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MXPA01001419A - SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS - Google Patents

SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS

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Publication number
MXPA01001419A
MXPA01001419A MXPA/A/2001/001419A MXPA01001419A MXPA01001419A MX PA01001419 A MXPA01001419 A MX PA01001419A MX PA01001419 A MXPA01001419 A MX PA01001419A MX PA01001419 A MXPA01001419 A MX PA01001419A
Authority
MX
Mexico
Prior art keywords
phenyl
oxo
propenyl
acid
amino
Prior art date
Application number
MXPA/A/2001/001419A
Other languages
Spanish (es)
Inventor
Jon Loren Collins
Milana Dezube
Jeffrey Alan Oplinger
Timothy Mark Willson
Original Assignee
Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of MXPA01001419A publication Critical patent/MXPA01001419A/en

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Abstract

The present invention discloses compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts, or solvates thereof. Preferably, the compounds of the invention are dual activators of hPPAR&ggr;and hPPAR&agr;.

Description

SUBSTITUTED DERIVATIVES OF OXAZOLES AND TIAZOLES AS ACTIVATORS OF hPPAR GAMMA AND hPPAR ALPHA Field of Invention The present invention relates to certain new compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it refers to compounds that exhibit activation, including double agonist activity, to proliferating peroxisome proliferator activated receptors.
(PPAR?) And alpha (PPARa) by which they allow to modulate the levels of lipids and glucose in the blood in mammals.
Background of the Invention Treatment of type 2 diabetes mellitus usually begins with a combination of diet and exercise, with progression to oral hypoglycemics (eg, sulphonylureas) and, in more severe cases, insulin. In the last decade a class of compounds known as thiazolidinediones (for example, US Pat Nos. 5,089,514, REF.NO. 127284 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that improve tissue insulin sensitivity. target (skeletal, liver, adipose muscle) in animal models of type 2 diabetes mellitus and also reduce lipid and insulin levels in these animal models.
It has been reported that thiazolidinediones are potent and selective activators of PPAR? and are they directly linked to the PPAR receptor? (J.M. Lehmann et al., J. Biol. Chem. 15953-12956, 270 (1995)), providing evidence that PPAR? it is a possible objective for the therapeutic actions of t i zolidindiones.
PCT patent publication WO 97/31907 discloses certain new compounds that bind to and activate PPAR ?. These compounds are indicated to be useful for the treatment of type 2 diabetes mellitus and other diseases.
Activators of the nuclear receptor PPAR ?, for example troglitazone, have been shown in the clinic to improve the action of insulin, reduce serum glucose and have small but significant effects on the reduction of triglyceride levels in serum in patients with type 2 diabetes. See, for example, DE Kelly et al., Curr. Opin. Endocrinol Diabetes, 90-96, 5 (2), (1998); M.D. Johnson and collaborators, Ann. Phar acother. , 337-348, 32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be the predominantly increased clearance of very low density lipoproteins (VLDL) through the induction of lipoprotein lipase (LPL) gene expression. See for example, B. Staels et al., Arterioscler, Thromn., Vasc. Biol., 1756-1764, 17 (9), (1997).
Fibrates or fibrates are a class of drugs that could lower serum triglycerides by 20-50%, decrease LDLc by 10-15%, increase LDL particle size from the smallest atherogenic density to normal LDL density , and increase the HDLc to 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are regulated through the activation of PPARa. See, for example, B. Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). The activation of PPARa results in the transcription of enzymes that increase the catabolism of fatty acids and decrease the synthesis of de-novo fatty acids in the liver resulting in decreased triglyceride synthesis and production / secretion of VLDL. In addition, activation of PPARa decreases the production of apoC-III. The reduction in apoC-III, an inhibitor of LPL activity, increases the clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shanon, Irel.), S29-S37, 124 (Suppl.), (1996).
In addition, a double agonist of PPARa and PPAR? It could be effective in reducing dyslipidemia and hyperinsulinemia associated with impaired glucose tolerance (IGT) or metabolic syndrome and could be effective in patients with crossed hyperlipidemia. See, for example, U.S. Pat. No. 5,478,852.
The PCT patent publication WO 98/05331 (Paterniti et al.) Refers to methods to treat diabetes and cardiovascular disease using PPAR agonists? in combination with a PPARa agonist, a compound that activates PPAR? and PPARa, Brief description of the invention.
Briefly, in one aspect, the present invention provides the compounds of the formula (I), and the tautomeric forms, the pharmaceutically acceptable salts and the solvates of the same, (i) wherein R1 is hydrogen or C3_3 alkyl; R 'is hydrogen Ci-β alkyl optionally substituted by one or more halogens; R3 is C1-6 alkyl, C4_7 cycloalkyl or cycloalkenyl, -OC -6 alkyl. -NR'R '(wherein each R' is independently hydrogen or C1_3 alkyl), a 5- or 6-membered heterocyclic group containing at least one ring atom of oxygen, nitrogen or sulfur (optionally substituted by one or more than halogen, C1-6alkyl optionally substituted by one or more halogens, -OCalkyl -6 optionally substituted by one or more halogens, -CN or -N02), or phenyl (optionally substituted by one or more halogen, C1-alkyl) -6 optionally substituted by one or more halogens, alkyl -OC? _6 optionally substituted by one or more halogen -CN or -N02); R 4 is a 5- or 6-membered heterocyclic group containing at least one oxygen, nitrogen or sulfur ring atom (optionally substituted by one or more halogens, C 1-6 alkyl optionally substituted by one or more halogens, alkyl -OC? 6 optionally substituted by one or more halogens, -CN or N02), or phenyl (optionally substituted by one or more halogens, C.sub.6 -alkyl optionally substituted by one or more halogens, alkyl -OC? _6 optionally substituted by one or more halogens, -NR'R '(as defined above), -CN or -N02); R5 is hydrogen, halogen or C3_3alkyl optionally substituted by one or more halogens; R < is hydrogen or C1-3 alkyl X is O and n is 1, 2 or 3 Preferably, the compounds of this invention activate the hPPAR receptors? and hPPARa.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention. As used herein, "a compound of the invention" means a compound of the formula (I) or a tautomeric form, pharmaceutically acceptable salt, or solvates thereof.
The invention further provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides a method for the treatment or prevention of a disease mediated by hPAAR? and / or hPPARa, factor or risk condition, comprising the administration of a therapeutically effective amount of a compound of this invention.
According to another aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of a disease mediated by hPPAR? and / or hPPARa.
The diseases mediated by hPPAR? and / or hPPARa, risk factors or conditions include hyperglycemia, dyslipidemia, type II diabetes mellitus that includes associated diabetic dyslipidemia, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesterolemia, hypertension, cardiovascular disease, which includes, atherosclerosis, regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia, bulimia and anorexia nervosa. In particular, the compounds of the present invention are useful in the treatment or prevention of hyperglycemia, dyslipidemia and type II diabetes mellitus that includes associated diabetic dyslipidemia.
Detailed description of the invention Preferably, R1 is hydrogen or methyl. More preferably, R1 is hydrogen.
Preferably, R2 is C? -8 alkyl optionally substituted by one or more halogens. Preferably the halogen is fluorine. More preferably, R2 is straight chain.
Preferably, R3 is pyridine, pyrazine, thiophene, furan, thiazole or phenyl (any of which could optionally be substituted by one or more of halogen, C? -6 alkyl optionally substituted by one or more halogen, optionally substituted -0C? by one or more halogens, -CN, or -N02), or C4- cycloalkyl. More preferably, R3 is phenyl (optionally substituted by one or more of halogen, C6-6 alkyl optionally substituted by one or more halogens, -OCalkyl -6 optionally substituted by one or more -CN or N02).
Preferably, R is phenyl (optionally substituted by one or more halogen, C? -6 alkyl optionally substituted by one or more halogens or -OC? _6 alkyl optionally substituted by one or more halogens). Preferably, the halogen is fluorine. More preferably, R4 is phenyl either substituted or unsubstituted with 1, 2 or 3 fluorine atoms.
Preferably, R5 is hydrogen or C? -3 alkyl optionally substituted by one or more halogens. More preferably R5 is hydrogen.
Preferably R6 is methyl or ethyl.
Preferably n is 2.
Preferably, the carbon atom bonded to CO2R1 is in the S configuration. In other words, preferably, the absolute configuration around the carbon is: CC 2R 'H * NH Appropriate compounds of the present invention include: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -3- (4-. {2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- (. { (Z) -1-met i 1- 3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propane (2S) -3- (4-. {2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy] phenyl) -2- ( { (Z) -1-methy1-3-oxo-3 - [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propane (2S) -3- (4-. {2- [2- (4-me-toxy-phenyl-1) -5-methyl-l, 3-oxazol-4-yl] -ethoxy} phenyl} -2- acid ( { (Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- (2- { 5-methyl-2- [4-trifluoromethyl) phenyl] -1,3-oxazol-4-yl} ethoxy) phenyl] propanic (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1-propenyl] amino} -3- (4- { 2- [2- (4-methoxyphenyl) -5-methyl-1, 3-oxazol-4-yl} ethoxy) phenyl] propane (2S) -2- acid. { [(Z) - 1 -et i l-3-oxo-3-phenyl-1-1 -propenyl] amino} -3- [4- (2- { 5-Methyl-2- [4- (trifluoromethyl) phenyl] -1,3-oxazol-4-yl} ethoxy) phenyl] propane (2S) -2 acid -. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl} ethoxy.] Phenyl] propane (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-l-propenyl] amino} -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl} ethoxy.] Phenyl] propane (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3-. { 4- [2- (5-methyl-2-phenyl-1,3-thiazole-4-yl.}. Ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -3- (4-fluorophenyl) -1-methyl-3-oxo-l-propenyl] amino} -3- (4- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propannoic acid (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,3,4-trifluorophenyl) -1-propenyl] amino) -3- (4- [2- (5-met i 1-2 -phenyl- 1,3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- acid. { [(Z) -1-met i 1-3- (4-nitrophenyl) -3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-y-yl) ethoxy] phenyl} propanic acid (2S) -2-. { [(Z) - 1-met Í1-3-OXO-3- [4 (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { - [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3 -oxo-1-propenyl] amino} -3- (4 - { 2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxa-zol-4-yl] -ethoxy} phenyl) propane (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,3,4-trifluorophenyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl] ethoxy] phenyl [propanoic] (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4 -. {2- 2- [2- (4-isopropoxyphenyl) -5-methyl-1,3-oxa-zol-yl] ethoxy} phenyl) propane (2S) -2- acid. { t (Z) - 1-et i 1- 3-oxo- 3 - [4 (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4 - [2- (5-Methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic acid (2S) -2-. { [(Z) -1-methyl-3- (4-methylphenyl) -3-oxo-1-propenyl} Not me} -3- . { 4- [2- (2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanoic acid (2S) -2- acid. { [(Z) -1- et il-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (2- (5-Met-il-2-phenyl) -1, 3-oxazol-4-yl) ethoxy] phenyl}. Propane (2S) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl] ethoxy} phenyl] -2-. [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.}. Propanoic (2S) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyllamino) -3- (4-. {2- 2- [2- (4-fluorophenyl) -5-methyl-1, 3-thiazol-4-yl] ethoxy.} Phenyl) propane (2S) -2- acid. { [(Z) -l-butyl-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-1-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { ([(Z) -3- (4-chlorophenyl) -1-methyl-3-oxo-l-propenyl] amino.}. -3- { 4- [2- (5-methyl-2-phenyl- 1, 3-oxa-zol-4-yl) -ethoxy] -phenyl} -propanoic acid (2S) -2- { [(Z) -1-met i 1-3- (3-nit-phenyl) -3- oxo-1-propenyl] amino.}. -3- { 4- [2- (5-met il-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl}. propanoic (2S) -2- acid. { [(Z) -3- [2-fluoro-3- (trifluoromethyl) phenyl] -l-methyl-3-oxo-l-propenyl} amino) -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxa-zol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (4-isopropoxy phenyl) -1-methyl-3-oxo-l-propenyl} Not me} -3-. { 4- [2- (5-met i 1-2 -phenyl -1, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-chlorophenyl) -1-met il-3-oxo-l-propenyl} Not me} -3-. { 4- [2- (5-met i 1-2 -phenyl-1,2-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-furyl) -1-met-il-3-oxo-1-propenyl} Not me} -3-. { 4- [2- (5-met i 1-2 -phenyl-1,3-oxa-zol-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2-pyrazinyl-1-propenyl] amino] -3- { 4- [2- (5-methyl-1-2-phenyl-1 , 3-oxazol-4-yl) ethoxy] phenyl}. Propanoic acid (2S) -2- { [(Z) -3- (2,4-di fluorophenyl) 1-methyl-3-oxo-l -propenyl.}. amino.}. -3- { 4- [2- (5-meth i 1-2 -phenyl-1-1, 3-oxazol-4-yl) ethoxy] phenyl}. propane (2S) -2- acid. { [(Z) -1-met-il-3-oxo-3- (1,3-thiazol-2-yl) -l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (3-thienyl) -l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxa-zol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2-pyridinyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-Methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl) propane (2S) -2- acid. { [(Z) -1-met i 1- 3 -phenyl-1-propenyl] amino} -3-. { 4- [2- (5-met i 1-2 -phenyl-1,3-thiazol-4-yl) ethoxy] phenyl Jpropanoic acid (2S) -2-. { [(Z) -3- (2-Fluoro-phenyl) -1-methyl-3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2,3-difluorophenyl) -1-methyl-3-oxo-l-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-Hydroxyphenyl) -1-met i 1-3-oxo-l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -3- (4- [2- (5-Met yl-2-phenyl-1,3-oxa-zol-4-yl) ethoxy] phenyl} -2- { [(Z) - acid] 3-oxo-3-phenyl-1-propyl-1-propenyl] amino.} Propanic (2S) -2- acid. { [(Z) -3- (4-methoxyphenyl) -1-met il-3-oxo-l-propenyl] amino} -3- (4- [2- (5-Methyl-2-phenyl-1, 3-oxazol-1-yl) ethoxy] phenyl} propanoic acid (2S) -3- (4-. {2- [2- (4-methoxy-phenyl-1) -5-methyl-l, 3-oxazol-4-yl] -ethoxy} phenyl) -2- acid. { [(Z) -l-methyl-3-oxo-3-pheny1-propenyl] amino} propanic acid (2S) -2-. { [(Z) -3-cyclohexyl-l-methyl-3-oxo-l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -3- (4- { 2- [2- (-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -1-met i 1-3-oxo-3-phenyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -1-heptyl-3 -oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-met il-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -1-methyl-3- (3-meth i-lphenyl) -3 -oxo-1-propenyl] amino} -3- . { - [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- ([(Z) -l-Ethyl-3-oxo-3-phenyl-1-propenyl] amino] -3-. {4- [2- (5-methyl-2) acid phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic acid (2S) -3-. { 4- [2- (5-met il-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -2- ( { (Z) -1-et i 1-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl}. amino) -3- (4 - {. 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane (2S) -2- acid. { [(Z) -1-et-3-oxo-3 - [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { -. { 2 - [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy} phenyl) propanic (2S) -2- acid. { [(Z) - 1 -et i 1- 3 -oxo- 3 - [4 (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4 - . { 2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy} phenyl) propanic (2S) -3- (4-. {2- [2- (4-f-luo-pheno-1) -5-methyl-l, 3-oxazol-4-yl) -ethoxy acid} phenyl } -2- . { [(Z) -3-oxo-3-phenyl-1- (tri-fluoromethyl) -1-propenyl] amino} propanic acid (2S) -2-. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4 - [(5-methyl-2-phenyl-l, 3-oxazol-4-yl) methoxy] phenyl} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3-pheny1-propenyl] amino} -3-. { 4- [2- (2-phenyl-5-propyl-l, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [(5-methyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] pheni 1} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4- [2- (5-Met yl-2-phenyl-1,1- 3-oxazol-4-yl) propoxy] phenyl] -2- ([(Z) -3) acid -oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.}. propanoic acid (2S) -3- { 4- [2- (5-ethyl-2-phenyl-1, 3- thiazol-4-yl) ethoxy] phenyl.} -2-. {[[(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanoic acid (2S) -3- (4-. {[2- (5-ethyl-2- (4-f-lorofeni 1) -1, 3-oxazol-4-yl) ethoxy] phenyl} -2- acid. { [(Z) -3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.}. Propane (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {2- 2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {3- [5-Ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- ([( Z) -3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propane (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4 - [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- ( { (Z) -1-Methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanoic (2S) -3- acid. { 4- [3- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] phenyl} -2- ( { (Z) - 1-met il-3-oxo- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanoic (2S) -3- acid. { 4- [3- (5-Ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} -2-. { [(Z) -1-met i 1-3 -oxo-phenyl] -1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl] -l- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} -2- ( { (Z) -1-met il -3-oxo-3 - [4- (trifluoromethyl) phenyl] -l-pro? Enyl.} Amino) propanoic (2S) -3- acid. { 4 - [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) met oxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl} amino) propanic acid (2S) -3-. { 4- [(5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] methoxy} phenyl) -2- ( { (Z) -3-oxo-3-phenyl) -l- (trifluoromethyl) -l-propenyl.}. amino.} propanic (2S) -2- ( { (Z) -1-et i 1 -3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3- acid. { 4 - [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} propanic (2S) -3- acid. { 4-. { [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] methoxy} phenyl) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. amino) propanoic (2S) -3- acid. { 4- [(5-et i 1-2-phenyl-1, 3-oxazol-4-yl) methoxy] phenyl} -2- (((Z) -1-met i 1 -3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl.} Amino) propanoic (2S) -3- (4- { [5-ethyl-2- (4-f-luoro-phenyl) -1,3-oxazol-4-yl] -methoxy} -phenyl) -2- (. { (Z) -1-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) propane (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl}. amino) -3- (4- [( 5-ethyl-2-phenyl-1, 3-thiazol-4-yl) methoxy] phenyl}. Propane (2S) -3- (4- { [5-Ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] ethoxy} phenyl) -2- (. {( Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -3- (4. {[[5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] methoxy] phenyl) -2- (. {( Z) -1-et il-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3- acid. { 4 - [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} propanic, and the pharmaceutically acceptable salts and solvates of the same.
Preferred compounds of the invention include (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-thiazole-4-yl) ethoxy] phenyl} propanic (2S) -2-[[(Z) -1-et-3-oxo-3-phei-1-1-propenyl] amino acid} -3- [4- (2- { 5-met il-2- [4-trifluoromethyl) phenyl] -1,3-oxazol-4-yl} ethoxy) phenyl] propanic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3- (2,3,3-trifluorophenyl) -l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-methyl-3- (4-nitrophenyl) -3-oxo-l-propenyl] amino} -3- (4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2 - (((Z) -l-methyl-3-oxo-3- [4 (trifluoromethyl) phenyl] -l-propenyl} amino] -3-. {4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,4,5-trifluoromethyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- [2-. { 5-methyl-2-phenyl-l, 3-oxazol-yl) ethoxy] phenyl} propanic (2S) -3- (4-. {2- 2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl) ethoxy] phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic acid) 2S) -2-. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyllamino) -3-. { 4 - . { 2 - [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl-methoxy} phenyl) propanic (2S) -2- acid. { [(Z) -l-butyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenylpropanoic acid (2S) -2- acid. { [(Z) -3- (4-chlorophenyl) -1-met i 1 -3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenylpropanoic acid (2S) -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxa-zol-4-yl) ethoxy] -phenyl} -2-. { [(Z) -3 -oxo-3-phenyl-1-propyl-1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4-trifluoromethyl) phenyl] -1-propenyl acid} amino) -3- (4 - { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy.} phenyl) propanoic (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl}. amino) -3- (4 -. { 2 - [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy.] Phenyl) propane (2S) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-l- (trifluoromethyl) -1-propenyl] a inolpropanoic (2S) -2- acid. { [(Z) -1-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [(5-methyl-2-phenyl-1,3-oxazole-1) met oxy] pheni 1} propanic acid (2S) -3-. { 4- [2- (5-ethyl-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [(5-Met-il-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl Ipropanoic acid (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl) ethoxy} phenyl) -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl) aminolpropanoic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl)} ) -l, 3-thiazol-4-yl] ethoxy.} phenyl) -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] propoxy] phenyl) -2- (. { (Z) -l-ethyl-3-oxo-3- [4 - (trifluoromethyl) phenyl] -1-propenyl}. Mino) propanoic (2S) -2- ( { (Z) -1-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyllamino) -3- acid. { 4- [3- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl Ipropanoic acid (2S) -3- (4-. {3- [5-Ethyl-2- (4-fluoro-phenyl) -1,3-oxazol-4-yl] -propoxy} -phenyl-2- [ { (Z) -1-methyl-3-oxo-3 - [4- (trifluoromethyl) phenyl] -1-propenyl} .amino) propanoic (2S) -3- acid. { 4- [3- [5-et i 1-2 -pheni-1, 3-oxazol-4-yl] propoxy] phenyl} -2- ( { (Z) -1-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) propane (2S) -3- (4- { [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] methoxy] phenyl} -2- { [(Z) -3-oxo-3-phenyl- 1- (trifluoromethyl) -1-propenyl} amino.} propanic (2S) -3- acid. { 4- [(5-et il-2-phenyl] -1,3-oxazol-4-yl) methoxy] phenyl} -2- ( { (Z) -1-met il-3-oxo-3- [4- (rifluoromethyl) phenyl] -1-propenyl} amino.} Propanic (2S) -3- (4-. {[[(5-ethyl-2- (4-fluorophenyl) -l, 3-oxa-zol-4-yl] methoxy] phenyl) -2- (. { (Z) -1-met il-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino.} Propane (2S) -3- (4-. {2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl) -2- (. { (Z) -1-et l-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino.} Propane and the pharmaceutically acceptable salts and solvates thereof.
Many of the compounds of the formula (I) are double activators of hPPAR? and hPPARa. As used herein, by "activating compound", or "activator", or the like, is meant those compounds that achieve at least 50% activation of hPPAR? human ("hPPAR?") or hPPARa (relative to the appropriate indicated positive control) in the subsequent transfection test at concentrations of 10 ~ 7 M or less. As used herein, a "double activator" is a compound that is an activator of hPPAR? and hPPARa.
The relation EC50hPPARa EC5ohPPAR? defines the relative activity of hPPARa and hPPAR ?. Preferably, the double activators of this invention have a relative activity of hPPARa to hPPAR? from 0.02 to 50.
Those skilled in the art will recognize that stereoisomers exist in the compounds of formula (I). Therefore, the present invention includes all stereoisomers and possible geometrical isomers of formula (I) and includes not only the racemic compounds but also the optically active isomers. When a compound of the formula (I) is desired as a simple enantiomer, it could be obtained either by resolution of the final product or by the stereospecific synthesis of the isomerically pure starting material or any convenient intermediate. The resolution of the final product, an intermediary or an initiator material could be made by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E.L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents by S.H. Wilen. Additionally, in situations where the tautomers of the compounds of the formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
It will also be appreciated by those skilled in the art that the compounds of the present invention could also be used in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of the formula (I) include the conventional salts formed from the pharmaceutically acceptable inorganic or organic acids or bases in addition to the acid addition salts of quaternary ammonium. The most specific examples of the appropriate acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxyleleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluene sulphonic, methanesulfonic, naphthalene-2-sulphonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, sheric, tannic and the like. Other acids such as oxalic, while not these themselves pharmaceutically acceptable, could be useful in the preparation of the salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of the appropriate basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N, N'-dibenzyl, ilendiamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-met ilglucamine and procaine salts. Subsequent references to a compound according to the invention include the compounds of the formula (I) and their pharmaceutically acceptable salts and solvates.
The terms C1-3 alkyl, C4.6 cycloalkyl, C6-6 alkylene, C2-6 alkenyl and the like, as used herein, denote the groups which could contain the indicated range of carbon atoms, for example from 1 to 3. carbon atoms. Unless otherwise indicated, such groups may be straight or branched chain.
The term "5- or 6-membered heterocyclic group" as used herein includes substituted or unsubstituted 5- or 6-membered heterocycloalkyl or heteroaryl groups, for example, substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, pyridyl, pyridine zinyl. , pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or tetrazolyl. Particularly preferred heterocycles are pyridine, pyrazine, thiophene, furan, and thiazole.
It will be appreciated by those skilled in the art that reference to treatment extends to prophylaxis in addition to the treatment of established diseases or symptoms. Furthermore, it will be appreciated that the amount of a compound of the invention required for use in the treatment will vary with the nature of the condition to be treated and the age and condition of the patient and will ultimately be at the discretion of the attending physician or veterinarian. . In general, however, the doses employed for the treatment of the adult human will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The preferred dosage could be conveniently presented in a single dosage or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
While it is possible that the compounds of the present invention can be administered therapeutically as the chemical of origin, it is preferable to present the active ingredient as a pharmaceutical formulation. Therefore, the present invention further provides a pharmaceutical formulation comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers of the same and, optionally, other therapeutic ingredients. and / or prophylactics.
Formulations of the present invention include those specially formulated for oral administration, oral, parenteral, transdermal, inhalation, intranasal, transmucosal, implant or rectal, however, oral administration is preferred. For buccal administration, the formulation could take the form of tablets or lozenges formulated in the conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (eg, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage or polyvinylpyrrolidone), fillers (eg, lactose, sugar, microcrystalline cellulose) , corn starch, calcium phosphate or sorbitol), lubricants (eg, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (eg, potato starch, sodium starch glycolate) or wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.
Alternatively, the compounds of the present invention could be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example, in addition, the formulations containing these compounds could be presented as a dry product for constitution. with water or other appropriate vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which could include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations could also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
Additionally, the formulations of the present invention can be formulated for parenteral administration by injection or continuous infusion. The formulations by injection could take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and could contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient could be in the form of powder for constitution with an appropriate vehicle, eg, pyrogen-free, sterilized water) before use.
The formulations according to the invention can also be formulated as a depot preparation. Such long acting formulations could be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, the compounds of the invention could be formulated with the appropriate polymeric or hydrophobic materials (for example, as an emulsion in an appropriate oil), ion exchange resins or as slightly soluble derivatives for example as a slightly soluble salt.
The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently 30-95% for the tablets and capsules and 3.5% for the liquid preparations.
The processes for the preparation of the compounds of the invention are further provided by the present invention. Unless otherwise indicated, R ', R1, R2, R3, R4, R5, R6, n, and X are as defined above.
A compound of the structural formula (I) can be prepared from the condensation of a compound of the formula (II) (II) with a compound of the formula (III), for example, in a polar organic solvent, such d ") as methanol, at temperatures of -20 ° C to 150 ° C, such as 65 ° C, in the presence of a dehydrating agent such as trimethyl orthoformate and / or molecular sieves.
Alternatively, a compound of the formula (I) wherein R5 is hydrogen can be prepared by the reaction of a compound of the formula (II) with a compound of (IVa) (iv) the formula (IVa) in an organic solvent such as methanol at temperatures of -20 ° C to 150 ° C, such as 65 ° C, in the presence of a base, such as diisopropylethylamine.
The compounds of the formula (I) wherein R2 is CF3 could be prepared from the reaction of the compounds of the formula (II) with the compounds of the formula (IVb) in an organic solvent such as methanol at the temperatures of - 20 ° C to 150 ° C, such as 23 ° C, in the presence of a base such as diisopropylamine.
The compounds of the formula (II) can be prepared by means of the alkylation of the compounds of the formula (V), preferably wherein R 1 is hydrogen, with the compounds of the formula (VI), wherein R "is an activating group such as mesylate followed by (VI) (V) the deprotection of the amine under acidic conditions such as 4.0 N HCl in dioxane solution at 20 ° C, or trifluoroacetic acid in dichloromethane at 20 ° C.
Alternatively, the compounds of formula (II) could be prepared from the reaction of the compounds of the formula (V), preferably wherein R 1 is methyl, with the compounds of the formula (VI), preferably wherein R "is hydrogen , in an organic solvent such as toluene at temperatures of -20 ° C to 150 ° C such as 20 ° C in the presence of triphenylphosphine and diethylazodicarboxylate in a Mitsunobu-type process. Standard hydrolysis conditions of the methyl ester such as hydroxide of lithium in tetrahydrofuran and water at 20 ° C followed by the deprotection of the amine as described above (see also Greene, TW and Wutz, PGM "Protective Groups in Organic Synthesis" 2nd edition, 1991, John Wiley and Sons for a discussion General installation / removal of the protecting group provides the compounds of the structural formula (II).
The compounds of the formula (V) are commercially available and the technique can also be prepared by the skilled artisan from commercially available compounds.
The compounds of the formula (VI), for example where R "is mesylate, can be prepared by the reaction of an alcohol of the formula (VI) wherein R" is hydrogen, with methanesulfonyl chloride in an organic solvent such as tetrahydrofuran at temperatures of -20 ° C to 150 ° C such as 0 ° C in the presence of an amine base such as triethylamine.
The alcohols of the formula (VI) wherein R "is hydrogen, could be prepared by the reduction of the corresponding carboxylic acid or the ester of the formula (IX) in an organic solvent such as diethyl ether at temperatures of -20 ° C. at 100 ° C, such as 0 ° C, in the presence of a metal halide reagent such as lithium aluminum hydride These acids or esters of the formula (IX) could be prepared by a two-step alkylation / cyclization process between a amide or thioamide or a compound of the formula (VII), and a bromoketoester compound of the formula (VIII), wherein R '"is alkyl The alkylation / cyclization reaction can be carried out in an organic solvent such as toluene or ethanol at temperatures of -20 ° C to 200 ° C, such as 110 ° C, in the presence of a base such as triethylamine For the preparation of (VIII), see Chem. Pharm. Bull. (1986), 34 (7), 2840-51, J. Med. Chem. (1992), 35 (14), 2617-26 patent WO 9731907.
