ES2366905T3 - METHYLENAMIDE DERIVATIVES SUBSTITUTED IN QUALITY OF THIROSINE PHOSPHATE PROTEIN MODULATORS (PTPS). - Google Patents

Abstract

Substituted methylenamide derivative of Formula (I): as well as its geometric isomers, its optically active forms such as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of alkyl (C1-C12), (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-C12) alkyl or (C1-C12) alkyl -heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl; R2a and R2b are each independently selected from the other from the group comprising or consisting of H or (C1-C12) alkyl; Cy is: a) a thienyl or phenyl group substituted with any of the following: - a phenyl - an oxadiazole group; - 1 or 2 moieties selected from the group consisting of -NH-CO-R3, -SO2-NR3R3 'or -CO-NR3R3', in which R3, R3 'are independently selected from H and (C1-C15) alkyl; b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl; c) when R2a and R2b are each H and R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2 or trifluoromethyl, a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7-C15) alkyl; od) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group, a substituted phenyl or biphenyl group with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl.

Description

Field of the Invention

The present invention relates to substituted methyleneamide derivatives of formula (I), in particular for the treatment and / or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising type I and / or II diabetes, inadequate tolerance to glucose, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS). The compounds of the present invention are particularly useful in the treatment of type II diabetes, obesity or appetite regulation. Specifically, the present invention relates to substituted methylenamide derivatives for modulation, especially inhibition of PTP activity, in particular PTP1B.

