solution of the ester with sodium or lithium hydroxide in 13157; 139 aqueous methanol, aqueous éthanol, aqueous tetrahydrofuran or mixturesthereof at températures between 20 °C and 75°C.
Ex# Structure ’HNMR MS (m/z)LR/HR Analysis D-2 NS— " οΛ N^Js. CHS > /γ° CHj OH Ή NMR (DMSO-de, 400 MHz) 8.05 (2H, d, J = 8.6 Hz), 7.96-7.94 (3H, m), 7.55 (1 H, dd, J =8.3 and 2.3 Hz), 6.70 (1H, d, j= 8.3 Hz), 4.45 (2H, t, J = 6.6Hz), 3.89 (1 H, dd, J = 7.6 and5.1 Hz). 3.22 (3H, s), 2.95-2.87(3H, m), 2.80 (1H. dd, J = 14.2and 7.8 Hz), 2.35 (3H, s) for LR 408(M+H)+ D-3 9¼° CHj OH Ή NMR (DMSO-d6, 400 MHz) 7.96(1 H. d, J = 2.3 Hz), 7.73(1H, s), 7.69 (1H, d, J = 7.8Hz), 7.55 (1H, dd, J = 8.6 and2.3 Hz), 7.37 (1H, t, J = 7.8 Hz),7.28 (1H, d, J = 7.1 Hz), 6.70(1H, d, 8.3 Hz), 4.44 (2H, t, J =3.8 Hz), 3.89 (1H, dd, J = 8.1ànd 4.8 Hz), 3.22 (3H, s), 2.92-2-88 (3H, m), 2.80 (1H, d, J =14.7 and 8.1 Hz), 2.36 (3H, s),2.31 (3H, s) Calcd for C22H25N2O5 397.1758. Found: 397.1775 Calcd forC22H24N2O5O.5H20C 65.17 H 6.22 N6.91. Found;C 65.03 H6.10 N 7.07 D-4 Ch€k"ïzxAn O-\_ ?V ch3 oh ’H NMR (DMSO-de, 400 MHz) : 7.98(1 H, d, J = 1.8 Hz), 7.92(2H, d, J =8.6 Hz), 7.58-7.55(3H, m), 6.72(1 H, d, J =8.6Hz), 4.46 (2H,t, J = 6.6 Hz),3.91 (1H, dd, J =7.8 and 4.6Hz), 3.24 (3H, s), 2.94-2.89(3H, m), 2.82(1 H, dd, J= 14.4and 7.6 Hz), 2.33 (3H, s). Calcd for C2,H22CIN2 o5 417.1212. Found: 417.1232 D-5 ~~ O*X CHj | /γ° CHj OH ’H NMR (DMSO-d6,400 MHz) : 12.71 (1H.S), 7.96(1 H, d, J = 2.3 Hz), 7.90 (2H, dd, J =7.6and 2.0), 7.55(1 H, dd, J =8.6and 2.3 Hz), 7.51-7.46 (3H, m),6.71 (1H, d, J =8.6 Hz), 4.44(2H, t, J = 6.6 Hz), 3.89 (1H,dd, J = 7.6 and 5.1 Hz), 3.22(3H, s), 2.92-2.88 (3H, m), 2.80(1H, dd, J =14.2 and 7.6 Hz),2.32 (3H, s). Calcd forC2i H22N2O5O.1H20C 65.65 H 5.82 N7.29. Found:C 65.45 H5.92 N 7.26. 13157 . 140 D-6 0\h3 CHa OH ’H NMR (DMSO-de, 400 MHz) 12.81 (1H, s), 7.96(1H,d,J =2.0 Hz), 7.90 (2H, dd, J =7.7and 1.9), 7.55 (1H,dd, J=8.6and 2.3 Hz), 7.51-7.46 (3H, m),6.70 (1H, d, J= 8.6 Hz), 4.44(2H, t, J= 6.8 Hz), 3.88 (1H,dd, J =7.6 and 4.8 Hz), 3.22(3H, s), 2.92-2.87 (3H. m), 2.80(1H,dd, J= 14.2 and 7.8 Hz),2.32 (3H, s). Calcd forC21H22N2O5O. 25H20 C65.19 H 5.86N 7.24.Found: C65.19 H 5.80N 7.03 D-7 HaC' XH J Y Ί o~\ n.zÀ CH3 > ch3 oh ’H NMR (DMSO-de, 400 MHz) : 12.54(1 H, s), 7.96 (1H, d,-J = 2.0 Hz), 7.83 (2H,d, J =9.1),7.55 (1H,dd, J =8.6 and 2.3Hz), 7.03 (2H, d, J =8.8 Hz),6.70 (1H, d, J =8.6 Hz), 4.43(2H, t, J =6.8 Hz), 3.90 (1H,dd, J = 7.8 and 4.8 Hz), 3.80(3H, s), 3.22 (3H, s), 2.92-2.86(3H, m), 2.80 (1H, dd, J=14.7and 7.6 Hz), 2.29 (3H, s) Calcd for C22H25N2O6 413.1707. Found: 413.1717 D-8 (Ol χΝχΧ~χ^Οχ^. R ch3 η CH> 0Λ^ο CHj OH Ή NMR (DMSO-d6,400 MHz) : 12.77 (1H, s), 7.96 (1H, d, J = 2.3 Hz), 7.55 (1H, dd, J=8.3and 2.3),7.48 (1H,d, J =7.8Hz), 7.41 (1H,d, J =8.1 Hz),7.39-7.37 (1H, m), 7.04 (1H, dd,J =8.1 and 2.5 Hz), 6.71 (1H,d, J = 8.6 Hz), 4.44 (2H, t, J =6.8 Hz), 3.89 (1H, dd, J= 7.8and 4.8 Hz), 3.81 (3H, s), 3.22(3H, s), 2.92-2.88 (3H, m), 2.80(1H,dd, J= 14.4 and 8.0 Hz),2.31 (3H, s). Calcd for C22H25N2O6 413.1707. Found: 413.1715 D-9 X-f Αζ.Ν-γ-'-χ^θ-γ-’Χ'=K/? O-\ Ns^L l OH Ή NMR (DMSO-d6,400 MHz) : 12.70(1 H, s), 8.04 (2H, d, J- 8.1 Hz), 7.91 (1H,d, J =2.0),7.80 (2H, d, J =8.3 Hz), 7.49(1H,dd, J =8.3 and 2.4 Hz),6.65 (1 H, d, J = 8.3 Hz), 4.40(2H, t, J =6.6 Hz), 3.84 (1H,dd,J = 7.6 and 4.7 Hz), 3.16(3H, s), 2.90-2.82 (3H, m), 2.74(1H,dd, J= 14.4 and 7.8 Hz),2.29 (3H, s). Calcd for C22H22F3N2 θ5 451.1476. Found: 451.1474 D-10 oÀ ch3 Ί CHa OH 'H NMR (DMSO-de, 400 MHz) : 12.76(1 H, s). 7.96 (1H, d, J = 2.3 Hz), 7.79 (2H, d, J =8.1),7.55 (1H, dd, J =8.6 and 2.5Hz), 7.29 (2H, d, J =8.1 Hz),6.68(1 H, d, J =8.3 Hz), 4.43(2H, t, J =6.8 Hz), 3.89 (1H,dd, J =7.8 and 4.8 Hz), 3.22(3H, s), 2.92-2.87 (3H, m). 2.80(1H, dd, J =14.2 and 7.8 Hz),2.34 (3H, s), 2.30 (3H, s). Calcd for C22H25N2O5 397.1758. Found: 397.1770 Calcd forC22H24N2O5O.3H20 C 65.75 H6.17N6.97. Found:C 65.74 H6.14 N 6.81 141 13157 D-11 0 'oh c ή h.c'° 9 h3c^s, b 1H NMR (MeOH-d4, 400 MHz):8.30 (1 H, s) 7.58 (1 H, d, >9.2Hz) 7.11 (2 H, d, >8.2 Hz) 6.71(2 H, d, >8.2 Hz) 6.31 (1 H, d,>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.18(1 H, dd, >13.5, 0.2Hz) 3.98 (2 H, q, >7.7 Hz) 3.52(3 H, s) 3.28 (2 H, t. >6.5 Hz)3.05-3.11 (1 H, m) 2.89-2.98(1 H, m) 1.44 (3 H, t, >7.7 Hz) LRMS: 410(M+H)*. D-12 0 OH JL -J -0 O N HjC Φ *3θ' b ’H NMR (MeOH-d4, 400 MHz):8.30 (1 H, s) 7.58 (1 H, d, >9.2Hz) 7.10 (2 H, d, >8.2 Hz) 6.74(2 H, d, >8.2 Hz) 6.31 (1 H, d.>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.18(1 H, dd, >13.5, 0.2Hz) 3.52 (3 H, s) 3.34 (3 H, s)3.28 (2 H, t, >6.5 Hz) 3.06 -3.11 (1 H, m) 2.89 - 2.98 (1 H,m) forLR396 (M+H)* D-13 0 <YV0H A J o O N \ CHî σ°. TH NMR (MeOH-d4l 400 MHz): 8.30 (1 H, s) 7.58 (1 H, d, >9.2Hz) 7.31-7.37 (2 H, m, >8.0,7.5, 0.2,0.2 Hz) 7.06-7.14 (3H, m) 6.96-7.04 (4 H, m)6.31(1 H, d, >9.2 Hz) 4.57 (2 H, t,>6.5 Hz) 4.18(1 H, dd,>13.5,0.2 Hz) 3.52 (3 H, s)3.28 (2 H. t, >6.5 Hz) 3.06 -3.11 (1 H. m) 2.89-2.97 (1 H. ............ for LR394 (M+H)4 D-14 O CpA" r° J CH, 9 σ° 1H NMR (MeOH-d4, 400 MHz):8.28-8.34 (1 H, m) 7.59 (1 H,m) 7.31 - 7.37 (2 H, m) 6.96 -7.14 (7 H, m) 6.27-6.34(1 H.m) 4.53 - 4.60 (2 H, m) 4.22-4.30 (1 H, m) 3.49 - 3.66 (2 H,m) 3.25 - 3.31 (2 H, m) 3.05 -3.11 (1 H, m) 2.89-2.97(1 H,m) 1.19 (3 H, t, >7.0 Hz) LRMS: 409(M+H)\ D-15 O 0H a-QÂjÜ £ 1H NMR (MeOH-d4, 400 MHz): 8.31 (1 H, s) 8.02 (2 H, d, >8.3Hz) 7.59(1 H, d, >9.1 Hz) 7.43(2 H, d, >8.3 Hz) 6.31 (1 H, d,>9.1 Hz) 4.20-4.29 (3 H, m)3.49-3.66 (2H, m) 3.05-3.11(1 H, m) 2.89-2.97 (1 H, m)2.70 (2 H, t, >8.0 Hz) 2.19(3H, s) 1.19 (3 H, t, >7.0 Hz) for LR432 (M+Hf 13157 142 D-16 ,γ- ‘H NMR (MeOH-cL,, 400 MHz):8.31 (1 H, s) 7.59(1 H, d, J=9.1Hz) 6.87 (2 H. d, >8.2 Hz) 6.73(2 H, d, >8.2 Hz) 6.31 (1 H, d,>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.43 (2 H, s) 4.26 (1 H. dd,>13.5, 0.2 Hz) 3.76 (2 H. s)3.49-3.66 (2 H, m) 3.38 (3 H,s) 3.28 (2 H, t, >6.5 Hz) 3.05 -3.11 (1 H, m) 2.89-2.97(1 H,m) 1.19 (3 H, t, >7.0 Hz) for LR391 (M+H)+ V / D-17 ί 0 é o. o œ 0 ΎΎ'ΌΗ ΓΟ CH, 1H NMR (MeOH-dj, 400 MHz):8.31 (1 H, s) 7.66-7.74 (5 H,m) 7.59(1 H, d, >9.1 Hz) 7.19(2 H, d. >8.2 Hz) 6.86 (2 H, d.