(VII) (VIII) (IX) The amides or thioamides of the formula (VII) are commercially available or can be prepared from the compounds readily available to one skilled in the art.
The compounds of the formula (III) are commercially available or can be easily prepared by one skilled in the art, for example by reacting a ketone of the formula (X) with an ester of the formula (XII), or by reacting a ketone of the formula (XIII) with an ester of the formula (XI), by reaction in an organic solvent, such as tetrahydrofuran, at temperatures of -20 ° C to 150 ° C, such as 20 ° C, in the presence of a base, such as sodium hydride, a metal cationic precipitator, such as dibenzo-18-corone-6, and catalytic amounts of an alcohol, such as ethanol (see, Popic, VV et al. Synthesis 1991, 195-197 (X) (XII) (XIII) (XI) The compounds of the formula (IVa) can be prepared from the addition of the compounds of the formula (XV) to the compounds of the formula (XIV) in an organic solvent such as tetrahydrofuran at temperatures of -100 °. C at 100 ° C such as -78 ° C followed by oxidation of the intermediate propargyl alcohol with an oxidant, such as manganese dioxide, in an organic solvent, such as dichloromethane, at temperatures from -20 ° C to 100 ° C, such as 20 ° C.
(XV) (XIV) Alternatively, certain ino-one compounds of the formula (IVa) can be prepared by dehydration of a compound of the formula (III) wherein R5 is hydrogen in an organic solvent, such as dichloromethane, at temperatures of -20 ° C to 100 ° C, such as 20 ° C, in the presence of triphenylphosphine, bromine and a base such as triethylamine. When R2 is CF3, R5 is hydrogen, and R3 is phenyl, a compound of 1 to formula (III) in an organic solvent, such as dichloromethane, at temperatures of -20 ° C to 100 ° C, such as 20 ° C, in the presence of triphenylphosphine, bromine and a base, such as triethylamine, produces a compound of the formula (IVb). The compounds of the formula (X), (XI), (XII), (XIII), (XIV) and (XV) are commercially available or can be prepared from the materials available to one skilled in the art.
The appropriate reaction conditions are described later in the appended examples. See also, for example, Chung et al., Selective Functionalization of (S) -Tyrosine, Tetrahedron, 49 (26), pp. 5767-5776, (1993), Solar et al., Selective O-Alkylate ion of Tyrosine, Journal of Organic Chemistry, 31, pp 1996-1997 (1966), O. Mitsunobu, Synthesis, p 1 (1981), and D.L. Hugues, Org. React. Vol. 42, p 335 (1992).
A compound of the formula (I) can be converted to another compound of the formula (I). A particular interconversion reaction involves the conversion of a compound of the formula (I) wherein R1 represents C3_3 / a alkyl to a compound of the formula (I) wherein R1 represents hydrogen, using appropriately the hydrolytic techniques for example, a alkali metal hydroxide, in the presence of an ether solvent for example, tetrahydrofuran and an alcoholic solvent for example, methanol or the like. Therefore, it will be appreciated by persons skilled in the art that the compounds falling within the general formula (I) could, in some cases, be described later in the intermediary section, as they are used for the preparation of the other compounds of the invention. formula (I).
For any of the processes and general schemes described above, it may be necessary and / or desirable to protect the reactive or sensitive groups. Protective groups are used according to the standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed in a convenient synthesis step using methods known in the art. Thus, for example, the amino groups can be protected by a selected group of aralkyl (for example, benzyl), acyl or sulfonyl, for example, allylsul fonyl, tert-butoxycarbonyl, phthalimide or tosyl; the subsequent removal of the protecting group which is carried out when desired by hydrolysis or hydrogenolysis as appropriate using the standard conditions. Thus, for example, the tert-butoxycarbonyl groups can be removed by hydrolysis under acidic conditions. The hydroxyl and carbonyl groups can be protected using any conventional hydroxyl or carbonyl protecting group. Examples of the appropriate hydroxyl and carbonyl protecting groups include the groups selected from alkyl, for example, the methyl, tert-butyl or methoxymethyl groups, aralkyl for example, benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl, acyl for example , the acetyl or benzoyl and silyl groups such as t-rialkylsilyl, for example, tert-but i limeime ti 1 il i lo. The hydroxyl protecting groups could be removed by conventional techniques. Thus, for example, the alkyl, silyl, acyl and heterocyclic groups can be removed by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl could similarly be removed by hydrolysis under acidic conditions. Aralkyl groups such as benzyl can be counted by hydrogenolysis in the presence of a noble metal catalyst such as palladium on natural carbon. Silyl groups can also be removed conventionally using a source of fluoride ions such as tetra-n-butylammonium fluoride.
The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to further exemplify the particular applications of the general processes described above. Therefore, the following section of examples is not intended to limit the scope of the invention contemplated herein.
E j emplos.
As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in contemporary scientific literature, for example, The Journal of the American Chemical Society. Unless stated otherwise, all initiator materials were obtained from the commercial suppliers and used without further purification. Specifically, the following abbreviations could be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); N (normal); nM (millimolar); mmol (millimoles); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); p.f. (melting point); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); more mass spectrum); ES + (elect roat omitted); Rf (retention fraction); tr (retention time); RP (reverse phase); MeOH (methanol); TFA (trifluoroacetic acid); HCl (hydrochloric acid); HC02H (formic acid); THF (tetrahydrofuran); CH3CN (acetonitrile); EtOH (ethanol); CDC13 (desadulterated chloroform); DMSO (dimethylsulfoxide); DMSO-d6 (disadulterated dimethylsulfoxide); EtOAc (ethyl acetate); DMC or CH2C12 (dichloromethane); DMF (dimethylformamide); Et 3 N (triethylamine); MgSO4 (magnesium sulfate); H20 (water); LAH (lithium aluminum hydride); NaH (sodium hydride); Na2C03 (sodium carbonate); Na2SO (sodium sulfate); Mn02 (manganese oxide); KCN (potassium cyanide); BH3'THF (borane tetrahydrofuran complex); NaOMe (sodium methoxide); IPA (isopropanol); Pd / C (palladium on carbon); NaOH (sodium hydroxide); LiOH (lithium hydroxide); DIEA (diisopropylethylamine); Et20 (diethyl ether; diethyl azodicarboxylate (DEAD); diisopropyl azodicarboxylate (DIAD); tert-butyloxycarbonyl (BOC); NaHC03 (saturated aqueous sodium bicarbonate): Brine refers to a saturated aqueous solution of NaCl. state otherwise, all temperatures are expressed in ° C (degrees Celsius) All reactions were carried out at room temperature unless otherwise indicated.
The 1 H NMR spectra were recorded on a Varian VXR-300 instrument, a Varian Unity-300 or a Varian Unity-400. The chemical changes are expressed in parts per million (ppm, units d). The coupling constants are in units of hertz (Hz). The division patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, wide, hept, heptuplete.
The low resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102, Micromass Plattaform 2 LC / Ms spectrometer or a SCIEX-APIiii. All mass spectra were taken under ionization by electroatomatization (ES, either in the form of a positive ion or in the form of a negative ion) or by fast atomic bombardment (FAB) methods. The infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1 mm NaCl cell. All reactions were monitored by thin layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, stained with iodine or 7% solutions of ethanolic phosphomolybdic acid or p-anisaldehyde . Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
The analytical purity was verified in a 1050 or 1100 system of the Hewlett Packard series equipped with a diode array spectrometer. The stationary phase was either a Dynamax C8 column (25 cm x 4.1 mm), a 60A C18 column (25 cm x 4.6 mm), a Vydac C18 column (5 m, 4.6 mm x 250 mm), a Supelco C18 column ( 5 m, 4.6 mm x 150 mm), or a Rainin C18 column (5 m, 4.6 mm, 250 mm). The flow rate was 1.0 to 1.5 ml / minute. (tO = 2.8 or 3.0 minutes) and the solvent systems were as described above. The enantiomeric purity was verified using either a Chiralpak AD column (25 cm x 4.6 mm) or a Chiralpak OD column (25 cm x 4.6 mm) in a 1050 HPLC system of the Hewlett Packard series with a diode array spectrometer or a Supercritical fluid system (SFC) using C02 / methanol as the mobile phase.
Intermediate 1: 2- [5-methyl-2-phenyl-1, 3-oxazol-4-yl] acetic acid methyl ester To a solution of 140 g (0.67 mol) of methyl 4-bromo-3-oxo-pentanoate in 300 mL of anhydrous toluene, was added 210 g (1.73 mol) of benzamide, 132 g (0.93 mol) of sodium hydrogen phosphate. sodium, and ~ 20 mL of EtOH. The suspension was stirred with heating at 95 ° C for 24 hours, then cooled to 0 ° C, filtered, and the solids were washed with cyclohexane (2 x 100 mL) followed by 20% EtOAc in hexanes (200 mL). . The combined filtrates were washed with 2 x 100 mL of 10% KOH solution and brine (100 mL). The organics were dried (MgSO 4), concentrated to a thin oil, and purified by chromatography on 1 kg of silica gel (230-400 mesh). Elution of the column gradient with 10% to 50% EtOAc in hexanes gave 54 grams (36% yield) of the title compound as a pale yellow oil; 1 H NMR (CDC13 400 MHz) d 8.0-7.98 (m, 2H), 7.43-7.40 (m, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 2.37 (s, 3H); Low resolution MS (ES +) m / e 232.4 (MH +); TLC Rf = 0.64 (hexanes / EtOAc 4/1).
Intermediate IB: 2- [5-ethyl-2-phenyl-l, 3-oxazol-4-yl] acetic acid ethyl ester The title compound (as described above for the preparation of Example 1) was prepared from ethyl 4-bromo-3-hexanoate (3.32 g, 14 mmol) and 6.76 g of benzamide (96 mmol) to give 710 mg of intermediary IB: TLC Rf = 0.69 (hexanes / EtOAc 2/1); * H NMR (CDC13, 300 MHz) d 7.98 (m, 2H), 7.41 (m, 3H), 4.18 (q.2H, J = 6.9), 3.57 (s, 2H), 2.72 (q, 2H, J = 7.5), 1.29-1.24 (m, 6H); Low resolution MS (ES +) m / e 260.1 (MH +).
Intermediary 1C: 2- [2-phenyl-5-propyl-1, 3-oxazol-4-yl] acetic acid ethyl ester The title compound (as described above for the preparation of Example 1) was prepared from ethyl 4-bromo-3-oxo-heptanoate (2.83 g, 11.4 mmol) and 5.51 g of benzamide (45 mmol) to give 820 mg of intermediate 1C: TLC Rf = 0.70 (hexanes / EtOAc 2/1); XH NMR (CDC13, 300 MHz) d 7.98 (m, 2H), 7.43-7.4 (m, 3H), 4.18 (q, 2H, J = 7.2), 3.56 (s, 2H), 2.66 (t, 2H, J = 7.5), 1.76 -1.68 (m, 2H), 1.27 (t, 3H, J = 7.2), 0.99 (t, 3H, J = 7.2); Low resolution MS (ES +) m / e 274.1 (MH +).
Intermediary ID: 5-methyl-2-phenyl-1,3-oxazole-4-carboxylic acid Commercial sources Intermediary 1E: 5-ethyl-2-phenyl-1,3-oxazole-4-carboxylic acid Intermediate 1E (as described below for the preparation of intermediate 2B) was prepared from 4.08 g of benzamide, 5.0 g of ethyl 3-bromo-2-oxo-pentaoate, and 10 mL of toluene. The solids were collected and washed with cold water after cooling the NaOH solution. Heating of these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 410 mg of the title compound (yield 9%) XH NMR (CDC13, 300 MHz) d 8.06-8.03 (m, 2H), 7.49-7.43 (m, 3H), 3.14 (q, 2H, J = 8.0), 1.34 (t, 3H, J = 8.0); MS of low resolution (ES +) m / e 217.8 (MH +).
Intermediate 2: 2- [5-methyl-2-phenyl-1, 3-thiazol-4-yl] acetic acid methyl ester A solution of 13.13 g of thiobenzamide (95.7 mmol) and 5.0 g of methyl 4-bromo-3-oxo-pentanoate (23.9 mmol) in 25 mL of dry toluene was heated at 90 ° C for 5 hours. The solution was poured into EtOAc / water and the aqueous phase was extracted with EtOAc. The organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude oil was purified by chromatography with silica gel eluted with hexanes / EtOAc (3/1 to 2/1) to provide 4.14 g of the title compound (yield (70%)) as a pale orange oil: XH NMR (CDC13, 400 MHz) d 7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).
Intermediary 2B: 2- [5-ethyl-2-phenyl-1,3-thiazol-4-yl] acetic acid A suspension of 8.7 g of thiobenzamide (63.3 mmol) and 10 g of ethyl 4-bromo-3-oxo-hexanoate (42.2 mmol) in 45 mL of toluene was refluxed for 6 hours, with the Dean water removal trap -Stark. It was cooled, methanol was added, and reflux was continued for 1 hour. It was cooled, partially concentrated (~ 1/2 volume), then 30 mL of the 2.0 M NaOH solution was added, the mixture was stirred at 80 ° C for 2 hours before cooling and extracting the aqueous ones with EtOAc. The aqueous phase was treated with 70 mL of 1.0 M citric acid by heating at (70 ° C) for 45 minutes. The mixture was extracted with EtOAc, and the extracts were dried with MgSO 4, filtered and concentrated to yield a yellow solid which was maintained at room temperature (yield ~ 80%, 8.4 g); 1ti NMR (CDC13, 300 MHz) d 7.95-7.87 (m, 2H), 7.48-7.45 (m, 3H), 3.86 (s, 2H), 2.85 (q, 2H, J = 7.5), 1.36 (t, 3H , J = 7.5).
Intermediary 2C: 5-ethyl-2-phenyl-1,3-thiazole-4-carboxylic acid Intermediate 2C was prepared as described above for the preparation of intermediate 2B from 4.61 g of thiobenzamide, 5.0 g of 3-bromo-2 -oxo-pent anoat or ethyl, and 14 mL of toluene. The solids were collected and washed with cold water after cooling the NaOH solution. Heating of these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 3.74 g (72% yield) of intermediate 2C: 1ti NMR (CDC13, 300 MHz) d 7913-7.91 (m, 2H), 7.51-7.50 (m, 3H), 3.39 (q, 2H, J = 7.8), 1.42 (t, 3H, J = 7.8); MS of low resolution (ES +) m / e 233.81 (MH +).
Intermediate 3: 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] acetic acid methyl ester A solution of 667 mg of methyl 4-bromo-3-oxo-pentanoate (4.80 mmol) in 6 mL of dry toluene was heated at 120 ° C for 16 hours. The resulting dark suspension was cooled to room temperature, diluted with 10 mL of EtOAc, and washed with NaHCO3 (1 x 10 mL). The organic layer was separated, dried with (MgSO), and the solvents were removed under reduced pressure. Purification of the material by flash column chromatography on silica gel using hexanes / EtOAc 4/1 as eluent to provide 308 mg of the title compound as a clear oil: XH NMR (CDC13, 400 MHz) d 7.97 (m, 2H) , 7.11 (m.2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).
Intermediate 3B: 2- [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] acetic acid The title compound was prepared from 5 g of 4-f luorobenzamide and 5.67 g of Ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 1.8 grams of intermediate 3B as a solid: A NMR (CDC13, 300 MHz) d 7.96 (dd, 2H, j = 8.8, 5.3) , 7.11 (t, 2H, J = 8.6), 3.61 (s, 2H), 2.69 (q, 2H, J = 7.5), 1.27 (t, 3H, J = 7.5).
Intermediary 3C: 5-ethyl-2- (4-fluorophenyl) -1,3-oxazole-4-carboxylic acid The title compound was prepared from 6.5 g of 4-fluorobenzamide and 6.08 g of ethyl 3-bromo-2-oxo-pentanoate (as described in example 2B) to give 1.55 g (22%) of intermediate 3C as a solid: XH NMR (CDC13, 300 MHz) d 8.12-8.08 (m, 2H), 7.23-7.17 (m, 2H), 3.19 (q, 2H, J = 7.5), 1.27 (t, 3H, J = 7.5).
Intermediate 4: 2- [2- (4-chlorophenyl) -5-methyl-1, 3-thiazol-4-yl] acetic acid ethyl ester A mixture of 8.75 g of 4-f luorobenzamide (56.4 mmole) and 11.79 g of methyl 4-bromo-3-oxo-pentanoate (56.4 mmole) in 45 mL of EtOH was refluxed for 14 hours. the solids formed were removed by cooling through filtration and the solvent was removed under reduced pressure. The residue was taken up in EtOAc and washed with water, brine, and dried with MgSO4. 1H NMR of the crude intermediate 4 that indicated sufficient purity to proceed in the next synthesis step. X H NMR (CDC13, 400 MHz) d 7.97 (m, 2 H) 7.11 (, 2 H), 3.73 (s, 3 H), 3.56 (s, 2 H), 2.36 (s, 3 H).
Intermediate 4B: 2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] acetic acid The title compound was prepared from 6.8 g of 4-f luorot ioben zamide and 7.42 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 2.9 grams (22%) of the intermediate 4B as a solid: H NMR (CDCl 3, 300 MHz) d 7.96 (dd, 2H, J = 8.8, 5.3), 7.11 (t, 2H, J = 8.6), 3.61 (s, 2H), 2.69 (q, 2H , J = 7.5), 1.27 (t, 3H, J = 7.5).
Intermediate 5: 2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] acetic acid methyl ester A mixture of 725 mg of 4-methoxybenzamide (4.80 mmol) and 1.0 g of 4-bromo-3-oxo-pent-anoat or methyl (4.80 mmol) was heated at 120 ° C for 2 hours, the resulting dark suspension was cooled to TA. Diluted with 2 mL of DCM and purified by flash column chromatography on silica gel using hexanes / EtOAc (3/1) as eluent to provide 189 mg of the title compound as a blanket solid: 1 ti NMR (CDC13, 400 MHz ) d 7.92 (d, 2H, J = 8.9), 6.93 (d, 2H, J = 8.9), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (s, 2H), 2.34 (s, 3H) ); Low resolution MS (FAB) m / e 285 (MH +), 284 (M +).
Intermediate 6: 2- [2- (4-trifluoromethylphenyl) -5-methyl, 3-oxazol-4-yl] acetic acid methyl ester A mixture of 3.62 g of 4-trif luoromethylbenzamide (19.1 mmol) and 4.0 g of methyl 4-bromo-3-oxo-pentanoate (19 mmol) in 15 mL of toluene and 10 mL of dioxane (with 2 mL of EtOH) it was at reflux temperature for 22 hours. The solution was concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water, brine and dried with MgSO4. The crude material was purified by chromatography on silica gel (10% -40% EtOAc in hexanes) to yield 130 mg of a yellow solid:: H NMR (CDC13.400 MHz) d 8.1 (d, 2H, J = 8.3) , 7.65 (d, 2H, J = 8.4), 3.75 (s, 3H), 3.58 (s, 2H), 2.39 (s, 3H); MS of low resolution (ES +) m / e 300.0 (MH +).
Intermediate 7: 2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] acetic acid ethyl ester A mixture of 2.8 g of 4-i-sopropoxybenzamide (15.6 mmol) and 3.26 g of methyl 4-bromo-3-oxo-pentanoate (15.6 mmol) in 10 mL of toluene and 1 mL of EtOH was refluxed for 24 hours. Solvents were removed and the crude residue was purified directly by silica gel chromatography (4/1 hexanes / EtOAc) to yield 1.31 g (28%) of intermediate 6: XH NMR (CDC13, 400 MHz) d 7.92 (d, 2H, J = 8.9), 6.93 (d, 2H, J = 8.9), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (s, 2H), 2.34 (s, 3H); Low resolution MS (FAB) m / e 285 (MH +).
Intermediate 8: 2- [5-methyl-phenyl-1,3-oxazol-4-yl] ethanol To a solution of 330 mg of intermediate 1 (1.43 mmol) in 5 mL of THF at 0 ° C was added dropwise 1.43 mL of 1.0 M LAH (1.43 mmol) in the Et20 solution. As the solution was stirred at 0 ° C for 1 hour, it was quenched by the addition of 0.054 mL of H20, 0.054 mL of 1.0 N NaOH solution, and 0.162 mL of H20, and MgSO4 was added. The mixture was filtered, the filtrate was concentrated, and the crude oil was dried under vacuum for several hours to give 280 mg of intermediate 8 as a pale yellow solid: 1 R NMR (CDC13, 400 MHz) d 7.97 (m, 2H), 7.42 (m, 3H), 3.92 (t, 2H, J = 5.6), 2.72 (t, 2H, J = 5.6), 2.33 (s, 3H); MS of low resolution (ES +) m / e 204 (MH +); TLC Rf = 0.21 (hexanes / EtOAc 1/1).
Intermediate 8B: 2- [5-ethyl-2-phenyl-1,3-oxazol-4-yl] ethanol The title compound was prepared (as described above for the preparation of intermediate 8 from intermediate IB (710 mg , 2.74 mmol) and 125 mg of LAH to give 480 mg (81% yield) of intermediate 8B: TLC Rf = 0.21 (hexanes / EtOAc 2/1); XH NMR (CDC13, 400 MHz) d 8.0-7.97 (m, 2H), 7.46-7.41 (m, 3H), 3.92 (t, 2 H, J = 5.6), 3.33 (width s, 1H), 2.75-2.66 (m, 4H), 1.27 (t, 3H, J = 7.6 ), Low resolution MS (ES +) m / e 218.15 (MH +).
Intermediate 8C: 2- [2-phenyl-5-propyl-l, 3-oxazol-4-yl] ethanol The title compound (as described above for the preparation of intermediate 8) was prepared from intermediate 1C (820 mg, 3.0 mmol) and 137 mg of LAH to give 360 mg (52% yield) of intermediate 8C: TLC Rf = 0.29 (hexanes / EtOAc 2/1); X H NMR (CDC13, 400 MHz) d 7.91 (m, 2 H), 7.39-7.32 (m, 3 H), 3.86 (t, 2 H, J = 5.6), 2.68-2.55 (m, 2 H), 4.48-2.41 (m , 2H), 1.68-1.53 (m, 2H), 0.91 (t, 3H, J = 7.6), low resolution MS (ES +) m / e 232.14 (MH +).
Intermediary 8D: [5-methyl-2-phenyl-1,3-oxazol-4-ylmethanol] The title compound was prepared by reducing the LAH of the intermediate ID. Thus, 670 mg of the intermediate ID (3.30 mmol) was stirred with 165 mg of LAH at 23 ° C for 2 hours. Chromatography on silica gel gave 120 mg (19% yield) of intermediate 8D: TLC Rf = 0.28 (hexanes / EtOAc 2/1); 1 H NMR (CDC13, 300 MHz) d 8.0-7.97 (m, 2H), 7.49-7.41 (m, 4.59 (s, 2H), 4.18-4.05 (broad s, 1H), 2.38 (s, 3H); low resolution (ES +) m / e 190.1 (MH +).
Intermediate 8E: 3- [5-methyl-2-phenyl-1,3-oxazol-4-yl] propanol The title compound was prepared from intermediate 8 by means of a carbon 1 homologation sequence as follows: The mesylate (3.88 g, 1.38 mmol) of the intermediate alcohol 8 (from Et3N, methanesulfonyl chloride, THF, a 0 ° C) was heated at 120 ° C with 1.08 g of KCN (16.6 mmol) for 14 hours, the aqueous ones were treated and chromatography on silica gel (EtOAc / hexanes) gave 860 mg (30%) of the cyanide intermediate . The hydrolysis for the acid intermediate was carried out by refluxing EtOH / water for 2.5 hours with NaOH (650 mg). Acidification of the aqueous phase gave 580 mg of the acid (62% yield). Reduction with LAH (95 mg, 3.0 mmol) in Et20 for 3 hours followed by silica gel chromatography afforded 370 mg of intermediate 8E (68% yield): TLC Rf = 0.14 (hexanes / EtOAc 2/1); XH NMR (CDC13, 400 MHz) d 7.98-7.93 (m, 2H), 7.45-7.37 (m, 3H), 3.75 (t, 2H, J = 8.7), 3.36 (br s, 1H), 2.64 (t, 2H, J = 6.9); 2.33 (s, 3H), 1.94-1.85 (m, 2H); MS of low resolution (ES +) m / e 218.17 (MH +).
Intermediate 8F: 3- [5-ethyl-2-phenyl-1,3-oxazol-4-yl] propanol The intermediate 8F was prepared from intermediate 8B by means of a carbon homologation process as described for the preparation of intermediate 8E. Thus, 495 mg of intermediate alcohol 8B was converted to intermediate 8F via intermediates of mesylate (380 m), cyanide (355 mg), and acid (280 mg). The reduction of borane (THF, 0 ° C, 6.5 mL of the BH3 / THF 1.0 M complex) in 273 mg of the intermediate acid gave 215 mg of the intermediate alcohol 8F; XH NMR (CDC13, 300 MHz) d 8.05 - 8.01 (m, 2H), 7.48 - 7.44 (m, 3H), 3.79 (t, 2H, J = 5.8), 2.78 -2.67 (m, 4H), 1.97 - 1.91 (m, 2 H), 1.31 (t, 3 H, J = 7.5); MS of low resolution (ES +) m / e 231.91 (MH +); TLC Rf = 0.49 (1/2 hexanes / EtOAc).
Intermediate 8G: [5-ethyl-2-phenyl-1,3-oxazol-4-yl] methanol Intermediate 8G (as described below for intermediate 9B) was prepared from 410 mg of intermediate 1E to give 335 mg (87%) of the title compound; XH NMR (CDC13, 300 MHz) d 7.96-7.940 (m, 2H), 7.39-7.37 (m, 3H), 4.54 (s, 2H), 2.71 (q, 2H, J = 7.5), 2. 38 (width s, 1H), 1.25 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 203.94 (MH +).
Intermediate 9: 2- [5-methyl-2-phenyl-1,3-thiazol-4-yl] ethanol A stirred solution at 0 ° C of 6.11 g of intermediate ester 2 (24.7 mmol) in 100 mL of THF was added 935 mg of LAN (25 mmol). The reaction was stirred for 20 minutes at 20 ° C, cooled to 0 ° C, and quenched with water. The solids were filtered, washed with Et20, and the filtrate was dried (MgSO4). Chromatography on silica gel with EtOAc in hexanes (40 to 50%) gave 2.33 g of intermediate 9 (38% yield): 1 H NMR (CDC 13, 400 MHz) d 7.85 (m, 2 H 9, 7.42 (m, 3 H), 3.99 (m, 3), 2.90 (m, 2H), 2.41 (s, 3H), low resolution MS (ES +) m / e 220.1 (MH +), TLC Rf = 0.43 (hexanes / EtOAc 1/1).
Intermediate 9B: 2- [5-ethyl-2-phenyl-1,3-thiazol-4-yl] ethanol To a solution of THF (15 mL) of 4.0 g of intermediate 2B (16.2 mmol) at 0 ° C, 57 mL of the 1.0 M BH3-THF complex in THF was added dropwise over 10 minutes. Stirred at 35-40 ° C for 3 hours before cooling to 0 ° C and quenching with 70 mL of MeOH. The concentrate was taken in 50 mL of n-butanol and refluxed for 45 minutes. The solution was concentrated and the collected residue was purified by chromatography on silica gel. Elution with 20-50% EtOAc in hexanes gave 2.4 g (64% yield) of a yellow viscous oil after concentration of the fractions of the separated product and dried under vacuum: 1 H NMR (CDC13, 300 MHz) d 7.86 - 7.83 (m, 2H), 7.41 -7.34 (m, 3H), 3.96 (t, 2H, J = 5.5), 2.89 (t, 2H, J = 5.5), 2.77 (q, 2H, J = 7.5), 1.27 (t, 3H, j = 7.5).
Intermediate 9C: [5-ethyl-2-phenyl-l, 3-thiazol-4-yl] methanol Intermediate 9C) was prepared as described above for intermediate 9B) from 3.74 g of intermediate 2C to give 2. 45 g (70%) of the title compound; 1 H NMR (CDCl 3, 300 MHz) d 7.93-7.90 (m, 2H), 7.47-7.4 (m, 3H), 4.75 (s, 2H), 3.02 (width, s, 1H), 2.89 (q, 2H, J = 7.2 ); Low resolution MS (ES +) m / e 219.88 (MH +).
Intermediate 10: 2- [2- (4-fluorophenyl) -5-methyl-1,3-oxazol-4-yl] ethanol A solution of 380 mg of the intermediate ester 3 (1.44 mmol) was stirred at 0 ° C. mL of THF was added 55 mg of LAH (1.44 mmol). The reaction was stirred for 20 minutes at 20 ° C, cooled to 0 ° C, and quenched with saturated aqueous NH 4 Cl solution. The solids were filtered, washed with Et20, and the filtrate was dried (MgSO4). Chromatography with silica gel with EtOAc / hexanes (1/2 to 2/1) as eluent gave 175 g of intermediate 10 (55% yield): XH NMR (CDC 13. 400 MHz) d 7.96 (m, 2H), 7.12 (m, 2H), 3.92 (d, 2H, J = 5.0), 3.21 (s, 1H), 2.71 (t, 2H, J = 5.6), 2.32 (s, 3H); Low resolution MS (FAB) m / e 221 (MH +); TLC Rf = 0.20 (hexanes / EtOAc 1/1).