Background of the invention
The prevalence of insulin resistance in non-glucose tolerant subjects is well known. Reaven et al (American Journal of Medicine, 60, 80 (1976)) used a continuous infusion of glucose and insulin (insulin / glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance exists in a diverse group of non-obese, non-ketosic subjects. These subjects varied between borderline glucose tolerance and frank fasting hyperglycemia. Diabetic groups in these studies included insulin-dependent subjects (DMID) and non-insulin-dependent subjects (DMNID).
Along with the sustained insulin resistance is the hyperinsulinemia that can be determined more easily, which can be measured by means of an accurate determination of the concentration of insulin in circulating plasma in the subjects' plasma. Hyperinsulinemia may be present as a result of insulin resistance, such as in obese and / or diabetic subjects (DMNID) and / or non-glucose tolerant subjects, or in DMID subjects, as a consequence of excessive insulin injection into comparison with a normal physiological release of the hormone by the endocrine pancreas.
The association of hyperinsulinemia and insulin resistance with obesity and with ischemic diseases of the large blood vessels (for example, atherosclerosis) has been established by numerous experimental, clinical and epidemiological studies (Stout, Metabolism, 34, 7 (1985 )). Statistically significant elevations of plasma insulin 1 or 2 hours after oral glucose loading correlate with an increased risk of coronary heart disease.
Since most of these studies excluded diabetic subjects, the data related to the risk of atherosclerotic diseases with the diabetic condition are not numerous, but they point in the same direction as for non-diabetic subjects. However, the incidence of atherosclerotic diseases in statistical data on morbidity and mortality in the diabetic population exceeds that of the non-diabetic population (Pyorala et al; Jarrett Diabetes / Metabolism Reviews, 5,547 (1989)).
The association of hyperinsulinemia and insulin resistance with Polycystic Ovary Syndrome (PCOS) is also well recognized (Diamanti-Kandarakis et al .; Terapeutic effects of metformin on insulin resistance and hyperandrogenism in polycistic ovary syndrome; European Journal of Endocrinology 138,269-274 (1998), Andrea Dunaif; Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis; Endocrine Reviews 18 (6), 774-800 (1997)).
Independent risk factors for obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin / glucose clamps, infusion of glucose marker and indirect calorimetry, it was shown that insulin resistance of essential hypertension is located in peripheral tissues (mainly, muscle) and correlates directly with the severity of the hypertension (DeFronzo and Ferrannini, Diabetes Care, 14, 173 (1991)). In hypertension of obese people, insulin resistance generates hyperinsulinemia, which is acquired as a mechanism to limit an additional weight gain through thermogenesis, but insulin also increases sodium renal reabsorption and stimulates the sympathetic nervous system in kidneys, heart and vasculature, creating hypertension.
It is assumed that insulin resistance generally results from a defect in the insulin receptor signaling system, at a site after insulin binding with the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues that respond to insulin (muscle, liver, adipose), clearly suggests that a defect in the transduction of insulin signals resides at an early stage in this cascade, specifically in the activity of the insulin receptor kinase, which appears to be reduced (Mounib Elchebly, Alan Cheng, Michel L. Tremblay; Modulation of insulin signaling by protein tyrosine phosphatases; J. Mol. Med. 78, 473-482 (2000) ).
The protein tyrosine phosphatases (PTP) have an important role in the regulation of protein phosphorylation and represent the kinase counterparts. Among the classic PTP, there are two types: (i) Non-receptor PTP o The interaction of insulin with its receptor causes phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase. PTP dephosphorylates the activated insulin receptor, attenuating tyrosine kinase activity. PTPs can also modulate post-receptor signaling by catalyzing the dephosphorylation of the cellular substrates of the insulin receptor kinase. Enzymes that seem more likely to be closely associated with the insulin receptor and, therefore, are more likely to regulate insulin receptor kinase activity include PTP1B, LAR, PTP-alpha and SH-PTP2 (Lori Klaman et al .; Increased Energy Expenditure, Decreased Adiposity, and Tissue-specific insulin sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice; Molecular and Cellular Biology, 5479-5489 (2000)).
PTP1B is a member of the PTP family. This 50 kDa protein contains a phosphatase domain conserved at residues 30-278 and is located on the cytoplasmic face of the endoplasmic reticulum by its 35 C-terminal end residues. Their interactions with other proteins are mediated by proline-rich regions and SH2 compatible sequence. It is believed that PTP1B acts as a negative regulator in insulin signaling.
McGuire et al. (Diabetes, 40, 939 (1991)) demonstrated that non-diabetic non-glucose tolerant subjects had considerably elevated levels of PTP activity in muscle tissue compared to normal subjects and that insulin infusion failed to suppress PTP activity as happened in insulin sensitive subjects.
Meyerovitch et al. (J. Clinical Invest., 84, 976 (1989)) observed a significantly higher PTP activity in the livers of two DMID rodent models, the genetically diabetic BB rat, and the STZ-induced diabetic rat. Sredy et al. (Metabolism, 44, 1074, (1995)) observed a similar increased PTP activity in the livers of obese ob / ob diabetic mice, which represent a typical rodent model of DMNID.
Zhang et al (Curr. Opin. Chem. Biol., 5 (4), 416-23 (2001)) found that PTPs are also involved in a wide variety of other disorders, including cancer. Bjorge, JD et al. (J. Biol. Chem., 275 (52), 41439-46 (2000)) indicate that PTP1B is the primary tyrosine phosphatase protein capable of dephosphorylating c-Src in several human breast cancer cell lines and suggest a regulatory role of PTP1B in the control of c-Src kinase activity.
Pathre et al (J. Neurosci. Res., 63 (2), 143-150 (2001)) describe that PTP1B regulates the extent of neurite mediated by cell-cell and cell-matrix adhesion molecules. Likewise, Shock L. P et al. (Mol. Brain. Res., 28 (1), 110-16 (1995)) demonstrate that a distinct overlapping PTP set is expressed in the developing brain and retinal Muller's glia, including two new PTPs that may participate in the neural cell communication
The insulin receptor (RI) is the prototypic tyrosine kinase receptor whose binding and dimerization of ligands results in autophosphorylation in multiple tyrosines. The recruitment and phosphorylation of IRS1-4 (depending on tissue) and PI3K then occur. Although it has been known since the 19th century that compounds containing vanadium relieve diabetes, it was only recently understood that these inhibitors stimulate the insulin signaling pathway by blocking the action of PTP. The evidence of the participation of IR (insulin receptor) and IRS-1 in this phenotype was that both proteins show greater tyrosine phosphorylation in mice with mutated PTP1B. Available data suggest that in particular PTP1B is a promising target for the development of drugs to treat diabetes and obesity (Brian P. Kennedy and Chidambaram Ramachandran; Protein Tyrosine Phosphatase-1B in Diabetes; Biochemical Pharmacology, Vol. 60,877-883, (2000)).
Another protein that participates in obesity is Leptin. Leptin is a peptide hormone that has a central role in food and adiposity (Leptin. Annu. Rev. Physiol. 62 p.413-437 (2000) by Ahima RS et al.). Recently, it has been suggested that PTP1B negatively regulates leptin signaling and provides a mechanism by which obesity can be regulated. Moreover, it is known that pharmacological inhibitors of PTP1B are promising as an alternative or complement to leptin in the treatment of obesity due to leptin resistance (Developmental Cell., Vol.2, p.497-503 (2002)) .
In WO 02/18321, among others, several small molecules have been proposed as PTP inhibitors. This document discloses several amino acid (oxo) acetic acid tyrosine phosphate protein inhibitors. WO 01/19830 discloses several other amino (oxo) acetic acid inhibitors of tyrosine phosphatases proteins.
The present invention relates to substituted methyleneamide derivatives of formula (I) image 1
as well as its geometric isomers, its optically active forms such as enantiomers, diastereomers and its 5 forms of racemate, as well as pharmaceutically acceptable salts thereof, wherein
R1 is selected from the group consisting of (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-C12) alkyl -aryl or (C1-C12) alkyl-heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl;
R2a
and R2b are each independently selected from the other from the group comprising or consisting of H or 10 (C1-C12) alkyl; Cy is: a) a thienyl or phenyl group substituted with any of the following:  a phenyl  an oxadiazole group;
15  1 or 2 moieties selected from the group consisting of -NH-CO-R3, -SO2-NR3R3 'or -CO-NR3R3', in which R3, R3 'are independently selected from H and (C1-C15) alkyl ;
b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl;
c) when R2a and R2b are each H and R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2 or trifluoromethyl,
A thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7C15) alkyl; or
d) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group,
a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl.
Such compounds are suitable for the treatment and / or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising type I and / or II diabetes, inadequate glucose tolerance, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, Obesity, polycystic ovary syndrome (PCOS). The compounds of the present invention are PTP inhibitors.
Detailed Description of the Invention
In the following paragraphs several chemical moieties that form the compounds according to the invention are defined and applied uniformly throughout the specification and the claims, unless a definition expressly stated otherwise provides a broader definition.
"PTP" are tyrosine phosphatases proteins and include for example PTP1B, TC-PTP, PTP- □, DEP-1, LAR, SHP-1, SHP-2, 35 GLEPP-1, PTP- □, PTP-µ, VHR, hVH5, LMW-PTP, PTEN.
"C1-C12 alkyl" or "C1-C15 alkyl" refers to straight or branched monovalent alkyl groups having 1 to 12 or 1 to 15 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, n-nonyl, n-dodecyl, tridecyl, pentadecyl, n- pentyl and the like in straight or branched forms thereof.
"Aryl" refers to an unsaturated aromatic carboxylic group of 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl). Preferred aryl includes phenyl, naphthyl, phenanthrenyl and the like.
"Heteroaryl" refers to a monocyclic heteroaromatic group or a fused ring bicyclic or tricyclic heteroaromatic group. Particular examples of heteroaromatic groups include pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl; 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a ] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, naptiridinyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl , isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, fteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
"C1-C12 alkyl heteroaryl" refers to C1-C12 alkyl groups having a heteroaryl substituent, which includes 2-furylmethyl, 2-thienylmethyl, 2- (1H-indole-3-yl) ethyl and the like.
"Alkenyl" refers to alkenyl groups that preferably have 2 to 6 carbon atoms and that have at least 1 or 2 alkenyl unsaturation sites. Preferable alkenyl groups include ethenyl (-CH = CH2), n-2-propenyl (allyl, -CH2CH = CH2) and the like.
"Alkynyl" refers to alkynyl groups having 2 to 18 carbon atoms and having at least 1-2 alkynyl unsaturation sites, for example ethynyl (-C≡CH), propargyl (-CH2C≡CH), or -C ≡CH-alkyl (C2-C16).
"Acyl" refers to the group -C (O) R where R includes "C1-C12 alkyl", "aryl", "heteroaryl", "C1-C12 alkyl aryl" or "C1C12 alkyl heteroaryl".
"Acyloxy" refers to the group -OC (O) R where R includes "C1-C12 alkyl", "aryl", "heteroaryl", "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl".
"Alkoxy" refers to the group -OR where R includes "C1-C12 alkyl" or "aryl" or "heteroaryl" or "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, phenoxy and the like.
"Alkoxycarbonyl" refers to the group -C (O) OR where R includes "C1-C12 alkyl" or "aryl" or "heteroaryl" or "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl".
"Aminocarbonyl" refers to the group -C (O) NRR 'where each R, R' independently includes hydrogen or C1-C12 alkyl or aryl or heteroaryl or "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl".
"Acylamino" refers to the group -NR (CO) R 'where each R, R' is independently hydrogen or "C1-C12 alkyl" or "aryl" or "heteroaryl" or "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl. "
"Halogen" refers to atoms of fluoro, chloro, bromo and iodo.
"Sulfonyl" refers to the group "-SO2-R", wherein R is selected from H, "aryl", "heteroaryl", "C1-C12 alkyl", "C1-C12 alkyl" substituted by halogens, for example, a group -SO2-CF3, "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl".
"Sulfoxy" refers to a group "-S (O) -R", wherein R is selected from H, "C1-C12 alkyl", "C1C12 alkyl" substituted by halogens, for example, a -SO-CF3 group, " aryl "," heteroaryl "," C1-C12 alkyl aryl "or" C1-C12 alkyl heteroaryl ".
"Thioalkoxy" refers to -SR groups, where R includes "C1-C12 alkyl" or "aryl" or "heteroaryl" or "C1-C12 alkyl aryl" or "C1-C12 alkyl heteroaryl". Preferred thioalkoxy groups include thiomethoxy, thioethoxy and the like.
"Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the compounds specified below of formula (I). Examples of such salts include, but are not limited to, base addition salts formed by reacting compounds of formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation such as those selected in the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (for example, calcium or magnesium), or with a primary, secondary or tertiary organic alkylamine. The amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2-ethylenediamine, tromethamine, ethanolamine, diethanolamine, Ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are contemplated within the scope of the present invention.
It also comprises salts that are formed from acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), as well as salts formed with organic acids such as acid acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid and polygalacturonic acid .
"Enantiomeric excess" (ee) refers to products that are obtained by asymmetric synthesis, that is, a synthesis that involves non-racemic and / or reactive starting materials or a synthesis that comprises at least one enantioselective stage, by means of the which provides a surplus of an enantiomer in the order of at least about 52%. In the absence of an asymmetric synthesis, for example, the corresponding esters of the
5 substituted methyleneamides of formula I, racemic products are generally obtained which, however, also have a PTP inhibitory activity.
Said formula also comprises its tautomers, its geometric isomers, its optically active forms, diastereoisomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the formula (I) are base addition salts formed by the reaction of
10 compounds of formula (I) with pharmaceutically acceptable bases such as N-methyl-D-glucamine, tromethamine, sodium, potassium or calcium salts of carbonates, bicarbonates or hydroxides.
The substituted methylenamide derivatives according to the present invention are those of formula (I): image 1
Formula (I) also comprises geometric isomers, optically active forms, including enantiomers, diastereomers and their racemate forms, as well as pharmaceutically acceptable salts thereof.
The substituents R1, R2a, R2b and Cy in the formula (I) are defined as follows:
R1 is selected from the group consisting of (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-C12) alkyl aryl or (C1-C12) alkyl heteroaryl, (C2-C12) alkenyl 20 or heteroaryl, (C2-C12) alkynyl aryl or heteroaryl.
In a preferred embodiment of the present invention, R1 is A, wherein A is aryl, heteroaryl, heterocycloalkyl (3-8 member) or cycloalkyl (3-8 member), in particular a phenyl.
R2a
and R2b are each independently selected from the other from the group comprising or consisting of H or (C1-C12) alkyl, preferably R2a and R2b are each H. 25 Cy is a) a thienyl or phenyl group substituted with any of the following :  a phenyl;  an oxadiazole group;
 1 or 2 moieties selected from the group consisting of –NH-CO-R3, -SO-NR3R3 'or -CO-NR3R3', in which R3, 30 R3 'are independently selected from H and (C1-C15) alkyl ;
b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl; c) when R2a and R2b are each H and R1 is -CH2-A being A phenyl or thienyl, optionally substituted by cyano, halogen, methoxy, hydroxy, phenoxy, -NO2 or trifluoromethyl,
a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7) alkyl
35 C15); od) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group,
a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3 or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl. According to one embodiment, R3 'is H and R3 is selected from the group consisting of dodecyl, octyl, pentadecyl,
tridecyl, (2-ethyl-) hexyl. According to another embodiment, Cy is substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl.
According to another embodiment, R2a and R2b are each H, R1 is -CH2-A, being A phenyl or thienyl, optionally
substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2, trifluoromethyl, while Cy is a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is alkyl (C7 -C12), particularly (C8-C12) alkyl and more particularly a dodecyl group.
Alternatively, R3 is (C7-C15) alkyl, particularly (C8-C15) alkyl and more preferably a dodecyl group.
The most preferred compounds are those of formula (I ') image 1
wherein R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group;
Cy is a phenyl or biphenyl group substituted with -NH-CO-R3, -CO-NH-R3 or an oxadiazole group substituted with R3 in which R3 is (C7-C15) alkyl, particularly (C8-C15) alkyl and more particularly a dodecyl group. Intermediate compounds or prodrugs that can be transformed to produce derivatives of
Substituted methylenamide of formula (I) by hydrolysis are esters of the compounds of formulas (I-1) and (I-2) and include the following: benzyl 4 - ({benzyl [ethoxy (oxo) acetyl] amino} methyl) ) ethyl benzoate (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate benzyl 4 - ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl (benzyl] amino} methyl) benzoate ethyl oxo { {4 - [(pentadecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} ethyl acetate {(4 - {[dodecyl] (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino } - (oxo) acetate 20 tert-butyl 4 - {{4 - [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} piperidine-1-carboxylate tert-butyl 4 - {{4 - [(dodecylamino ) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} piperidine-1-carboxylate ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) ethyl acetate {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetate tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) -acetyl] amino } -methyl) -piperidine-1-carboxylate ethyl {{4 - [(tert-butoxycarbonyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetate ethyl {(4-aminobenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo ) ethyl acetate oxo {[4- (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} ethyl acetate [benzyl (4 - {[4- (hexyloxy) benzoyl] amino} benzyl) amino] (oxo) ethyl acetate (benzyl {4 - [(tert-butoxycarbonyl) amino] benzyl} amino) (oxo) ethyl acetate [(4-aminobenzyl) (benzyl) arnino] (oxo) ethyl acetate oxo {[4- (trifluoromethyl) benzyl] [ 4- (undec-10-enoylamino) benzyl] amino} ethyl acetate oxo {{4 - [(9E) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} -acetate ethyl {benzyl [4 - (tridecanoylamino) benzyl] amino} (oxo) ethyl acetate {{4 - [(2-hydroxydecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetate 35 ethyl oxo {[4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} -ethyl acetate {({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
tert-butyl 4 - ({{4 - [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} -methyl) -piperidine-1-carboxylate
ethyl [{4 - [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] piperidin-4-yl} methyl) amino] (oxo) acetate
ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} (oxo) acetate
ethyl (benzyl {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate
ethyl [benzyl ({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate
tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} methyl) -piperidine-1-carboxylate
ethyl [{4 - [(dodecylamino) carbonyl] benzyl} (piperidin-4-ylmethyl) amino] (oxo) acetate
ethyl [cyclopentyl ({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate
Another aspect of the present invention is the use of the compounds of formula (I) as a medicament.
Preferred substituted methyleneamide derivatives are those wherein R2a and R2b are each H, R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2, trifluoromethyl, Cy is a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C15) alkyl, particularly (C8-C15) alkyl and more particularly a dodecyl group.
Particularly preferred substituted methyleneamide derivatives are those wherein R2a and R2b are each H, R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with (C1-C6) alkyl or a cycloalkyl group , Cy is a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl , particularly (C8-C15) alkyl and more particularly a dodecyl group.
The compounds of formula (I) are useful in the treatment and / or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia comprising type I and / or II diabetes, inadequate glucose tolerance, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity or polycystic ovary syndrome (PCOS).
In one embodiment, the compounds according to formula (I) are particularly useful in the treatment and / or prevention of type II diabetes, obesity and for the regulation of appetite in mammals.
The compounds according to formula (I) are suitable for the modulation of the activity of PTP, in particular of PTP1B. Therefore, it is believed that the compounds of the present invention are useful for the treatment and / or prevention of disorders that are mediated by PTP, in particular PTP1B. Such treatment involves the modulation, notably down-regulation or inhibition, of PTP, particularly PTP1B.
Another aspect of the present invention is related to a pharmaceutical composition comprising a methyleneamide derivative according to Formula (I) and at least one other drug (in particular an anti-diabetes agent). In one embodiment, the other agents for diabetes are selected from the group comprising or consisting of insulin (or insulin mimics), aldose reductase inhibitors, alpha-glucosidase inhibitors, sulfonylurea agents, biguanides (e.g., metformin), thiazolidines (e.g., pioglitizona, rosiglitizona, cf. WO 02/100396) or PPAR agonists, or c-Jun Kinase or GSK-3 inhibitors.
Insulins useful with the method of the present invention include fast-acting insulins, intermediate-acting insulins, long-acting insulins, and combination of fast-acting and intermediate-acting insulins.
Aldose reductase inhibitors useful in the method of the present invention include those known in the art. These include the non-taxable list of:
a) the spiro-isoquinoline-pyrrolidine tetrone compounds disclosed in US Patent No. 4,927,831 (Malamas), which includes ARI-509, also known as minalrestat or Spiro [[isoquinoline-4 (1H), 3 '-pyrrolidine] -1,2', 3,5 '(2H) -tetrone and analogs thereof,
b) 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluoro- (9CI);
c) the compounds of US Patent No. 4,439,617, which includes Tolrestat, also known as Glycine, N - [[6-methoxy-5- (trifluoromethyl) -1-naphthalenyl] thioxomethyl] -N-methyl - (9CI) or AY27773 and the like thereof;
d) Sorbinil (Record No. 68367-52-2), also known as Espiro [4H-1-benzopyran-4,4'imidazoline] -2'5'-dione, 6-fluoro-2,3-dihydro-, (4S) - (9CI) or CP 45634;
e) Metosorbinil;
f) Zopolrestat, which is 1-phthalazineacetic acid, 3,44-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2benzothiazolyl] methyl] - (9CI) (Registration No. 110703-94-1); g) Epalrestat, which is 3-thiazolidineacetic acid, 5 - [(2E) -2-methyl-3-phenyl-2-propenylidene] -4-oxo-2-thioxo-, (5Z) - (9CI) (Registration No 82150-09-9); h) Zenarestat (Registration No. 112733-40-6) or 3 - [(4-Bromo-2-fluorophenyl) -methyl] -7-chloro-3,4-dihydro2,4-dioxo-1 (2H) - acetic quinazoline; i) Imirestat, also known as 2,7-difluorospiro (9H-fluorene-9,4'-imidazolidine) -2 ', 5'-dione; j) Ponalrestat (Record No. 72702-95-5), which is 1-phthalazineacetic acid, 3 - [(4-bromo-2-fluorophenyl) methyl] 3,4-dihydro-4-oxo- (9CI) and also known as Stalil or Statil; k) ONO-2235, which is 3-thiazolidineacetic acid, 5 - [(2E) -2-methyl-3-phenyl-2-propenylidene-4-oxo-2-thioxo-, (5Z) - (9CI); l) GP-1447, which is {3 - [(4,5,7-trifluorobenzothiazol-2-yl) methyl] -5-methylphenylacetic acid}; m) CT-112, which is 5- (3-ethoxy-4-pentyloxyphenyl) -2,4-thiazolidinedione; n) BAL-ARI 8, which is Glycine, N [(7-fluoro-9-oxo-9H-xanten-2-yl) sulfonyl] -N-methyl-) 9CI), Reg. No. 124066-40-6 ));
o) AD-5467, which is 2,3-dihydro-2,8-bis (1-methyl ethyl) -3-thioxox-4H-1,4-benzoxazine-4-acetic acid of the chloride salt form (Acid 4H-1,4-benzoxazine-4-acetic acid, 2,3-dihydro-2,8-bis (1-methylethyl) -3-thioxo- (9CI);
p) ZD5522, which is (3 ', 5'-dimethyl-4'-nitrometylsulfonyl-2- (2-tolyl) acetanilide); q) 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-l, 4-benzoxazine-4-acetic acid; r) 1 - [(3-Bromo-2-benzofuranyl) sulfonyl] -2,4-imidazolidinedione (M-16209), s) NZ-314, which is 1-imidazolidineacetic acid, 3 - [(3-nitrophenyl) methyl ] -2,4,5-trioxo-9 (CI) (Registration
No. 128043-99-2), t) 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3 - [(5-trifluoromethyl) -2-benzothiazolyl] -methyl]; u) M-79175, which is Spiro [4H-1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione; 6-fluoro-2,3-dihydro-2
methyl-, (2R, 4S) - (9CI); v) SPR-210, which is 2H-1,4-benzothiazine-2-acetic acid, 3,4-dihydro-3-oxo-4 - [(4,5,7-trifluoro-2benzothiazolyl) methyl] - (9CI ); w) Spiro [pyrrolidine-3,6 '(5'H) -pyrrolo [1,2,3-de] [1,4] benzoxazine] -2,5,5'-trione, 8'-chloro-2'-3'-dihydro (9CI) (also known as AND 138 or 8-chloro-2 ', 3'-dihydrospiro [pyrolizine-3,6' (5H) -pyrrolo [1,2,3-de] - [1 , 4] benzoxazine] 2,5,5'-trione); x) 6-fluoro-2,3-dihydro-2 ', 5'-dioxo- (2S-cis) -spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamide (also known as SNK -860);
or a pharmaceutically acceptable salt form of one or more of these compounds.
Preferred aldose reductase inhibitors include minalrestat, Tolrestat, Sorbinil, Metosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat and Ponalrestat or the pharmaceutically acceptable salt forms thereof.
Alpha-glucosidase inhibitors useful for the method of the present invention include miglitol or acarbose or the pharmaceutically acceptable salt form thereof.
Sulfonylurea agents useful with the method of the present invention include glipizide, Gliburide (Glibenclamide) Chlorpropamide, Tolbutamide, Tolazamide and Glimepiride or the pharmaceutically acceptable salt forms thereof.
Preferably, said complementary pharmaceutically active agent is selected from the group consisting of a fast acting insulin, an intermediate acting insulin, a long acting insulin, a combination of intermediate and fast acting insulins, Inalrestat, Tolrestat, Sorbinil, Metosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat, Ponalrestat, ONO-2235, GP-1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M16209, NZ-314, M-79175, SPR-210, DNA 138 or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Another additional object of the invention is a process for preparing substituted methyleneamide derivatives according to formula I.
The substituted methyleneamide derivatives of the present invention can be prepared from materials of
5 Item easily available using the following general methods and procedures. It will be appreciated that when typical or preferred experimental conditions are provided (ie, reaction temperatures, time, moles of reagents, solvents, etc.) other experimental conditions can also be used, unless otherwise indicated. Optimum reaction conditions may vary with the particular reagents or solvents used, but such conditions may be determined by one skilled in the art by means of
10 routine optimization procedures.
The compounds of formula (Ia) are obtained by means of the following general methods and procedures. image 1
The substituents of (Ia) are as defined above and R8 is H, (C1-C6) alkyl or a cycloalkyl group (3-8 members).
In general, substituted methylamide derivatives according to general formula (I) can be obtained by means of several processes, using both solution phase and solid phase chemistry protocols. Depending on the nature of Cy, R1, R2a, R2b and R8, some processes will be preferred before others, with the person skilled in the art assuming this selection of the most suitable process.
Preparation using phase in solution:
In general, the substituted methylenamide derivative of formula (I) can be obtained by the initial synthesis of the esters (Ia) and subsequent hydrolysis to give rise to the substituted methyleneamide derivative of the general formula (I).
a) Methylenamide derivatives substituted by carboxamide and sulfonamide of formula (I)
The general preparation of carboxamide and sulfonamide substituted methylenamide derivatives of formula (I), wherein R1, R2a, R2b and Cy are as defined above, will be illustrated below (see Scheme A below).
The substituted methyleneamide derivatives of formula (I) can be prepared by coupling the corresponding carboxylic acid derivatives (LG2-CO-CO-R8), wherein LG2 is a suitable leaving group -including CI, Nhydroxysuccinimide or benzotriazol-1-yl- and the primary or secondary amine Cy-CR2aR2b-NHR1. The preparation of said amide derivatives is carried out using conditions and methods well known to those skilled in the art to prepare an amide bond from an amine and a carboxylic acid or carboxylic acid derivative (for example, acid chloride ), with standard coupling agents, such as, for example, DIC, EDC, TBTU, DECP, DCC, PyBOP®, isobutyl chloroformate and others in the presence or absence of bases such as TEA, DIEA, NMM in a suitable solvent such such as DCM, THF or DMF. The substituted methylenamides of formula (la) are then subjected to hydrolysis using hydroxide (eg, NaOH) and leading to the desired compounds of
35 Formula (I). image 1
The general preparation according to the invention also includes compounds of Formula (I), in which Cy is particularly substituted by -CO-NR3R3 ', -NH-CO-R3 or -SO2-R3R3' as described in the schemes a then, where R3 and R3 'are as defined above, and where the chemical transformations of the
5 compounds of formula (Ia) also allow obtaining the compounds of formula (I).
b) Methylenamide derivatives substituted by carboxamide and sulfonamide of formula (I-1)
The general preparation of carboxamide and sulfonamide substituted methyleneamide derivatives of formula (I-1), that is, compounds of formula (I), wherein Cy is as defined above and replaced with -CO-NR3R3, will be illustrated below. '(X = -CO-) or -SO2-NR3R3' (X = -SO2-) (see Scheme 1 below).
The substituted methyleneamide derivatives of formula (I-1), wherein Cy is substituted with -CO-NR3R3 ', can be prepared from the corresponding carboxylic acid derivatives (II-1), wherein LG1 is a leaving group suitable -which includes OH, Cl, O-alkyl or O-aralkyl- and from a primary or secondary amine -NHR3R3 ', wherein R3, R3' are independently selected from each other from the group consisting of H, (C1-alkyl) -C15), (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C2) alkyl
C12) aryl or heteroaryl, (C2-C12) alkenyl, aryl or heteroaryl, (C2-12) alkynyl, aryl or heteroaryl. A general protocol for such preparation is provided later in the Examples (see Method A), using conditions and methods well known to those skilled in the art to prepare an amide bond from an amine and a carboxylic acid or acid derivative. carboxylic (for example, acid chloride), with standard coupling agents, such as, for example, DIC, EDC, TBTU, DECP, DCC, PyBOP®, isobutyl chloroformate or others in
The presence or absence of bases such as TEA, DIEA, NMM, in a suitable solvent such as DCM, THF or DMF.
Substituted methyleneamides of formula (I-1), wherein Cy is substituted with -SO2-NR3R3 '(X = -SO2-) can also be prepared from the corresponding sulfonic acid derivatives (II-1), where LG1 is a leaving group such as, for example, OH, CI, O-Alkylaryl or O-Alkyl, and a primary or secondary amine NHR3R3 '(see Scheme 1; Method A).
Method A image 1
The carboxylic acid and sulfonic acid (II-1) derivatives (where X = -CO- or -SO2-) can be obtained from the corresponding amine (III-1 '), where P = H, by coupling with the ester as indicated in Step 1. Thus, LG2 is a leaving group (for example, CI, N-hydroxysuccinimide, benzotriazol-1-yl).
Said amines (III-1 '), in which P is H, can be obtained by deprotection of their corresponding protected form, wherein P is a protective group such as, for example, Boc or Fmoc. For all protection and unprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", 3rd edition,
10 John Wiley & Sons Inc., 1999 (NY).
According to another process, the substituted methyleneamides of formula (I-1), wherein Cy is substituted with -CONR3R3 'or -SO2NR3R3' (X = -CO- or -SO2-), can be prepared from the corresponding amines (III-1) by means of coupling with the LG2-CO-CO-OR8 ester wherein R8 is an alkyl group and LG2 is a leaving group such as for example CI, N-hydroxysuccinimide or benzotriazol-1-yl, such as described above in Scheme 1
15 (Method B).
Compounds (III-1), wherein P is H or any protective group such as Boc or Fmoc, can be prepared by adding the corresponding carboxylic acid or sulfonic acid (III-1 ') derivatives (X = -CO- , X = SO2- respectively), whereby LG1 is a leaving group such as OH, Cl or O-alkyl, with primary NHR3R3 'amines following solution phase chemistry protocols such as those described in
20 Examples and are shown in Scheme 1 (Method B).
c) Substituted methylenamide derivatives of formula (I-2)
According to another process, the substituted methylenamide derivatives of formula (I-2), that is, substituted methyleneamide derivatives of formula (I), wherein Cy is substituted with -NR3COR3 'and R3 and R3' are as defined above, they can be prepared from the corresponding amine (II-2), where P 'is H, and LG1-CO-R3' (XI) (X
25 = -CO-) following the protocols described in the Examples and shown in Scheme 2 (Method C). LG1 is a suitable leaving group such as, for example, CI, OH or O-alkyl. image 1
The amines of formula (II-2), where P 'is H, can be obtained by deprotection of their corresponding protected form, where P' is a protective group such as, for example, Boc or Fmoc.
The amines of formula (II-2), wherein P 'is H or any protective group such as Boc or Fmoc, can be obtained from the corresponding amine (III-2'), where P is H, by means of coupling with the ester as indicated in Step 1. Thus, LG2 is a protective group (for example, CI, N-hydroxysuccinimide, benzotriazol-1yl).
Said amines (III-2 '), where P is H, can be obtained by deprotection of their corresponding protected form, where P is a protective group such as, for example, Boc or Fmoc.
According to one embodiment, the substituted methyleneamide derivatives of formula (I-2), wherein Cy is as defined above, can be substituted by -NR3COR3 'and can be prepared from the corresponding amines (III-2), wherein P is H, by coupling the LG2-CO-COOR8 ester, where R8 is (C1-C6) alkyl, preferably ethyl or methyl, and LG2 is a leaving group as described above (see Scheme 2 ( Method D)).
The amines (III-2), where P is H, can be obtained by deprotection of their corresponding protected form, where P is a protective group such as Boc or Fmoc.
Compounds (III-2), wherein P is H or any protective group such as Boc or Fmoc, are prepared by adding the corresponding amines (III-2 '), where P' is H, with derivatives of formula LG1-CO-R3 '(XI) (X = CO-), whereby LG1 is a suitable leaving group such as, for example, CI, OH or O-alkyl following the protocols described in the Examples and as shown above in Method D.
Compounds of formula (I-2), wherein X is different from carbonyl functionality can be prepared by replacing compounds of formula (XI) with those containing the appropriate functional groups, for example, sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates , substituted alkyl halides, epoxides and others to provide sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, α, β-substituted amino alcohols or others, respectively.
d) Preparation of the precursor compounds of formula (I-3)
According to another process, the substituted methylenamide derivatives of formula (I-3), that is, substituted methyleneamide derivatives of formula (I), wherein Cy is substituted with an oxadiazole (as an example for a heteroaryl) and R3 it is as defined above, they can be prepared from the corresponding acid derivative of formula (II-1), wherein LG1 is a suitable leaving group such as, for example, CI, OH or O-alkyl imide oxime of formula ( X) following protocols such as those described in the Examples and shown in Scheme 3 (Method E). Therefore, the starting acid derivatives of formula (II-1) are reacted with imide oxime of formula (X) using standard coupling agents, such as DIC, EDC, TBTU, DECP, DCC, PyBOP®, Isobutyl chloroformate and others in a suitable solvent such as DCM, followed by exposure to a base, such as pyridine, to promote cyclisation provided by the oxadiazole of formula (I-3).
According to an alternative process, the substituted methyleneamides of formula (I-3) can be prepared from the corresponding amines (III-3) by coupling with the LG2-CO-CO-OR8 ester where R8 is a group alkyl or cycloalkyl and LG2 is a leaving group such as, for example, Cl, N-hydroxysuccinimide or benzotriazol1-yl, as described in Scheme 3 (Method F).
The compounds (III-3), where P is H, can be obtained by deprotection of their corresponding protected form, where P is a protective group such as, for example, Boc or Fmoc.
Compounds (III-3), wherein P is H or any protective group such as Boc or Fmoc, can be prepared from its precursor of formula (III-1 ') and amide oxime of formula (X) following the protocols such as those described in the Examples and shown in Scheme 3 (Method F).
10 Scheme 3 image 1
e) Preparation of the precursor compounds of formula (I-4)
According to another process, the substituted methylenamide derivatives of formula (I-4), that is, substituted methyleneamide derivatives of formula (I), wherein Cy is substituted with X, and X is a halogen atom (for example ,
Br, I, Cl) or a suitable leaving group such as -OSO2CF3, can be prepared from the corresponding acid derivative of formula (II-4), following protocols such as those described in the Examples and shown in the Scheme 4 (Method G).
Therefore, the derivatives of formula (II-4) can be reacted with a substituted alquina of formula (XII) in the presence or not of additives, such as copper (I) salts together with palladium catalysts (eg tetrakis
20 (triphenylphosphine) palladium, and amines (eg, triethylamine). Preferred conditions involve the use of copper (I) bromide, tetrakis (triphenylphosphine) palladium in triethylamine, for example 90˚C.
According to another process, the substituted methyleneamides of formula (I-4) can be prepared from the corresponding amines (III-4) by coupling with the LG2-CO-CO-OR8 ester wherein R8 is an alkyl group and LG2 is a leaving group such as CI, N-hydroxysuccinimide or benzotriazol-1-yl, as described in the
25 Scheme 4 (Method H).
The compounds (III-4), where P is H, can be obtained by deprotection of their corresponding protected form, where P is a protective group (for example, Boc or Fmoc).
The compounds (III-4), where P is H or any protective group (for example Boc or Fmoc), can be prepared from its precursor of formula (III-4 ') and an alquina of formula (XII) following protocols as described in
30 the Examples and is shown in Scheme 4 (Method H).
G method image 1
f) Preparation of the precursor compounds of formula (III)
The precursor compounds of the formulas (III), (including III-1 ', III-1, III-2', III-2, III-3, III-4 or III-4 ') mentioned in Schemes 1, 2, 3 and 4, where Cy may be substituted with a Q moiety, such as a substituted or unsubstituted aryl
or substituted or unsubstituted heteroaryl, for example, an oxadiazole, a substituted or unsubstituted cycloalkyl moiety or -CONR3R3 ', -COOR3, -NP'R3, -NR3COR3', -CO-LG1, -SO2NR3R3 ', -C≡C-R3 wherein R3 and R3 'may be independently substituted from each other, substituted or unsubstituted (C1-C15) alkyl or X where X is as defined in e), may be prepared from the corresponding precursors of formulas (VII), (VIII) or (IX) using a
10 variety of synthetic strategies for which some examples are indicated in Scheme 5 below.
 The compounds of formula (III), wherein 2Rb is H, can be prepared, for example, by alkylation of the amines (IV), where R1 is as defined above and where P is H or a suitable protecting group such as, for example, Boc or Fmoc, with the carbonyl derivatives (IX), wherein R2a is as defined above. The reaction (see Scheme 5, Method I) can be carried out in the presence of a
Suitable reducing agent, including NaBH (OAc) 3, NaBH3CN, NaBH4 or hydrogen and an appropriate catalyst such as Pd / C or PtO2.
• Alternatively, the compounds of formula (III) can be prepared by alkylation of amines of formula
(IV) with the derivatives of formula (VIII), wherein LG is a suitable leaving group that includes CI, Br, I, OH, OMs, OTs (see Method J). R2a and R2b are as defined above.
In addition, the compounds of formula (III) can be prepared by alkylation of amines of formula (VII) with the alkylating agents of formula (VI), wherein LG is the leaving group mentioned above (Scheme 5, Method K).
 Another additional alternative is presented in Scheme 5, Method L. This embodiment illustrates the preparation of compounds of formula (III) by alkylation of the amines of formula (VII) with carbonyl derivatives (V), wherein A is as defined above, in the presence of a reducing agent such as, for example, NaBH (OAc) 3, NaBH3CN, NaBH4 or hydrogen with an appropriate catalyst such as, for example, Pd / C or PtO2, to provide compounds of formula (III ), wherein R1 is -CH-R5-A in which R5 is selected from the group consisting of (C1-C12) alkyl, preferably (C1-C6) alkyl, (C2-C12) alkenyl, (C2C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8-membered), (C1-C12) alkyl or (C1-alkyl)
C12) -heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl. image 1
The precursor compounds of the formulas (IV), (V), (VI), (VII), (VIII) or (IX) are commercially available or readily obtainable from commercial starting materials such as those selected from:
(dl) -trans-2-benzyloxycyclopentylamine, 1- (1-naphthyl) ethylamine, 1,2,3,4-tetrahydro-1-naphthylamine, 1,2-dodecylene oxide, 1-aminoindane, 1-deoxy-1 - (methylamino) glucitol, 2-amino-2-hydroxymethyl) -1,3-propanediol, 2- (2,4,6-trimethyl-phenyl) ethylamine, 2- (3-chlorophenyl) ethylamine, 2- (3- methoxyphenyl) ethylamine, 2- (4-biphenyl) ethylamine, 2- (4-methoxyphenyl) ethylamine, 2,2-diphenylethylamine, 2-amino-1-methoxypropane, 2-fluorobenzaldehyde, 2-formylthiazole, 2-morpholino-1,3- Thiazol-5carbaldehyde, 2-phenoxyphenethylamine, 2-phenylglycine ethyl ester hydrochloride, 2-pyridinecarboxaldehyde, 2-quinoxaloyl hydrochloride, 2-thiophenecarboxaldehyde, 3- (benzyloxy) aniline, 3- (trifluoromethyl) benzaldehyde 3,3-benzaldehyde , 3,5-dichlorobenzylamine, 3-aminophenyl sulfone trifluoromethyl, 3-carboxybenzaldehyde, 3-chlorobenzaldehyde, 3cianobenzaldehído, 3-hydroxybenzaldehyde, 3-iodobenzoyl hydrochloride, 3-nitrobenzaldehyde, 3fenilbencilamina hydrobromide, 3-phenylpropylamine, 3-pyridinecarboxaldehyde, 3 -thiophenecarboxaldehyde, 4- (1,2,3-thiadiazol-4-yl), benzylamine hydrochloride, 4- (aminomethyl) -1-N-Boc-aniline, 4- (dimethylamino) phenyl isocyanate, 4- (methylsulfonyl) benzaldehyde, 4- (trifluoromethyl) benzylamine, 4-amino-1-benzylpiperidine, 4-benzamidobenzylamine, 4-bromoaniline, 4-chloromethylbenzoyl chloride, 4-chloro-benzaldehyde, 4-cyanobenzaldehyde, 4-dimethylaminobenzaldehyde, 4-formic acid benzyl 4-formyl-benzoic acid benzyl, 4-hydroxybenzaldehyde, 4-methoxybenzene-sulfonyl chloride, 4-nitrobenzaldehyde, 4-n-pentylbenzylamine hydrochloride, 4-pentylbenzylamine hydrochloride, 4-phenoxyaniline, 4-phenoxybenzylamine-4-phenoxyamine , 4-phenoxyphenethylamine, 4-phenylbutylamine, 4-pyridinecarboxaldehyde, 4-tolyl boronic acid, 5-formyl-2-thiophenecarboxylic acid, 6- (trifluoromethyl) pyridine-3carboxaldehyde, aniline, benzaldehyde, benzoylperoxide, benzyloxy acid, ethyl chloro -acetic, cis-delta chloride 9-trans-tetradecenoyl, cycle hexyl isocyanate, cyclopentanone, dl-3-amino-3-phenylpropionic acid, dI-alphamethyl-benzyl-amine, dodecylamine, Fmoc- (3-aminomethyl) -benzoic acid, Fmoc- (4-aminomethyl) -benzoic acid, chloride hexanoyl, isopropylamine, lithium hydroxide monohydrate, t-butyl ester of 1-phenylglycine, methyl 4formylbenzoate, N-bromo-succinimide, octylamine, p-anisaldehyde, pentadecylamine, piperonal, piperonylamine, sodium cyanoborohydride, sodium triacetox, and sodium triacetox tetrabutylammonium, tetradec-9-enoyl chloride, tetrakis-triphenylphosphine palladium (0), thiophene-2-ethylamine, trans-2-phenyl-cyclopropylamine hydrochloride, trans-3 (trifluoromethyl) cinnamoyl chloride, tridecanoic acid, tridecanoyl chloride .
A preferred process for preparing compounds of formula (III) is indicated in Scheme 5 above, Method I. There, the reductive amination of carbonyl compounds of formula (IX), wherein Q is -COO-Bn, is carried out with amines of formula (IV) and a reducing agent such as NaBH (OAc) 3 in a suitable solvent such as DCE or THF. The process, therefore, provides the amine of formula (III), wherein Q is C (O) OBn.
According to the methods described in Scheme 1 (Method A), the resulting amine (III) is coupled with an LG2-CO-COO-R8 ester, wherein R8 is a (C1-C6) alkyl or cycloalkyl, preferably ethyl or methyl, and LG2 is a leaving group such as, for example, CI, in the presence of a base such as DIEA in an aprotic solvent (such as, for example, DCM or THF), thus providing substituted methylenamide derivatives of formula ( II-1). Deprotection of subsequent benzyl using standard methods of H2 / Pd and followed by coupling of the resulting acid, wherein X is CO and LG1 is -OBn, with amines -NHR3R3 ', with the use of standard carbodiimide-mediated, or anhydride-mediated methods. mixed standard, provides the desired compounds of formula (I-1), wherein R 8 is ethyl or methyl (see Scheme 1). These latter compounds can be hydrolyzed to provide compounds of formula (Ia) of the present invention, wherein R 8 is H, by treatment with a hydroxide such as, for example, NaOH in an appropriate protic solvent (such as for example EtOH ), followed by acidification of the reaction mixture.
According to another preferred process of preparing compounds of formula (Ia), carbonyl derivatives of formula (IX) (see Scheme 5), wherein Q is -CONR3R3 'can be prepared from its precursor of commercially available starting materials available or readily obtainable in which Q is -COOH and HNR3R3 'amines using standard carbodiimide or standard mixed anhydride mediated methods. The reductive amination of carbonyl derivatives of formula (IX) wherein Q is -CONR3R3 'with amines of formula (IV) and a reducing agent such as NaBH (OAc) 3 in a suitable solvent such as DCE or THF provides the amine of formula (III) wherein Q is -CONR3R3 ', followed by the methods described in Method I, Scheme 5. The resulting amine (III) is coupled with the ester LG2-CO-COO-R8, where R8 is a (C1-C6) alkyl or cycloalkyl, preferably ethyl or methyl, and LG2 is a leaving group such as CI, in the presence of a base such as DIEA in an aprotic solvent (such as, for example, DCM or THF), providing the ester (I-1). These latter compounds can be hydrolyzed to form compounds of formula (Ia) of this invention, wherein R 8 is H, by means of its treatment with hydroxide such as for example NaOH in an appropriate protic solvent (such as for example EtOH), followed by acidification of the reaction mixture.
The basic salts of the compounds of formula (I) are prepared in a conventional manner as is known to one skilled in the art. In particular, the salts of N-Me-D-glucamine and tromethamine (ie, 2-amino-2- (hydroxymethyl) -1,3-propanediol) of the present invention provide water soluble derivatives and improved bioavailability.
The methods of preparing the substituted methyleneamides of formula (I) of the present invention according to the above protocols have the specific advantage of being convenient and economical in the sense that they involve only a few steps.
g) Preparation using solid phase and / or mixed solid / solution phase:
According to another general approach, substituted methyleneamides according to the general formula (Ia), where the substituents R1, R2a, R2b and Cy are as defined above, can be prepared by solid phase and / or phase synthesis protocols. mixed solid / in solution such as those described in the examples and shown in Schemes 1, 2, 3, 4, 5 and 6 above using well-known technical approaches (such as IRORI®). One skilled in the art will appreciate that basically the same conditions, methods and reagents as described in Schemes 1,2, 3 and 4 above for the solution phase synthesis of the compounds of formula (la) can be applied to the synthesis in solid and / or mixed phase of solid / solution phase of said compounds. In the context of said solid phase / solution synthesis protocol, R3 is as defined above. The resin cleavage is carried out under acidic conditions, providing the corresponding substituted methyleneamide derivatives of formula (la). It should be understood that, in addition to the types of resin mentioned in the Examples such as, for example Sasrin aldehyde resins, other suitable reagents, particularly resins, known to one skilled in the art could be employed for solid phase synthesis of the compounds. of general formula (the).
The filled circles drawn below in Scheme 6 illustrate the resin beads to which the compounds bind during solid phase synthesis.
In a particularly preferred process, resin-bound amines of the formula NHR3R6 (D), wherein R6 represents any suitable resin (Scheme 6) and R3 defined above in the specification, are prepared from commercially available resins per se or easily obtainable, such as for example Sasrin aldehyde or bromine Wang resins and amines, using standard amination or reductive alkylation conditions well known to those skilled in the art. The NHR3R6 resin-bound amines (D) can be acylated with compounds of formula (VIII-1 ') wherein X is -CO- and LG1 is Cl using standard conditions that involve a base such as DIEA in an aprotic solvent such as DCM or THF, providing compounds of formula (VIII) (Scheme 6, Method N).