>8.3 Hz) 6.31 (1 H, d, >9.2Hz) 4.57 (2 H, t, >6.5 Hz) 4.26(1 H,dd, >13.5,0.2 Hz) 3.49-3.66 (2 H, m) 3.28 (2 H, t, >6.5Hz) 3.05-3.11 (1 H, m) 2.89-2.97(1 H, m) 1.19 (3 H, t, >7.0Hz) for LR473 (M+Hf D-18 c> Q °.,o h3c^s; 0 0 YY^OHt J .0 N ( CH, lH NMR (MeOH-d4,400 MHz): 8.31 (1 H, s) 7.59(1 H, d, >9.1Hz) 7.11 (2 H, d, >8.2 Hz) 6.71(2H,d, >8.2 Hz) 6.31 (1 H, d,>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.26(1 H, dd, >13.5, 0.2Hz) 3.98 (2 H, q, >7.7 Hz) 3.49- 3.66 (2 H, m) 3.28 (2 H, t,>6.5 Hz) 3.05-3.11 (1 H, m)2.89-2.97 (1 H, m) 1.44 (3 H, t>7.7 Hz) 1.19 (3 H, t, >7.0Hz) for LR425 (M+H)+ D-19 4 9- oh3c'% 0 CH, 1H NMR (MeOH-d4, 400 MHz):8.31 (1 H, s) 7.59(1 H, d, >9.1Hz) 7.10 (2 H, d, >8.2 Hz) 6.74(2 H, d, >8.2 Hz) 6.31 (1 H, d,>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.26 (1 H,dd, >13.5, 0.2Hz) 3.49 - 3.66 (2 H, m) 3.34 (3H, s) 3.28 (2 H, t, >6.5 Hz)3.05-3.11 (1 H, m) 2.89-2.97(1 H, m) 1.19 (3 H, t, >7.0 Hz) for LR411 (M+H)‘ D-20 Ή NMR (MeOH-d4, 400 MHz): 8.31 (1 H, s) 7.59 (1 H, d, >9.1Hz) 7.34 (2 H, d. >8.2 Hz) 7.24(2 H, d, >8.2 Hz) 6.31 (1 H, d,>9.2 Hz) 4.57 (2 H, t, >6.5Hz) 4.26 (1 H,dd, >13.5, 0.2Hz) 3.49 - 3.66 (2 H, m) 3.28 (2H, t, >6.5 Hz) 3.05-3.11 (1 H,m) 2.89-2.97 (1 H, m) 1.19(3H. t, >7.0 Hz) for LR400 (M+H)" 13157 β F o ιίγΛ»o-V r° ) CH, ) D-21 Φ r° CH, 0 fYYA r° CH, ’H NMR (MeOH-cL,, 400 MHz): 8.31 (1 H, s) 7.59 (1 H, d, J=9.1Hz) 6.94 (2 H, d, J=8.2 Hz) 6.66(2 H, d, ^=8.3 Hz) 6.31 (1 H. d,J=9.2 Hz) 4.57 (2 H, t, J=6.5Hz) 4.26(1 H, dd, J=13.5, 0.2Hz) 4.01 (2 H, q, J=6.9 Hz) 3.49- 3.66 (2 H, m) 3.28 (2 H, t,J=6.5 Hz) 3.05-3.11 (1 H, m)2.89 - 2.97 (1 H, m) 1.40 (3 H, t,J=7.0 Hz) 1.19 (3 H, t, J=7.0HZ) for LR360 (M+H)+ D-22 ν' h3c'° 0 Cf/®cA»r f° J CH, 5 1H NMR (MeOH-d4, 400 MHz):8.31 (1 H, s) 7.59 (1 H. d, J=9.1Hz) 6.97 (2 H, d. J=8.2 Hz) 6.77(2 H, d, J=8.2 Hz) 6.31 (1 H, d,Λ9.2 Hz) 4.57 (2 H, t, J=6.5Hz) 4.26(1 H, dd, J=13.5, 0.2Hz) 3.78 (3 H, s) 3.49 - 3.66 (2H, m) 3.28 (2 H, t, J=6.5 Hz)3.05-3.11 (1 H, m) 2.89-2.97(1 H, m) 1.19 (3 H, t, J=7.0 Hz) for IR346 (M+H)’ D-23 /A °TCH> (TV i OH WAn οίch3 (MeOD, 400 MHz): 8.03 (1 H, d,J = 2.8 Hz), 7.84-7.82 (2H, m),7.35-7.34 (3H, m), 7.26 (1H,dd,J =8.6,2.5 HZ), 7.16(1 H, d, J= 8.6 Hz), 4.20 (2H, t, J = 6.4Hz), 4.06 (1H, dd, J =8.6, 4.6Hz), 3.52-3.44(1 H, m), 3.22-3.14 (1H,m), 3.03 (1H, dd, J =13.9,4.6 Hz), 2.88 (2H,t, J =6.3 Hz). 2.92 (1H,d, J =9.1Hz), 2.26 (3H, s), 0.94 (3H, t, J| = 7.0 Hz) forLR397 (M+H)+ 13157 144 D-24 (CDCI3, 400 MHz): 8.25 (1H,d, J=1.5 Hz), 7.95 (2H. dd, J = 7.6,1.8 Hz), 7.44-7.36 (3H, m),7.28-7.22 (2H, m), 4.19 (1H, dd,J- 7.1,4.6 Hz), 4.02 (2H, t, J =6.1 Hz), 3.80-3.72 (1 H, m),3.47-3.39 (1H, m), 3.34 (1H,dd,J= 15.2, 7.1 Hz), 3.2O0H, dd,J= 15.2, 4.3 Hz), 2.67 (2H, t, J= 7.2 Hz), 2.27 (3H, s), 2.19-2.12 (2H, m), 1.17 (3H,t, J=7.0 Hz) for LR 411 (M+H)* D-25 0 o >CH-, H3C~<v T JC n o 0H ch3 (CDCf3,400 MHz)·: 8.16 (1H, d,J = 2.3 Hz). 7.24-7.19 (2H, m),4.27 (2H, t, J =6.8 Hz), 4.17(1H, dd, J =7.6, 3.8 Hz), 3.79-3.72 (1 H, m), 3.47-3.40 (1H,m), 3.32 (1H, dd, J=15.4. 7.6Hz), 3.18(1 H, dd, J =15.4, 3.5Hz), 3.09 (2H, t, J = 6.7 Hz),2.59 (3H, s), 2.34 (3H, S), 1.17(3H,t, J = 7.0 Hz) for LR351 (M+Hf D-26 /-y_xSYCHs AtAh \=MNVoÂ,N ch3 (MeOD, 400 MHz): 8.01 (1H, d,J= 3.0 Hz), 7.74-7.71 (2H, m),7.34-7.27 (3H, m), 7.24 (1H,dd,J = 8.6,2.8 Hz), 7.14 (1H,d,J= 8.6 Hz), 4.27 (2H, t, J= 6.6Hz), 4.06 (1 H, dd, J = 8.7, 4.7Hz), 3.51-3.44 (1H, m), 3.22-3.14(1 H, m), 3.08 (2H, t, J =6.4 Hz), 3.02 (1H, dd, J= 14.2, 4.6 Hz), 2.89(1 H, dd, J = 13.9, 8.6 Hz), 2.34 (3H, s), 0.93 (3H, t, J =7.1 Hz) for LR413(M+H)+ D-27 ίΥ~Λ 0H ÎV^jC^'0 N °'CH3xJcAch, (MeOD, 400 MHz): 7.86-7.82(3H,m), 7.47(1 H, dd, J =8.6,2.0 Hz), 7.39-7.36 (3H, m), 6.62(1H, d, J =8.3 Hz), 4.14 (2H, t,J =6.2 Hz), 3.22-3.20 (3H, m),2.85 (2H, dd, J = 22.5,13.9Hz), 2.60 (2H, t, J = 7.1 Hz),2.19 (3H, s), 2.03 (2H, dd, J =12.9,6.1 Hz), 1.26 (3H, s) for LR 411 (M+H)+ D-28 COv0H o-CH, (MeOD, 400 MHz): 8.02 (1H, dJ = 2.5 Hz), 7.85-7.83 (2H, m),7.39-7.33 (3H, m), 7.26 (1H, ddJ = 8.6, 2.8 Hz), 7.20(1 H, d, J= 8.6 Hz), 3.96 (2H, t, J =6.1Hz), 3.20 (3H, s), 3.05 (2H, dd,J = 21.0, 13.9 Hz), 2.61 (2H, t,J = 7.2 Hz), 2.20 (3H, s), 2.07-2.01 (2H,m), 1.24 (3H, s) for LR411 (M+H)" 13157 . '140 D-29 LaVAn (MeOD. 400 MHz): 8.02 (1 H, d,J- 2.8 Hz), 7.87-7.83 (2H, m),7.39-7.36 (3H,m), 7.27(1 H, dd,J= 8.6, 2.8 Hz), 7.19 (1H, d, J= 8.6 Hz), 4.22 (2H, t, J =6.4Hz), 3.19 (3H, s), 3.05 (2H, dd, J = 21.2, 13.9 Hz), 2.91 (2H, t, J =6.4 Hz), 2.29 (3H, s), 1.23(3H, s) forLR397 (M+H)* D-30 c-fWjT fpÇ0H (MeOD, 400 MHz): 7.87-7.84(3H, m), 7.48 (1H, dd, J = 8.6,2.3 Hz), 7.41 (2H,d, J =8.6Hz), 6.61 (1H,d, J = 8.6 Hz),4.42 (2H,t, J=6.6 Hz), 3.22(3H, s), 2.91-2.88 (3H, m), 2.83(1H, d, J = 13.9 Hz), 2.27 (3H,s), 1.25 (3H, s) for LR 431 (M+H)* D-31 A-fVY ΓΡρ (MeOD, 400 MHz): 8.04 (2H, d,J = 8.1 Hz), 7.84(1 H, d, J =2.0Hz), 7.70 (2H,d, J = 8.3 Hz),7.46 (1H, dd, J =8.5, 2.4 Hz),6.60 (1 H,d, J =8.3 Hz), 4.43(2H, t, J =6.6 Hz), 3.22 (3H, s),2.91 (2H, t, J = 6.4 Hz), 2.88(1H, d, J =14.2 Hz), 2.82 (1H,d, J=14,2 Hz), 2.28 (3H, s),1.25 (3H, s) forLR465 (M+H)* D-32 /~\PY ιίΥχ™ < X - JL J z o (MeOD, 400 MHz): 7.84 (1H, d, J =2.0 Hz), 7.47 (1H, dd, J =8.5,2.4 Hz), 6.59 (1H, d, J =8.6 Hz), 4.32 (2H, t, J = 6.6 Hz),3.23 (3H,s), 2.89 (1H,d, J-14.2 Hz), 2.83 (1H, d, J= 13.9Hz), 2.78 (2H,t, J = 6.7 Hz),2.64 (1H,tt, J= 11.6, 3.5 Hz),2.13 (3H, s), 1.93-1.89 (2H, m),1.75-1.71 (2H, m), 1.65-1.62(1H, m). 1.50-1.40 (2H, m),1.37-1.27 (2H,m), 1.26 (3H, s),1.23-1.19(1 H, m) for LR403 (M+H)* D-33 0 /"V,SA |Ρ^χ·ΟΗ (MeOD, 400 MHz): 7.85 (1 H. d, J =2.3 Hz), 7.77 (2H, dd, J =7.6,1.8 Hz), 7.47 (1H, dd, J-8.6,2.3 Hz), 7.39-7.31 (3H, m),6.61 (1H, d, J =8.6 Hz), 4.49(2H, t, J = 6.7 Hz), 3.23 (3H, s),3.11 (2H,t, J =6.7 Hz), 2.89(1H, d, J=13.9 Hz). 