Intermediate 10B: 2- [5-ethyl-2- (4-fluorophenyl) -1, 3-oxazol-4-yl] and anol The title compound was prepared as described above for Example 9B. It was prepared from 1.3 g of intermediate 3B 1.14 g of intermediate 10B (94%) as a viscous, yellow oil; XH NMR (CDC13, 400 MHz) d 7.98-7.94 (m, 2H), 7.10 (t, 2H, J = 8.7), 3.89 (t, 2H, J = 5.6), 2.71 (t, 2H, J = 5.7) , 2.66 (t, 2H, J = 7.5), 1.25 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 236.17 (MH +); TLC Rf = 0.37 (hexanes / EtOAc 1/1).
Intermediate 10C: 3- [5-ethyl-2- (fluorophenyl) -1, 3-oxazol-4-yl] propanol Intermediate 10C was prepared from intermediate 10B by means of a carbon homologation process as described for the preparation of intermediate 8E. Thus, 720 mg of intermediate alcohol 10B was converted to intermediate 10C by intermediates mesylate (828 mg), cyanide (495 mg), and acid (440 mg). The reduction of borane (THF, 0 ° C, 6.5 mL of the BH3 / THF 1.0 M complex) instead of the LAH reduction in 430 mg of the intermediate acid gave 320 mg of the intermediate alcohol 10C; XH NMR (CDC13, 400 MHz) d 7.98-7.93 (m, 2H), 7.09 (t, 2H, J = 8.6), 3.72 (t, 2H, J = 5.8), 2.70-2.56 (m, 4H), 1.91. -1.84 (m, 2H), 1.24 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 250.15 (MH +); TLC Rf = 0.55 (1/2 hexanes / EtOAc).
Intermediary 10D: [5-ethyl-2- (4-fluorophenyl) -1, 3-oxazol-4-yl] methanol The title compound was prepared as described above for Example 9B. It was prepared from 1.52 g of intermediate 3C 735 mg of intermediate 10D (51%); XH NMR (CDC13, 300 MHz) d 8.05 - 8.04 (m, 2H), 7.18 - 7.16 (m, 2H), 4.64 (s, 2H), 2.82 - 2.78 (m, 2H), 2.30 (s wide, 1H) , 1.35-1.31 (m, 3H); MS of low resolution (ES +) m / e 221.94 (MH +); TLC Rf = 0.60 (1/2 hexanes / EtOAc).
Intermediate 11: 2- [2- (4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] ethanol The title compound was prepared from the crude ester intermediate and 1.07 g of LAH as described above for the preparation of intermediate 10 to produce 2.8 g of intermediate 11 (yield 21% during two steps, preparation of intermediates 4 plus 11) : A NMR (CDC13, 400 MHz) d 7.96 (m, 2H), 7.12 (m, 2H), 3.92 (d, 2H, J = 5.0), 3.21 (s, 1H), 2.71 (t, 2H, J = 5.6), 2.32 (s, 3H); Low resolution MS (FAB) m / e 221 (M +).
Intermediate 11B: 2- [5-ethyl-2- (4-fluorophenyl) -1,3-thiazol-4-yl] ethanol The title compound was prepared as described for Example 9B. Prepared from 2.7 g of intermediate 4B 1.75 g of intermediate 11B (68%) as a viscous, colorless oil; XH NMR (CDC13, 400 MHz) d 7.85-7.80 (m, 2H), 7.07 (t, 2H, J = 8.7), 3.95 (t, 2H, J = 5.6), 2.88 (t, 2H, J = 5.5) , 2.77 (q, 2H, J = 7.5), 1.27 (t, 3H, J = 7.5); Low resolution MS (ES + ') m / e 252.17 (MH +); TLC Rf = 0.47 (hexanes / EtOAc 1/1).
Intermediate 12: 2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethanol To a stirred solution of 185 mg of intermediate 42 (0.71 mmol) in 5 mL of THF at 0 ° C was added 0.71 mL (0.71 mmol, 1.0 equivalents) of a 1.0 M LiAIH4 solution in THF. The resulting solution was stirred at room temperature for 45 minutes then cooled to 0 ° C and quenched by careful addition of 0.027 mL of H20, followed by the addition of 0.027 mL of 15% NaOH and 0.080 mL of H20. The resulting suspension was filtered to remove solids and the filtrate was concentrated under reduced pressure to provide 164 mg of the title compound as a light gauge oil: XH NMR (CDC13, 400 MHz) d 7.92, (d, 2H, J = 8.8 ), 6.94 (d, 2H, J = 8.8), 3.92 (dt, 2H, J = 5.7, 11.5), 3.86 (s, 3H), 3.35 (t, 1H, J = 6.2), 2.71 (t, 2H, J = 5.7), 2.32 (s, 3H).
Intermediate 13: 2- [2- (4-trifluoromethyl-phenyl) -5-methyl-1, 3-oxazol-4-yl] ethanol The title compound was prepared from 390 mg of the intermediate intermediate 6 (as described above for the preparation of intermediate 10) to yield 170 mg of intermediate 13: TLC Rf = 0.24 (hexanes / EtOAc 1/1), H NMR (400 MHz, CDC13) d 8.08 (d, 2H, J = 8.2), 7.68 (d, 2H, J = 8.4), 3.93 (q, 2H, J = 11.4, 5.8), 2.99 (t, 1H, J = 6.0), 2.74 (t, 2H, J = 5.8), 1.56 (s, 3H).
Intermediary 14: 2- [2- (4-isopropoxyphenyl) -5-methyl-1,3-oxazol-4-yl] ethanol The title compound was prepared from 1.3 g of the ester intermediate 7 (as described above for the preparation of intermediate 10) to produce 540 mg of intermediate 14; TLC Rf = 0.21 (hexanes / EtOAc 1/1), XH NMR (400 MHz, CDC13) d 7.87 (d, 2H, J = 8.8), 6.9 (d, 2H, J = 9.0), 4.6 (hept, 1H, J = 6.0), 3.9 (q, 2H, J = 11.4, 5.7), 3.35 (t, 1H, J = 6.0), 2.69 (t, 2H, J = 5.6), 2.3 (s, 3H), 1.35 (d , 6H, J = 6.0).
Intermediate 15: 5- [2- (4-methanesulfonyloxy) ethyl] -4-methyl-2-phenyl-1,3-oxazole To a solution of 9.41 g of the intermediate alcohol 8 (46.3 mmol) in (300 mL) of CH2C12 at 0 ° C was added 3.94 mL of methanesulfonyl chloride (50.9 mmol) followed by 7.75 mL of triethylamine (55.6 mmol). After 1 hour of gradual warming to 20 ° C, the solution was washed with water (3x), brine (lx), and dried in MgSO4. The concentration gave 12.92 g of intermediate 15 (99%) by homogeneous TLC analysis: (Rf = 0.24, hexanes / EtOAc 1/1); XH NMR (CDC13.400 MHz) d 7.67 (m, 2H), 7.43 (, 3H), 4.53 (t, 2H, J = 6.5), 2.95 (s, 3H), 2.95 (t, 2H, J = 6.5) 2.36 (s, 3H); MS of low resolution (ES +) m / e 281.9 (MH +); TLC Rf = 0.35 (hexanes / EtOAc 1/1).
Intermediary 16: 1- (phenyl) -1, 3-pentanedione The title compound was prepared according to Popio, V.V. and collaborators, Synthesis (March 1991), pages 195-197. To a stirred suspension of NaH (1.2 g, 50 mmol) and ethyl propionate (5.73 mL, 50 mmol) in 20 mL of THF at 20 ° C was added EtOH (2 drops), acetophenone (3.0 g, 25 mmol) in 20 g. mL of THF, and diben zo-18-corone-6 (150 mg, 0.4 mmol,) in 20 mL of THF. It was stirred for 30 minutes, then at reflux temperature for 1 hour. It was cooled (0 ° C), then 25 mL of 10% H2SO4 solution was added and the aqueous ones were extracted with Et20. The organics were washed with H20, aqueous Na2CO3, and brine. The solution was dried over Na 2 SO and concentrated. Purification by chromatography with silica gel (1% to 10% EtOAc in hoxans) gave 4.0 of intermediate ld as a light oil. 1 H NMR indicated a -10: 1 mixture of tautomers favoring the enol form: XH NMR (400 MHz, CDC13, enol form) d 7.87 (m, 2H), 7.52-7.4 (m, 3H), 6.17 (s, 1H ), 2.47 (q, 3H, J = 7.5), 1.21 (t, 3H, J = 7.5).
Intermediates 17, 18 and 20-23 were prepared analogously to the method described above for the preparation of intermediate 16.
Intermediate 17: 1- (phenyl) -1, 3-hexanedione The title compound (as described above for the preparation of intermediate 16) was prepared from 3.0 g of acetophenone and 5.8 g of ethyl butyrate to yield 4.0 grams of intermediate 17 as an oil: TLC Rf = 0.51, (1 / 9 EtOAc / hexanes); : H NMR (400 MHz, CDC13) d 7.88 (m, 2H), 7.48 (m, 3H), 6.17 (s, 1H), 2.4 (t, 2H, J = 7.6), 1.72 (q, 2H, J = 7.6), 1.0 (t, 3H, J = 7.2); MS of low resolution (ES +) m / e 213.0 (M + Na +).
Intermediary 18: 1 - (phenyl) -1, 3-heptanedione The title compound (as described above for intermediate 16) was prepared from 2.2 g of acetophenone (18.3 mmol) and 4.51 g of ethyl valerate (35 mmol) to yield 2.6 grams of intermediate 18: TLC Rf = 0.52 (1/9 EtOAc / hexanes); XH NMR (400 MHz, CDC13) d 7.87 (m, 2H), 7.48 (m, 3H), 6.17 (s, 1H), 2.42 (t, 2H, J = 7.6), 1.67 (m, 2H), 1.4 ( m, 2H), 0.95 (t, 3H, J = 7.2); MS of low resolution (ES +) m / e 205.1 (MH +). 227.1 (M + Na +).
Intermediary 19: 1 - (phenyl) -1, 3-decandione To a solution of 1 g of benzoylacetone (6.1 mmol) in 6 mL of THF at 78 ° C was added 8.2 mL of a 1.5 M LDA solution (12.3 mmol) in THF. It was heated at 0 ° C for 2 hours, then 2.6 L of 1-iodohexane (12.3 mmol) was added. The mixture was stirred at room temperature for 3 hours before quenching with the saturated aqueous NH4C1 solution and dilution with Et20. The organics were dried with (Na2SO4), filtered, concentrated, and purified by chromatography on silica gel (15/1 hexanes / Et20) to yield intermediate 19: TLC Rf = 0.52, (1/10 EtOAc / hexanes); : H NMR (400 MHz, CDC13) d 7.88 (m, 2H), 7.54-7.43 (m, 3H), 6.17 (s, 1H), 2.42 (t, 2H, J = 7.6), 1.66 (m, 2H) , 1.4-1.25 (m, 8H), 0.85 (m, 3H); MS of low resolution (ES +) m / e 269.0 (M + Na +).
Intermediate 20: 1- (2-fluorophenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.0 g of 2'-f luoroacet ofenone and 2.86 mL of EtOAc for intermediate 20: XH NMR (400 MHz, CDC13, enol form) d 7.70 (dt, 1H, J = 1.79, 7.69), 7.45 (m, 1H), 7.24 (m, 1H), 7.10 (m, 1H), 6.28 (s, 1H), 2.20 (s, 3H).
Intermediate 21: 1- (3-methylphenyl) -1, 3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.72 mL of 3 '-met i lacetophenone and 3.95 mL of EtOAc to yield 2.94 grams of intermediate 21 as an oil: 1 H NMR (400 MHz , CDCI3, enol form) d 7.70 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H), 2.41 (s, 3H), 2.20 (s, 3H); Low resolution MS (ES +) m / e 177.1 (MH +).
Intermediary 22: 1- (4-methoxyphenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 3.0 g of 4'-methoxyacet ofenone and 3.95 ml of EtOAc. Purification by recrystallization from toluene / hexane gave the title compound: XH NMR (400 MHz, CDC13, enol form) d 7.70 (d, 2H, J = 8.20), 7.34 (d, 2H, J = 8.20) , 6.17 (s, 1H), 3.87 (s, 3H), 2.17 (s, 3H); Low resolution MS (ES) m / e 193.1 (MH +).
Intermediary 23: 1- (2-hydroxyphenyl) -1,3-butanedione The title compound was purchased from Aldrich Chemical Co.
Intermediate 24: 1- (4-trifluoromethylphenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 51.53 g of 4'-trifluoroacetophenone and 53.4 mL of EtOAc to yield 35.78. g of intermediate 24: TLC analysis: Rf = 0.70 (hexanes / EtOAc 2/1), XH NMR (400 MHz, CDC13, enol form) d 7.96 (d, 2H, J = 7.0), 7.7 (d, 2H, J = 7.0), 6.2 (s, 1H), 2.23 (s, 3H).
Intermediary 25: 1- (4- rifluoromethylphenyl) -1, 3-pentanedione The title compound (as described above for intermediate 16) was prepared from 1.5 g of 4 '-tri f luoromet i lace tofenone and 1.54 mL of methyl propionate to yield 0.69 g of intermediate 25: TLC Analysis: Rf = 0.75- (hexanes / EtOAc 2/1),? H NMR (400 MHz, CDC13 enol form) d 7.92-7.86 (m, 2H), 7.12 (t, 2H, J = 8.6), 6.1 (s, 1H), 2.45 (q, 2H, J = 7.5), 1.21 (t, 3H, J = 7.5).
Intermediary 26: 1- (4-fluorophenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.42 mL of 4 '-fluoroacet ofenone and 3.95 mL of EtOAc to produce intermediate 26 as an oil: XH NMR (400 MHz, CDC13, enol form ) d 7.89 (dd, 2H, J = 8.90, 5.40), 7.13 (dd, 2H, J = 17.2, 8.60), 6.13 (s, 1H), 2.19 (s, 3H).
Intermediary 27: 1- (4-methylphenyl) -1, 3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.0 g of 4'-methalacet ofenone and 2.9 mL of EtOAc to yield 1.68 grams of intermediate 27: TLC Analysis: Rf = 0.61 (5 / 1 hexanes / EtOAc), NMR (400 MHz, CDC13, enol form) d 7.72 (d, 2H, J = 8.2), 7.24 (d, 2H, J = 7.4), 6.15 (s, 1H), 2.4 (s) , 3H), 2.2 (s, 3H).
Intermediate 28: 1- (4-chlorophenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.0 g of 4'-chloroacetophenone and 2.53 mL of EtOAc to yield 1.7 grams of intermediate 28: TLC Analysis: Rf = 0.73 (hexanes / EtOAc 2 /1); 1 H NMR (400 MHz, CDC13, enol form) d 7.82 (d, 2H, J = 8.0), 7.42 (d, 2H, J = 8.0), 6.13 (s, 1H), 2.22 (s, 3H).
Intermediary 29: 1- (4-isopropoxyphenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.42 g of 4'-isopropoxyacet ofenone and 2.65 mL of EtOAc to yield 2.25 grams of intermediate 29: TLC Analysis: Rf = 0.73 (hexanes / EtOAc 2/1), l H NMR (400 MHz, CDC13, enol form) d 7.84 (d, 2H, J = 8.9), 6.9 (d, 2H, J = 9.0), 6.1 (s, 1H), 4.62 (hept , 1H, J = 6.0), 2.16 (s, 3H), 1.36 (d, 6H, J = 6.0).
Intermediate 30: 1- (2-chlorophenyl) -1,3-butanedione The title compound (as described above for intermediate 16) was prepared from 2.0 g of 2'-chloroacetophenone and 2.53 mL of EtOAc to yield 0.5 g of intermediate 30: TLC analysis: Rf = 0.76 (hexanes / EtOAc 2/1), XH NMR (400 MHz, CDC13, enol form) d 7.6-7.55 (m, 1H), 7. 45-7.43 (m, 1H), 7.4-7.32 (m, 1H), 6.05 (s, 1H), 2.18 (s, 3H).
Intermediary 31: 1- (3-thienyl) -1, 3-butanedione The title compound (as described above for intermediate 16) was prepared from 1.5 g of 3 -acet i lt iofen and 2.32 mL of EtOAc to yield 1.28 grams of intermediate 31 as a yellow oil: TLC Rf = 0.65 ( hexanes / EtOAc, 2/1), NMR (400 MHz CDC13, primary enol form, -85: 15) d 8.0 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 6.0 (s) , 1H), 2.18 (s, 3H).
Intermediary 32: 1- (4-fluorophenyl) -1, 3-pentadione The title compound (as described above for intermediate 16) was prepared from 0.525 g of 4'-f luoroacetophenone and 0.73 mL of methyl propionate to yield 120 mg of intermediate 32: TLC analysis: Rf = 0.77 ( hexanes / EtOAc, 2/1), A NMR (400 MHz, CDC13, enol form) d 7.98 (d, 2H, J = 8.3), 7.7 (d, 2H, J = 8.3), 6.12 (s, 1H), 1.55 (s, 3H); low resolution mass spectrum (ES +) 195 (MH +).
Intermediary 33: 1- (ciciohexyl) -1, 3-butanedione The title compound was prepared as described above, from 1.5 g of cyclohexyl methyl ketone and 2.32 mL of EtOAc to yield 1.06 grams of intermediate 33 as a yellow oil: RF TLC = 0.65 (hexanes / EtOAc, 3/1); XH NMR (400 MHz, CDC13, enol form) d 5.5 (s, 1H), 2.19-2.12 (m, 1H), 2.08 (s, 3H), 1.85-1.55 (m, 5H), 1.41-1.15 (m , 5H).
Intermediate 34: 1- (2-pyrazinyl) -1,3-butanedione To a solution of methyl 2-methyl ester incarboxy (1.5 g, 10.86 mmol) in 3 mL of acetone and 10 mL of THF was slowly added 590 mg (10.86 mmol) of NaOMe and the resulting mixture was refluxed for 4 hr. The mixture was filtered, the filtrate was acidified and extracted with CH2C12, and the organics were dried with MgSO4 to yield homogeneous 940 mg (53%) by TLC: Rf = 0.5 (EtOAc / hexanes, 2/1); XH NMR (400 MHz, CDC13, enol form) d 9.27 (d, 1H, J = 1.4), 8.7 (d, 1H, J = 2.4), 8.6 (t, 1H, J = 1.8), 2.26 (s, 3H).
Intermediate 35: 1- (2-pyridinyl) -1,3-butanedione Intermediate 36 was prepared as described above for intermediate 35 from 2.0 g of methyl 2-pyridylcarboxylate and 4.0 mL of acetone to yield 1.08 g of the title compound (45% yield) as a light brown oil: of TLC: Rf = 0.73 (EtOAc / hexanes, 2/1); XH NMR (400 MHz, CDC13, mixture of enol / non-enol forms ~ 80/20) d 8.66 (m, 1H), 8.05 (m, 1H), 7.85 (m, 1H), 7.46 (m, 1H) , 6.8 (s, 1H), 2.34 (s, 3H), (singles of the non-enol form observed at 4.28 2.35); low resolution mass spectrum (ES +) 164.1 (MH +).
Intermediary 36: 1- (2, 3, 4-trifluorophenyl) -2-butin-1-one Propi 1 lithium (720 mg, 14.05 mmol) was added at 0 ° C to the stirred solution of 1.5 g (9.37 mmol) of 2, 3, 4-t ri f luorobenza ldehyde and the solution was allowed to stir for 1 hour with heating at room temperature. The solution was diluted with EtOAc and washed with H20 and brine. The organics were dried with MgSO and concentrated (intermediate alcohol production, 1.88 g). The crude product was stirred in 30 mL of CH2C12 with 4 g of MnO2 at 20 ° C for 2.5 h. The mixture was filtered through a pad of celite / silica gel and concentrated to yield 1.31 g (47% overall yield) of the homogeneous crude product by TLC analysis: Rf 0.6 (hexanes / EtOAc, 2/1); __ NMR (300 MHz, CDC13) d 7.9-7.8 (m, 1H), 7.1-6.95 (m, 1H), 2.13 (s, 3H).
Intermediates 37-43 were prepared analogous to the method described above for the preparation of intermediate 36.
Intermediate 37: 1- (2-fluoro-3-trifluoromethylphenyl) -1, 3-pentanedione The title compound (as described above for intermediate 36) was prepared from 0.5 g of 2'-fluoro-3'-tri fluoromet i lbenza ldehyde and 1.03 g of Mn02 to yield 0.46 g (overall yield of 75%) of intermediate 37: XH NMR (400 MHz, CDC13) d 8.19 (m, 1H), 7.84 (M, 1H), 7.32 (m, 1H), 2.1 (s, 3H).
Intermediary 38: l- (2,3,4,5) -trifluorophenyl) -2-butin-1-one Intermediate 38 (as described above for intermediate 36) was prepared from 1-propini 11 itio, 0.5 g of 2 ', 4', 5'-t ri f luorobenzaldehyde, and 0.87 g of Mn02 to yield 0.39 g (63% overall yield) of the title compound:: H NMR (400 MHz, CDC13) d 7.91-7.82 (m, 1H), 7.05-6.96 (m, 1H), 2.14 (s, 3H), For the Alcohol intermediate: 1 H NMR (400 MHz, CDC13) d 7.54-7.48 (m, 1H), 6.97-6.88 (m, 1H), 5.64 (s, 1H), 1.91 (s, 3H).
Intermediate 39: 1- (2,4-difluorophenyl) -2-butin-l-one Intermediate 39 (as described above for intermediate 36) was prepared from 1-propinyl it io, 500 mg of 2 ', 4'-difluorobenzaldehyde, and 1.5 g of Mn02 to yield 400 mg of the homogeneous title compound by TLC (Rf = 0.63, hexanes / EtOAc 2/1): XH NMR (400 MHz, CDC13) d 8.13-8.06 (m, 1H), 6.99-6.94 (m, 1H), 6.91-6.85 (m, 1H), 2.14 (s, 3H).
Intermediate 40: 1- (2,3-difluorophenyl) -2-butin-l-one Intermediate 40 (as described above for intermediate 36) was prepared from 1 -propini 11 itio, 500 mg of 2,3-difluorobenzaldehyde, and 1.5 g of Mn02 to yield 440 mg of the homogeneous title compound by TLC (Rf = 0.5, hexanes / EtOAc 2/1): XH NMR (400 MHz, CDCl 3) d 7.82-7.86 (m, 1H), 7.43-7.35 (m, 1H), 7.22-7.15 (m, 1H), 2.15 (s, 3H).
Intermediate 41: 1- (4-nitrophenyl) -2-butin-l-one Intermediate 41 (as described above for intermediate 36) was prepared from 1 -propini 11 itio, 1.0 grams of 4'-nit robben za ldehí do, and 1.0 g of Mn02 to yield 430 mg of the title compound homogeneous by TLC analysis: Rf = 0.55, hexanes / EtOAc 2/1): XH NMR (400 MHz, CDC13) d 8.32-8.28 (m, 4H), 2.12 (s, 3H).
Intermediary 42: 1- (3-nitrophenyl) -2-butin-l-one Intermediate 42 (as described above for intermediate 36) was prepared from 1-propynyl iod, 0.5 g of 3'-nit robenzaldehyde, and 1.5 g of Mn02 to yield 280 mg of the title compound by TLC analysis : RF = 0.50, hexanes / EtOAc 2/1): XH NMR (400 MHz, CDCl 3) d 8.95 (t, 1H, J = 1.8), 8.47 (t, 1H, J = 1.7), 8.44 (t, 1H, J = 1.7), 7.7 (t, 1H, J = 8.0), 2.33 (s, 3H).
Intermediary 43: 1- (2-thiazolyl) -2-butin-l-one Intermediate 43 (as described above for intermediate 36) was prepared from 1-propium 11-thio, 2-thiophene carboxaldehyde (108 mg) and 300 mg of MnO2 to yield 65 mg of the title compound: TLC analysis : Rf = 0.50, hexanes / EtOAc 1/1): X H NMR (400 MHz, CDCl 3) d 8.1 (t, 1 H, J = 2.8), 7.71 (d, 1 H, J = 2.9), 2.21 (s, 3 H); low resolution mass spectrum (ES +) 152.1 (MH +).
Intermediate 44: 3-Bromo-4, 4, 4-trifluoro-1-phenylbut-2-en-l-one (mixture of the E and Z isomers, ~85: 15) To a solution of 7.58 g (28.9 mmol) of triphenylphosphine in 60 mL of CH2C12 at 0 ° C was added 1.49 mL (28.9 mmol) of bromine dropwise. The solution was warmed to room temperature and 5.0 g (23.1 mmol) of thiofluoroacet and 1-acetophenone in 25 mL of CH2C12 and 6.45 mL (43.3 mmol) of triethylamine were added. The mixture was stirred for two hours until no further change was observed by TLC analysis (hexanes / EtOAc 3/1). The mixture was washed with 1.0 N HCl, and brine. The organics were dried with MgSO4, concentrated and the residue was purified by silica gel chromatography (hexanes / EtOAc 20/1) to give 1.6 g of impure material and 1.15 g (25% yield) of intermediate 44 as an oil : TLC Rf = 0.74 (hexanes / EtOAc, 3/1): XH NMR (400 MHz, CDC13) d 7.95-7.5 (series of multiplets, 5H); 19 F NMR (282 MHz, CDC13) singlet, d -100.5 ppm).
Intermediate 45: (2S) -2-amino-3- acid. { - [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic Dianion coupling method: To a solution of 5.4 g (19.3 mmol) of N- (Boc) -L-tyrosine in 5 mL of DMSO and 10 mL of H20 was added 1.7 g (42.5 mmol) of freshly milled NaOH granules . The mixture was heated to 55-60 ° C and the solution of 6.5 g (23.1 mmol) of the intermediate of mesylate 15 in 10 mL of DMSO was added dropwise for ~ 5 minutes. The resulting mixture was stirred vigorously for 8 hours at 55-60 ° C., cooled to 20 ° C, and poured into 100 mL of H20 and extracted with Et20 (2 x 50 mL). The aqueous phase was separated and acidified to a pH of ~ 2-3 with glacial acetic acid / HCl. The resulting suspension was extracted with EtOAc several times, dried (MgSO 4 and the organics were concentrated to a tan oil) The oil was triturated with hexanes / EtOAc (3/1) to give a cream colored solid. re-crystallize from hot MeOH / H20 (2.5 / 1) to yield 5.5 g (61% yield) of the Boc-protected intermediate as a white solid after drying in a vacuum oven at 60 ° C for -14 hours To a solution of 43.54 g (93.3 mmol) of the Boc-protected intermediate in 150 mL of dioxane was added 200 mL of 4.0 N HCl in a dioxane solution and the mixture was stirred for 7 hours with the gradual formation of a solid. The solids were filtered (rinsed with Et02), suspended in 1 L of H20 and the pH was adjusted to a pH of ~ 5 with 15% NaOH The resulting white solids were collected by filtration, washed with H20 and CH3CN, and dried overnight at 70 ° C in a vacuum oven to give 32.9 g (96%) of the intermediate 45 as a white solid: XH NMR (DMSO-d6. 300 MHz) d 7.95 (m, 2H), 7.55 (m, 3H), 7.22 (d, 2H, J = 8.5), 6.9 (d, 2H, J = 8.5), 4.21 (t, 2H, J = 6.4) , 3.1 (dd, 1H, J = 14.3, 4.1), 4.17 (m, 1H), 2.96 (t, 2H, J = 6.6), 2.83 (dd, 1H, J = 14.3, 8.4), 2.53 (s, 3H ), a-metine proton assumed under the peak of H20; MS of low resolution (ES +) m / e 367.4 (MH +).
Mitsunobu Alternative Coupling Method To a solution of 4.46 g (21.9 mmol) of the alcohol intermediate 8, 5.88 g (19.9 mmol) of N- (Boc) -Lt-irosine methyl ester and 6.26 (23.9 mmol) of triphenylphosphine in 150 mL of 45 ° toluene C a solution of 3.81 g (21.9 mmol) of DEAD in 50 mL of toluene was added dropwise. The resulting clear solution was stirred at 20 ° C for 8 hours, concentrated and the residue redissolved in Et02 (200 mL). To this was added 75 mL of an IN NaOH solution. The mixture was stirred rapidly for 30 minutes until no phenol was present by TLC. The aqueous phase was extracted with EtOAc and the combined organics were dried (MgSO4) and concentrated. The crude tan solid was purified by chromatography on silica gel (CH2C12 / Et20, 12/1 to 8/1) to give an impure product. A second column eluted with CH2Cl2 / hexane (4/1), CH2C12 and CH2C12 / Et20 (10/1) gave 5.5 g (57% yield) of a light yellow oil. To this oil in 150 mL of THF, 13.7 mL of 1.0 M LiOH in an H20 solution was added dropwise. To this was added an additional 75 mL of THF and 5 mL of MeOH to give a clear solution.
The solution was stirred at 20 ° C and the progress of the reaction was monitored by TLC (CH2Cl2 / MeOH, 9/1). THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc / 1.0 N HCl. The organics were washed with H20, dried with MgSO4, concentrated and the resulting crude oil was purified by silica gel chromatography (ETOAc / hexanes, gradient from 1/1 to 8/1) to give 3.22 g (61%) of a foam. To this foam in 15 mL of dioxane was added dropwise 15 mL of 4.0 N HCl in a dioxane solution at 20 ° C. The mixture was stirred for 4 hours yielding a precipitated white solid. The solids were filtered with Et20, then dissolved in H20 and the pH was adjusted to a pH of -5 with the dropwise addition of a 1.0 N NaOH solution. The resulting white precipitate was collected by filtration and dried in a vacuum oven at 60 ° C to produce 1.72 g of Intermediary 45 as a white solid.
Intermediate 46: (2S) -2-amino-3- (4. {2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} acid. phenyl) propanic.