According to the methods presented in Scheme 5 (Method J), the displacement of the leaving group LG of the last intermediates bound to resin (VIII-1) by their reaction with NHPR1 (IV) amines in the presence of iodide such as TBAI or Nal in a suitable solvent, such as for example NMP at suitable temperature, such as 80 ° C, can provide resin bonded compounds of Formula (III-1). Finally, this compound is coupled with the ester LG2-CO-COO-R8, wherein R8 is preferably ethyl or methyl and LG2 is a leaving group such as CI, in the presence of a base such as DIEA in an aprotic solvent (such as , for example, DCM or THF) by providing Scheme 6 image 1
In another preferred synthetic approach (Method N), resin-bound amines of formula NHR6R3 (D), wherein R6 represents a suitable resin (Scheme 6), can be acylated with compounds of formula (VII-1 '), wherein X is -10 CO-, LG1 is OH, R1, R2a, R2b, R3 and R5 are as defined above and P is a protecting group such as Fmoc or Pht, using standard conditions that involve a coupling reagent such as PyBOP for example ®, in a suitable solvent such as NMP or DCM, which provides resin bound compounds of formula (VII-1). The same resin-bound amines of formula NHR6R3 can be sulfonylated with compounds of formula (VII-1 '), wherein X is -SO2-, LG1 is CI and P is a protecting group such as Fmoc or Pht, using standard conditions that
15 involve a base such as DIEA, which provides resin bound compounds of formula (VII-1). The latter intermediaries can be deprotected by following standard conditions and then rented following the methods presented in Scheme 5 (Method H) to provide compounds of formula (III-1). Finally, these compounds are converted into the desired substituted methyleneamides of formula (Ia), following the methods described above.
When used as pharmaceutical agents, the methyleneamide derivatives of the present invention are generally administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient are also within the scope of the present invention. One skilled in the art knows the variety of carrier compounds, diluents or excipients suitable for formulating a composition.
25 pharmaceutical.
The compounds of the invention, together with an adjuvant, carrier, diluent or excipient conventionally employed, can be placed in the form of pharmaceutical compositions and unit dosages thereof, and in such form can be used as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, all for oral use or in form
30 of sterile injectable solutions for parenteral use (including subcutaneous use). Said pharmaceutical compositions and unit dosage forms may comprise ingredients in conventional proportions, with or without additional compounds or active ingredients, and said unit dosage forms may contain any suitable effective amount of active ingredient proportional to the intended daily dosage range that should be be used
When used as pharmaceutical agents, the substituted methyleneamide derivatives of the present invention are generally administered in the form of a pharmaceutical composition. Said compositions may be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. In general, the compounds of the present invention are administered in a therapeutically effective amount. The amount of the compound actually administered will generally be determined by a doctor in light of the
40 corresponding circumstances, including the condition to be treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the symptoms of the pharmaceutical compositions of these inventions can be administered by means of a variety of pathways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically specific units useful as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampules or syringes and pre-measures of liquid compositions or pills, tablets, capsules or the like, in the case of solid compositions. In said compositions, the substituted methyleneamide derivative according to the invention is generally a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40%), the remainder being several vehicles or carriers and processing aids useful to form the desired dosage form.
Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle, suspending and dispersing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a slide such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
Injectable compositions are generally based on sterile saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the substituted methyleneamide derivatives of formula (I) in said compositions generally constitute a minor component, generally in a range between 0.05 and 10% by weight, the rest being the injectable carrier and the like.
The components described above for compositions administered orally or for injection are merely representative. Other materials, in addition to processing techniques and the like, are presented in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Marck Publishing Company, Easton, Pennsylvania.
The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the materials incorporated in Remington's Pharmaceutical Sciences.
Next, the present invention will be illustrated by means of some examples. The following abbreviations are used hereafter in the accompanying examples: min (minute), h (hour), g (gram), mg (milligram), mmol (millimol), mp (melting point), eq (equivalents), mL (milliliter), μL (microliters), APCI (chemical ionization at atmospheric pressure), ESI (electrospray ionization), L (liters), AcOEt (ethyl acetate), Boc (tert-Butoxycarbonyl), CH3CN (Acetonitrile), DBU ( diazabicyclo [5.4.0] undec-7-ene), DCC (dicyclohexyl carbodiimide), DCE (dichloroethane), DIEA (diisopropylethylamine), Fmoc (9-Fluorenylmethoxycarbonyl), CDCI3 (deuterated chloroform), c-Hex (cyclohexanes), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DMAP (4-dimethylaminopyridine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethylsulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3 -ethylcarbodiimide), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol), HOBt (1-hydroxybenzotriazole), K2CO3 (potassium carbonate), MeOH (methanol), CD3OD (deuterated methanol), M gSO4 (magnesium sulfate), NaH (sodium hydride), NaHCO3 (sodium bicarbonate), NaBH3CN (sodium cyanoborohydride), NaBH4 (sodium borohydride), NaBH (OAc) 3 (sodium triacetoxyborohydride), NMM (N- methyl morpholine), NMP (N-methylpyrrolidone), nBuLi (n-butyllithium), Pd (PPh3) 4 (tetrakis triphenylphosphine palladium), Pet ether (petroleum ether), Pht (phthalimide), PyBOP® (bentototriariate bentotriate phosphate -1-yl-oxy-tris-pyrrolidine-phosphonium), TA (room temperature), SPE (solid phase extraction), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TBTU (2- tetrafluoroborate 2- (1-H-benzotriazol-1il) -1,1,3,3-tetramethyluronium).
The HPLC, MS and NMR data provided in the examples described below were obtained as follows. HPLC: Waters Symmetry C8 50 mm x 4.6 mm column; UV detection at 254 nm; flow: 2 mL / min; Conditions A: 8 min gradient of 0.1% TFA in H2O to 0.07% THF in CH3CN; Conditions B: 10 min gradient of 0.1% TFA in H2O to 0.07% TFA in CH3CN. Semi-preparative reverse phase HPLC was obtained as follows: Supelcosil ABZ + Plus column (25 cm x 21.2 mm, 12 μm); UV detection at 254 nm and 220 nm; flow 20 mL / min; Condition C: 10 min gradient of 30% CH3CN in 0.1% TFA in CH3CN at 100% CH3CN followed by 5 min elution at 100% CH3CN. The MS data provided in the examples described below were obtained as follows: Mass spectrum: PE sciex API 150 EX (APCI or ESI) or LC / MS Waters ZMD (ESI). The NMR data provided in the examples described below were obtained as follows: 1H-NMR: Bruker DPX-300MHz.
Example 1: (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
Step a) Formation of the secondary amine of formula (III) following Method I (see Scheme 5), for example, 4- (benzylamino-methyl) -benzoic acid benzyl ester
To a solution of 4-formyl benzoic acid benzyl ester (5.00 g, 20.81 mmol) (compound described in Bioorg. Med.Chem .; 5; 9; 1873-82 (1997)) and benzylamine (2,453 g, 22.89 mmol) in DCE (150 mL) NaBH (OAc) 3 (6.175 g, 29.14 mmol) was added at once and the resulting mixture was stirred overnight at RT. 30 mL of a saturated aqueous solution of NaHCO3 to the reaction mixture, the aqueous layer was separated and extracted with DCM (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 4/1 to 1/1 in about 1 h) to provide the title compound as a colorless oil (4.780 g, 69%) . 1H NMR (CDCl3, 300 MHz) δ 7.95 (m, 2H), 7.37-7.16 (m, 12H), 5.27 (s, 2H), 3.77 (s, 2H), 3 , 70 (s, 2H). M + (ESI): 332.2. HPLC (Condition B), Tr: 4.26 min (HPLC purity: 98.5%).
Step b) Formation of the oxamic ester of formula (II-1) following Method A (see Scheme 1), for example, benzyl ester of 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] -benzoic acid
To a solution of 4- (benzylamino-methyl) -benzoic acid (4.50 g, 13.58 mmol) and TEA (2,748 g, 27.16 mmol) benzyl ester in anhydrous THF (100 mL) at 0 ° C Under an inert atmosphere, the chloro-oxo-acetic acid ethyl ester (2,781 g, 20.37 mmol) diluted in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 h. The solvent was evaporated and 100 mL of DCM was added. 20 mL of a saturated aqueous NaHCO3 solution was added and the aqueous layer was separated and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel chromatography (AcOEt / c-Hex 4/1 to 2/1 in about 1 h) to provide the title compound as a colorless oil (5.810 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 7.95 (m, 2H), 7.37-7.11 (m, 12H), 5.30 (s, 2H), 4.44 (m, 2H), 4 , 31-4.22 (m, 4H), 1.22 (t, J = 7.5 Hz, 3H), M + (APCI): 432.0. HPLC (Condition B), Tr: 7.2 min (HPLC purity: 99.4%).
Step c) Formation of the oxamic ester of formula (II-1), for example 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] benzoic acid
H2 (1 atm) was slowly bubbled through a suspension of 10% Pd / C (300 mg) in EtOH (50 mL) for 15 min at RT. To this suspension was then added a solution of benzyl ester of 4 - [(benzyl-ethoxyoxalylamino) -methyl] -benzoic acid (5,500 g, 12.75 mmol) diluted in 15 mL of EtOH. The resulting reaction mixture was stirred under H2 (1 atm) for 5 h at RT. The reaction mixture was filtered on a celite pad to remove the catalyst. The solvent was evaporated to provide the title compound as a colorless oil used in the following steps without further purification (4.217 g, 97%), 1H NMR (CDCl3, 300 MHz) δ 8.07 (m, 2H), 7, 37-7.11 (m, 7H), 4.51 (m, 2H), 4.39-4.30 (m, 4H), 1.27 (m, 3H), M- (APCI): 340, 0; M + APCI): 342.0. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 99.1%).
Step d) Formation of the oxamic ester of formula (I-1) following Method A (see Scheme 1), for example, ethyl (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate, using 1-ethyl-3- (3dimethylaminopropyl) carbodiimide hydrochloride
To a solution of 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] -benzoic acid (1500 mg, 4.39 mmol) in anhydrous THF (15 mL) at RT was added EDC (1.261 g, 6.58 mmol ) and dodecylamine (1,018 g, 5.49 mmol) under an inert atmosphere. The resulting mixture was stirred overnight at RT. The solvent was evaporated and the residue was dissolved in DCM (30 mL) and washed with a 1N aqueous solution of HCl (2 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a colorless oil. This crude product was purified by column chromatography on silica gel (AcOEt / c-Hex 3/1 to 1/1 in about 15 min) to provide the title compound as a colorless oil (500 mg, 22%). 1H NMR (CDCl3, 300 MHz) δ 7.75 (m, 2H), 7.37-7.26 (m, 7H), 6.09 (br s, 1H), 4.5 (m, 2H), 4.36-4.30 (m, 4H), 3.45 (m, 2H), 1.62 (m, 3H), 1.36-1.27 (m, 20H), 0.88 (m, 3H), M- (ESI): 507.2. HPLC (Condition A), Tr: 6.98 min (HPLC purity: 99.9%).
Step e) Formation of the oxamic acid of formula (I), for example, (benzyl {4 - [(dodecylamino) carbonyl] benzylamino) (oxo) acetic acid
To a solution of ethyl (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate (690 mg, 1.36 mmol) in EtOH (4 mL) was added a 1N aqueous solution of NaOH (1 , 36 mL, 1.36 mmol) and the resulting reaction mixture was stirred at RT for 2 h. The solvents were evaporated and the residue was dissolved in EtOAc (20 mL) and washed with a 1N aqueous solution of HCl (5 mL). The aqueous layer was separated and washed with EtOAc (2 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the title compound as a white solid (603 mg, 93%). 1H NMR (CD3OD, 300 MHz) δ 7.80 (m, 2H), 7.45-7.28 (m, 6H), 7.22 (m, 1H), 4.54 (s, 2H), 4 , 50 (s, 2H), 3.38 (t, 2H, J = 6.5 Hz), 1.64 (m, 2H), 1.38-1.21 (m, 18H), 0.88 ( t, 3H, J = 6.6 Hz), M- (ESI): 479.2 Example 2: (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid, tromethamine salt (ie , 2-amino2-hydroxymethyl) -1,3-propanediol)
A mixture of (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid (1,842 g, 3.83 mmol), tris (hydroxymethyl) amino methane (0.494 g, 3.83 mmol) and EtOH (38 mL) was heated until a homogeneous solution was obtained. The solvent was removed in vacuo and the residue was dissolved in a 9/1 mixture of H2O / EtOH. The resulting solution was then lyophilized to provide the title compound as a white fluffy powder (2,299 g, 99%). M- (LC / MS (ESI)): 479.5; M + (LC / MS (ESI)): 481.3. HPLC (Condition A), Tr: 6.0 min (HPLC purity: 98.6%). Analysis calculated for C29H40N2O4.C4H11NO3: C, 65.86; H, 8.54; N, 6.98%. Found: C, 65.10; H, 8.78; N, 6.90%
Example 3: (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid, N-methyl-D-glucamine salt (ie, 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine provided the title compound as a white solid (89%). M- (LC / MS (ESI)): 479.3; M + (LC / MS) ESI)): 481.3. HPLC (Condition A), Tr: 6.1 min (HPLC purity: 99.25%). Analysis calculated for C29H40N2O4.C7H17NO5 = 1.2 H2O: C, 61.99; H, 8.24; N, 6.02%. Found: C, 61.84; H, 8.60; N, 5.99%
Example 4: oxo {(4 - [(pentadecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid
Step a) Formation of benzyl 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) benzoate.
The same procedure used in the preparation of Example 1 (step b) but using 4-trifluoromethylbenzylamine gave the title compound as a yellow oil (74%). M + (LC / MS (ESI)): 400.3. HPLC (Condition A), Tr: 3.76 min (HPLC purity: 97.6%).
Stage b) Formation of benzyl 4 - ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoate
The same procedure used in the preparation of Example 1 (step b) but using benzyl 4 - ({[4 (trifluoromethyl) benzyl] amino} methyl) benzoate provided the title compound as a colorless oil (95%). 1H NMR (CDCl3) 300 MHz) δ 7.95 (t, 2H, J = 8.3 Hz), 7.48 (m, 2H), 7.37-7.13 (m, 9H), 5.25 (br s, 2H), 4.41 (br s, 2H), 4.27-4.18 (m, 4H), 1.20 (t, 3H, J = 7.0 Hz), M- (LC / MS (ESI)): 498.1; M + LC / MS (ESI)): 500.3. HPLC (Condition A), Tr: 6.14 min (HPLC purity: 98.9%).
Step c) Formation of 4 - ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) -benzoic acid
The same procedure used in the preparation of Example 1 (step c) but using benzyl 4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoate provided the title compound as a colorless foam (84%). M- (LC / MS (ESI)): 408.2; M + LC / MS (ESI)): 410.1. HPLC (Condition A), Tr: 4.43 min (HPLC purity: 98.9%).
Step d) Formation of ethyl oxo {{4 - [(pentadecylamino) carbonyl] benzyl} [4- (trifluoro-methyl) benzyl] amino} acetate
The same procedure used in the preparation of Example 1 (step d) but using 4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid gave the title compound as a white solid ( 78%) M- (ESI): 617.2. HPLC (Condition A), Tr: 7.54 min (HPLC purity: 97.7%).
Step e) Formation of oxo {{4 - [(pentadecylamino) carbonyl] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 [(pentadecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} -acetate provided the title compound as a foam colorless (84%). 1H NMR (CD3OD, 300 MHz) δ 7.77 (m, 2H), 7.58 (m, 3H), 7.44 (d, 1H, J = 8.3 Hz), 7.38 (d, 1H , J = 8.3 Hz), 7.30 (d, 1H, J = 8.3 Hz), 4.56-4.50 (m, 4H), 3.37 (t, 2H, J = 7, 2 Hz), 1.64 (m, 2H), 1.30 (m, 24H), 0.91 (t, 3H, J = 6.6 Hz), M- (LC / MS (ESI)): 589 ,one; M + (LC / MS (ESI)): 591.1. HPLC (Condition A), Tr: 7.25 min (HPLC purity: 98.1%).
Example 5: (benzyl {4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
Step a) Formation of the secondary amine of formula (III) following Method I (see Scheme 5), for example, 4- (benzylamino-methyl) -benzoic acid benzyl ester
To a solution of 4-formyl benzoic acid benzyl ester (5.00 g, 20.81 mmol) and benzylamine (2,453 g, 22.89 mmol) in DCE (150 mL) was added once NaBH (OAc) 3 (6.175 g, 29.14 mmol) and the resulting mixture was stirred overnight at RT. 30 mL of a saturated aqueous solution was added to the reaction mixture, the aqueous layer was separated and washed with DCM (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 4/1 to 1/1 in about 1h) to provide the title compound as a colorless oil (4.780 g, 69%). 1H NMR (CDCl3, 300 MHz) δ 7.95 (m, 2H), 7.37-7.16 (m, 12H), 5.27 (s, 2H), 3.77 (s, 2H), 3 , 70 (s, 2H) M + (ESI): 332.2. HPLC (Condition B), Tr: 4.26 min (HPLC purity: 98.5%).
Step b) Formation of the oxamic ester of formula (II-1) following Method A (see Scheme 1), for example, of the benzyl ester of 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] -benzoic acid
To a solution of 4- (benzylamino-methyl) -benzoic acid (4.50 g, 13.58 mmol) and TEA (2,748 g, 27.16 mmol) benzyl ester in anhydrous THF (100 mL) at 0 ° C Under an inert atmosphere, the ethyl ester of chloro-oxo-acetic acid (2,781 g, 20.37 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 h. Most of the solvents were evaporated and 100 mL of DCM was added. 20 mL of a saturated aqueous solution of NaHCO3 was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 4/1 to 2/1 in about 1h) to provide benzyl ester of 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] benzoic acid as a colorless oil (5.810 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 7.95 (m, 2H), 7.37-7.11 (m, 12H), 5.30 (s, 2H), 4.44 (m, 2H), 4 , 31-4.22 (m, 4H), 1.22 (m, 3H). M + (APCI): 432.0. HPLC (Condition B), Tr: 7.2 min (HPLC purity: 99.4).
Step c) Formation of the oxamic ester of formula (II-1), for example, 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] benzoic acid
H2 (1 atm) was slowly bubbled through a suspension of 10% Pd / C (300 mg) in EtOH (50 mL) for 15 min at RT. To this suspension was then added a solution of 4 - [(benzyl-ethoxy-oxalylamino) -methyl] -benzoic acid benzyl ester (5,500 g, 12.75 mmol) diluted in 15 mL of EtOH. The resulting reaction mixture was stirred under 1 atm of H2 for 5 h at RT. The reaction mixture was filtered on a celite pad to remove the catalyst. The EtOH was evaporated to provide the title compound as a colorless oil used in the following steps without further purification (4.217 g, 97%). 1H NMR (CDCl3, 300 MHz) δ 8.07 (m, 2H), 7.37-7.11 (m, 7H), 4.51 (m, 2H), 4.39-4.30 (m, 4H), 1.27 (m, 3H). M- (APCI): 340.0; M + (APCI): 342.0. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 99.1%).
Step d) Formation of the oxamic ester of formula (I-1) following Method A (See Scheme 1), for example ethyl (benzyl {4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) acetate, using cyclohexylcarbodiimide supported
To a solution of 4 - [(benzyl-ethoxyoxalyl-amino) -methyl] -benzoic acid (102 mg, 0.3 mmol) and pentadecylamine (39.9 mg, 0.2 mmol) in DCM (2 mL) was added at once the N-cyclohexylcarbodiimide, N-methyl polystyrene HL (Novabiochem, 355 mg, 0.6 mmol, charge: 1.69 mmol / g) and the resulting mixture was stirred overnight at RT. The resin was filtered and the solvents evaporated in vacuo to provide a colorless oil. This crude product was purified by silica gel column chromatography (EtOAc) to provide the title compound as a colorless oil (39 mg, 35%). 1H NMR (CDCl3, 300 MHz) δ 7.75 (m, 2H), 7.37-7.26 (m, 7H), 6.13 (br s, 1H), 4.5 (m, 2H), 4.36-4.30 (m, 4H), 3.45 (m, 2H), 1.62 (m, 2H), 1.36-1.27 (m, 26H), 0.88 (t, J = 8.0 Hz, 3H), M- (APCI): 549.1; M + (APCI): 551.4
HPLC (Condition A), Tr: 7.46 min (HPLC purity: 98.2%).
Step e) Formation of the oxamic acid of formula (I-1), for example, (benzyl {4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
To a solution of ethyl (benzyl {4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) acetate (28.0 mg, 0.051 mmol) in EtOH (1 mL) was added NaOH (14.9 mg, 0, 37 mmol) dissolved in H2O (0.37 mL) and the resulting reaction mixture was stirred at RT for 2 h. The solvents were evaporated and then EtOAc (5 mL) and a 1N aqueous solution of HCl (1 mL) were added to the residue. The aqueous layer was separated and extracted with EtOAc (2x 5mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a white solid (27.5 mg, 96%). 1H NMR (CD3OD, 300 MHz) δ 7.70 (m, 2H), 7.37 (d, 1H, J = 8.3 Hz), 7.30-7.10 (m, 6H), 4.39 (m, 4H), 3.26 (t, 2H, J = 7.0 Hz), 1.54 (m, 2H), 1.26 (m, 24H), 0.90 (t, J = 7, 5 Hz, 3H), M (APCI): 521.6. HPLC (Condition A), Tr: 6.96 min (HPLC purity: 98.4%).
Example 6: (benzyl {4 [(tridecylamino) carbonyl] benzyl} amino (oxo) acetic acid
Stage a) Formation of ethyl (benzyl {4 - [(tridecylamino) carbonyl] benzyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 5, step d, but using tridecylamine provided the title compound as a colorless oil (40%). M + (APCI): 523.2; M-APCI): 521.2. HPLC (Condition A), Tr: 7.06 min (HPLC purity: 99.2%).
The same procedure used in the preparation of Example 5, step e, but using ethyl (benzyl {4 [(tridecylamino) carbonyl] benzyl} amino) (oxo) acetate provided the title compound as a white solid (94%). 1H NMR (CD3OD, 300 MHz) δ 7.73 (m, 2H), 7.40 (m, 1H), 7.29-7.16 (m, 6H), 4.45-4.36 (m, 4H), 3.34 (t, 2H, J = 7.2 Hz), 1.57 (m, 2H), 1.30-1.23 (m, 20H), 0.84 (t, 3H, J = 6.6 Hz). M- (APCI): 493.2. HPLC (Condition A), Tr: 6.47 min (HPLC purity: 99.6%).
Example 7: [benzyl (4 - {[dodecyl (methyl) amino] carbonyl} benzyl) amino] (oxo) acetic acid
Stage a) Formation of ethyl (benzyl {4 - [(tridecylamino) carbonyl] benzyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 5, step d, but using dodecyl methyl amine gave the title compound as a colorless oil (54%). HPLC (Condition A), Tr: 7.13 min (HPLC purity: 92.5%).
Stage b) Formation of [benzyl (4 - {[dodecyl (methyl) aminocarbonyl} benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 5, step e, but using ethyl (benzyl {4 [(tridecylamino) carbonyl] benzyl} amino) (oxo) acetate provided the title compound as a colorless oil (86%). 1H NMR (CD3OD, 300 MHz) δ 7.46 (m, 1H), 7.38-7.24 (m, 8H), 4.51-4.43 (m, 4H), 3.54 (m, 1H), 3.30 (m, 1H), 3.07 (s, 1.5H), 2.95 (d, 1.5H, J = 4.1 Hz), 1.69-1.58 (2m , 2H), 1.40-1.18 (m, 18H), 0.89 (m, 3H). M- (LC / MS (ESI)): 493.5; M + (LC / MS (ESI)): 495.8. HPLC (Condition A), Tr: 6.47 min (HPLC purity: 99.9%).
Example 8: {(4 - {[dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Step a) Formation of ethyl {(4 - {[dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoro-methyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 5, step d, but using 4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid and dodecyl methyl amine provided the compound of title as a colorless oil (56%). HPLC (Condition A), Tr: 7.41 min (HPLC purity: 82%).
Step b) Formation of {(4 - {[dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 5, step e, but using ethyl {(4 {[dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetate provided the title compound as a colorless oil (68%). 1H NMR (CD3OD, 300 MHz) δ 7.7-7.52 (m, 3H), 7.50-7.30 (m, 5H), 4.62-4.5 (m, 3.5H), 3.85 (m, 0.5H), 3.54 (m, 1H), 3.30 (m, 1H), 3.07 (s, 1.5H), 2.95 (m, 1.5H) , 1.72-1.52 (2m, 2H), 1.50-1.10 (m, 18H), 0.95 (m, 3H). M- (LC / MS (ESI)): 562.1; M + (LC / MS (ESI)): 563.8. HPLC (Condition A), Tr: 6.81 min (HPLC purity: 90.5%).
Example 9: ([1- (tert-Butoxycarbonyl) -4-piperidinyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
Step a) Formation of tert-butyl 4 - ({4 - [(benzyloxy) carbonyl] benzyl} amino) piperidine-1-carboxylate
The same procedure used in the preparation of Example 5, step a, but using 1-Boc-4-amino-piperidine gave the title compound as a colorless oil (83%). M + (LC / MS (ESI)): 425.5. HPLC (Condition A), Tr: 3.52 min (HPLC purity: 97.8%).
Step b) Formation of tert-butyl 4 - {{4 - [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] -amino} piperidine-1-carboxylate
The same procedure used in the preparation of Example 5, step b, but starting from tert-butyl 4 ({4 - [(benzyloxy) carbonyl] benzyl} amino) piperidine-1-carboxylate provided the title compound as a foam yellow (99%). M + (APCI): 523.4. HPLC (Condition A), Tr: 5.7 min (HPLC purity: 98.4%).
Step c) Formation of 4 - ({[1- (tert-butoxycarbonyl) piperidin-4-yl] [ethoxy (oxo) acetyl] -amino} methyl) benzoic acid
The same procedure used in the preparation of Example 5, step c, but starting from tert-butyl 4 {{4 - [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} piperidine-1-carboxylate provided the title compound as a white foam (99%). HPLC (Condition A), Tr: 4.1 min (HPLC purity: 95.7%).
Step d) Formation of tert-butyl 4 - {(4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) -acetyl] amino} piperidine-1-carboxylate
The same procedure used in the preparation of Example 5, step d, but starting from 4 - ({[1 (tert-butoxycarbonyl) piperidin-4-yl] [ethoxy (oxo) acetyl] amino} methyl) benzoic acid provided the title compound as a colorless oil (25%). M- (LC / MS (ESI)): 600.8; M + (LC / MS (ESI)): 602.5. HPLC (Condition A), Tr: 6.75 min (HPLC purity: 99.1%).
The same procedure used in the preparation of Example 5, step e, but starting from tert-butyl 4 {{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} piperidine-1-carboxylate provided the title compound as a yellow oil (55%). 1H NMR (CD3OD, 300 MHz) δ 7.79 (m, 2H), 7.47 (d, 0.5H, J = 8.3 Hz), 7 , 24 (d, 1.5H, J = 8.3 Hz), 4.64 (m, 2H), 4.08 (m, 2H), 3.90 (m, 1H), 3.40 (t, 2H, J = 7.2 Hz), 2.73 (m, 2H), 1.64 (m, 1H), 1.50 (m, 5H), 1.35-1.13 (m, 28H), 0.91 (t, J = 7.9 Hz, 3H). M- (LC / MS (ESI)): 572.8; M + (LC / MS (ESI)): 574.5 HPLC (Condition A), Tr: 6.18 min (HPLC purity: 99.2%).
Example 10: ((4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl} amino} (oxo) acetic acid
Step a) Formation of the amide of formula (IX) wherein Q is -CONR3R3 ', for example N-dodecyl-4-formylbenzamide, using isobutyl chloroformate
To a solution of 4-formyl benzoic acid (22.5 g, 149.9 mmol) and 4-methyl morpholine (18.2 g, 180.0 mmol) in anhydrous THF (200 mL) at -15 ° C was added by Isobutyl chloroformate drip (22.5 g, 165.0 mmol) under an inert atmosphere. After 15 min, dodecylamine (30.56 g, 164.9 mmol) was added at once and the resulting mixture was stirred 3 h at RT. The solvent was evaporated in vacuo and the resulting residue was dissolved in DCM (200 mL) and washed with a 0.1 N aqueous solution of HCl (3 x 30), with brine (1 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a white powder (45 g). This crude product was purified by silica gel column chromatography (EtOAc / c-Hex 4/1 to 1/1 in about 1 h) to provide the title compound as a fluffy white solid (38 g, 80%). 1H NMR (CDCl3, 300 MHz) δ 10.06 (s, 1H), 7.76 (m, 4H), 6.18 (m, 1H), 3.44 (q, 2H, J = 13 Hz, J = 7.2 Hz), 1.61 (m, 2H), 1.4 to 1.2 (m, 18H), 0.86 (t, 3H, J = 7.0 Hz). M- (LC / MS (ESI)): 316.3; M + (LC / MS (ESI)): 318.3. HPLC (Condition A), Tr: 5.9 min (HPLC purity: 98.7%).
Step b) Formation of the secondary amine of formula (HI) following method I (See Scheme 5), for example Ndodecyl-4 - [(4-trifluoromethyl-benzylamino) -methyl] -benzamide
To a solution of N-dodecyl-4-formyl-benzamide (3 g, 9.45 mmol) and 4-trifluoromethyl-benzylamine (1.82 g, 10.4 mmol) in DCE (25 mL) was added at once NaBH (OAc) 3 (2.80 g, 13.23 mmol) and the resulting mixture was stirred overnight at RT. 5 mL of a saturated aqueous solution of NaHCO3 was added to the reaction mixture, the aqueous layer was separated and washed with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by column chromatography on silica gel (EtOAc / c-Hex 15/85 at 75/25 in about 1h) to provide the title compound as a white solid (2.66 g, 59%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, 2H, J = 8.3 Hz), 7.61 (d, 2H, 8.1 Hz), 7.49 (d, 2H, J = 8 , 1 Hz), 7.40 (d, 2H, J = 8. 2 Hz), 6.12 (br s, 1H), 3.86 (s, 4H), 3.43 (q, 2H, J = 13.0 Hz, J = 7.0 Hz), 1.63 (m, 2H), 1.6 to 1.2 (br s, 18H), 0.86 (t, 3H, J = 7.0 Hz ). M- (LC / MS (ESI)): 475.32; M + (LC / MS (ESI)): 477.4 HPLC (Condition A), Tr: 4.97 min (HPLC purity: 95.1%).
Step c) Formation of the oxamic ester of formula (II-I) following method A (See Scheme 1), for example ethyl {{4 [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} - (oxo) acetate
To a solution of N-dodecyl-4 - [(4-trifluoromethyl-benzylamino) -methyl] -benzamide (2.60 g, 5.46 mmol) and TEA (1.104 g, 10.91 mmol) in anhydrous THF (20 mL) at 0 ° C under an inert atmosphere, the ethyl ester of chloro-oxo-acetic acid (1,117 g, 8.18 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 1.25 h. The solvents were evaporated and 50 mL of DCM was added. 20 mL of H2O was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/3 to 1/2 in about 1h) to provide the title compound as a yellow solid (2,770 g, 88%). 1H NMR (CDCl3, 300 MHz) δ 7.73 (m, 2H), 7.60 (m, 2H), 7.37-7.23 (m, 4H), 6.09 (br s, 1H), 4.5 (s, 2H), 4,374.32 (m, 4H), 3.43 (m, 2H), 1.60 (m, 2H), 1.36-1.20 (m, 21H), 0 , 86 (m, 3H). M- (LC / MS (ESI)): 575.5; M + (LC / MS (ESI)): 577.4. HPLC (Condition A), Tr: 6.84 min (HPLC purity: 99.2%).
Step d) Formation of the oxamic acid of formula (I), for example {{4- (dodecylamino) carbonyl] -benzyl} [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1, step e, but starting from ethyl {{4 [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a white powder (83%). 1H NMR (CD3OD, 300 MHz) δ 7.79 (m, 2H), 7.65 (m, 2H), 7.51 (d, 1H, J = 8.1 Hz), 7.41 (m, 2H ), 7.30 (d, 1H, J = 8.1 Hz), 4.6 (m, 4H), 3.33 (t, 2H, J = 7.1 Hz), 1.62 (m, 2H ), 1.37-1.31 (m, 18H), 0.88 (t, 3H, J = 6.5 Hz). M- (LC / MS (ESI)): 547.3; M + (LC / MS (ESI)): 549.5. HPLC (Condition A), Tr: 6.34 min (HPLC purity: 99.2%). Analysis calculated for C30H39F3N2O4: C, 65.68; H, 7.16; N, 5.11%. Found: C, 65.65; H, 7.18; N, 5.08%
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {{4 (dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided the title compound as a white powder (81%). M- (LC / MS (ESI)): 548.1; M + (LC / MS (ESI)): 550.2. HPLC (Condition A), Tr: 6.3 min (HPLC purity: 99%). Analysis calculated for C30H39F3N2O4.C7H17NO5 = 1.1 H2O: C, 58.19; H, 7.39; N, 5.50%. Found: C, 58.09; H, 7.66; N; 5.45%
Example 12: {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N-dodecyl-4 - ({[3- (trifluoromethyl) benzyl] amino} methyl) benzamide
The same procedure used in the preparation of Example 10, step b, but starting from 3trifluoromethyl-benzylamine provided the title compound as a colorless oil (55%). 1H NMR (DMSO-d6, 300 MHz) δ 8.38 (t, 1H, J = 5.5 Hz), 7.78 (d, 2H, J = 8.2 Hz), 7.71 (s, 1H ), 7.65-7.51 (m, 3H), 7.41 (d, 2H, J = 8.1 Hz), 3.75 (s, 2H), 3.72 (s, 2H), 3 , 38-3.28 (m, 2H), 1.50 (m, 2H), 1.23 (br s, 18H), 0.84 (t, 3H, J = 8.0 Hz). M + (LC / MS (ESI)): 477.5. HPLC (Condition A), Tr: 4.90 min (HPLC purity: 95.3%).
Stage b) Formation of ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 10, step c, but starting from N-dodecyl4 - ({[3- (trifluoromethyl) benzyl] amino} methyl) benzamide provided the title compound as a colorless oil (97% ). M + (LC / MS (ESI)): 577.6. HPLC (Condition A), Tr: 6.98 min (HPLC purity: 97.4%).
Step c) Formation of {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 10, step d, but starting from ethyl {{4 [(dodecylamino) carbonyl] benzyl} [3-
(trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (82%). 1H NMR (DMSO-d6, 300 MHz) δ 7.85-7.55 (m, 6H), 7.35 (d, 1H, J = 8.2 Hz), 7.23 (d, 1H, J = 8.2 Hz), 4.55 (d, J = 6.0 Hz, 2H), 4.50 (d, J = 12.4 Hz, 2H), 3.22 (t, J = 7.4 Hz , 2H), 1.58-1.39 (m, 2H), 1.37-1.11 (m, 18H), 0.85 (t, J = 6.7 Hz, 3H). M (LC / MS (ESI)): 547.4; M + (LC / MS (ESI)): 549.4. HPLC (Condition A), Tr: 6.69 min (HPLC purity: 97.9%).
Example 13: {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- (methylamino) ) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {{4 [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided the compound of title as a white fluffy powder (82%). M- (LC / MS (ESI)): 547.4; M + (LC / MS (ESI)): 549.4. HPLC (Condition A), Tr: 6.69 min (HPLC purity: 99.1%). Analysis calculated for C30H39F3N2O4.C7H17NO5: C 59.74; H 7.59; N 5.65%. Found: C 59.13; H 7.90; N 5.57%
Example 14: ({[1- (tert-Butoxycarbonyl) -4-piperidinyl] methyl) (4 - [(dodecylamino) carbonyl] benzyl) amino (oxo) acetic acid
Step a) Formation of tert-butyl 4 - [({4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -piperidine-1-carboxylate
The same procedure used in the preparation of Example 10, step b, but starting from 4 (aminomethyl) -1-N-Boc-piperidine provided the title compound as a colorless oil (31%). M- (ESI): 514.2. HPLC (Condition B), Tr: 6.2 min (HPLC purity: 96.2%).
Step b) Formation of tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) -acetyl] amino} methyl) piperidine-1-carboxylate
The same procedure used in the preparation of Example 10, step c, but starting from tert-butyl 4 - [({4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] piperidine-1-carboxylate provided the compound of title as a colorless oil (81%). 1H NMR (CDCl3, 300 MHz) δ 7.75 (m, 2H), 7.30 (m, 2H), 6.25 (br s, 1H), 4.49-4.30 (m, 2H), 4.40-4.20 (m, 2H), 4.05 (br s, 2H), 3.42 (m, 2H), 3.20-3.05 (m, 2H), 2.60 (m , 2H), 1.9-1.7 (m, 1H), 1.55 (m, 4H), 1,401.0 (m, 31H), 0.86 (m, 3H). M- (APCI): 614.2; M + (APCI): 616.4. HPLC (Condition B), Tr: 8.8 min (HPLC purity: 97.8%).
Step c) Formation of ({[1- (tert-butoxycarbonyl) -4-piperidinyl] methyl} {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 10, step d, but starting from tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} -methyl) piperidine -1-carboxylate provided the title compound as a colorless oil (97%). 1H NMR (CDCl3, 300 MHz) δ 7.72 (m, 2H), 7.26 (m, 2H), 6.21 (m, 1H), 4.84 (br s, 1H), 4.69 ( br s, 1H), 4.10 (m, 2H), 3.45 (m, 3H), 3.20 (m, 1H), 2.63 (m, 2H), 1.85 (m, 1H) , 1.61 (m, 4H), 1.45 Example 15: oxo {[4- (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} acetic acid
Step a) Formation of the secondary amine of formula (III) following method I (See Scheme 5), for example tert-butyl 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) phenylcarbamate
To a solution of 4- (aminomethyl) -1-N-Boc-aniline (1,778 g, 8.0 mmol) and 4-trifluoro-methyl-benzaldehyde (1,156 g, 6.64 mmol) in DCE (50 mL) is NaBH (OAc) 3 (2.374 g, 11.20 mmol) was added at once and the resulting mixture was stirred overnight at RT. 15 mL of a saturated aqueous solution of NaHCO3 was added to the reaction mixture, the aqueous layer was separated and washed with DCM (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/1 then 7/3) to provide the title compound as a colorless oil (2.688 g, 88%). 1H NMR (DMSO-d6, 300 MHz) δ 9.3 (s, 1H), 7.66 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz ), 7.37 (d, 2H, J = 8.5 Hz), 7.20 (d, 2H, J = 8.5 Hz), 3.73 (s, 2H), 3.59 (s, 2H ), 1.47 (s, 9H). M- (LC / MS (ESI)): 379.2; M + (LC / MS (ESI)): 381.4. HPLC (Condition A), Tr: 3.38 min (HPLC purity: 99.1%).
Step b) Formation of the oxamic ester of formula (II-2) following method C (See Scheme 2), for example ethyl {{4 [(tert-butoxycarbonyl) amino] benzyl} [4- (trifluoromethyl-) benzyl] amino } - (oxo) acetate
To a solution of tert-butyl 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) phenylcarbamate (2.69 g, 7.07 mmol) and DIEA (1.83 g, 14.13 mmol) in DCM Anhydrous (30 mL) at 0 ° C under an inert atmosphere, the chloro-oxo-acetic acid ethyl ester (1.06 g, 7.77 mmol) was added dropwise. The reaction mixture was stirred 3 h at 0 ° C, then 1 h at RT. A 1N aqueous solution of HCl (5 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL), dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4) to provide the title compound as a colorless oil (2.980 g, 88%). M- (LC / MS (ESI)): 479.3. HPLC (Condition A), Tr: 5.65 min (HPLC purity: 99.9%).
Step c) Deprotection of the oxamic ester of formula (II-2) (See Scheme 2), formation of for example ethyl {(4-aminobenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
To a solution of ethyl {{4 - [(tert-butoxycarbonyl) amino] benzyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate (2,980 g, 6.2 mmol) in DCM (40 mL) is TFA (10 mL) was added and the resulting reaction mixture was stirred for 4 h at RT. The solvents were evaporated in vacuo to provide an orange oil. This crude product was dissolved in Et2O, washed with a saturated aqueous solution of NaHCO3, water (2x 20 mL) and brine (1x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide an orange oil (2,245 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.59 (m, 2H), 7.33 (m, 2H), 7.01 (m, 2H), 6.65 (m, 2H), 4.49 (s , 1H), 4.40-4.28 (m, 4H), 4.20 (s, 1H), 1.38-1.26 (m, 3H) M- (LC / MS (ESI)): 379 ,one. HPLC (Condition A), Tr: 3.3 min (HPLC purity: 92.4%).
Step d) Formation of the oxamic ester of formula (I-2) following method C (See Scheme 2), for example ethyl oxo {[4- (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} acetate
To a cold solution (0 ° C) of ethyl {(4-aminobenzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetate (800 mg, 2.10 mmol) and DIEA (326 mg, 2.52 mmol) in DCM (10.0 mL) tridecanoyl chloride (539 mg, 2.31 mmol) was added under an inert atmosphere. The resulting reaction mixture was stirred 1 h at 0 ° C and then 3.5 h at RT. A 1N aqueous solution of HCl (2 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL), dried over MgSO4, filtered and concentrated to provide a colorless oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4) to provide the title compound as a colorless oil (1.067 g, 88%). 1H NMR (CDCl3, 300 MHz) δ 7.59 (m, 2H), 7.50 (m, 2H), 7.38 (d, 2H, J = 8.1 Hz), 7.29 (d, 2H , J = 8.0 Hz), 7.18 (m, 2H), 4.47 (m, 2H), 4.37-4.28 (m, 4H), 2.34 (t, 2H, J = 7.5 Hz), 1.71 (m, 2H), 1.38-1.26 (m, 21H), 0.87 (t, J = 8.1 Hz, 3H) M- (LC / MS ( ESI)): 575.2; M + (LC / MS (ESI)): 577.0. HPLC (Condition A), Tr: 7.1 min (HPLC purity: 98.2%).
Step e) Formation of the oxamic ester of formula (I-2), for example oxo {[4- (tridecanoylamino) -benzyl] [4 (trifluoromethyl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1, step e, but starting from ethyl oxo {[4 (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} acetate gave the title compound as a white powder ( 99%) 1H NMR (CD3OD, 300 MHz) δ 7.65-7.12 (m, 8H), 4.54 (s, 2H), 4.45 (s, 2H), 2.34 (t, J = 6, 9 Hz, 2H), 1.69-1.63 (m, 2H), 1.40-1.22 (m, 18H), 0.87 (t, J = 8.6 Hz, 3H). M- (LC / MS (ESI)): 547.5; M + (LC / MS (ESI)): 549.3. HPLC (Condition A), Tr: 6.56 min (HPLC purity: 99.6%). Analysis calculated for C30H39F3N2O4.C7H17NO5: C, 59.74; H, 7.59; N, 5.65%. Found: C, 59.54; H, 7.68; N, 5.53%
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo {[4- (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} acetic acid provided the title compound as a powder white (83%). M- (LC / MS (ESI)): 547.5; M + (LC / MS (ESI)): 549.3. HPLC (Condition A), Tr: 6.56 min (HPLC purity: 99.6%). Analysis calculated for C30H39F3N2O4.C7H17NO5: C, 59.74; H, 7.59; N, 5.65%. Found: C, 59.54; H, 7.68; N, 5.53%
Example 17: [benzyl (4 - {[4- (hexyloxy) benzoyl] amino} benzyl) amino] (oxo) acetic acid
Stage a) Formation of tert-butyl 4 - [(benzylamino) methyl] phenylcarbamate
The same procedure used in the preparation of Example 15, step a but using 4- (aminomethyl) -1-N-Bocaniline and benzaldehyde provided the title compound as a white solid (61%). M + (ESI): 313.2. HPLC (Condition A), Tr: 2.89 min (HPLC purity: 99.4%).
Stage b) Formation of ethyl (benzyl {4 - [(tert-butoxycarbonyl) amino] benzyl} amino) (oxo) -acetate
The same procedure used in the preparation of Example 15, step b but using tert-butyl 4 [(benzylamino) methyl] phenylcarbamate provided the title compound as a brown foam (89%). M- (APCI): 411.0; M + APCI): 413.2. HPLC (Condition A), Tr: 5.32 min (HPLC purity: 98.1%).
Stage c) Formation of ethyl [(4-aminobenzyl) (benzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15, step c but using ethyl (benzyl {4 - [(tert-butoxycarbonyl) amino] benzyl} amino) (oxo) acetate provided the title compound as a brown oil (99.9%) . HPLC (Condition A), Tr: 2.69 min (HPLC purity: 91.5%).
Step d) Formation of ethyl [benzyl (4 - {[4- (hexyloxy) benzoyl] amino} benzyl) amino] - (oxo) acetate
The same procedure used in the preparation of Example 15, step d but using 4-hexyloxybenzoyl chloride and ethyl [(4-aminobenzyl) (benzyl) amino] (oxo) acetate provided the title compound as a colorless oil (58%) . M- (ESI): 515.2. HPLC (Condition A), Tr: 6.0 min (HPLC purity: 94.9%).
Step e) Formation of [benzyl (4 - {[4- (hexyloxy) benzoyl] amino} benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 15, step e using ethyl [benzyl (4 - {[4 (hexyloxy) benzoyl] amino} benzyl) amino] (oxo) acetate provided the title compound as a white gum (99, 9%) 1H NMR (CD3OD, 300 MHz) δ 7.93 (d, 2H, J = 8.3 Hz), 7.67 (m, 2H), 7.38-7.25 (m, 7H), 7.02 (d, 2H, J = 9.0 Hz), 4.43 (m, 4H), 4.06 (t, 2H, J = 6.4 Hz), 1.81 (m, 2H), 1.50 (m, 2H), 1.38 (m, 4H), 0.88 (t, J = 7.9 Hz, 3H). M (LC / MS (ESI)): 487.4; M + (LC / MS (ESI)): 489.4. HPLC (Condition A), Tr: 5.42 min (HPLC purity: 96.4%).
Example 18: oxo {[4- (trifluoromethyl) benzyl] [4- (10-undecenoylamino) benzyl] amino} -acetic acid
Stage a) Formation of ethyl oxo {[4- (trifluoromethyl) benzyl] [4- (undec-10-enoylamino) -benzyl] amino} acetate
The same procedure used in the preparation of Example 15, step d using ethyl {(4-aminobenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate and undec-10-enoyl chloride provided the title compound as an oil colorless (71%). HPLC (Condition A), Tr: 6.7 min (HPLC purity: 99%).
Stage b) Formation of oxo {[4- (trifluoromethyl) benzyl] [4- (10-undecenoylamino) benzyl] amino) acetic acid
The same procedure used in the preparation of Example 15, step e using ethyl oxo {[4- (trifluoromethyl) benzyl] [4- (undec-10-enoylamino) benzyl] amino} acetate provided the title compound as a colorless oil ( 89%). 1H NMR (CDCl3, 300 MHz) δ 10.2 (s, 1H), 8.03 (d, 1H, J = 8.0 Hz), 7.61-7.51 (m, 3H), 7.50 -7.44 (t, 1H, J = 9.0 Hz), 7.38 (d, 1H, J = 7.9 Hz), 7.29 (d, 1H, J = 7.1 Hz), 7 , 17 (d, 1H, J = 7.7 Hz), 7.11 (d, 1H, J = 7.7 Hz), 5.84-5.75 (m, 1H), 5.02-4, 91 (m, 2H), 4.58-4.44 (m, 4H), 2.38 (m, 2H), 2.06 (m, 2H), 1.7 (br s, 2H), 1, 29 (br s, 10H). M- (LC / MS (ESI)): 516.9; M + (LC / MS (ESI)): 519.2. HPLC (Condition A), Tr: 5.7 min (HPLC purity: 99.4%).
Example 19: oxo {{4 - [(9E) -9-tetradecenoylamino] benzyl)} [4- (trifluoromethyl) benzyl] amino} acetic acid
Stage a) Formation of ethyl oxo {{4 - [(9E) -tetradec-9-enoylamino] benzyl} [4- (trifluoro-methyl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15, step d using ethyl {(4-aminobenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate and tetradec-9-enoyl chloride provided the title compound as an oil colorless (81%). M- (LC / MS (ESI)): 588.0. HPLC (Condition A), Tr: 7.3 min (HPLC purity: 96.9%).
The same procedure used in the preparation of Example 15, step e using ethyl oxo {{4 - [(9E) -tetradec-9enoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} acetate provided the title compound as an oil colorless (94%). 1H NMR (CD3OD, 300 MHz) δ 7.58-7.00 (m, 8H), 5.30-5.19 (m, 2H), 4.45 (s, 2H), 4.37 (s, 2H), 2.26 (t, 2H, J = 7.3 Hz), 1.98-1.88 (m, 4H), 1.66-1.53 (m, 2H), 1.32-1 , 16 (m, 12H), 0.80 (t, 3H). M- (LC / MS (ESI)): 559.7; M + (LC / MS (ESI)): 561.2. HPLC (Condition A), Tr: 6.72 min (HPLC purity: 98.9%).
Example 20: oxo {{4 - [(9E) -9-tetradecenoylamino] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- ( methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo {{4 - [(9E) -9-tetradecenoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid provided the title compound as a white fluffy powder (93.8%). M- (LC / MS (ESI)): 559.7; M + (LC / MS (ESI)): 561.2. HPLC (Condition A), Tr: 6.72 min (HPLC purity: 98.9%). Analysis calculated for C31H39F3N2O4.C7H17NO5: C, 60.38; H, 7.47; N, 5.56%. Found: C, 60.19; H, 7.70; N, 5.36%
Example 21: {benzyl [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid
Stage a) Formation of ethyl {benzyl [4- (tridecanoylamino) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 5, step d using ethyl [(4-aminobenzyl) (benzyl) amino] (oxo) acetate and tridecanoic acid provided the title compound as a colorless oil (39%). M- (ESI): 507.2. HPLC (Condition A), Tr: 7 min (HPLC purity: 91.3%).
Stage b) Formation of oxo {{4 - [(9E) -9-tetradecenoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic acid
The same procedure used in the preparation of Example 15, step e using ethyl {benzyl [4 (tridecanoylamino) benzyl] amino} (oxo) acetate provided the title compound as a white gum (99%). 1H NMR (CD3OD, 300 MHz) δ 7.54 (m, 2H), 7.38-7.15 (m, 7H), 4.43 (m, 4H), 2.38 (t, 2H, J = 7.3 Hz), 1.69 (m, 2H), 1.27 (m, 18H), 0.90 (t, J = 8.0 Hz, 3H). M- (ESI): 479.2. HPLC (Condition A), Tr: 6.19 min (HPLC purity: 94.9%).
Example 22: {{4 - [(2-hydroxidedecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino (oxo) acetic acid
Step a) Formation of ethyl {{4 - [(2-hydroxidedecyl) amino] benzyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
To a solution of ethyl {(4-aminobenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate (38 mg, 0.10 mmol) and 1,2dodecylene oxide (22 mg, 0.12 mmol) in 1.0 mL of CH3CN were added at once magnesium perchlorate (27 mg, 0.12 mmol) under an inert atmosphere. The reaction mixture was stirred 24 at RT. 2 mL of H2O was added and the resulting mixture was extracted with EtOAc (2x 5mL), dried over MgSO4, filtered and the solvents evaporated in vacuo to provide a slightly yellow oil (61 mg).
Purification by SiO2 (AcOEt / c-Hex) provided the title compound as a colorless oil (15.3 mg, 27%). 1H NMR (CDCl3, 300 MHz) δ 7.61-7.46 (m, 2H), 7.36-7.21 (m, 2H), 7.05-6.88 (m, 2H), 6, 61-6.47 (m, 2H), 4.43 (s, 1H), 4.38-4.17 (m, 4H), 4.14 (s, 1H), 3.17 (br s, 1H ), 3.25-3.13 (m, 1H), 3.01-2.81 (m, 1H), 1.55-1.05 (m, 23H), 0.81 (t, J = 7 , 9 Hz, 3H). M + (LC / MS (ESI)): 565.4. HPLC (Condition A), Tr: 5.96 min (HPLC purity: 94.8%).
Step b) Formation of {{4 - [(2-hydroxidedecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1, step e using ethyl {{4 - [(2-hydroxydecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a yellow solid (90%) 1H NMR (CD3OD, 300 MHz) δ 7.57 (m, 2H), 7.46 (m, 1H), 7.33 (m, 1H), 7.18 (d, 1H, J = 7.5 Hz ), 7.10 (d, 1H, J = 7.2 Hz), 6.83 (m, 2H), 4.69 (br s, 1H), 4.48 (br s, 2H), 4.38 (s, 1H), 3.72 (br s, 1H), 3.25-3.15 (m, 1H), 3.13-2.98 (m, 1H), 1.47 (br s, 2H ), 1.26 (br s, 16H), 0.86 (br s, 3H). M- (LC / MS (ESI)): 535.0; M + (LC / MS (ESI)): 537.1. HPLC (Condition A), Tr: 5.11 min (HPLC purity: 88.5%).
Example 23: oxo {[4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N-hydroxidedecanimidamide
To a solution of undecyl cyanide (1,810 g, 9.98 mmol) in EtOH (20 mL) was added a 50% aqueous solution of hydroxylamine (1 mL) and the resulting reaction mixture was stirred at 70 ° C for 48h. The solvents were evaporated and the resulting white solid was dissolved in EtOAc (100 mL) and washed with H2O (2x 20mL), dried over MgSO4, filtered and the solvents evaporated in vacuo to provide the title compound as a solid. white (2.001g, 94%). 1H NMR (CDCl3, 300 MHz) δ 6.21-4.99 (br s, 1H), 4.49 (br s, 2 H), 2.07 (t, J = 7.6 Hz, 2H), 1.55-1.40 (m, 2H), 1.34-1.09 (m, 16H), 0.81 (t, J = 7.0 Hz, 3H)
To a solution of benzyl 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) benzoate (3.60 g, 9.01 mmol) and triethylamine (1.094 g, 10.82 mmol) in DCM (50 mL) di-tert-butyl dicarbonate (2.164 g, 9.91 mmol) was added and the resulting reaction mixture was stirred at RT for 5 h. H2O (10 mL) was added and the mixture was extracted with DCM (3x 50 mL). The combined organic layers were washed with a 1N aqueous solution of HCl (10 mL), a saturated aqueous solution of NaHCO3, water (2x 20 mL) and brine (1x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a colorless oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 5/95) to provide the title compound as a colorless oil (4.303 g, 96%). 1H NMR (CDCl3, 300 MHz) δ 8.12 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.607.22 (m, 9H), 5.46 (s, 2H), 4.57 (s, 2H), 4.58 (s, 2H), 1.56 (s, 9H). HPLC (Condition A), Tr: 6.55 min (HPLC purity: 99.7%).
Step c) Formation of 4 - ({(tert-butoxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) -benzoic acid
H2 (1 atm) was bubbled slowly through a 10% Pd / C suspension (917 mg) in EtOH (25 mL) for 15 min at RT. To this suspension was then added a solution of benzyl 4 - ({(tert-butoxycarbonyl) [4 (trifluoromethyl) benzyl] amino} methyl) benzoate (4.303 g, 8.61 mmol) diluted in EtOH (5 mL). The resulting reaction mixture was stirred under 1 atm of H2 for 4.5 h at RT. The reaction mixture was filtered on a celite pad to remove the catalyst. The EtOH was evaporated to provide the title compound as a colorless oil that was used in the following steps without further purification (3,520 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.45-7.21 (m , 4H), 5.54 (s, 2H), 4.45 (s, 2H), 1.50 (s, 9H). HPLC (Condition A), Tr: 5.42 min (HPLC purity: 96.1%).
Step d) Formation of tert-butyl 4 - {[(dodecanimidoylamino) oxy] carbonyl} benzyl [4- (trifluoromethyl) benzyl] carbamate
To a solution of 4 - ({(tert-butoxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) -benzoic acid (102 mg, 0.25 mmol), N-hydroxidedecanimidamide (70 mg, 0.33 mmol) and DMAP (3 mg, 0.03 mmol) in anhydrous DCM (15 mL) EDC (62 mg, 0.33 mmol) was added and the resulting reaction mixture was stirred at RT for 14 h. Evaporation of the solvents provided an oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 80/20) to provide the title compound as a colorless oil (36 mg, 24%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.40-7.20 (m , 4H), 4.88 (br s, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 2.36 (t, J = 8.2 Hz, 2H), 1, 75-1.59 (m, 2H), 1.49 (s, 9H), 1.45-1.16 (m, 16H), 0.89 (t, J = 7.0 Hz, 3H). HPLC (Condition A), Tr: 5.42 min (HPLC purity: 96.1%).
Stage e) Formation of tert-butyl 4- (trifluoromethyl) benzyl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] carbamate
A solution of tert-butyl 4 - {[(dodecanimidoylamino) oxy] carbonyl} benzyl [4- (trifluoro-methyl) benzyl] carbamate in pyridine was stirred under an inert atmosphere at 120 ° C for 4 h. The resulting brown solution was evaporated (under high vacuum) and the resulting oil was purified by silica gel column chromatography (AcOEt / c-Hex 20/80) to provide the title compound as a colorless oil (50 mg, 71 %). 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.35-7.14 (m , 4H), 4.43 (s, 2H), 4.35 (s, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1.80-1: 65 (m, 2H) , 1.41 (s, 9H), 1.36-1.12 (m, 16H), 0.89 (t, J = 7.0 Hz, 3H)
Step f) Formation of N- [4- (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine hydrochloride
To a cold solution (0 ° C) of tert-butyl 4- (trifluoromethyl) benzyl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] carbamate (43 mg, 0.07 mmol) in DCM (3 mL) a solution of HCl (4N in dioxane, 3 mL) was added and the resulting reaction mixture was stirred 3h at 0 ° C, then 14h at RT. Evaporation of the solvent provided the title compound as a white powder that was used in the following steps without further purification (29 mg, 99%). M- (APCI): 486.0; M + (APCI): 488.2 HPLC (Condition A), Tr: 5.4 min (HPLC purity: 82%).
Step g) Formation of ethyl oxo {[4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