2.83 (1H,d, J= 14.2 Hz), 2.36 (3H, s),1.26 (3H, s) for LR413 (M+H)* D-34 (MeOD, 400 MHz): 7.84 (1 H, d J = 2.3 Hz), 7.43 (1H, dd, J =8.5, 2.4 Hz), 7.17 (2H, dd, J =8.1,0.8 Hz), 7.09-7.05 (1H, m),6.94 (1 H, dt, J = 7.8,1.0 Hz),6.53(1 H, d, J =8.3 Hz), 4.49(2H,t, J =5.3 Hz), 3.87 (2H,t,„= 5.3 Hz), 3.23 (3H, s), 3.18 for LR386 (M+H)" 13157 . 140 (3H, s), 2.88(1 H, d, J =13.9Hz), 2.82(1 H, d, J = 13.9 Hz),1.26 (3H, S) D-35 0 PV (Ύλ011ÎH JL A J ZP \=7 N -^O N ‘ (Dimethyl sulfoxide-d6, 300MHz): 7.91 (3H, m), 7.49 (4H,m), 7.40 (3H, m), 6.69 (1H.il, J= 8.5 Hz), 4.44 (2H,t, J =6.7Hz). 3.44 (2H, m), 3.18 (3H, s),2.89 (2H, m), 2.31 (3H, s), 1.19(3H, s) forLR395 (M)’ Calcd 322H24N2O5 C66.65, H 6.10,N 7.07. Found:322H24N2O5O.O6H2O C56.16, H 6.15,N 6.96. D-36 O O-4Y jCT^ (MeOD, 400 MHz): 7.83 (1 H, d, J =1.8 Hz), 7.69 (1 H, s), 7.65(1H, d, J =7.6 Hz), 7.46(1 H,dd, J =8.6, 2.3 Hz), 7.25 (1H,t,J=7.6 Hz), 7.19 (1H, d, J=7.6Hz), 6.59 (1H,d, J =8.3 Hz),4.39 (2H,t, J =6.6 Hz), 3.19(3H, s), 2.87 (2H, t, J = 6.4 Hz),2.87 (1H,d, J =13.9 Hz), 2.80(1H, d, J = 13.9 Hz), 2.30 (3H,s), 2.24 (3H, s), 1.21 (3H, s) for LR411 (M+H)+ D-37 ~v<fy4Y ry>ïo« (MeOD, 400 MHz): 7.83 (1H, d,J =2.3 Hz), 7.79-7.76 (2H, m),7.46 (1H, dd, J =8.5, 2.4 Hz),6.90 (2H, d, J = 8.8 Hz). 6.59(1H. d, J =8.6 Hz),4.38 (2H, t, J= 6.7 Hz), 4.00 (2H, q, J = 7.1Hz), 3.21 (3H, s), 2.88 (1H, d, J= 13.9 Hz), 2.86 (2H, t, J =6.6Hz), 2.81 (1H, d, J= 13.9 Hz),2.22 (3H, s), 1.31 (3H, t, J = 7.0Hz), 1.24 (3H, s) for LR441 (M+Hf D-38 Κ3θ0ιρ>ΟΗ (CDCI3, 400 MHZ): 7.93 (1 H, d, J =2.3 Hz), 7.45 (1H, dd, J =8.5, 2.4 Hz), 6.63 (1H, d, J =8.6 Hz), 4.40 (2H, t, J = 6.8 Hz),3.37 (3H, s), 3.05-2.96 (1 H, m),2.97 (1H, d, J =14.4 Hz), 2.92(1H, à, J- 14.4 Hz), 2.86 (2H,î, J =6.7 Hz), 2.20 (3H, s), 1.43(3H, s), 1.30 (3H, s). 1.28 (3H, . s) forLR363 (M+H)* D-39 vw/ xy>ooH N-N 1 (MeOD, 400 MHz): 7.82 (1 H, d J =2.0 Hz), 7.44 (1H, dd, J =8.6, 2.3 Hz), 6.57(1 H, d, J =8.6 Hz), 6.45 (1H, s), 4.39 (2H,t, J = 6.4 Hz), 4.00 (3H, s), 3.20(3H, s), 2.86 (2H, t,J = 6.6 Hz),2.86(1 H, d, J = 14.2 Hz), 2.80(1H, d, J= 14.2 Hz), 2.22 (3H,s), 2.14 (3H, s), 1.23 (3H, s) forLR 415(M+H)+ 13157 ; 147 D-40 ίί'^ΥθΥ^Ίι fY/QH LJ LA/'. JL J A (MeOD, 400 MHz): 7.82 (1H, d, J =2.3 Hz), 7.44(1 H, dd, J = 8.0, 1.9 Hz), 7.34-7.29 (2H, m), 7.22 (2H, d, J =8.6 Hz), 7.09-7.03(1 H, m), 6.98-6.91 (4H,m), 6.60 (1H,d, J =8.6 Hz),4.33 (2H, t, J =7.1 Hz), 3.20(3H, s), 3.00 (2H, t, J =7.0 Hz),2.82 (1H,d, J =14.2 Hz), 2.80(1H, d,J=14.2 Hz), 1.23 (3H,S) for LR408 (M+H)* D-41 Fc L 1 ~ JL J z o (MeOD, 400 MHz): 7.81 (1H,d,J = 2.3 Hz), 7.44 (1H, dd, J-8.6, 2.3 Hz), 7.27 (2H, d, J =8.6 Hz), 7.07 (2H, d, J = 7.8Hz), 6.57 (1H, d, J =8.6 Hz),4.33 (2H,t, J =6.7 Hz), 3.20 (3H,S), 2.97 (2H,t, J = 6.7 Hz),2.84 (1H,d, J= 14.2 Hz), 2.82(1H, d, J = 14.2 Hz), 1.24 (3H,s).......... forLR400 (M+H)+ D-42 0 fUY ΓΡ^ΟΗ ?=/ νΑ/ολη^ 1 F (MeOD. 400 MHz): 7.83 (1H,d,J =1.8 Hz), 7.65 (1H,d, J =7.6Hz), 7.46 (1H, dd, J= 8.6, 2.3Hz), 7.29(1 H, s), 7.25 (1H, t, J= 7.6 Hz), 7.19(1 H, d, J =7.6. Hz), 6.59 (1H,d, J =8.3 Hz),4.39 (2H,t, J = 6.6 Hz), 3.19(3H, s), 2.87 (2H, t, J = 6.4 Hz),2.87 (1H,d, J- 13.9 Hz), 2.80(1H, d, J= 13.9 Hz), 2.24 (3H,s), 1.21 (3H, s) for LR415 (M+H)* D-43 P'/' rY/OH \ A Jl J Z Û -o (MeOD, 400 MHz): 7.81 (1H,d,J= 2.3 Hz), 7.45-7.38 (2H, m),7.32-7.24 (2H, m), 6.91 (1H, dd,J =8.0, 2.4 Hz), 6.58(1 H, d, J= 8.3 Hz), 4.38 (2H, t, J =6.7Hz), 3.74 (3H, s), 3.18 (3H, s),2.86 (2H, t, J =6.7 Hz), 2.85(1H, d, J = 13.9 Hz), 2.79 (1H,d, J =13.9 Hz), 2.22 (3H, s),1.22 (3H, s) for LR427 (M+H)*
Préparations of startinq materials for Examples D-1 to D-43 (Préparations d-1 to d-
42V
Préparation d-1
Ethyl 2-ethoxv-3-f6-r2-(5-methvl-2-phenvl-1.3-oxazol-4-vl)ethoxvlpyridin-3-
W,W,W,M-tetramethylguanidine (0.305 mL, 2.43 mmol) was added dropwise to asolution of 6-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde (250 mg, 5 13157
14B 10 0.811 mmol) and (1,2-diethoxy-2- oxoethyl)(triphenyl)phosphonium chloride (696 mg, 1.62 mmol) in chloroform (4 mL). The mixture was stirred for 16hours then partitioned between saturated ammonium chloride solution and ethylacetate. The organic phase was washed with brine, dried over magnésium sulfate,filtered and evaporated* and evaporated. The residue was purified by flash columnchromatography (1:2 ethyl acetate:hexanes) to yield the title compound as a whitesolid (330 g, 96%). LRMS (mÆ); 423 (M+Hf. 'H NMR (CDCIa, 300 MHz) 8.42 (1H, m), 8.10 (1H, m), 7.97 (1H, m), 7.40 (2H, m),7.28 (3H, m), 6.90 (1H, s), 6.73 (1H, m), 4.60 (2H, t, J = 7 Hz), 4.30 (2H, q, J = 7Hz), 4.01 (2H, q, J= 7 Hz), 2.99 (2H, t, J= 7 Hz), 2.34 (3H, s), 1.36 (6H, m)
Préparation d-2
Ethyl 2-ethoxv-3-{6-[2-f5-methvl-2-phenvl-1.3-oxazol-4-vl)ethoxv1Pvridin-3- yQpropanoate 15
20 25 A solution of ethyl 2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}acrylate (328 mg, 0.776 mmol) in éthanol (10 mL) washydrogenated at 50psi over 10% palladium on carbon (33 mg) for 3 hours. Themixture was filtered through celite and the solid was washed with ethyl acetate.The filtrate and washings were evaporated and the residue was purified by flashcolumn chromatography (1:2 ethyl acetate:hexanes) to yield the title compound asa colorless oil (183 mg, 56%). LRMS (m/z): 425 (M+H)+. 1H NMR (CDC,a, 300 MHz) 7.99 (3H, m), 7.42 (4H, m), 6.65 (1 H. m), 4.54 (2H, t, J= 1 Hz), 4.18 (2H, q, J = 7 Hz), 3.93 (1H, m), 3.63 (1H, m), 3.36 (1H, m), 2.90 (4H,m), 2.33 (3H, s), 1.25 (3H, t, J = 7 Hz), 1.16 (3H, t, J= 7 Hz).
Préparation d-3
Préparation of 2-(benzyloxv)-5-bromopyridine
30 To a solution of 5-bromopyridin-2(1H)-one (100 mmol, 17.4 g, 1.0 eq.) in benzene (170 mL) was added silver (I) carbonate (67.0 mmol, 18.5 g, 0.67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20.5 g, 1.2