DEAD (1.26 mL, 8.16 mmol) was added dropwise to a solution of 2.14 g (8.16 mmol) of triphenylphosphine in 16 mL of THF at 0 ° C. This solution was then added to a mixture of 2.41 g (8.16 mmoles) of N- (Boc) -L-tyrosine methyl ester (see, for example, A. Kolodzie jc zyl et al., J. Org. Chem., 4_6 (9), pages 1944-1946 (1981)) and intermediate 9 in 16 mL of THF at 0 ° C. The solution was stirred at 20 ° C for 20 hours and concentrated to an oil. The crude material was purified by silica gel chromatography (hexanes: EtOAc 4: 1) to yield 2.78 grams, 69% yield) of the Protected Amino Acid Intermediate. The deprotection was achieved as follows: Hydrolysis of the ester - To a solution of 2.77 g (5.58 mmol) of the previous ester in 45 mL of THF and 15 mL of H20 at 0 ° C was added 8.5 mL (8.5 mmoles) of an aqueous solution of 1.0 M LiOH.
After 2 hours at 20 ° C, EtOAc was added and the mixture was acidified with 0.1 N HCl. The aqueous phase was extracted with EtOAc and the organics were dried (MgSO 4) and concentrated to give a white crystal-like solid (2.67). g). Boc deprotection - The solid from the hydrolysis of the previous ester (2.64 g, 5.47 mmol) was taken in 60 mL of CH2C12 and treated with 30 mL of TFA with stirring for 1 hour. The solution was concentrated, the residue was dissolved in ~ 400 mL of H20, and the pH was adjusted to a pH of ~7 with a 1.0 N NaOH solution. The suspension was filtered and the collected solids were dried for 48 hours at 70 ° C under vacuum to produce 1.61 g (77% yield for deprotection, 53% overall yield) of intermediate 46 as a beige fluffy solid: XH NMR (DMSO-d6, 300 MHz) d 7.93 (dd, 2H, J = 8.7, 5.4), 7.3 (t, 2H, J = 8.7), 7.12 (d, 2H, J = 8.0), 6.83 (d, 2H, J = 8.2), 4.15 (t, 2H, J = 5.4), 7.3 (t, 2H, J = 8.7), 7.12 (d, 2H, J = 8.0), 6.83 (d, 2H, J = 8.2), 4.15 (t, 2H, J = 6.5), 3.02 (dd) , 1H, J = 14.2, 4.3), 2.89 (t, 2H, J = 6.5), 2.76 (dd, 1H, J = 14.4, 8.2), 2.34 (s, 3H); Low resolution MS (ES +) m / e 384.9 (MH +).
Intermediates 47-51 were prepared analogous to the method described above for the preparation of intermediate 46.
Intermediate 47: (2S) -2-amino-3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} propanic Intermediate 47 was prepared from 2.41 g of N- (Boc) -Lt i ros ina methyl ester and 1.79 g of intermediate 10 to yield 1.61 g (51% overall yield) of the title compound as a solid: XH NMR (DMSO-d6, 400 MHz) d 7.82 (d, 2H, J = 7.5), 7.42 (m, 3H), 7.12 (d, 2H, J = 8.2), 6.82 (d, 2H, J = 8.4), 4.23 (t, 2H, J = 6.6), 3.1 (t, 2H, J = 6.6), 2.83 (dd, 1H, J = 14.1, 3.7), 2.53 (s, 3H), second methylene proton assumed under the peak of H20; MS of low resolution (ES +) m / e 383.1 (MH +).
Intermediate 48: (2S) -2-amino-3- (4-. {2- 2- [2- (4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] ethoxy) phenyl) propane .
Intermediate 48 was prepared from 224 mg of N- (Boc) -L-t-methyl ester methyl ester and 180 mg of Intermediate 11 to produce 149 mg (overall yield 51%) of the title compound as a solid: * H NMR (DMS0-d6, 400 MHz) d 7.82 (dd, 2H, J = 8.6, 5.5), 7.23 (t, 2H, J = 8.7) , 7.08 (d, 2H, J = 8.4), 6.8 (d, 2H, J = 8.5), 4.56 (br, s, 1H), 4.19 (t, 2H, J = 6.5), 3.56 (m, 1H), 3.03 (t, 2H, J = 6.6), 2.95 (m, 1H), 2.79 (d, 1H, J = 14.5, 7.5), 2.37 (s, 3H), low resolution MS (ES +) m / e 400.9 ( MH +).
Intermediate 49: (2S) -2-amino-3- (4. {2 - [2- (4-methoxyphenyl) -5-methyl-1, 3-oxazol-4-yl] ethoxy) phenyl) propane .
Intermediate 49 was prepared from 735 mg of N- (Boc) -Lt-irosine methyl ester and 580 mg of Intermediate 12 to yield 220 mg (22% overall yield) of the title compound as a solid: XH NMR ( DMS0-d6, 400 MHz) d 8.16 (d, 2H, J = 8.2), 7.92 (d, 2H, J = 8.4), 7.21 (d, 2H, J = 8.5), 6.93 (d, 2H, J = 8.5 ), 4.25 (t, 2H, J = 6.5), 3.1 (dd, 1H, J = 14.4, 4.8), 3.0 (t, 2H, J = 6.5), 2.76 (dd, 1H, J = 14.4, 7.9), 2.46 (s, 3H), low resolution MS (ES +) m / e 434.9 (MH +).
Intermediate 50: (2S) -2-amino-3- [4- (2. {5-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-oxazol-4-yl} acid. ethoxy) phenyl] propanoic.
Intermediate 50 was prepared from 185 mg of N- (Boc) -L-t-irosine methyl ester and 170 mg of intermediate 13 to produce 130 mg (overall yield 48%) of the title compound as a solid: 1 H NMR (DMSO-d 6 400 MHz) d 8.16 (d, 2 H, J = 8.2), 7.92 (d, 2 H, J = 8.4), 7.21 (d , 2H, J = 8.5), 6.93 (d, 2H, J = 8.5), 4.25 (t, 2H, J = 6.5), 3.1 (dd, 1H, J = 14.4, 4.8), 3.0 (y, 2H, J = 6.5), 2.76 (dd, 1H, J = 14.4, 7.9), 2.46 (s, 3H), low resolution MS (ES +) m / e 434.9 (MH +).
Intermediate 51: (2S) -2-amino-3- (4. {2 - [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] e oxy} acid. phenyl) propanic.
Intermediary 51 was prepared from 598 mg of N- (Boc) -L-t-irosine methyl ester and 530 mg of Intermediary 14 to produce 540 mg (63% overall yield) of the title compound as a solid: X H NMR (DMSO-d 6, 400 MHz) d 7.77 (d, 2 H, J = 8.7), 7.12 (d, 2 H, J = 8.6), 6.9 ( d, 2H, J = 8.9), 6.82 (d, 2H, J = 8.5), 4.65 (hept, 1H, J = 6.0), 4.13 (t, 2H, J = 6.6), 3.0 (dd, 1H, J = 14.4, 4.5), 2.85 (t, 2H, J = 6.4), 2.76 (dd, 1H, J = 14.4, 8.0), 2.31 (s, 3H), 1.25 (d, 6H, J = 6.0); Low resolution MS (ES +) m / e 425.2 (MH +).
Intermediate 52: (2S) -2-amino-3- acid. { 4- [2- (5-ethyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanoic To a mixture of 640 mg (2.95 mmol, 1.1 equivalents) of the Alcohol Intermediate 8B, 790 mg (2.67 mmol, 1.0 equivalents) of N- (Boc) -Lt-irosine methyl ester and 773 mg (2.95 mmol, 1.0 equivalent) of triphenylphosphine in 15 mL of anhydrous toluene at 50 ° C, 702 mg (3.47 mmoles, 1.3 equivalents) of DIAD was added as a solution in 10 mL of toluene. It was stirred 2.5 hours at 50 ° C. It was cooled, concentrated, purified by loading directly onto a column of silica gel. Elution with EtOAc / hexanes (1/20 to 1/1) gave 1.15 grams (87% yield) of the methyl ester-protected BOC intermediate of sufficient purity to carry forward in the following deprotection reactions [1 H NMR (DMSO-d6, 300 MHz) d 8.07-8.03 (M, 2H), 7.47 (m, 3H), 7.03 (d, 2H, J = 8.5), 6.85 (d, 2H, J = 8.5), 4.58-4.51 (m, 1H), 4.26 (t, 2H, J = 6.5), 3.72 (s, 3H), 3.06-3.0 (m, 4H),, 2.78 (q, 2H, J = 7.5), 1.43 (s, 9H), 1.34 (t, 3H, J = 7.6)]; Checkouts: At a THF / H20 (15 mL / 5 mL) of 900 of the above protected amino acid at 0 ° C was added 2.64 mL of a 1.0 M LiOH solution in water. It was stirred 2.5 hours. The mixture was diluted in 30 mL of EtOAc and the pH was adjusted to ~6 by the addition of 0.1 M HCl. The aqueous phase was extracted with EtOAc. The organics were dried (MgSO4) and concentrated, then taken in DCM (15 mL) at 0 ° C and treated with 7.5 mL of TFA. The solution was concentrated after 1 hour, then concentrated several times from DCM to yield 1.4 g of crude intermediate 52 (TFA salt). This solid was stirred with 50 mL of Et20 for 30 minutes. The solids were collected by filtration and dried under vacuum for 12 hours to yield 740 mg (67%) of the title compound as an almost white solid: XH NMR (DMSO-d6, 300 MHz) d 8.18 (br s, 2H ), 7.93-7.90 (m, 2H), 7.51-7.48 (m, 3H, 7.15 (d, 2H, J = 8.5), 6.89 (d, 2H, J = 8.4), 4.18 (t, 2H, J = 7.5) ), 4.11 (m, 1H), 3.01-2.99 (m, 2H), 2.95-2.90 (m, 2H), 2.75 (q, 2H, J = 7.5), 1.23 (t, 3H, J = 7.5); low resolution (ES +) m / e 381.07 (MH +).
Intermediate 53: (2S) -2-amino-3- acid. { 4- [2- (2-phenyl-5-propyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanic The amino acid intermediate 53 was prepared as described for the preparation of intermediate 46. From 460 mg of N- (Boc) -L-tyrosine methyl ester and 360 mg of intermediate 8C, 410 mg was prepared (overall yield 67%) ) of the title compound as a solid: XH NMR (DMSO-de, 300 MHz) d 7.90-7.87 (m, 2H), 7.48-7.46 (m, 3H), 7.13 (d, 2H, J = 8.4), 6.85 (d, 2H, J = 8.4), 4.17 (t, 2H, J = 6.3), 4.0 (t, 1H, J = 6.3), 2.99 (t, 1H, J = 6.3), 2.92 (t, 1H, J = 6.3), 2.69 (t, 2H, J = 7.2), 1.66 (q, 2H, J = 7.5), 0.93 (t, 3H, J = 7.2) low resolution MS (ES +) m / e 395.09 (MH +); TLC Rf = 0.24 (10/1, DCM / MeOH).
Intermediate 54: (2S) -2-amino-3- acid. { 4- [(5-methyl-2-phenyl-l, 3-oxazol-4-yl) methoxy] phenyl} propanoic The amino acid intermediate 54 was prepared as described for the preparation of intermediate 46. From 187 mg of methyl ester of N- (Boc) -L-tyrosine and 120 mg of intermediate 8D (with DIAD replacing DEAD) was prepared. mg (53% overall yield) of the title compound as a solid: XH NMR (DMSO-d6, 300 MHz) d 7.89-7.85 (m, 2H), 7.43-7.36 (m, 3H), 7.12 (d, 2H , J = 8.5), 6.9 (d, 2H, J = 8.5), 4.9 (s, 2H), 3.63 (m, 1H), 3.0 (dd, 1H, J = 14.4, 4.5), 2.85 (dd, 1H, J = 14.4, 8.1), 2.37 (s, 3H); MS of low resolution (ES +) m / e 353.07 (MH +).
Intermediate 55: (2S) -2-amino-3- acid. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} propanic The amino acid intermediate 55 was prepared as described for the preparation of the intermediate 46. From 503 mg of N- (Boc) -L-tyrosine methyl ester and 370 mg of intermediate 8E to yield 443 mg (68% overall yield) of the title compound as a solid:? Ti NMR (DMSO-ds) , 300 MHz) d 7.90-7.86 (m, 2H), 7.52-7.44 (m, 3H), 7.14 (d, 2H, J = 8.5), 6.86 (d, 2H, J = 8.4), 3.94 (t, 2H , J = 6.2), 3.75 (m, 1H), 3.03 (dd, 1H, J = 14.3, 5.1), 2.90 (dd, 1H, J = 14.3, 7.2), 2.59 (t, 2H, J = 7.3), 2.27 (s, 3H), 2.0 (m, 2H); TLC Rf = 0.22 (10/1, DCM / MeOH); Low resolution MS (ES +) m / e 381.12 (MH +).
Intermediate 56: (2S) -2-amino-3- (4. {2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl ) propanic.
Intermediate 56 was prepared as described above for the preparation of intermediate 52. From 534 mg of N- (Boc) -Lt irosine methyl ester and 500 mg of intermediate 11B, 900 mg of the methyl ester of the BOC intermediate was prepared. protected (94% yield, XH NMR (DMSO-d6, 300 MHz) d 7.9 (dd, 2H, 8.7, 5.2), 7.13 (t, 2H, J = 8.6), 7.04 (d, 2H, J = 8.5) , 6.85 (d, 2H, J = 8.6), 4.97 (d, 1H, J = 7.9), 4.55 (m, 1H), 4.32 (t, 2H, J = 6.8), 3.73 (s, 3H), 3.21 ( t, 2H, J = 6.7), 3.10-3.02 (m, 2H), 2.89 (q, 2H, J = 7.5), 1.44 (s, 9H), 1.36 (t, 3H, J = 7.5); from 850 mg of the protected intermediate, 900 mg of intermediate 56 was prepared as a solid. 1 H NMR (DMSO-d 6, 300 MHz) d 8.0 (br s, 2 H), 7.91-7.87 (m, 2 H), 7.30 (d, 2 H, J = 8.8, 2.1), 7.14 (d, 2 H, J = 8.6 ), 6.90 (d, 2H, J = 8.6), 4.27 (m, 2H, J = 6.5), 4.12 (M, 1H), 3.11 (t, 2H, J = 6.5), 3.0 (m, 2H), 2.86 (q, 2H, J = 7.5), 1.26 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 414.85 (MH +).
Intermediate 57: (2S) -2-amino-3- acid. { 4- [2 - (5-ethyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} propanoic Intermediate 57 was prepared as described above for the preparation of intermediate 52. From 575 mg of N- (Boc) -Lt-irosine methyl ester and 500 mg of intermediate 9B, 940 mg of the methyl ester of the protected BOC intermediate was prepared. (94% yield, XH NMR (DMSO-d6, 300 MHz) d 7.93 (m, 2H), 7.47-7.41 (m, 3H), 7.04 (d, 2H, J = 8.4), 6.86 (d, 2H, J = 8.6), 4.96 (d, 1H, J = 8.2), 4.56 (m, 1H), 4.34 (t, 2H, J = 6.8), 3.73 (s, 3H), 3.23 (t, 2H, J = 6.9 ), 3.04 (m, 2H), 2.90 (q, 2H, J = 7.5), 1.44 (s, 9H), 1.37 (t, 3H, J = 7.5), 900 mg of the protected intermediate was prepared 900 mg of intermediate 57 as a solid.
(DMSO-d6, 300 MHz) d 8.16 (br s, 2 H), 7.85 (m, 2 H), 7.5-7.43 (m, 3 H), 7.14 (d, 2 H, J = 8.6), 6.90 (d, 2H, J = 8.6), 4.27 (m, 2H, J = 6.5), 4.12 (m, 1H), 3.12 (t, 2H, J = 6.5), 3.0 (m, 2H), 2.86 (q, 2H, J = 7.5), 1.26 (t, 3H, J = 7.5).
Intermediate 58: (2S) -2-amino-3- (4. {2- [5-ethyl-2- (4-fluorophenyl) -1, 3-oxazol-4-yl] ethoxy} phenyl ) propanic.
Intermediate 58 was prepared as described above for the preparation of intermediate 52. From 230 mg of N- (Boc) -Lt i ros methyl ester and 200 mg of intermediate 70B, 350 mg of intermediate methyl ester was prepared Protected BOC (88% yield, 1 H NMR (DMSO-d6, 300 MHz) d 8.07-8.01 (m, 2H), 7.15 (t, 2H, J = 8.7), 7.04 (d, 2H, J = 8.5) , 6.84 (d, 2H, J = 8.5), 4.50 (m, 1H), 4.24 (t, 2H, J = 6.5), 3.72 (s, 3H), 3.04-2.99 (m, 2H), 2.77 (q, 2H, J = 7.5), 1.44 (s, 9H), 1.33 (t, 3H, J = 7.5): from 340 mg of the protected intermediate, 350 mg of intermediate 58 was prepared as an almost white-colored crude. (DMSO-de, 400 MHz) d 8.13 (br s, 2H), 7.91 (dd, 2H, J = 8.8, 5.3), 7.3 (t, 2H, J = 8.9), 7.10 (d, 2H, J = 8.6 ), 6.85 (d, 2H, J / = 8.4), 4.13 (t, 2H, J = 6.4), 4.08 (m, 1H), 2.98-2.95 (m, 2H), 2.88 (t, 2H, J = 6.5 ), 2.70 (q, 2H, J = 7.4), 1.19 (t, 3H, J = 7.5), low resolution MS (ES +) m / e 399.13 (MH +).
Intermediate 59: (2S) -2-amino-3- (4. {3- [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] propoxy] phenyl ) propanic.
Intermediate 59 was prepared as described above for the preparation of intermediate 52. From 370 mg of the N- (Boc) -Lt-irosine methyl ester and 310 mg of intermediate 10C, 575 mg of the methyl ester of the protected BOC intermediate was prepared. (87% yield; XH NMR (CDC13, 400 MHz) d 7.95 (dd, 2H, J = 8.6, 5.4), 7.09 (t, 2H, J = 8.7), 6.99 (d, 2H, J = 8.4), 6.79 (d, 2H, J = 8.5), 4.50 (m, 1H), 3.92 (t, 2H, J = 7.1), 3.68 (s, 3H), 3.05-2.93 (m, 2H), 2.69-2.59 (m , 2H), 2.16-2.08 (m, 2H), 1.39 (s, 9H), 1.17 (t, 3H, J = 7.6): from 562 mg of the protected intermediate, the TFA salt of intermediate 59 was prepared as a solid crude (87%); XH NMR (DMSO-de, 400 MHz) d 7.97-7.9 (m, 2H), 7.33 (t, 2 H, J = 8.8), 7.14 (d, 2H, J = 8.3), 6.88 (d, 2H, J = 8.1), 3.97 (m, 3H), 3.25-3.01 (m, 2H), 2.68-2.60 (m, 4H), 2.04-1.99 (m, 2H), 1.16 (t, 3H) , J = 7.4), low resolution MS (ES +) m / e 413.18 (MH +).
Intermediate 60: (2S) -2-amino-3- acid. { 4- [3- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} propanic Intermediate 60 was prepared as described above for the preparation of intermediate 52. From 266 mg of N- (Boc) -Lt iros ine methyl ester and 208 mg of intermediate 8F, 360 mg of the methyl ester of the BOC intermediate was prepared. protected (79% yield; XH NMR (CDC13.300 MHz) d 8.06-8.03 (m; 2H), 7.46-7.44 (m, 3H), 7.04 (d, 2H, J = 8.4), 6.85 (d, 2H , J = 8.4), 4.97 (d, 1H, J = 7.6), 4.57 (m, 1H), 3.99 (t, 2H, J = 6.0), 3.74 (s, 3H), 3.05 (m, 2H), 2.77 -2.65 (m, 4H), 2.19 (t, 2H, J = 6.6), 1.45 (s, 9H), 1.24 (t, 3H, J = 7.5): from 352 mg of the protected intermediate the salt of Raw TFA of intermediate 60. The TFA salt was suspended in water and the pH was adjusted to -7.0 with 10% NaOH The resulting solids were filtered and dried to yield intermediate 60; H NMR (DMSO-de, 400 MHz) d 7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J = 8.5), 6.82 (d, 2H, J = 8.5), 3.92 (t, 2H, J = 6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J = 1 4.3, 4.8), 2.8 (dd, 1H, J = 14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13 (t, 3H, J = 7.4); Low resolution MS (ES +) m / e 392.9 (MH +); TLC Rf = 0.44 (DCM / MeOH, 4/1).
Intermediate 61: (2S) -2-amino-3- acid. { 4- [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} propanic Intermediate 61 was prepared as described above for the preparation of intermediate 62. From 465 mg of the N- (Boc) -Lt-irosine methyl ester and 320 mg of intermediate 8G, 520 mg of the methyl ester of the protected BOC intermediate was prepared. (69% yield; XH NMR (CDC13.300 MHz) d 8.09-8.06 (m, 2H), 7. 47-7.46 (m, 3H), 7.08 (d, 2H, J = 8.7), 6.97 (d, 2H, J = 8.7), 5.02 (s, 2H), 5.01 (s, 1H), 4.59- 4.55 (m, 1H), 3.74 (s, 3H), 3.08-3.02 (m, 2H), 2.83 (q, 2H, J = 7.5), 1.45 (s, 9H), 1.32 (t, 3H, J = 7.5); from 510 mg of the protected intermediate the crude TFA salt of intermediate 61 was prepared. The TFA salt was suspended in water and the pH adjusted to ~ 7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 315 mg of intermediate 61; 1H NMR (DMSO-de 300 MHz) d 7.96-7.94 (m, 2H), 7.52-7.51 (m, 3H), 7.18 (d, 2H, J = 8.4), 6.95 (d, 2H, J = 8. 4), 4.97 (s, 3H), 3.10-3.05 (m, 1H), 2.86-2.79 (m, 4H), 1.22 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 366.86 (MH +); TLC Rf = 0.52 (DCM / MeOH, 4/1).
Intermediate 62: (2S) -2-amino-3- acid. { 4- [(5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} propanic Intermediate 62 was prepared as described above for the preparation of intermediate 52. From 3.27 g of N- (Boc) -Lt-irosine methyl ester and 2.43 g of intermediate 9C was prepared 5.07 g of the methyl ester of the protected BOC intermediate (yield 92%; XH NMR (CDC13, 300 MHz) d 7.89-7.86 (m, 2H), 7.42-7.38 (m, 3H), 7.01 (d, 2H, J = 6.3), 6.94 (d, 2H, J = 6.3), 5.11 (s, .2H), 4.94 (d, 1H, J = 6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m, 2H), 2.90 (q, 2H, J = 5.7), 1.39 (s, 9H), 1.30 (t, 3H, J = 5.7): from 5.05 g of the protected intermediate the crude TFA salt of intermediate 62 was prepared as in the example 52. The TFA salt was suspended in water and the pH was adjusted to -7.0 with 10% NaOH The resulting solids were filtered and dried to yield 4.28 g of intermediate 62; A NMR (DMSO-d6, 400 MHz) d 7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H), 6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H) , 3.05-3.02 (m, 1H), 2.91-2 .81 (m, 4H), 1.21 (T, 3H, J = 7.4); MS of low resolution (ES +) m / e 382.94 (MH +); TLC Rf = 0.33 (DCM / MeOH, 4/1).
Intermediate 63: (2S) -2-amino-3- (4. {[[5-e-l, 2- (4-fluorophenyl) -l, 3-oxazol-4-yl] methoxy] phenyl) propanic Intermediate 63 was prepared as described above for the preparation of intermediate 52. From 962 mg of methyl ester of N- (Boc) -Lt iros ina and 720 mg of intermediate 10D was prepared 1.32 g of the methyl ester of the intermediate BOC protected (81% yield; XH NMR (CDC13, 300 MHz) d 8.07-8.03 (m, 2H), 7.19-7.13 (m, 2H), 7.08 (d, 2H, J = 8.4), 6.97 (d, 2H , J = 8.4), 4.99-4.97 (m, 3H), 4.58-4.57 (, 1H), 3.74 (s, 3H), 3.09-3.03 (s, 2H), 2.82 (q, 2H, J = 7.5), 1.59 (s, 9H), 1.30 (t, 3H, J = 7.5): from 1.31 g of the protected intermediate the crude TFA salt of intermediate 63 was prepared. The TFA salt was suspended in water and the pH was adjusted a ~ 7.0 with 10% NaOH The resulting solids were filtered and dried to yield 1.01 g of the title compound: 1 H NMR (DMSO-de, 300 MHz) d 8.01-7.97 (m, 2H), 7.36 (t, 2H, J = 9.0), 7.18 (d, 2H, J = 8.4), 6.96 (d, 2H, J = 8.4) , 4.97 (s, 2H), 3.53-3.51 (M, 2H), 3.09-3.04 (m, 2H), 2.84 (q, 2H, J = 7.5), 1.22 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 384.87 (MH +); TLC Rf = 0.44 (DCM / MeOH, 4/1).
Example 1; (2S) -2- acid. { [(Z) -1-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic A suspension of 3.0 g (8.2 mmoles) of intermediate 45 and 1.86 (11.5 mmoles) of benzoylacetone in 26 mL of MeOH and 6 mL of trimethyl orthoformate, went to reflux temperature for 16 hours with the solution that occurs a few times After 4 hours. The solution was cooled, concentrated and the resulting crude products were purified by chromatography on silica gel eluting with 1% to 100% MeOH in CH2C12. Fractions of the homogeneous column by TLC were combined and concentrated to give 1.8 g (43% yield) of Example 1 as a tan solid: TLC (EtOAc / MeOH (7: 3): Rf = 0.19; XH NMR (DMSO-d6.400 MHz) d 11.40 (d, 1H, J = 8.89), 7.88 (d, 2H, J = 7.86), 7.77 (d, 2H, J = 7.35), 7.46 (m, 3H), 7.39 (m, 3H), 7.10 (d, 2H, J = 8.55), 6.80 (d, 2H, J = 8.20), 5.78 (s, 1H), 4.14 (m, 3H), 3.10 (m, 1H), 2.87 (m, 2H), 2.77 (m, 1H), 2.34 (s, 3H), 1.71 (s, 3H); MS of low resolution (ES +) m / e 511.1 (MH +); RP-HPLC (Vydac C-18, 25 cm x 4.6 mm, 30-100% CH 3 CN in H20) with 1% HC02H buffer: 30 minutes; 1 mL / minute: tr = 18.14 minutes (t0 1.43); Daicel AD (2) (25 cm x 4.6 mm, 20% I PA in hexane) with 0.1% TFA buffer: 15 minutes; 0.8 mL / minute: tr = 6.87 minutes (t0 1.43), 99.9% ee.
Example 2: (2S) -3- (4- { 2- [2- (4-fophenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} phenyl) -2- ( . {(Z) -1-methyl-3-oxo-3- [4- (trifomethyl) phenyl] -1-propenyl} amino) propanoic.
A mixture of 75 mg (0.2 mmol) of intermediate 46, 45 mg (0.2 mmol) of intermediate 24, and 57 μL (0.41 mmol) of triethylamine in 0.5 mL of trimethyl orthoformate and 2.5 mL of MeOH was refluxed for 10 hours. The solvents were evaporated under reduced pressure and the residue was purified directly by chromatography on silica gel. Elution with 5% -20% MeOH in CH2C12 gave 30 mg (26% yield) of Example 2 as a solid (foam): TLC (DCM / MeOH, 4/1): Rf = 0.58; X H NMR (DMSO-de, 300 MHz) d 11.59 (d, 1H, J = 9.8), 8.03 (m, 4H), 7.81 (d, 2H, J = 8.8), 7.38 (t, 2H, J = 9.2) , 7.19 (d, 2H, J = 8.8), 6.88 (d, 2H, J = 8.8), 5.76 (s, 1H), 4.21 (t, 2H, J = 6.6), 4.17 (m, 1H), 3.20 ( m, 1H), 2.96 (t, 2H, J = 6.6), 2.82 (m, 1H), 2.39 (s, 3H), 1.76 (s, 3H); MS of low resolution (ES +) m / e 597.0 (MH +).
Example 3 (2S) -3- (4-. {2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- acid ( {(Z) -1-methyl-3-oxo-3- [4- (trifomethyl) phenyl] -1-propenyl} amino) propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.18 mmol) of intermediate 51 and 41 mg (0.18 mmol) of intermediate 24 to yield 48 mg (43% yield) of Example 3: TLC (DCM / MeOH, 4/1): Rf = 0.42; X H NMR (DMSO-d 6, 400 MHz) d 11.5 (d, 1H, J = 8.9), 7.95 (d, 2H, J = 7.2), 7.77 (d, 2H, J = 8.7), 7.72 (t, 2H, J = 8.2), 7.1 (d, 2H, J = 8.4), 6.97 (d, 2H, J = 8.9), 6.79 (d, 2H, J = 8.5), 5.58 (s, 1H), 4.65 (m, 1H ), 4.11 (t, 2H, J = 6.5), 4.1 (m, 1H), 3.16 (dd, 1H, J = 13.7, 3.6), 2.84 (t, 2H, J = 6.5), 2.74 (dd, 1H, 13.7, 9.0), 2.28 (s, 3H), 1.67 (s, 3H), 1.25 (d, 6H, J = 6.0); MS of low resolution (ES +) m / e 637.1 (MH +).