To a cold solution (0 ° C) of N- [4- (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine hydrochloride (45 mg, 0.09 mmol) and DIEA (24 mg, 0.19 mmol) in anhydrous DCM (1 mL), the ethyl ester of chloro-oxo-acetic acid (24 mg, 0.19 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 3 h. Evaporation of the solvents in vacuo provided an orange oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/9) to provide the title compound as a colorless oil (38 mg, 75%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8 , 2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.39-7.21 (m, 4H), 4.50 (s, 2H), 4.37 (s , 2H), 4.29 (dq, J = 7.1 Hz, J2 = 2.3 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 1.85-1.65 (m, 2H), 1.41-1.05 (m, 19H), 0.89 (t, J = 7.0 Hz, 3H). HPLC (Condition A), Tr: 7.5 min (HPLC purity: 88.8%).
Step h) Formation of oxo {[4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1, step e using ethyl oxo {[4 (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate provided the title compound as a white powder (89%). 1H NMR (CDCl3, 300 MHz) δ 8.10-7.99 (m, 2H), 7.61-7.50 (m, 2H), 7.32 (d, J = 8.6 Hz, 2H) , 7.27 (d, J = 7.9 Hz, 2H), 4.98 (s, 2H), 4.58 (s, 2H), 2.74 (t, J = 8.0 Hz, 2H) , 1.81-1.66 (m, 2H), 1.42-1.04 (m, 16H), 0.81 (t, J = 6.7 Hz, 3H). M + (APCI): 558.4. HPLC (Condition A), Tr: 7.4 min (HPLC purity: 98.6%).
Example 24: {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (trifluoromethyl) -benzyl) amino} (oxo) acetic acid
Stage a) Formation of 2- (tien-2-ylmethyl) -1H-isoindole-1,3 (2H) -dione
A solution of thiophene-2-methylamine (4.203 g, 37.13 mmol) and phthalic anhydride (5.00 g, 33.76 mmol) in toluene (100 mL) was stirred and heated at reflux for 3 h to remove water that formed by azeotropic distillation (Dean-Stark). The solvent was then evaporated in vacuo. The residue was dissolved in DCM (100 mL), washed with water (3 x 30 mL), dried over MgSO4, filtered and concentrated to give the title compound as a white solid (7.78 g, 95%) . 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, 1H, J = 5.4 Hz), 7.83 (d, 1H, J = 5.4 Hz), 7.69 (d, 1H, J = 5.4 Hz), 7.68 (d, 1H, J = 5.4 Hz), 7.20 (d, 0.5H, J = 5.2 Hz), 7.19 (d, 0.5H , J = 5.2 Hz), 7.14 (m, 1H), 6.92 (d, 0.5H, J = 5.1 Hz), 6.91 (d, 0.5H, J = 5, 1 Hz), 5.01 (s, 2H). HPLC (Condition A), Tr: 4.11 min (HPLC purity: 99.2%).
Step b) Formation of 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] thiophene-2-sulfonyl chloride
To a cold solution (-78 ° C) of 2- (thien-2-ylmethyl) -1H-isoindole-1,3 (2H) -dione (6.78 g, 27.87 mmol) in DCM (56 mL) was added drip (in about 10 min) chlorosulfonic acid (16.237 g, 139.3 mmol, 9.33 mL, d: 1.74) diluted in DCM (9.3 mL). The reaction mixture was stirred 2 h at -78 ° C, then 1 h at -40 ° C and overnight at RT. The resulting brown solution was poured on ice. The mixture was extracted with DCM (3x 200 mL) and the combined organic layers were washed with water (3x 200 mL), dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4 to 1/3 to 1/2 in about 1 h) to provide the title compound as a white solid (6.42 g , 67%). 1H NMR (CDCl3, 300 MHz) δ 7.89 (d, 1H, J = 5.5 Hz), 7.87 (d, 1H, J = 5.5 Hz), 7.76 (d, 1H, J = 5.5 Hz), 7.75 (d, 1H, J = 5.5 Hz), 7.71 (d, 1H, J = 4.0 Hz), 7.18 (d, 1H, J = 4 , 0 Hz), 5.05 (s, 2H). HPLC (Condition A), Tr: 4.6 min (HPLC purity: 94.8%).
Step c) Formation of 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -N-dodecylthio-pheno-2-sulfonamide
To a solution of 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] thiophene-2-sulfonyl chloride (2.00 g, 5.85 mmol), DIEA (1.134 g, 8.78 mmol) in DCM (20 mL) dodecyl amine (1.41 g, 7.61 mmol) was added at RT and the reaction mixture was stirred for 2 h at RT. A 1 M aqueous solution of HCl (10 mL) was added and the aqueous layers were extracted with DCM (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4 to 4/1 in approximately 0.5 h) to provide the title compound as a white solid (2.10 g, 73 %). 1H NMR (CD3OD, 300 MHz) δ 7.91 (m, 2H), 7.85 (m, 2H), 7.43 (d, 1H, J = 3.7 Hz), 7.17 (d, 1H , J = 3.7 Hz), 5.05 (s, 2H), 2.90 (t, 2H, J = 6.9 Hz), 1.50-1.38 (m, 2H), 1.35 -1.16 (m, 18H), 0.86 (t, J = 7.9 Hz, 3H) M (LC / MS): 489.3; M + (LC / MS): 491.2. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 95.9%).
Step d) Deprotection of 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -N-dodecyl-thiophene-2-sulfonamide; formation of 5- (aminomethyl) -N-dodecylthiophene-2-sulfonamide
To a solution of 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -N-dodecylthiophene-2-sulfonamide (2,069 g, 4.22 mmol) in EtOH ( 20 mL) hydrazine hydrate (0.614 mL, 633 mg, d: 1.030, 12.65 mmol) was added. The resulting reaction mixture was stirred at reflux for 3h and then cooled to RT. The white precipitate was removed by filtration and the solvents evaporated in vacuo. The residue was dissolved in DCM (20mL) and the precipitate was removed by filtration. The collected solvents were concentrated to provide a colorless oil that became solid at rest (1.5 g, 99%). 1H NMR (DMSO-d6, 300 MHz) δ 7.37 (m, 1H), 6.94 (m, 1H), 3.91 (s, 2H), 2.78 (m, 2H), 1.95 -1.65 (m, 20H), 0.86 (t, J = 7.6 Hz, 3H). M- (LC / MS (ESI)): 359.2; M + (LC / MS (ESI)): 361.2. HPLC (Condition A), Tr: 4.5 min (HPLC purity: 95%).
Stage e) Formation of N-dodecyl-5 - ({[4- (trifluoromethyl) benzyl] amino} methyl) thiophene-2-sulfonamide
To a solution of 5- (aminomethyl) -N-dodecylthiophene-2-sulfonamide (797 mg, 2.21 mmol) and 4-trifluoromethylbenzaldehyde (350 mg, 2.01 mmol) in DCE (50 mL) was added at once NaBH (OAc) 3 (596 mg, 2.81 mmol) and the resulting mixture was stirred overnight at RT. 30 mL of a saturated aqueous solution of NaHCO3 was added to the reaction mixture, the aqueous layer was separated and washed with DCM (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellowish oil. This crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4 to 1/2 in about 1h) to provide the title compound as a colorless oil (675 mg, 64%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.46 (m, 2H), 7.37 (d, 0.7H, J = 8.0 Hz), 6.88 (d , 1H, J = 3.8 Hz), 4.00 (s, 2H), 3.90 (s, 2H), 3.02 (m, 2H), 1.85-1.55 (m, 2H) , 1.5 (m, 2H), 1.22 (s, 18H), 0.87 (t, 3H, 6.6 Hz). M- (LC / MS (ESI)): 517.2; M + (LC / MS (ESI)): 519.2 HPLC (Condition A), Tr: 5.27 min (HPLC purity: 97.2%).
The same procedure used in the preparation of Example 1, step b but using N-dodecyl-5 - ({[4 (trifluoromethyl) benzyl] amino} methyl) thiophene-2-sulfonamide provided the title compound as a colorless oil (360 g, 45%).
1H NMR (CDCl3, 300 MHz) δ 7.66 (t, 2H, J = 9.0 Hz), 7.42 (m, 2H), 7.37 (d, 0.7H, J = 8.0 Hz ), 6.87 (d, 0.3H, J = 3.8 Hz), 6.86 (d, 0.7H, J = 3.8 Hz), 4.60 (m, 2H), 4.52 (m, 2H), 4.36 (m, 2H), 3.02 (m, 2H), 1.50 (m, 3H), 1.40-1.20 (m, 21H), 0.86 ( t, 3H, 6.6 Hz) M- (APCI): 617.2; M + (APCI): 619.2 HPLC (Condition A), Tr: 7.1 min (HPLC purity: 99.9%).
Step g) Formation of {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1, step e but using ethyl {({5 [(dodecylamino) sulfonyl] thien-2-yl} methyl) [4- (trifluoromethyl) benzyl] amino} (oxo) -acetate provided the title compound as a colorless foam (96%). 1H NMR (CD3OD, 300 MHz) δ 7.61 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 7.32 (m, 1H), 7.08 (m , 0.5H), 6.85 (m, 0.5H), 4.71 (m, 4H), 2.88 (m, 2H), 1.46 (m, 2H), 1.27 (m, 18H), 0.87 (t, J = 8.1 Hz, 3H). M- (LC / MS (ESI)): 589.1; M + (LC / MS (ESI)): 591.3. HPLC (Condition A), Tr: 6.58 min (HPLC purity: 99.9%).
Example 25: {((5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (trifluoromethyl) benzyl] -amino (oxo) acetic acid, Nmethyl-D-glucamine (ie 1-deoxy) salt -1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {({5 [(dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (trifluoromethyl) -benzyl] amino} ( oxo) acetic gave the title compound as a white powder (92%). M- (LC / MS (ESI)): 589.1; M + (LC / MS (ESI)): 591.3. HPLC (Condition A), Tr: 6.58 min (HPLC purity: 99.9%). Analysis calculated for C27H37F3N2O5S2.C7H17NO5: C, 51.96; H, 6.93; N, 5.35%. Found: C, 51.54; H, 6.96; N, 5.26%
Example 26: [{4 - [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) amino (oxo) acetic acid
Step a) Formation of tert-butyl 4 - [({4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -piperidine-1-carboxylate
The same procedure used in the preparation of Example 10, step b, but starting from 4 (aminomethyl) -1-N-Boc-piperidine provided the title compound as a colorless oil (74%). 1H NMR (DMSOd6, 300 MHz) δ 8.36 (t, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.2 Hz), 7.37 (d, 2H, J = 7.9 Hz), 3.90 (m, 2H), 3.71 (s, 2H), 3.22 (m, 2H), 2.66 (m, 2H), 2.33 (d, 2H , J = 6.4 Hz), 1.67 (m, 2H), 1.49 (m, 3H), 1.37 (s, 9H), 1.23 (br s, 18H), 1,020.80 ( m, 5H) M- (LC / MS (ESI)): 514.4; M + (LC / MS (ESI)): 516.7. HPLC (Condition A), Tr: 4.77 min (HPLC purity: 97.8%).
Step b) Formation of tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) -acetyl] amino} methyl) piperidine-1-carboxylate
The same procedure used in the preparation of Example 10, step c, but using tert-butyl 4 - [({4 [(dodecylamino) carbonyl] benzyl} amino) methyl] piperidine-1-carboxylate provided the title compound as an oil colorless (97%). M- (LC / MS (ESI)): 614.2; M + (LC / MS (ESI)): 616.3. HPLC (Condition A), Tr: 6.86 min (HPLC purity: 98.6%).
Step c) Formation of ethyl [{4 - [(dodecylamino) carbonyl] benzyl} (piperidin-4-ylmethyl) -amino] (oxo) acetate hydrochloride
To a cold solution (0 ° C) of tert-butyl 4 - ({{4 - [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} methyl) piperidine-1-carboxylate (3.84 g, 6.24 mmol ) in DCM (25 mL) a 4 N solution of HCl in dioxane (31.1 mL) was added and the resulting reaction mixture was stirred 4 h at 0 ° C. Evaporation of the solvents provided a white amorphous solid (73%). 1H NMR (DMSO-d6, 300 MHz) δ 9.03 (m, 0.5H), 8.70 (m, 0.5H), 8.50 (m, 1H), 7.85 (m, 2H) , 7.33 (m, 2H), 4.56 (d, 2H, J = 8.9 Hz), 4.40-4.20 (m, 2H), 3.35-3.10 (m, 7H ), 2.80 (m, 2H), 1.70 (m, 2H), 1.52 (m, 2H), 1,431.15 (m, 21H), 0.86 (m, 3H). M- (LC / MS (ESI)): 514.4; M + (LC / MS (ESI)): 516.4. HPLC (Condition A), Tr: 4.68 min (HPLC purity: 99.4%).
Step d) Formation of ethyl [{4 - [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) -sulfonyl] piperidin-4yl} methyl) amino] (oxo) acetate
To a solution of ethyl [{4 - [(dodecylamino) carbonyl] benzyl} (piperidin-4-ylmethyl) -amino] (oxo) acetate (900 mg, 1.63 mmol), DIAE (527 mg, 4, 07 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous THF (50 mL) 4-methoxybenzene sulfonyl chloride (404 mg, 1.96 mmol) dissolved in THF (2.0 mL) was added. The reaction mixture was stirred 14 h at RT. The solvent was evaporated and the resulting residue was dissolved in DCM (100 mL), washed with water (20 mL) and the aqueous layer was extracted with DCM (3x 50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (AcOEt / c-Hex 1/4 to 1/1 in about 1 h) to provide the title compound as a white foam (992 mg, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, 2H, J = 8.3 Hz), 7.69 (d, 2H, J = 9.2 Hz), 7.27 (t, 2H, J = 7.9 Hz), 7.07 (m, 2H), 6.12 (m, 1H), 4.60 (s, 1H), 4.48 (s, 1H), 3.89 (s, 3H ), 3.76 (m, 2H), 3.13 (d, 1H, J = 6.8 Hz),
Step e) Formation of [{4 - [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1, step e but using ethyl [{4 [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] piperidin-4-yl} methyl) amino] ( oxo) acetate provided the title compound as a white powder (94%). 1H NMR (CD3OD, 300 MHz) δ 7.76 (m, 2H), 7.66 (m, 1H), 7.38 (d, 1H, J = 8.3 Hz), 7.32 (d, 1H , J = 7.9 Hz), 7.08 (m, 2H), 4.60 (m, 2H), 3.87 (s, 3H), 3.66 (m, 2H), 3.55 (m , 1H), 3.36 (t, 2H, J = 7.1 Hz), 3.16 (m, 2H), 2.17 (m, 2H), 1.61 (m, 5H), 1.35 -1.18 (m, 21H), 0.87 (t, 3H, J = 8.0 Hz). M (LC / MS (ESI)): 656.2; M + (LC / MS (ESI)): 658.3. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 99.9%).
Example 27: [{4 - [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) amino] (oxo) acetic acid, N-methyl-D- salt glucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and [{4 [(dodecylamino) carbonyl] benzyl} ({1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl ) amino] (oxo) acetic gave the title compound as white granules (94.1%). M- (LC / MS (ESI)): 656.2; M + (LC / MS (ESI)): 658.3. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 99.9%). Analysis calculated for C35H51N3O7S.C7H17NO5: C, 59.13; H, 8.03; N, 6.57%. Found: C, 58.73; H, 8.10; N, 6.57%
Example 28: {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino) - (oxo) acetic acid
Step a) Formation of resin-bound amines of formula (D) (See Scheme 5), for example resin-bound dodecylamine
PS-MB-CHO HL resin (Argonaut Technologies Inc., 30 mg, 1.42 mmol / g, 0.0426 mmol, 100-200 mesh) swelled in 1% HAc in DCE / TMOF (80/20) (1.0 mL) for 15 min at RT. Dodecylamine (24 mg, 0.128 mmol) and sodium triacetoxyborohydride (27 mg, 0.128 mmol) were added and the reaction mixture was stirred at RT for 14
h. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the resin-bound dodecylamine that was used directly in the next step.
Step b) Formation of resin-bound amides of formula (VIII-1) (See Scheme 5, Method K), for example resin-bound 4-chloromethyl-N-dodecyl-benzamide.
The resin-bound dodecylamine (described in step a, 0.0426 mmol) was swollen in DCM (1.0 mL) for 15 min at RT. DIEA (28 mg, 0.213 mmol) and 4-chloromethylbenzoyl chloride (40 mg, 0.213 mmol) were added and the reaction mixture was stirred at 0 ° C for 2h then 14 h at RT. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the resin-bound 4-chloromethyl-Ndodecyl-benzamide that was used directly in the next step.
Step c) Formation of resin-bound secondary amines of formula (III-1) (See Scheme 5), for example Ndodecyl-4 - ({[1- (1-naphthyl) ethyl] amino} methyl) benzamide resin-bound
The resin-bound 4-chloromethyl-N-dodecyl-benzamide (described in step b, 0.0426 mmol) was swollen in NMP (0.25 mL) for 15 min at RT. DIEA (33 mg, 0.256 mmol), tetrabutyl ammonium iodide (94.4 mg, 0.256 mmol) and 1-naphthalen-1-yl-ethylamine (44 mg, 0.256 mmol) dissolved in NMP (0.75 mL) were added ) and the reaction mixture was stirred 14 h at 80 ° C. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the resin-bound N-dodecyl-4 - ({[1- (1-naphthyl) ethyl] amino} -methyl) benzamide which was used directly in the next step.
Step d) Formation of the resin-bound oxamic ester of formula (I-1) (See Scheme 1), for example ethyl {{4 [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} ( oxo) resin-bound acetate
The resin-bound N-dodecyl-4 - ({[1- (1-naphthyl) ethyl] amino} methyl) benzamide (described in step c, 0.0426 mmol) swelled in DCM (1.0 mL) during 15 min at 0 ° C. DIEA (28 mg, 0.213 mmol) and chloro-oxo-acetic acid ethyl ester (29 mg, 0.213 mmol) were added and the reaction mixture was stirred 3 h at 0 ° C and then 14 h at RT. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} - (oxo) acetate bonded to resin which was used directly in the following stage.
Ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} - (oxo) acetate bonded to resin (described in step d, 0.0426 mmol) was swollen in THF (0.300 mL) for 15 min at RT. Lithium hydroxide monohydrate (36 mg, 0.852 mmol) diluted in H2O (0.060 mL) was added and the resulting reaction mixture was stirred 14 h at RT. The resin was washed successively with THF (1x 15 min), H2O (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH ( 1x 5 min), THF (3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the resin-bound {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} (oxo) acetic acid which was used directly in the next step .
Step f) Excision of the resin-bound oxamic acid of formula (I-1); formation of oxamic acid of formula (II) (See Scheme I), for example {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} (oxo) acetic acid
The resin-bound {{4 - [(dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} (oxo) -acetic acid (described in step e, 0.0426 mmol) was poured into TFA / DCM 20/80 (2 mL) for 1 h at RT. The resin was filtered and the solvents evaporated in vacuo to provide a colorless oil. The crude product was purified on an SPE column (Sorbent NH2, Isolute® 1g, 0.71 mmol / g) as described below: the column was equilibrated with DCM (2 x 10 mL) and the crude product (diluted in 1 mL DCM) was poured into the column. The column was washed with DCM (2x 5 mL) and then with dioxane (2x 5 mL) and the title compound finally eluted with 2N HCl in dioxane (2x 2 mL). Evaporation of the fractions containing HCl in vacuo provided the title compound as a colorless oil (6.5 mg). M (LC / MS (ESI)): 543.0; M + (LC / MS (ESI)): 545.8. HPLC (Condition A), Tr: 6.67 min (HPLC purity: 99.1%).
Example 29: [{4 - [(dodecylamino) carbonyl] benzyl) (2-carboxy-1-phenylethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 2-phenylglycine hydrochloride ethyl ester in step c provided the title compound as a white powder (15 mg). M- (LC / MS (ESI)): 523.1; M + (LC / MS (ESI)): 525.9. HPLC (Condition A), Tr: 5.57 min (HPLC purity: 95.7%).
Example 30: [{4 - [(dodecylamino) carbonyl] benzyl] (2-methoxy-1-methylethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 2-amino-1-methoxypropane in step c provided the title compound as a colorless oil (3.7 mg). M- (LC / MS (ESI)): 461.3; M + (LC / MS (ESI)): 463.3. HPLC (Condition A), Tr: 5.9 min (HPLC purity: 98.1%).
Example 31: (4-Bromo {4 - [(dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 4-bromoaniline in step c provided the title compound as a colorless oil (2 mg). M + (LC / MS (ESI)): 548.3. HPLC (Condition A), Tr: 6.44 min (HPLC purity: 90.5%).
Example 32: ({4 - [(dodecylamino) carbonyl] benzyl} anilino (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using aniline in step c gave the title compound as a colorless oil (3.1 mg). M- (LC / MS (ESI)): 465.1; M + (LC / MS (ESI)): 467.2. HPLC (Condition A), Tr: 6.1 min (HPLC purity: 91.9%).
Example 33: ([2- (3-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 2- (3-chlorophenyl) ethylamine in step c gave the title compound as a colorless oil (5 mg). M- (LC / MS (ESI)): 527.1; M + (LC / MS (ESI)): 530.6. HPLC (Condition A), Tr: 6.66 min (HPLC purity: 96.1%).
Example 34: {{4 - [(dodecylamino) carbonyl] benzyl} [2- (3-methoxyphenyl) ethyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 2- (3-methoxyphenyl) ethylamine in step c provided the title compound as a yellow oil (8.9 mg). M- (LC / MS (ESI)): 523.1; M + (LC / MS (ESI)): 525.3. HPLC (Condition A), Tr: 6.35 min (HPLC purity: 97.2%).
Example 35: {{4 - [(dodecylamino) carbonyl] benzyl} [((d, 1) -trans-2-phenylcyclopropyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using (d, 1) -trans-2-phenylcyclopropylamine hydrochloride in step c provided the title compound as a colorless oil (5.5 mg). M (LC / MS (ESI)): 505.3; M + (LC / MS (ESI)): 507.2. HPLC (Condition A), Tr: 6.42 min (HPLC purity: 80.0%).
Example 36: ([(d, 1) -trans-2- (benzyloxy) cyclopentyl] {4 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using ( d, 1) -2-benzyloxycyclopentylamine
in step c it provided the title compound as a yellow oil (12.3 mg). M- (LC / MS (ESI)): 563.3; M + (LC / MS (ESI)): 565.4. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 97.7%). Example 37: {{4 - [(dodecylamino) carbonyl] benzyl} -4-phenoxyanilino) (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 4-phenoxyaniline in step c
provided the title compound as a yellow oil (11.2 mg). M- (LC / MS (ESI)): 557.7; M + (LC / MS (ESI)): 559.4. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 94.3%).
Example 38: [{4 - [(dodecylamino) carbonyl] benzyl} (1,2,3,4-tetrahydro-1-naphthalenyl) amino] (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 1 , 2,3,4-tetrahydro-1-naphthylamine in step c provided the title compound as a colorless oil (11.6 mg).
M- (LC / MS (ESI)): 519.0; M + (LC / MS (ESI)): 521.0. HPLC (Condition A), Tr: 6.62 min (HPLC purity: 81.1%). Example 39: ((1-Benzyl-4-piperidinyl) {4 - [(dodecylamino) carbonyl] benzyl) amino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 4-amino-1-benzylpiperidine in the
step c provided the title compound as a white powder (4.3 mg). M- (LC / MS (ESI)): 562.0; M + (LC / MS (ESI)): 564.7. HPLC (Condition A), Tr: 4.69 min (HPLC purity: 68.8%).
Example 40: {{4 - [(dodecylamino) carbonyl] benzyl} [2- (4-phenoxyphenyl) ethyl] amino} (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 4-phenoxyphenethylamine in the step c provided the title compound as a colorless oil (4 mg). M- (LC / MS (ESI)): 585.6; M + (LC / MS (ESI)): 587.3. HPLC (Condition A), Tr: 6.91 min (HPLC purity: 97.1%).
Example 41: {{4 - [(dodecylamino) carbonyl] benzyl} [2- (2-phenoxyphenyl) ethyl] amino} (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 2-phenoxyphenethylamine in the step C
provided the title compound as a colorless oil (4.7 mg). M- (LC / MS (ESI)): 584.9; M + (LC / MS (ESI)): 586.9. HPLC (Condition A), Tr: 6.93 min (HPLC purity: 97.9%). Example 42: ((2- [1,1'-biphenyl] -4-ylethyl) {4 - [(dodecylamino) carbonyl] benzyl) -amino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 2- (4-biphenyl) ethylamine in stage c
provided the title compound as a colorless oil (3.9 mg). M- (LC / MS (ESI)): 569.1; M + (LC / MS (ESI)): 571.2. HPLC (Condition A), Tr: 6.92 min (HPLC purity: 96.5%).
Example 43: (([1,1'-biphenyl] -3-ylmethyl) {4 - [(dodecylamino) carbonyl] benzyl} -amino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 3- Phenylbenzylamine in step c provided the title compound as a colorless oil (6.2 mg). M- (LC / MS (ESI)): 555.7; M + (LC / MS (ESI)): 557.0. HPLC (Condition A), Tr: 6.54 min (HPLC purity: 81%).
Example 44: (3- (benzyloxy) {4 - [(dodecylamino) carbonyl] benzyl) anilino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 3- (benzyloxy) aniline in step c
provided the title compound as a yellow oil (10.3 mg). M- (LC / MS (ESI)): 571.0; M + (LC / MS (ESI)): 573.4. HPLC (Condition A), Tr: 6.35 min (HPLC purity: 94.5%). Example 45: ([4- (benzoylamino) benzyl] {4 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid The same procedure used in the preparation of Example 28 but using 4-benzamidobenzylamine in the
step c provided the title compound as a yellow oil (1.8 mg). M- (LC / MS (ESI)): 598.8; M + (LC / MS (ESI)): 600.1. HPLC (Condition A), Tr: 5.93 min (HPLC purity: 55.1%).
Example 46: N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benzyl} -3-phenyl-beta-alanine The same procedure used in the preparation of Example 28 but using dl-3-amino-3 acid -phenylpropionic in step c provided the title compound as a white powder (7.5 mg). M- (LC / MS (ESI)): 537.7; M + (LC / MS (ESI)): 539.0. HPLC (Condition A), Tr: 5.57 min (HPLC purity: 57.3%).
The same procedure used in the preparation of Example 28 but using 4- (1,2,3-thiadiazol-4-yl) benzylamine hydrochloride in step c provided the title compound as a brown powder (7.4 mg). M- (LC / MS (ESI)): 562.9; M + (LC / MS (ESI)): 565.7. HPLC (Condition A), Tr: 6.02 min (HPLC purity: 94.2%).
Example 48: {[4 - [(dodecylamino) carbonyl] benzyl} (4-pentylbenzyl) amino} (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using 4-pentyl-benzylamine hydrochloride in step c provided the title compound as a colorless oil (9.3 mg). M- (LC / MS (ESI)): 549.0; M + (LC / MS (ESI)): 551.1. HPLC (Condition A), Tr: 7.04 min (HPLC purity: 97.1%).
Example 49: [{4 - [(dodecylamino) carbonyl] benzyl} (1-phenylethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 but using d, 1- □ -methylbenzylamine in step c provided the title compound as a white powder (14.6 mg). M- (LC / MS (ESI)): 493.1; M + (LC / MS (ESI)): 495.0. HPLC (Condition A), Tr: 6.11 min (HPLC purity: 92.1%).
Example 50: (benzyl {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
Step a) Formation of resin-bound amines of formula (D) (See Scheme 5), for example resin-bound dodecylamine
The same procedure used in the preparation of Example 28, step a, provided the title compound.
Step b) Formation of resin-bound protected amines of formula (VII-1) (See Scheme 5), for example the 9Hfluoren-9-ylmethyl 3 - [(dodecylamino) carbonyl] benzylcarbamate resin bonded
The resin-bound dodecylamine (described in step a, 0.0426 mmol) was swollen in NMP (0.25 mL) for 15 min at RT. DIEA (44 mg, 0.340 mmol), Fmoc- (3-aminomethyl) -benzoic acid (64 mg, 0.175 mmol) and PyBOP® (89 mg, 0.175 mmol) were dissolved in NMP (0.75 mL) and stirred for 15 min at RT The solution was added to the resin and the resulting reaction mixture was stirred 14 h at RT. The resin was washed successively with NMP (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step c) Fmoc deprotection of the resin-bound protected amines of formula (VII-1) (See Scheme 5); for example formation of resin-bound 3- (aminomethyl) -N-dodecylbenzamide
The resin-bound 9H-fluoren-9-ylmethyl 3 - [(dodecylamino) carbonyl] benzylcarbamate (described in step b, 0.0426 mmol) was treated with a 20% (v / v) solution of piperidine in DMF ( 4 mL, 1x 5 min, then again 2x 15 min with a new solution of piperidine in DMF). The resin was washed successively with DMF (1x 15 min), MeOH (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF (3x 10 min), MeOH ( 1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step d) Formation of resin-bound secondary amines of formula (III-1) (See Scheme 5, Method L), for example 3 - [(benzylamino) methyl] -N-dodecylbenzamide resin-bound
The resin-bound 3- (aminomethyl) -N-dodecylbenzamide (described in step c, 0.0426 mmol) was swollen in THF / TMOF 80/20 (1.0 mL) for 15 min at RT. Benzaldehyde (45 mg, 0.426 mmol) was added and the mixture was stirred 14 h at RT. The resin was washed with 10% TMOF in anhydrous THF (2x 15 min, then 2x 60 min), then with anhydrous THF (1x 30 min). The resin was then poured into anhydrous THF (1.0 mL) and sodium triacetoxyborohydride (27 mg, 0.128 mmol) was added and the mixture was stirred 14 h at RT. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF (3x 10 min), MeOH ( 1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step e) Formation of resin-bound oxamic ester of formula (I-1) (See Scheme 1), for example, ethyl (benzyl {3 [(dodecylamino) carbonyl] benzyl} amino) (oxo) resin-bound acetate
The same procedure used in the preparation of Example 28, step d, but using the resin-bound 3 - [(benzylamino) methyl] N-dodecylbenzamide (described in step d, 0.0426 mmol) gave the title compound to be used directly in the next stage.
The same procedure used in the preparation of Example 28, step e, but using the ethyl (benzyl {3 [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate bonded resin (described in step e, 0.0426 mmol ) provided the title compound that was used directly in the next stage.
Step g) Excision of the resin-bound oxamic acid of formula (I-1); formation of oxamic acid of formula (I) (See Scheme 1), for example (benzyl {3 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 28, step f, but using resin bonded (benzyl {3 [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid (described in step f, 0.0426 mmol ) provided the title compound as a yellow oil (15.5 mg). 1H NMR (CD3OD, 300 MHz) δ 7.70-7.08 (m, 9H), 4.43 (s, 2H), 4.41 (s, 2H), 3.34-3.20 (m, 2H), 1.61-1.45 (m, 2H), 1.37-1.10 (m, 18H), 0.80 (t, J = 8.6 Hz, 3H). M- (LC / MS (ESI)): 479.4; M + (LC / MS (ESI)): 481.2. HPLC (Condition A), Tr: 6.28 min (HPLC purity: 80.3%).
Example 51: {{3 - [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4- (methylsulfonyl) benzaldehyde in step d provided the title compound as a yellow oil (16.2 mg). 1H NMR (CD3OD, 300 MHz) δ 8.00-7.25 (m, 8H), 4.61-4.46 (m, 4H), 3.32-3.23 (m, 2H), 3, 01 (s, 3H), 1.60-1.45 (m, 2H), 1.36-1.12 (m, 18H), 0.80 (t, J = 8.7 Hz, 3H). M- (LC / MS (ESI)): 557.0; M + (LC / MS (ESI)): 559.1. HPLC (Condition A), Tr: 5.71 min (HPLC purity: 86.5%).
Example 52: ((3-Cyanobenzyl) {3 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 506.6
Example 53: {{3 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 548.9
Example 54: [(4-Chlorobenzyl) (3 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) -amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 4-n-pentylbenzyl amine hydrochloride in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-chloro-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 507.7
Example 55: oxo {[4 ({[2- (2-thienyl] ethyl] amino} carbonyl) benzyl] [4- (trifluoromethyl) -benzyl) amino) acetic acid
The same procedure used in the preparation of Example 50 using thiophene-2-ethylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4- (trifluoro-methyl) benzaldehyde in step d provided the compound of the title. M + (LC / MS (ESI)): 491.6
Example 56: {benzyl [(3 '- {[(2,2-diphenylethyl] amino] carbonyl} [1,1'-biphenyl] -4-yl) acid
methyl] amino (oxo) acetic
Stage a) Formation of tert-Butyl-3-bromo benzoate
To a mixture of 3-bromobenzoic acid (100 g, 0.5 mol), silver carbonate (276 g, 1 mol) and dry molecular sieves (100 g) taken in dry CH2Cl2 (2 L), tert-butyl bromide was added (115 mL, 1 mol) drip at 0 ° C and the reaction mixture was stirred overnight at RT. The solid was filtered and washed with dichloromethane. The organic layer was washed with 10% aqueous NaHCO3 solution (2x 500mL), water (2x 500 mL), brine and dried. The solvent was removed in vacuo to provide tert-butyl-3-bromobenzoate (70 g, 57%).
Stage b) Formation of tert-butyl-3- (4-tolyl) bromobenzoate
To a mixture of tert-butyl-3-bromobenzoate (65 g, 0.25 mol), 4-tolyl boronic acid (41.3 g, 0.30 mol) and sodium carbonate (150 g) in a mixture of toluene (500mL) and water (50 mL) tetrakis-triphenylphosphine palladium (0) (14.5 g, 0.05 mol) was added and the reaction mixture was refluxed overnight. It was cooled to RT, the toluene layer was separated. The organic layer was washed with water, brine, dried. The solvent was removed in vacuo to provide tert-butyl-3- (4-tolyl) benzoate (62 g, 90%).
To a solution of tert-Butyl-3- (4-tolyl) benzoate (60 g, 0.22 mol) in CCl4 (800 mL) were added NBS (47.8 g, 0.268 mol) and benzoylperoxide (10 g) and The reaction mixture was refluxed overnight. It was cooled to RT and filtered. The filtrate was concentrated to provide 4- (3-tert-butoxy carbonyl phenyl) benzyl bromide (65 g, 84%).
Stage d) Formation of 4- (3-Carboxyphenyl) benzylamine hydrochloride
Ammonia gas was passed through a cooled solution of 4- (3-tert-butoxycarbonylphenyl) benzyl bromide (65 g, 0.18 mol) in methanol (2 L) for 6 h. Then the reaction mixture was stirred at RT overnight. The methanol was removed in vacuo. To the residue was added 6N aqueous HCl solution (200 mL) and stirred overnight. It was fully concentrated to obtain 4- (3-carboxyphenyl) benzylamine as a hydrochloride salt (20 g, 41%).
Stage e) Formation of N-Fmoc-4- (3-carboxyphenyl) benzylamine
A solution of 4- (3-carboxyphenyl) benzylamine hydrochloride (20 g, 0.075 mol) in 10% Na2CO3 (350 mL) and dioxane (100 mL) was cooled to 0 ° C with stirring. A solution of Fmoc-OSu (30.7 g, 0.091 mol) in dioxane (100 mL) was added in one portion and the reaction mixture was stirred at RT for 3h. It was acidified with 1.5 N aqueous HCl solution and extracted with EtOAc (3 x 400 mL). The organic layer was washed with water (3x 500 mL), brine, dried over Na2SO4 and concentrated, purified by column chromatography using dichloromethane / methanol
(9: 1) to provide N-Fmoc-4- (3-carboxyphenyl) benzylamine (16 g). This was further purified by recrystallization from THF / Pet ether, which gave the pure title product (8 g).
Step f) Formation of {benzyl [(3 '- {[(2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2,2-diphenyl-ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 569.5
Example 57: {(3-cyanobenzyl) [(3 '- {[(2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2,2-diphenyl-ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyano-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 594.4
Example 58: {(4-Chlorobenzyl) [(3 '- {[(2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2,2-diphenyl-ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4-chloro-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 605.3
Example 59: {[(3 '- {[(2,2-diphenylethyl) amino} carbonyl} [1,1'-biphenyl] -4-yl) methyl] [4 (trifluoromethyl) benzyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 using 2,2-diphenyl-ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- (trifluoromethyl) benzaldehyde in step d provided The title compound. M + (LC / MS (ESI)): 637.4
Example 60: ((3-cyanobenzyl) {[3 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) [1,1'-biphenyl] -4-yl] methyl} amino (oxo) acetic
The same procedure used in the preparation of Example 50 using 4-phenoxy-phenethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 610.4
Example 61: oxo {{[3 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) [1,1'-biphenyl] -4-yl] methyl} [4 (trifluoromethyl) benzyl] amino }acetic
The same procedure used in the preparation of Example 50 using 4-phenoxy-phenethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the compound of the title. M + (LC / MS (ESI)): 653.4
Example 62: [(3-Cyanobenzyl) ({3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using octylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 526.4
The same procedure used in the preparation of Example 50 using octylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4-chlorobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 537.4
Example 64: {({3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using octylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- (trifluoromethyl) -benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 569.4
Example 65: {(3-cyanobenzyl) [(3 '- {[' (3-phenylpropyl) amino} carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 3-phenylpropyl-amine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 532.4
Example 66: [(3-Cyanobenzyl) ({3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, N-Fmoc-4 (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 582.5
Example 67: [(4-Chlorobenzyl) ({3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, N-Fmoc-4 (3-carboxyphenyl) benzylamine in step b and 4-chlorobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 592.5
Example 68: {({3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) [4- (trifluoro-methyl) benzyl] amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, N-Fmoc-4 (3-carboxyphenyl) benzylamine in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 625.5
Example 69: {benzyl [(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 4-n-pentylbenzyl amine hydrochloride in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and benzaldehyde in step d provided the compound of Title. M + (LC / MS (ESI)): 549.5
Example 70: {(3-cyanobenzyl) [(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 4-n-pentyl-benzylamine hydrochloride in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 574.5
Example 71: {(4-Chlorobenzyl) [(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 4-n-pentylbenzyl amine hydrochloride in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4-chlorobenzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 584.3
Example 72: oxo {[(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl} amino} acetic acid
The same procedure used in the preparation of Example 50 using 4-n-pentyl-benzylamine hydrochloride in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 617.5
Example 73: oxo {[(3 '- {[(4-phenylbutyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 50 using 4-phenylbutyl-amine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- (trifluoro-methyl) benzaldehyde in step d provided The title compound. M + (LC / MS (ESI)): 589.5
The same procedure used in the preparation of Example 50 using 2- (2,4,6-trimethyl-phenyl) -ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 3-cyanobenzaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 560.5
Example 75: {(4-Chlorobenzyl) [(3 '- {[(2-mesitylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2- (2,4,6-trimethyl-phenyl) -ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4-chlorobenzaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 570.4
Example 76: {[(3 '- {[(2-mesitylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2- (2,4,6-trimethyl-phenyl) -ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4- ( trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 603.5
Example 77: ((4-Chlorobenzyl) {[3 '- ({[2- (4-methoxyphenyl) ethyl] amino} carbonyl) [1,1'-biphenyl] -4-yl] methyl} amino (oxo) acetic
The same procedure used in the preparation of Example 50 using 2- (4-methoxyphenyl) ethylamine in step a, N-Fmoc-4- (3-carboxyphenyl) benzylamine in step b and 4-chlorobenzaldehyde in step d provided the compound of the title. M + (LC / MS (ESI)): 558.3
Example 78: [{4 - [(dodecylamino) carbonyl] benzyl} (4-methoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and p-anisaldehyde in step d provided the title compound as a yellow oil (20, 2 mg) M- (LC / MS (ESI)): 509.2; M + (LC / MS (ESI)): 511.3. HPLC (Condition A), Tr: 6.19 min (HPLC purity: 80.2%).
Example 79: {{4 - [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4- (methylsulfonyl) benzaldehyde in step d provided the title compound as a yellow oil (21.7 mg). M- (LC / MS (ESI)): 557.2; M + (LC / MS (ESI)): 559.1. HPLC (Condition A), Tr: 5.71 min (HPLC purity: 92.3%).
Example 80: [{3 - [(dodecylamino) carbonyl] benzyl} (4-methoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and p-anisaldehyde in step d provided the title compound as a yellow oil (18, 3 mg) M- (LC / MS (ESI)): 509.4; M + (LC / MS (ESI)): 511.2. HPLC (Condition A), Tr: 6.22 min (HPLC purity: 76.1%).
Example 81: {{3 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl) amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3- (trifluoromethyl) benzaldehyde in step d provided the title compound as a yellow oil (19.4 mg). M- (LC / MS (ESI)): 547.2; M + (LC / MS (ESI)): 549.3. HPLC (Condition A), Tr: 6.58 min (HPLC purity: 91%).
Example 82: ({4 - [(dodecylamino) carbonyl] benzyl} {[6- (trifluoromethyl) -3-pyridinyl] -methyl} amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 6- (trifluoromethyl) pyridine-3-carboxaldehyde in step d provided the title compound as a light yellow oil (33 mg). M- (LC / MS (ESI)): 548.3; M + (LC / MS (ESI)): 550.4. HPLC (Condition A), Tr: 6.03 min (HPLC purity: 83.5%).
Example 83: 4 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) -methyl] -benzoic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and methyl 4-formylbenzoate in step d provided the title compound as a white solid (33 mg) M- (LC / MS (ESI)): 523.8; M + (LC / MS (ESI)): 525.3. HPLC (Condition A), Tr: 5.45 min (HPLC purity: 92.6%).
Example 84: ({3 - [(dodecylamino) carbonyl] benzyl} [4-hydroxy (oxide) amino] -benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-nitrobenzaldehyde in step d gave the title compound Example 85: acid [{3 - [(dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] (oxo) acetic
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 2-fluorobenzaldehyde in step d provided the title compound as a yellow solid (26 mg ). M- (LC / MS (ESI)): 497.3; M + (LC / MS (ESI)): 499.4. HPLC (Condition A), Tr: 6.19 min (HPLC purity: 78%).
Example 86: [{3 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 2-pyridinecarboxaldehyde in step d provided the title compound as a brown oil (29 mg ). M- (LC / MS (ESI)): 480.3; M + (LC / MS (ESI)): 482.4. HPLC (Condition A), Tr: 4.67 min (HPLC purity: 89%).
Example 87: [{3 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3-thiophenecarboxaldehyde in step d provided the title compound as an orange oil (24 mg ). M- (LC / MS (ESI)): 485.2; M + (LC / MS (ESI)): 487.4. HPLC (Condition A), Tr: 6.13 min (HPLC purity: 64%).
Example 88: [{3 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-hydroxybenzaldehyde in step d provided the title compound as an orange oil (29 mg ). M- (LC / MS (ESI)): 495.3; M + (LC / MS (ESI)): 497.3. HPLC (Condition A), Tr: 5.55 min (HPLC purity: 81.1%).
Example 89: [{3 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-phenoxybenzaldehyde in step d provided the title compound as a yellow oil (30 mg ). M- (LC / MS (ESI)): 571.5; M + (LC / MS (ESI)): 573.3. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 77.3%).
Example 90: ({3 - [(dodecylamino) carbonyl] benzyl} {[6- (trifluoromethyl) -3-pyridinyl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 6- (trifluoromethyl) pyridine-3-carboxaldehyde in step d provided the title compound as a light yellow oil (32 mg). M + (LC / MS (ESI)): 550.5. HPLC (Condition A), Tr: 6.19 min (HPLC purity: 79.8%).
Example 91: 3 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -benzoic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3-carboxybenzaldehyde in step d provided the title compound as a light yellow oil (33 mg) M + (LC / MS (ESI)): 525.3 HPLC (Condition A), Tr: 5.53 min (HPLC purity: 76%).
Example 92: 5 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -2-thiophenecarboxylic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 5-formyl-2-thiophenecarboxylic acid in step d provided the title compound as a light yellow oil (31 mg). M- (LC / MS (ESI)): 529.2; M + (LC / MS (ESI)): 531.2. HPLC (Condition A), Tr: 5.32 min (HPLC purity: 54%).
Example 93: ({4 - [(dodecylamino) carbonyl] benzyl} {4- [hydroxy (oxide) amino] benzyl} -amino (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-nitrobenzaldehyde in step d provided the title compound as a brown oil (28 mg ). M- (LC / MS (ESI)): 524.2; M + (LC / MS (ESI)): 526.3. HPLC (Condition A), Tr: 6 min (HPLC purity: 58.5%).
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and piperonal in step d provided the title compound as an orange oil (27 mg). M- (LC / MS (ESI)): 523.2; M + (LC / MS (ESI)): 526.4 HPLC (Condition A), Tr: 6.08 min (HPLC purity: 59.8%).
Example 95: [{4 - [(dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 2-fluorobenzaldehyde in step d provided the title compound as a yellow solid (30 mg ). M- (LC / MS (ESI)): 497.3; M + (LC / MS (ESI)): 499.5. HPLC (Condition A), Tr: 6.2 min (HPLC purity: 79.1%).
Example 96: [{4 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-phenoxybenzaldehyde in step d provided the title compound as a light yellow oil (28 mg) M- (LC / MS (ESI)): 571.2; M + (LC / MS (ESI)): 573.4. HPLC (Condition A), Tr: 6.67 min (HPLC purity: 64.5%).
Example 97: 4 [(((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) -methyl] -benzoic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and methyl 4-formylbenzoate in step d provided the title compound as a white solid (28 mg) M- (LC / MS (ESI)): 523.2; M + (LC / MS (ESI)): 525.2. HPLC (Condition A), Tr: 5.49 min (HPLC purity: 62.9%).
Example 98: 5 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -2-thiophenecarboxylic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 5-formyl-2-thiophenecarboxylic acid in step d provided the title compound as a light yellow oil (28 mg) .M- (LC / MS (ESI)): 529.2; M + (LCMS (ESI)): 531.7. HPLC (Condition A), Tr: 5.37 min (HPLC purity: 58%).
Example 99: [{3 - [(dodecylamino) carbonyl] benzyl} (2-thienylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 2-thiophenecarboxaldehyde in step d provided the title compound as a colorless oil (6, 8 mg) M- (LC / MS (ESI)): 485.4; M + (LC / MS (ESI)): 487.3. HPLC (Condition A), Tr: 6.11 min (HPLC purity: 97.6%).
Example 100: [{4 - [(dodecylamino) carbonyl] benzyl} (isopropyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step be isopropylamine in step d provided the title compound as a light yellow oil (21 mg). M- (LC / MS (ESI)): 431.3; M + (LC / MS (ESI)): 433.3 HPLC (Condition A), Tr: 4.12 min (HPLC purity: 85.5%).
Example 101: ((3,5-dichlorobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3,5-dichlorobenzylamine in step d provided the title compound as a light yellow oil (24 mg). M- (LC / MS (ESI)): 547.2; M + (LC / MS (ESI)): 551.1. HPLC (Condition A), Tr: 6.61 min (HPLC purity: 82%).
Example 102: [(3,5-Dichlorobenzyl) (4 - {[(3,3-diphenylpropyl) amino] carbonyl} -benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 3,3-diphenylpropylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3,5-dichlorobenzylamine in step d provided the title compound as a light yellow oil ( 22 mg) M- (LC / MS (ESI)): 573.0; M + (LC / MS (ESI)): 575.0. HPLC (Condition A), Tr: 5.13 min (HPLC purity: 81.2%).
Example 103: [(4 - {[(2-1,1'-biphenyl] -4-ylethyl) amino] carbonyl} benzyl) (3,5-dichlorobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 2- (4-biphenyl) ethylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3,5-dichlorobenzylamine in step d provided the title compound as an oil light yellow (21 mg). M- (LC / MS (ESI)): 559.6. HPLC (Condition A), Tr: 5.06 min (HPLC purity: 79.7%).
The same procedure used in the preparation of Example 50 using 2- (4-biphenyl) -ethylamine in step a, 4-chloromethylbenzoyl chloride in step b and piperonylamine in step d provided the title compound as a light yellow oil ( 23 mg) M- (LC / MS (ESI)): 535.1; M + (LC / MS (ESI)): 537.0. HPLC (Condition A), Tr: 4.46 min (HPLC purity: 79.1%).
Example 105: (2,3-dihydro-1H-inden-1-yl {4 - [(dodecylamino) carbonyl] benzyl} -amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 1-aminoindane in step d provided the title compound as a light yellow oil (23 mg). M- (LC / MS (ESI)): 505.2; M + (LC / MS (ESI)): 507.7 HPLC (Condition A), Tr: 6.28 min (HPLC purity: 67.9%).
Example 106: {2,3-dihydro-1H-inden-1-yl [4 - ({[2- (4-phenoxyphenyl) ethyl] amino} -carbonyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 using 4-phenoxy-phenethylamine in step a, 4-chloromethylbenzoyl chloride in step b and 1-aminoindane in step d provided the title compound as a light yellow oil (21 mg ). M- (LC / MS (ESI)): 533.3; M + (LC / MS (ESI)): 535.0. HPLC (Condition A), Tr: 4.67 min (HPLC purity: 67.3%).
Example 107: [{4 - [(dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-pyridinecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a white solid (5 mg). M- (LC / MS (ESI)): 480.3; M + (LC / MS (ESI)): 482.3. HPLC (Condition A), Tr: 4.35 min (HPLC purity: 93.7%).
Example 108: ([4- (dimethylamino) benzyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-dimethylaminobenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography. reverse (Condition C), providing the title compound as a brown oil (2 mg). M- (LC / MS (ESI)): 522.3; M + (LC / MS (ESI)): 524.6. HPLC (Condition A), Tr: 4.57 min (HPLC purity: 80.5%).
Example 109: [{4 - [(dodecylamino) carbonyl] benzyl} (3-pyridinylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 3-pyridinecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a white solid (6 mg). M- (LC / MS (ESI)): 480.3; M + (LC / MS (ESI)): 482.5. HPLC (Condition A), Tr: 4.41 min (HPLC purity: 86.8%).
Example 110: ((4-cyanobenzyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-cyanobenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a yellow oil (6 mg). M- (LC / MS (ESI)): 504.4; M + (LC / MS (ESI)): 506.2. HPLC (Condition A), Tr: 5.85 min (HPLC purity: 87.3%).
Example 111: [{4 - [(dodecylamino) carbonyl] benzyl} (1,3-thiazol-2-ylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 2-formylthiazole in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a yellow oil (4 mg). M- (APCI): 486.2; M + (APCI): 488.2 HPLC (Condition A), Tr: 5.48 min (HPLC purity: 85.4%).
Example 112: ({4 - [(dodecylamino) carbonyl] benzyl} {[2- (4-morpholinyl) -1,3-thiazol-5-yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 2-morpholino-1,3-thiazol-5-carbaldehyde in step d provided a crude product that was purified by reverse phase HPLC chromatography (Condition C), providing the title compound as an orange oil (5 mg). M- (LC / MS (ESI)): 571.3; M + (LC / MS (ESI)): 573.4. HPLC (Condition A), Tr: 4.62 min (HPLC purity: 97.7%).
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-pyridinecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as an orange oil (5 mg). M- (LC / MS (ESI)): 480.5; M + (LC / MS (ESI)): 482.3. HPLC (Condition A), Tr: 4.34 min (HPLC purity: 89.7%).
Example 114: [{3 - [(dodecylamino) carbonyl] benzyl} (3-pyridinylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3-pyridinecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a yellow oil (7 mg). M- (LC / MS (ESI)): 480.4; M + (LC / MS (ESI)): 482.3. HPLC (Condition A), Tr: 4.36 min (HPLC purity: 89.7%).
Example 115: [{3 - [(dodecylamino) carbonyl] benzyl} (3-hydroxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 3-hydroxybenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a yellow oil (4 mg). M- (LC / MS (ESI)): 495.4; M + ((LC / MS (ESI)): 497.3 HPLC (Condition A), Tr: 5.58 min (HPLC purity: 82.5%).
Example 116: ((4-cyanobenzyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 4-cyanobenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as an orange oil (5 mg). M- (LC / MS (ESI)): 504.3; M + (LC / MS (ESI)): 506.3. HPLC (Condition A), Tr: 5.86 min (HPLC purity: 97.5%).
Example 117: [{3 - [(dodecylamino) carbonyl] benzyl} (1,3-thiazol-2-ylmethyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 2-formylthiazole in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a red oil (4 mg). M- (LC / MS (ESI)): 486; M + (LC / MS (ESI)): 488.5. HPLC (Condition A), Tr: 5.49 min (HPLC purity: 68.3%).
Example 118: ({3 - [(dodecylamino) carbonyl] benzyl} {[2- (4-morpholinyl) -1,3-thiazol-5-yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and 2-morpholino-1,3-thiazol-5-carbaldehyde in step d provided a crude product that was purified by reverse phase HPLC chromatography (Condition C), providing the title compound as an orange oil (4 mg). M- (LC / MS (ESI)): 571.4; M + (LC / MS (ESI)): 573.0. HPLC (Condition A), Tr: 4.59 min (HPLC purity: 96.3%).
Example 119: ((1,3-benzodioxol-5-ylmethyl] {3 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (3-aminomethyl) -benzoic acid in step b and piperonal in step d provided a crude product that was purified by reverse phase HPLC chromatography ( Condition C), providing the title compound as a white solid (6.3 mg). M- (LC / MS (ESI)): 523.3; M + (LC / MS (ESI)): 525.4. HPLC (Condition A), Tr: 6.07 min (HPLC purity: 97.4%).
Example 120: [{(4 - [(dodecylamino) carbonyl] benzyl} (2-thienylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 2-thiophenecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a white powder (2.4 mg). M- (LC / MS (ESI)): 485.2; M + (LC / MS (ESI)): 487.4. HPLC (Condition A), Tr: 5.9 min (HPLC purity: 90.4%).
Example 121: [{4 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 2-pyridinecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound Example 122: [{4 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 3-thiophenecarboxaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a white powder (2.6 mg). M- (LC / MS (ESI)): 485.4; M + (LC / MS (ESI)): 487.4. HPLC (Condition A), Tr: 5.9 min (HPLC purity: 95%).
Example 123: [{4 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 4-hydroxybenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a white powder (3.3 mg). M- (LC / MS (ESI)): 495.4; M + (LC / MS (ESI)): 497.3. HPLC (Condition A), Tr: 5.47 min (HPLC purity: 95.3%).
Example 124: 3 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) -methyl] -benzoic acid
The same procedure used in the preparation of Example 50 using dodecylamine in step a, Fmoc- (4-aminomethyl) -benzoic acid in step b and 3-carboxybenzaldehyde in step d provided a crude product that was purified by phase HPLC chromatography reverse (Condition C), providing the title compound as a colorless oil (5.7 mg). M- (LC / MS (ESI)): 523.2; M + (LC / MS (ESI)): 525.4. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 95.5%).
Example 125: [benzyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid
Step a) Formation of resin-bound amines of formula (D) (See Scheme 5), for example resin-bound dodecylamine
The same procedure used in the preparation of Example 28, step a, provided the title compound that was used directly in the next step.
Step b) Formation of the resin-bound protected amines of formula (VII-1) (See Scheme 5, Method L), for example 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindole- 2-yl) methyl] -N-dodecyl-thiophene-2-sulfonamide resin bonded