eq.) was added via syringe in a steady stream. The mixture was heated to 50 °C 13157 149 10 15 and stirred in the dark for approximately 24 hours. LCZMS of the reaction mixtureindicates two peaks both with M+H = 265 corresponding to the desired molecularweight. On the basis oi relative polaritïes, the more polar peak was thought to bethe N-alkylated product and consisted of approximately 20 % of the total. Thereaction mixture was allowed to cool to room température and the silver sait wasremoved by filtration of the mixture through a pad of celite. The filter cake waswashed with benzene and the organic layer was washed twice with 2% sodiumbicarbonate and twice with water. The organic layer was dried over magnésiumsulfate and concentrated in vacuo. The crude residue was purified on a BiotageSp4 65i over a gradient of 5-95% hexanes in ethyl acetate to afford the titlecompound as a golden oil (25.1 g, 95%). LRMS: 265 (M+Hf. 1H NMR (DMSO-ds, 400 MHz): 8.29 (1 H, s) 7.72 (1 H, d, J=8.5 Hz) 7.31 - 7.43 (5H. m) 6.54 (1 H, d, J=8.5 Hz) 5.34 (2 H, S)
Préparation d-4
Préparation of 6-(benzyloxv)nicotinaldehvde
n-Butyl lithium (2.5M, 95.9 mmol, 38.4 mL, 1.05 eq.) was added dropwise viasyringe to a stirred solution of 2-(benzyloxy)-5-bromopyridine (91.3 mmol, 24.1 g, 20 1.0 eq.) in THF (260 mL, c = 0.35) cooled to -78 °C. Upon completion of addition, the solution was allowed to continue stirring at the same low température for 1hour. At this point, /V,Mdimethylfarmamide (183 mmol, 13.4 g, 2.0 eq.) was addeddropwise as a solution in 5 mL THF. Stirring was continued at the same lowtempérature for a further 30 minutes at which point the reaction was quenched by 25 addition of 5% sodium bicarbonate. The mixture was transferred to a separatoryfunnei and extracted with ether (3 x 250 mL). The combined organic layers werewashed with brine, dried over anhydrous magnésium sulfate and concentrated invacuo. The résultant yellow oil was purified on a Biotage Sp4 65i over a gradientofO - 50% hexanes in ethyl acetate to afford the title compound (14.1 g, 73%). 30 LRMS: 214 (M+Hf. 1H NMR (DMSO-d6, 400 MHz): 10.02 (1 H, s) 8.86 (1 H, s) 8.03 (1 H, d, J=9.3 Hz)7.31 - 7.43 (5 H, m) 6.50 (1 H, d, J=9.3 Hz) 5.33 (2 H, s)
Préparation d-5
Préparation of ethyl (2Z)-3-f6-(benzvloxv)pyridin-3-vn-2-ethoxyacrvlate 13157 . 150 Ο
Το a solution of 6-(benzyloxy)nicotinaldehyde (1.0 eq., 33.1 mmol, 7.05 g) and(1,2-diethoxy-2-oxoethyl)(tnphenyi)pbosphonium chloride (2.0 eq., 66.2 mmol, 28.4g) in chloroform (165 mL, 0.2 M) was added tetramethylguanidine (3.0 eq., 99.3mmol, 11.4 g). The flask was capped with a hollow glass stopper and stirred atroom température ovemight. TLC analysis after approximately 18 hours indicatedthe presence of a small amount of unreacted starting material. The reactionmixture was heated to reflux and TLC reanalyzed after 2 hours. The reaction wasquenched with saturated ammonium chloride. The layers were separated and theorganic layer was washed with brine, dried over magnésium sulfate andconcentrated in vacuo. A large amount of triphenylphosphine oxide precipitated.The residue was triturated with ether and filtered. Washed filter cake with etherand concentrated combined filtrâtes in vacuo to afford a pale yellow soiid whichwas dissolved in a minimal amount of DCM and loaded onto Biotage Sp4 65i andeiuted over a gradient of 10 -100 % hexanes to ethyl acetate. Obtained 12.3 g ofa clear, colorless oil (37.6 mmol, quant.).
LRMS: 328 (M+H)T 1H NMR (DMSO-de, 400 MHz): 8.33 (1 H, s) 7.92 (1 H, d, J=8.0 Hz) 7.31 - 7.43 (5H, m) 6.76 (1 H, d, J=8.1 Hz) 6.60 (1 H, s) 5.37 (2 H, s) 4.23 (2 H, q, J=7.1 Hz)3.90 - 3.99 (2 H, m) 1.34 (6 H, dt, J=15.8,7.0 Hz)
Préparation d-6
Préparation of ethyl 2-ethoxv-3-(6-oxo-1,6-dihydropvridin-3-vl)Dropanoate o
To a Pan shaker bottle containing a solution of ethyl (2Z)-3-(6-(benzyloxy)pyridin-3-yl]-2-ethoxyacrylate in éthanol was added 10% Pd on carbon ( - 1.23 g). Thebottle was purged with hydrogen and degassed under reduced pressure threetimes. The mixture was placed under 50 psi hydrogen and shaken at roomtempérature ovemight. After ~ 20 hours shaking was stopped and the bottle wasdegassed in vacuo. TLC analysis indicated consumption of starting material. Themixture was filtered through a pad of celite to remove palladium. The filter cakewas washed with an additional portion of éthanol. This solution was concentratedin vacuo to yield the reduced and debenzylated pyridone as a golden oil. This oii 13157 . 151 was purified on a Biotage Sp4, 65i, 80 mL/min over a gradient of 0 - 10%MeOH in DCM to yteld 2.77 g of a clear, colorless oil (11.6 mmol, 31%). LRMS: 240 (M+H)*. 1H NMR (DMSO-d6, 400 MHz): 7.29 (1 H, d, J=9.5 Hz) 7.19 (1 H, d, J=5.2 Hz)5 6.55 (1 H, d, J=9.5 Hz) 4.20 (2 H, q, J=7.0 Hz) 4.10 (1 H, dd. J=9.6, 0.3 Hz) 3.59 - 3.73(2 H, m) 2.65 - 2.70 (1 H, m) 2.53-2.61 (1 H, m) 1.23(6 H, td, J=7.0, 3.6 Hz)Préparation d-7
10 To a solution of (5-benzyloxy-pyridin-2-yl)-methanol (2.3619 g, 10.9728 mmol) indichloromethane (120 mL) and pyridine (2.68 mL, 32.9184 mmol) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (6.9812 g, 16.4592 mmol). Theresulting solution was stirred, under an atmosphère of nitrogen at ambienttempérature, for 16 hours and then diluted with diethyl ether (100 mL) followed by 15 partial concentration under reduced pressure. The residue was taken up in diethylether (150 mL), and précipitâtes were removed by extraction with 1:1 10% aqueoussodium thiosulfatersaturated aqueous sodium bicarbonate (2 x 100 mL). Theorganic layer was washed with water (100 mL) and saturated aqueous sodiumchloride (100 mL), dried (anhydrous magnésium sulfate), filtered, and concentrated 20 in vacuo to afford the pure title compound (1.1694 g, 50%) as a pale yellow oil.LRMS (m/z): 214 {IW+Hf. 1H NMR (CDCI3l 300 MHz): 9.98 (1H, d, J= 0.8 Hz), 8.49 (1H, d, J= 2.5 Hz), 7.94(1H, d, J = 8.7 Hz), 7.44-7.40 (4H, m), 7.38-7.33 (2H, m), 5.19 (2H, s).