Example 4: (2S) -3- (4- { 2- [2- (4-methoxyphenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} phenyl) -2- ( . {(Z) -1-methyl-3-oxo-3- [4- (trifomethyl) phenyl] -1-propenyl} amino) propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.25 mmol) of intermediate 49 and 58 mg (0.25 mmol) of intermediate 24 to yield 66 mg (43% yield) of Example 4: TLC (DCM / MeOH, 4/1): Rf = 0.48; X H NMR (DMSO-d 6, 400 MHz) d 11.5 (d, 1 H, J = 8.9), 7.95 (d, 2 H, J = 8.2), 7.80 (d, 2 H, J = 8.7), 7.72 (t, 2 H, J = 8.4), 7.1 (d, 2H, J = 8.4), 7.0 (d, 2H, J = 8.9), 6.79 (d, 2H, J = 8.5), 5.58 (s, 1H), 4.11 (t, 2H , J = 6.5), 4.1 (m, 1H), 3.78 (s, 3H), 3.15 (dd, 1H, J = 13.6, 3.6), 2.84 (t, 2H, J = 66), 2.75 (dd, 1H, 13.7, 9.0), 2.28 (s, 3H), 1.67 (s, 3H); MS of low resolution (ES +) m / e 609.0 (MH +).
Example 5: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- [2-. { 5-me i1-2- [4- (trifomethyl) phenyl] -1,3-oxazol-4-yl} and oxy) phenyl] propanic.
The title compound (as described above for the preparation of Example 2) was prepared from 40 mg (0.092 mmol) of intermediate 50 and 17 mg (0.092 mmol) of intermediate 16 to produce 21 mg of Example 5: TLC ( DCM / MeOH, 4/1): Rf = 0.50; X H NMR (DMSO-d 6, 400 MHz) d 11.59 (d, 1 H, J = 9.8), 8.09 (d, 2 H, J = 9.0), 7.85 (d, 2 H, J = 8.8), 7.78 (m, 2 H) , 7.39 (m, 3H), 7.12 (d, 2H, J = 8.0), 6.80 (d, 2H, J = 8.0), 5.54 (s, 1H), 4.15 (t, 2H, J = 6.6), 4.17 (m, 1H), 3.11 (m, 1H), 2.90 (t, 2H, J = 6.6), 2.72 (m, 1H), 2.33 (s, 3H), 1.98 (m, 2H), 0.9 (t, 3H, J 7. 5); Low resolution MS (ES +) m / e 593.1 (MH +).
Acid example (2S) -2-. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1 -propenyl] amino} -3- (4- { 2- [2- (-me-oxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.25 mmol) of intermediate 49 and 62 mg (0.32 mmol) of intermediate 32 to yield 90 mg of Example 6: TLC ( DCM / MeOH, 4/1): Rf = 0.46; XH NMR (DMSO-d6.400 MHz) d 11.45 (d, 1H, J = 9.6), 7.84 (m, 4H), 7.19 (t, 2H, J = 8.8), 7.10 (d, 2H, J = 8.4) , 7.01 (d, 2H, J = 8.4), 7.01 (d, 2H, J = 8.8), 6.78 (d, 2H, J = 8.4), 5.51 (s, 1H), 4.11 (t, 2H, J = 6.8 ), 4.03 (m, 1H), 3.11 (m, 1H), 2.84 (t, 2H, J = 6.8), 2.71 (dd, 1H, J = 14.0, 9.2), 2.31 (s, 3H), 1.98 (m , 2H), 0.90 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 571.2 (MH).
Example 7: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- (2-. {5-methyl-2- [4- (rifluoromethyl) phenyl] -1,3-oxazol-4-yl} ethoxy) phenyl] propane.
The title compound was prepared (as described above for the preparation of the Example 2) from 40 mg (0.092 mmol) of intermediate 50 and 15 mg (0.092 mmol) of be zoilacetone to produce 32 mg of Example 7: TLC (DCM / MeOH, 4/1): R £ = 0.48; X H NMR (DMSO-de, 300 MHz) d 11.49 (d, 1H, J = 9.8), 8.17 (d, 2H, J = 8.9), 7.9 (d, 2H, J = 8.9), 7.85 (m, 2H) , 7.44 (m, 3H), 7.19 (d, 2H, J = 8.8), 6.89 (d, 2H, J = 8.8), 5.60 (s, 1H), 4.23 (t, 2H, J = 6.0), 4.16 ( m, 1H), 3.21 (m, 2H), 2.99 (t, 2H, J = 6.0), 2.82 (dd,, 1H, J = 14.2, 9.8), 2.42 (s, 3H), 1.78 (s, 3H); Low resolution MS (ES +) m / e 579.0 (MH +).
Example 8: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.195 mmol) of intermediate 46 and 34 mg (0.2 mmol) of intermediate 16 to yield 32 mg of Example 8: TLC ( DCM / MeOH, 4/1): Rf = 0.63; X H NMR (DMSO-d 6, 300 MHz) d 11.57 (d, 1 H, J = 9.6), 7.97 (m, 2 H), 7.86 (d, 1 H, J = 7.2), 7.42 (m, 5 H), 7.18 (d , 2H, 8.4), 6.87 (d, 2H, J = 8.4), 5.61 (s, 1H), 4.20 (t, 2H, J = 6.6), 4.14 (m, 1H), 3.22 (m, 2H), 2.94 (t, 2H, J = 6.6), 2.83 (dd, 1H, J = 13.8, 9.3); Low resolution MS (ES +) m / e 543 (MH +).
Example 9: (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1 -propenyl] amino} -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] e oxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 500 mg (1.56 mmol) of intermediate 46 and 315 mg (1.56 mmoles) of intermediate 32 to yield 412 mg of Example 9: TLC ( DCM / MeOH, 4/1): Rf = 0.53; X H NMR (DMSO-d 6, 300 MHz) d 11.53 (d, 1 H, J = 9.3), 7.99 (m; 2 H), 7.95 (m, 2 H), 7.39 (t, 2 H, J = 8.7), 7.26 (t , 2H, J = 8.7), 7.17 (d, 2H, J = 8.1), 6.86 (d, 2H, J = 8.1), 5.60 (s, 1H), 4.20 (t, 2H, J = 6.6), 4.12 ( m, 1H), 3.21 (m, 2H), 2.94 (t, 2H, J = 6.6), 2.78 (dd, 1H, J = 13.8.8.4), 2.38 (s, 3H), 2.05 (m, 2H), 0.96 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 561.4 (MH +).
Example 10: (2S) -2- [. { (Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3-. { 4- [2- (5-methyl-2-phenyl-1, 3-ti-zol-4-yl) -ethoxy] -phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 290 mg (0.76 mmol) of intermediate 47 and 150 mg (0.76 mmol) of intermediate 24 to yield 140 mg (31% yield) of Example 10: TLC (DC / MeOH, 4/1): Rf = 0.47; X H NMR (DMSO-d 6, 300 MHz) d 11.52 (d, 1H, J = 8.9), 7.96 (d, 2H, J = 8.1), 7.80 (m, 2H), 7.72 (d, 2H, J = 8.4) , 7.42 (m, 3H), 7.10 (d, 2H, J = 8.4), 6.80 (d, 2H, J = 8.4), 5.61 (s, 1H), 4.20 (t, 2H, J = 6.6), 4.15 ( m, 1H), 3.17 (m, 1H), 3.05 (t, 2H, J = 6.5), 2.77 (dd, 1H, J = 13.6, 8.6), 2.41 (s, 3H), 1.69 (s, 3H); MS of low resolution (ES +) m / e 595.0 (MH +).
Example 11: (2S) -2- acid. { [(Z) -3- (-fluorof nyl) -1-methyl-3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic A solution of 100 mg (0.27 mmol) of intermediate 45 and 49 mg (0.27 mmol) of intermediate 26 in 2.5 mL of MeOH and 0.5 mL of trimethyl orthoformate was refluxed at 80 ° C for 16 hours. The reaction solution was concentrated and purified by flash silica gel chromatography using 7/3 EtOAc / MeOH as the eluent to provide 83 mg of Example 11: TLC (EtOAc / MeOH, 7/3): Rf = 0.28; ? E NMR (DMSO-d6) d 11.38 (d, 1H, J = 7.00), 7.84 (m, 4H), 7.45 (m, 3H), 7.16 (t, 2H, J = 8.72), 7.09 (d, 2H) , J = 7.69), 6.77 (d, 2H, J = 7.69), 5.49 (s, 1H), 4.11 (m, 2H), 4.01 (m, br, 1H), 3.13 (m, 1H), 2.86 (m , 2H), 2.72 (s, br, 1H), 2.30 (s, 3H), 1.62 (s, 3H); MS of low resolution (ES +) m / e 529 (MH +); RP-HPLC / Vydac C-18, 25 cm x 4.6 mm; 30-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes; 1 mL / minute: tr = 20.10 minutes (t0 = 1.53).
Example 12: (2S) -2- acid. { [(Z) -1-methyl-3-oxo-3- (2,3,4-trifluorophenyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-pheny1-1,3-oxazol-4-yl) ethoxy] enyl} propanic A mixture of 680 mg (1.85 mmol) of the intermediate 45, 367 mg (1.85 mmol) of intermediate 36, and 0.67 mL (3.7 mmol) of DIEA in 15 mL of MeOH was refluxed overnight (14 hours) . The solvent was evaporated under reduced pressure and the residue was purified directly by chromatography on silica gel. Elution with 5% -20% MeOH in CH2C12 gave 612 mg (58% yield) of the title compound as a solid: TLC (DCM / MeOH, 4/1): Rf = 0.50; X H NMR (DMSO-d 6, 300 MHz) d 11.35 (d, 1 H, J = 9.0), 7.87 (m, 2 H), 7.48 (m, 4 H), 7.3 (q, 1 H, J = 5.4), 7.10 (d , 2H, J = 8.7), 6.78 (d, 2H, J = 8.7), 5.25 (s, 1H), 4.18 (m, 3H), 3.19 (m, 2H), 2.86 (t, 2H, J = 6.3) , 2.74 (dd, 1H, J = 13.8, 9.0), 2.32 (s, 3H), 1.64 (s, 3H); MS of low resolution (ES +) m / e 56 .9 (MH +).
Example 13: (2S) -2- acid. { [(Z) -l-methyl-3- (4-nitrophenyl) -3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 12) was prepared from 120 mg (0.33 mmol) of intermediate 45 and 62 mg (0.33 mmol) of intermediate 41 to yield 105 mg (58% yield) of Example 13: TLC (DCM / MeOH, 4: 1): Rf = 0.60; X H NMR (DMSO-d 6, 300 MHz) d 11.66 (d, 1 H, J = 9.0), 8.29 (d, 2 H, J = 8.4), 8.08 (d, 2 H, J = 8.4), 7.97 (m, 2 H) , 7.56 (, 3H), 7.19 (d, 2H, J = 8.0), 6.88 (d.2H, 8.0), 5.72 (s, 1H) 4.18 (m, 3H), 3.23 (m, 1H), 2.96 (t, 2H, J = 6.2), 2.85 (dd, 1H, J = 13.4, 9.6), 2.39 (s, 3H), 1.79 (s, 3H); MS of low resolution (ES +) m / e 556.4 (MH +).
Example 14: (2S) -2- ( { (Z) -l-methyl-3-oxo-3- [- (trifluoromethyl) enyl] -1-propenyl} amino) -3- acid. { - [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic A solution of 676 mg (1.85 mmol) of intermediate 45 and 510 mg (2.22 mmol) of intermediate 24 in 30 mL of MeOH and 6 mL of trimethyl orthoformate with 4 A sieves (300 mg) was refluxed at room temperature. 80 ° C for 16 hours. The reaction solution was concentrated and purified by flash silica gel column chromatography using DCM / MeOH 15/1 followed by DCM / MeOH 10/1 as the eluent to provide 329 mg of Example 14: TLC (DCM / MeOH ( 9: 1): Rf = 0.29; XH NMR (DMSO-d6, 300 MHz) d 11.59 (d, 1H, J = 9.0), 8.03 (d, 1H, J = 8.1), 7.95 (m, 2H), 7.80 (d, 2H, J = 8.1), 7.56 (m, 3H), 7.19 (d, 2H, J = 8.4), 6.87 (d, 2H, J = 8.4), 5.66 (s, 1H), 4.18 (m, 3H), 3.23 (m, 2H), 2.95 (t, 2H, J = 6.6), 2.82 (d, 1H, J = 13.8, 9.0), 2.39 (s, 3H), 1.75 (s, 3H); MS of low resolution (ES +) m / e 579 (MH +); RP-HPLC (Vydac C-18, 25 cm x 4 mm, 30-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes; 1 mL / minutes; tr = 21.47 minutes (t0 = 1.53).
Example 15 (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3 -oxo-1-propenyl] amino} -3- (4- { 2- [2- [4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl } propanic The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.177 mmol) of Intermediate 51 and 39 mg (0.194 mmol) of Intermediary 32 to yield 70 mg of Example 15: TLC ( DCM / MeOH (4: 1): Rf = 0.55; XH NMR (DMSO-de, 300 MHz) d 11.53 (d, 1H, J = 9.6), 7.89 (dd, 2H, J = 8.8, 5.7), 7.85 ( d, 2H, J = 8.8), 7.26 (t, 2H, J = 8.8), 7.18 (d, 2H, J = 8.5), 7.05 (d, 2H, J = 8.8), 6.86 (d, 2H, J = 8.5), 5.60 (s, 1H), 4.73 (hept.1H, J = 6.0), 4.19 (t, 2H, J = 6.7), 4.13 (br, s, 1H), 3.19 (m, 1H), 2.92 ( t, 2H, J = 6.6), 2.80 (dd, 1H, J = 14.0, 9.2), 2.36 (s, 3H), 2.07 (m, 2H), 1.34 (d, 6H, J = 6.0), 0.99 (t , 3H, J = 7.5), low resolution MS (ES +) m / e 601.1 (MH +).
Example 16: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,4,5-trifluorophenyl) -1-propeni1} Not me } -3- . { - [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 12) was prepared from 677 mg (1.85 mmol) of the Intermediate 45 or 366 mg (1.85 mmol) of Intermediary 38 to yield 482 mg (yield of 1.85) of the Example 16: TLC (DCM / MeOH (4: 1): Rf = 0.55; XH NMR (DMSO-d6, 300 MHz) d 11.39 (d, 1H, J = 8.9), 7.86 (m, 2H), 7.69-7.59 (m, 1H), 7.54-7.40 (m, 4H), 7.10 (d, 2H, J = 8.5), 6.79 (d, 2H, J = 8.5), 5.3 (s, 1H), 4.12 (t, 2H, J = 6.5), 4.1 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J = 6.5), 2.76 (dd, 1H, J = 13.7, 8.9), 2.3 (s, 3H), 1.64 (s, 3H); low resolution MS (ES +) m / e 565.1 (MH +).
Example 17: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4-. {2- 2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.177 mmol) of Intermediate 51 and 34 mg (0.194 mmol) of Intermediate 16 to yield 30 mg of Example 17: TLC ( DCM / MeOH (4: 1): Rf = 0.63; XH NMR (DMSO-d6, 400 MHz) d 11.49 (d, 1H, J = 9.6), 7.77 (m, 4H), 7.37 (m, 3H), 7.10 (d, 2H, J = 8.8), 6.97 (d, 2H, J = 9.2), 6.79 (d, 2H, J = 9.2), 5.54 (s, 1H), 4.66 (septuplet, 1H, J = 6.0), 4.12 (t, 2H, J = 6.8), 4.04 (m, 1H), 3.35 (m, 1H), 3.11 (m, 1H), 2.84 (t, 2H, J = 6.8), 2.72 (dd, 1H, J = 13.9, 9.2), 2.28 (2, 3H), 1.26 (d, 6H, J = 6.0), 0.91 (t, 3H, J = 7.6), low resolution MS (ES +) m / e 583.1 (MH +).
Example 18: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (rifluoromethyl) phenyl] -1-propenyl} amino) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 197 mg (0.41 mmol) of the Intermediate 45"(as the TFA salt) and 100 mg (0.41 mmol) of the intermediate 25 to produce 110 mg (45% yield) of Example 18: TLC (DCM / MeOH (4: 1): Rf = 0.60; XH NMR (DMSO-d6, 400 MHz) d 11.45 (d, 1H, J = 9.2), 7.85 (m, 4H), 7.47 (m, 3H), 7.17 (t, 2H, J = 8.8), 7.09 (d, 2H, J = 8.4), 6.78 (d, 2H, J = 8.4), 5.51 (s, 1H), 4.12 (t, 2H, J = 6.4), 4.02 (m, 1H), 3.10 (m, 2H), 2.86 (t, 2H, J = 6.4), 2.71 (dd, 1H, J = 13.9.9.2 ), 2.31 (s, 3H), 1.98 (s, 3H), 0.90 (t, 3H, J = 7.6), low resolution MS (ES +) m / e 593 (MH +).
Example 19: (2S) -2- acid. { [(Z) -l-methyl-3- (4-methylphenyl) -3 -oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound was prepared as described above for the preparation of the Example 2) from 790 mg (1.64 mmol) of the Intermediary 45 (as the salt of TFA) and 0.29 g (1.64 mmol) of Intermediary 27 (with 660 μL of DCA that replaces Et3N) to produce the crude product contaminated with DCA). A second chromatography column on silica gel eluting with DCM: MeOH 8: 1 gave 70 mg of Example 19 as a beige solid: TLC (DCM / MeOH (4: 1): Rf = 0. 58; X H NMR (DMSO-d 6, 400 MHz) d 11.43 (d, 1 H, J = 9. 0), 7.96 (m, 2H), 7.74 (d, 2H, J = 8.1), 7.54 (m, 3H), 7.24 (d, 2H, J = 8.1), 7.18 (d, 2H, J = 8. 4), 6.87 (d, 2H, J = 8.4), 5.57 (s, 1H), 4.21 (t, 2H, J = 6.6), 4.08 (m, 1H), 3.23 (m, 2H), 2.95 (t, 2H, J = 6.6), 2.80 (dd, 1H, J = 13.8, 9.0), 2. 39 (s, 3H), 2.37 (s, 3H), 1.71 (s, 3H); MS of low resolution (ES +) m / e 525.2 (MH +).
Example 20: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 1.03 g (2.1 mmol) of Intermediate 45 (as the TFA salt) and 740 mg (4.2 mmoles) of - Intermediary 16 to produce 500 mg of Example 20 as a white solid: TLC (EtOAc / MeOH, 7: 3): Rf = 0.35; XH NMR (DMSO-d6, 400 MHz) d 11.55 (d, 1H, J = 9.6), 7.93 (d, 2H, J = 7. 8), 7.84 (d, 2H, J = 7.8), 7.57 (m, 3H), 7.52 (m, 3H), 7.18 (d, 2H, J = 8.4), 6.87 (d, 2H, J = 8. 4), 5.58 (s, 1H), 4.21 (t, 2H, J = 6.6), 4.16 (m, 1H), 3.21 (m, 1H), 2.95 (t, 2H, J = 6.6), 2.80 (dd, 1H, J = 13.5, 9.0), 2.42 (s, 3H), 2.08 (s, 2H), 1.04 (t, 3H, J = 7.8); Low resolution MS (ES +) m / e 525 (MH +).
Example 21: (2S) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl] ethoxy} phenyl) -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic A solution of 120 mg (0.31 mmol) of the intermediate 48, 62 mg (0.31 mmol) of intermediate 44, and 110 μL (2 equivalents) of DIEA in MeOH (3.5 mL) was left at reflux temperature for 10 hours. The solvents were removed under reduced pressure and the crude products were purified by chromatography on silica gel (gradient, CH2Cl2 / MeOH 15/1 to 10/1) to give 78 mg (46% yield) of Example 21 as a solid. TLC (DCM / MeOH) (4: 1): Rf = 0.62; 1 H NMR (DMSO-de, 400 MHz) d 10.9 (br, s, 1H), 7.9-7.83 (m, 4H), 7.6-7.43 (m,, 3H), 7.27 (t, 2H, J = 8.8) , 7.05 (d, 2H, J = 8.4), 6.78 (d, 2H, J = 8.4), 6.13 (s, 1H), 4.2 (t, 2H, J = 6.6), 4.08 (br, s, 1H), 3.1 (m, 1H), 3.08 (t, 2H, J = 6.7), 2.86 (dd, 1H, J 13.6, 7.7), 2.37 (s, 3H); MS of low resolution (ES +) m / e 599.0 (MH +).
Example 22: (2S) -2- (. {((Z) -l-ethyl-3-oxo- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino] -3- (4- {.2 2- [(4-fluorophenyl) -5-methyl-l, 3-yiazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.19 mmol) of intermediate 48 and 46 mg (0.19 mmol) of intermediate 25 to yield 26 mg of Example 22: TLC ( DCM / MeOH, (4: 1): Rf = 0.58; XH NMR (DMSO-de, 400 MHz) d 11.59 (d, 1H, J = 9.3), 7.97 (d, 2H, J = 8.1), 7.85 (m , 2H), 7.72 (d, 2H, J = 8.4), 7.29 (m, 2H), 7.10 (d, 2H, J = 8.4), 6.79 (d, 2H, J = 8.4), 5.60 (s, 1H) , 4.20 (t, 2H, J = 6.6), 4.12 (m, 1H), 3.16 (m, 1H), 3.06 (t, 2H, J = 6.6), 2.75 (dd, 1H, J = 13.8, 9.0), 2.38 (s, 3H), 2.02 (m, 2H), 0.92 (t, 3H, J = 7.5), low resolution MS (ES +) m / e 627.0 (MH +).
Example 23: (2S) -2- acid. { [(Z) -l-butyl-3-oxo-3-phenyl-1-propenyl] amino) -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 1.0 g (2.05 mmol) of intermediate 45 (as the TFA salt) and 0.86 g (0.42 mmol) of intermediate 18 to yield 290 mg (25% yield) of Example 23 as a solid: TLC (EtOAc / MeOH, 7: 3): Rf = 0.55; XH NMR (DMSO-d6, 400 MHz) d 11.59 (d, 1H, J = 9.7), 7.86 (m, 2H), 7.76 (m, 2H), 7.48-7.34 (m, 6H), 7.10 (d, 2H, J = 8.5), 7.10 (t, 2H, J = 8.4), 6.8 (d, 2H, J = 8.6), 5.52 (s, 1H), 4.12 (t, 2H, J = 6.5), 4.02 (m, 1H) , 3.16 (m, 1H), 2.86 (t, 2H, J = 6.5), 2.75 (dd, 1H, J = 13.5, 9.5), 2.31 (s, 3H), 1.9 (m, 2H), 1.3-1.1 ( m, 4H), 0.73 (t, 3H, J = 6.9); MS of low resolution (ES +) m / e 553.2 (MH +).
Example 24: (2S) -2- acid. { [(Z) -3- (4-chlorophenyl) -1-methyl-3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 54 mg (0.27 mmol) of intermediate 28 to yield 76 mg of Example 24: TLC ( DCM / MeOH (4: 1): Rf = 0.52; XH NMR (DMSO-de, 300 MHz) d 11.52 (d, 1H, J = 9.6), 7.97 (m, 2H), 7.87 (d, 2H, J = 8.6), 7.55 (m, 5H), 7.18 (d, 2H, J = 8.5), 6.86 (d, 2H, J = 8.5), 5.59 (s, 1H), 4.21 (t, 2H, J = 6.1), 4.09 (m, 1H), 3.22 (m, 1H), 2.96 (t, 2H, J = 6.1), 2.78 (dd, 1H, J = 13.9, 9.4), 2.39 (s, 3H), 1.73 (s, 3H) ).
Example 25: (2S) -2- acid. { [(Z) -l-methyl-3- (3-nitrophenyl) -3-oxo-1 -propenyl] amino} -3- . { - [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 12) was prepared from 120 mg (0.25 mmol) of intermediate 45 and 48 mg (0.25 mmol) of intermediate 42 to yield 67 mg of Example 25: TLC ( DCM / MeOH, (4: 1): Rf = 0.52; XH NMR (DMSO-de, 400 MHz) d 11.52 (d, 1H, J = 9.1), 8.52 (s, 1H), 8.24 (d, 1H, J = 8.2), 8.21 (d, 2H, J = 7.7), 7.87 (d, 2H, J = 7.7), 7.66 (t, 1H, J = 7.9), 7.45 (m, 3H), 7.10 (d, 2H J = 8.2), 6.79 (d, 2H, J = 8.3), 5.74 (s, 1H), 4.13 (t, 2H, J = 6.6), 4.07 (br, s, 1H), 3.15 (m, 1H), 2.87 (t, 2H, J = 6.4), 2.75 (m, 1H), 2.31 (s, 3H), 1.68 (s, 3H), low resolution MS (ES +) m / e 556.3 (MH +).
Example 26: (2S) -2- ( { (Z) -3- [2-fluoro-3-trifluoromethyl) phenyl] -1-methyl-3-oxo-1-propenyl acid} amino) -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound was prepared (as described above for the preparation of the Example 12) from 190 mg (0.52 mmol) of intermediate 45 and 120 mg (0.52 mmol) of intermediate 37 to yield 102 mg (35% yield) of Example 26: XH NMR (DMSO-d6, 400 MHz) d 11.36 (d, 1H, J = 8.9), 7.9 (m, 3H), 7.77 (t, 1H, J = 6.9), 7.46 ((m, 3H), 7.42 (m, 1H), 7.11 (d, 2H J = 8.5), 6.81 (d, 2H, J = 8.5), 5.22 (s, 1H), 4.14 (t, 2H, J = 6.6), 4.1 (m, 1H), 3.13 (m, 1H), 2.87 (t , 2H, J = 6.6), 2.78 (dd, 1H, J = 13.7, 8.5), 2.31 (s, 3H), 1.68 (s, 3H), low resolution MS (ES +) m / e 597.4 (MH +).
Example 27 (2S) -2- acid. { [(Z) -3- (4-isopropoxyphenyl) -1-methyl-3-oxo-1-propenyl] amino} 3- . { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 435 mg (0.91 mmol) of intermediate 45 (as the TFA salt) and 200 mg (0.91 mmol) of intermediate 29 to produce 125 mg of Example 27 as a beige crystalline solid: TLC (DCM / MeOH (4: 1): Rf = 0.50; XH NMR (DMS0-d6, 400 MHz) d 11.29 (d, 1H, J = 8.8), 7.88 (m , 2H), 7.70 (d, 2H, 8.8), 7.48 (m, 3H), 7.09 (d, 2H, J = 8.0), 6.85 (d, 2H, J = 8.8), 6.78 (d, 2H, J = 8.0), 5.46 (s, 1H), 4.62 (septuplet 1H, J = 6.4), 4.12 (t, 2H, J = 6.4), 4.0 (m, 1H), 3.14 (m, 2H), 2.87 (t, 2H , J = 6.4), 2.70 (dd, 1H, J = 13.2, 9.6), 2.31 (s, 3H), 1.61 (s, 3H), 1.21 (d, 6H, J = 6.4), low resolution MS (ES + ) m / e 569 (MH +).
Example 28: (2S) -2- acid. { [(Z) -3- (2-chlorophenyl) -1-methyl-3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 54 mg (0.27 mmol) of intermediate 29 to yield 44 mg of Example 27: TLC ( DCM / MeOH, (4: 1): Rf = 0.47; XH NMR (DMSO-de 400 MHz) d 11.12 (d, 1H, J = 9.0), 7.91 (m, 2H), 7.44 (m, 3H), 7.39 (m, 1H), 7.33 (m, 3H), 7.17 (d, 2H, J = 7.2), 6.80 (d, 2H, J = 7.2), 4.97 (s, 1H), 4.14 (m, 3H), 3.16 (m, 1H), 2.88 (m, 2H), 2.77 (m, 1H), 2.32 (s, 3H), 1.61 (s, 3H), low resolution MS (ES +) m / e 545.0 (MH).
Example 29: (2S) -2 - acid. { [(Z) -3- (2-furyl) -1-methyl-3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 630 mg (1.31 mmol) of intermediate 45 (as the TFA salt) and 200 mg (1.31 mmol) of 1- (2 - fur il) -1,3-butadione (purchased from Acros Organics) to yield 230 mg (35% yield) of Example 29 as a light brown solid: TLC (DCM / MeOH, (4: 1): R £ = 0.62; XH NMR (DMSO-de 300 MHz) d 11.07 (d, 1H, J = 8.7), 7.88 (m, 2H), 7.69 (d, 1H, J = 1.0), 7.48 (m, 3H), 7.09 (d, 2H, J = 8.5), 6.86 (m, 3H), 6.52 (d, 1H, J = 1.5), 5.33 (s, 1H), 4.13 (t, 2H, J = 6.6), 4.03 (m, 1H), 3.14 (m, 1H), 2.87 (t, 2H, J = 6.6), 2.70 (dd, 1H, J = 13.6, 9.0), 2.34 (s, 3H), 1.62 (s, 3H); low resolution (ES +) m / e 501.2 (MH +).
Example 30: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2-pyrazinyl) -1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 292 mg (0.61 mmol) of intermediate 45 (as the TFA salt) and 100 mg (0.61 mmol) of intermediate 35 to produce 135 mg (43%) of Example 30: TLC (DCM / MeOH (4: 1): Rf = 0.22; 1 H NMR (DMSO-d6.400 MHz) d 11.58 (d, 2H, J = 8.8), 9.08 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 7.87 (d, 2H, J = 7.6), 7.45 (m, 3H), 7.11 (d, 2H, J = 8.0), 6.81 (d, 2H, J = 8.0), 6.04 (s, 1H), 4.13 (m, 3H), 3.17 (m ^ lH), 2.87 (t, 2H, J = 6.4), 2.78 (dd, 1H, J = 13.2, 9.2 ), 2.31 (s, 3H), 1.71 (s, 3H), low resolution MS (ES +) m / e 511.1 (MH +).
Example 31_: (2S) -2- acid. { [(Z) -3- (2,4-difluorophenyl) -1-methyl-3-oxo-l-propenyl] amino} -3- (4- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propane.