Ejemplo

310: ácido {[4-({[(2-butil-1-benzofuran-3-il)metil]amino}carbonil)bencil][4

(trifluorometil)ben

cil]amino}(oxo)ac ético

Etapa

a) Formación de etil {[4-({[(2-butil-1-benzofuran-3-il)metil]amino}carbonil)-bencil][4

(trifluorometil)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa d) pero utilizando ácido 4({[etoxi(oxo)acetil][4-(trifluorometil)bencil]amino}metil)benzoico y clorhidrato de [(2-butil-1-benzofuran-3-il)metil]amina, HOBT y TEA en DCM proporcionó el compuesto del título como un sólido blanco (33%). 1H NMR (CDCl3, 300 MHz) δ 7,66 (m, 2H), 7,51 (m, 3H), 7,35-7,18 (m, 7H), 6,05 (br s, 1H), 4,64 (s, 2H), 4,44 (s, 2H), 4,29 (m, 4H), 2,78 (m, 2H), 1,66 (m, 2H), 1,46 (m, 2H), 1,24 (m, 3H), 0,88 (m, 3H). M-(LC/MS(ESI)): 593; M+(LC/MS(ESI)): 595. HPLC (Condición A), Tr: 6,38 min (pureza de la HPLC: 99,6%).
Etapa b) Formación de ácido {[4-({[(2-butil-1-benzofuran-3-il)metil]amino}carbonil)bencil][4(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[4-({[(2-butil-1benzofuran-3-il)metil]amino}carbonil)bencil][4-(trifluorometil)-bencil]amino}(oxo)acetato proporcionó el compuesto del título como un polvo blanco (93%). 1H NMR (CDCl3, 300 MHz) δ 7,71-7,26 (m, 12H), 6,22 (br s, 1H), 4,89 (s, 1H), 4,74 (br s, 3H), 4,55 (s, 2H), 2,86 (m, 2H), 2,10-1,27 (m, 4H), 0,95 (m, 3H). M-(LC/MS(ESI)): 565; M+(LC/MS(ESI)):
567. HPLC (Condición A), Tr: 5,71 min (pureza de la HPLC: 99,8%).
Ejemplo 311: ácido {(4-{[4-(benciloxi)benzoil]amino}bencil)[4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de etil{(4-{[4-(benciloxi)benzoil]amino} bencil)[4-(trifluorometil)bencil]amino}(oxo) acetato
A una solución de ácido 4-(benciloxi)benzoico (180 mg, 0,79 mmol) en piridina anhidro (3 mL) a TA se agregó por goteo cloroformiato de isobutilo (0,100 mL, 0,79 mmol) bajo una atmósfera inerte. Después de 30 min, se agregó una solución de etil{(4-aminobencil)[4-trifluorometil)bencil]amino}(oxo)acetato (100 mg, 0,26 mmol) en piridina anhidro (1 mL) por goteo y la mezcla resultante se calentó a 70ºC durante 30 min. La mezcla de reacción se diluyó con una solución acuosa 5N de HCl (11 mL) y se extrajo con Et2O (2x 5 mL). Las capas orgánicas combinadas se secaron sobre MgSO4 y el disolvente se retiró a presión reducida. Este residuo se purificó mediante cromatografía instantánea sobre gel de sílice (Et2O/c-Hex 1/1 a Et2O) para proporcionar el compuesto del título como un aceite incoloro (125 mg, 79%). 1H NMR (CDCl3, 300 MHz) δ 7,86 (m, 2H), 7,77 (br s, 1H), 7,63 (m, 4H), 7,44-7,21, (m, 9H), 7,08 (m, 2H), 5,16 (s, 2H), 4,54-4,33 (m, 6H), 1,35 (m, 3H). M-(LC/MS(ESI)): 589; M+(LC/MS(ESI)): 591. HPLC (Condición A), Tr: 6,04 min (pureza de la HPLC: 99,7%).
Etapa b) Formación de ácido {(4-{[4-(benciloxi)benzoil]amino}bencil)[4-(trifluorometil)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-{[4(benciloxi)benzoil]amino}bencil)[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un sólido beige (48%). 1H NMR (CD3OD, 300 MHz) δ 7,96 (d, 2H, J = 8,7 Hz), 7,69 (m, 4H), 7,55-7,33 (m, 8H), 7,25 (d, 1H, J = 8,3 Hz), 7,16 (d, 2H, J = 8,7 Hz), 5,22 (s, 2H), 4,62 (s, 2H), 4,54 (s, 2H). M-(LC/MS(ESI)): 561; M+(LC/MS(ESI)): 563. HPLC (Condición A), Tr: 5,35 min (pureza de la HPLC: 97,0%).
Etapa a) Formación de clorhidrato de (3,5-diclorobencil)(4-nitrobencil)amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 3,5-diclorobencilamina y 4-nitrobenzaldehído proporcionó el compuesto del título como un polvo amarillo (71%). 1H NMR (CD3OD, 300 MHz) δ 8,37 (d, 2H, J = 8,8 Hz), 7,83 (d, 2H, J = 8,8 Hz), 7,61 (br s, 3H), 4,48 (s, 2H), 4,38 (s, 2H). M-(LC/MS(ESI)): 309; M+(LC/MS(ESI)): 311 HPLC (Condición A), Tr: 2,78 min (pureza de la HPLC: 93,0%).
Etapa b) Formación de etil [(3,5-diclorobencil)(4-nitrobencil)amino](oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de (3,5diclorobencil)(4-nitrobencil)amina proporcionó el compuesto del título como un polvo amarillo (77%). 1H NMR (CDCl3, 300 MHz) δ 8,22 (m, 2H), 7,46-7,30 (m, 3H), 7,13 (br s, 1H), 7,06 (br s, 1H), 4,60 (s, 1H), 4,51 (s, 1H), 4,45 (s, 1H), 4,37 (m, 3H), 1,35 (m, 3H). M-(LC/MS(ESI)): 409. HPLC (Condición A), Tr: 5,57 min (pureza de la HPLC: 97,7%).
Etapa c) Formación de etil [(4-aminobencil)(3,5-diclorobencil)amino](oxo)acetato
Se agregó una suspensión de PtO2 (250 mg) en EtOAc (5 mL) a una solución de etil [(3,5-diclorobencil)(4nitrobencil)amino](oxo)acetato (2,00 g, 4,86 mmol) en EtOH/EtOAc (2/1, 90 mL) bajo H2 (1 atm). La mezcla de reacción se agitó vigorosamente a TA durante 30 min. La mezcla de reacción se filtró a través de una almohadilla de Celite y gel de sílice para eliminar el catalizador. Los disolventes se retiraron a presión reducida. El residuo se purificó mediante cromatografía instantánea sobre gel de sílice (c-Hex/EtOAc 2/1) para proporcionar el compuesto del título como un aceite amarillo claro (1,21 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7,31-7,05 (m, 5H), 6,71 (m, 2H), 4,39 (m, 4H), 4,25 (br s, 2H), 1,36 (m, 3H). HPLC (Condición A), Tr: 3,4 min (pureza de la HPLC: 94,1%).
Etapa d) Formación de etil{(3,5-diclorobencil)[4-(tridecanoilamino)-bencil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa d) pero utilizando etil [(4-aminobencil)(3,5diclorobencil)amino](oxo)acetato proporcionó el compuesto del título como un aceite amarillo claro (59%). 1H NMR (CDCl3, 300 MHz) δ 7,52 (m, 2H), 7,32-7,05 (m, 6H), 4,47-4,27 (m, 6H), 2,37 (t, 2H, J = 7,5 Hz), 1,73 (m, 2H), 1,381,26 (m, 21H), 0,88 (t, 3H, J = 6,6 Hz). HPLC (Condición A), Tr: 7,52 min (pureza de la HPLC: 99,0%).
Etapa e) Formación de ácido {(3,5-diclorobencil)[4-(tridecanoilamino)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(3,5-diclorobencil)[4(tridecanoilamino)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un polvo blanco (81%). 1H NMR (CDCl3, 300 MHz) δ 7,50 (br s, 2H), 7,30-7,06 (m, 6H), 4,91 (s, 2H), 4,50 (m, 2H), 2,36 (m, 2H), 1,72 (m, 2H), 1,25 (br s, 18H), 0,88 (br s, 3H). M-(LC/MS(ESI)): 547; M+(LC/MS(ESI)): 549. HPLC (Condición A), Tr: 6,46 min (pureza de la HPLC: 99,5%).
Ejemplo 313: ácido {(3,5-diclorobencil)[4-(tridecanoilamino)bencil]amino}(oxo)acético, sal de N-metil-D-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(3,5-diclorobencil)[4(tridecanoilamino)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (88%). M-(LC/MS(ESI)): 547; M+(LC/MS(ESI)): 549. HPLC (Condición A), Tr: 6,48 min (pureza de la HPLC: 99,5%). Análisis calculado para C29H38Cl2N2O4.C7H17NO5=1,1 H2O: C, 56,55; H, 7,54; N, 5,50%. Encontrado: C, 56,52; H, 7,50; N, 5,47%
Ejemplo 314: ácido {{4-[(4-octilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de etil {{4-[(4-octilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-etinil-4-octilbenceno bajo condiciones de microondas (300W, 120ºC, 5 min) proporcionó el compuesto del título como un aceite amarillo claro (37%). 1H NMR (CDCl3, 300 MHz) δ 7,63 (m, 2H), 7,54-7,33 (m, 6H), 7,21 (m, 4H), 4,55 (s, 1H), 4,52 (s, 1H), 4,36 (m, 4H), 2,62 (m, 2H), 1,62 (m, 2H), 1,32 (m, 13H), 0,89 (m, 3H). HPLC (Condición A), Tr: 7,91 min (pureza de la HPLC: 97,2%).
Etapa b) Formación de ácido {{4-[(4-octilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[(4octilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo claro (89%). 1H NMR (CDCl3, 300 MHz) δ 7,64 (m, 2H), 7,50 (m, 4H), 7,36 (m, 2H), 7,19 (m, 4H), 5,04 (s, 1H), 4,98 (s, 1H), 4,62 (s, 1H), 4,59 (s, 1H), 2,62 (m, 2H), 1,62 (m, 2H), 1,27 (br s, 10H), 0,89 (m, 3H). M(LC/MS(ESI)): 548. HPLC (Condición A), Tr: 7,53 min (pureza de la HPLC: 98,5%).
Etapa a) Formación de terc-butil 4-(trifluorometil)bencil[4-(5-undecil-1,2,4-oxadiazol-3-il)bencil] carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa e) pero utilizando terc-butil 4[[(dodecanoiloxi)amino](imino)metil]bencil[4-(trifluorometil)bencil]carbamato proporcionó el compuesto del título como un aceite incoloro (71%). 1H NMR (CDCl3, 300 MHz) δ 8,05 (d, 2H, J = 8,1 Hz), 7,60 (d, 2H, J = 7,9 Hz), 7,31 (m, 4H), 4,45 (m, 4H), 2,95 (t, 2H, J = 7,5 Hz), 1,88 (m, 2H), 1,50 (s, 9H), 1,27 (br s, 16H), 0,88 (m, 3H). HPLC (Condición A), Tr: 7,93 min (pureza de la HPLC: 99,9%).
Etapa b) Formación de terc-butil 4-[[(dodecanoiloxi)amino](imino)metil]bencil[4-(trifluorometil)bencil] carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 10 (etapa a) pero utilizando terc-butil 4[(hidroxiamino)(imino)metil]bencil[4-(trifluorometil)bencil]carbamato y ácido dodecanoico proporcionó el compuesto del título como un aceite incoloro (95%). 1H NMR (CD3OD, 300 MHz) δ 7,68 (d, 2H, J = 7,9 Hz), 7,59 (d, 2H, J = 8,0 Hz), 7,27 (m, 4H), 5,08 (br s, 2H), 4,42 (m, 4H), 2,49 (m, 2H), 1,72 (m, 2H), 1,49 (s, 9H), 1,27 (br s, 16H), 0,88 (m, 3H). HPLC (Condición A), Tr: 7,06 min (pureza de la HPLC: 86,0%).
Etapa c) Formación de terc-butil 4-[(hidroxiamino)(imino)metil]bencil[4-(trifluorometil)bencil] carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa a) pero utilizando terc-butil 4cianobencil[4-(trifluorometil)bencil]carbamato proporcionó el compuesto del título como una espuma blanca (88%).1H NMR (CDCl3, 300 MHz) δ 7,60 (m, 4H), 7,28 (m, 4H), 5,05 (br s, 3H), 4,43 (m, 4H), 1,49 (s, 9H). M-(LC/MS(ESI)): 422; M+(LC/MS(ESI)): 424. HPLC (Condición A), Tr: 3,67 min (pureza de la HPLC: 96,1%).
Etapa d) Formación de terc-butil 4-cianobencil[4-(trifluorometil)bencil] carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa b) pero utilizando clorhidrato de 4-({[4(trifluorometil)bencil]amino}metil)benzonitrilo y DIEA proporcionó el compuesto del título como un aceite incoloro (92%); 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 4H), 7,30 (m, 4H), 4,44 (m, 4H), 1,48 (s, 9H). M-(LC/MS(ESI)): 389. HPLC (Condición A), Tr: 6,02 min (pureza de la HPLC: 99,8%).
Etapa e) Formación de clorhidrato de 4-({[4-(trifluorometil)bencil]amino}metil)benzonitrilo
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-cianobenzaldehído proporcionó el compuesto del título como un sólido blanco (83%). 1H NMR (DMSO-d6, 300 MHz) δ 10,01 (br s, 2H), 7,92 (d, 2H, J = 8,4 Hz), 7,80 (s, 4H), 7,77 (d, 2H, J = 8,4 Hz), 4,28 (s, 4H). HPLC (Condición A), Tr: 2,59 min (pureza de la HPLC: 98,3%).
Etapa f) Formación de clorhidrato de N-[4-(trifluorometil)bencil]-N-[4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa f) pero utilizando terc-butil 4(trifluorometil)bencil[4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]carbamato proporcionó el compuesto del título como un polvo blanco (94%). 1H NMR (DMSO-d6, 300 MHz) δ 9,64 (br s, 2H), 8,05 (m, 2H), 7,76 (m, 6H), 4,30 (br s, 4H), 2,99 (m, 2H), 1,77 (m, 2H), 1,23 (br s, 16H), 0,84 (m, 3H). HPLC (Condición A), Tr: 5,35 min (pureza de la HPLC: 99,9%).
Etapa g) Formación de etil oxo{[4-(trifluorometil)bencil][4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amino) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-[4(trifluorometil)bencil]-N-[4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amina proporcionó el compuesto del título como un aceite incoloro (96%). 1H NMR (CDCl3, 300 MHz) δ 8,08 (m, 2H), 7,63 (m, 2H), 7,36 (m, 4H), 4,57 (s, 2H), 4,42 (s, 2H), 4,39 (m, 2H), 2,96 (m, 2H), 1,88 (m, 2H), 1,43-1,27 (m, 19H), 0,89 (m, 3H). HPLC (Condición A), Tr: 7,36 min (pureza de la HPLC: 99,9%).
Etapa h) Formación de ácido oxo{[4-(trifluorometil)bencil][4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amino)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[4(trifluorometil)bencil][4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite incoloro (90%). 1H NMR (CDCl3, 300 MHz) δ 8,08 (m, 2H), 7,64 (m, 2H), 7,35 (m, 4H), 5,04 (m, 2H), 4,64 (s, 2H), 2,96 (m, 2H), 1,88 (m, 2H), 1,50-1,15 (m, 16H), 0,88 (m, 3H). M-(LC/MS(ESI)): 558. HPLC (Condición A), Tr: 6,85 min (pureza de la HPLC: 99,9%). Análisis calculado para C30H36F3N3O4=0,2 H2O: C, 63,98; H, 6,51; N, 7,46%. Encontrado: C, 63,93; H, 6,56; N, 7,44%
Ejemplo 316: ácido oxo{[4-(trifluorometil)bencil][4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amino}acético, sal de N-metilD-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido oxo{[4(trifluorometil)bencil][4-(5-undecil-1,2,4-oxadiazol-3-il)bencil]amino}acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (79%). M-(LC/MS(ESI)): 558. HPLC (Condición A), Tr: 6,85 min (pureza Ejemplo 317: ácido {{4-[2-(4-octilfenil) etil]bencil}(4-(trifluorometil)bencil]amino}-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido{{4-[(4octilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético en EtOAc proporcionó el compuesto del título como un aceite incoloro (54%). 1H NMR (CDCl3, 300 MHz) δ 7,61 (m, 2H), 7,34 (m, 2H), 7,13 (m, 8H), 5,42 (br s, 1H), 4,97 (s, 1H), 4,87 (s, 1H), 4,59 (s, 1H), 4,55 (s, 1H), 2,89 (br s, 4H), 2,57 (m, 2H), 1,59 (m, 2H), 1,27 (br s, 10H), 0,89 (m, 3H). M-(LC/MS(ESI)): 552; M+(LC/MS(ESI)): 554. HPLC (Condición A), Tr: 7,13 min (pureza de la HPLC: 98,5%).
Ejemplo 318: ácido {(4-{[4-(heptiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de etil{(4-{[4-(heptiloxi)fenil]etinil}bencil)[4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-etinil-4(heptiloxi)benceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un aceite amarillo claro (43%). HPLC (Condición A), Tr: 7,57 min (pureza de la HPLC: 94,2%).
Etapa b) Formación de ácido {(4-{[4-(heptiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-{[4(heptiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo claro (90%). M-(LC/MS(ESI)): 550. HPLC (Condición A), Tr: 6,71 min (pureza de la HPLC: 94,6%).
Ejemplo 319: ácido {{4-[(4-butilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de etil {{4-[(4-butilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-butil-4-etinilbenceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un aceite amarillo claro (50%). HPLC (Condición A), Tr: 7,24 min (pureza de la HPLC: 96,8%).
Etapa b) Formación de ácido {{4-[(4-butilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[(4butilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo claro (92%). M-(LC/MS(ESI)): 492. HPLC (Condición A), Tr: 6,25 min (pureza de la HPLC: 96,2%).
Ejemplo 320: ácido {{4-[(4-hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de 4-[(4-hexilfenil)etinil]benzaldehído
Se agitó una mezcla de 4-bromobenzaldehído (5,00 g, 27,0 mmol), 1-etinil-4-hexilbenceno (6,29 g, 33,4 mmol), Et3N (4,70 mL, 33,4 mmol), cloruro de bis(trifenilfosfina)paladio (950 mg, 1,35 mmol) y trifenilfosfina (180 mg, 0,68 mmol) en THF anhidro (100 mL) a TA durante 30 min bajo una atmósfera inerte. Luego se agregó bromuro de cobre(I) (82 mg, 0,43 mmol) y la mezcla resultante se agitó durante toda la noche a TA. El disolvente se retiró por evaporación. El residuo se disolvió en Et2O (100 mL), se lavó con agua (50 mL), se secó sobre MgSO4 y el disolvente se retiró a presión reducida. El sólido marrón resultante se trituró en hexano (25 mL), se retiró por filtración y se lavó con hexano para proporcionar el compuesto del título como un sólido beige (7,73 g, 91%). HPLC (Condición A), Tr: 5,88 min (pureza de la HPLC: 91,9%).
Etapa b) Formación de clorhidrato de N-{4-[(4-hexilfenil)etinil]bencil}-N-[4-(trifluorometil)bencil]-amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4(trifluorometil)bencilamina y 4-[(4-hexilfenil)etinil]benzaldehído proporcionó el compuesto del título como un sólido beige (68%). 1H NMR (DMSO-d6, 300 MHz) δ 9,74 (br s, 2H), 7,83 (d, 2H, J = 8,5 Hz), 7,77 (d, 2H, J = 8,5 Hz), 7,59 (m, 4H), 7,46 (d, 2H, J = 8,3 Hz), 7,25 (d, 2H, J = 8,3 Hz), 4,28 (s, 2H), 4,22 (s, 2H), 2,59 (t, 2H, J = 7,5 Hz), 1,56 (m, 2H), 1,27 (br s, 6H), 0,84 (t, 3H, J = 6,7 Hz). M+(LC/MS(ESI)): 450. HPLC (Condición A), Tr: 4,87 min (pureza de la HPLC: 99,6%).
Etapa c) Formación de etil {{4-[(4-hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-{4-[(4hexilfenil)etinil]bencil}-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite amarillo claro (96%). 1H NMR (CDCl3, 300 MHz) δ 7,63 (m, 2H), 7,52 (m, 2H), 7,46 (m, 2H), 7,37 (m, 2H), 7,21 (m, 4H), 4,55 (s, 1H), 4,52 (s, 1H), 4,37 (m, 4H), 2,63 (t, 2H, J = 7,7 Hz), 1,62 (m, 2H), 1,35 (m, 9H), 0,89 (t, 3H, J = 6,7 Hz). HPLC (Condición A), Tr: 6,50 min (pureza de la HPLC: 99,2%).
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[(4hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un sólido gomoso amarillo claro (90%). 1H NMR (CDCl3, 300 MHz) δ 7,64 (m, 2H), 7,52 (m, 2H), 7,46 (m, 2H), 7,37 (m, 2H), 7,21 (m, 4H), 6,12 (br s, 1H), 4,95 (s, 1H), 4,89 (s, 1H), 4,61 (s, 1H), 4,58 (s, 1H), 2,63 (t, 2H, J = 7,8 Hz), 1,63 (m, 2H), 1,32 (m, 6H), 0,90 (t, 3H, J = 6,8 Hz). M'(LC/MS(ESI)): 520. HPLC (Condición A), Tr: 5,94 min (pureza de la HPLC: 99,1%).
Ejemplo 321: ácido {{4-[(4-hexilfenil)etinil]bencil}[4-(trifluorometil)bencil)amino}-(oxo)acético, sal de N-metil-Dglucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {{4-[(4hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (94%). M-(LC/MS(ESI)): 520. HPLC (Condición A), Tr: 5,94 min (pureza de la HPLC: 99,6%). Análisis calculado para C31H30F3NO3.C7H17NO5=1,3 H2O: C, 61,66; H, 6,75; N, 3,78%. Encontrado: C, 61,63; H,6,63; N, 3,70%
Ejemplo 322: ácido oxo{(4-{[4-(pentiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]-amino}acético
Etapa a) Formación de etil oxo{(4-{[4-(pentiloxi)fenil]etinil}bencil)[4-(trifluoro-metil)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-etinil-4(pentiloxi)benceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un aceite amarillo claro (33%). HPLC (Condición A), Tr: 6,80 min (pureza de la HPLC: 74,0%).
Etapa b) Formación de ácido oxo{(4-{[4-(pentiloxi)fenil]etinil)bencil)[4-(trifluorometil)-bencil]amino)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{(4-{[4(pentiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo claro (79%). M-(LC/MS(ESI)): 522. HPLC (Condición A), Tr: 6,68 min (pureza de la HPLC: 74,9%).
Ejemplo 323: ácido oxo{{4-[(4-propilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}acético
Etapa a) Formación de etil oxo{{4-[(4-propilfenil)etinil]bencil)[4-(trifluorometil)-bencil]amino} acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-etinil-4-propilbenceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un aceite amarillo claro (45%). HPLC (Condición A), Tr: 6,65 min (pureza de la HPLC: 97,5%).
Etapa b) Formación de ácido oxo{{4-[(4-propilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{{4-[(4propilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo claro (80%). M-(LC/MS(ESI)): 478. HPLC (Condición A), Tr: 6,44 min (pureza de la HPLC: 96,9%).
Ejemplo 324: ácido [[2-(3-clorofenil)etil](4-dodec-1-inilbencil)amino](oxo)acético
Etapa a) Formación de 4-dodec-1-inilo benzaldehído
El mismo procedimiento utilizado en la preparación del Ejemplo 275 (etapa a) pero utilizando 1-dodecino proporcionó el compuesto del título como un aceite amarillo (77%). 1H NMR (CDCl3, 300 MHz) δ 9,97 (s, 1H), 7,78 (d, 2H, J = 8,4 Hz), 7,51 (d, 2H, J = 8,4 Hz), 2,43 (t, 2H, J = 7,0 Hz), 1,66-1,55 (m, 2H), 1,50-1,38 (m, 2H), 1,36-1,21 (m, 12H), 0,87 (t, 3H, J = 6,9 Hz). HPLC (Condición A), Tr: 5,92 min (pureza de la HPLC: 89,4%).
Etapa b) Formación de clorhidrato de N-[2-(3-clorofenil)etil]-N-(4-dodec-1-inilbencil)amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando [2-(3clorofenil)etil]amina y 4-dodec-1-inilbenzaldehído proporcionó el compuesto del título como un polvo blanco (50%).1H NMR (DMSO-d6, 300 MHz) δ 9,27 (br s, 1H), 7,51-7,24 (m, 8H), 4,15 (br s, 2H), 3,14 (br s, 2H), 2,98 (m, 2H), 1,99 (m, 2H), 1,55-1,40 (m, 16H), 0,85 (t, 3H, J = 6,6 Hz). M-(LC/MS(ESI)): 411. HPLC (Condición A), Tr: 5,30 min (pureza de la HPLC: 99,9%).
Etapa c) Formación de etil [[2-(3-clorofenil)etil](4-dodec-1-inilbencil)amino]-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-[2-(3clorofenil)etil]-N-(4-dodec-1-inilbencil)amina proporcionó el compuesto del título como un aceite amarillo claro (80%).1H NMR (CDCl3, 300 MHz) δ 7,37-6,93(m, 8H), 4,30 (m, 2H), 4,43-4,07 (m, 4H), 3,40 (m, 2H), 2,77 (m, 2H), 2,39 (m, 2H), 1,53-1,30 (m, 16H), 0,87 (t, 3H, J = 6,6 Hz). M+(LC/MS(ESI)): 511. HPLC (Condición A), Tr: 7,04 min (pureza de la HPLC: 99,6%).
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil [[2-(3-clorofenil)etil](4dodec-1-inilbencil)amino](oxo)acetato proporcionó el compuesto del título como una espuma blanca (87%). 1H NMR (DMSO-d6, 300 MHz) δ 7,39-7,22 (m, 6H), 7,11 (m, 2H), 4,56 (s, 1H), 4,43 (s, 1H), 3,32 (br s, 2H), 2,84 (m, 1H), 2,72 (m, 1H), 2,39 (m, 2H), 1,54-1,23 (m, 16H), 0,88 (t, 3H, J = 6,6 Hz). M-(LC/MS(ESI)): 480. HPLC (Condición A), Tr: 6,44 min (pureza de la HPLC: 99,8%).
Ejemplo 325: ácido [[2-(3-clorofenil)etil](4-dodec-1-inilbencil)amino](oxo)acético, sal de N-metil-D-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido [[2-(3-clorofenil)etil](4-dodec1-inilbencil)amino](oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (90%). M+(LC/MS(ESI)): 481. HPLC (Condición A), Tr: 6,33 min (pureza de la HPLC: 99,1%).
Ejemplo 326: {(4-oct-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético
Etapa a) Formación de etil{(4-oct-1-inilbencil)[4-(trifluorometil)-bencil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-octino proporcionó el compuesto del título como un aceite amarillo claro (9%). 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 2H), 7,36 (m, 4H), 7,15 (m, 2H), 4,52 (s, 1H), 4,48 (s, 1H), 4,35 (m, 4H), 2,42 (dt, 2H, J = 6,9, 1,4 Hz), 1,62 (m, 2H), 1,46 (m, 2H), 1,34 (m, 7H), 0,92 (t, 3H, J = 6,7 Hz) M+(LC/MS(ESI)): 474. HPLC (Condición A), Tr: 6,10 min (pureza de la HPLC: 99,1%).
Etapa b) Formación de ácido {(4-oct-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-oct-1-inilbencil)[4(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (92%). 1H NMR (CDCl3, 300 MHz) δ 7,63 (m, 2H), 7,37 (m, 4H), 7,15 (m, 2H), 6,11 (br s, 1H), 4,89 (s, 1H), 4,82 (s, 1H), 4,58 (s, 1H), 4,54 (s, 1H), 2,42 (t, 2H, J = 7,0 Hz), 1,62 (m, 2H), 1,48 (m, 2H), 1,34 (m, 4H), 0,92 (t, 3H, J = 6,8 Hz). M(LC/MS(ESI)): 444. HPLC (Condición A), Tr: 5,43 min (pureza de la HPLC: 94,8%).
Ejemplo 327: ácido {[4-(11-hidroxiundec-1-inil)bencil][4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de etil {[4-(11-hidroxiundec-1-inil)bencil][4-(trifluorometil)-bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 10-undecin-1-ol proporcionó el compuesto del título como un aceite amarillo (30%). 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 2H), 7,36 (m, 4H), 7,15 (m, 2H), 4,53 (s, 1H), 4,48 (s, 1H), 4,35 (m, 4H), 3,65 (t, 2H, J = 6,6 Hz), 2,42 (dt, 2H, J = 7,0,1,4 Hz), 1,64-1,30 (m, 17H). M+(LC/MS(ESI)): 532. HPLC (Condición A), Tr: 5,61 min (pureza de la HPLC: 98,2%).
Etapa b) Formación de ácido {[4-(11-hidroxiundec-1-inil)bencil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[4-(11-hidroxiundec1-inil)bencil][4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (86%). 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 2H), 7,36 (m, 4H), 7,15 (m, 2H), 4,85 (s, 1H), 4,75 (s, 1H), 4,69 (br s, 2H), 4,58 (s, 1H), 4,52 (s, 1H), 3,66 (m, 2H), 2,42 (t, 2H, J = 6,8 Hz), 1,64-1,24 (m, 14H). M-(LC/MS(ESI)): 502; M+(LC/MS(ESI)): 504. HPLC (Condición A), Tr: 4,93 min (pureza de la HPLC: 91,7%).
Ejemplo 328: ácido {[4-(11-metoxi-11-oxoundec-1-inil)bencil][4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de metil 11-[4-({[etoxi(oxo)acetil][4-(trifluorometil)bencil]amino-}metil)fenil]undec-10-inoato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando metil 10-undecinoato proporcionó el compuesto del título como un aceite incoloro (20%). 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 2H), 7,36 (m, 4H), 7,15 (m, 2H), 4,51 (m, 2H), 4,36 (m, 4H), 3,68 (s, 3H), 2,42 (dt, 2H, J = 6,9, 1,4 Hz), 2,32 (t, 2H, J = 7,5 Hz), 1,63 (m, 4H), 1,47-1,24 (m, 11H). M-(LC/MS(ESI)): 558; M+(LC/MS(ESI)): 560. HPLC (Condición A), Tr: 5,98 min (pureza de la HPLC: 97,3%).
Etapa b) Formación de ácido {[4-(11-metoxi-11-oxoundec-1-inil)bencil][4-(trifluorometil)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando metil 11-[4({[etoxi(oxo)acetil] [4-(trifluorometil)bencil]amino}metil)fenil]undec-10-inoato y aplacamiento después de un minuto proporcionó el compuesto del título como un aceite incoloro (61%). M-(LC/MS(ESI)): 530. HPLC (Condición A), Tr: 5,35 min (pureza de la HPLC: 83,6%).
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando metil 11-[4({[etoxi(oxo)acetil][4-(trifluorometil)bencil]amino}metil)fenil]undec-10-inoato proporcionó el compuesto del título como un aceite amarillo claro (84%). 1H NMR (CDCl3, 300 MHz) δ 8,60 (br s, 2H), 7,62 (m, 2H), 7,35 (m, 4H), 7,14 (m, 2H), 4,77 (s, 1H), 4,68 (s, 1H), 4,57 (s, 1H), 4,51 (s, 1H), 2,39 (m, 4H), 1,64-1,24 (m, 12H). M-(LC/MS(ESI)): 516. HPLC (Condición A), Tr: 4,78 min (pureza de la HPLC: 95,7%).
Ejemplo 330: ácido {(4-{[4-(benciloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de etil{(4-{[4-(benciloxi)fenil]etinil}bencil)[4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-(benciloxi)-4etinilbenceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un sólido amarillo claro (28%). HPLC (Condición A), Tr: 6,36 min (pureza de la HPLC: 95,9%).
Etapa b) Formación de ácido {(4-{[4-(benciloxi)fenil]etinil}bencil)[4-(trifluorometil)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-{[4(benciloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo claro (86%). M-(LC/MS(ESI)): 542. HPLC (Condición A), Tr: 6,21 min (pureza de la HPLC: 96,5%).
Ejemplo 331: ácido {(4-{2-[4-(heptiloxi)fenil]etil}bencil)[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido {(4-{[4(heptiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]amino}(oxo)acético en EtOAc proporcionó el compuesto del título como un aceite incoloro (54%). M-(LC/MS(ESI)): 554. HPLC (Condición A), Tr: 5,95 min (pureza de la HPLC: 95,1%).
Ejemplo 332: ácido {{4-[2-(4-butilfenil)etil]bencil}[4-(trifluorometil)bencil]-amino}-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido {{4-[(4butilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético en EtOAc proporcionó el compuesto del título como un aceite incoloro (38%). M-(LC/MS(ESI)): 496. HPLC (Condición A), Tr: 5,62 min (pureza de la HPLC: 95,5%).
Ejemplo 333: ácido {{4-[2-(4-hexilfenil)etil]bencil}[4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de etil {{4-[2-(4-hexilfenil)etil]bencil}[4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando etil {{4-[(4hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato en EtOAc proporcionó el compuesto del título como un aceite incoloro (94%). 1H NMR (CDCl3, 300 MHz) δ 7,64 (d, 0,8H, J = 8,1 Hz), 7,60 (d, 1,2H, J = 8,1 Hz), 7,39 (d, 0,8H, J = 8,1 Hz), 7,33 (d, 1,2H, J = 8,1 Hz), 7,18 (m, 4H), 7,11 (s, 4H), 4,54 (s, 1,2H), 4,49 (s, 0,8H), 4,42-4,30 (m, 4H), 2,90 (m, 4H), 2,59 (t, 2H, J = 7,8 Hz), 1,61 (m, 2H), 1,39-1,30 (m, 9H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 552; M+(LC/MS(ESI)): 554. HPLC (Condición A), Tr: 6,46 min (pureza de la HPLC: 99,2%).
Etapa b) Formación de ácido {{4-[2-(4-hexilfenil)etil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[2-(4hexilfenil)etil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (95%). 1H NMR (CDCl3, 300 MHz) δ 7,63 (m, 2H), 7,35 (m, 2H), 7,19 (m, 4H), 7,11 (s, 4H), 5,03 (s, 1H), 4,93 (s, 1H), 4,61 (s, 1H), 4,56 (s, 1H), 2,90 (m, 4H), 2,59 (t, 2H, J = 7,8 Hz), 1,61 (m, 2H), 1,32 (m, 6H), 0,89 (t, 3H, J = 6,8 Hz). M-LC/MS(ESI)): 524; M+(LC/MS(ESI)): 526. HPLC (Condición A), Tr: 5,95 min (pureza de la HPLC: 99,5%). Análisis calculado para C31H34F3NO3=0,2 H2O: C, 70,36; H, 6,55; N, 2,65%. Encontrado: C, 70,32; H, 6,56; N, 2,57%
Ejemplo 334: ácido {{4-[2-(4-hexilfenil)etil]bencil}[4-(trifluorometil]bencil)amino}-(oxo)acético, sal de N-metil-Dglucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {{4-[2-(4hexilfenil)etil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (92%). M-(LC/MS(ESI)): 524; M+(LC/MS(ESI)): 526. HPLC (Condición A), Tr: 5,90 min (pureza de la HPLC: 99,5%). Análisis calculado para C31H34F3NO3.C7H17NO5=0,4 H2O: C, 62,69; H, 7,17; N, 3,85%. Encontrado: C,62,63; H,7,25; N,3,83%
Ejemplo 335: ácido oxo{(4-{2-[4-(pentiloxi)fenil]etil}bencil)[4-(trifluorometil)bencil]-amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido oxo{(4-{[4(pentiloxi)fenil]etinil}bencil)[4-(trifluorometil)bencil]amino}acético en EtOAc proporcionó el compuesto del título como un aceite amarillo (49%). M-(LC/MS(ESI)): 526. HPLC (Condición A), Tr: 5,62 min (pureza de la HPLC: 74,1%).
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido oxo{{4-[(4propilfenil)etinil]bencil}[4-(trifluorometil)bencil]amino}acético en EtOAc proporcionó el compuesto del título como un aceite incoloro (51%). M-(LC/MS(ESI)): 482. HPLC (Condición A), Tr: 5,43 min (pureza de la HPLC: 89,2%).
Ejemplo 337: ácido 11-[4-({(carboxicarbonil)[4-(trifluorometil)bencil]amino}-metil)-fenil]undecanoico
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido 11-[4({(carboxicarbonil)[4-(trifluorometil)bencil]amino}metil)fenil]undec-10-inoico en EtOAc proporcionó el compuesto del título como un aceite incoloro (20%). M-(LC/MS(ESI)): 520. HPLC (Condición A), Tr: 5,03 min (pureza de la HPLC: 96,1%).
Ejemplo 338: ácido {[4-11-hidroxiundecil)bencil][4-(trifluorometil)bencil]amino}-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa c) pero utilizando ácido {[4-(11hidroxiundec-1-inil)bencil][4-(trifluorometil)bencil]amino}(oxo)acético proporcionó el compuesto del título como un aceite incoloro (45%). M-(LC/MS(ESI)): 506; M+(LC/MS(ESI)): 508. HPLC (Condición A), Tr: 5,19 min (pureza de la HPLC: 86,3%).
Ejemplo 339: ácido {(4-dodec-1-inilbencil)[4-(trifluorometil)fenil]amino}(oxo)acético
Etapa a) Formación de N-(4-dodec-1-inilbencil)-N-[4-(trifluorometil)fenil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-(trifluorometil)anilina y 4-dodec-1-inilbenzaldehído proporcionó el compuesto del título como un aceite amarillo claro (42%). 1H NMR (CDCl3, 300 MHz) δ 7,40-7,23 (m, 8H), 4,35 (s, 2H), 2,40 (m, 2H), 1,62-1,27 (m, 16H), 0,88 (t, 3H, J = 6,8 Hz). HPLC (Condición A), Tr: 7,0 min (pureza de la HPLC: 99,4%).
Etapa b) Formación de etil{(4-dodec-1-inilbencil)[4-(trifluorometil)fenil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-(4-dodec-1-inilbencil)N-[4-(trifluorometil)fenil]amina proporcionó el compuesto del título como un aceite incoloro (81%). 1H NMR (CDCl3, 300 MHz) δ 7,60 (m, 2H), 7,33 (m, 2H), 7,20 (m, 4H), 4,94 (s, 2H), 4,04 (q, 2H, J = 7,14 Hz), 2,39 (m, 2H), 1,58 (m, 2H), 1,43 (m, 2H), 1,26 (m, 12H), 0,99 (m, 3H), 0,88 (t, 3H, J = 6,8 Hz). M+(LC/MS(ESI)): 516. HPLC (Condición A), Tr: 6,81 min (pureza de la HPLC: 91,8%).
Etapa c) Formación de ácido {(4-dodec-1-inilbencil)[4-(trifluorometil)fenil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dodec-1inilbencil)[4-(trifluorometil)fenil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (95%). 1H NMR (CDCl3, 300 MHz) δ 7,59 (d, 2H, J = 8,31 Hz), 7,32 (d, 2H, J = 8,28 Hz), 7,09 (m, 4H), 5,03 (s, 1H), 4,93 (s, 1H), 2,39 (m, 2H), 1,60 (m, 2H), 1,42 (m, 2H), 1,27 (br s, 12H), 0,87 (m, 3H). HPLC (Condición A), Tr: 6,22 min (pureza de la HPLC: 97,1%).
Ejemplo 340: ácido {(4-dodec-1-inil]bencil)[4-(trifluorometil)fenil]amino}(oxo)acético, sal de N-metil-D-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(4-dodec-1-inilbencil)[4(trifluorometil)fenil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (99%). HPLC (Condición A), Tr: 6,07 min (pureza de la HPLC: 96,7%).
Ejemplo 341: ácido oxo([4-(trifluorometil)bencil]{4-[2-(3-undecil-1,2,4-oxadiazol-5-il)-etil)bencil}amino)acético
Etapa a) Formación de terc-butil 4-{3-[(dodecanimidoilamino)oxi]-3-oxopropil}bencilcarbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 10 (etapa a) pero utilizando ácido 3-(4-{[(tercbutoxicarbonil)amino]metil}fenil)propanoico proporcionó el compuesto del título como un sólido amarillo claro (99%).1H NMR (CDCl3, 300 MHz) δ 7,21 (s, 4H), 5,03-4,58 (m, 3H), 4,27 (d, 2H, J = 5,6 Hz), 3,01 (t, 2H, J = 7,4 Hz), 2,75 (t, 2H, J = 7,4 Hz), 2,23 (t, 2H, J = 7,9 Hz), 1,57 (m, 2H), 1,46 (s, 9H), 1,25 (br s, 16H), 0,89 (t, 3H, J = 6,6 Hz). M(LC/MS(ESI)): 474; M+(LC/MS(ESI)): 476. HPLC (Condición A), Tr: 5,29 min (pureza de la HPLC: 99,0%).
Etapa b) Formación de terc-butil 4-[2-(3-undecil-1,2,4-oxadiazol-5-il)etil]-bencil-carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa e) pero utilizando terc-butil 4-{3[(dodecanimidoilamino)oxi]-3-oxopropil}bencilcarbamato proporcionó el compuesto del título como un sólido amarillo claro (71%). 1H NMR (CDCl3, 300 MHz) δ 7,22 (d, 2H, J = 8,3 Hz), 7,16 (d, 2H, J = 8,3 Hz), 4,80 (br s, 1H), 4,27 (m, 2H), 3,13 (m, 4H), 2,70 (t, 2H, J = 7,5 Hz), 1,73 (m, 2H), 1,46 (s, 9H), 1,29 (m, 16H), 0,88 (t, 3H, J = 6,8 Hz). HPLC (Condición A), Tr: 6,07 min (pureza de la HPLC: 98,0%).
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa f) pero utilizando terc-butil 4-[2-(3-undecil1,2,4-oxadiazol-5-il)etil]bencilcarbamato proporcionó el compuesto del título como un sólido blanco (82%). 1H NMR (CDCl3, 300 MHz) δ 7,25 (d, 2H, J = 8,3 Hz), 7,17 (d, 2H, J = 8,3 Hz), 3,85 (s, 2H), 3,13 (m, 4H), 2,70 (t, 2H, J = 7,7 Hz), 1,97 (br s, 2H), 1,73 (m, 2H), 1,30 (m, 16H), 0,88 (t, 3H, J = 6,8 Hz). M+(LC/MS(ESI)): 358. HPLC (Condición A), Tr: 4,17 min (pureza de la HPLC: 98,0%).
Etapa d) Formación de N-[4-(trifluorometil)bencil]-N-{4-[2-(3-undecil-1,2,4-oxadiazol-5-il)etil]bencil}amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-[2-(3-undecil-1,2,4oxadiazol-5-il)etil]bencilamina y 4-(trifluorometil)benzaldehído proporcionó el compuesto del título como un aceite amarillo claro (68%). 1H NMR (CDCl3, 300 MHz) δ 7,60 (d, 2H, J = 8,1 Hz), 7,53 (d, 2H, J = 8,1 Hz), 7,33 (d, 2H, J = 7,9 Hz), 7,19 (d, 2H, J = 7,9 Hz), 3,86 (s, 2H), 3,79 (s, 2H), 3,13 (m, 4H), 2,70 (t, 2H, J = 7,7 Hz), 1,72 (m, 2H), 1,29 (m, 16H), 0,88 (t, 3H, J = 6,8 Hz). M+(LC/MS(ESI)): 516. HPLC (Condición A), Tr: 4,83 min (pureza de la HPLC: 93,5%).
Etapa e) Formación de etil oxo([4-(trifluorometil)bencil]{4-[2-(3-undecil-1,2,4-oxa-diazol-5-il)etil]bencil}amino)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-[4(trifluorometil)bencil]-N-{4-[2-(3 -undecil-1,2,4-oxadiazol-5-il)etil]bencil}amina proporcionó el compuesto del título como un aceite incoloro (67%). 1H NMR (CDCl3, 300 MHz) δ 7,60 (m, 2H), 7,37 (d, 1H, J = 8,3 Hz), 7,32 (d, 1H, J = 8,3 Hz), 7,17 (m, 4H), 4,52 (s, 1H), 4,47 (s, 1H), 4,35 (m, 4H), 3,15 (br s, 4H), 2,71 (t, 2H, J = 7,7 Hz), 1,73 (m, 2H), 1,37-1,25 (m, 19H), 0,88 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 614; M+(LC/MS(ESI)): 616. HPLC (Condición A), Tr: 6,37 min (pureza de la HPLC: 97,3%).
Etapa f) Formación de ácido oxo([4-(trifluorometil)bencil]{4-[2-(3-undecil-1,2,4-oxadiazol-5-il)etil]bencil}amino)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo([4(trifluorometil)bencil] {4-[2-(3 -undecil-1,2,4-oxadiazol-5-il)etil]bencil}amino)acetato proporcionó el compuesto del título como un aceite incoloro (92%). 1H NMR (CDCl3, 300 MHz) δ 7,61 (m, 2H), 7,35 (m, 2H), 7,19 (m, 4H), 5,03 (s, 1H), 4,91 (s, 1H), 4,61 (s, 1H), 4,55 (s, 1H), 3,14 (br s, 4H), 2,70 (m, 2H), 1,71 (m, 2H), 1,32 (m, 16H), 0,88 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 586. HPLC (Condición A), Tr: 5,87 min (pureza de la HPLC: 99,9%). Análisis calculado para C32H40F3N3O4=0,5 H2O C, 64,41; H, 6,93; N, 7,04%. Encontrado: C, 64,31; H, 6,93; N, 6,97%.
Ejemplo 342: ácido oxo([4-(trifluorometil)bencil]{4-[2-(3-undecil-1,2,4-oxadiazol-5-il)etil]bencil}amino)acético, sal de N-metil-D-glucamina (es decir 1-desoxi-1-(metilamino)-glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido oxo([4(trifluorometil)bencil]{4-[2-(3-undecil-1,2,4-oxadiazol-5-il)etil]bencil}amino)acético y N-metil-D-glucamina proporcionó el compuesto del título como un aceite incoloro (97%). M-(LC/MS(ESI)): 586; M+(LC/MS(ESI)): 588. HPLC (Condición A), Tr: 5,88 min (pureza de la HPLC: 99,5%).
Ejemplo 343: ácido {{4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencil}[4-(trifluorometil)-bencil]amino}(oxo)acético
Etapa a) Formación de terc-butil 4-{3-[(nonanimidoilamino)oxi]-3-oxopropil}-bencil-carbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 10 (etapa a) pero utilizando ácido 3-(4-{[(tercbutoxicarbonil)amino]metil}fenil)propanoico proporcionó el compuesto del título como un sólido amarillo claro (99%).1H NMR (CDCl3, 300 MHz) δ 7,21 (s, 4H), 5,00-4,50 (m, 3H), 4,27 (d, 2H, J = 5,6 Hz), 3,00 (t, 2H, J = 7,3 Hz), 2,73 (t, 2H, J = 7,3 Hz), 2,19 (t, 2H, J = 7,5 Hz), 1,56 (m, 2H), 1,46 (s, 9H), 1,26 (br s, 10H), 0,88 (t, 3H, J = 6,8 Hz). M(LC/MS(ESI)): 432; M+(LC/MS(ESI)): 434. HPLC (Condición A), Tr: 4,70 min (pureza de la HPLC: 97,8%).
Etapa b) Formación de terc-butil 4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencilcarbamato
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa e) pero utilizando terc-butil 4-{3[(nonanimidoilamino)oxi]-3-oxopropil}bencilcarbamato proporcionó el compuesto del título como un sólido amarillo claro (76%).
Etapa c) Formación de 4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencilamina
El mismo procedimiento utilizado en la preparación del Ejemplo 23 (etapa f) pero utilizando 4-[2-(3-octil-1,2,4oxadiazol-5-il)etil]bencilamina proporcionó el compuesto del título como un sólido blanco (87%). 1H NMR (CDCl3, 300 MHz) δ 7,25 (d, 2H, J = 7,7 Hz), 7,17 (d, 2H, J = 7,7 Hz), 3,84 (s, 2H), 3,13 (m, 4H), 2,70 (t, 2H, J = 7,7 Hz), 1,78 (br s, 2H), 1,73 (m, 2H), 1,30 (m, 10H), 0,88 (t, 3H, J = 6,8 Hz). M+(LC/MS(ESI)): 316. HPLC (Condición A), Tr: 3,51 min (pureza de la HPLC: 98,0%).
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-[2-(3-octil-1,2,4oxadiazol-5-il)etil]bencilamina y 4-(trifluorometil)benzaldehído proporcionó el compuesto del título como un aceite amarillo claro (65%). 1H NMR (CDCl3, 300 MHz) δ 7,60 (d, 2H, J = 8,3 Hz), 7,51 (d, 2H, J = 8,3 Hz), 7,30 (d, 2H, J = 7,9 Hz), 7,18 (d, 2H, J = 7,9 Hz), 3,86 (s, 2H), 3,78 (s, 2H), 3,12 (m, 4H), 2,70 (t, 2H, J = 7,7 Hz), 1,73 (m, 2H), 1,28 (m, 10H), 0,88 (t, 3H, J = 6,6 Hz). M+(LC/MS(ESI)): 474. HPLC (Condición A), Tr: 4,31 min (pureza de la HPLC: 97,9%).