Préparation d-8 25 3-(5-Benzvloxv-pvridin-2-vl)-2-ethoxv-acrvlic acid ethvl ester
O
To a solution of 5-benzyloxy-pyridine-2-carbaldehyde (1.1694 g, 5.4842 mmol),(ethoxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride (4.7043 g,10.9684 mmol) in chioroform (30 mL), under an atmosphère of nitrogen at ambient 30 température, was added tetramethylguanidine (2.1 mL, 16.4526 mmol) dropwise.
The resulting solution was stirred for 16 hours and then quenched with saturated aqueous ammonium chloride (50 mL). The phases were separated and the organic phase washed with saturated aqueous sodium chloride (50 mL), dried 1 57 . (anhydrous magnésium suifate), filtered and concentrated in vacuo to afford thecrude product. The residue was purified by flash column chromatography(hexanes to ethyl acetate) to yield the pure title compound (1.8051 g, 100%) as ayellow oil. LRMS (m/z): 328 (M+H)*. 1H NMR (CDCI3, 300 MHz): 8.37 (1H, d, J= 2.6 Hz), 8.18 (1H, d, J= 8.9 Hz), 7.44-7.33 (5H, m), 7.25 (1 H, dd, 8.9, 3.0 Hz), 7.13 (1 H, s), 5.13 (2H, s), 4.27 (2H, q,J = 7.2 Hz), 4.05 (2H, q, J = 7.2 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.0Hz).
Préparation d-9 2-Ethoxv-3-f5-hvdroxv-pyridin-2-vlt-propionic acid ethyl ester
To a solution of 3-(5-benzyloxy-pyridin-2-yl)-2-ethoxy-acrylic acid ethyl ester(1.8051 g, 5.5144 mmol) in dry éthanol (40 mL) was added palladium (0.1805 g, 10wt. % on activated carbon). The resulting solution was stirred at ambienttempérature under an atmosphère of hydrogen (50psi) for 16 hours. The resultingsolution was filtered through a 3” bed of Celite and washed with éthanol (200 mL).The filtrate was then concentrated in vacuo to afford the pure title compound(1.2231 g, 93%) as a pale yellow oil. LRMS (m/z): 240 (M+H)\ ’H NMR (CDCI3, 300 MHz): 8.14 (1H, s), 7.20-7.11 (2H, m), 4.19-4.10 (3H, m),3.71 (1H, q, J = 7.0 Hz), 3.63-3.53 (1H, m), 3.36-3.26 (1H, m), 3.18-3.03 (1H, m),1.18 (3H, t, J =7.2 Hz), 1.07 (3H,t, J = 7.1 Hz).
Préparation d-10 ethyl 2-ethoxy-3-f6-f2-(4-phenoxvphenvl)ethoxylpyridin-3-yl)propanoate
To an argon-purged solution of the appropriate bromopyridine (0.636mmol) in toluene (12 mL) was added palladium (II) acetate (11.4 mg, 0.0508 mmol)and racemic-2-(Di-t-butylphosphino)-1,1'-binaphthyl (25.4 mg, 0.0636 mmol). Theactivated complex was allowed to form over approximately ten minutes, at whichpoint césium carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956 13157 . 153 mmol) were added. The mixture was heated to 115 °C and stirred at this température for approximatety 12-18 hours. The mixture was cooled to roomtempérature and filtered through a pad of silica. The filter pad was washed with 2-3 aliquots of ethyl acetate and the combined organic filtrâtes were combined and 5 concentrated in vacuo. The resulting residue was either purified by flashchromatography, or subjected to the general hydrolysis procedure.
Préparations d-11 tod-18
Préparations d-11 to d-18 were prepared by procedures analoqous to those used for Préparation d-10
Prep # Structure 1H NMR MS (m/z) (LR or HR) d-11 ry-'A'' d-12 Z I d-13 0 9 œ d-14 -Z 0 d-15 0 ιχΛ'" 0 ΪΊ r ô V ° 10 13157 . 154
d-16 0'"^ .4 F-yû F d-17 O O Y <° ti r° d-18 O JL O
Préparation d-19 2-Bromo-5-(bromomethyl)pyridine
Br
5 Br N
Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefuliy to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridineclumped together and the mixture was heated to 160 °C. Within 5 minutes of 10 stirring at >150 °C the mixture went very dark in color with gas évolution. Themixture was stirred at this same température for approximately 2.5 hours at whichpoint it was cooled to room température. The mixture was cooled further to 0 °Cwhereupon saturated sodium bicarbonate was added very cautiously (highlyexothermicl). As foaming became less vigorous, ice was added to the mixture until 15 foaming subsided. Solid sodium bicarbonate was then carefuliy added to achieve a pH of ~ 8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnésium sulfate.
Concentrated in vaeuo to afford a dark solid. This matériel was dissolved in a 13157 . 155 minimal amounî of DCM and purified using a Biotage Sp4 65i over a gradientof 0 - 100 % ethyl acetate in hexanes to afford the title compound as a pale yellowsolid (5.57 g, 44%). LRMS: 252 (M+Hf . 1H NMR (DMSO-de, 400 MHz); 8.39 (1 H, s) 7.59 (1H, d, J = 8.5 Hz) 7.48 (1H, d, J= 8.5 Hz) 4.46 (2H, S)
Préparation d-20
Préparation of dimethyl f(6-bromopvridin-3-vDmethyl1(methoxy)malonate
To a slurry of potassium t-butoxide (46.6 mmol, 5.22 g, 1.3 eq.) in anhydrous DMF(250 mL) cooled to 0 °C was added methoxy dimethylmalonate (46.6 mmol, 7.55 g,1.3 eq.) via syringe in small portions. The enolate was allowed to form overapproximately 30 minutes at which point 2-bromo-5-(bromomethyl)pyridine wasadded portionwise. The reaction mixture was allowed to warm slowly to roomtempérature over 3 hours. The reaction mixture was diluted with ethyl ether andtransferred to a separatory funnel containing saturated ammonium chloride. Thelayers were shaken and separated and the organic layer was washed with water.The organic layer was then dried over anhydrous magnésium sulfate andconcentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65iover a gradient of 0 - 100 % ethyl acetate in hexanes to afford a colorless oil thatsolidified on standing (12.1 g, quant.) LRMS: 333 (M+H)+. 1H NMR (DMSO-de, 400 MHz): 8.27 (1 H, s) 7.45 - 7.55 (2 H, m) 3.82 (6 H, s) 3.57(3 H, s) 3.42 (2 H, s)
Préparation d-21
Préparation of methyl 3-(6-bromopvridin-3-vl)-2-methoxypropanoate
O
To a solution of dimethyl [(6-bromopyridin-3-yl)methyl](methoxy)malonate (3.55mmol, 1.18 g, 1.0 eq.) in anhydrous DMF (2 mL) was added lithium bromide (3.20mmol, 0.278 g, 0.9 èq.) foliowed by water (3.55 mmol, 0.064 g, 1.0 eq,). Thesolution was placed in a oil bath preheated to 165 °C. Rapid gas évolutioncommenced. Bubble formation ceased within 30 minutes and LC/MS of thereaction mixture at this time indicated reaction was complété. Cooled to room 13157 . 15b température and diluted with water. Extracted aqueous layer with ethyl ether(4x 25 ml). Combined organic layers and washed with brine. Dried organic layerover anhydrous magnésium sulfate and concentrated in vacuo to afford 536 mg ofa brown oil that was a single spot by TLC. Used in next step without further 5 purification. LRMS: 275 (M+Hf. NMR (DMSO-ds, 400 MHz): 8.23 (1 H, s) 7.42 - 7.51 (2 H. m) 4.26 (1 H, d,J=6.1 Hz) 3.79 (3 H, s) 3.51 <3 H, s) 2.97 - 3.03 (1 H, m) 2.82 - 2.88 (1 H, m).
Préparation d-22 10 ethyl 3-fe-i2-f4-f(ethvfsulfonvHoxvlphenvl}ethoxv)pyridin-3-v(l-2- methoxypropanoate
Préparations d-23 to d-38
Préparations d-23 to d-38 were prepared by procedures analooous to those used 15 for Préparation d-22.