The title compound (as described above for the preparation of Example 12) was prepared from 120 mg (0.33 mmol) of intermediate 45 and 59 mg (0.33 mmol) of intermediate 39 to yield 63 mg (35% yield) from Example 31: TLC (DCM / MeOH (4: 1): Rf = 0.72; XH NMR (DMSO-d6, 400 MHz) d 11.37 (d, 1H, J = 9.4), 7.87 (m, 2H), 7.72 ( q, 1H, J = 6.4), 7.43 (m, 3H), 7.14 (m, 4H), 6.79 (d, 2H, J = 8.8), 5.25 (s, 1H), 4.13 (m, 3H), 3.18 ( m, 1H), 2.85 (t, 2H, J = 6.0), 2.77 (dd, 1H, J = 14.0, 9.8), 2.29 (s, 3H), 1.62 (s, 3H), low resolution MS (ES +) m / e 545.1 (MH).
Example 32: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (1, 3-thiazol-2-yl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 12) was prepared from 200 mg (0.43 mmol) of intermediate 45 (as the TFA salt) and 65 mg (0.43 mmol) of intermediate 43 to yield 202 mg of the crude product. This material was rechromatographed on a column of silica gel eluting with DCM / MeOH (gradient 6/1 to 4/1) to yield 22 mg of Example 32. Rf = 0.42; X H NMR (DMSO-300 MHz) d 11.25 (d, 1 H, J = 9.0), 7.94 (m, 4 H), 7.54 (m, 3 H), 7.17 (d, 2 H, J = 8.4), 6.88 (d , 2H, J = 8.4), 5.84 (s, 1H), 4.22 (t, 2H, J = 6.6), 4.18 (m, 1H), 3.1 (dd, 1H, J = 14.0, 4.0), 2.96 (t, 2H, J = 6.6), 2.83 (dd, 1H, J = 13.8, 9.0), 2.43 (s, 3H), 1.76 (s, 3H); MS of low resolution (ES +) m / e 518.1 (MH +).
Example 33: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (3-thienyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 428 mg (0.89 mmol) of intermediate 45 (as the TFA salt) and 150 mg (0.89 mmol) of intermediate 31 to produce 210 mg of Example 33: TLC (DCM / MeOH, 4/1): Rf = 0.60; X H NMR (DMSO-de, 400 MHz) d 11.8 (d, 1 H, J = 9.2), 7.88 (m, 3 H), 7.42 (m, 5 H), 7.08 (d, 2 H, J = 8.4), 6.78 (d , 2H, J = 8.4), 5.39 (s, 1H), 4.12 (t, 2H J = 6.4), 4.01 (m, 1H), 3.23 (m, 1H), 3.09 (m, 1H), 2.86 (t, 2H, J = 6.4), 2.69 (dd, 1H, J = 13.6, 9.2), 2.31 (s, 3H), 1.60 (s, 3H); Low resolution MS (ES +) m / e 517.1 (MH +).
Example 34: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2-pyridinyl) -1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 441 mg (0.92 mmol) of intermediate 45 (as the TFA salt) and 150 mg (0.92 mmol) of intermediate 35 to produce 240 mg of Example 34: TLC (DCM / MeOH, 4/1): Rf = 0.46; X H NMR (DMSO-d 6, 400 MHz) d 11.49 (d, 1H, J = 9.2), 8.52 (d, 1H, J = 4.8), 7.90 (m, 4H), 7.47 (m, 4H), 7. 11 (d, 2H, J = 8.4), 6.80 (d, 2H, J = 8.4), 6.13 (s, 1H), 4.12 (m, 3H), 3.16 (m, 2H), 2.87 (t, 2H, J - 6.4), 2.77 (dd, 1H, J = 13.6, 9.2), 2.34 (s, 3H), 1.71 (s, 3H); Low resolution MS (ES +) m / e 510.1 (M-H).
Example 35: (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 49 mg (0.27 mmol) of intermediate 32 to yield 83 mg of Example 35: TLC ( EtOAc / MeOH, (7: 3): Rf = 0.28; 1H NMR (DMSO-de 400 MHz) d 11.38 (d, 1H, J = 7.00), 7.84 (m, 4H), 7.45 (m, 3H), 7.16 (t, 2H, J = 8.72), 7.09 (d, 2'H, J = 7.69), 6.77 (d, 2H, J = 7.69), 5.49 ( s, 1H), 4.11 (m, 2H), 4.01 (m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (s, br, 1H), 2.30 (s, 3H) 1.62 (s, 3H); MS of low resolution (ES +) m / e 529 (MH +); RP-HPLC (Vydac C-18, 25 cm x 4 mm, 30-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes; 1 mL / minutes; tr = 20.10 minute (t0 = 1.53).
Example 36: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 0.5 g (1.31 mmol) of intermediate 46 and 215 mg (1.31 mmol) of benzoyl acetone and 260 μL (1.31 mmol) of dicyclohexylamine (replacing TEA) to produce 245 mg of the Example 36 as an opaque yellow solid. TLC (EtOAc / MeOH (3: 1): Rf = 0.56; XH NMR (DMSO-d6, 400 MHz) d 11.4 (d, 1H, J = 9.1), 7.81 (m, 2H), 7.75 (m, 2H), 7.42 (m, 3H), 7.36 (m, 3H), 7.0 (d, 2H, J = 8.4), 6.78 (d, 2H, J = 8.6), 5.51 (s, 1H), 4.55 (m, 1H), 4.20 (t, 2H, J = 6.7), 4.0 (br s, 1H), 3.14-3.04 (m, 3H), 2.7 (m, 1H), 2.38 (s, 3H), 1.68 ( s, 3H); MS of low resolution (ES +) m / e 527.1 (MH +).
Example 37: (2S) -2- acid. { [(Z) -3- (2-fluorophenyl) -1-methyl-3-oxo-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 58 mg (0.32 mmol) of intermediate 20 to yield 55 mg of Example 37: TLC ( EtOAc / MeOH (7: 3): Rf = 0.25; XH NMR (DMSO-de, 400 MHz) d 11.42, (d, 1H, J = 8.93), 7.95 (m, 2H), 7.70 (dd, 1H, J = 1.78, 7.69), 7.51 (m, 4H), 7.23 (m, 4H), 6.88 (d, 2H, J = 8.50), 5.36 (s, 1H), 4.22 (m, 2H), 4.16 (br s, 1H), 3.18 (m, 1H), 2.94 (m, 2H), 2.84 (m, 1H), 2.40 (s, 3H), 1.70 (s, 3H), low resolution MS (ES +) m / e 545.1 ( MH), RP-HPLC (Vydac C-18, 25 cm x 4.6 mm, 30-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes, 1 mL / minutes, tr = 19.47 minutes (t0 = 1.43 ).
Example 38: (2S) -2- acid. { [(Z) -3- (2,3-difluorophenyl) -l-methyl-3-oxo-l-propenyl] amino} -3- . { 4- [2- (5-me i1-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 12) was prepared from 120 mg (0.33 mmol) of intermediate 45 and 59 mg (0.33 mmol) of intermediate 40 to yield 32 mg (18% yield) from Example 38: TLC (DCM / MeOH, (4: 1): Rf = 0.72; XH NMR (DMSO-d6, 300 MHz) d 11.43 (d, 1H, J = 9.8), 7.97 (m, 2H), 7.56 (m, 5H), 7.28 (m, 1H), 7.19 (d, 2H, J = 8.0), 6.91 (d, 2_i, J = 8.0), 5.34 (s, 1H), 4.21 (m, 3H), 3.21 (m, 2H), 2.98 (t, 2H, J = 6.6), 2.84 (m, 1H), 2.40 (s, 3H), 1.78 (s, 3H), low resolution MS (ES +) m / e 547 ( MH +).
Example 39: (2S) -2- acid. { [(Z) -3- (2-Hydroxyphenyl) -1-methyl-3-oxo-1-propenyl] amino} -3- . { - [2- (5-methyl-2-pheny1-1,3-oxazol-4-yl) ethoxy] phen} propanic A solution of 100 mg (0.27 mmol) of intermediate 45 and 58 mg (0.33 mmol) of 2- (acetoacetyl) phenol (Aldrich Chemical Co.) in 5.0 mL of MeOH, 1.0 mL of trimethyl orthoformate and 4a screens (50 mg) was refluxed at 80 ° C for 16 hours. The reaction solution was concentrated and purified by flash column chromatography on silica gel using DCM / MeOH 20/1 to 10/1 as the eluent to provide 135 mg of Example 39; TLC (DCM / MeOH (10: 1): Rf = 0.32; XH NMR (DMSO-d6, 300 MHz) d 11.16 (d, 1H, J = 8.72), 7.96 (m, 2H), 7.78 (m, 1H) , 7.54 (m, 3H), 7.33 (m, 1H), 7.20 (m, 2H), 6.84 (m, 4H), 5.69 (s, 1H), 4.26 (m, 2H), 4.17 (brs, 1H), 3.20 (dd, 1H, J = 3.93, 13.67), 2.95 (m, 2H), 2.81 (m, 1H), 2.40 (s, 3H), 1.75 (s, 3H), low resolution MS (ES +) m / e 527.0 (MH +), RP-HPLC (Vydac C-18, 25 cm x 4.6 mm, 50-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes, 1 mL / ml, tr = 15.97 minutes ( t0 = 1.43).
Example 40: (2S) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1-propyl-1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 2) was prepared from 1.0 g (2.05 mmol) of intermediate 45 (as the TFA salt) and 0.8 mg (4.2 mmol) of intermediate 17 to produce 400 mg of Example 40 as a white solid: XH NMR (DMSO-de, 400 MHz) d 11.55 (d, 1H, J = 9.6), 7.87 (m, 2H), 7.75 (m, 2H), 7.45 (m, 3H ), 7.35 (m, 3H), 7.10 (d, 2H, J = 8.6), 6.80 (d, 2H, J = 8.5), 5.52 (s, 1H), 4.12 (t, 2H, J = 6.6), 4.07 (m, 1H), 3.21 (dd, 1H, J = 13.7, 3.7), 2.85 (t, 2H, J = 6.5), 2.73 (dd, 1H, J = 13.7, 8.6), 2.3 (s, 3H), 1.90 (m, 2H), 1.4-1.25 (m, .2H), 0.76 (t, 3H, J = 7.4); Low resolution MS (ES +) m / e 539.2 (MH +).
Example 41: (2S) -2- acid. { [(Z) -3- (4-methoxyphenyl) -1-methyl-3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-m.e il-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanóiso.
The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 52 mg (0.27 mmol) of intermediate 22 to yield 126 mg of Example 41. TLC ( EtOAc / MeOH (7: 3): Rf = 0.44; XH NMR (DMSO-de, 400 MHz) d 11.30 (d, 1H, J = 7.0), 7.87 (m, 2H), 7.73 (d, 2H J = 8.72 ), 7.45 (m, 3H), 7.10 (d, 2H, J = 8.37), 6.88 (d, 2H, J = 8.89), 6.77 (d, 2H, J = 8.37), 5.74 (s, 1H), 4.11 (m, 2H), 4.01 (m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.31 (s, 3H), 1.65 (s, 3H); Low resolution MS (ES ") m / e 539 (MH); RP-HPLC (Vydac C-18, 25 cm x 4.6 mm, 10-50% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes.
Example 42: (2S) -3- (4-. {2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy] phenyl acid} -2- . { [(Z) -1-methyl-3-oxo-3-phenyl-1-propenyl-1 -propenyl] amino} -propanoic The title compound was prepared (as described above for the preparation of the Example 2) from 75 mg (0.19 mmol) of intermediate 49 and 31 mg (0.19 mmol) of benzoi lacetona to yield 30 mg of Example 42: TLC (DCM / MeOH (4: 1): Rf = 0.45; XH NMR (DMSO-d6, 400 MHz) d 11.5 (d, 1H, J = 9.1), 7.89 (d, 2H, J = 8. 8), 7.84 (m, 2H), 7.45 (m, 3H), 7.18 (d, 2H, J = 8. 4), 7.09 (d, 2H, J = 8.8), 6.88 (d, 2H, J = 8. 6), 5.63 (s, 1H), 4.2 (t, 2H, J = 6.5), 4.1 (m, 1H), 3.86 (s, 3H), 3.2 (m, 1H), 2.93 (t, 2H, J = 6.6), 2.83 (d, 1H, J = 13.2, 6.4), 2.37 (s, 3H), 1.76 ( s, 3 H); Low resolution MS (ES ") m / e 539.2 (M-H).
Example 43: (2S) -2- acid. { [(Z) -3-cyclohexyl-l-methyl-3-oxo-l-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 428 mg (0.89 mmol) of intermediate 45 (dome TFA salt) and 150 mg (0.89 mmol) of intermediate 33 to yield 245 mg (53% yield) of Example 43 as a beige crystalline solid: TLC (DCM / MeOH, (4: 1): Rf = 0.69; XH NMR (DMSO-d6 , 400 MHz) d 10.79 (d, 1H, J = 9.0), 7.89 (m, 2H), 7.50-7.41 (m, 3H), 7.05 (d, 2H, J = 8.4), 6.77 (d, 2H, J = 8.4), 4.7 (s, 1H), 4.12 (t, 2H, J = 6.5), 3.9 (br s, 1H), 3.04 (dd, 1H, J = 13.6, 4.0), 2.87 (t, 2H, J = 6.5), 2.64 (dd, 1H, J = 13.6, 8.9), 2.32 (s, 3H), 1.19 (m, 1H), 1.6 (, 4H), 1.5 (s, 3H), 1.25-1.05 (m, 4H), low resolution MS (ES +) m / e 517.3 (MH +).
Example 44 (2S) -3- (4-. {2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy] phenyl acid} -2 -. { [(Z) -1-methyl-3 -oxo-3-phenyl-1-propenyl-1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 2) was prepared from 75 mg (0.18 mmol) of intermediate 51 and 32 mg (0.194 mmol) of benzoylacetone to yield 55 mg of Example 44: TLC (DCM / MeOH (4: 1): Rf = 0.50; XH NMR (DMSO-d6, 400 MHz) d 11.5 (d, 1H, J = 9.0), 7.85 (m, 4H), 7.45 (m, 3H), 7.18 ( d, 2H, J = 8.4), 7.06 (d, 2H, J = 8.8), 6.87 (d, 2H, J = 8.5), 5.82 (s, 1H), 4.74 (m, 1H), 4.19 (t, 2H , J = 6.6), 4.1 (m, 1H), 3.19 (m, 1H), 2.92 (t, 2H, J = 6.6), 2.81 (dd, 1H, J = 13.9, 9.1), 2.36 (s, 3H) , 1.74 (s, 3H), 1.34 (d, 6H, J = 6.0), low resolution MS (ES-) m / e 567.2 (MH-).
Example 45: (2S) -2 - acid. { [(Z) -l-heptyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared, from 102 mg (0.28 mmol) of intermediate 45 and 69 mg (0.28 mmol) of intermediate 19 to yield 77 mg of Example 45: TLC (EtOAc / MeOH, 7/3: Rf = 0.56; XH NMR (DMSO-de 400 MHz) d 11.55 (d, 1H, J = 9.6), 7.86 (d, 2H, J = 6.8), 7.76 (d, 2H, J = 6.4), 7.46 (m, 3H), 7.38 (m, 3H), 7.10 (d, 2H, J = 8.4), 6.78 (d, 2H, J = 8.4), 5.5 (s, 1H), 4.10 (t, 2H, J = 6.6), 4.0 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J = 6.5), 2.69 (dd, 1H, J = 13.6, 9.6), 2.31 (s, 3H), 1.87 (m, 2H), 1.25-1.1 (m, 10H), 0.78 (t, 3H, J = 6.8), low resolution MS (ES +) m / e 595.1 (MH +).
Example 46: (2S) -2- acid. { [(Z) -l-methyl-3- (3-methylphenyl) -3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) e oxy] phenyl} propanic The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 45 and 48 mg (0.27 mmol) of intermediate 21 to yield 104 mg of Example 46. XH NMR (DMSO-dg 400 MHz) d 11.47 (d, 1H, J = 9.06), 7.95 (m, 2H), 7.65 (m, 2H), 7.54 (m, 3H), 7.31 (m, 2H), 7.19 (m. d, 2H, J = 8.51), 6.88 (d, 2H, J = 8.51), 5.64 (s, 1H), 4.23 (m, 1H), 4.23 (m, 3H), 3.21 (m, 1H), 2.96 ( m, 2H), 2.86 (m, 1H), 2.60 (s, 3H), 1.80 (sf 3H); Low resolution MS (ES +) m / e 525.2 (MH +); RP-HPLC (Vydac C-18, 25 cm x 4.6 mm, 50-100% CH3CN in H20) with 0.1% HC02H buffer: 30 minutes; 1 mL / minutes; tr = 15.57 minutes (t0 = 1.43).
Example 47: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4- { 2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.25 mmol) of intermediate 49 and 45 mg (0.25 mmol) of intermediate 16 to yield 95 mg (68% yield) of Example 47 as a solid: TLC Rf = 0.2-0.3 (slight trait, CH2Cl2 / MeOH, 4/1); X H NMR (DMSO-de, 400 MHz) d 11.5 (d, 1H, J = 9.0), 7.85 (m, 4H), 7.45 (m, 3H), 7.18 (d, 2H, J = 8.4), 7.06 (d , 2H, J = 8.8), 6.87 (d, 2H, J = 8.5), 5.82 (s, 1H), 4.74 (m, 1H), 4.19 (t, 2H, J = 6.6), 4.1 (m, 1H) , 3.19 (m, 1H), 2.92 (t, 2H, J = 6.6), 2.81 (dd, 1H, J = 13.9, 9.1), 2.36 (s, 3H), 1.74 (s, 3H), 1; Low resolution MS (ES +) m / e 555.1 (MH +).
Example 48: (2S) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3 -oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 12) was prepared from 1.3 g (3.55 mmol) of intermediate 45 and 0.7 g (3.55 mmol) of intermediate 44 to yield 0.84 g (42% yield) from Example 48 as a solid: TLC (DCM / MeOH (4: 1): Rf = 0.55; XH NMR (DMSO-d6, 300 MHz) d 10.99 (s, 1H), 7.94 (m, 4H), 7.68 (m , 6H), 7.14 (d, 2H, J = 8.4), 6.84 (d, 2H, J = 8.4), 6.21 (s, 1H), 4.19 (m, 3H), 3.17 (m, 1H), 2.92-2.85 (m, 3H), 2.36 (s, 3H), low resolution MS (ES +) m / e 565.0 (MH +).
Example 49: (2S) -3- acid. { 4- [2- (5-methyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -2 -. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 12) was prepared from 120 mg (0.31 mmol) of intermediate 46 and 62 mg (0.31 mmol) of intermediate 44 to yield 78 mg of Example 49: TLC ( DCM / MeOH (4: 1): Rf = 0.58; XH NMR (DMSO-de 300 MHz) d 10.92 (br s 1H), 7.88 (d, 2H, J =), 7.81 (m, 2H, J = 8.3 ), 6.13 (s, 1H), 4.19 (t, 2H, J = 6.5), 4.10 (br s 1H), 3.15-3.11 (m, 1H), 3.05 (t, 2H, J = 6.6), 2.87 (dd) , 1H, J = 13.7, 7.7), 2.37 (s, 3H), low resolution MS (ES +) m / e 581.0 (MH +).
Example 50: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] e-oxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 150 mg (0.39 mmol) of intermediate 46 and 95 mg (0.39 mmol) of intermediate 25 to yield 79 mg (33% yield) of Example 50: TLC (DCM / MeOH 4/1): Rf = 0.62; X H NMR (DMSO-d 6, 300 MHz) d 11.59 (d, 1H, J = 9.0), 7.97-7.88 (m, 4H), 7.72 (d, 2H, J = 8.4), 7.29 (t, 2H, J = 9.0), 7.11 (d, 2H, J = 8.4), 6.78 (d, 2H, J = 8.4), 5.59 (s, 1H), 4.11 (m, 3H), 3.17 (m, 2H), 2.85 (t, 2H, J = 6.3), 2.77 (m, 1H), 2.29 (s, 3H), 2.03 (m, 2H), 0.91 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 611.2 (MH +).
Example 51: (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3- (4- { 2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 151 mg (0.39 mmol) of intermediate 51 and 92 mg (0.39 mmol) of intermediate 25 to yield 91 mg (36% yield) of Example 51: TLC (DCM / MeOH, 4/1): Rf = 0.60; X H NMR (DMSO-d 6, 300 MHz) d 11.6 (d, 1 H, J = 9.6), 7.96 (d, 2 H, J = 8.1), 7.78-7.70 (m, 4 H), 7.10 (d, 2 H, J = 8.4), 6.96 (d, 2H, J = 8.7), 6.78 (d, 2H, J = 8.4), 5.59 (s, 1H), 4.62 (sept, 1H, J = 6.0), 4.13 (m, 3H), 3.16 (m, 1H), 2.84-2.72 (m, 3H), 2.26 (s, 3H), 2.05-1.96 (m, 2H), 1.24 (d, 6H, J = 6.0), 0.91 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 651.3 (MH +).
Example 52: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (rifluoromethyl) phenyl] -1-propenyl} amino) -3- (4 - { 2- [2 - (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 150 mg (0.38 mmol) of the intermediate. 49 and 93 mg (0.38 mmol) of. intermediate 25 to yield 45 mg (19% yield) of Example 52: TLC (DCM / MeOH, 4/1): Rf = 0.63; X H NMR (DMSO-d 6, 300 MHz) d 11.6 (d, 1 H, J = 9.6), 7.96 (d, 2 H, J = 8.1), 7.81-7.70 (m, 4 H), 7. 11 (d, 2H, J = 8.4), 7.0 (d, 2H, J = 8.7), 6.78 (d, 2H, J = 8.4), 5.6 (s, 1H), 4.18-4.07 (m, 3H), 3.77 (s, 3H), 3.17 (m, 1H), 2.85-2.72 (m, 3H), 2.26 (s, 3H), 2.05-1.96 (m, 2H), 0.91 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 623.2 (MH +).
Example 53: (2S) -3- (4-. {2- [2- (4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] ethoxy] phenyl) -2- acid . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 12) was prepared from 203 mg (0.53 mmol) of intermediate 46 and 130 mg (0.63 mmol) of intermediate 44 to yield 154 mg (50% yield) of Example 53: TLC (DCM / MeOH, 4: 1): Rf = 0.65; X H NMR (DMSO-d 6, 400 MHz) d 11.5 (d, 1 H, J = 8.9), 7.95 (d, 2 H, J = 7.2), 7.77 (d, 2 H, J = 8.7), 7.72 (d, 2 H, J = 8.2), 7.1 (d, 2H, J = 8.4), 6.97 (d, 2H, J = 8.9), 6.79 (d, 2H, J = 8.5), 5.58 (s, 1H), 4.65 (m, 1H ), 4.11 (t, 2H, J = 6.5), 4.1 (m, 1H), 3.16 (dd, 1H, J = 13.7, 3.6), 2.84 (t, 2H, J = 6.5), 2.74 (dd, 1H, J = 13.7, 9.0), 2.28 (s, 3H), 1.67 (s, 3H), 1.25 (d, 6H, J = 6.0); MS of low resolution (ES +) m / e 637.1 (MH +).
Example 54: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} propanic The title compound (as described above for the preparation of Example 1) was prepared from a suspension of 113 mg (0.32 mmol) of interate 54 and 52 mg (0.32 mmol) of benzoylacetone to yield 44 mg (28%) from Example 54: TLC (DCM / MeOH, 4/1): Rf = 0.55; XH NMR (DMSO-de, 300 MHz) d 11.43 (d, 1H, J = 9.0), 7.92-7.88 (m, 2H), 7.8 (m, 2H), 7.48 (m, 3H), 7.38-7.38 (d, 3H), 7.16 (d, 2H, J = 8.4), 6.9 (d, 2H, J = 8.4), 5.53 (s, 1H), 4.91 (s, 1H), 4.15 (m, 1H), 3.2 (m, 2H), 2.83-2.74 (m, 1H), 2.37 (s, 3H), 1.67 (s, 3H); Low resolution MS (ES +) m / e 497.07 (MH +).
Example 55: (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) ethoxyphenyl} -2-. { [(Z) -1-methyl-3-oxo-3-phenyl-1-propenyl] amino} -propanoic The title compound was prepared (as described above for the preparation of the Example 1) from a suspension of 205 mg (0.54 mmol) of interate 52 and 87 mg (0.54 mmol) of benzoylacetone to yield 145 mg (51%) of Example 55: TLC (DCM / MeOH 4: 1): Rf = 0.60; X H NMR (DMSO-de, 300 MHz) d 11.42 (d, 1H, J = 9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.48-7.32 (m, 6H), 7.11 (d, 2H, J = 8.4), 6.77 (d, 2H, J = 8.4), 5.53 (s, 1H), 4.1 (t, 1H, J = 6.3), 3.2-3.14 (m, 2H), 2.86 ( t, 2H, J = 6.3), 2.79-2.74 (m, 1H), 2.67 (q, 2H, J = 7.5), 1.65 (s, 3H), 1.17 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 525.2 (MH +).
Example 56: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (2-phenyl-5-propyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic The title compound (as described above for the preparation of Example 1) was prepared from a suspension of 204 mg (0.52 mmol) of interate 53 and 84 mg (0.52 mmol) of benzoylacetone to yield 137 mg (49%) of Example 56: TLC (DCM / MeOH, 4/1): Rf = 0.55; XH NMR (DMSO-de, 300 MHz) d 11.42 (d, 1H, J = 9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.49-7.32 (m, 6H), 7.11 ( d, 2H, J = 8.4), 6.77 (d, 2H, J = 8.4), 5.53 (s, 1H), 4.1 (t, 1H, J = 6.3), 3.19-3.13 (m, 2H), 2.86 (t , 2H, J = 6.3), 2.78-2.71 (m, 1H), 2.64 (t, 2H, J = 7.2), 1.65-1.54 (m, 5H), 0.88 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 539.19 (MH +).
Example 57: (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} propanic The title compound was prepared (as described above for the preparation of Example 1) from a suspension of 205 mg (0.54 mmol) of interate 55 and 88 mg (0.54 mmol) of benzoylacetone to produce 142 mg (50% yield) of Example 57: TLC (DCM / MeOH, 4/1): Rf = 0.66; Rf = 0.66; X H NMR (DMSO-de, 300 MHz) d 11.44 (d, 1H, J = 9.0), 7.88-7.85 (m, 2H), 7.78-7.75 (m, 2H), 7.49-7.43 (m, 3H), 7.37 -7.32 (m, 3H), 7.12 (d, 2H, J = 8.4), 6.78 (d, 2H J = 8.4), 5.54 (s, 1H), 4.13 (m, 1H), 3.87 (t, 1H, J = 6.0), 3.22-3.16 (m, 1H), 2.77 (d, 1H, J = 14.4, 9.2), 2.56 (t, 2H, J = 7.2), 2.22 (s, 3H), 2.00-1.93 (m, 2H), 1.66 (s, 3H); MS of low resolution (ES +) m / e 525.15 (MH +).
Example 58: (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2 -. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic A mixture of 100 mg (0.26 mmol, 1.0 equivalent) of interate 52, 110 mg (0.39 mmol, 1.5 equivalents) of interate 44, and 0.14 mL (0.8 mmol, 3.0 equivalents) of DIEA in 2 mL of MeOH was stirred for 2.5 hours at room temperature (22 ° C). The solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (20 mL) and washed with 10 mL of 0.1 N HCl solution and 10 mL of brine. The organics were dried with NaSO4, filtered, concentrated, and the residue was purified directly by chromatography on silica gel. Elution with 10% -20% MeOH in EtOAc gave 55 mg (36% yield) of the title compound as a solid after drying under vacuum for several hours: TLC (DCM / MeOH 4: 1): Rf = 0.65; XH NMR (DMSO-d6.400.
MHz) d 10.95 (br s, 1H), 7.88-7.93 (m, 4H), 7.52- 7.41 (m, 6H), 7.72 (d, 2H, J = 8.2), 7.02 (d, 2H, J = 8.4), 6.73 (d, 2H, J = 8.5), 6.06 (s, 1H), 4.09 (t, 2H, J = 6.5), 3.99 (m, 1H), 3.0 (m, 1H, NH), 2.86-2.79 (m, 4H), 2.66 (q, 2H, J = 7.5), 1.15 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 579.08 (MH +).
Example 59: (2S) -3- acid. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} -2 -. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 58) was prepared from 100 mg (0.26 mmol) of intermediate 55 and 110 mg (0.39 mmol) of intermediate 44 to yield 65 mg (42% yield) of Example 59: TLC (DCM / MeOH 4: 1): Rf = 0.58; XH NMR (DMSO-de 400 MHz) d 10.74 (d, 1H, J = 9.4), 7.90 (d, 2H, J = 7.5), 7.86-7.82 (m, 2H), 7.54 (m, 1H), 7.48 -7.40 (m, 5H), 7.09 (d, 2H, J = 8.4), 6.81 (d, 2H, J = 8.4), 6.25 (s, 1H), 4.3 (br s, 1H), 3.89 (t, 2H , J = 6.1), 3.09 (dd, 1H, J = 14.0, 4.8), 2.96 (dd, 1H, 14.0 7.9), 2.2 (s, 3H), 2.0-1.92 (m, 2H); MS of low resolution (ES +) m / e 579.08 (MH +).
Example 60: (2S) -3- acid. { 4 - [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) toxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 58) was prepared from 180 mg (0.35 mmol) of intermediate 57 (as its TFA salt) and 148 mg (0.53 mmol) of intermediate 44 to produce 113 mg (54% yield) of Example 60: TLC (DCM / MeOH 85/15): Rf = 0.50; XH NMR (DMSO-d6.300.