Etapa e) Formación de etil {{4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencil}[4-(trifluoro-metil)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-{4-[2-(3-octil-1,2,4oxadiazol-5-il)etil]bencil}-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite incoloro (74%). 1H NMR (CDCl3, 300 MHz) δ 7,61 (m, 2H), 7,37 (d, 1H, J = 7,9 Hz), 7,31 (d, 1H, J = 7,9 Hz), 7,17 (m, 4H), 4,52 (s, 1H), 4,46 (s, 1H), 4,35 (m, 4H), 3,14 (m, 4H), 2,71 (t, 2H, J = 7,5 Hz), 1,73 (m, 2H), 1,37-1,23 (m, 13H), 0,87 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 572; M+(LC/MS(ESI)): 574. HPLC (Condición A), Tr: 5,92 min (pureza de la HPLC: 99,9%).
Etapa f) Formación de ácido {{4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencil}[4-(trifluorometil)-bencil]amino)(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[2-(3-octil-1,2,4oxadiazol-5-il)etil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (91%). 1H NMR (CDCl3, 300 MHz) δ 7,64 (m, 2H), 7,37 (m, 2H), 7,19 (m, 4H), 5,04 (s, 1H), 4,93 (s, 1H), 4,63 (s, 1H), 4,56 (s, 1H), 3,17 (m, 4H), 2,73 (t, 2H, J = 7,7 Hz), 1,75 (m, 2H), 1,31 (m, 10H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 544; M+(LC/MS(ESI)): 546 HPLC (Condición A), Tr: 5,38 min (pureza de la HPLC: 99,2%).
Ejemplo 344: ácido {{4-[2-(3-octil-1,2,4-oxadiazol-5-il)etil]bencil}[4-(trifluorometil]-bencil]amino}(oxo)acético, sal de Nmetil-D-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {{4-[2-(3-octil-l,2,4-oxadiazol5-il)etil]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un sólido gomoso blanco (96%). M-(LC/MS(ESI)): 544; M+(LC/MS(ESI)): 546. HPLC (Condición A), Tr: 5,37 min (pureza de la HPLC: 99,0%).
Ejemplo 345: ácido {{4-[(4-octilbenzoil)amino]bencil}[4-(trifluorometil)bencil]-amino}-(oxo)acético
Etapa a) Formación de etil {{4-[(4-octilbenzoil)amino]bencil}[4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 311 (etapa a) pero utilizando ácido 4-octilbenzoico proporcionó el compuesto del título como un aceite incoloro (93%). 1HNMR (CDCl3, 300 MHz) δ 7,81 (m, 3H), 7,63 (m, 4H), 7,42-7,21 (m, 6H), 4,54 (s, 1H), 4,49 (s, 1H), 4,37 (m, 4H), 2,68 (m, 2H), 1,64 (m, 2H), 1,28 (m, 13H), 0,89 (m, 3H). M-(LC/MS(ESI)): 595; M+(LC/MS(ESI)): 597. HPLC (Condición A), Tr: 7,19 min (pureza de la HPLC: 99,2%).
Etapa b) Formación de ácido {{4-[(4-octilbenzoil)amino]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{4-[(4octilbenzoil)amino]bencil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un sólido blanco (93%). 1H NMR (CDCl3, 300 MHz) δ 7,95 (m, 1H), 7,80 (m, 2H), 7,61 (m, 4H), 7,39-7,23 (m, 6H), 5,13 (br s, 1H), 4,91 (s, 1H), 4,77 (s, 1H), 4,58 (s, 1H), 4,53 (s, 1H), 2,68 (m, 2H), 1,63 (m, 2H), 1,28 (br s, 10H), 0,89 (m, 3H). M-(LC/MS(ESI)): 567; M+(LC/MS(ESI)): 569. HPLC (Condición A), Tr: 6,64 min (pureza de la HPLC: 99,5%). Análisis calculado para C32H35F3N2O4: C, 67,59; H, 6,20; N, 4,93%. Encontrado: C, 67,32; H, 6,21; N, 4,86%
Ejemplo 346: ácido{{4-[(4-octilbenzoil)amino]bencil}[4-(trifluorometil)bencil]amino}-(oxo)acético, sal de N-metil-Dglucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {{4-[(4octilbenzoil)amino]bencil}[4-(trifluorometil)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (92%). M-(LC/MS(ESI)): 567; M+(LC/MS(ESI)): 569. HPLC (Condición A), Tr: 6,68 min (pureza de la HPLC: 99,4%). Análisis calculado para C32H35F3N2O4.C7H17NO5=0,6 H2O: C, 60,47; H, 6,92; N, 5,42%. Encontrado: C, 60,48; H, 7,11; N, 5,41%
Ejemplo 347: ácido oxo{[(1-tridecanoilpiperidin-4-il)metil][4-(trifluorometil)bencil]-amino}acético
Etapa a) Formación de clorhidrato de terc-butil 4-(2-{[4-trifluorometilbencil]amino}metil)piperidina-1-carboxilato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando terc-butil 4(aminometil)piperidina-1-carboxilato y 4-(trifluorometil)benzaldehído proporcionó el compuesto del título como un sólido blanco (65%). 1H NMR (DMSO-d6, 300 MHz) δ 9,16 (br s, 1H), 7,84 (d, 2H, J = 8,3 Hz), 7,77 (d, 2H, J = 8,3 Hz), 4,25 (br s, 2H), 3,92 (m, 2H), 2,84 (m, 2H), 2,70 (br s, 2H), 1,89 (br s, 1H), 1,72 (br s, 2H), 1,39 (br s, 9H), 1,05 (m, 2H).
Etapa b) Formación de terc-butil 4-(2-{etoxi(oxo)acetil][4-(trifluorometil)bencil]amino}-metil)piperidina-1-carboxilato.
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de terc-butil 4-(2-{[4-trifluorometilbencil]amino}metil)piperidina-1-carboxilato proporcionó el compuesto del título como un aceite incoloro (94%). M-(LC/MS(ESI)): 471. HPLC, TA: 5,78 min (pureza de la HPLC: 99,9%). 1H NMR (CDCl3, 300 MHz) δ 7,62 (m, 2H), 7,39 (m, 2H), 4,68 (s, 1H), 4,54 (s, 1H), 4,45-4,20 (m, 2H), 4,19-4,00 (m, 2H), 3,19 (d, 1H, J = 7,2 Hz), 3,12 (d, 1H, J = 7,2 Hz), 2,63 (m, 2H), 1,81 (m, 1H), 1,59 (m, 2H), 1,48-0,95 (m, 14H).
Etapa c) Formación de clorhidrato de etil oxo-{(2-piperidin-4-ilmetil)[4-(trifluorometilbencil]amino}-acetato.
El mismo procedimiento utilizado en la preparación de Ejemplo 23 (etapa f) pero utilizando terc-butil 4-(2{etoxi(oxo)acetil][4-(trifluorometil)bencil]amino}-metil)piperidina-1-carboxilato proporcionó el compuesto del título como un sólido gomoso incoloro (99%). HPLC, TA: 3,12 min (pureza de la HPLC: 99,5%).
Etapa d) Formación de etil oxo{[(1-tridecanoilpiperidin-4-il)metil][4-trifluorometil)-bencil]amino}acetato.
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa d) pero utilizando clorhidrato de etil oxo-{(2piperidin-4-ilmetil)[4-(trifluorometilbencil]amino}acetato, ácido tridecanoico, HOBT y TEA en DCM proporcionó el compuesto del título como un aceite amarillo (66%). M-(LC/MS(ESI)): 567; M+(LC/MS(ESI)): 569. HPLC (Condición A), Tr: 7,24 min (pureza de la HPLC: 99,4%).
Etapa e) Formación de ácido oxo{[(1-tridecanoilpiperidin-4-il)metil][4-(trifluorometil)bencil]-amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[(1tridecanoilpiperidin-4-il)metil] [4-trifluorometil)bencil]amino}acetato proporcionó el compuesto del título como un sólido gomoso naranja (58%). 1H NMR (DMSO-d6, 300 MHz) δ 7,75 (m, 2H), 7,50 (m, 2H), 4,63 (m, 2H), 4,35 (br t, 1H), 3,83 (br d, 1H), 3,20-2,80 (m, 3H), 2,41 (br q, 1H), 2,24 (t, 2H, J = 7,4 Hz), 1,90 (br s, 1H), 1,65-1,35 (m, 4H), 1,23 (br s, 18H), 1,15-0,70 (m, 5H). M-(LC/MS(ESI)): 539. HPLC (Condición A), Tr: 6,68 min (pureza de la HPLC: 98,3%).
Etapa a) Formación de etil {{[1-(4-octilbenzoil)piperidin-4-il]metil}[4-trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa d) pero utilizando clorhidrato de etil oxo-{(2piperidin-4-ilmetil)[4-(trifluorometilbencil]amino}acetato, ácido 4-n-octilbenzoico, HOBT y TEA en DCM proporcionó el compuesto del título como un aceite incoloro (84%). 1H NMR (CDCl3, 300 MHz) δ 7,63 (m, 2H), 7,40 (m, 2H), 7,327,17 (m, 4H), 4,70 (s, 1H), 4,55 (s, 1H), 4,40 (q, 2H, J = 7,2 Hz), 4,20 (q, 2H, J = 7,2 Hz), 3,4-3,1 (m, 2H), 2,85 (br s, 2H), 2,6 (m, 2H), 1,95 (br s, 1H), 1,6 (m, 4H), 1,47-1,1 (m, 17H), 0,88 (m, 3H). M-(LC/MS(ESI)): 587. HPLC (Condición A), Tr: 6,26 min (pureza de la HPLC: 99,2%).
Etapa b) Formación de ácido {{[1-(4-octilbenzoil)piperidin-4-il]metil)[4-(trifluorometil)-bencil]amino)(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{[1-(4octilbenzoil)piperidin-4-il]metil}[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como una espuma blanca (67%). 1H NMR (CDCl3, 300 MHz) δ 7,61 (m, 2H), 7,39 (m, 2H), 7,31 (m, 2H), 7,22 (m, 2H), 4,80 (m, 3H), 3,86 (m, 1H), 3,49 (br s, 1H), 3,25 (br s, 1H), 2,94 (m, 2H), 2,60 (t, 2H, J = 7,5 Hz), 2,15-1,45 (m, 4H), 1,28 (m, 13H), 0,88 (t, 3H, J = 6,6 Hz). M-(LC/MS(ESI)): 559; M+(LC/MS(ESI)): 561. HPLC (Condición A), Tr: 5,68 min (pureza de la HPLC: 99,5%).
Ejemplo 349: ácido {{[1-(4-octilbenzoil)piperidin-4-il]metil}[4-(trifluorometil)bencil]-amino}(oxo)acético, sal de N-metilD-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {{[1-(4-octil-benzoil)piperidin4-il]metil}[4-(trifluorometil)bencil]amino}(oxo)acético y N-metil-D-glucamina proporcionó el compuesto del título como un polvo blanco (90%). M-(LC/MS(ESI)): 559; M+(LC/MS(ESI)): 561. HPLC (Condición A), Tr: 5,56 min (pureza de la HPLC: 97,1%). Análisis calculado para C31H39F3N2O4.C7H17NO5=3,5 H2O: C, 55,73; H, 7,75; N, 5,13%. Encontrado: C, 55,68; H,7,56; N,5,17%
Ejemplo 350: ácido {[(3-dec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de 3-bromo-1-benzofuran-5-carbaldehído
A una solución de 2,3-dibromo-2,3-dihidro-1-benzofuran-5-carbaldehído (10 g) en etanol seco (25 mL) se agregó una solución de KOH en etanol seco (14 mL) y se sometió a reflujo 70ºC durante 2h. La mezcla de reacción se enfrió, se diluyó con agua y se extrajo con EtOAc (3x 50 mL). La capa orgánica se lavó con agua, salmuera y se secó. El disolvente se retiró al vacío y el residuo se purificó mediante cromatografía instantánea (Éter de pet/EtOAc 99,5/0,5) para proporcionar el compuesto del título como un sólido amarillo claro (3,3 g, 45%).
1H NMR (DMSO-d6, 300 MHz) δ 10,12 (s, 1H), 8,47 (s, 1H), 8,14 (d, 1H, J = 1,5 Hz), 7,97 (dd, 1H, J = 8,6, 1,5 Hz), 7,87 (d, 1H, J = 8,6 Hz).
Etapa b) Formación de clorhidrato de N-[(3-bromo-1-benzofuran-5-il)metil]-N-[4-(trifluorometil)-bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 3-bromo-1-benzofuran5-carbaldehído proporcionó el compuesto del título como un sólido beige (77%). 1H NMR (DMSO-d6, 300 MHz) δ 10,00 (br s, 2H), 8,35 (s, 1H), 7,81-7,64 (m, 7H), 4,32 (s, 2H), 4,26 (s, 2H). M+(LC/MS(ESI)): 386,1. HPLC (Condición A), Tr: 3,11 min (pureza de la HPLC: 96,4%).
Etapa c) Formación de etil{[(3-bromo-1-benzofuran-5-il)metil] [4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-[(3bromo-1-benzofuran-5-il)metil]-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite incoloro (84%). 1H NMR (CDCl3, 300 MHz) δ 7,71 (s, 0,5H), 7,69 (s, 0,5H), 7,65 (d, 1H, J = 8,1 Hz), 7,61 (d, 1H, J = 8,1 Hz), 7,50 (d, 0,5H, J = 8,4 Hz), 7,48 (d, 0,5H, J = 8,5 Hz), 7,41-7,25 (m, 4H), 4,64 (s, 1H), 4,56 (s, 1H), 4,49 (s, 1H), 4,43 (s, 1H), 4,40 (q, 1H, J = 7,2 Hz), 4,35 (q, 1H, J = 7,2 Hz), 1,38 (t, 1,5H, J = 7,2 Hz), 1,33 (t, 1,5H, J = 7,2 Hz). M+(LC/MS(ESI)): 484,0. HPLC (Condición A), Tr: 4,95 min (pureza de la HPLC: 99,0%).
Etapa d) Formación de etil{[(3-dec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil{[(3-bromo-1benzoforan-5-il)metil][4-(trifluorometil)bencil]amino}(oxo)acetato y 1-decino proporcionó el compuesto del título como un aceite amarillo (40%). 1H NMR (CDCl3, 300 MHz) δ 7,78 (s, 0,5H), 7,76 (s, 0,5H), 7,65 (d, 1H, J = 7,9 Hz), 7,61 (d, 1H, J = 7,9 Hz), 7,52-7,33 (m, 4H), 7,22 (m, 1H), 4,64 (s, 1H), 4,56 (s, 1H), 4,47 (s, 1H), 4,41 (s, 1H), 4,39 (q, 1H, J = 7,2
Hz), 4,34 (q, 1H, J = 7,2 Hz), 2,49 (m, 2H), 1,66 (m, 2H), 1,49 (m, 2H), 1,40-1,26 (m, 11H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 540,5; M+(LC/MS(ESI)): 542,7. HPLC (Condición A), Tr: 6,07 min (pureza de la HPLC: 98,0%).
Etapa e) Formación de ácido {[(3-dec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[(3-dec-1-inil-1benzofuran-5-il)metil] [4-(trifluorometil)bencil]amino}-(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (91%). 1H NMR (CDCl3, 300 MHz) δ 7,78 (s, 0,5H), 7,77 (s, 0,5H), 7,63 (m, 2H), 7,47 (m, 2H), 7,36 (m, 2H), 7,22 (m, 1H), 5,07 (s, 1H), 5,03 (s, 1H), 4,71 (s, 1H), 4,62 (s, 1H), 2,49 (t, 2H, J = 7,0 Hz), 1,67 (m, 2H), 1,49 (m, 2H), 1,30 (m, 8H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 512,4. HPLC (Condición A), Tr: 5,54 min (pureza de la HPLC: 92,4%).
Ejemplo 351: ácido {[(3-dodec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de etil{[(3-dodec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)-bencil]amino)(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil {[(3-bromo-1benzofuran-5-il)metil][4-(trifluorometil)bencil]amino}(oxo)acetato y 1-dodecino proporcionó el compuesto del título como un aceite amarillo (34%). HPLC (Condición A), Tr: 6,39 min (pureza de la HPLC: 99,2%).
Etapa b) Formación de ácido {[(3-dodec-1-inil-1-benzofuran-5-il)metil][4-(trifluorometil)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[(3-dodec-1-inil-1benzofuran-5-il)metil][4-(trifluorometil)bencil]-amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (86%). M-(LC/MS(ESI)): 540,4. HPLC (Condición A), Tr: 5,91 min (pureza de la HPLC: 96,3%).
Ejemplo 352: ácido oxo{({3-[(4-propilfenil)etinil]-1-benzofuran-5-il}metil)[4-(trifluoro-metil)bencil]amino}acético
Etapa a) Formación de etiloxo{({3-[(4-propilfenil)etinil]-1-benzofuran-5-il}metil)[4-(trifluorometil)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil {[(3-bromo-1benzofuran-5-il)metil][4-(trifluorometil)bencil]amino}(oxo)acetato y 1-etinil-4-propilbenceno bajo condiciones de microondas (300W, 120ºC, 10 min) proporcionó el compuesto del título como un aceite amarillo (5%). M(LC/MS(ESI)): 545,8; M+(LC/MS(ESI)): 548,2 HPLC (Condición A), Tr: 5,85 min (pureza de la HPLC: 92,4%).
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etiloxo{({3-[(4-propilfenil) etinil]-1-benzofuran-5-il}metil)[4-(trifluorometil)bencil]amino}acetato proporcionó el compuesto del título como una espuma amarilla clara (75%). M-(LC/MS(ESI)): 518,2; M+(LC/MS(ESI)): 520,0. HPLC (Condición A), Tr: 5,30 min (pureza de la HPLC: 84,0%).
Ejemplo 353: ácido [(4-dodec-1-inilbencil)(4-fluorobencil)amino](oxo)acético
Etapa a) Formación de clorhidrato de N-(4-bromobencil)-N-(4-fluorobencil)amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-fluorobencilamina proporcionó el compuesto del título como un sólido blanco (98%). 1H NMR (CD3OD, 300 MHz) δ 7,65 (m, 2H), 7,57 (m, 2H), 7,47 (m, 2H), 7,22 (m, 2H), 4,22 (s, 2H), 4,20 (s, 2H). HPLC (Condición A), Tr: 2,23 min (pureza de la HPLC: 97,4%).
Etapa b) Formación de etil[(4-bromobencil)(4-fluorobencil)amino](oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-(4bromobencil)-N-(4-fluorobencil)amina proporcionó el compuesto del título como un aceite amarillo claro (87%). 1H NMR (CDCl3, 300 MHz) δ 7,51 (d, 1H, J = 8,2 Hz), 7,48 (d, 1H, J = 8,3 Hz), 7,24-7,00 (m, 6H), 4,45 (s, 1H), 4,43 (s, 1H), 4,37 (q, 1H, J = 7,2 Hz), 4,35 (q, 1H, J = 7,2 Hz), 4,30 (s, 1H), 4,28 (s, 1H), 1,36 (t, 1,5H, J = 7,2 Hz), 1,35 (t, 1,5H, J = 7,2 Hz). M+(LC/MS(ESI)): 394,0. HPLC (Condición A), Tr: 4,58 min (pureza de la HPLC: 95,3%).
Etapa c) Formación de etil[(4-dodec-1-inilbencil)(4-fluorobencil)amino](oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil[(4-bromobencil)(4fluorobencil)amino](oxo)acetato y 1-dodecino proporcionó el compuesto del título como un aceite amarillo claro (23%). 1H NMR (CDCl3, 300 MHz) δ 7,39 (m, 2H), 7,25-7,00 (m, 6H), 4,45 (s, 1H), 4,44 (s, 1H), 4,36 (m, 2H), 4,30 (s, 1H), 4,28 (s, 1H), 2,42 (t, 2H, J = 7,1 Hz), 1,62 (m, 2H), 1,46 (m, 2H), 1,37-1,25 (m, 15H), 0,89 (t, 3H, J = 6,6 Hz). M+(LC/MS(ESI)): 480,3. HPLC (Condición A), Tr: 6,28 min (pureza de la HPLC: 99,8%).
Etapa d) Formación de ácido [(4-dodec-1-inilbencil)(4-fluorobencil)amino](oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil[(4-dodec-1inilbencil)(4-fluorobencil)amino](oxo)acetato proporcionó el compuesto del título como un aceite amarillo (87%). 1H NMR (CDCl3, 300 MHz) δ 7,40 (m, 2H), 7,25-7,02 (m, 6H), 4,95 (s, 1H), 4,93 (s, 1H), 4,53 (s, 1H), 4,51 (s, 1H), 2,41 (t, 2H, J = 6,8 Hz), 1,62 (m, 2H), 1,45 (m, 2H), 1,28 (br s, 12H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 450,2. HPLC (Condición A), Tr: 5,75 min (pureza de la HPLC: 99,0%).
Ejemplo 354: ácido [bis(4-oct-1-inilbencil)amino](oxo)acético
Etapa a) Formación de etil[bis(4-oct-1-inilbencil)amino](oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil[(4-bromobencil)(4oct-1-inilbencil)amino](oxo)acetato y 1-octino proporcionó el compuesto del título como un aceite amarillo claro (32%). 1H NMR (CDCl3, 300 MHz) δ 7,38 (m, 4H), 7,16 (d, 2H, J = 8,3 Hz), 7,12 (d, 2H, J = 7,9 Hz), 4,45 (s, 2H), 4,35 (q, 2H, J = 7,2 Hz), 4,28 (s, 2H), 2,42 (t, 4H, J = 7,1 Hz), 1,62 (m, 4H), 1,47 (m, 4H), 1,33 (m, 11H), 0,92 (t, 6H, J = 6,8 Hz). M+(LC/MS(ESI)): 514,0. HPLC (Condición A), Tr: 6,54 min (pureza de la HPLC: 99,3%).
Etapa b) Formación de ácido [bis(4-oct-1-inilbencil)amino](oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil[bis(4-oct-1inilbencil)amino](oxo)acetato proporcionó el compuesto del título como un aceite amarillo (94%). 1H NMR (CDCl3, 300 MHz) δ 7,39 (m, 4H), 7,14 (m, 4H), 4,93 (s, 2H), 4,52 (s, 2H), 2,42 (t, 4H, J = 7,0 Hz), 1,62 (m, 4H), 1,47 (m, 4H), 1,34 (m, 8H), 0,92 (t, 6H, J = 6,8 Hz). M-(LC/MS(ESI)): 484,3. HPLC (Condición A), Tr: 6,04 min (pureza de la HPLC: 98,7%).
Ejemplo 355: ácido {[(6-dodec-1-inilpiridin-3-il)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de 6-dodec-1-inilnicotinaldehído
Una mezcla de 6-bromonicotinaldehído (500 mg, 2,69 mmol), 1-dodecino (680 mg, 4,09 mmol), trifenilfosfina (23 mg, 0,09 mmol), trietilamina (470 ml, 3,38 mmol) y cloruro de bis(trifenilfosfina)paladio(II) (94 mg, 0,13 mmol) en THF (10 mL) se agitó bajo argón a TA durante 30 min. Se agregó yoduro de cobre(I) (21 mg, 0,11 mmol) y la mezcla se agitó durante 21 horas a TA. El disolvente se retiró a presión reducida. El residuo se diluyó con una solución saturada acuosa de NH4CI (20 mL) y se extrajo con Et2O (50 ml + 2x 20 mL). Las capas orgánicas combinadas se secaron sobre MgSO4 y el disolvente se retiró a presión reducida. El residuo se purificó mediante cromatografía instantánea (c-Hex/EtOAc 4/1) para proporcionar el compuesto del título como un aceite amarillo (218 mg, 29%). 1H NMR (CDCl3, 300 MHz) δ 10,1 (s, 1H), 9,00 (s, 1H), 8,11 (d, 1H, J = 8,1 Hz), 7,52 (d, 1H, J = 8,1 Hz), 2,49 (t, 2H, J = 7,1 Hz), 1,67 (m, 2H), 1,47 (m, 2H), 1,28 (m, 12H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 270,3; M+(LC/MS(ESI)): 272,4. HPLC (Condición A), Tr: 5,23 min (pureza de la HPLC: 98,3%).
Etapa b) Formación de N-[(6-dodec-1-inilpiridin-3-il)metil]-N-[4-(trifluorometil)-bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 6-dodec-1inilnicotinaldehído proporcionó el compuesto del título como un sólido amarillo claro (54%). M+(LC/MS(ESI)): 431,4. HPLC (Condición A), Tr: 4,47 min (pureza de la HPLC: 98,8%).
Etapa c) Formación de etil{[(6-dodec-1-inilpiridin-3-il)metil][4-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-[(6-dodec-1-inilpiridin3-il)metil]-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite incoloro (93%). 1H NMR (CDCl3, 300 MHz) δ 8,38 (d, 0,5H, J = 2,0 Hz), 8,34 (d, 0,5H, J = 2,0 Hz), 7,64 (m, 2,5H), 7,56 (dd, 0,5H, J = 7,9,2,0 Hz), 7,41-7,31 (m, 3H), 4,54 (s, 1H), 4,49 (s, 1H), 4,42-4,32 (m, 4H), 2,46 (m, 2H), 1,65 (m, 2H), 1,46 (m, 2H), 1,39-1,28 (m, 15H), 0,89 (t, 3H, J = 6,8 Hz). M-(LC/MS(ESI)): 529,3; M+(LC/MS(ESI)): 531,4. HPLC (Condición A), Tr: 5,60 min (pureza de la HPLC: 100%).
Etapa d) Formación de ácido {[(6-dodec-1-inilpiridin-3-il)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil{[(6-dodec-1-inilpiridin3-il)metil][4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como una espuma blanca (90%). 1H NMR (CDCl3, 300 MHz) δ 8,65 (s, 0,5H), 8,58 (s, 0,5H), 7,84 (d, 0,5H, J = 8,3 Hz), 7,69 (d, 0,5H, J = 8,2 Hz), 7,58 (m, 2H), 7,45 (m, 2H), 7,35 (d, 1H, J = 7,9 Hz), 5,38 (br s, 1H), 4,72 (s, 1H), 4,70 (s, 1H), 4,60 (s, 1H), 4,50 (s, 1H), 2,45 (t, 2H, J = 7,0 Hz), 1,63 (m, 2H), 1,42 (m, 2H), 1,27 (br s, 12H), 0,88 (t, 3H, J = 6,6 Hz). M-(LC/MS(ESI)): 501,2; M+(LC/MS(ESI)): 503,0. HPLC (Condición A), Tr: 4,76 min (pureza de la HPLC: 99,5%).
Ejemplo 356: ácido {(3-dodec-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético
Etapa a) Formación de 3-dodec-1-inilbenzaldehído
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 3-bromobenzaldehído proporcionó el compuesto del título (59%).
Etapa b) Formación de N-(3-dodec-1-inilbencil)-N-[4-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 3-dodec-1inilbenzaldehído y 4-(trifluorometil)bencilamina proporcionó el compuesto del título (37%). M+(LC/MS(ESI)): 430,5. HPLC (Condición A), Tr: 4,82 min (pureza de la HPLC: 94,7%).
Etapa c) Formación de etil{(3-dodec-1-inilbencil)[4-(trifluorometil)bencil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-(3-dodec-1-inilbencil)N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título (99%). HPLC (Condición A), Tr: 6,48 min (pureza de la HPLC: 100%).
Etapa d) Formación de ácido {(3-dodec-1-inilbencil)[4-(trifluorometil)bencil]amino)(oxo acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil{(3-dodec-1inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (95%). 1H NMR (CD3OD, 300 MHz) δ 7,71-7,61 (m, 2H), 7,52 (d, 1H, J = 7,9 Hz), 7,41 (d, 1H, J = 8,3Hz), 7,34-7,14 (m, 4H), 4,62 (m, 2H), 4,54 (m, 2H), 2,45 (t, 2H, J = 6,8 Hz), 1,70-1,58 (m, 2H), 1,57-1,46 (m, 2H), 1,45-1,28 (m, 12H), 0,92 (m, 3H). M-(LC/MS(ESI)): 500,4. HPLC (Condición A), Tr: 5,94 min (pureza de la HPLC: 98,4%).
Ejemplo 357: ácido {[2-(2-fluorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il]bencil]-amino}(oxo)acético
Etapa a) Formación de N-[2-(2-fluorofenil)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
A una solución de 4-(3-undecil-1,2,4-oxadiazol-5-il)benzaldehído (32,8 mg, 0,1 mmol) en THF anhidro (0,6 mL) se agregó la 2-(2-fluorofenil)etilamina (11,8 mg, 0,1 mmol) y Ti(iPrO)4 (0,035 mL, 0,12 mmol). La mezcla se agitó durante 3 h a 60ºC luego se agregó triacetoxiborohidruro de sodio (53 mg, 0,25 mmol) y la mezcla de reacción se agitó durante toda la noche a TA. Se agregó THF (0,75 mL) seguido por la resina PS-DEAM (Argonaut, 148 mg, 1,68 mmol/g) y la mezcla de reacción se agitó a TA durante toda la noche. La mezcla de reacción se filtró y los filtrados se eluyeron a través de una columna SCX (Isolute, 1 g) con DCM (6 mL), luego NH3 (2M en MeOH, 4 mL). Las fracciones deseadas (monitoreo con TLC) se concentraron al vacío para proporcionar el producto del título.
A una solución de N-[2-(2-fluorofenil)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina (45,1 mg, 0,1 mmol) en DCM anhidro (0,6 mL) se agregó la resina de poliestireno morfolinometil (Novabiochem, HL, 39,5 mg, 0,15 mmol, 3,8 mmol/g) y la mezcla resultante se enfrió a 0ºC. Se agregó etilcloruro de oxalilo (4,7 mg, 0,13 mmol) en DCM anhidro (0,4 mL). La mezcla de reacción se agitó durante 2 h a TA, luego se agregó la PL-AMS-Resin (Polymer Laboratories, 52 mg, 0,1 mmol, 1,93 mmol/g) y la mezcla se agitó durante 1,5 h. Las resinas se retiraron por filtración, se lavaron con DCM y los filtrados se concentraron al vacío para proporcionar el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(2-fluorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(2fluorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (26% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 522,3. HPLC (Condición A), Tr: 5,76 min (pureza de la HPLC: 98,9%).
Ejemplo 358: ácido {[2-(2-fluorofenil)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
Etapa a) Formación de N-[2-(2-fluorofenil)etil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(2-fluorofenil)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(2-fluorofenil)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(2-fluorofenil)etil]N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 552,5. HPLC (Condición A), Tr: 6,31 min (pureza de la HPLC: 91,2%).
Etapa c) Formación de ácido {[2-(2-fluorofenil)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil{[2-(2-fluorofenil)etil][3(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (24% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 522,4; M+(LC/MS(ESI)): 524,2. HPLC (Condición A), Tr: 5,76 min (pureza de la HPLC: 98,5%).
Ejemplo 359: ácido {[2-(2-fluorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il]bencil)amino}-(oxo)acético
Etapa a) Formación de N-[2-(2-fluorofenil)etil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 2-(2-fluorofenil)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(2-fluorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(2-fluorofenil)etil]N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(2-fluorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil{[2-(2-fluorofenil)etil][4(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (29% (rendimiento general de la etapa a)). M- (LC/MS(ESI)): 480,2. HPLC (Condición A), Tr: 5,21 min (pureza de la HPLC: 98,4%).
Ejemplo 360: ácido {[2-(3,4-diclorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il]bencil]-amino}(oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(3,4-diclorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(3,4diclorofenil)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (23% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 572,2. HPLC (Condición A), Tr: 6,04 min (pureza de la HPLC: 99,2%).
Ejemplo 361: ácido {[2-(3,4-diclorofenil)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(3,4-diclorofenil)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(3,4-diclorofenil)etil] [3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(3,4diclorofenil)etil] [3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (18% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 572,3; M+(LC/MS(ESI)): 574,0. HPLC (Condición A), Tr: 6,04 min (pureza de la HPLC: 97,9%).
Ejemplo 362: ácido {[2-(3,4-diclorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il]bencil]-amino}(oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(3,4-diclorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M(LC/MS(ESI)): 558,5; M+(LC/MS(ESI)): 560,1. HPLC (Condición A), Tr: 6,07 min (pureza de la HPLC: 78,5%).
Etapa c) Formación de ácido {[2-(3,4-diclorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(3,4diclorofenil)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (14% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 532,0. HPLC (Condición A), Tr: 5,52 min (pureza de la HPLC: 89,6%).
Ejemplo 363: ácido {[2-(1,1'-bifenil-4-il)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
Etapa a) Formación de N-[2-(1,1'-bifenil-4-il)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(1,1'-bifenil-4-il)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(1,1'-bifenil-4-il)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(1,1’-bifenil-4il)etil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 610,3. HPLC (Condición A), Tr: 6,60 min (pureza de la HPLC: 77,8%).
Etapa c) Formación de ácido {[2-(1,1'-bifenil-4-il)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(1,1'-bifenil-4il)etil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (4% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 580,3. HPLC (Condición A), Tr: 6,10 min (pureza de la HPLC: 95,3%).
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(1,1'-bifenil-4-il)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(1,1'-bifenil-4-il)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(1,1'-bifenil-4il)etil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(1,1'-bifenil-4-il)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(1,1'-bifenil-4il)etil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (24% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 580,1; M+(LC/MS(ESI)): 582,3. HPLC (Condición A), Tr: 6,10 min (pureza de la HPLC: 97,8%).
Ejemplo 365: ácido {[2-(1,1'-bifenil-4-il)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
Etapa a) Formación de N-[2-(1,1'-bifenil-4-il)etil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 2-(1,1'-bifenil-4-il)etilamina proporcionó el compuesto del título como un aceite.
Etapa b) Formación de etil {[2-(1,1'-bifenil-4-il)etil][4-(3-octil-l,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(1,1'-bifenil-4il)etil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(1,1'-bifenil-4-il)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(1,1'-bifenil-4il)etil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (13% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 538,3. HPLC (Condición A), Tr: 5,63 min (pureza de la HPLC: 97,8%).
Ejemplo 366: ácido oxo{5,6,7,8-tetrahidronaftalen-1-il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-5,6,7,8-tetrahidronaftalen-1-il-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 5,6,7,8-tetrahidronaftalen-1-ilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 460,4. HPLC (Condición A), Tr: 6,36 min (pureza de la HPLC: 73,3%).
Etapa b) Formación de etil oxo{5,6,7,8-tetrahidronaftalen-1-il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-5,6,7,8tetrahidronaftalen-1-il-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)benciI]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de oxo{5,6,7,8-tetrahidronaftalen-1-il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{5,6,7,8tetrahidronaftalen-1-il[4-(3 -undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un polvo blanco (23% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 530,3. HPLC (Condición A), Tr: 5,95 min (pureza de la HPLC: 94,7%).
Ejemplo 367: ácido oxo{5,6,7,8-tetrahidronaftalen-1-il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-5,6,7,8-tetrahidronaftalen-1-il-N-[3-(3-undecil-1,2,4-oxa-diazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 5,6,7,8-tetrahidronaftalen-1-ilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 460,4. HPLC (Condición A), Tr: 6,32 min (pureza de la HPLC: 68,9%).
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-5,6,7,8tetrahidronaftalen-1-il-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 560,4. HPLC (Condición A), Tr: 6,52 min (pureza de la HPLC: 73,3%).
Etapa c) Formación de ácido oxo{5,6,7,8-tetrahidronaftalen-1-il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{5,6,7,8tetrahidronaftalen-1-il[3-(3 -undecil-1,2,4-oxadiazol-5-il)bencil]amino} acetato proporcionó el compuesto del título como un sólido amarillo (7% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 530,2; M+(LC/MS(ESI)): 532,3. HPLC (Condición A), Tr: 5,94 min (pureza de la HPLC: 90,3%).
Ejemplo 368: ácido [[4-(3-octil-1,2,4-oxadiazol-5-il)bencil](5,6,7,8-tetrahidronaftalen-1-il)amino](oxo)acético
Etapa a) Formación de N-5,6,7,8-tetrahidronaftalen-1-il-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 5,6,7,8-tetrahidronaftalen-1-ilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 418,4. HPLC (Condición A), Tr: 5,83 min (pureza de la HPLC: 82,3%).
Etapa b) Formación de etil oxo{5,6,7,8-tetrahidronaftalen-1-il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-5,6,7,8tetrahidronaftalen-1-il-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido [[4-(3-octil-1,2,4-oxadiazol-5-il)bencil](5,6,7,8-tetrahidronaftalen-1-il)amino](oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{5,6,7,8tetrahidronaftalen-1-il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un sólido blanco (11% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 488,2. HPLC (Condición A), Tr: 5,43 min (pureza de la HPLC: 95,6%).
Ejemplo 369: ácido {(1,1'-bifenil-3-ilmetil)[4-( 3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
Etapa a) Formación de N-(1,1'-bifenil-3-ilmetil)-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y bromhidrato de 1,1'-bifenil-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 496,5. HPLC (Condición A), Tr: 4,99 min (pureza de la HPLC: 90,9%).
Etapa b) Formación de etil{(1,1'-bifenil-3-ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino} (oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1,1'-bifenil-3-ilmetil)N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 596,1. HPLC (Condición A), Tr: 6,51 min (pureza de la HPLC: 91,8%).
Etapa c) Formación de ácido {(1,1’-bifenil-3-ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino} (oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1,1’-bifenil-3ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (6% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 566,3. HPLC (Condición A), Tr: 6,06 min (pureza de la HPLC: 99,5%).
Ejemplo 370: ácido {(1,1'-bifenil-3-ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
Etapa a) Formación de N-(1,1'-bifenil-3-ilmetil)-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y bromhidrato de 1,1'-bifenil-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 496,5. HPLC (Condición A), Tr: 4,99 min (pureza de la HPLC: 87,7%).
Etapa b) Formación de etil{(1,1'-bifenil-3-ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1,1'-bifenil-3-ilmetil)N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1,1'-bifenil-3ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (17% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 566,1; M+(LC/MS(ESI)): 568,2. HPLC (Condición A), Tr: 5,99 min (pureza de la HPLC: 94,5%).
Ejemplo 371: ácido {(1,1'-bifenil-3-ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
Etapa a) Formación de N-(1,1'-bifenil-3-ilmetil)-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y bromhidrato de 1,1'-bifenil-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 454,6. HPLC (Condición A), Tr: 4,52 min (pureza de la HPLC: 81%).
Etapa b) Formación de etilo {(1,1'-bifenil-3-ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1,1'-bifenil-3-ilmetil)N-[4-(3-octil-l,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(1,1’-bifenil-3-ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1,1'-bifenil-3ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (4% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 524,2. HPLC (Condición A), Tr: 5,51 min (pureza de la HPLC: 90,8%).
Ejemplo 372: ácido {(1-benzotien-3-ilmetil)[4-(3 -undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
Etapa a) Formación de N-(1-benzotien-3-ilmetil)-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 1-benzotien-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 476,4. HPLC (Condición A), Tr: 4,82 min (pureza de la HPLC: 77,5%).
Etapa b) Formación de etil{(1-benzotien-3-ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1-benzotien-3ilmetil)-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(1-benzotien-3-ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1-benzotien-3ilmetil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (15% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 546,2. HPLC (Condición A), Tr: 5,88 min (pureza de la HPLC: 98,3%).
Ejemplo 373: ácido {(1-benzotien-3-ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
Etapa a) Formación de N-(1-benzotien-3-ilmetil)-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 1-benzotien-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 476,3. HPLC (Condición A), Tr: 4,79 min (pureza de la HPLC: 86,7%).
Etapa b) Formación de etil{(1-benzotien-3-ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1-benzotien-3ilmetil)-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 576,7. HPLC (Condición A), Tr: 6,37 min (pureza de la HPLC: 87,9%).
Etapa c) Formación de ácido {(1-benzotien-3-ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)-bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1-benzotien-3ilmetil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (23% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 546,1. HPLC (Condición A), Tr: 5,84 min (pureza de la HPLC: 98,0%).
Etapa a) Formación de N-(1-benzotien-3-ilmetil)-N-[4-(3-octil-1,2,4-oxadiazol-5-il)-bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 1-benzotien-3-ilmetilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 434,3. HPLC (Condición A), Tr: 4,30 min (pureza de la HPLC: 89,9%).
Etapa b) Formación de etil{(1-benzotien-3-ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(1-benzotien-3ilmetil)-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(1-benzotien-3-ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(1-benzotien-3ilmetil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (9% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 504,1. HPLC (Condición A), Tr: 5,34 min (pureza de la HPLC: 88,7%).
Ejemplo 375: ácido oxo{[2-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}acético
Etapa a) Formación de N-[2-(trifluorometil)bencil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 488,5. HPLC (Condición A), Tr: 4,78 min (pureza de la HPLC: 95,4%).
Etapa b) Formación de etil oxo{[2-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2(trifluorometil)bencil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{[2-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)-bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[2(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite incoloro (38% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 558,1. HPLC (Condición A), Tr: 5,94 min (pureza de la HPLC: 98,7%).
Ejemplo 376: ácido oxo{[2-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-[2-(trifluorometil)bencil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 488,4. HPLC (Condición A), Tr: 4,78 min (pureza de la HPLC: 95,4%).
Etapa b) Formación de etil oxo{[2-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino} acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2(trifluorometil)bencil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{[2-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[2(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite incoloro (13% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 558,2. HPLC (Condición A), Tr: 5,87 min (pureza de la HPLC: 97,8%).
Ejemplo 377: ácido {[4-(3-octil-1,2,4-oxadiazol-5-il)bencil][2-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de N-[2-(trifluorometil)bencil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 446,4. HPLC (Condición A), Tr: 4,23 min (pureza de la HPLC: 96,5%).
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2(trifluorometil)bencil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite. M-(LC/MS(ESI)): 544,2; M+(LC/MS(ESI)): 546,1. HPLC (Condición A), Tr: 5,95 min (pureza de la HPLC: 92,7%).
Etapa c) Formación de ácido {[4-(3-octil-1,2,4-oxadiazol-5-il)bencil][2-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[2(trifluorometil)bencil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite incoloro (18% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 516,2. HPLC (Condición A), Tr: 5,35 min (pureza de la HPLC: 99,0%).
Ejemplo 378: ácido oxo{[3-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-[3-(trifluorometil)bencil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 3-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 488,4. HPLC (Condición A), Tr: 4,84 min (pureza de la HPLC: 64,4%).