Préparation # Structure 'H NMR MS (m/z)(LR or HR) d-23 xcA' P. 0 0 d-24 0 Jt ^0 O N ' Φ o° 13157 . 15/ d-25 rw' \=/ (CDCI3, 300 MHz): 7.90-7.99 (3H, m),7.35-7.47 (4H, m), 6.65 (1 H, d. J= 8.5Hz), 4.27 (2H, t, J= 6.3 Hz), 4.17 (2H, t,J= 7.0 Hz), 3.29 <3H, s), 2.91 (2H, q, J =14.1 Hz), 2.66 (2H, t, J= 7.4 Hz), 2.27(3H. s), 2.16 (3H, s), 2.13 (2H, m), 1.25(3H, t, J=7.2 HZ) for LR 439 (M+H)+ d-26 '=' N'^z~<0 N ' (CDCIj, 400 MHz): 7.91-7.88 (3H, m), 7.41 (1 H, dd, J = 8.6, 2.5 Hz), 7.39-7.36 (2H, m), 6.62 (1 H, d, J = 8.3 Hz). 4.51 (2H, t, J = 6.8 Hz), 3.70 (3H, s), 3.28 (3H, s), 2.97-2.93 (3H, m), 2.86 (1 H, d, J = 14.2 Hz), 2.32 (3H, s), 1.32 (3H, s) for LR 445 (M+H)* d-27 Λ ΖΛ /θΥ' ΓΥ/ ο' F-?—\ 7—6 JL fi J ' O F ^=7 ' (CDCI3,400 MHz): 8.07 (2H, d, J =8.07), 7.91 (1H, d, J = 2.3 Hz), 7.66 (2H,d, J = 8.3 Hz), 7.41 (1H, dd, J= 8.5,2.4Hz), 6.62 (1H. d, J= 8.3 Hz), 4.52 (2H, t,J = 6.7 Hz), 3.70 (3H, s), 3.28 (3H, s),2.97 (2H, t, J = 6.7 Hz), 2.95 (1 H, d, J =14.2 Hz), 2.86 (1H, d, J= 14.2 Hz), 2.34(3H,S), 1.33 (3H, s) forLR 479 (M+H)+ d-28 (CDCI3,400 MHz): 7.90 (1 H, d, J = 2.3Hz), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 6:61(1H, d, J = 8.3 Hz), 4.42 (2H, t, J = 6.8Hz), 3.71 (3H, s), 3.29 (3H, s), 2.95 (1H,d, J= 13.9 Hz). 2.86 (1H, d, J= 14.2 Hz),2.86 (2H, t, J = 7.1 Hz). 2.67 <1H, tt, J =11.6, 3.5 Hz). 2.19 (3H, s), 2.02-1.98(2H, m), 1.81-1.77 (2H, m), 1.69-1.65(1H, m), 1.54-1.46 (2H, m), 1.38-1.31(2H, m), 1.33 (3H, s), 1.28-1.24 (1 H, m) forLR 417 (M+H)+ d-29 (Vf jûP^0' \=/ N-^/^o N 1 (CDCIj, 400 MHz): 7.92 (1H, d, J = 2.3Hz), 7.85 (2H, dd, J= 8.0,1.6 Hz), 7.41(1H, dd, J= 8.5, 2.4 Hz), 7.39-7.35 (3H,m), 6.63 (1H, d, J = 8.6 Hz), 4.59 <2H, t,J= 7.0 Hz), 3.70 (3H, s), 3.28 (3H, s),3.18 {2H, t, J= 7.0 Hz), 2.95 (1H, d, J =14.2 Hz), 2.87 (1H, d, J = 14.2 Hz), 2.42(3H, s), 1.33 (3H, s) forLR 427 (M+H)+ d-30 0 1 fY^0' ΝγΝ^/^θΛ^ P (CDCI3,400 MHz): 7.90 (1H, d, J =2.3Hz), 7.41 (1H, dd, J= 8.5,2.4 Hz), 7.33(1H,d,J=7.6 Hz), 7.21 (1H, d, J=7.6Hz), 7.13 (1H, dt, J = 7.6,1.0 Hz), 6.97(1H, dt, J= 7.8,1.3 Hz), 6.60 (1H, d, J =8.6 Hz), 4.56 (2H, t, J= 5.4 Hz). 3.92(2H, t, J = 5.4 Hz), 3.70 (3H, s), 3.28(6H, s), 2.95 (1H, d, J= 13.9 Hz), 2.86(1H, d, J =14.2 Hz), 1.32 (3H, s) forLR 400 (M+H)+ 158 d-31 JbP O N A/ 0 (CDCI3, 400 MHz): 7.91 (1H, d, J = 2.3 Hz), 7.81 (1H, s), 7.75 (1H, d, J =7.8 Hz), 7.41 (1H, dd, J =8.5, 2.4 Hz), 7.29(1H, t, J = 7.7 Hz), 7.19 (1H, d, J = 7.6Hz), 6.62 (1H, d, J= 8.3 Hz), 4.52 (2H, t,J = 6.8 Hz), 3.70 (3H, s), 3.28 (3H. s),2.96 (2H, t, J= 6.8 Hz), 2.95 (1H, d, J =13.9 Hz), 2.86 (1H, d, J = 13.9 Hz), 2.38(3H, s), 2.32 (3H, s), 1.33 (3H, s) for LR 425 (M+H)4 d-32 (CDCI3, 400 MHz): 7.91 (1H, d, J = 2.0 Hz), 7.89-7.86 (2H, m), 7.59 (1H. dd, J =8.5, 2.2 Hz), 6.92-6.90 (2H, m), 6.62 (1 H,d, J = 8.3 Hz), 4.51 (2H, t, J = 6.8 Hz),4.06 (2H, q, J = 7.1 Hz), 3.70 (3H, s),3.28 (3H, s), 2.95 (2H, t, J= 6.8 Hz),2.96 (1H, d, J = 13.9 Hz), 2.87 (1H, d, J= 13.9 Hz), 2.30 (3H, s), 1.42 (3H, t, J =7.1 Hz), 1.33 (3H,s) for LR 455 (M+H)4 d-33 \ o-ZΜI ' H'V' jO ΌΎ 0 1 (CDCI3, 400 MHz): 7.90 (1H, d, J = 2.3Hz), 7.41 (1H, dd, J= 8.5, 2.4 Hz), 6.61(1H, d, J = 8.3 Hz), 4.42 (2H, t, J = 6.8Hz), 3.70 (3H, s), 3.28 (3H, s), 3.00-2.93(1H, m), 2.95 (1H, d, J = 14.2 Hz), 2.86(2H, t, J = 6.8 Hz), 2.86 (1 H, d, J = 14.2Hz), 2.20 (3H, s), 1.33 (3H, s), 1.30 (3H.s), 1.28 (3H, s) for LR 377 (M+H)4 d-34 γν<°χ N'N N-< i B N O VB 7 O/ (CDCfe, 400 MHz): 7.91 (1H, d, J = 2.3Hz). 7.42 (1H, d'd, J= 8.5, 2.4 Hz), 6.61(1H, d, J= 8.3 Hz), 6.48 (1H, s), 4.51(2H, t, J = 6.7 Hz), 4.15 (3H, s), 3.71(3H, s), 3.28 (3H, s), 2.96 (1 H, d, J =13.9 Hz), 2.94 (2H, t, J = 6.6 Hz). 2.87(1 H, d, J = 13,9 Hz), 2.30 (3H, s), 2.27(3H, s), 1.33 (3H, s) for LR 429 (M+H)4 d-35 cm f "n O 'X'O'· 7 0 1 {CDCIs, 400 MHz): 7.91 (1H, d, J = 2.3Hz), 7.42 (1H, dd, J= 8.0, 1.9 Hz), 7.33-7.28 (2H, m), 7.23 (2H, d. J= 8.6 Hz),7.08-7.04 (1H, m), 6.99-6.92 (4H, m),6.64 (1H, d, J = 8.6 Hz), 4.45 (2H, t, J =7.1 Hz), 3.70 (3H, s), 3.20 (3H, s), 3.04(2H, t, J =7.0 Hz), 2.92 (1H, d, J= 14.2Hz), 2.87 (1H, d, J= 14.2 Hz), 1.33 (3H,s) for LR 422 (M+H)4 d-36 BB '^'O> 0 N Ba o" 7 P (CDCI3, 400 MHz): 7.90 (1H, d, J = 2.3Hz), 7.42 (1H, dd, J= 8.5, 2.4 Hz), 7.28(2H, d, J= 8.6 Hz), 7.13 (2H, d, J = 8.1Hz), 6.63 (1H, d, J =8.3 Hz), 4.46 (2H, t,J = 6.8 Hz), 3.71 (3H, s), 3.28 (3H, s),3.06 (2H, t, J= 6.8 Hz), 2.95 (1H, d, J =14.2 Hz), 2.86 (1H, d, J = 13.9 Hz), 1.33(3H, s) forLR 414 (M+H)4 d-37 s~\ O-/< V-4 I y=/ n-1- F i 'N 'xV J) (CDCI3,400 MHz): 7.91 (1H, d, J = 2.0Hz), 7.74(1 H, d, J = 7.8 Hz), 7.41 (1H.dd, J = 8.2, 2.5 Hz), 7.34 (1H, t, J = 7.7Hz), 7.38 (1H, s). 7.18 (1H, d, J = 8.1Hz), 6.62 (1H, d, J= 8:3 Hz), 4.51 (2H, t,J = 6.7 Hz), 3.70 (3H, s), 3.28 (3H, s),2.96 (2H, t, J = 6.8 Hz), 2.95 (1H, d, J = for LR 429 (M+H)4 13,157 13.9 Hz), 2.86 (1H, d, J = 13.9 Hz), 2.32(3H, s), 1.32 (3H, s) d-38 >=/ N'^· > -0 (CDCI3i 400 MHz): 7.91 (1H, d, J =2.0Hz), 7.41 ( 1 H, dd, J ~ 8.5,2.4 Hz), 7.34-7.29 (2H, m), 6.96-6.93 (2H, m), 6.62(1H, d, J = 8.5 Hz), 4.52 (2H, t, J = 6.8Hz), 3.70 (3H, s), 3.28 (3H, s), 2.96 (2H.t, J =6.8 Hz), 2.95 (1H, d, J= 13.9 Hz),2.86 (1H, d, J= 13.9 Hz), 2.32 (3H, s),2.16 (3H, s), 1.32 (3H, s) for LR 441 (M+H)+
13157 . 160
The compounds of the invention hâve been tested for activités against PPAR-gamma and PPAR-alpha. The activités are tabulated below in Ki (pm). |PPAR-Example # gamma PPAR- alpha Ki(pm) - Example # PPAR- IPPAR- Example # PPAR- gamma Ki (pm) PPAR- alpha Ki (pm) ;amma KiÛun) alpha Ki (pin) Ki (pm) A-02 0.55 B-02 2.2 C-03 2.9 A-03 10 19 B-03 31 9 C-05 15 A-05 E/M 0.33 2.6 B-04 1.5 48 C-06 Γ 9.5 41 A-05 S/E 3.4 7.5 B-05 1.33 2.04 C-07 11 22 A-05 S/E 0.19 1.1 B-05 2.9 3.2 C-09 1.4 4.6 A-07 0.12 B-05 2 3.6 C-10 2.1 19 A-10 1.5 4.4 B-06 0.37 0.13 C-11 2 25 A-11 0.58 0.12 B-07 0.65 12 C-12 1.6 9.4 A-12 0.051 0.35 B-08 0.48 3.1 C-14 8 3.2 A-13 3.5 10 B-09 1.9 2.2 C-15 14 3.2 A-14 1.3 0.15 B-10 0.17 0.19 C-17 26 3.2 A-15 1.2 0.16 B-11 7.9 0.96 C-18 3.5 0.065 A-16 2.8 1.5 B-12 33 0.3 C-20 1.5 3.1 A-17 1.9 1.6 B-13 9 C-21 0.053 0.066 A-18 1.7 14 B-14 2.3 0.021 C-22 0.8 2.1 A-19 0.059 0.7 B-16 1.8 0.084 C-23 0.19 2.5 A-20 0.18 0.14 B-17 1.2 0.047 C-24 0.083 0.022 A-21 0.088 0.31 B-18 0.082 C-25 0.066 0.018 A-22 0.17 0.85 B-19 0.74 0.34 C-26 0.068 0.016 A-23 039 0.18 B-20 1.6 C-27 0.026 0.015 A-24 0.78 0.018 B-21 0.99 4 C-28 0.03 0.088 A-25 3.2 4.2 B-22 0.15 0.46 C-29 0.006 0.12 A-26 0.15 0.33 B-23 3.4 2.7 C-30 0.033 0.11 A-27 2.4 1.3 B-24 1.6 1 C-31 0.026 0.093 A-28 E/M 0.044 0.93 B-27 0.22 C-32 0.035 0.15 A-28 S/E 0.081 1.1 B-28 7.8 C-33 0.05 0.01 A-28 S/E 0.94 2.9 C-02 0.39 C-36 1.7 21 5 E/M is defined as enantiomerie mixture, including racemic mixture.S/E is defined as single enantiomer. 13157 161