MHz) d 10.72 (d, 1H, J = 10.13), 7.94 (d, 2H, J = 7. 3), 7.87-7.83 (m, 2H), 7.67-7.39 (m, 5H), 7.13 (d, 2H, J = 8.6), 6.86 (d, 2H, J - 8.5), 6.32 (s, 1H), 4.26 (t, 2H, J = 6.5), 3.17-3.01 (m, 4H), 2.81 (q, 2H, J = 7.4), 1.22 (t, 3H J = 7.4); MS of low resolution (ES +) m / e 594.9 (MH +).
Example 61: (2S) -3- (4 -. {2- [5-ethyl-2- (4-fluorophenyl) -1,3-thiazole-4-yl] ethoxy] phenyl) -2 acid -. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 58) was prepared from 130 mg (0.26 mmol) of intermediate 58, 106 mg (0.38 mmol) of intermediate 44, and 0.14 mL of diisopropylethylamine in 5 mL of MeOH. The crude product was recrystallized from hot CH3CN to yield 67 mg (43% yield) of Example 61: TLC (DCM / MeOH 85/15): Rf = 0.44; X H NMR (DMSO-d 6, 300 MHz) d 10.72 (d, 1 H, J = 10.3), 7.97-7.92 (m, 4 H), 7.62-7.56 (m, 1 H), 7.52-7.46 (m, 3 H), 7.32 (t, 2H, J = 8.7), 7.13 (d, 2H, J = 8.6), 6.85 (d, 2H J = 8.6), 6.32 (s, 1H), 4.35 (m, 1H), 4.16 (t, 2H , J = 6.5), 3.13 (dd, 1H, J = 14.0, 4.8), 3.02 (dd, 1H, J = 14.0, 7.7), 2.89 (t, 2H, J = 7.4), 1.19 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 596.9 (MH +).
Example 62: (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl} -2- acid . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} -propanoic The title compound (as described above for the preparation of Example 58) was prepared from 200 mg (0.38 mmol) of intermediate 59, 127 mg (0.57 mmol) of intermediate 44, and 0.2 mL of diisopropylethylamine in 2.5 mL of MeOH. The crude product was recrystallized from hot CH3CN to yield 106 mg (46% yield) of Example 62: TLC (DCM / MeOH, 4/1): Rf = 0.61; X H NMR (DMSO-d 6, 300 MHz); d 10.72 (d, 1H, J = 10.2), 7.95-7.91 (m, 4H), 7.76-7.61 (m, 3H), 7.31 (t, 2H, J = 8.7), 7.13 (d, 2H, J = 8.1 ), 6.85 (d, 2H, J = 8.4), 6.32 (s, 1H), 4.42-4.37 (m, 1H), 3.92 (t, 1H, J = 5.7), 3.15-2.98 (m, 3H), 2.60 -2.65 (m, 4H), 2.0 (t, 2H, J = 6.3), 1.10 (t, 3H, J = 7.5), 1.19 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 610.96 (MH +).
Example 63: (2S) -3- (4-. {2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl) -2- acid . { [(E) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-prope il] amino} -propanoic The title compound (as described above for the preparation of Example 58) was prepared from 130 mg (0.25 mmol) of intermediate 56, 103 mg (0.37 mmol) of intermediate 44, and 0.17 mL of diisopropylethylamine in 5 mL of MeOH. The crude product was recrystallized from hot CH3CN to yield 110 mg (72% yield) of Example 63: TLC (DCM / MeOH, 85/15): Rf = 0.45; XH NMR (DMSO-300 MHz) d 10.72 (d, 1H, J = 10.2), 7.96-7.86 (m, 4H), 7.59 (m, 1H), 7.52-7.46 (m, 3H), 7.28 (t , 2H, J = 8.8), 7.13 (d, 2H, J = 8.6), 6.85 (d, 2H, J = 8.5), 6.32 (s, 1H), 4.38 (m, 1H), 4.25 (t, 2H, J = 6.5), 3.31-2.98 (m, 4H), 2.81 (q, 2H, J = 7.4), 1.22 (t, 2H, J = 7.4); MS of low resolution (ES +) m / e 612.9 (MH +).
Example 64: (2S) -3- (4 -. {3- [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-yl] propoxy] phenyl) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl-3-amino} -propanoic The title compound (as described above for the preparation of Example 2) was prepared from 95 mg (0.18 mmol) of intermediate 59 (TFA salt), 44 mg (0.18 mmol) of intermediate 25, and 0.55 of triethylamine in MeOH (1.5 mL) and trimethyl orthoformate (0.5 mL) to yield 44 mg (38% yield) of Example 64 after chromatography on silica gel (elution of 5% -15% MeOH in DCM): TLC (DCM / MeOH, 4/1): Rf = 0.53; X H NMR (DMSO-d 6, 300 MHz) d 11.63 (d, 1 H, J = 9.3), 7.99-7.89 (m, 4 H), 7.73 (d, 2 H, J = 8.1), 7.30 (t, 2 H, J = 8.7), 7.13 (d, 2H, J = 8.1), 6.79 (d, 2H, J = 8.1), 5.62 (s, 1H), 4.20 (m, 1H), 3.87 (m, 2H), 3.20 (m, 2H), 2.77 (m, 2H), 2.61-2.54 (m, 4H), 2.05-1.96 (m, 4H), 1.10 (t, 3H, J = 7.72), 0.92 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 638.93 (MH +).
Example 65: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3- acid. { 4- (3- (5-ethyl-2-phenyl-1, 3-oxazol-4-yl) propoxy] phenyl}. Propane.
The title compound (as described above for the preparation of Example 2) was prepared from 50 mg (0.13 mmol) of intermediate 60, 31 mg (0.13 mmol) of intermediate 25, and 0.44 mL of triethylamine in MeOH (1.0 mL) and trimethyl orthoformate (0.5 mL) to yield 22 mg (28% yield) of Example 65 after chromatography on silica gel (elution of 5% -15% MeOH in DCM): TLC (DCM / MeOH, 4/1): Rf = 0.50; 1 H NMR (DMSO-d 6, 300 MHz) d 11.70 (d, 1H, J = 9.6), 8.05 (d, 2H, J = 7. 8), 7.95 (d, 2H, J = 7.8), 7.81 (d, 2H, J = 8.1), 7.55-7.52 (m, 3H), 7.20 (d, 2H, J = 8.4), 6. 86 (d, 2H, J = 8.4), 5.69 (s, 1H), 4.28-4.22 (m, 1H), 3.96 (d, 2H, J = 6.0), 3.28-3.20 (m, 2H), 2. 89-2.81 (m, 1H), 2.72-2.63 (m, 4H), 2.05-1.96 (m, 4H), 1.18 (t, 3H, J = 7.5), 0.99 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 620.98 (MH +).
Example 66: (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] propoxy] phenyl} -2- acid ( { (Z) -1-methyl-3-oxo-3- [4-trifluoromethyl) phenyl] -1-propenyl} amino) -propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 90 mg (0.17 mmol) of intermediate 59, 40 mg (0.17 mmol) of intermediate 24, and 0.05 mL of triethylamine in MeOH (1.5 mL) and trimethyl orthoformate (0.5 mL) to yield 54 mg (51% yield) of Example 66 after chromatography on silica gel (elution of 5% -15% MeOH in DCM): TLC (DCM / MeOH , 4/1): Rf = 0.60; X H NMR (DMSO-d 6, 300 MHz) d 11.53 (d, 1H, J = 9.0), 7.98-7.90 (m, 4H), 7.73 (d, 2H, J = 8.4), 7.30 (t, 2H, J = 8.7), 7.13 (d, 2H, J = 8.4), 6.79 (d, 2H, J = 8.4), 5.61 (s, 1H), 4.23-4.19 (m, 1H), 3.89 (t, 2H, J = 6.0 ), 3.22-3.17 (m, 2H), 2.83-2.75 (m, 2H), 2.64-2.55 (m, 4H), 1.97 (t, 2H, J = 6.3), 1.71 (s, 3H), 1.10 (t , 3H, J = 7.5); Low resolution MS (ES +) m / e 625.15 (MH +).
Example 67: (2S) -3- acid. { 4- [3- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} -2-. { ((Z) -1-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl] amino) propane.
The title compound (as described above for the preparation of Example 2) was prepared from 57 mg (0.14 mmol) of intermediate 60, 33 mg (0.14 mmol) of intermediate 24, and 0.042 mL of triethylamine in MeOH (1.5 mL) and trimethyl orthoformate (0.5 mL) to yield 24 mg (28% yield) of Example 67 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4). / 1): Rf = 0.62; X H NMR (DMSO-d 6, 300 MHz) d 11.53 (d, 1 H, J = 9.0), 7.97 (d, 2 H, J = 8.4), 7.89 (d, 2 H, J = 7.8), 7.73 (d, 2 H, J = 8.4), 7.46 (m, 3H), 7.12 (d, 2H, J = 8.1), 6.79 (d, 2H, J = 8.4), 5.62 (s, 1H), 4.25-4.19 (m, 1H), 3.90 (t, 2H, J = 6.0), 3.21-3.15 (m, 1H), 2.58-2.83 (m, 5H), 1.98 (t, 2H, J = 5.7), 1.72 (s, 3H), 1.11 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 607.18 (MH +).
Example 68: (2S) -3- acid. { 4- [3- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} -2-. { ((Z) -3-Oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} - propanoic.
The title compound was prepared (as described above for the preparation of the Example 58) from 100 mg (0.25 mmol) of the intermediate 60, 85 mg (0.38 mmol) of intermediate 44, and 0.14 mL of diisopropylethylamine in 2.0 mL of MeOH. Recrystallization was attempted from hot CH3CN without success. Chromatography on silica gel with MeOH / DCM (10% -20%) gave 68 mg (45% yield) of Example 68: TLC (DCM / MeOH, 4/1): Rf = 0.60; XH NMR (DMSO-de, 300 MHz) d 10.96 (br s, 1H), 7.90-7.87 (m, 4H), 7.54-7.46 (m, 6H), 7.07 (d, 2H, J = 8.4), 6.78 (d , 2H, J = 8.1), 6.12 (s, 1H), 4.11-4.03 (m, 1H), 3.89 (t, 2H, J = 6.0), 3.12-3.07 (m, 1H), 2.91-2.83 (m, 1H), 2.66-2.57 (m, 4H), 1.98 (t, 2H, J = 5.7), 1.11 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 593.02 (MH +).
Example 69: (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} -2- . { ((Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} - propanoic.
The title compound (as described above for the preparation of Example 58) was prepared from 1.5 g (3.02 mmol) of intermediate 62, 1.01 g (4.53 mmol) of intermediate 44, and 1.6 mL of diisopropylethylamine in 2.0 mL of MeOH. Recrystallization was attempted from hot CH3CN without success. Chromatography on silica gel with MeOH / DCM (10% -20%) gave 1.5 g (60% yield) of Example 69: TLC (DCM / MeOH, 4/1): Rf = 0.43; X H NMR (DMSO-de, 300 MHz) d 10.98 (br s, 1 H), 7.91-7.85 (m, 4 H), 7.55-7.45 (m, 6 H), 7.11 (d, 2 H, J = 8.4), 6.92 ( d, 2H, J = 8.4), 6.15 (s, 1H), 5.07 (s, 2H), 4.13-4.06 (m, 1H), 3.16-3.09 (m, 1H), 2.95-2.85 (m, 4H), 1.21 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 580.95 (MH +).
Example 70: (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} -2 -. { ((Z) -1-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl] amino.} - propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 1.35 g (2.72 mmol) of intermediate 62, 630 mg (2.72 mmol) of intermediate 24, and 0.8 mL of triethylamine in MeOH (20). mL) and trimethyl orthoformate (5 mL) to yield 1.04 g (65% yield) of Example 70 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4). / 1): Rf = 0.45; X H NMR (DMSO-d 6, 300 MHz) d 11.57 (d, 1H, J = 8.7), 7.96 (d, 2H, J = 8.4), 7.85 (m, 2H), 7.71 (d, 2H, J = 8.4) , 7.44 (m, 3H), 6.92 (d, 2H, J = 8.4), 5.6 (s, 1H), 5.05 (s, 2H), 4.21-4.27 (m, 1H), 3.27-3.22 (m, 1H) , 2.89-2.81 (m, 4H), 1.72 (s, 3H), 1.19 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 594.96 (MH +).
Example 71: (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl) -2-. { ((Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} - propanoic.
The title compound (as described above for the preparation of Example 58) was prepared from 100 mg (0.27 mmol) of intermediate 61, 91 mg (0.41 mmol) of intermediate 44, and 0.14 mL of diisopropylethylamine in 2.0 mL of MeOH. Recrystallization was attempted from hot CH3CN without success. Chromatography on silica gel with MeOH / DCM (10% -20%) gave 91 mg (59% yield) of Example 71: TLC (DCM / MeOH, 4/1): Rf = 0.57; X H NMR (DMSO-de, 300 MHz) d 10.96 (br s, 1 H), 7.94-7.89 (m, 4 H), 7.58-7.44 (m, 6 H), 7.12 (d, 2 H, J = 8.4), 6.89 ( d, 2H, J = 8.1), 6.16 (s, 1H), 4.93 (s, 2H), 4.20-4.11 (m, 1H), 3.16-3.11 (m, 1H), 2.96-2.88 (m, 1H), 2.77 (q, 2H, J = 7.5), 1.17 (t, 3H, J = 7.5); Low resolution MS (ES +) m / e 564.88 (MH +).
Example 72: (2S) -3- (4 - {- (5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl) methoxy} phenyl) -2- acid. { ((Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} - propanoic.
The title compound (as described above for the preparation of Example 58) was prepared from 700 mg (1.82 mmol) of the intermediate 63, 610 mg (2.73 mmol) of intermediate 44, and 0.95 mL of diisopropylethylamine in 12 mL of MeOH. Chromatography on silica gel with MeOH / DCM (10% -20%) gave 580 mg (55% yield) of Example 72: TLC (DCM / MeOH, 4/1): Rf = 0.50; X H NMR (DMSO-de, 300 MHz) d 11.95 (br s, 1 H), 7.99-7.89 (m, 4 H), 7.58-7.53 (m, 3 H), 7.34 (t, 2 H, J = 8.7), 7.12 ( d, 2H, J = 8.1), 6.89 (d, 2H, J = 8.7), 6.16 (s, 1H), 4.92 (s, 2H), 4.21-4.11 (m, 1H), 3.16-3.11 (m, 2H) ), 2.96-2.91 (m, 1H), 2.79 (q, 2H, J = 7.5), 1.17 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 582.92 (MH +).
Example 73: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) -phenyl] -1-propenyl} amino] -3- acid { 4- [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl] -propanoic acid.
The title compound (as described above for the preparation of Example 2) was prepared from 100 mg (0.27 mmol) of intermediate 61, 67 mg (0.27 mmol) of intermediate 25, and 0.8 mL of triethylamine in MeOH (2.0 mL) and trimethyl orthoformate (0.5 mL) to yield 54 mg (51% yield) of Example 73 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4). / 1): Rf = 0.54; X H NMR (DMSO-d 6, 300 MHz) d 11.63 (d, 1 H, J = 9.3), 7.98-7.90 (m, 4 H), 7.73 (d, 2 H, J = 8.1), 7.50-7.48 (m, 3 H) , 7.16 (d, 2H, J = 8.7), 6.90 (d, 2H, J = 8.7), 5.6 (s, 1H), 4.93 (s, 2H), 4.24-4.18 (m, 1H), 3.24-3.19 ( m, 1H), 2.84-2.72 (m, 4H), 2.08-1.98 (m, 2H), 1.16 (t, 3H, J = 7.8), 0.91 (t, 3 H, J = 7.5); MS of low resolution (ES +) m / e 593.10 (MH +).
Example 74: (2S) -3- acid. { 4- . { [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] me oxy} phenyl) -2-. { ((Z) -l-ethyl-3 -oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) -propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 160 mg (0.42 mmol) of intermediate 63, 102 mg (0.42 mmol) of intermediate 25, and 0.12 mL of triethylamine in MeOH (3.0 mL) and trimethyl orthoformate (0.75 mL) to yield 117 mg (46% yield) of Example 74 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4). / 1): Rf = 0.57; 1ti NMR (DMSO-d6, 300 MHz) d 11.63 (d, 1H, J = 9.6), 7.99-7.93 (m, 4H), 7.72 (d, 2H, J = 8.1), 7.32 (t, 2H, J = 8.7), 7.16 (d, 2H, J = 8.7), 6.90 (d, 2H, J = 8.1), 5.6 (s, 1H), 4.91 (s, 2H), 4.26-4.20 (m, 1H), 3.24- 3.19 (m, 1H), 2.84-2.72 (m, 4H), 2.07-2.00 (m, 2H), 1.15 (t, 3H, J = 7.5), 0.91 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 611.10 (MH +).
Example 75: (2S) -3- acid. { 4- . { [5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} -2- ( { (Z) -1-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) -propanoic acid.
The title compound was prepared (as described above for the preparation of the Example 2) from 98 mg (0.27 mmol) of intermediate 61, 62 mg (0.27 mmol) of intermediate 24, and 0.08 mL of triethylamine in MeOH (2.0 mL) and trimethyl orthoformate (0.5 mL) to produce 95 mg ( 61% yield) of Example 75 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4/1): Rf = 0.59; X H NMR (DMSO-d 6, 300 MHz) d 11.55 (d, 1H, J = 9.0), 7.98-7.90 (m, 4H), 7.73 (d, 2H, J = 8.4), 7.51-7.48 (m, 3H) , 7.17 (d, 2H, J = 8.4), 6.91 (d, 2H, J = 8.4), 5.61 (s, 1H), 4.93 (s, 2H), 4.24-4.18 (m, 1H), 3.23-3.16 ( m, 1H), 2.86-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 579.05 (MH +).
Example 76: (2S) -3- (4. {[[5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] methoxy] phenyl) -2- acid. { ((Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) -propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 176 mg (0.46 mmol) of intermediate 63, 105 mg (0.46 mmol) of intermediate 24, and 0.14 mL of triethylamine in MeOH (3.0 mL) and trimethyl orthoformate (0.75 mL) to yield 152 mg (56% yield) of Example 76 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4 / 1): Rf = 0.55; X H NMR (DMSO-d 6, 300 MHz) d 11.55 (d, 1H, J = 9.0), 7.99-7.94 (m, 4H), 7.73 (d, 2H, J = 8.4), 7.33 (t, 2H, J = 8.7), 7.16 (d, 2H, J = 8.4), 6.90 (d, 2H, J = 8.7), 5.61 (s, 1H), 4.93 (s, 2H), 4.23-4.18 (m, 1H), 3.22- 3.18 (m, 1H), 2.85-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 597.09 (MH +).
Example 77: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (rifluoromethyl) -phenyl] -1-propenyl} amino) -3- acid. { 4- [(5-ethyl-2-phenyl-l, 3-thiazol-4-yl) methoxy] phenyl} -propanoic The title compound (as described above for the preparation of Example 2) was prepared from 1.44 mg (2.90 mmol) of intermediate 62, 710 mg (2.90 mmol) of intermediate 25, and 0.85 mL of triethylamine in MeOH (20). mL) and trimethyl orthoformate (5 mL) to yield 985 mg (56% yield) of Example 77 after chromatography on silica gel (5% -15% MeOH in DCM): TLC (DCM / MeOH, 4). / 1): Rf = 0.45; X H NMR (DMSO-d 6, 300 MHz) d 11.65 (d, 1 H, J = 9.3), 7.97 (d, 2 H, J = 8.1), 7.85 (m, 2 H), 7.71 (d, 2 H, J = 8.1) , 7.44 (m, 3H), 7.44 (d, 2H, J = 8.1), 7.16 (d, 2H, J = 8.1), 5.61 (s, 1H), 5.05 (s, 2H), 4.26-4.19 (m, 1H), 3.26-3.21 (m, 1H), 2.89-2.77 (m, 4H), 2.07-2.0 (m, 2H), 1.19 (t, 3H, J = 7.5), 0.91 (t, 3H, J = 7.5 ); MS of low resolution (ES +) m / e 609.07 (MH +).
Example 78: (2S) -3- (4-. {2- [5-ethyl-2- (4-fluorophenyl) -1, 3-oxazol-4-yl] ethoxy} phenyl) -2- acid . { ((Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1. 1-propenyl}. Amino) -propanoic.
The title compound was prepared (as described above for the preparation of the Example 2) from 150 mg (0.29 mmol) of intermediate 58 (salt of TFA), 108 mg (0.3 mmol) of intermediate 25, and 0.1 mL of triethylamine in MeOH and trimeityl orthoformate to yield 70 mg (38% yield) of Example 78: TLC (DCM / MeOH, 4/1): Rf = 0.26; XH NMR (DMSO-d6.300.
MHz) d 11.62 (d, 1H, J = 9.3), 7.99-7.93 (m, 4H), 7. 74 (d, 2H, J = 8.4), 7.32 (t, 2H, J = 8.9), 7.13 (d, 2H, J = 8.4), 6.80 (d, 2H, J = 8.5), 5.61 (s, 1H), 4.14 (m, 3H), 3.4-3.1 (m, 2H, obscured by the water peak) , 2.88 (t, 2H, J = 6.4), 2.70 (q, 2H, J = 7.4), 2.02 (m, 2H), 1.19 (t, 3H, J = 7.5), 0.94 (t, 3H, J = 7.5 ); Low resolution MS (ES +) m / e 625.2 (MH +).
Example 79: (2S) -3- (4- { [5-ethyl-2- (4-fluorophenyl) -1,3-thiazol-4-yl] fyl} -2-. ((Z) -1-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) -propanoic.
The title compound (as described above for the preparation of Example 2) was prepared from 150 mg (0.28 mmol) of intermediate 56 (TFA salt), 108 mg (0.3 mmol) of intermediate 25, and 0.1 mL of triethylamine in MeOH and trimethyl orthoformate to yield 60 mg (33% yield) of Example 79: TLC (DCM / MeOH, 90/10): Rf = 0.26; XH NMR (DMSO-d6.300.
MHz) d 11.63 (d, 1H, J = 9.4), 7.98 (d, 2H, J = 8.0), 7.9-7.85 (m, 2H), 7.74 (d, 2H, J = 8.3), 7.27 (t, 2H , J = 8.7), 7.13 (d, 2H, J = 8.4), 6.80 (d, 2H, J = 8.3), 5.62 (s, 1H), 4.25 (m, 3H), 3.4-3.2 (m, 2H, darkened by the water peak), 3.07 (t, 2H, J = 6.3), 2.85-2.77 (m, 2H), 2.06-1.99 (m, 2H), 1.21 (t, 3H, J = 7.4), 0.93 ( t, '3H, J = 7.4); Low resolution MS (ES +) m / e 641.12 (MH +).
Example 80: (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -propanoic The title compound (as described above for the preparation of Example 2) was prepared from 150 mg (0.29 mmol) of intermediate 57 (TFA salt, 108 mg (0.3 mmol) of intermediate 25, and 0.1 mL of triethylamine in MeOH and trimethyl orthoformate to yield 40 mg (22% yield) of Example 80: TLC (DCM / MeOH, 90/10): Rf = 0.28; 1 R NMR (DMSO-d6, 300 MHz) d 11.62 (d, 1H, J = 9.4), 7.98 (d, 2H, J = 8. 2), 7.85 (m, 2H), 7.74 (d, 2H, J = 8.3), 7.48- 7.42 (m, 3H), 7.13 (d, 2H, J = 8.4), 6.80 (d, 2H, J = 8.3 ), 5.63 (s, 1H), 4.23 (t, 2H, J = 6.5), 4.2 (m, 1H), 3.2-3.05 (m, 3H), 2.89-2.75 (m, 3H), 2.07-2.03 (m , 2H), 1.23 (t, 3H, J = 7.5), 0.94 (t, 3H, J = 7.5); MS of low resolution (ES +) m / e 622.91 (MH +).
The following intermediates A-G were prepared to make the radioligand for the binding test described below.
Intermediary Aj 2- (4- (2- (phenylmethyloxycarbonylamino) ethylphenoxy) -2-methylbutanoic acid.
A solution of 4- (2- (phenylmethyloxycarbonylamino) ethyl) phenyl (5.74 g; 21. 16 mmol) in 2-butanone (17 mL) and chloroform (6 g) was added dropwise to a mixture of sodium hydroxide (9.0 g, 225 mmol) and 2-butanone (67 mL) while maintaining the reaction temperature below 30 ° C. The mixture was allowed to stir at 30 ° C for 4 hours. Ether (100 mL) was added and the resulting solid was collected by filtration and washed with ether (100 mL). The solid was dissolved in water (70 mL) and any residual ether was removed by evaporation. IN hydrochloric acid was added to adjust the pH to 1, and the resulting oil was extracted with dichloromethane (3 x 50 mL). The combined extracts were dried (Na2SO4) and evaporated to give a yellow oil (3.82 g, 49%). XH NMR (CDCl3) d 7.26 (s, 5H), 7.09 (d, 2H, J = 7.9 Hz), 6.88 (d, 2H, J = 8.4 Hz), 5.09 (s ~, 2H), 4.75 (br s, 1H), 3.42-3.44 (m, 2H), 2.75 (t, 2H, J = 6. 7 Hz), 1.92-2.00 (m, 2H), 1.47 (s, 3H), 1.04 (t, 3H, J = 2.6 Hz). Mass spectroscopy ES-, m / e (M + H) + = 372.
Intermediate B 2- (4- (2- (phenylmethyloxycarbonylamino) ethyl) phenoxy) -2-methyl butyrate methyl.
A solution of intermediate A (2.0 g, 5.38 mmol) in dimethylformamide (12 mL) was treated with potassium carbonate (2.23 g, 16.14 mmol) and methyl iodide (1.54 g, 10.76 mmol) and the resulting mixture was stirred at pH 23. ° C for 2 hours. The mixture was filtered and the collected solid was washed with ethyl acetate (70 mL). The filtrate was washed with brine (4 x 50 mL), dried (Na 2 SO 4) and evaporated. The residue was purified by chromatography on silica gel using hexane, then 33% ethyl acetate-hexane as the eluent to give a colorless oil (1.27 g, 61%). 1tt NMR (DMSO-de) d 7.31 (m, 5H), 7.06 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H, J = 8.4 Hz), 4.98 (s, 2H), 3.67 (s, 3H), 3.15 (, 2H), 2.62 (t, 2H, J = 7.1 Hz), 1.86 (m, 2H), 1.38 (m, 2H), 1.38 (s, 3H), 0.86 (t, 3H, J = 7.3 Hz). Mass spectrometry ES +, m / e (M + H) + = 408.
Intermediate C: methyl 2- (4- (2-aminoethyl) phenoxy) -2-methyl butyrate acetate salt.
A solution of intermediate B (1.27 g, 3.29 mmol) in methanol (50 mL) and acetic acid (0.4 g) was treated with 10% palladium on carbon and stirred under a hydrogen atmosphere (50 psi) for 2 hours. . The catalyst was filtered through celite and the solvent was evaporated to give a yellow oil in the quantitative field (1.04 g). : H NMR (CDC13) d 7.06 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 6.70 (br s, 2H), 3.76 (s, 3H), 3.02 (br s) , 2H), 2.82 (m, 2H), 1.99 (s, 3H), 1.92 (m, 2H), 1.48 (s, 3H), 0.96 (t, 3H, J = 7.4 Hz). Mass spectrometry ES +, m / e (M + H) + = 252.
Intermediate D 2- (4 - (2- (2,4-difnylsulfonylamino) ethyl) phenoxy) -2-methyl butyrate.
A solution of intermediate C (2 g, 6.42 mmol) in CH2C12 (40 mL) was treated with a saturated sodium bicarbonate solution and the organic layer was separated. The aqueous layer was extracted with CH2C12 (5 x 50 mL) and the combined organic layers were dried (Na2SO4) and evaporated to give the free base as a yellow oil (1.61 g, 100%). This was dissolved in CH2C12 (40 mL) and treated with pyridine (0.45 g, 5.61 mmol) and 2,4-dinitrophenylsulfonyl chloride (1.5 g, 5.61 mmol), and the mixture was allowed to stir at 23 ° C for 3 hours. . Water (60 mL) was added and the organic layer was separated, washed with water (3 x 40 mL) and saturated sodium bicarbonate (40 mL). The organic layer was dried (Na2SO4) and evaporated and the residue was purified by chromatography using 15% -20% EtOAc-hexane as the eluent to give a light yellow solid (1.38 g.; 51%). XH NMR (CDC13) d 8.63 (d, 1H, J = 2.3 Hz), 8.49 (dd, 1H, J = 8.4 Hz, J '= 2.3 Hz), 8.07 (d, 1H, J = 8.4 Hz), 6.89 ( d, 2H, J = 8.4 Hz), 6.54 (d, 2H, J = 8.4 Hz), 5.34 (t, 1H, J = 5.3 Hz), 3.78 (s, 3H), 3.48 (q, 2H, J = 8.3 Hz), 2.75 (t, 2H, J = 6.6 Hz), 1.92 (m, 2H), 1.42 (s, 3H), 0.93 (t, 3H, J = 7.5).
Intermediate E 2- (4- (2- ((2,4-dini-phenylsulfonyl) (hept-2-en-l-yl) amino) ethyl) phenoxy) -2-methyl butyrate methyl.
A solution of intermediate D (315 mg, 0.654 mmol) in THF (15 mL) was treated with triphenylphosphine (343 mg, 1,308 mmol), hept-2-en-1-ol (150 mg, 1,308 mmol) and diethylamine. zodicarboxy la to (228 mg, 1308 mmol) and the mixture was allowed to stir at 23 ° C for 1 hour. The solvent was evaporated and the residue was purified by chromatography using 10-15% EtOAc-hexane as the eluent to give a semi-solid (400 mg,> 100%). TLC and NMR show that the desired compound is present together with 1,2- (diethoxycarbonyl) hydrazine.