Example # PPAR-;amma<i (μτη) PPAR- alpha Ki (μηι) Example # PPAR- gamma Κί(μτη) PPAR- alpha Ki(pm) Example # PPAR- >anima Ki (μη») PPAR- alpha Ki (μηι) C-38 7.2 C-64 0.052 0.014 C-90 0.017 0.11 C-40 3.7 0.7 C-66 0.023 0.031 C-91 0.39 1.8 C-42 33 13 C-67 0.044 0.25 C-92 1.1 2.8 C-44 36 C-68 4.2 C-93 0.011 0.3 C-45 0.22 7.7 C-69 1.1 2.5 C-94 7 046 2 3.5 C-70 6.4 C-95 0.97 8.6 047 3.5 8.3 C-71 9.7 D-02 0.46 0.29 048 0.018 0.24 C-72 7.1 D-03 0.011 0.3 C-48 E/M 0.15 0.31 C-73 0.042 D-04 0.44 0.29 048 S/E 0.014 0.047 C-74 0.64 0.9 D-05 2.8 C-48 S/E 2.4 C-74 S/E D-06 0.027 0.13 049 0.21 1.6 C-74 S/E 0.47 4.2 D-07 0.017 0.32 049 21 41 C-75 0.82 D-08 0.002 0.015 049 , 0.043 0.34 C-76 2.3 7.3 D-09 0.061 0.05 050 0.043 1.1 C-77 0.15 2.9 D-10 ’ 0.019 0.033 051 0.18 2.9 C-78 0.006 0.015 D-11 6.2 5.1 052 0.3 0.15 C-78 S/E 3.9 D-12 8.1 053 0.093 0.64 C-78 S/E 0.003 0.014 D-13 0.36 0.19 053 S/E 3.6 C-79 0.0D7 0.015 D-14 1.5 2.6 053 S/E 0.027 0.4 C-80 0.062 0.053 D-15 0.35 0.22 054 0.02 1.2 C-81 0.015 0.75 D-16 6.4 055 6 C-82 0.016 D-17 0.031 0.91 056 0.081 0.078 C-83 0.008 0.004 D-18 0.45 0.62 057 1.1 1.8 C-84 0.021 0.064 D-19 1.7 6.4 059 0.009 0.054 C-85 0.004 0.013 D-20 0.48 0.84 060 0.015 0.055 C-86 0.005 0.013 D-21 2.1 10 061 0.31 0.24 C-87 0.012 0.025 D-23 E/M 0.073 6.5 063 0.094 0.021 C-89 0.04 0.03 D-23 S/E 5 E/WI is defined as enantiomeric mixture, including racemic mixture.S/E is defined as single enantiomer 13157 . 162
Example # PPAR-gammaKi (gm) PPAR- alpha Ki (gm) Exemple # PPAR-gammaKi (gm) PPAR- alpha Ki (gm) D-23 S/E 0.039 1.1 D-33 0.69 0.55 D-24 no SPA no SPA D-34 9.1 3.2 D-24 0.58 0.93 D-35 0.56 0.33 D-25 2.9 D-35 S/E 027 0.57 D-26 no SPA no SPA D-35 S/E 4.8 9 D-26 S/E 1.9 D-36 0.23 0.73 D-26 S/E 0.042 0.67 D-37 0.53 4.7 D-27 7.8 D-38 9.6 D-28 1.6 4.8 D-39 5 D-29 0.4 0.8 D-40 9.6 1.8 D-29 S/E 1.2 D-41 5.9 D-29 S/E 0.69 3 D-42 0.7 1 D-31 1 0.088 D-44 0.15 2.6 D-32 1.5 0.059 D-45 0.058 0.09
E/M is defined as enantiomeric mixture, including racemic mixture. S/E is defined as single enantiomer 5
While the invention bas been illustrated by référencé to spécifie andpreferred embodiments, those skilled in the art will recognize that variations andmodifications may be made through routine expérimentation and practice of theinvention. Thus, the invention is intended not to be limited by the foregoing 10 description, but to be defined by the appended daims and their équivalents.

Claims (15)

13157 153 10 15 We Clairn:1. A compound of formula (I):
or a pharmaceutically acceptable sait or solvaté thereof, wherein: Ring Q is (C6-C10)aryl or (4-10)-membered heterocyclyl; R1 is H, halo, (C,-C6)a1kyl, (C,-Ce)alkoxy, CN, CF3, -O-CF3, -O-SO2-(Cr 11d12x C«)alkyl, -O-SO2-(CR11R12WCs-C10)aryl, -(CRllR12),(C3-C1o)cycloalkyl-(CR1lR12)(l (CRMRn),(C6-C10)aryl-(CRnR12).,,-(CR11 R12)t- (4-10)-membered (I) -{CRMR1zWCî-C10>cycloalkyl-(CR11R'2)rO-, -(CR11R,2)t(C6-C1o)aryl-(CR11R’2)rO-.heterocyclyi-(CR1'lR12)tl or -(CR11R12)r(4-10)-membered heterocyclyl-(CR11R12),-0-;wherein the ring carbon atoms of R1 are optionally substituted by 1 to 3 R13 groups;and the ring nitrogen atoms of R1 are optionally substituted by 1 to 3 (Ci-C8)alkyl; R2 is H, (CrCe)alkyl, -(CR11R12)r(C3-Cw)cycloalkyl, -(CR11R12)t-(C6-C10)aryl, or -(CR11R12)t(4-10)-menrtbered heterocyclyl; and wherein the carbonatoms of R2 are optionally substituted by 1 to 3 R13 groups; and the ring nitrogenatoms of R2 are optionally substituted by 1 to 3 (CrCB)alkyl; R3 is selected from the group consisting of: A) B) C) D)
‘0——-R and Y is-(C=O)-or-SO2-;Y” is NR10 or-O-; 20 13157 . 164 p is 0,1, or 2; each q, r, and t are indepertdently 0, 1,2, 3,4, or 5; each n is independently 0,1,2,3, or 4; each k is independenüy 1, 2, or 3; each m and s are independenüy 0,1, 2, or 3; each j is 0,1, or 2; Each R4 is -(CR11R12)n-, -(CR11R’2)n-S-(CR11R,2)„-, -<CR11R12)n-NR10- -(CR11R12)n-NR1°-(CR11R12)n-O-, -(CR11R12)n-O-(ÇR1,R12),<-NR’0-, -(CR11R12)n-O- -(CR11R12)n-O-(CR11 R1Z)k-O-(CR11R12)n-, -(CR11R12)n-CR11=CR12-(CR11R12)n-, or-CH=CK-(CR11R12)-0-(CH2)n-; Each R5is a bond or -(CR^R^^-Z-iCR^R^K; wherein Z is -CR11R12-, -O- , -NR10a-, or-S<O)r; Each R6 is -(C=O)-OH, -(C=O)-OM+, -(C=O)-(C,-C8)alkyl, -(0=0)-0-(0,-C8)alkyl, -(C=O)-NR1CR11, -{C=C)-NR10-SO2-R11, -SO2-NH-R10, -NH-SO2-R10,-(C=0)-NH-0=N, or R® has a formula:
N—N H o ; or is an aikali métal cation or an alkaline earth métal cation; Each R7 and R8 is independenüy H, (C,-Ce)alkyl, (Ci-C8)alkoxy,-(CR^R^MCj-CwIcycloalkyl, -(CR1’R12)l(C6-C,0)aryll -(CR11R12)t(C6-C10)aryl-O-,-<CR11R12)i(4-10)-membered heterocyclyl or -(CR11R12)((4-10)-memberedheterocyclyl-O-; Or R7 and R8 may optionally be taken together with the carbon to whichthey are attached to form a (C3-C,o)cycioalkyl or a (3-10)-membered heterocyclyl; Each of Ar1, Ar2, Ar3, and Ar4 represents (C6-C,o)aryl or (5-10)-memberedheterocyclyl; wherein the ring carbon atoms of each of Ar1, Ar2, Ar3, and Ar4 areoptionally substituted by 1 to 3 R13 groups; Ring A represents a 3, 4, 5, 6 or 7-membered ring optionally containing 1to 4 heteroatoms which may be the same or different and which are selected from -N(R10a)-, O, and S(O)j, wherein j is 0,1, or 2, with the proviso that the ring does notcontain two adjacent O or SfO), atoms, and wherein the carbon atoms of the ring Amoiety are optionally substituted by 1 to 3 R13 groups; R9 is (C,-C8)alkyl, -(CR”R12),(C6-Ç10)aryl or -(CR"R12),(4-10)-memberedheterocyclyl, wherein t is independently 0, 1,2, 3, 4, or 5, wherein said R9 groupsare substituted with 1 to 3 groups independently selected from -(CRl1R12)qNR10R11, 10 15 20 25 30 A3A57 . 165 -(CR11R12)qNR1D<CrC6)alkanoyi, -(CR11R12)qO(CR11R12)fR’°, and -(CR11R12)qRlD; andwherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups areoptionatly substituted with 1 to 3 R13 groups; R9a and R10 are irdependently H or (CrC8)alkyl; R11 and R12 are independently H, (C,-C8)alkyl, hydroxy, or (CrC6)alkoxy; R10a is setected from H, (CrC8)alkyl, -(C=O)-R14, -SO2NR15R16, or-S(0)j{Ct-C6)all<yf; Each R13 and R13aare independently setected from the group consisting ofhalo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (C1-C6)alkoxy,(CrC10)alkyl, (CrC^alkenyl, (C2-Cs)alkynyl, -O-(CR'1R12)k-O-(CR”R12)n-, -(C=O)-R14, -(C=O)-O-R15, -O-(C=O)-R1S, -NR1S(C=O)-R16, -NR1S(C=O)-O-R16, -(C=O)-NR15R16, -NR15R1b, -NR1sOR16, -SO2NR15R16, -S(O)j(C,-C6)alkyl. -O-SO2-R14, -NR’s-SO2-R’6, R1s-(CR1’R12),(C6-C10 aryl), -(CRnR12),(4-10)-membered heterocyclyl, -(CRHR’2)„(C=O)(CR11R12)t(C6-Cw)aryl, -(CR11R12)q(C~O)(CR11Rl2)i(4-1Û)-membered heterocyclyl, -(CR”R12)iO(CR11R12)q(C6-Cjo)aryl, -(CR11R12)tO(CR11R12)q<4-10)-memberedheterocyclyl, -(CR11R12)qSO2{CR11R12)t(C6-C10)aryl, and -{CR1’R12)qSO2(CR11R12)t<4-10)-membered heterocyclyl; 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R13 and Ri3a groups are opfionallysubstituted with an oxo (=0) moiety, and the alkyl, alkenyl, alkynyl, aryl andheterocyclic moieties of the foregoing R13 and R13a groups are optionally substitutedwith 1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, -OR15, -(C=O)-R15, -(C=0)-0-R15, -0-(C=O)-R15, -NR15(C=O)-R16, -(C=0)-NR15R16, -NR1SR16, -NR1SOR16, (CrC6)alkyl,(C2-C6)alkenyl, (C2-Cs)alkynyl, -(CR11R12)((C6-C10)aryi, and -(CR11 R12),(4-10)-membered heterocyclyl; each R14, R15, and R16 is independently selected from H, (Ci-C6)alkyl,-(CR11R12)i(C6-Cw)aryl, and -(CR11R12),(4-10)-membered heterocyclyl; 1 or 2 ringcarbon atoms of the heterocyclic group are optionally substituted with an oxo (=0)moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R14, R15 andR,e groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, -NR”R12, trifluoromethyl, trifluoromethoxy, (CrC6)alkyl, (C2-C8)alkenyi, (C2-C5)alkynyl, hydroxy, and (CcC6) alkoxy; R17 is H, (Ci-C8)a1kyl, -O-(C,-C8)alkyl, halo, CN, OH, CF3, or -0-CF3;and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group whichis not attached to a halo,SO or SO2 group or to a N, O or S atom optionally bears on said group a 35 166 substituent selected from hydroxy, halo, (CrC4)alkyl, (CrC4)alkoxy, -NH2, -NH(CC8)alkyl, and —N((G}-C8)atkyt)2·