Intermediate F 2- (4- (2- (hept-2-en-l-ylamino) ethyl) phenoxy) -2-methyl butanoate.
A solution of intermediate E (400 mg, 0.654 mmol) in CH2C12 (5 mL) was treated with triethylamine (132 mg, 1,308 mmol) and mercaptoacetic acid (78 mg, 0.85 mmol) and the mixture was allowed to stir at 23 ° C. for 1 hour. The mixture was diluted with EtOAc (30 mL) and washed with water (3 x 120 mL) and aqueous sodium bicarbonate (30 mL). The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography using 10% EtOAc-hexane, then 50% EtOAc-hexane, then MeOH as the eluent to provide an oil (177 mg, 78% of the intermediary 24). XH NMR (CDC13) d 7.06 (d, 2H, J = 7.5 Hz), 6.75 (d, 2H, J = 7.5 Hz), 5.59 (m, 2H), 3.76 (s, 2H), 3.30 (d, 2H, J = 6.3 Hz), 2.87 (m, 4H), 1.96 (m, 4H), 1.47 (s, 3H), 1.28 (m, 5H), 0.96 (t, 3H, J = 7.6 Hz), 0.86 (t, 3H, J = 6.9 Hz).
Intermediate G: 2- (4- (2- (l-hept-2-enyl-3- (2,4-difluorophenyl) ureido) ethyl) phenoxy) -2-methylbutyrate methyl.
A solution of intermediate F (157 mg, 0.452 mmol) in methylene chloride (5 mL) was treated with 2,4-difluorophenyl isocyanate (140 mg, 0.904 mmol) and the mixture was allowed to stand at 23 ° C for 18 hours . The mixture was evaporated and the residue was purified by chromatography using 10%, then 15% ethyl acetate-hexane as the eluent to give a yellow semi-solid (212 mg, 93%). It was contaminated with bis- (2,4-difluorophenyl) urea which co-eluted in the column. XH NMR (CDC13) d 8.85 (br s, 1H), 8.02 (, 1H), 7.09 (d, 2H, J = 8.4 Hz), 6.77-6.90 (m, 4H), 5.70 (m, 1H), 5.36 ( m, 1H), 3.76 (s, 3H), 3.54 (t, 2H, J = 7.3 Hz), 2.84 (t, 2H, J = 7.1 Hz), 1.55 (br s, 1H), 1.46 (s, 3H) , 1.25-1.35 (m, 5H), 0.96 (t, 3H, J = 7.3 Hz), 0.88 (t, 3H, J = 7.4 Hz). CI / AP + mass spectrometry, m / e (M + H) + = 503. 2- (4- (2- (l-Hept-2-enyl-3- (2,4-difluorophenyl) ureido) ethyl) phenoxy) -2-methylbutanoic acid (Precursor of Radioligand).
A solution of intermediate G (370 mg, 0.736 mmol) in methanol (15 mL) was treated with IN NaOH (7.5 mL) and the mixture was heated at reflux temperature for 2 hours. The mixture was acidified with IN HCl and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried (Na2SO) and evaporated. The residue was purified by chromatography on silica gel using 20% ethyl acetate-hexane, then ethyl acetate as the eluent to give a tan oil (280 mg; 78%). X H NMR (CDCl 3) d 7.95-8.09 (m, 1 H), 7.14 (d, 2 H, J = 7.1 Hz), 6.90 (d, 2 H, J = 7.4 Hz), 6.81 (d, 2 H, J = 5.2 Hz) , 5.66 (m, 1H), 5.37 (m, 1H), 3.56 (t, 2H, J = 7.4 Hz), 2.87 (t, 2H, J = 7.4 Hz), 2.00 (m, 4H), 1.44 (s, 3H), 1.27 (m, 6H), 1.03 (t, 3H, J = 7.3 Hz), 0.88 (t, 3H, J = 7.3 Hz). Mass spectrometry ES-, m / e (M + H) + = 489.
Radioligand: 2- (4- (2- (2,3-di tri thio-1-heptyl -3- (2,4-difluorophenyl) ureido) ethyl) phenoxy) -2-methylbutanoic acid.
A solution of the radioligand precursor prepared above (10 mg) in anhydrous DMF (3.5 mL) was transferred to a reaction vessel containing 10% Pd / C (9.8 mg). The reaction vessel was evacuated and degassed by means of a freeze-thaw evacuation cycle and then exposed to tritium gas (10.1 Ci). After 4 hours, the mixture was filtered through celite, it was evaporated and the residue was dissolved in acetonitrile. A portion of this solution (0.8 mL, 26.6 Ci) was purified by HPLC (Dynamax C8, 25 minutes acetonitrile gradient: 0.1% TFA 4: 1 to acetonitrile: 0.1% TFA 9: 1, 235 nm ). The fractions containing the pure material were combined and evaporated under nitrogen. The residue was redissolved in acetonitrile to provide a solution of the title compound (82.0 Ci / mmol, radiochemical purity, 99%). 2- (4- (2- (1-Heptyl -3- (2,4-difluorophenyl) ureido) ethyl) phenoxy) -2-methylbutanoic acid.
The unlabeled ("cold") version of the previous radioligand was prepared as a control. A solution of intermediate G (10 mg) in anhydrous DMF (3.5 mL) was transferred to a reaction vessel containing 10% Pd / C (9.8 mg). The reaction vessel was evacuated and degassed by means of a freeze-thaw evacuation cycle and then exposed to hydrogen gas. After 4 hours, the mixture was filtered through celite and evaporated. The residue was purified by chromatography using 2% MeOH / Ch 2 C 12 as the eluent to give a gum (7 mg).
The radioligand prepared above was used in the PPARα binding assay described below (in addition to 3H-BRL 49653 for the PPAR binding test?) To show that the active compounds in the transfection tests were also the ligands for PPARa and PPAR ?.
Binding test: The compounds were tested for their ability to bind to hPPAR? or hPPAR using a Proximity Scintillation Test (SPA). The binding domain of the PPAR ligand (LBD) was expressed in E. col i as the polyHis end fusion proteins and purified. The LBD was then labeled with biotin and immobilized in modified streptavidin scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand (3H-BRL 49653 for PPARα and 2 - (4 - (2 - (2, 3-di-t-thio-1-hept i 1-3- ( 2,4-difluorophenyl) ureido) ethyl) phenoxy-2-methylobutanoic acid for hPPARa) and the varying concentrations of the test compound, and then the balance of the radioactivity binding to the beads was measured by a scintillation counter. Non-specific binding, as verified by the control wells containing 50 μM of the corresponding unlabeled ligand, was subtracted from each data point.For each compound tested, the graphs of the radioligand concentration against the CPM of the bound radioligand were developed and the apparent Ki values were estimated from the less non-linear fit of the data assuming the simple competitive binding.The details of this test have been reported anywhere (see, Blanchard, SG et al., Development of a Scint i 1 lat io n Proximity Assay for Peroxisone Proliferator-Act ivated Gamma Receptor Ligand Binding Domain. An a l. Bi or ch em. 1998, 257, 112-119).
Preferably, the compounds of this invention bind to both hPPARμ and hPPARa. All of the above examples 1-80 did not bind to hPPARμ and hPPARa. The apparent pKi values were > 6.3 for all Examples 1-80 in the binding tests of hPPARμ and hPPARa described above (pKi = -log of the concentration of the test compound required to reach an apparent Ki value according to the equation Ki = IC50 / I + [L] / Kd, where IC50 = the concentration of the test compound required to inhibit 50% of the specific binding of the radioligand, [L] is the concentration of the radioligand used, and K is the dissociation constant for the radioligand in the receptor ).
Transfection test The compounds were screened for functional potency in transient transfection tests on CV-1 cells for their ability to activate PPAR subtypes (transactivation test). A previously established chimeric receptor system was used to allow comparison of the relative transcriptional activity of the receptor subtypes in the same target gene and to avoid activation of the endogenous receptor to complicate the interpretation of the results. See, for example, Lehmann, J.M .; Moore, L.B .; Smi th-01 i see, T.A .; Wilkison, W.O .; Willson, T.M .; Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligan for peroxisome proliferator-activated receptor? (PPAR?), J. Bi ol. . Ch em. , 1995, 270, 12953-6. The ligand binding domain for murine and PPARa and PPAR? of human were each fused to the GAL4 DNA binding domain of the yeast transcription factor. CV-1 cells are transiently transfected with the expression vectors for the respective PPAR chimera together with a reporter construct containing five copies of the activation expression of the GAL4 DNA site binding of secreted placental alkaline phosphatase ( SPAP) and ß-galactosidase. After 16 hours, medium was exchanged into DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24 hours, the cell extracts were prepared and tested for alkaline phosphatase and β-galactosidase activity. The activity of alkaline phosphatase was corrected for transfection efficiency by using β-galactosidase activity as the internal standard (see, for example, Kliewer, S.A. et al., Cell 83, 813-819 (1995)). Rosigli tazona (BRL 49653) was used as a positive control in the hPPAR test ?. The positive control in the hPPARa test was 2- [4 - (2- (3- (4-fluorophenyl) -1-heptylureido) ethyl) -phenoxy] -2-methylpropionic acid, which can be prepared as described in Brown , Peter J., et al., Sín t is published on 7, 778-782 (1997), or patent publication WO 9736579.
All the above examples showed at least 50% activation of hPPARa and hPPAR? at concentrations of 10-7 M or less.
In Vivo Evaluation Male Zicker rats with diabetic fat were lightly anesthetized with isoflurane gas and bled by tail vein to obtain baseline concentrations after fasting for plasma glucose, serum lipids and insulin. The animals were matched from the baseline by plasma glucose and randomly taken in vehicles or treatment groups with administration of the compound by an oral tube, b.i.d., beginning at 8.5 weeks of age. The selected compounds were administered as a suspension in 0.5% methylcellulose for 7 consecutive days. Changes in body weight and food consumption were monitored from the representative animals of each group, over a period of 48 hours. After 7 days of treatment, the animals were anesthetized, blood samples were obtained and analyzed for plasma glucose and lactate concentration, serum triglyceride, total cholesterol and HDL, free non-esterified fatty acids and insulin. The livers were weighed and corrected for body weight. The values in Table 1 for% glucose reduction represent a summary of the percent reduction of vehicle control animals on day 7 relative to normalization defined in this model as the plasma glucose levels of 140 mg / dL.
Table 1. Biological Activity.
Use% Glucose reduction 1 39 7 34 12 '61 16 59 < - .. 20 50 21 82 22 49 23 86 24 45 40 79 48 81 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.

Claims (19)

  1. Claims 1. A compound of the formula (I), or a tautomeric form, pharmaceutically acceptable salt, or solvate thereof. OR) characterized in that R1 is hydrogen or C3 alkyl; R is hydrogen or C? -8 alkyl optionally substituted by one or more halogens; R3 is C6 -6 alkyl. C4-7 cycloalkyl or cycloalkenyl, -OC -6 alkyl. -NR'R '(wherein each R' is independently hydrogen or C1-3 alkyl), a 5- or 6-membered heterocyclic group containing at least one ring atom of oxygen, nitrogen or sulfur (optionally substituted by one or more halogen, C?-C alquilo alkyl optionally substituted by one or more halogen, C alquilo-C?-alkyl optionally substituted by one or more halogens, -CN or -N02), or phenyl (optionally substituted by one or more halogen, C alquilo-alkyl) ? 6 optionally substituted by one or more halogens, alkyl -OC? -6 optionally substituted by one or more halogen -CN or -N02); R is a 5- or 6-membered heterocyclic group containing at least one oxygen, nitrogen or sulfur ring atom (optionally substituted by one or more halogens, C? -6 alkyl optionally substituted by one or more halogen, -OC alkyl? -6 optionally substituted by one or more halogens, -CN or N02), or phenyl (optionally substituted by one or more halogens, C6_6alkyl optionally substituted by one or more halogens, optionally -OC_6alkyl substituted by one or more more halogens, -NR 'R', -CN or -N02); R is hydrogen, halogen or C1-3 alkyl optionally substituted by one or more halogens; R6 is hydrogen or C? -3 alkyl; X is O S; Y n is 1, 2 or 3. The compound according to claim 1 characterized in that R1 is hydrogen or methyl. 3. The compound according to any of claims 1-2, characterized in that R2 is C? _8 alkyl optionally substituted by one or more halogens. 4. The compound according to any of claims 1-3 characterized in that R3 is, pyridine, pyrazine, thiophene, furan, thiazole, or phenyl (any of which may be optionally substituted by one or more of halogen, C? -6 alkyl) optionally substituted by one or more halogens, alkyl -OC? -6 optionally substituted by one or more halogens, -CN, or -N02) or cycloalkyl C -7. 5. The compound according to claim 4 characterized in that R3 is phenyl (optionally substituted by one or more of halogen, C? -6 alkyl optionally substituted by one or more halogen, alkyl -0C? _6 optionally substituted by one or more halogen, - CN, or -N02). 6. The compound according to any one of claims 1-5 characterized in that R4 is phenyl (optionally substituted by one or more of halogen, C6-6 alkyl optionally substituted by one or more halogen, -OC -6 alkyl optionally substituted by one or more halogens). 7. The compound according to any of claims 1-6 characterized in that R5 is hydrogen, or C3_3alkyl optionally substituted by one or more halogens. The compound according to claim 7 characterized in that R; It is hydrogen. 9. The compound according to any of claims 1-8 characterized in that R6 is methyl or ethyl. 10. The compound according to any of claims 1-9 characterized in that n is 2. 11. The compound according to claim 1, characterized in that it is selected from the group consisting of: (2S) -2- ([(Z) -l-Methyl-3-oxo-3-phenyl-1-propenyl] amino] -3-. {4- [2- (5-methe- 2-phene 1-1, 3-oxazol-4-yl) ethoxy] phenyl.} Propane (2S) -3- (4-. {2- [2- (4-f-luo-pheno-1) -5-methyl-l, 3-oxazol-4-yl] -ethoxy} phenyl} -2- acid ( { (Z) - 1 -met i 1-3 -oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -3- (4-. {2- 2- (4-isopropoxyphenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} phenyl) -2- (. { (Z) -1-met-il-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -3- (4- { 2- [2- (-methoxy-phenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- (. { (Z) -1-met-l-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- (2- { 5-methyl-2- [4-t rif luoromet il) phenyl] -1, 3-oxazol-4-yl (ethoxy) phenylpropanoic (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1-propenyl] amino} -3- (4 - { 2- [2- (4-methoxyphenyl) -5-methyl-1, 3-oxazol-4-yl} ethoxy) phenylpropanoic acid (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- (2- { 5-Methyl-2- [4- (trifluoromethyl) phenyl] -1,3-oxazol-4-yl} ethoxy) phenyl] propane (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-1, 3-oxazol-4-yl} ethoxy} phenyl] propanic acid (2S) -2- { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1-propenyl] amino.}. -3- (4- { 2- [2- (4-fluorophenyl) ) -5-methyl-l, 3-oxazol-4-yl] ethoxy.] Phenyl] propane (2S) -2- acid. { [(Z) -1-met-U-3-OXO-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-thiazol-4-yl) ethoxy] phenylpropanoic acid (2S) -2- acid. { [(Z) -3- (4-fluorophenyl) -1-met i 1-3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-met il-2-phenyl-1,3-oxa-zol-4-yl) ethoxy] phenyl} propanic (2S) -2-[[(Z) -1-met-3-oxo-3- (2,3-, 4-trifluorophenyl) -1-propenyl] amino acid} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-methyl-3- (4-n-t-phenyl) -3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl Ipropanoic acid (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-1-propenyl] amino} -3- (4- { 2- [2- (4-isopropoxyphenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy.} Phenyl) propanoic (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,4,5-trifluorophenyl) -l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- (4 - {2 - [2- (4-isopropoxyphenyl) -5-methyl-1, 3-oxazol-4-yl] ethoxy.} Phenyl) propanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4 (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4- [2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic (2S) -2- acid. { [(Z) -l-methyl-3- (4-methylphenyl) -3-oxo-l-propenyl} Not me} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Jpropanoic acid (2S) -2-. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxa-zol-4-yl) ethoxy] phenyl} propanic (2S) -3- (4-. {2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl] ethoxy} phenyl] -2- { . ((Z) -3-Oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} Propane (2S) -2 - ([(Z) -l-ethyl-3-oxo-3-phenyl-1- (trifluoromethyl) -l-propenyl} amino) -3- (4 -. {2- [2- (4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] ethoxy] phenyl) propane (2S) -2- acid. { [(Z) -l-butyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-1-yl) ethoxy] phenylpropanoic acid (2S) -2 - (([[Z) -3- (4-chlorophenyl) -l-methyl-3-oxo-l-propenyl] amino] -3-. {4- [2- ( 5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl Ipropanoic acid (2S) -2- acid. { [(Z) -l-methyl-3- (3-nitrophenyl) -3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic acid (2S) -2-. { [(Z) -3- [2-fluoro-3- (trifluoromethyl) phenyl] -l-methyl-3-oxo-l-propenyllamino) -3-. { 4- [2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (4-isopropoxy-phenyl-1) -1-met-il-3-oxo-l-propenyl} Not me} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-chlorophenyl) -1-met i 1 -3-oxo-l-propenyl} Not me} -3-. { 4- [2- (5-methyl-2-phenyl-1,2-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-furyl) -1-met i 1 -3-oxo-1-propenyl} Not me} -3-. { 4- [2- (5-Met-il-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenpropropanoic acid (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2-pyrazinyl) l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2,4-difluorophenyl) l-methyl-3-oxo-l-propenyl} Not me} -3- (4- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic acid (2S) -2- { [(Z) -l-methyl -3-oxo-3- (1, 3-thiazol-2-yl) -l-? Ropenyl] amino.}. -3- { 4- [2- (5-met il-2-phenyl-1 , 3-oxazol-4-yl) ethoxy] phenyl. (2S) -2- acid. { [(Z) -1-methyl-3-oxo-3- (3-thienyl) -1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-l, 3-oxa-zol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -1-methy1-3-OXO-3- (2-pyridinyl) -1-propenyl] amino} -3- . { 4 - [2- (5-met il-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-ethyl-3- (4-fluorophenyl) -3-oxo-l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenylpropanoic acid (2S) -2- acid. { [(Z) -1-methyl-3-phenyl-1 -propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-thiazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -3- (2-fluorophenyl) -l-methyl-3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] -phenylpropanoic acid (2S) -2-. { [(Z) -3- (2,3-difluorophenyl) -1-methyl-3-oxo-l-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -3- (2-Hydroxyphenyl) -l-methyl-3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -3- acid. { 4- [2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1-propyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -3- (4-met oxy phenyl) -l-methyl-3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-1-yl) ethoxy] phenyl} propanic (2S) -3- (4-. {2- [2- (4-methoxy phenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-1-propenyl] a inolpropanoic (2S) -2- acid. { [(Z) -3-cyclohexyl-l-methyl-3-oxo-l-propenyl] amino} -3-. { 4- [2- (5-Methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenylpropanoic acid (2S) -3- (4-. {2- 2- (4-isopropoxyphenyl)) -5-methyl-l, 3-oxazol-4-yl] ethoxy.) Phenyl) -2-. { [(Z) -1-methyl-3-oxo-3-phenyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -1-Heptyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -l-methyl-3- (3-met il-phenyl-1) -3-oxo-1-propenyl] amino} -3- . { 4- [2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { - [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -3- acid. { 4- [2- (5-met i 1-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-met i 1-2-pheni 1 -1,3-thiazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanoic acid (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. amino) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy} phenyl) propane (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4- . { 2- [2- (4-isopropoxy phenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy} phenyl) propanic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4 - . { 2- [2- (4-methoxyphenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy} phenyl) propanic (2S) -3- (4-. {2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl) ethoxy acid} phenyl } -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] aminolpropanoic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4 - [(5-Methyl-2-phenyl-l, 3-oxazol-4-yl) methoxy] phenylpropanoic acid (2S) -3-. { 4- [2- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} propanic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [2- (2-phenyl-5-propyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -2- acid. { [(Z) -1-met i 1-3 -oxo-3-phenyl-1-propenyl] amino} -3- . { - [(5-methyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] phenyl} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-oxa-zol-4-yl) -ethoxy] -phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-met i 1-2 -phenyl-1, 3-oxazol-4-yl) propoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] aminolpropanoic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] aminolpropanoic acid (2S) -3- (4- { [2- (5-ethyl-2- (4- fluorophenyl) -l, 3-oxazol-4-yl) ethoxy] phenyl.} -2- { [(Z) -3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.} propane (2S) -3- (4-. {3- [5-Ethyl-2- (-fluorophenyl) -1,3-oxazol-4-yl] propoxy] phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {2- 2- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- acid. { [(Z) -3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) propanic (2S) -2- acid. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyllamino) -3-. { 4- [(5-ethyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] phenyl} propanic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- (. { (Z) -l-methyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propane (2S) -3- acid. { 4- [3- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] phenyl} -2- ( { (Z) -l-methyl-3-oxo- [4- (trifluoromethyl) phenyl] -l-propenyl}. Amino) propanoic (2S) -3- acid. { 4- [3- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) propoxy] phenyl} -2-. { [(Z) -l-methyl-3-oxo-phenyl] -l- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [(5-et i 1-2 -phenyl-1, 3-oxazol-4-yl) methoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl] -l- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { - [(5-ethyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} -2- ( { (Z) - 1 -met i 1-3 -oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanic (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-oxa-zol-4-yl) methoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl lamino) propanoic (2S) -3- acid. { 4- [(5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] methoxy.} Phenyl) -2- (((Z) -3-oxo-3-phenyl-1 - (trifluoromethyl) -l-propenyl}. amino.} propanic acid (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.}. Amino) -3- { 4- [(5-ethyl-2-phenyl-l, 3-oxazol-4-yl) methoxy] phenyl Ipropanoic (2S) -3- acid. { 4-. { [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] methoxy} phenyl) -2- ( { (Z) -l-ethyl-3-oxo-3- [4 - (trifluoromethyl) phenyl] -1-propenyl.} amino) propanoic (2S) -3- acid. { 4- [(5-ethyl-2-phenyl-1,3-oxazol-4-yl) methoxy] phenyl} -2- ( { (Z) - 1-methy1-3 -oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanic (2S) -3- (4. {[[5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] methoxy] phenyl) -2- (. {( Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl.} Amino) propanoic (2S) -2- ( { (Z) -1-et-il-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3- acid. { 4 - [(5-ethyl-2-phenyl-l, 3-thiazol-4-yl) methoxy] phenylpropanoic acid (2S) -3- (4- { [5-ethyl-2- (4-fluorophenyl)) -l, 3-oxazol-4-yl] ethoxy.} phenyl) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl .}. amino) propanic (2S) -3- (4- { [5-ethyl-2- (4-fluoropheni-1) -1,3-thiazol-4-yl] methoxy} phenyl) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} .amino) propanoic (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (tri-foromethyl) phenyl] -1-propenyl} amino) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-thiazole-4-yl) me toxy] phenyl} propanic, and the pharmaceutically acceptable salts and solvates thereof. 12. A compound according to claim 1, characterized in that it is selected from the group consisting of (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3-phenyl-l 'propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-thiazol-4-yl) ethoxy] phenylpropanoic acid (2S) -2-. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- (2- { 5-met i 1-2- [4-trifluoromet il-phenyl] -1, 3-oxazol-4-yl-ethoxy) phenyl] propanoic acid (2S) -2- acid. { [(Z) -l-methyl-3-oxo-3- (2,3,4-trifluorophenyl) -1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -l-methyl-3- (4-nitrophenyl) -3-oxo-1-propenyl] amino} -3-. { 4- [2- (5-met il-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl (propanoic) (2S) -2- ( { (Z) -1-met il-3-oxo-3- [4 (2)) acid (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4- [2- (5-met il-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic (2S) -2- acid. { [(Z) -1-met-il-3-oxo-3- (2,4,5-tri f-loromet il) -1-propenyl] amino} -3- . { 4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] phenyl Ipropanoic acid (2S) -2-. { [(Z) -l-ethyl-3-oxo-3-phenyl-1-propenyl] amino} -3- [4- [2-. { 5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} propanic (2S) -3- (4- { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl) ethoxy] phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic acid) 2S) -2-. { [(Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3-. { 4-. { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-thiazol-4-yl-methoxy} phenyl) propanic (2S) -2- acid. { [(Z) -l-butyl-3-oxo-3-phenyl-1-propenyl] amino} -3-. { 4- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenylpropanoic acid (2S) -2- ([(Z) -3- (4-chlorophenyl) -1-met i 1-3-oxo-1-propenyl] amino] -3-. {4- [2- (5-met il-2-feni 1-1, 3-oxazol-4-yl) ethoxy] phenillpropanoic (2S) -3- acid. { 4- [2- (5-met i 1-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1-propyl-1-propenyl] amino} propanic acid (2S) -3-. { 4- [2- (5-met il-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -2- ( { (Z) -1-e-t-yl-3-oxo-3- [4-trifluoromethyl) phenyl] -1-propenyl acid} amino) -3- (4 - { 2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy.} phenyl) propanoic (2S) -2- ( { (Z) -1-et-il-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl} amino) -3- (4 - { 2- [2- (4-methoxy phenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} phenyl) propane (2S) -3- (4- (2- [2- (4-fluorophenyl) -5-methyl-l, 3-oxazol-4-yl] ethoxy) phenyl) -2- ([(Z) -3) acid -oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino.}. propanoic (2S) -2- acid. { [(Z) -1-met il-3-oxo-3-phene-1-propenyl] amino} -3- . { 4- [(5-methyl-2-phenyl-l, 3-oxazol-4-yl) methoxy] phenylpropanoic acid (2S) -3- acid. { 4- [2- (5-ethyl-phenyl-1,3-oxazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} propanic acid (2S) -2-. { [(Z) -1-met il-3-oxo-3-phenyl-1-propenyl] amino} -3- . { 4- [(5-met il-2-phenyl-1, 3-oxazol-4-yl) propoxy] phenylpropanoic acid (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] phenyl} -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) ethoxy] phenyl} -2- . { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- acid. { 4- [2- (5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl) ethoxy} phenyl) -2-. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic (2S) -3- (4-. {3- [5-Ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- ([( Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl) amino} propanic (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-thiazol-4-yl] ethoxy} phenyl) -2- acid. { [(Z) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl] amino} propanic acid (2S) -3- (4-. {3- [5-ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl) -2- ( { (Z) -l-ethyl-3-oxo-3 - / [4- (trifluoromethyl) phenyl] -1- propenyl.} Amino) propanoic (2S) -2- ( { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -l-propenyl} amino) -3- acid. { 4 - [3- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenyl} propanic (2S) -3- (4-. {3- [5-Ethyl-2- (4-fluorophenyl) -l, 3-oxazol-4-yl] propoxy] phenyl-2- [ { (Z) -1-met i 1-3 -oxo-3- [4 - (trifluoromethyl) phenyl] -1- propenyl.} Amino) propanoic (2S) -3- acid. { 4- [3- [5-ethyl-2-phenyl-l, 3-oxazol-4-yl] propoxy] phenyl} -2- ( { (Z) -l-methyl-3-oxo-3- [4 - (trifluoromethyl) phenyl] -1-propenyl}. Amino) propanoic (2S) -3- (4- { [5-ethyl-2- (4-fluorophenyl) -1, 3-oxazol-4-yl] methoxy] phenyl] -2- ([(Z)) -3-oxo-3-phenyl-1- (trifluoromethyl) -1-propenyl}. Amino.} Propanic acid (2S) -3-. {4- [(5-ethyl-2-phenyl-1, 3-oxazol-4-yl) methoxy] phenyl] -2- ( { (Z) -1-met yl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl. Amino Ipropanic (2S) -3- (4-. {[[(5-ethyl-2- (4-fluorophenyl) -1,3-oxazol-4-yl] methoxy] phenyl) -2- (. { (Z) -l-methyl-3-oxo-3- [4 - (trifluoromethyl) phenyl] -1-propenyl}. Amino.} Propanic (2S) -3- (4-. {2- [5-ethyl-2- (4-fluorophenyl) -1,3-thiazol-4-yl] ethoxy} phenyl) -2- (. { (Z) -l-ethyl-3-oxo-3- [4- (trifluoromethyl) phenyl] -1-propenyl}. Amino.} Propane and the pharmaceutically acceptable salts and solvates thereof. 13. The compound according to any of claims 1-12, characterized in that the compound is a double activator of hPPAR? and hPPARa. 14. A pharmaceutical composition, characterized in that they comprise a therapeutically effective amount of a compound of any of claims 1-13. 15. The pharmaceutical composition according to claim 14, characterized in that it also comprises a pharmaceutically acceptable diluent or carrier. 16. The compound according to any of claims 1-13, characterized in that it is used in therapy. 17. A method for the treatment or prevention of a disease mediated by hPPARa and / or hPPAR ?, risk factor, or condition, characterized in that it comprises administering a composition according to claim 14 or claim 15 to a patient in need of such prevention or treatment. 18. The use of a compound of any of claims 1-13, which is used for the manufacture of a medicament for the treatment of a disease mediated by hPPAR? and hPPARa, risk factor or condition. 19. The method of claim 17 or the use of claim 18, characterized in that the disease, risk factor, or condition is hyperglycemia, dyslipidemia or type II diabetes mellitus that includes the associated diabetic dyslipidemia.
MXPA/A/2001/001419A 1998-08-07 2001-02-07 SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS MXPA01001419A (en)

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GB9817118.4 1998-08-07

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