2. The compound according ίο claim 1 wherein R3 is A) -R4-Ar1-Ar2-R5. ,R6 r7/ R8
3. The compound according to claim 1 wherein R3 is B) ;—R—Y Y\ Ar3-R5 R11 R12
4. The compound according to claim i wherein R3 is C)
10
5. The compound according to claim 1 wherein R3 is D)
6. The compound according to claim 2 having a formula:R2 R1
R4 —Ar1—Ar2—R V R6 ,7Xr r7Z R. I wherein said -Ar’-Ar2- is selected from the group consisting of: 13157.
10 15 I 20
wherein the ring carbon atoms of each of Ar1 and Ar2 are optionallysubstituted by 1 to 3 R13 groups selected from the group consisting of halo, (CrC8)alkyl, and (Ci-Ce)alkoxy.
7. The compound according to claim 2 selected from the group consisting of 1- ({3'-[2-(5-Methyl-2-phenyl-1,3-ûxazol-4-yl)ethoxy]-1,T-biphenyl-3-yl}oxy)cyclobutanecarboxylic acid (Example A-4); 2- ({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1 '-biphenyl-3-y!}oxy)butanoic acid (Exemple A-5); 2-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)butanoic acid {Example A-6); 1-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-y!}phenoxy)cyclobutanecarboxylic acid (Example A-7); 1-[(3'4[2-(3-fluorophenyl)-5-metliyl-1, 3-oxazol-4-yl]methoxy}biphenyl-3-yl)oxy]cyclobutanecarboxylic acid (Example A-11 ); 1- ({3'-[3-(5-methyl-2-phenyl-1,3-oxazoW-yl)propoxy]biphenyl-3-yl)oxy)cyclobutanecarboxylic acid (Example A-12); 1 -[(3'-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}biphenyl-3-yl)oxy]cyclobutanecarboxylic acid (Example A-17); 2- [(3'-{2-I2-(3-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}biphenyl-3-yl)oxy]-2-methylpropanoic acid (Example A-21); 2-methyl-2-({3'-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyJbiphenyl-3-yl}oxy)propanoic acid (Example A-24); 25 13157 . 168 2-ethoxy-3-{3’-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]biphenyl-3-yl}propanoic acid (Example A-28); and the pharmaceutically acceptable salts thereof.
8. The compound according to claim 3 having a formula:
wherein Y is -(C=O)- or -SO2-, Y" is NR10, and p is 1.
9. The compound according to claim 3 selected from the group consisting of
2-Methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyljphenoxy}propanoic acid (Example B-5); 2-methyl-2-{3-|({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxylcarbonyl}amino)methyl]phenoxy}propanoic acid (Example B-6); 2-methyl-2-{4-t({r3-(5-methyl-2-phenyl-1,3-oxazoM-yl)propoxy]carbonyl}amino)methyl]phenoxy}propanoic acid (Example B-7); 2-{3-fluoro-4-[({J2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}-2-methylpropanoic acid(Example B-9); 2-{3-[({(2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyljphenoxy}butanoic acid (Example B-13); 2-{3-{({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]carbonyl}amino)methyllphenoxy}butanoic acid (Example B-14); 1'{3-E({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)carbonyl}amino)methyljphenoxy}cyclobutanecarboxylic acid(Example B-15); 2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl]amino}carbonyl)oxyjmethyl}phenoxy)propanoic acid (Example B-21); 2-ethoxy-3-{3-[(([3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]phenyl}propanoic acid (Example B-23); 2-ethoxy-3-{3-(({[2-(5-methyl-2-pheny(-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenyl}propanoîc acid (Example B-24);and the pharmaceutically acceptable salts thereof. 13157 . 169
10. The compound according to daim 4 having a formula:
wherein said ring A is selected fforn fhe group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cydohexyl,
N ; R,oa
wherein — is an optional double bond. 10 13157. 170
11. The compound according to daim 4 selected from the groupconsisting of 1 -{4-[3-(5-meth yl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclobutanecarboxylic acid (Example C-16); 1 -{4-[2-(5’methyl-2-phenyl-1,3-oxazoi-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid (Example C-19); 2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid (Example C-48); 2-({5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}methyl)tetrahydrofuran-2-carboxylic acid (Example C-49); 2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl)methyl)tetrahydro-2H-pyran-2-carboxylic acid (Example C-56); 2-[(6-{2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)meihyl]tetrahydrofuran-2-carboxylic acid (Example C-59); 2-[(6-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)methyl]tetrahydrofuran-2-carboxylic acid (Example C-62); 2-{5-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-ylmethyl}-tetrahydro-furan-2-carboxylic acid (Example C-77); -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydrofuran-2-carboxylic acid (Example C-78);2-{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-2-ylmethyl}- tetrahydro-furan-2-carboxylicacid (Example C-91); and the pharmaceutically acceptable salts thereof.
12. The compound according to claim 5 having a formula: 13157. 171
13. The compound according to claim 12 selected from the groupconsisting of 2-etho xy-3-{6-[2-(5-methyl-2-pheny I-1,3-oxazol-4-yl)ethoxy]pyridin-5 3-yl}propanoic acid (Example D-1); 2-methoxy-3-(6-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)propanoic acid (Example D-3); 2-methoxy-3-{6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl}propanoicacid (Example D-13); 2-ethoxy-3-[6-(2-{4-[(phenylsulfonyl)oxy]phenyl}ethoxy)pyridin-3- yl]propanoic acid (Example D-17);
2-Ethoxy-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic acid (Example D-23);
2-Methoxy-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazol-4-yl)-15 propoxy]-pyridin-3-yl}-propionic acid (Example D-27);
2- Methoxy-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic acid (Example D-29); 3- (6-{2-(2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-yl)-2-methoxy-2-methyl-propionicacid (Example D-30);
2-Methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyl oxazol-4-yl)- ethoxy]-pyridin-3-yl}-propionic acid (Example D-35);
2-Methoxy-3-(6-{2-[2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-pyridin-3-yl)-2-methyl-propionic acid (Example D-43); and the pharmaceutically acceptable salts thereof. 13157. 172
14. Use of an alpha substituted carboxylic acid compound according to claim1 in the manufacture of a médicament for treating non-insulin dépendentdiabètes mellitus, polycystic ovarian syndrome, obesity, hyperglycemia,hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, 5 hyperinsulinemia, abnormal insulin and/or evidence of glucose disorders, insulinrésistance syndrome, and PPAR-related disorders in a mammal.
15. A composition comprising ât least one compound according toclaim 1 and a pharmaceufically acceptable carrier thereof; said compound is 10 optionally in combination with other agents such as α-glucosidase inhibitors,aldose reductase inhibitors, biguanide préparations, statin base compounds,squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promotersand angiotensin-converting enzyme inhibitors.
15
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