Etapa b) Formación de etil oxo{[3-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[3(trifluorometil)bencil]-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{[3-(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[3(trifluorometil)bencil][4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo (14% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 558,3. HPLC (Condición A), Tr: 5,85 min (pureza de la HPLC: 97,8%).
Ejemplo 379: ácido oxo{[3-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-[3-(trifluorometil)bencil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 3-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 488,5. HPLC (Condición A), Tr: 4,86 min (pureza de la HPLC: 66,8%).
Etapa b) Formación de etil oxo{[3-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[3(trifluorometil)bencil]-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{[3-(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[3(trifluorometil)bencil][3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo (44% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 558,1; M+(LC/MS(ESI)): 560,2. HPLC (Condición A), Tr: 5,84 min (pureza de la HPLC: 97,3%).
Ejemplo 380: ácido {[4-(3-octil-1,2,4-oxadiazol-5-il)bencil][3-(trifluorometil)bencil]-amino}(oxo)acético
Etapa a) Formación de N-[3-(trifluorometil)bencil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 3-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 446,4. HPLC (Condición A), Tr: 4,31 min (pureza de la HPLC: 73,9%).
Etapa b) Formación de etil oxo{[3-(trifluorometil)bencil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[3(trifluorometil)bencil]-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{[3(trifluorometil)bencil][4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo (20% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 516,1. HPLC (Condición A), Tr: 97,9 min (pureza de la HPLC: 97,9%).
Ejemplo 381: ácido {(2-metoxibencil)[4-(3-undecil-l,2,4-oxadiazol-5-il)bencil]-amino}-(oxo)acético
Etapa a) Formación de N-(2-metoxibencil)-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-metoxibencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 450,5. HPLC (Condición A), Tr: 4,70 min (pureza de la HPLC: 92,7%).
Etapa b) Formación de etil{(2-metoxibencil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(2-metoxibencil)-N[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(2-metoxibencil)[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(2-metoxibencil)[4-(3undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite incoloro (43% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 520,3; M+(LC/MS(ESI)): 522,4. HPLC (Condición A), Tr: 5,76 min (pureza de la HPLC: 98,6%).
Ejemplo 382: ácido {(2-metoxibencil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}-(oxo)acético
Etapa a) Formación de N-(2-metoxibencil)-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 2-metoxibencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 450,5. HPLC (Condición A), Tr: 4,72 min (pureza de la HPLC: 92,6%).
Etapa b) Formación de etil{(2-metoxibencil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(2-metoxibencil)-N[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(2-metoxibencil)[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(2-metoxibencil)[3-(3undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un sólido blanco (17% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 520,3; M+(LC/MS(ESI)): 522,3. HPLC (Condición A), Tr: 5,70 min (pureza de la HPLC: 98,9%).
Ejemplo 383: ácido {(2-metoxibencil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}-(oxo)acético
Etapa a) Formación de N-(2-metoxibencil)-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 2-metoxibencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 408,4. HPLC (Condición A), Tr: 4,12 min (pureza de la HPLC: 91,9%).
Etapa b) Formación de etil{(2-metoxibencil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(2-metoxibencil)-N[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(2-metoxibencil)[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(2-metoxibencil)[4-(3octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (33% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 478,2. HPLC (Condición A), Tr: 5,15 min (pureza de la HPLC: 98,0%).
Etapa a) Formación de N-{4-[(trifluorometil)sulfonil]bencil}-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y clorhidrato de 4-[(trifluorometil)sulfonil]bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 552,7. HPLC (Condición A), Tr: 4,85 min (pureza de la HPLC: 36%).
Etapa b) Formación de etil oxo{{4-[(trifluorometil)sulfonil]bencil}[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-{4[(trifluorometil)sulfonil]bencil}-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{{4-[(trifluorometil)sulfonil]bencil}[4-(3-undecil-1,2,4-oxadiazol-5il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{{4[(trifluorometil)sulfonil]bencil}[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo (15% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 622,1; M+(LC/MS(ESI)): 624,1. HPLC (Condición A), Tr: 5,80 min (pureza de la HPLC: 79,4%).
Ejemplo 385: ácido oxo{{4-[(trifluorometil)sulfonil]bencil}[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acético
Etapa a) Formación de N-{4-[(trifluorometil)sulfonil]bencil}-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y clorhidrato de 4-[(trifluorometil)sulfonil]bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 552,5. HPLC (Condición A), Tr: 4,85 min (pureza de la HPLC: 62,0%).
Etapa b) Formación de etil oxo{{4-[(trifluorometil)sulfonil]bencil}[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-{4[(trifluorometil)sulfonil]bencil}-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido oxo{{4-[(trifluorometil)sulfonil]bencil}[3-(3-undecil-1,2,4-oxadiazol-5il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{{4[(trifluorometil)sulfonil]bencil}[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino} acetato proporcionó el compuesto del título como un aceite amarillo (37% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 622,1; M+(LC/MS(ESI)): 624,0. HPLC (Condición A), Tr: 5,79 min (pureza de la HPLC: 81,4%).
Ejemplo 386: ácido ([4-(3-octil-1,2,4-oxadiazol-5-il)bencil]{4-[(trifluorometil)sulfonil]-bencil}amino}(oxo)acético
Etapa a) Formación de N-{4-[(trifluorometil)sulfonil]bencil}-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y clorhidrato de 4-[(trifluorometil)sulfonil]bencilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 4,36 min (pureza de la HPLC: 43,4%).
Etapa b) Formación de etil oxo{{4-[(trifluorometil)sulfonil]bencil}[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-{4[(trifluorometil)sulfonil]bencil}-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido ([4-(3-octil-1,2,4-oxadiazol-5-il)bencil]{4-[(trifluorometil)sulfonil]bencil}amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil oxo{{4[(trifluorometil)sulfonil]bencil}[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite amarillo (24% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 580,1; M+(LC/MS(ESI)): 582,1. HPLC (Condición A), Tr: 5,26 min (pureza de la HPLC: 81,1%).
Etapa a) Formación de N-1,3-benzodioxol-5-il-N-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y l,3-benzodioxol-5-ilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 5,15 min (pureza de la HPLC: 97,2%).
Etapa b) Formación de etil {1,3-benzodioxol-5-il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-1,3-benzodioxol-5-ilN-[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {1,3-benzodioxol-5-il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {1,3-benzodioxol-5il[4-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite marrón (46% (rendimiento general de la etapa a)). M+(LC/MS(ESI)): 478,2 (-C02). HPLC (Condición A), Tr: 5,55 min (pureza de la HPLC: 96,4%).
Ejemplo 388: ácido {1,3-benzodioxol-5-il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}-(oxo)acético
Etapa a) Formación de N-1,3-benzodioxol-5-il-N-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 3-(3-undecil-1,2,4oxadiazol-5-il)benzaldehído y 1,3-benzodioxol-5-ilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 450,4. HPLC (Condición A), Tr: 5,12 min (pureza de la HPLC: 95,4%).
Etapa b) Formación de etil {1,3-benzodioxol-5-il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-1,3-benzodioxol-5-ilN-[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {1,3-benzodioxol-5-il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {1,3-benzodioxol-5il[3-(3-undecil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite marrón (56% (rendimiento general de la etapa a)). M+(LC/MS(ESI)): 522,1. HPLC (Condición A), Tr: 5,55 min (pureza de la HPLC: 94,7%).
Ejemplo 389: ácido {1,3-benzodioxol-5-il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}-(oxo)acético
Etapa a) Formación de N-1,3-benzodioxol-5-il-N-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa a) pero utilizando 4-(3-octil-1,2,4oxadiazol-5-il)benzaldehído y 1,3-benzodioxol-5-ilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 408,4. HPLC (Condición A), Tr: 4,54 min (pureza de la HPLC: 85,5%).
Etapa b) Formación de etil {1,3-benzodioxol-5-il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-1,3-benzodioxol-5-ilN-[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {1,3-benzodioxol-5-il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {1,3-benzodioxol-5il[4-(3-octil-1,2,4-oxadiazol-5-il)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite marrón (48% (rendimiento general de la etapa a)). M+(LC/MS(ESI)): 478,2 (-CO2). HPLC (Condición A), Tr: 4,91 min (pureza de la HPLC: 97,5%).
Ejemplo 390: ácido {[(4-dodec-1-inil-1-naftil)metil][4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de clorhidrato de (4-bromo-1-naftil)metilamina
Una mezcla de 1-bromo-4-metilnaftalina (25 g, 0,113 mol), NBS (22,2 g, 0,123 mol) y peróxido de benzoilo (5 g) en CCl4 (750 mL) se sometió a reflujo durante 5 h. La mezcla de reacción se enfrió, la succinimida se retiró por filtración y se concentró para proporcionar bromuro bruto (34 g) y se utilizó para la siguiente reacción sin ninguna purificación. A una solución fría (-40ºC) de amoníaco líquido (2 L) se agregó 1-bromo-4-bromometil naftalina (bruto, 34 g) disuelta en 200ml de CH2Cl2 durante un período de 45 min. La mezcla de reacción luego se agitó a -40ºC durante 18h. A continuación la mezcla de reacción se dejó agitar a TA y se concentró al vacío para proporcionar un residuo amarillo.
El residuo luego se trató con HCl 3N (250 mL), el sólido obtenido se retiró por filtración y se lavó con CH2Cl2 (2x 250 mL). El sólido se secó al vacío para proporcionar clorhidrato de (4-bromo-1-naftil) metilamina (25 g, 80%). pureza de la HPLC: 96,6%
Etapa b) Formación de clorhidrato de N-[(4-bromo-1-naftil)metil]-N-[4-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando (4-bromo-1naftil)metilamina y 4-(trifluorometil)benzaldehído proporcionó el compuesto del título como un aceite marrón (58%). HPLC (Condición A), Tr: 3,40 min (pureza de la HPLC: 98,4%).
Etapa c) Formación de etil{[(4-bromo-1-naftil)metil][4-(trifluorometil)bencil]-amino) (oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-[(4bromo-1-naftil)metil]-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título (98%). M-(LC/MS(ESI)): 491,4; M+(LC/MS(ESI)): 496,1. HPLC (Condición A), Tr: 5,25 min (pureza de la HPLC: 97,9%).
Etapa d) Formación de etil {[(4-dodec-1-inil-1-naftil)metil][4-(trifluorometil)-bencil]amino}(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil {[(4-bromo-1naftil)metil] [4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó
el compuesto del título como un aceite amarillo (74%). HPLC (Condición A), Tr: 6,64 min (pureza de la HPLC: 100%).
Etapa e) Formación de ácido {[(4-dodec-1-inil-1-naftil)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[(4-dodec-1-inil-1naftil)metil][4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (48% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 550,2. HPLC (Condición A), Tr: 6,15 min (pureza de la HPLC: 99,3%). Análisis calculado para C33H36F3NO3=0,5 H2O: C, 70,70; H, 6,65; N, 2,50%. Encontrado: C, 70,44; H, 6,72; N, 2,29%
Ejemplo 391: ácido {[(4-dec-1-inil-1-naftil)metil][4-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de clorhidrato de N-[(4-bromo-1-naftil)metil]-N-[4-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando (4-bromo-1naftil)metilamina y 4-(trifluorometil)benzaldehído proporcionó el compuesto del título como un aceite marrón (58%). HPLC (Condición A), Tr: 3,40 min (pureza de la HPLC: 98,4%).
Etapa b) Formación de etil{[(4-bromo-1-naftil)metil][4-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando clorhidrato de N-[(4bromo-1-naftil)metil]-N-[4-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite incoloro (98%).
Etapa c) Formación de etil {[(4-dec-1-inil-1-naftil)metil][4-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil {[(4-bromo-1naftil)metil][4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó
el compuesto del título como un aceite amarillo (87%). M-(LC/MS(ESI)): 550,1; M+(LC/MS(ESI)): 552,5. HPLC (Condición A), Tr: 6,36 min (pureza de la HPLC: 96,4%).
Etapa d) Formación de ácido {[(4-dec-1-inil-1-naftil)metil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[(4-dec-1-inil-1naftil)metil][4-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite marrón (91%). 1H NMR (CDCl3, 300 MHz) δ 8,43-8,37 (m, 1H), 7,90-7,76 (m, 1H), 7,61-7,48 (m, 5H), 7,28-7,08 (m, 3H), 5,37 (s, 0,7H), 5,05 (s, 1,3H), 4,79 (s, 1,3H), 4,61 (s, 0,7H), 2,57 (t, 2H, J = 7,0Hz), 1,77-1,65 (m, 2H), 1,59-1,48 (m, 2H), 1,42-1,25 (m, 8H), 0,89 (m, 3H). M-(LC/MS(ESI)): 522,3. HPLC (Condición A), Tr: 5,83 min (pureza de la HPLC: 97,7%).
Etapa a) Formación de N-[1-(3-clorofenil)-1-metiletil]-N-{4-[(4-hexilfenil)-etinil]bencil}amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-[(4hexilfenil)etinil]benzaldehído y l-(3-clorofenil)-1-metiletilamina proporcionó el compuesto del título como un aceite marrón (80%). HPLC (Condición A), Tr: 4,73 min (pureza de la HPLC: 98,7%).
5 Etapa b) Formación de etil([1-(3-clorofenil)-1-metiletil]{4-[(4-hexilfenil)etinil]-bencil}amino)(oxo) acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando N-[1-(3-clorofenil)-1metiletil]-N-{4-[(4-hexilfenil)etinil]bencil}amina proporcionó el compuesto del título como un aceite marrón (95%). HPLC (Condición A), Tr: 6,26 min (pureza de la HPLC: 99,3%).
Etapa c) Formación de ácido ([1-(3-clorofenil)-1-metiletil]{4-[(4-hexilfenil)etinil]-bencil}amino)(oxo)acético
10 El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil([1-(3-clorofenil)-1metiletil]{4-[(4-hexilfenil)etinil]bencil}-amino)(oxo)acetato proporcionó el compuesto del título como un polvo amarillo (89%). M-(LC/MS(ESI)): 514,1. HPLC (Condición A), Tr: 5,84 min (pureza de la HPLC: 99,1%).
Etapa d) Formación de ácido ([1-(3-clorofenil)-1-metiletil]{4-[(4-hexilfenil)etinil]-bencil}amino)(oxo)acético, sal de Nmetil-D-glucamina (es decir 1-desoxi-1-(metilamino)glucitol)
15 El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido ([1-(3-clorofenil)-1-metiletil]{4[(4-hexilfenil)etinil]bencil}amino)(oxo)acético proporcionó el compuesto del título como un polvo blanco (94%). M(LC/MS(ESI)): 514,7. HPLC (Condición A), Tr: 5,81 min (pureza de la HPLC: 99,4%). Análisis calculado para C32H34ClNO3.C7H17NO5=0,8 H2O: C, 64,55; H, 7,31; N, 3,86%. Encontrado: C, 64,6; H, 7,43; N, 3,87%
Ejemplo 393: ácido oxo{[4-(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino}acético
20 Etapa a) Formación de 4-(1,3-dioxolan-2-il)benzonitrilo
A una solución de 4-cianobenzaldehído (25 g, 0,190 mol) en tolueno seco (300 mL) se agregó etilenglicol (15 g, 0,228 mol) y PTSA (0,5 g) y se dejó hasta alcanzar reflujo a 130ºC con eliminación azeotrópica de agua durante 12h. La mezcla de reacción se enfrió, se lavó con NaHCO3 acuoso al 10% (100 mL), se secó y se concentró al vacío. Elsólido bruto se recristalizó a partir de Éter de pet/EtOAc para proporcionar el 4-(1,3-dioxolan-2il)benzonitrilo (17 g,
25 51%) como un sólido blanco. TLC (Éter de pet/EtOAc 4/1), Rf = 0,6
Etapa b) Formación de 4-(1,3-dioxolan-2-il)bencenocarbotioamida
A una solución de 4-(1,3-dioxolan-2il)benzonitrilo (2 g, 0,01 1mol) en piridina seca (50 mL)
y TEA (5,75 g, 0,057 mol) se pasó gas H2S (generado recientemente) durante 1h con agitación a
TA. La mezcla de reacción se diluyó con agua (100 mL), se extrajo con éter dietílico (100 mL), se lavó con salmuera
30 (50 mL) y se secó. El disolvente se retiró al vacío y el producto bruto se purificó mediante cromatografía en columna sobre gel de sílice (Éter de pet/EtOAc, 3/7) para proporcionar 4-(1,3-dioxolan-2-il)bencenocarbotioamida (1,9 g,86%) como un sólido amarillo. TLC (Éter de pet/EtOAc 3/7), Rf = 0,35
Etapa c) Formación de 1-bromotridecan-2-ona
A una solución de cloruro de ácido láurico (10,0 g, 45,7 mmol) en THF anhidro (91 mL) a 0ºC se agregó por goteo
35 una solución de trimetilsilildiazometano (2 M en éter, 45,7 mL, 91,4 mmol). La mezcla se agitó 1 h a 0ºC luego durante toda la noche a TA. Los disolventes se evaporaron al vacío para proporcionar un aceite amarillo. Este producto bruto se disolvió en DCM (50 mL) y se agitó en presencia de la PL-AMS-Resin (Polymer Laboratories, 1,54 mmol/g, 5 g) durante 5 h a TA. La resina se retiró mediante filtración y se lavó con DCM. Los filtrados combinados se evaporaron para proporcionar un aceite amarillo. Este producto bruto se disolvió en Et2O, se enfrió a 0ºC y se
40 agregó una solución acuosa concentrada de HBr (48%, 10 mL) por goteo cuidadosamente. Después de 1 h de reacción, la mezcla se decantó y la capa orgánica se secó sobre MgSO4, se filtró y se evaporó para proporcionar el producto del título como un sólido beige (8,32 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 3,87 (s, 2H), 2,63 (t, 2H, J = 7,5Hz), 1,67-1,54 (m, 2H), 1,30-1,21 (m, 16H), 0,87 (m, 3H)
Etapa d) Formación de 4-(4-undecil-1,3-tiazol-2-il)benzaldehído
45 Una solución de 1-bromotridecan-2-ona (5,54 g, 20 mmol) y 4-(1,3-dioxolan-2-il)bencenocarbotioamida (4,19 g, 20 mmol) en EtOH (50 mL) se sometió a reflujo durante toda la noche. Después de la evaporación del disolvente, el residuo se recogió en éter, se lavó con agua, salmuera, se secó sobre MgSO4 y se filtró. Los disolventes se evaporaron al vacío para proporcionar un aceite amarillo. La purificación mediante gel de sílice proporcionó el producto del título como un sólido amarillo (4,05 g, 59%). 1H NMR (CDCl3, 300 MHz) δ 10,0 (s, 1H), 8,11 (d, 2H, J = 8,3 Hz), 7,93 (d, 2H, J = 8,6 Hz), 6,98 (s, 1H), 2,84 (t, 2H, J = 7,2 Hz), 1,78-1,72 (m, 2H), 1,50-1,20 (m, 16H), 0,87 (t, 3H, J = 6,8 Hz). M+(LC/MS(ESI)): 344,3
Etapa e) Formación de N-[4-(trifluorometil)bencil]-N-[4-(4-undecil-1,3-tiazol-2-il)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa a) pero utilizando 4-(4-undecil-1,3-tiazol2-il)benzaldehído y 4-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite incoloro (90%).1H NMR (CDCl3, 300 MHz) δ 7,78 (d, 2H, J = 8,3 Hz), 7,45 (d, 2H, J = 8,1 Hz), 7,35 (d, 2H, J = 8,1 Hz), 7,25 (d, 2H, J = 8,3 Hz), 6,72 (s, 1H), 3,689 (s, 2H, J-7,3 Hz), 3,74 (s, 2H), 2,67 (t, J = 2H, 7,7 Hz), 1,95-1,72 (m, 1H), 1,62-1,55 (m, 2H), 1,37-1,05 (m, 16H), 0,74 (t, 3H, J = 6,7 Hz). M+(LC/MS(ESI)): 503,4. HPLC (Condición A), Tr: 4,99 min (pureza de la HPLC: 91,2%).
Etapa f) Formación de etiloxo{[4-(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino} acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 15 (etapa b) pero utilizando 4-(4-undecil-1,3-tiazol-2il)benzaldehído proporcionó el compuesto del título como un aceite incoloro (93%). 1H NMR (CDCl3, 300 MHz) δ 7,98-7,88 (m, 2H), 7,65-7,56 (m, 2H), 7,40-7,23 (m, 4H), 6,89 (d, 1H, J = 3,8Hz), 4,54 (d, 2H, J = 4,5Hz), 4,41-4,29 (m, 4H), 2,82 (t, 2H, J = 7,7 Hz), 1,81-1,70 (m, 2H), 1,40-1,21 (m, 19H), 0,87 (m, 3H). HPLC (Condición A), Tr: 6,52 min (pureza de la HPLC: 98,9%).
Etapa g) Formación de ácido oxo{[4-(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etiloxo{[4(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino}acetato proporcionó el compuesto del título como un aceite incoloro (95%). M-(LC/MS(ESI)): 573,3; M+(LC/MS(ESI)): 575,1. HPLC (Condición A), Tr: 5,98 min (pureza de la HPLC: 98,6%).
Etapa h) Formación de ácido oxo{[4-(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino}acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando ácido oxo{[4(trifluorometil)bencil][4-(4-undecil-1,3-tiazol-2-il)bencil]amino}acético proporcionó el compuesto del título como un polvo blanco (93%). M-(LC/MS(ESI)): 573,4; M+(LC/MS(ESI)): 575,3. HPLC (Condición A), Tr: 5,99 min (pureza de la HPLC: 99,3%). Análisis calculado para C31H37F3N2O3S.C7H17NO5=0,1H2O: C, 59,14; H, 7,08; N, 5,45%. Encontrado: C, 58,87; H, 6,96; N, 5,38%
Ejemplo 394: ácido {(-dec-1-inilbencil)[2-(2-fluorofenil)etil]amino}(oxo)acético
Etapa a) Formación de N-(4-dec-1-inilbencil)-N-[2-(2-fluorofenil)etil]amina
A una solución de 4-dec-1-inilbenzaldehído (24,2 mg, 0,1 mmol) en THF anhidro (0,6 mL) se agregó la 2-(2fluorofenil)etilamina (13,9 mg, 0,1 mmol) y MgSO4 anhidro (50 mg). La mezcla se agitó durante toda la noche a TA. La mezcla de reacción se filtró y se evaporó para proporcionar un residuo oleoso. Este producto bruto se recogió en MeOH (0,5 mL) luego se agregó el triacetoxiborohidruro de sodio (53 mg, 0,25 mmol) y la mezcla de reacción se agitó durante toda la noche a TA. Los disolventes se evaporaron al vacío para proporcionar un sólido. Este sólido se suspendió en DCM (0,75 mL) y eluyó a través de una columna SCX (Isolute, 1 g) con DCM (6 mL), luego NH3 (2M en MeOH, 4 mL). Las fracciones deseadas (monitoreo por TLC) se concentraron al vacío para proporcionar el producto del título como un aceite amarillo. M+(LC/MS(ESI)): 366,3. HPLC (Condición A), Tr: 4,64 min (pureza de la HPLC: 80,5%).
Etapa b) Formación de etil{(4-dec-1-inilbencil)[2-(2-fluorofenil)etil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(4-dec-1-inilbencil)N-[2-(2-fluorofenil)etil]amina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 6,18 min (pureza de la HPLC: 65,5%).
Etapa c) Formación de ácido {(4-dec-1-inilbencil)[2-(2-fluorofenil)etil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dec-1-inilbencil)[2(2-fluorofenil)etil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (5% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 436,3. HPLC (Condición A), Tr: 5,45 min (pureza de la HPLC: 87,5%).
Ejemplo 395: ácido {(4-dodec-1-inil]bencil)[2-(2-fluorofenil)etil]amino}(oxo)acético
Etapa a) Formación de N-(4-dodec-1-inilbencil)-N-[2-(2-fluorofenil)etil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-dodec-1inilbenzaldehído y 2-(2-fluorofenil)etilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 394,4. HPLC (Condición A), Tr: 5,00 min (pureza de la HPLC: 93,6%).
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(4-dodec-1inilbencil)-N-[2-(2-fluorofenil)etil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(4-dodec-1-inilbencil)[2-(2-fluorofenil)etil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dodec-1inilbencil)[2-(2-fluorofenil)etil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (21% (rendimiento general de la etapa a)). HPLC (Condición A), Tr: 5,78 min (pureza de la HPLC: 82,2%).
Ejemplo 396: ácido {{[4-(dodeciloxi)-1-naftil]metil}[2-(2-fluorofenil)etil]amino}-(oxo)acético
Etapa a) Formación de N-{[4-(dodeciloxi)-1-naftil]metil}-N-[2-(2-fluorofenil)-etil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-(dodeciloxi)-1naftaldehído y 2-(2-fluorofenil)etilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 5,48 min (pureza de la HPLC: 86,4%).
Etapa b) Formación de etil {{[4-(dodeciloxi)-1-naftil]metil}[2-(2-fluorofenil)etil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-{[4-(dodeciloxi)-1naftil]metil}-N-[2-(2-fluorofenil)etil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {{[4-(dodeciloxi)-1-naftil]metil}[2-(2-fluorofenil)etil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{[4-(dodeciloxi)-1naftil]metil}[2-(2-fluorofenil)etil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (7% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 534,3. HPLC (Condición A), Tr: 6,25 min (pureza de la HPLC: 92,8%).
Ejemplo 397: ácido {[2-(2-fluorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acético
Etapa a) Formación de N-[2-(2-fluorofenil)etil]-N-[4-(octiloxi)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4(octiloxi)benzaldehído y 2-(2-fluorofenil)etilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 4,37 min (pureza de la HPLC: 76,0%).
Etapa b) Formación de etil {[2-(2-fluorofenil)etil][4-(octiloxi)bencil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(2-fluorofenil)etil]N-[4-(octiloxi)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(2-fluorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(2fluorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un sólido blanco (22% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 428,3. HPLC (Condición A), Tr: 5,19 min (pureza de la HPLC: 64,2%).
Ejemplo 398: ácido {(4-dec-1-inilbencil)[2-(trifluorometil)bencil]amino}(oxo)acético
Etapa a) Formación de N-(4-dec-1-inilbencil)-N-[2-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-dec-1inilbenzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 402,3. HPLC (Condición A), Tr: 4,71 min (pureza de la HPLC: 86,5%).
Etapa b) Formación de etil{(4-dec-1-inilbencil)[2-(trifluorometil)bencil]-amino}-(oxo)-acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(4-dec-1-inilbencil)N-[2-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 6,31 min (pureza de la HPLC: 80,7%).
Etapa c) Formación de ácido {(4-dec-1-inilbencil)[2-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dec-1-inilbencil)[2(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (7% Ejemplo 399: ácido {(4-dodec-1-inilbencil)[2-(trifluorometil)bencil]amino}(oxo)acético
Etapa a) Formación de N-(4-dodec-1-inilbencil)-N-[2-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-dodec-1inilbenzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 430,4. HPLC (Condición A), Tr: 5,05 min (pureza de la HPLC: 96,9%).
Etapa b) Formación de etil{(4-dodec-1-inilbencil) [2-(trifluorometil)bencil]-amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(4-dodec-1inilbencil)-N-[2-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {(4-dodec-1-inilbencil)[2-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dodec-1inilbencil)[2-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (17% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 500,2. HPLC (Condición A), Tr: 5,92 min (pureza de la HPLC: 82,5%).
Ejemplo 400: ácido {{4-(dodeciloxi)-1-naftil]metil}[2-(trifluorometil)bencil]amino}-(oxo)acético
Etapa a) Formación de N-{[4-(dodeciloxi)-1-naftil]metil}-N-[2-(trifluorometil)-bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-(dodeciloxi)-1naftaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 5,54 min (pureza de la HPLC: 98,0%).
Etapa b) Formación de etil {{[4-(dodeciloxi)-1-naftil]metil}[2-(trifluorometil)-bencil]amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-{[4-(dodeciloxi)-1naftil]metil}-N-[2-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {{[4-(dodeciloxi)-1-naftil]metil}[2-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {{[4-(dodeciloxi)-1naftil]metil}[2-(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (8% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 570,4. HPLC (Condición A), Tr: 6,30 min (pureza de la HPLC: 79,2%).
Ejemplo 401: ácido {[4-(octiloxi)bencil][2-(trifluorometil)bencil]amino}(oxo)acético
Etapa a) Formación de N-[4-(octiloxi)bencil]-N-[2-(trifluorometil)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4(octiloxi)benzaldehído y 2-(trifluorometil)bencilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 4,24 min (pureza de la HPLC: 91,0%).
Etapa b) Formación de etil {[4-(octiloxi)bencil][2-(trifluorometil)bencil]-amino}(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[4-(octiloxi)bencil]-N[2-(trifluorometil)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[4-(octiloxi)bencil][2-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[4-(octiloxi)bencil][2(trifluorometil)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (13% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 464,3. HPLC (Condición A), Tr: 5,33 min (pureza de la HPLC: 92,2%).
Ejemplo 402: ácido {(4-dec-1-inilbencil)[2-(3,4-diclorofenil)etil]amino}(oxo)acético
Etapa a) Formación de N-(4-dec-1-inilbencil)-N-[2-(3,4-diclorofenil)etil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-dec-1inilbenzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 416,3. HPLC (Condición A), Tr: 4,91 min (pureza de la HPLC: 72,4%).
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-(4-dec-1-inilbencil)N-[2-(3,4-diclorofenil)etil]amina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 6,45 min (pureza de la HPLC: 62,5%).
Etapa c) Formación de ácido {(4-dec-1-inilbencil)[2-(3,4-diclorofenil)etil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {(4-dec-1-inilbencil)[2(3,4-diclorofenil)etil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite naranja (11% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 486,1. HPLC (Condición A), Tr: 5,76 min (pureza de la HPLC: 89,8%).
Ejemplo 403: ácido [[2-(3,4-diclorofenil)etil](4-dodec-1-inilbencil)amino](oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-(4-dodec-1-inilbencil)amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-dodec-1inilbenzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite. M+(LC/MS(ESI)): 444,4. HPLC (Condición A), Tr: 5,27 min (pureza de la HPLC: 83,9%).
Etapa b) Formación de etil [[2-(3,4-diclorofenil)etil](4-dodec-1-inilbencil)amino]-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-(4-dodec-1-inilbencil)amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido [[2-(3,4-diclorofenil)etil](4-dodec-1-inilbencil)amino]-(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil [[2-(3,4diclorofenil)etil](4-dodec-1-inilbencil)amino](oxo)acetato proporcionó el compuesto del título como un aceite amarillo (4% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 514,1. HPLC (Condición A), Tr: 6,08 min (pureza de la HPLC: 96,1%).
Ejemplo 404: ácido ([2-(3,4-diclorofenil)etil]{[4-(dodeciloxi)-1-naftil]metil}amino)-(oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-{[4-(dodeciloxi)-1-naftil]metil}amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4-(dodeciloxi)-1naftaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 5,72 min (pureza de la HPLC: 82,0%).
Etapa b) Formación de etil ([2-(3,4-diclorofenil)etil]{[4-(dodeciloxi)-1-naftil]-metil}amino) (oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-{[4-(dodeciloxi)-1-naftil]metil}amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido ([2-(3,4-diclorofenil)etil]{[4-(dodeciloxi)-1-naftil]metil}amino)(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil ([2-(3,4diclorofenil)etil]{[4-(dodeciloxi)-1-naftil]metil}amino)(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (6% (rendimiento general de la etapa a)). M-(LC/MS(ESI)): 584,0. HPLC (Condición A), Tr: 6,50 min (pureza de la HPLC: 63,7%).
Ejemplo 405: ácido {[2-(3,4-diclorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acético
Etapa a) Formación de N-[2-(3,4-diclorofenil)etil]-N-[4-(octiloxi)bencil]amina
El mismo procedimiento utilizado en la preparación del Ejemplo 394 (etapa b) pero utilizando 4(octiloxi)benzaldehído y 2-(3,4-diclorofenil)etilamina proporcionó el compuesto del título como un aceite. HPLC (Condición A), Tr: 4,69 min (pureza de la HPLC: 71,8%).
Etapa b) Formación de etil {[2-(3,4-diclorofenil)etil][4-(octiloxi)bencil]amino}-(oxo)acetato
El mismo procedimiento utilizado en la preparación del Ejemplo 357 (etapa b) pero utilizando N-[2-(3,4diclorofenil)etil]-N-[4-(octiloxi)bencil]amina proporcionó el compuesto del título como un aceite.
Etapa c) Formación de ácido {[2-(3,4-diclorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 1 (etapa e) pero utilizando etil {[2-(3,4diclorofenil)etil][4-(octiloxi)bencil]amino}(oxo)acetato proporcionó el compuesto del título como un aceite amarillo (6% Ejemplo 406: ácido ({4-[(4-hexilfenil)etinil]bencil}{1-metil-1-[4-(trifluorometil)-fenil]etil} amino)(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 392 pero utilizando 1-metil-1-[4(trifluorometil)fenil]etilamina y 4-[(4-hexilfenil)etinil]benzaldehído (en etapa a) proporcionó el compuesto del título como un polvo blanco. M-(LC/MS(ESI)): 548,1. HPLC (Condición A), Tr: 5,89 min (pureza de la HPLC: 98,7%).
Ejemplo 407: ácido {[4-(5-ciclohexilpent-1-inil)bencil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando pent-4-inilciclohexano proporcionó el compuesto del título como un aceite amarillo. M-(LC/MS(ESI)): 484,2. HPLC (Condición A), Tr: 5,53 min (pureza de la HPLC: 98,8%).
Ejemplo 408: ácido {{3-[(4-hexilfenil)etinil]bencil}[4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 1-etinil-4-hexilbenceno proporcionó el compuesto del título como un polvo blanco. M-(LC/MS(ESI)): 520,0. HPLC (Condición A), Tr: 5,68 min (pureza de la HPLC: 99,9%).
Ejemplo 409: ácido {[4-(4-etil-3-hidroxioct-1-inil)bencil][4-(trifluorometil)bencil]-amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando 4-etiloct-1-in-3-ol proporcionó el compuesto del título como una espuma amarilla. M-(LC/MS(ESI)): 488,2. HPLC (Condición A), Tr: 4,79 min (pureza de la HPLC: 98,9%).
Ejemplo 410: ácido {(2-dec-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético
El mismo procedimiento utilizado en la preparación del Ejemplo 226 (etapa c) pero utilizando etil {(2-bromobencil)[4(trifluorometil)bencil]amino}(oxo)acetato y dec-1-ino proporcionó el compuesto del título como un aceite amarillo claro. M-(LC/MS(ESI)): 472,0. HPLC (Condición A), Tr: 5,51 min (pureza de la HPLC: 99,6%).
Ejemplo 411: ácido {(4-dec-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético, sal de L-lisina
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(4-dec-1-inilbencil)[4(trifluorometil)bencil]amino}(oxo)acético y L-lisina proporcionó el compuesto del título como un polvo blanco. M(LC/MS(ESI)): 472,3. HPLC (Condición A), Tr: 5,59 min (pureza de la HPLC: 99,4%).
Ejemplo 412: ácido {(4-dec-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético, sal de trometamina (es decir (2amino-2-hidroximetil)-1,3-propanodiol)
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(4-dec-1-inilbencil)[4(trifluorometil)bencil]amino}(oxo)acético y tris (hidroximetil)amino metano proporcionó el compuesto del título como un sólido blanco. M-(LC/MS(ESI)): 472,3. HPLC (Condición A), Tr: 5,58 min (pureza de la HPLC: 99,5%).
Ejemplo 413: ácido {(4-dec-1-inilbencil)[4-(trifluorometil)bencil]amino}(oxo)acético, sal de L-arginina
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(4-dec-1-inilbencil)[4(trifluorometil)bencil]amino}(oxo)acético y L-arginina proporcionó el compuesto del título como un polvo blanco. M(LC/MS(ESI)): 472,4. HPLC (Condición A), Tr: 5,55 min (pureza de la HPLC: 99,6%).
Ejemplo 414: {(4-dec-1-inilbencil)[4-(trifluorometil)bencil]-amino}-(oxo)acetato de sodio
El mismo procedimiento utilizado en la preparación del Ejemplo 2 pero utilizando ácido {(4-dec-1-inilbencil)[4(trifluorometil)bencil]amino}(oxo)acético e hidróxido de sodio proporcionó el compuesto del título como un sólido blanco. M-(LC/MS(ESI)): 472,2. HPLC (Condición A), Tr: 5,54 min (pureza de la HPLC: 99,6%).
Ejemplo 415: Preparación de una formulación farmacéutica
Las formulaciones farmacéuticas que utilizan los compuestos de fórmula (I) pueden prepararse de acuerdo con procedimientos convencionales conocidos por los expertos en la técnica.
Los siguientes ejemplos de formulaciones ilustran composiciones farmacéuticas representativas utilizando compuestos de fórmula (I), aunque se subraya que la presente invención no debe interpretarse como limitada a dichas formulaciones, las cuales figuran a continuación.
Un derivado de metilenamida sustituido de fórmula (I) se mezcla como un polvo seco con un aglutinante de gelatina seco en una relación en peso aproximada de 1:2. Se agrega una cantidad menor de estearato de magnesio como un lubricante. La mezcla se forma en comprimidos de 240-270 mg (80-90 mg de derivado de metilenamida sustituido activo por comprimido) en una prensa de comprimidos.
Formulación 2 - Cápsulas
Un derivado de metilenamida sustituido de fórmula (I) se mezcla como un polvo seco con un diluyente de almidón en una relación en peso aproximada de 1:1. La mezcla se coloca en cápsulas de 250 mg (125 mg de derivado de metilenamida sustituido con cápsula).
Formulación 3 - Líquido
Se combinan un derivado de metilenamida sustituido de fórmula (I) (1250 mg), sacarosa (1,75 g) y goma xantano (4 mg), se pasan a través de un tamiz U.S. con malla No. 10 y luego se mezclan con una solución preparada previamente de celulosa microcristalina y carboximetilcelulosa de sodio (11:89, 50 mg) en agua. Se diluyen benzoato de sodio (10 mg), sabor y color con agua y se agregan con agitación. Luego se agrega suficiente agua.
Formulación 4 - Comprimidos
Un derivado de metilenamida sustituido de fórmula (I), se mezcla como un polvo seco con un aglutinante de gelatina seco en un relación en peso aproximada de 1:2. Se agrega una cantidad menor de estearato de magnesio como un lubricante. La mezcla se forma en comprimidos de 300-600 mg (150-300 mg de derivado metilenamida sustituido activo) en una prensa de comprimidos.
Formulación 5 - Inyección
Un derivado de metilenamida sustituido de fórmula (I), se disuelve en un medio acuoso de solución salina estéril tamponada inyectable hasta una concentración de aproximadamente 5 mg/ml.
Ejemplo 416 : Ensayos biológicos
Los compuestos de fórmula (I) pueden someterse a los siguientes ensayos:

(1)

El ensayo enzimático de PTP

(2)

El ensayo in vivo en ratones db/db

The resin-bound dodecylamine (described in step a, 0.0426 mmol) was swollen in DCM (1.0 mL) for 15 min at RT. DIEA (33 mg, 0.256 mmol) and 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] thiophene-2sulfonyl chloride (44 mg, 0.128 mmol) and The resulting reaction mixture was stirred 14 h at RT. The resin was washed successively with NMP (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step c) Phthalimide deprotection of the resin-bound protected amines of formula (VII-1) (See Scheme 5); for example, formation of the resin-bound 5- (aminomethyl) -N-dodecylthiophene-2-sulfonamide
Resin-bonded 5 - [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -N-dodecylpheno-2-sulfonamide (described in step b, 0.0426 mmol) It was treated with a 60% (v / v) solution of hydrazine monohydrate in DMF (1.15 mL) and stirred at RT for 14 h. The resin was washed successively with DMF (1x 15 min), MeOH (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF (3x 10 min), MeOH ( 1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step d) Formation of the resin-bound secondary amines of formula (III-1) (See Scheme 5, Method L), for example 5 - [(benzylamino) methyl] -N-dodecylthiophene-2-sulfonamide resin
The same procedure used in the preparation of Example 50, step d, using benzaldehyde and resin-bound 5 (aminomethyl) -N-dodecylphene-2-sulfonamide (described in step c, 0.0426 mmol) provided the title compound which was used directly in the next stage.
Step e) Formation of the resin-bound oxamic ester of formula (I-1) (See Scheme 1), for example ethyl [benzyl ({5 [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] - (oxo ) resin-bound acetate
The same procedure used in the preparation of Example 28, step d, but using resin-bound 5 - [(benzylamino) methyl] N-dodecylpheno-2-sulfonamide (described in step d, 0.0426 mmol) provided the compound of the title that was used directly in the next stage.
The same procedure used in the preparation of Example 28, step e, but using ethyl [benzyl ({5 [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) -acetate-bound acetate (described in step e, 0.0426 mmol) provided the title compound that was used directly in the next stage.
Step g) Excision of the resin-bound oxamic acid of formula (I-1); Formation of the oxamic acid of formula (I) (See Scheme 1), for example [benzyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} -methyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28, step f, but using resin-bonded [benzyl ({5 [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid (described in step f, 0.0426 mmol) provided the title compound as a white gum (20 mg). M- (LC / MS (ESI)): 521.2; M + (LC / MS (ESI)): 523.0. HPLC (Condition A), Tr: 6.17 min (HPLC purity: 86.2%).
Example 126: [cyclopentyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl] amino] (oxo) acetic acid
Stage a) Formation of the resin-bound 5 - [(cyclopentylamino) methyl] -N-dodecylthiophene-2-sulfonamide
The resin-bound 5- (aminomethyl) -N-dodecylphenophene-2-sulfonamide (Example 125, step c, 0.23 mmol) was swollen in a mixture of 1% HAc in DMF for 15 min at RT. Then cyclopentanone (97 mg, 1.15 mmol) and sodium cyanoborohydride (144 mg, 2.3 mmol) were added and the reaction mixture was stirred 14 h at RT. The resin was washed successively with DMF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Stage b) Formation of ethyl [cyclopentyl ({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate bonded to resin
The same procedure used in the preparation of Example 28, step d but using resin-bound 5 ((cyclopentylamino) methyl] -N-dodecylthiophene-2-sulfonamide provided the title compound that was used directly in the next step.
Step c) Excision of the ethyl [cyclopentyl ({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate bonded to resin; formation of ethyl [cyclopentyl ({5 - [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 28, step f but using ethyl [cyclopentyl ({5 [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate bonded to resin gave a yellow oil. This crude product was purified by column chromatography on silica gel to provide the title compound (11 mg, 10%). M- (LC / MS (ESI)): 527.2; M + (LC / MS (ESI)): 529.4. HPLC (Condition A), Tr: 6.94 min (HPLC purity: 91.0%).
Stage d) Formation of [cyclopentyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1, step e, but using ethyl [cyclopentyl ({5 [(dodecylamino) sulfonyl] thien-2-yl} methyl) amino] (oxo) acetate provided the title compound as a foam colorless (96%). 1H NMR (CD3OD, 300 MHz) δ 7.25 (m, 1H), 7.0 (m, 1H), 4.64 (s, 1H), 4.30 (m, 1H), 2.76 (t , 2H, J = 7.3Hz), 1.81 (m, 2H), 1.79-1.41 (m, 8H), 1.29 (m, 19H), 0.91 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 499.2; M + (LC / MS (ESI)): 501.2. HPLC (Condition A), Tr: 6.09 min (HPLC purity: 78.7%).
Example 127: (({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) {3- [hydroxy (oxide) -amino] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 3-nitrobenzaldehyde in step d provided the title compound as an orange oil (29 mg). M (LC / MS (ESI)): 566.3; M + (LC / MS (ESI)): 568.2. HPLC (Condition A), Tr: 6.23 min (HPLC purity: 61.7%).
Example 128: [({5 - [(dodecylamino) sulfonyl] -2-thienyl) methyl) (4-methoxybenzyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and panisaldehyde in step d provided the title compound as a yellow oil (27 mg). M- (LC / MS (ESI)): 551.2; M + (LC / MS (ESI)): 553.4. HPLC (Condition A), Tr: 6.26 min (HPLC purity: 73.3%).
Example 129: [({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) (2-fluorobenzyl) amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 2-fluorobenzaldehyde in step d provided the title compound as a yellow solid (28 mg). M (LC / MS (ESI)): 539.1; M + (LC / MS (ESI)): 541.2. HPLC (Condition A), Tr: 6.33 min (HPLC purity: 70%).
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 4 (methylsulfonyl) benzaldehyde in step d provided the title compound as a yellow oil (36 mg). M (LC / MS (ESI)): 599.2; M + (LC / MS (ESI)): 601.3. HPLC (Condition A), Tr: 5.81 min (HPLC purity: 69.4%).
Example 131: [({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) (4-phenoxybenzyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 4-phenoxybenzaldehyde in step d provided the title compound as a yellow oil (33 mg). M (LC / MS (ESI)): 613.2; M + (LC / MS (ESI)): 615.0. HPLC (Condition A), Tr: 6.78 min (HPLC purity: 68.5%).
Example 132: 4 - {[(carboxycarbonyl) ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) -amino] methyl} benzoic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and methyl 4-formylbenzoate in step d provided the title compound as a yellow oil (5 mg). M- (LC / MS (ESI)): 565.3; M + (LC / MS (ESI)): 567.3. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 99.9%).
Example 133: (({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) {[6- (trifluoromethyl) -3-pyridinyl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 6 (trifluoromethyl) pyridine-3-carboxaldehyde in step d provided the title compound as an orange oil (30 mg). M- (LC / MS (ESI)): 590.3; M + (LC / MS (ESI)): 592.2. HPLC (Condition A), Tr: 6.25 min (HPLC purity: 61.7%).
Example 134: {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl] [3- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 3 (trifluoromethyl) benzaldehyde in step d provided the title compound as a yellow oil (19 mg). M (LC / MS (ESI)): 589.3; M + (LC / MS (ESI)): 591.3. HPLC (Condition A), Tr: 6.43 min (HPLC purity: 81.5%).
Example 135: [(3-Chlorobenzyl) ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 125 using dodecylamine in step a and 3-chlorobenzaldehyde in step d provided the title compound as a yellow oil (21 mg). M (LC / MS (ESI)): 556; M + (LC / MS (ESI)): 558. HPLC (Condition A), Tr: 6.32 min (HPLC purity: 81.9%).
Example 136: {[(5 - {[(3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) methyl] [3- (trifluoro-methyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 125 using 3,3-diphenyl-propylamine in step a and 3- (trifluoromethyl) benzaldehyde in step d provided the title compound as a yellow oil (17 mg). M (LC / MS (ESI)): 615.3; M + (LC / MS (ESI)): 61,7,3. HPLC (Condition A), Tr: 5.12 min (HPLC purity: 75.7%).
Example 137: {(3-Chlorobenzyl) [(5 - {[(3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) -methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 125 using 3,3-diphenyl-propylamine in step a and 3-chlorobenzaldehyde in step d provided the title compound as a yellow oil (15 mg). M (LC / MS (ESI)): 582.5; M + (LC / MS (ESI)): 585.1. HPLC (Condition A), Tr: 5.01 min (HPLC purity: 72.1%).
Example 138: (oxo) {{[5 - ({[2- (4-phenoxyphenyl) ethyl] amino} sulfonyl) -2-thienyl] methyl} [3- (trifluoromethyl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 125 using 4-phenoxyphenethylamine in step a and 3 (trifluoromethyl) benzaldehyde in step d provided the title compound as a yellow oil (22 mg). M (LC / MS (ESI)): 617.0; M + (LC / MS (ESI)): 619.0. HPLC (Condition A), Tr: 5.15 min (HPLC purity: 77.1%).
Example 139: ((3-Chlorobenzyl) {[5 - ({[2- (4-phenoxyphenyl) ethyl] amino} sulfonyl) -2-thienyl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 125 using 4-phenoxy-phenethylamine in step a and 3-chlorobenzaldehyde in step d provided the title compound as a yellow oil (20 mg). M (LC / MS (ESI)): 584; M + (LC / MS (ESI)): 586. HPLC (Condition A), Tr: 5.0 min (HPLC purity: 79%).
Example 140: {[(5 - {[(2- [1,1'-biphenyl] -4-ylethyl) amino] sulfonyl} -2-thienyl) methyl] [3- (trifluoromethyl) benzyl] amino} (oxo )acetic
The same procedure used in the preparation of Example 125 using 2- (4-biphenyl) -ethylamine in step a and 3- (trifluoromethyl) benzaldehyde in step d provided the title compound as a yellow oil (20 mg). M (LC / MS (ESI)): 601.2; M + (LC / MS (ESI)): 603.0. HPLC (Condition A), Tr: 5.13 min (HPLC purity: 71.4%).
Step a) Formation of tert-butyl 4 - [({4 - [(benzyloxy) carbonyl] benzyl} amino) methyl] -piperidine-1-carboxylate
The same procedure used in the preparation of Example 1, step a but using 4- (aminomethyl) -1-Bocpiperidine gave the title compound as a white solid (8.045 g, 63%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, 2H, J = 8.3 Hz), 7.45-7.30 (m, 7H), 5.35 (s, 2H), 4.10 (m, 2H), 3.83 (s, 2H), 2.67 (t, 2H, J = 12.3 Hz), 2.48 (d, 2H, J = 6.5 Hz), 1.70 (d, 2H, J = 13.4 Hz), 1.59 (m, 1H), 1.43 (s, 9H), 1.16-1.02 (m, 2H). M + (LC / MS (ESI)): 439.6. HPLC (Condition A), Tr: 3.66 min (HPLC purity: 91.9%).
Step b) Formation of tert-butyl 4 - ({{4 - [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] -amino} methyl) piperidine-1-carboxylate
The same procedure used in the preparation of Example 1, step b but using tert-butyl 4 - [({4 [(benzyloxy) carbonyl] benzyl} amino) methyl] piperidine-1-carboxylate provided the title compound as a yellow foam (8.50 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 8.05 (m, 2H), 7.46-7.29 (m, 7H), 5.35 (br s, 2H), 4.67 (s, 1H), 4.52 (s, 1H), 4.39-4.25 (m, 2H), 4.10 (m, 2H), 3.08 (d, 1H, J = 7.1 Hz), 2.61 (m, 2H), 1.90-1.65 (m, 1H), 1.57 (m, 2H), 1.43 (s, 9H), 1.36 (t, 2H, J = 7.1 Hz), 1.20-1.02 (m, 2H). M- (LC / MS (ESI)): 537.8; M + (LC / MS (ESI)): 539.5. HPLC (Condition A), Tr: 5.68 min (HPLC purity: 98.4%).
Step c) Deprotection of tert-butyl 4 - ({{4 - [(benzyloxy) carbonyl] benzyl} - [ethoxy (oxo) -acetyl] amino} methyl) piperidine-1-carboxylate; formation of 4 - ({{[1- (tert-butoxy-carbonyl) piperidin-4-yl] methyl} [ethoxy (oxo) acetyl] -amino} methyl) benzoic acid
The same procedure used in the preparation of Example 1, step c but using tert-butyl 4 - ({{4 [(benzyloxy) carbonyl] benzyl} [ethoxy (oxo) acetyl] amino} methyl) piperidine-1-carboxylate provided the title compound as a white foam (6.80 g, 96%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (m, 2H), 7.37 (m, 2H), 4.70 (s, 1H), 4.55 (s, 1H), 4.40-4 , 20 (m, 2H), 4.09 (m, 2H), 3.40-3.10 (m, 2H), 3.62 (m, 2H), 1.90-1.68 (m, 1H ), 1.59 (m, 2H), 1.43 (s, 9H), 1.30-1.00 (m, 5H). M- (APCI): 447.0. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 98.4%).
Step d) Formation of 4 - {[[ethoxy (oxo) acetyl] (piperidin-4-ylmethyl) amino] methyl} benzoic acid
To a solution of 4 - ({{[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} [ethoxy (oxo) acetiI] -amino} methyl) benzoic acid (5.80 g, 12.93 mmol) in DCM (150 mL) TFA (9.90 mL) was added and the resulting reaction mixture was stirred at RT for 3 h, evaporated in vacuo to give the title compound as a pink oil (7.93 g, 99 , 9%). 1H NMR (DMSO-d6, 300 MHz) δ 8.7 (m, 1H), 8.39 (m, 1H), 7.96 (d, 1H, J = 8.3 Hz), 7.94 (d , 1H, J = 8.3 Hz), 7.39 (d, 1H,
J = 8.3 Hz), 7.37 (d, 1H, J = 8.3 Hz), 4.64 (s, 1H), 4.58 (s, 1H), 4.33 (q, 0, 9H, J = 7.2 Hz), 4.23 (q, 1.1H, J = 7.2 Hz), 3.33-3.22 (m, 2H), 3.18 (d, 1H, J = 7.6 Hz), 3.10 (d, 1H, J = 7.2 Hz), 2.90-2.69 (m, 2H), 1.98 (m, 1H), 1.40-1 , 21 (m, 3H), 1.16 (t, 2H, J = 7.1 Hz). HPLC (Condition A), Tr: 1.87 min (HPLC purity: 98.9%).
Step e) Formation of 4 - {[[ethoxy (oxo) acetyl] ({1 - [(9H-fluoren-9-ylmethoxy) carbonyl] piperidin-4yl} methyl) amino] methyl} benzoic acid
To a solution of 4 - {[[ethoxy (oxo) acetyl] (piperidin-4-ylmethyl) amino] methyl} benzoic acid (7.650 g, 16.54 mmol) in dioxane / H2O (1/1) (120 mL) Fmoc-OSu (6.697 g, 19.85 mmol) and a 1 M aqueous solution of NaHCO3 (10 mL) were added. The resulting reaction mixture was stirred for 1.25 h, then concentrated in vacuo. The oily residue dissolved in DCM (120 mL) was washed with a 1N aqueous solution until pH 1 was reached, dried over MgSO4, filtered and the solvents evaporated in vacuo. This crude product was purified by column chromatography on silica gel (AcOEt / c-Hex 1/4 to 1/1 in about 1 h) to provide the title compound as a white powder (3.755 g, 40%). 1H NMR (CDCl3, 300 MHz) δ 8.1 (m, 2H), 7.75 (d, 2H, J = 7.6 Hz), 7.55 (d, 2H, J = 7.2 Hz), 7.38 (m, 4H), 7.29 (t, 2H, J = 7.3 Hz), 4.70 (s, 1H), 4.56 (s, 1H), 4.45-4.07 (m, 7H), 3.0 (m, 2H), 2.45 (m, 2H), 1.7-1.5 (m, 1H), 1.40 (m, 2H), 1.38 ( t, 1H, J = 7.0 Hz), 1.31-1.21 (m, 3H), 1.0-0.8 (m, 2H). M- (LC / MS (ESI)): 569.4; M + (LC / MS (ESI)): 571.8. HPLC (Condition A), Tr: 4.83 min (HPLC purity: 99.3%).
Stage J) Formation of resin-bound dodecylamine
The same procedure used in the preparation of Example 28, step a, provided the title compound that was used directly in the next step.
Step g) Formation of the 9H-fluoren-9-ylmethyl 4 - ({{4 - [(dodecylamino) -carbonyl] benzyl} ethoxy (oxo) acetyl] amino} methyl) piperidine-1-carboxylate resin
The same procedure used in the preparation of Example 50, step b using 4 - {[[ethoxy (oxo) acetyl] ({1 [(9H-fluoren-9-ylmethoxy) carbonyl] piperidin-4-yl} methyl) - amino] methyl} benzoic and resin-bound dodecylamine provided the title compound.
The same procedure used in the preparation of Example 50, step c using 9H-fluoren-9-ylmethyl 4 - ({{4 [(dodecylamino) carbonyl] benzyl} [ethoxy (oxo) -acetyl] amino} methyl) piperidine- Resin-bonded 1-carboxylate provided the title compound that was used directly in the next step.
Step i) Formation of ethyl (({1 - [(cyclohexylamino) carbonyl] piperidin-4-yl} methyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate bonded to resin
Ethyl [{4 - [(dodecylamino) carbonyl] benzyl} (piperidin-4-ylmethyl) amino] - (oxo) acetate bound resin (described in step h, 0.0426 mmol) was swollen in THF (0, 5 mL) for 15 min at RT. Cyclohexyl isocyanate (18 mg, 0.143 mmol) dissolved in THF (0.9 mL) and TEA (29 mg, 0.282 mmol) was added and the reaction mixture was stirred 14 h at RT. The resin was washed successively with THF (1x 15 min), MeOH (1x 15 min), THF (1x 15 min), MeOH (3x 10 min), DMF (3x 10 min), MeOH (1x 5 min), THF ( 3x 10 min), MeOH (1x 5 min), DCM (3x 10 min) and with Et2O (1x 10 min). The resin was then dried under vacuum to provide the title compound that was used directly in the next step.
Step j) Formation of (({1 - [(cyclohexylamino) carbonyl] -4-piperidinyl} -methyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic resin bonded
The same procedure used in the preparation of Example 28, step e, but using the ethyl (({1 [(cyclohexylamino) carbonyl] piperidin-4-yl} methyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) ( oxo) resin-bound acetate (described in step i, 0.0426 mmol) provided the title compound that was used directly in the next step.
Step k) Formation of (({1 - [(cyclohexylamino) carbonyl] -4-piperidinyl} methyl) {4 - [(dodecylamino) carbonyl] benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28, step f, but using (({1 [(cyclohexylamino) carbonyl] -4-piperidinyl} methyl) {4 - [(dodecyl-amino) carbonyl] benzyl} amino) resin-bound (oxo) acetic acid (described in step j, 0.0426 mmol) provided the title compound as a white solid (23 mg). M- (ESI): 611.4; M + (ESI): 613.4. HPLC (Condition A), Tr: 5.9 min (HPLC purity: 93.1%).
Example 142: ([(1 - {[4- (dimethylamino) anilino] carbonyl} -4-piperidinyl) methyl] {4 - [(dodecylamino) carbonyl] benzyl} amino (oxo) acetic acid
The same procedure used in the preparation of Example 141 using dodecylamine in step f and 4 (dimethylamino) phenyl isocyanate in step i provided the title compound as a brown oil (17 mg). M (ESI): 648.2; M + ESI): 650.4. HPLC (Condition A), Tr: 4.49 min (HPLC purity: 95.9%).
Example 143: {{4 - [(dodecylamino) carbonyl] benzyl}} [(1-hexanoyl-4-piperidinyl) -methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 141 using dodecylamine in step f and hexanoyl chloride in step i provided the title compound as a yellow oil (17 mg). M- (ESI): 584.4; M + (ESI): 586.4. HPLC (Condition A), Tr: 6.06 min (HPLC purity: 83.3%).
Example 144: ({4 - [{dodecylamino) carbonyl] benzyl} {[1- (3-iodobenzoyl) -4-piperidinyl] -methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 141 using dodecylamine in step f and 3-iodobenzoyl chloride in step i provided the title compound as a brown solid (14 mg). M- (ESI): 716.2. HPLC (Condition A), Tr: 6.12 min (HPLC purity: 90.8%).
Example 145: {{4 - [(dodecylamino) carbonyl] benzyl} [(1 - {(2E) -3- [3- (trifluoromethyl) -phenyl] -2-propenoyl} -4-piperidinyl) methyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 141 using dodecylamine in step f and trans-3- (trifluoromethyl) cinnamoyl chloride in step i provided the title compound as a white foam (19 mg). M- (ESI): 684.2; M + (ESI): 686.4. HPLC (Condition A), Tr: 6.28 min (HPLC purity: 95%).
Example 146: ({4 - [(dodecylamino) carbonyl) benzyl} {[1- (2-quinoxalinylcarbonyl) -4-piperidinyl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 141 using dodecylamine in step f and 2-quinoxaloyl chloride in step i provided the title compound as a brown oil (18 mg). M- (ESI): 642.4. HPLC (Condition A), Tr: 5.74 min (HPLC purity: 88.1%).
The same procedure used in the preparation of Example 141 using 4-phenoxybenzylamine in step f and 4-methoxybenzenesulfonyl chloride in step i provided the title compound as a brown foam (33 mg). M- (LC / MS (ESI)): 670.8; M + (LC / MS (ESI)): 672.0. HPLC (Condition A), Tr: 4.67 min (HPLC purity: 92.6%).
Example 148: [{[1- (3-iodobenzoyl) -4-piperidinyl] methyl} (4 - {[(4-phenoxybenzyl) -amino] carbonyl} benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 141 using 4-phenoxybenzyl amine in step f and 3-iodobenzoyl chloride in step i provided the title compound as a brown oil (35 mg). M (LC / MS (ESI)): 730.7; M + (LC / MS (ESI)): 732.4. HPLC (Condition A), Tr: 4.68 min (HPLC purity: 90.9%).
Example 149: oxo {(4 - {[(4-phenoxybenzyl) amino] carbonyl} benzyl) [(1 - {(2E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl} -4piperidinyl) methyl ] amino} acetic
The same procedure used in the preparation of Example 141 using phenoxybenzylamine in step f and trans-3- (trifluoromethyl) cinnamoyl chloride in step i provided the title compound as a brown foam (33 mg). M- (LC / MS (ESI)): 698; M + (LC / MS (ESI)): 700.0. HPLC (Condition A), Tr: 4.95 min (HPLC purity: 89.3%).
Example 150: {{4 - [(dodecylamino) carbonyl] phenyl} [2- (methoxycarbonyl) benzyl] -amino} (oxo) acetic acid
Stage a) Preparation of N-dodecyl-4-nitrobenzamide
A solution of 4-nitro-benzoyl chloride (12.664 g, 68.25 mmol) and DIEA (9.7 g, 75.05 mmol) in anhydrous DCM (200 mL) was added dropwise to a solution of dodecylamine (12,650 g, 68.25 mmol in 50 mL of DCM) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min, then for 1.5 h at RT. The solvents were evaporated and the residue was dissolved in boiling AcOEt, washed with water, a 10% aqueous HCl solution, water, and dried over MgSO4 and filtered. The solvents were evaporated to provide a yellow solid (23.02 g). This residue was washed twice with diethyl ether (50 mL) to provide after evaporation of the solvent the title compound as a light yellow powder (20.31 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (t, 1H, J = 5.5 Hz), 8.30 (d, 2H, J = 9.0 Hz), 8.04 (d, 2H , J = 9.0 Hz), 3.25 (q, 2H, J = 6.3 Hz), 1.43-1.58 (m, 2H), 1.12-1.35 (m, 18H) , 0.83 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 6.55 min (HPLC purity: 93.2%).
Stage b) Preparation of 4-amino-N-dodecylbenzamide
The same procedure used in the preparation of Example 1 (step c) but using N-dodecyl-4-nitrobenzamide and hydrogen at a pressure of 20 bar at 50 ° C gave the title compound (98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (t, 1H, J = 5.6 Hz), 7.53 (d, 2H, J = 8.7 Hz), 6.50 (d, 2H , J = 8.7 Hz), 8.30 (s, 2H), 3.16 (m, 2H), 1.36-1.52 (m, 2H), 1.12-1.33 (m, 18H), 0.83 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 4.87 min (HPLC purity: 99.7%).
Step c) Preparation of methyl 2 - [({4 - [(dodecylamino) carbonyl] phenyl} amino) methyl] -benzoate
To a solution of 4-amino-N-dodecylbenzamide (0.304 g, 1.0 mmol), acetic acid (0.060 g, 1.0 mmol) and methyl 2-formylbenzoate (0.164 g, 1.0 mmol) in ethanol (2 mL) NaBH3CN (0.075 g, 1.20 mmol) was added all at once. The resulting mixture was stirred overnight at RT. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to provide a colorless oil. This crude product was purified by column chromatography on silica gel to provide the title compound as a colorless oil (0.212 g, 47%). M + (LC / MS (ESI)): 453.6. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 100%).
Stage d) Preparation of methyl 2 - ({{4
[(dodecylamino) carbonyl] phenyl} [ethoxy (oxo) acetyl] amino} methyl) benzoate
The same procedure as used for the preparation of Example 1 (step b) but using methyl amine 2 - [({4 - [(dodecylamino) carbonyl] phenyl} amino) methyl] benzoate provided the title compound as an oil yellow (74%). M + (LC / MS (ESI)): 553.3; M- (LC / MS (ESI)): 552.0. HPLC (Condition A), Tr: 6.77 min (HPLC purity: 98.9%).
Step e) Preparation of {{4 - [(dodecylamino) carbonyl] phenyl} [2- (methoxycarbonyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using methyl 2 - ({{4 [(dodecylamino) carbonyl] phenyl} [ethoxy (oxo) acetyl] amino} methyl) benzoate provided the title compound as a colorless oil (91%). M- (LC / MS (ESI)): 527.0; M + (LC / MS (ESI)): 529.0. HPLC (Condition A), Tr: 6.50 min (HPLC purity: 84.2%).
iodobenzyl) amino] (oxo) acetic
Step a) Preparation of methyl-3-bromo-4-methylbenzoate
A mixture of 3-bromo-4-methylbenzoic acid (40 g, 0.186 mol) and SOCl2 (88 g, 0.74 mol) in methanol (600 mL) was refluxed for 12 h. The solvent was distilled off and the crude residue was diluted with ethyl acetate (50 mL). The ethyl acetate layer was washed with a 10% NaHCO3 solution, water, brine and dried. The solvent was removed in vacuo to provide methyl-3-bromo-4-methylbenzoate (40 g, 95%) as a solid.
Stage b) Preparation of 2-bromo-4-methoxycarbonyl benzylbromide
A mixture of methyl-3-bromo-4-methylbenzoate (40 g, 0.17 mol), NBS (34 g, 0.19 mol) and benzoyl peroxide (4.0 g) in CCI4 (500 mL) was subjected at reflux for 6 h. The reaction mixture was cooled and the solid was filtered off. The filtrate was concentrated in vacuo to provide 2-bromo-4-methoxycarbonylbenzyl bromide (50 g, 93%) as a solid.
Step c) Preparation of 3-Bromo-4-aminomethylbenzamide
A mixture of 2-bromo-4-methoxycarbonyl benzylbromide (50 g, 0.162 mol), methanol (500 mL) and liquid ammonia (2.5 L) was stirred at -10 ° C for 24 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (750 mL). The solid precipitate that was obtained was filtered and dried under vacuum to provide 3-bromo-4-aminomethyl benzamide (35 g, 94%).
Stage d) Preparation of 2-Bromo-4-carboxybenzylamine
A mixture of 3-bromo-4-aminomethylbenzamide (35 g, 0.15 mol), methanol (250 mL) and 20% NaOH solution (185 mL) was refluxed for 30 h. The reaction mixture was concentrated, acidified with an aqueous solution of HCl (6N) to provide a solid precipitate. The solid was filtered, washed with water and dried under vacuum to provide 2-bromo-4-carboxybenzylamine (26 g, 74%).
Step e) Preparation of N- (Fmoc) -2-Bromo-4-carboxybenzylamine
To a solution of 2-bromo-4-carboxybenzylamine (20 g, 0.086 mol) in dioxane (250 mL), an aqueous solution of Na2CO3 (10%, 350 mL) was added with stirring. The reaction mixture was cooled to 10 ° C, Fmoc-OSu (32 g, 0.096 mol) was added portionwise and allowed to stir at RT for 8h. The solid precipitate was filtered off and washed with diethyl ether (2 x 200 mL). The solid was acidified with 3N HCl and filtered by suction. The crude solid was recrystallized from methanol / diethyl ether to provide N- (Fmoc) -2-bromo-4-carboxybenzylamine (26 g, 67%) as a solid.
Stage f) Preparation of N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate
Oxalyl chloride (635 mg, 5.0 mmol) was added dropwise to a suspension of 2-bromo-4-carboxybenzylamine (452 mg, 1.0 mmol) in DCM. A catalytic amount of DMF was added and then stirred overnight at room temperature. The solvent was then removed in vacuo to provide the title compound.
Step g) Preparation of [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - (4-iodobenzyl) amino] (oxo) acetic acid
The same procedure as used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate and DIEA in step b 4-iodo-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 697.2
Example 152: [(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4- iodine-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 677.2
Example 153: [{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} (4-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step 4-iodo-benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 685.2
Step a) Preparation of methyl-3,5-dibromo-4-bromomethyl benzoate
A mixture of methyl-3,5-dibromo-4-methylbenzoate (50 g, 0.16 mol), NBS (31.7 g, 0.17 mol) and benzoyl peroxide (5.0 g) in CCl4 (500 mL) was refluxed for 4 h under the illumination of a 200W lamp. The reaction mixture was cooled and the solid was filtered off. The filtrate was concentrated in vacuo to provide methyl-3,5-dibromo-4-bromomethyl benzoate (62 g, 98%) as a solid.
Stage b) Preparation of 3,5-dibromo-4-aminomethylbenzamide
To a solution of methyl-3,5-dibromo-4-bromomethyl benzoate (50 g, 0.129 mol) in methanol (750 mL) at -40 ° C, ammonia (approximately 1 L) was collected by passing ammonia gas. After stirring the reaction mixture at 40 ° C for 24 h, excess ammonia was removed by passing N2 gas at room temperature. The reaction mixture was then concentrated and the residue was diluted with water (1L). The solid precipitate was filtered off and dried by suction. The solid was further dried under vacuum to provide 3,5-dibromo-4-aminomethyl benzamide (40 g, 98%).
Step c) Preparation of 2,6-dibromo-4-carboxy benzylamine
A mixture of 3,5-dibromo-4-aminomethyl benzamide (40 g, 0.129 mol), methanol (500 mL) an aqueous solution of NaOH (10%, 310 mL) was refluxed for 20 h. The reaction mixture was concentrated to 150 mL and cooled to 0 ° C. The solid precipitate obtained was filtered, washed with diethyl ether (500 mL). The solid obtained was acidified with an aqueous solution of HCl (1.5 N, 100 mL) until pH = 6 was reached to provide a precipitated solid. The solid was filtered, washed with water and dried under vacuum to provide 2,6-dibromo-4-carboxy benzylamine (35 g, 87%) as a solid.
Step d) Preparation of N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine
To a solution of 2,6-dibromo-4-carboxybenzylamine (20 g, 0.064 mol) in dioxane (500 mL), an aqueous solution of Na2CO3 (10%, 410 mL) was added with stirring. After stirring at 26 ° C for 15 min Fmoc-OSu (30.5 g, 0.09 mol) was added in portions for 2 h and allowed to stir at room temperature for 24 h. The solid precipitate was filtered off and washed with diethyl ether (3 x 200 mL), followed by methanol (3 x 200 mL). The solid salt was acidified with an aqueous solution of HCl (3 N, 100 mL) until pH = 2 was reached. The precipitate was filtered by suction and dried. The crude solid was recrystallized from methanol / diethyl ether to provide N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (30 g, 87%) as a solid.
Step e) Preparation of [(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (4yodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine in step b and 4-iodo-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 757.2
Example 155: ((4-iodobenzyl) {[4 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1,1'-biphenyl-4-yl] methyl} amino) (oxo) acetic
Stage a) Preparation of tert-butyl-4-bromo benzoate
A mixture of 4-bromobenzoic acid (100 g, 0.5 mol), trifluoromethanesulfonic acid (2.6 mL, 0.03 mol) and isobutylene (1.5 L) in dichloromethane (1.5 L) was stirred at RT in a closed autoclave for 5 days. The organic layer was washed with an aqueous solution of NaHCO3 (10%), water, brine, dried and concentrated to provide tert-butyl-4-bromobenzoate (90 g, 71%).
Stage b) Preparation of tert-butyl-4- (4-tolyl) benzoate
To a mixture of tert-butyl-4-bromobenzoate (40 g, 0.15 mol), 4-tolylboronic acid (23.3 g, 0.17 mol) and sodium carbonate (150 g) in toluene (350 mL) and water (350 mL) tetrakis (triphenylphosphine) palladium (0) (8.7 g, 0.007 mol) was added and the reaction mixture was refluxed for 10 h under nitrogen atmosphere. The organic layer was separated, washed with water, dried and concentrated to provide tert-butyl-4- (4-tolyl) benzoate (32 g, 77%).
Step c) Preparation of 4- (4-tert-butoxycarbonyl phenyl) benzyl bromide
To a solution of tert-butyl-4- (4-tolyl) benzoate (32 g, 0.12 mol) in carbon tetrachloride (500 mL) was added Nbromosuccinimide (23.3 g, 0.13 mol) and peroxide of benzoyl (4.0 g). The reaction mixture was refluxed for 10 h. After cooling to RT, the reaction mixture was filtered. The filtrate was concentrated and the crude was recrystallized from petroleum ether to provide 4- (4-tert-butoxycarbonylphenyl) benzyl bromide (26 g, 69%).
A solution of 4- (4-tert-butoxycarbonyl) benzyl bromide (25 g, 0.071 mol) in methanol (2 L), cooled to -20 ° C, was passed through the reaction mixture ammonia for 5 h. The reaction mixture was stirred at RT for 30 h. The methanol was removed in vacuo. To the residue was added a solution of HCl (6N, 200 mL) and stirred at RT overnight. The solvents were evaporated in vacuo and the resulting residue was washed with diethyl ether to provide 4- (4-carboxyphenyl) benzylamine hydrochloride (10 g, 53%).
Step e) Preparation of N-Fmoc-4- (4-carboxyphenyl) benzylamine
4- (4-Carboxyphenyl) benzylamine hydrochloride (10 g, 0.038 mol) was placed in a mixture of 10% Na2CO3 (100 mL) and dioxane (25 mL). To this was added a solution of Fmoc-OSu (15.4 g, 0.045 mol) in dioxane (50 mL) at 10 ° C and the reaction stirred at RT for 4 h. The solvent was removed under reduced pressure and the residue was acidified with an aqueous HCl solution (1.5 N), extracted with EtOAc and the crude product was recrystallized from EtOAc to provide N-Fmoc-4- (4-carboxyphenyl). ) benzylamine (8.5 g, 45%).
Step f) Preparation of ((4-iodobenzyl) {[4 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1,1'-biphenyl-4-yl] methyl} amino) (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine in step b and 4-iodo-benzaldehyde in step d gave the title compound . M + (LC / MS (ESI)): 711.3
Example 156: {[2-Bromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] [(4'-fluoro-1,1'-biphenyl-3yl) methyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamino in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3- (4fluorophenyl) ) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 681.3
Example 157: {[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] [(4'-fluoro-1,1'-biphenyl- 3il) methyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 3- (4fluorophenyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 665.3
Example 158: {(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [(4'-fluoro-1,1'-biphenyl-3yl) methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3- (4fluorophenyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 645.3
Example 159: {[2,6-dibromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] [4'-fluoro-1,1'-biphenyl-3yl) methyl] amino } (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (4-fluorophenyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 761.3
Example 160: {[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] [4'-fluoro-1,1'-biphenyl -3il) methyl] amino} (oxo) acetic
The same procedure that was used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b 3- (4-fluorophenyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 745.2
Example 161: {(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [(4'-fluoro-1,1'-biphenyl-3yl) methyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (4- fluorophenyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 725.3
Example 162: {{2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [(4'-fluoro-1,1'-biphenyl-3-yl) methyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (4-fluorophenyl) benzaldehyde in the step d Example 163: ([(4'-fluoro-1,1'-biphenyl-3-yl) methyl] {[4 '- ({[2- (4-phenoxyphenyl) ethyl] -amino} carbonyl) - 1,1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 4'-fluoro-biphenyl-3-carbaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 679.4
Example 164: {({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) [(4'-fluoro-1,1'-biphenyl-3yl) methyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 4'-fluoro-biphenyl-3-carbaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 651.5
Example 165: {(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [2- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 2 ( trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 635.3
Example 166: {(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [2 (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 2- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 713.3
Example 167: oxo {{[4 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1,1'-biphenyl-4-yl] methyl} [2 (trifluoromethoxy) benzyl] amino} acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 2- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 669.3
Example 168: {({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) [2-trifluoro-methoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 2- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 641.3
Example 169: [[2-Bromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3-phenoxy- benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 679.3
Example 170: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 663.3
Example 171: [(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (3-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3- Phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 643.3
Example 172: [[2,6-dibromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3-phenoxy-benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 759.2
Example 173: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- phenoxy-benzaldehyde in stage d
provided the title compound. M + (LC / MS (ESI)): 743.3 Example 174: [(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (3-phenoxybenzyl) amino] (oxo) acid acetic The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a,
N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 723.3
Example 175: [{2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} (3-phenoxybenzyl) -amino] (oxo) acetic acid The same procedure used in the preparation of Example 50 but using dodecylamine in the step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 731.3
Example 176: oxo ((3-phenoxybenzyl) {[4 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1,1'-biphenyl-4-yl] methyl} amino) acetic acid same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a,
N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 677.4 Example 177: oxo [[(4 '- {[(4-pentylbenzyl) amino] carbonyl} -1,1'-biphenyl-4-yl) methyl] ( 3-phenoxybenzyl) amino] acetic The same procedure as was used in the preparation of Example 50 using 4-pentyl-benzylamine in step a,
N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 64
Example 178: [({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) (3-phenoxybenzyl) amino] (oxo) acetic acid The same procedure used in the preparation of Example 50 using dodecylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 3-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 649.4
179: [[2-Bromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (2-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 2-iodine- benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 713.0
Example 180: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (2-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 2-iodo-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 697.0
Example 181: [(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (2-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 2- iodine-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 677.0
Example 182: [{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} (2-iodobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b-2-iodo-benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 685.1
Example 183: ([2-Bromo-4 - ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] {[2 '- (trifluoromethyl) -1,1'-biphenyl-4-yl] methyl} amino (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step 2'-trifluoromethyl -biphenyl-4carbaldehyde in step a provided the title compound. M + (LC / MS (ESI)): 731.2
Example 184: ([4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] {[2 '- (trifluoromethyl) -1,1'- biphenyl-4-yl] methyl} amino) (oxo) acetic
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 2'-trifluoromethyl-biphenyl Example 185: ((2-bromo-4 - {[(pentylbenzyl) amino] carbonyl} benzyl) {[2 '- (trifluoromethyl) -1,1'-biphenyl-4yl] methyl} amino ) (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step 2 ' -trifluoromethyl-biphenyl-4-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 695.2
Example 186: ({2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} {[2 '- (trifluoromethyl) -1,1'-biphenyl-4yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 2'-trifluoromethyl-biphenyl- 4carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 703.3
Example 187: ([4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] {[2 '- (trifluoromethyl) -1,1 '-biphenyl-4-yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step 2 ' -trifluoromethyl-biphenyl-4-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 793.1
Example 188: ((2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) {[2 '- (trifluoromethyl) -1,1'-biphenyl-4yl] methyl} amino) ( oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 2'-trifluoromethyl- Biphenyl-4-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 773.2
Example 189: ({2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} {[2 '- (trifluoromethyl) -1,1'-biphenyl-4yl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 2'-trifluoromethyl-biphenyl-4-carbaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 781.2
Example 190: (({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) {[2' - (trifluoromethyl) -1,1'-biphenyl-4yl] methyl} amino) (oxo) acetic
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 2'-trifluoromethyl-biphenyl-4-carbaldehyde in the stage d provided the title compound.
M + (LC / MS (ESI)): 701.5
Example 191: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (1,1'-biphenyl-2-ylmethyl) amino] (oxo) acetic
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by biphenyl-2-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 647.3
Example 192: [(1,1'-biphenyl-2-ylmethyl) (2-bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} -benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by biphenyl- 2-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 627.3
Example 193: ((1,1'-biphenyl-2-ylmethyl) {2-bromo-4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by biphenyl-2-carbaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 635.4
Example 194: {(1,1'-biphenyl-2-ylmethyl) [2,6-dibromo-4 - ({[2- (4-phenoxyphenyl) ethyl] -amino} carbonyl) benzyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step by biphenyl-2-carbaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 741.2
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in the step by biphenyl- 2-carbaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 725.2
Example 196: [(1,1'-biphenyl-ylmethyl) (2,6-dibromo-4 - {[(4-pentylbenzyl) amino] -carbonyl} benzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in the step by biphenyl-2-carbaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 705.3
Example 197: ((1,1'-biphenyl-2-ylmethyl) {2,6-dibromo-4 - [(dodecylamino) carbonyl] -benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step by biphenyl-2-carbaldehyde in step d provided The title compound. M + (LC / MS (ESI)): 713.3
Example 198: {(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoro-methoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4 ( trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 635.2
Example 199: {{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethoxy) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4 (trifluoromethoxy) benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 643.3
Example 200: {(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [4 (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 4- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 714.3
Example 201: {(2-Bromo-4 - {[(- 4-pentylbenzyl) amino] carbonyl} benzyl) [3- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3 ( trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 635.2
Example 202: {{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3 (trifluoromethoxy) benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 634.3
Example 203: {(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [3- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 715.2
Example 204: {{2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 723.3
Example 205: {({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) [3- (trifluoromethoxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 3- (trifluoromethoxy) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 641.4
The same procedure used in the preparation of Example 50 but using 4-phenoxyphenethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4-phenoxy- benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 679.3
Example 207: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 4-phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 663.3
Example 208: [(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4- Phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 643.3
Example 209: [{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step 4-phenoxy-benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 651.3
Example 210: [[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 4- Phenoxy-benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 743.3
Example 211: [(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-phenoxybenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step 4-phenoxy-benzaldehyde in step d he provided the title compound. M + (LC / MS (ESI)): 723.2
Example 212: {[4 - ({[2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 2- (4-biphenyl) ethylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step by 4 (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 639.2
Example 213: {(2-Bromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4 ( trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 619.3
Example 214: {{2-Bromo-4- [dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 4 (trifluoromethyl) benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 627.3
Example 215: {(2,6-dibromo-4 - {[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N- (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 699.2
Example 216: {{2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 4- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 707.3
The same procedure used in the preparation of Example 50 but using 4-pentyl-benzylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 4- (trifluoromethyl) benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 617.4
Example 218: {{2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2-bromo-4- (chlorocarbonyl) benzylcarbamate (Example 151) and DIEA in step b and 3 (trifluoromethyl) benzaldehyde in the stage d provided the title compound. M + (LC / MS (ESI)): 627.3
Example 219: {{2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 50 but using dodecylamine in step a, N (Fmoc) -2,6-dibromo-4-carboxybenzylamine (Example 154) in step b and 3- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 707.3
Example 220: oxo {[(4 '- {[(4-pentylbenzyl) amino] carbonyl} -1,1'-biphenyl-4-yl) methyl] [3 (trifluoromethyl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 50 using 4-pentyl-benzylamine in step a, N-Fmoc-4- (4-carboxyphenyl) benzylamine (Example 155) in step b and 3- (trifluoromethyl) benzaldehyde in step d provided the title compound. M + (LC / MS (ESI)): 617.4
Example 221: {(4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Preparation of 4-dibenzo [b, d] furan-4-ylbenzonitrile
To a mixture of dibenzofuran-4-boronic acid (40 g, 0.19 mol), 4-bromobenzonitrile (34 g, 0.19 mol), sodium carbonate (120 g) in toluene (500 mL) and water (500 mL) tetrakis (triphenylphosphine) palladium (0) (11 g, 0.0095 mol) was added with stirring under N2 atmosphere. The reaction mixture was refluxed for 20 h. The toluene layer was separated, washed with water, dried and concentrated. The crude product was purified by column chromatography on silica gel (chloroform) to give the title compound (40 g, 79%).
Stage b) Preparation of 1- (4-dibenzo [b, d] furan-4-ylphenyl) methanamine
To a solution of 4- (4-cyanophenyl) dibenzofuran (20 g, 0.074 mol) in isopropyl alcohol (1.5 L) Raney nickel (10 g) was added with stirring. The reaction mixture was heated to reflux, treated with hydrazine hydrate (100 mL) and refluxed for 6 h. The reaction mixture was cooled, filtered through celite and washed with isopropyl alcohol. The filtrate was concentrated and the crude product was purified by silica gel column chromatography (CHCl3 / MeOH; 9: 1) to give the title compound as a solid (6.5 g, 32%). 1H NMR (THF-d8, 300 MHz) δ 7.30-8.30 (m, 13H), 3.98 (s, 2H)
Step c) Preparation of N- (4-dibenzo [b, d] furan-4-ylbenzyl) -N- [4- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 1 (step a) using 1- (4-dibenzo [b, d] furan-4-phenyl) methanamine and 4- (trifluoromethyl) benzaldehyde provided the title compound (51%). M + (LC / MS (ESI)): 432.4. HPLC (Condition A), Tr: 4.28 min (HPLC purity: 97.9%). 1H NMR (CDCl3, 300 MHz) δ 7.75-8.00 (m, 5H), 7.35-7.61 (m, 11H), 3.93 (s, 2H), 3.90 (s, 2H)
Step c) Preparation of ethyl {(4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 1 (step b) using N- (4-dibenzo [b, d] furan-4-benzyl) -N- [4- (trifluoromethyl) benzyl] amine provided the title compound (98% ). M + (LC / MS (ESI)): 531.6. HPLC (Condition A), Tr: 6.38 min (HPLC purity: 100%). 1H NMR (CDCl3, 300 MHz) δ 7.85-8.05 (m, 4H), 7.55-7.72 (m, 4H), 7.55-7.30 (m, 7H), 4, 30-4.67 (m, 6H), 1.25-1.45 (m, 3H)
Step d) Preparation of {(4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) using {(4-dibenzo [b, d] furan-4-benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound (90 %). M- (LC / MS (ESI)): 502.0. HPLC (Condition A), Tr: 5.95 min (HPLC purity: 98.5%). 1H NMR (CD3OD, 300 MHz) δ 7.90-8.05 (m, 2H), 7.75-7.90 (m, 2H), 7.25-7.90 (m, 11H), 4, 59 (s, 2H), 4.56 (s, 2H)
Example 222: {(4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy- 1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 using {(4-dibenzo [b, d] furan-4-ylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white fluffy solid (95%). M + (APCI): 562.6. HPLC (Condition A), Tr: 5.98 min (HPLC purity: 98.3%). Analysis calculated for C29H19F3NO4.C7H18NO5 = 1.1 H2O: C, 60.18; H, 5.50; N, 3.90%. Found: C, 60.12; H, 5.56; N, 3.82%
Example 223: ((4 - [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} -amino (oxo) acetic acid
Stage a) Formation of 4- (aminomethyl) -N-dodecylbenzamide
At 0 ° C, to a solution of 4 - {[(tert-butoxycarbonyl) amino] methyl} benzoic acid (2.0 g) and NMM (1.02 g, 1.11 mL) in anhydrous THF (50 mL) was added drip isobutyl chloroformate (1.2 mL). After stirring for 20 min, dodecylamine (1,875 g) was added dropwise. After 1h the ice-water bath was removed and the mixture was stirred for 14 h at RT. A 1N aqueous solution of HCl (50 mL) was added and the mixture was extracted with AcOEt (2 x 50 mL). The combined organic layers were washed with water (150 mL), dried over MgSO4 and removed by evaporation to provide an oil (3.61 g). This crude product was purified by flash chromatography on silica gel (c-Hex / AcOEt 2/1) to provide tert-butyl 4 - [(dodecylamino) carbonyl] benzylcarbamate as a colorless oil (2.35 g, 70%). M + (LC / MS (ESI)): 419.5; M- (LC / MS (ESI)): 418.5. HPLC (Condition A), Tr: 6.35 min (HPLC purity: 99.6%).
To a solution of tert-butyl 4 - [(dodecylamino) carbonyl] benzylcarbamate (2.35 g) in DCM (30 mL) was added a solution of HCl (4N in dioxane, 30 mL). The resulting mixture was stirred at RT for 1 h. Evaporation of the solvents provided the 4- (aminomethyl) -N-dodecylbenzamide hydrochloride compound as a white powder (1.97 g, 98%). M + (LC / MS (ESI)): 319.4; M- (LC / MS (ESI)): 317.4. HPLC (Condition A), Tr: 4.20 min (HPLC purity: 100%). 1H NMR (DMSO-d6, 300 MHz) δ 8.52 (br s, 3H), 7.87 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 4.06 (br s, 2H), 3.25-3.30 (m, 2H), 1.45-1.55 (m, 2H), 1.30-1.56 (m, 18H ), 0.84 (t, J = 8.3 Hz, 3H).
A suspension of 4- (aminomethyl) -N-dodecylbenzamide hydrochloride (1.97 g) in AcOEt (100 mL) was washed with a saturated aqueous solution of NaHCO3 (50 mL). The organic layer was dried over MgSO4 and evaporated to give the title compound as a white solid (1.6 g).
Stage b) Formation of N-dodecyl-4 - [({1- [4- (trifluoromethyl) phenyl] ethyl} amino) methyl] benzamide
At 0 ° C, to a solution of 4- (aminometiI) -N-dodecylbenzamide (0.955 g) and 4-trifluoro acetophenone (0.564 g) in THF (20 mL), titanium tetraisopropoxide (1.065 g) was added. The resulting mixture was stirred for 1 h at RT. MeOH (4 mL) was added and the reaction mixture was cooled to 0 ° C. Then NaBH4 (0.227 g) (rapid gas evolution) was added portionwise. After 1 h at RT, a 1N aqueous solution of NaOH was added and the resulting reaction mixture was extracted with AcOEt (3 x 50 mL). The combined organic layers were dried over MgSO4 and evaporated to provide a white solid (1,523 g). Purification by flash chromatography on silica gel (40/60 AcOEt / c-Hex) provided the title compound as a white solid (1.001 g, 68%). M- (APCI): 491.2. HPLC (Condition A), Tr: 5.12 min (HPLC purity: 96.6%). 1H NMR (CDCl3, 300 MHz) δ 7.107.71 (m, 8H), 4.93 (br s, 1H), 3.90-3.96 (m, 1H), 3.70 (br s, 1H) , 3.42 (s, 2H), 3.32 (s, 2H), 1.42-1.55 (m, 2H), 1,101.43 (m, 21H), 0.86 (m, 3H)
Step c) Formation of ethyl ({4 - [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetate
The same procedure as used for the preparation of Example 1 (step b) using N-dodecyl-4 - [({1- [4 (trifluoromethyl) phenyl] ethyl} amino) methyl] benzamide provided the title compound as a colorless oil (80%). 1H NMR (CDCl3, 300 MHz) δ 7.55-7.64 (m, 4H), 7.38 (m, 2H), 7.13 (m, 2H), 5.81-6.00 (m, 1H), 4.30-4.75 (m, 2H), 3.41 (m, 2H), 1.41-1.70 (m, 6H), 1.10-1.40 (m, 19H) , 0.86 (m, 3H).
Step d) Formation of ({4 - [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl ({4 [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetate provided the compound of title as a colorless oil (95%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24-8.41 (m, 1H), 7.78-8.28 (m, 8H), 7.15 (q, 0.4H, J = 5 , 5 Hz), 5.13 (q, 0.6H, J = 6.9 Hz), 4.38-4.65 (m, 1.4H), 4.10-4.22 (m, 0, 6H), 3.08-3.27 (m, 2H), 1.37-1.60 (m, 5H), 1.10-1.35 (m, 18H), 0.84 (t, 3H, J = 6.7 Hz). M- (LC / MS (ESI)): 560.9; M + (LC / MS (ESI)): 562.9 HPLC (Condition A), Tr: 6.36 min (HPLC purity: 99.6%). Analysis calculated for C31H40F3N2O4 = 0.1 H2O: C, 65.96; H, 7.36; N, 4.96%. Found: C, 65.92; H, 7.41; N, 4.89%
Example 224: ({4 - [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} -amino) - (oxo) acetic acid, Nmethyl-D-glucamine salt (ie 1- deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 using ({4 [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white powder (95%). M- (LC / MS (ESI)): 560.9; M + (LC / MS (ESI)): 562.9. HPLC (Condition A), Tr: 6.38 min (HPLC purity: 99.8%). Analysis calculated for C31H40F3N2O4.C7H18NO5 = 0.7 H2O: C, 59.24; H, 7.77; N, 5.45%. Found: C, 59.36; H, 7.90; N, 5.43%
methyl) benzyl] amino} (oxo) acetic
Stage a) Preparation of tert-butyl-4-bromobenzoate
To a stirred solution of 4-bromobenzoic acid (100 g, 0.5 mol) in dry CH2C12 (1.5 L) was added silver carbonate (275 g, 1 mol) and molecular sieves (4A, 100 g). The reaction mixture was cooled to 0 ° C and then tert-butyl bromide (115 mL) was added dropwise over a period of 45 min. The reaction mixture was allowed to stir at RT for 20 h and the solid was filtered off. The filtrate was washed with an aqueous solution of NaHCO3 (10%), water, brine and dried. The solvent was removed in vacuo to the title compound (100 g, 79%) as a colorless liquid.
Step b) Preparation of tert-butyl 4'-methyl-1,1'-biphenyl-4-carboxylate
To a solution of tert-butyl-4-bromobenzoate (48 g, 0.186 mol), 4-tolylbenzeneboronic acid (25.3 g, 0.186 mol), Na2CO3 (200 g in 500 mL of water) in toluene (750 mL ) under N2 Pd (PPh3) 4 (10.7 g, 0.009 mol) was added and the reaction mixture was refluxed for 10 h. After cooling to RT, the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined layer was washed with brine and concentrated. The crude product was purified by silica gel column chromatography (pet./ethyl acetate ether, 4: 1) to provide tert-butyl-4- (4-tolyl) benzoate (40g, 80%) as a solid.
Step c) Preparation of tert-butyl 4 '- (bromomethyl) -1,1'-biphenyl-4-carboxylate
A mixture of tert-butyl 4'-methyl-1,1'-biphenyl-4-carboxylate (40.0 g, 0.15 mol), NBS (32.0 g, 0.18 mol) and benzoylperoxide (5, 0 g) in CCl4 (600 mL) was heated to reflux for 6 h under N2. After cooling to RT, the solid was filtered and concentrated in vacuo to provide a crude product. The crude solid was washed with Pet / chloroform ether to provide the title compound as a solid (40 g, 78%).
Step d) Preparation of tert-butyl 4 '- (aminomethyl) -1,1'-biphenyl-4-carboxylate
A solution of tert-butyl 4 '- (bromomethyl) -1,1'-biphenyl-4-carboxylate (35.0 g) in methanol (1 L) at -30 ° C was purged with ammonia gas for 2 h. The reaction mixture was then allowed to stir at 0 ° C for 30 h. The solid precipitate was removed by filtration, washed with water (2x 1 L), dried by suction. The solid was recrystallized from methanol to the title compound as a white solid (20 g, 71%).
Step e) Formation of tert-butyl 4 '- ({[4- (trifluoromethyl) benzyl] amino} methyl) -1,1-biphenyl-4-carboxylate
To a solution of tert-butyl 4 '- (aminomethyl) -1,1'-biphenyl-4-carboxylate (2.0 g) and 4- (trifluoromethyl) -benzaldehyde (0.88 mL) in DCE (40 mL) sodium triacetoxyborohydride (1.904 g) was added at once. The resulting mixture was stirred for 14 h at RT. Water (50 mL) was added and the mixture was extracted with DCM (3x). The combined organic layers were washed with water (50 mL), then dried over MgSO4, removed by evaporation to provide a yellow oil. This crude product was purified by flash chromatography (c-Hex / AcOEt 4/1) to provide the title compound as a white powder (1.30 g, 43%). M + (LC / MS (ESI)): 442.02 HPLC (Condition A), Tr: 4.25 min (HPLC purity: 93.7%). 1H NMR (DMSO, 300 MHz): δ 7.97 (d, 2H, J = 7.9 Hz), 7.80 (d, 2H, J = 7.9 Hz), 7.69 (d, 2H, J = 8.3 Hz), 7.60 (d, 2H, J = 7.9 Hz), 7.48 (d, 2H, J = 7.9 Hz), 3.79 (s, 2H), 3 , 74 (s, 2H), 1.56 (s, 9H).
Step f) Formation of tert-butyl 4 '- ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} -methyl) -1,1'-biphenyl-4-carboxylate
To a solution of tert-butyl 4 '- ({[4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl-4-carboxylate (1.29 g) and triethylamine (0.81 mL) in Cold anhydrous DCM (40 mL) was added dropwise a solution of ethyl oxalyl chloride (0.49 mL, in anhydrous DCM (2 mL)). The resulting mixture was stirred for 2h then water was added. After extraction with DCM (3x 50 mL), the combined organic layers were washed with water (3x 30 mL), dried over MgSO4 and evaporated to provide a yellow oil (1.44 g). This crude product was purified by flash chromatography on silica gel (c-Hex / AcOEt 6/1 then 4/1) to provide the title compound as yellow oil (1.38 g, 79%). M + (LC / MS (ESI)): 542.0; M- (LC / MS (ESI)): 540.8. HPLC (Condition A), Tr: 6.67 min (HPLC purity: 90.9%)
Step g) Formation of 4 '- ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl-4-carboxylic acid
To a solution of tert-butyl 4 '- ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl-4-carboxylate (1.37 g) in DCM (15 mL) TFA (15 mL) was added. The resulting mixture was stirred for 30 min. Evaporation of the solvents gave the title compound as a colorless oil (1.10 g, 67%). M + (LC / MS (ESI)): 486.1; M (LC / MS (ESI)): 484.6. HPLC (Condition A), Tr: 4.13 min (HPLC purity: 91.7%)
1H NMR (DMSO, 300 MHz) δ 7.94 (d, 2H, J = 7.9 Hz), 7.72-7.61 (m, 6H), 7.42 (d, 1H, J = 7, 9 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.25 (d, 1H, J = 8.3 Hz), 4.49 (m, 4H), 4.20 (m , 2H), 1.10 (m, 3H).
To a solution of 4 '- ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl-4-carboxylic acid (100 mg), EDC (47 mg) and HOBt (28 mg) in DCM (4 mL) octylamine (0.041 mL) was added. The resulting reaction mixture was stirred for 3h. DCM (15 mL) and an aqueous solution of HCl (1N, 10 mL) were added. The aqueous layer was extracted with DCM (3x15 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (15 mL) and dried over MgSO4. Evaporation of the solvents provided an oil that was purified by flash chromatography on silica gel (c-Hex / AcOEt 2/1) to provide the title compound as a colorless oil (41 mg, 33%). M + (LC / MS (ESI)): 597.8; M- (LC / MS (ESI)): 595.0. HPLC (Condition A), Tr: 6.61 min (HPLC purity: 99.87%)
Step i) Formation of {({4 '- [(octylamino) carbonyl] -1,1'-biphenyl-4-yl) methyl) [4- (trifluoromethyl) benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl {({4 '- [(octylamino) carbonyl] 1,1'-biphenyl-4-yl} methyl) [4- (trifluoromethyl) benzyl] amino } (oxo) acetate provided the title compound as a colorless oil (77%). M + (LC / MS (ESI)): 570.5; M- (LC / MS (ESI)): 567.5. HPLC (Condition A), Tr: 5.70 min
(HPLC purity: 97.7%). 1H NMR (CDCl3, 300 MHz) δ 7.72-7.17 (m, 12H), 6.45-6.26 (m,
1H), 4.47 (s, 4H), 3.41 (s, 2H), 1.56-1.18 (m, 12H), 0.81 (m, 3H).
Example 226: oxo ((4-tetradec-1-inyl] benzyl) [4- (trifluoromethyl) benzyl] amino] acetic acid
Stage a) Formation of N- (4-bromobenzyl) -N- [4- (trifluoromethyl) benzyl] amine hydrochloride
A solution of 4-bromobenzaldehyde (5.81 g, 31.4 mmol) and 4- (trifluoromethyl) -benzylamine (5.00 g, 28.6 mmol) in toluene (100 mL) was heated at reflux for 75 min with azeotropic water removal. The toluene was evaporated under reduced pressure. The residue was taken up in methanol (100 mL) and cooled to 0 ° C. NaBH4 (2.16 g, 57.1 mmol) was added portionwise and the reaction mixture was stirred at 0 ° C for 1.5h. The reaction mixture was poured into water (200 mL) / brine (200 mL) and extracted with Et2O (500 mL and 200 mL). The organic layers were washed with brine, combined and dried over MgSO4. The solvent was removed under reduced pressure. The residue was diluted with Et2O (200 mL) and HCl (1N in Et2O, 40 mL) was added. A white solid precipitated. Filtration, washing with Et2O (3x20 mL) and drying under vacuum at 50 ° C for 18 hrs gave the title compound as a white solid (9.74 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 9.77 (s, 2H), 7.82 (d, 2H, J = 8.5 Hz), 7.76 (d, 2H, J = 8.5 Hz ), 7.64 (d, 2H, J = 8.3 Hz), 7.51 (d, 2H, J = 8.3 Hz), 4.25 (s, 2H), 4.17 (s, 2H ). M + (LC / MS (ESI)): 344.1. HPLC (Condition A), Tr: 3.16 min (HPLC purity: 99.7%).
Stage b) Formation of ethyl {(4-bromobenzyl) [4- (trifluoromethyl) benzyl] amino) (oxo) acetate
The same procedure as used for the preparation of Example 1 (step b) using N- (4-bromobenzyl) N- [4- (trifluoromethyl) benzyl] amine provided the title compound as a white solid (83%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.51 (m, 2H), 7.40 (d, 1H, J = 7.9 Hz), 7.34 (d, 1H , J = 7.9 Hz), 7.16 (d, 1H, J = 8.3 Hz), 7.11 (d, 1H, J = 8.3 Hz), 4.55 (s, 1H), 4.47 (s, 1H), 4.41-4.32 (m, 4H), 1.36 (m, 3H). M + (LC / MS (ESI)): 444.0, M (LC / MS (ESI)): 442.1. HPLC (Condition A), Tr: 5.99 min (HPLC purity: 99.1%).
Step c) Formation of ethyl oxo {(4-tetradec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} acetate
A mixture of ethyl {(4-bromobenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate (100 mg, 0.23 mmol), 1-tetradecin (66 mg, 0.34 mmol), copper bromide (I) (4.5 mg, 0.031 mmol) and tetrakis (triphenylphosphine) palladium (11 mg, 0.0095 mmol) in Et3N (1 mL) was heated at 90 ° C for 75 min. After cooling to RT, the reaction mixture was diluted with an aqueous HCl solution (1N, 10 mL) and extracted with Et2O (2 x 20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (cyclohex./Et2O 4: 1) to provide the title compound as a yellow oil (63 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.33 (m, 4H), 7.14 (m, 2H), 4.51 (s, 1H), 4.47 (s , 1H), 4.34 (m, 4H), 2.40 (m, 2H), 1.58-1.26 (m, 23H), 0.88 (m, 3H). HPLC (Condition A), Tr: 8.21 min (HPLC purity: 99.3%).
Step d) Formation of oxo {(4-tetradec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] -amino} -acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl oxo {(4-tetradec-1inylbenzyl) [4- (trifluoromethyl) benzyl] amino} acetate provided the title compound as a light yellow oil (77%) . 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.34 (m, 4H), 7.12 (m, 2H), 5.01 (s, 1H), 4.95 (s , 1H), 4.57 (s, 1H), 4.53 (s, 1H), 2.38 (m, 2H), 1.57 (m, 2H), 1.41 (m, 2H), 1 , 24 (brs, 16H), 0.86 (m, 3H). MT (LC / MS (ESI)): 528.0. HPLC (Condition A), Tr: 7.85 min (HPLC purity: 98%).
Stage a) Formation of ethyl {(4-dodec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) using 1-dodecin provided the title compound as a light yellow oil (21%). 1H NMR (CDCl3, 300 MHz) δ 7.58 (m, 2H), 7.32 (m, 4H), 7.13 (d, 1H, J = 8.2 Hz), 7.09 (d, 1H , J = 8.1 Hz), 4.48 (s, 1H), 4.44 (s, 1H), 4.31 (m, 4H), 2.38 (dt, 2H, J = 7.0, 1.3 Hz), 1.57 (m, 2H), 1.41 (m, 2H), 1.33-1.24 (m, 15H), 0.85 (t, 3H, J = 6.7 Hz) HPLC (Condition A), Tr: 7.87 min (HPLC purity: 99.9%).
Step b) Preparation of {(4-dodec-1-inylbenzyl) [4- (trifluoroomethyl) benzyl] amino} (oxo) -acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl {(4-dodec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a light yellow oil ( 95%) 1H NMR (CDCl3, 300 MHz) δ 8.78 (brs, 1H), 7.53 (m, 2H), 7.28 (m, 4H), 7.08 (m, 2H), 4.81 (brs , 1H), 4.74 (brs, 1H), 4.47 (m, 2H), 2.36 (m, 2H), 1.57 (m, 2H), 1.41 (m, 2H), 1 , 25 (brs, 12H), 0.86 (t, 3H, J = 7.0). M- (LC / MS (ESI)): 499.9. HPLC (Condition A), Tr: 7.36 min (HPLC purity: 99.3%).
Example 228: {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} - (oxo) acetic acid
Step a) Preparation of N-dodecyl-4 - ({[4- (trifluoromethyl) phenyl] amino} methyl) benzamide
To a solution of N-dodecyl-4-formyl-benzamide (Example 10, step a) (1.00 g, 3.115 mmol), acetic acid (0.227 g, 3.78 mmol) and 4-trifluoromethyl-phenylamine (0.609 g , 3.78 mmol) in DCE (25 mL) was added once NaBH (OAc) 3 (0.801 g, 3.78 mmol). The resulting mixture was stirred overnight at 70 ° C. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a colorless oil. This crude product was purified by column chromatography on silica gel (4/1 c-Hex / AcOEt at 3/1 in approximately 0.5h) to provide the title compound as a colorless oil (0.824 g, 63%). 1H NMR (CD3OD, 300 MHz) δ 7.74 (d, 2H, J = 8.3 Hz), 7.43 (d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J = 8.7 Hz), 6.63 (d, 2H, J = 8.3 Hz), 4.42 (s, 2H), 3.35 (m, 2H), 1.58 (m, 2H), 1.27 (m, 18H), 0.88 (m, 3H). M + (LC / MS (ESI)): 463.0; M- (LC / MS (ESI)): 461.3. HPLC (Condition A), Tr: 6.84 min (HPLC purity: 98.5%).
Step b) Preparation of ethyl {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetate
The same procedure as used for the preparation of Example 1 (step b) using N-dodecyl-4 - ({[4 (trifluoromethyl) phenyl] amino} methyl) benzamide provided the title compound as a colorless oil (56% ). 1H NMR (CDCl3, 300 MHz) δ 7.68 (m, 2H), 7.57 (m, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 6.04 (s , 1H), 4.59 (s, 2H), 4.03 (m, 2H), 3.41 (m, 2H), 1.55 (m, 2H), 1.24 (m, 18H), 1 , 00 (m, 3H), 0.87 (m, 3H). M + (APCI): 563.2; M- (APCI): 561.2. HPLC (Condition A), Tr: 6.74 min (HPLC purity: 98.7%).
Step c) Preparation of {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step c) using ethyl {{4 [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetate and lithium hydroxide dihydrate provided the compound of title as a white solid (89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (s, 1H), 7.77 (m, 4H), 7.45 (d, 2H, J = 7.9 Hz), 7.27 (d , 2H, J = 7.5 Hz), 5.07 (s, 2H), 3.20 (m, 2H), 1.48 (m, 2H), 1.28 (m, 18H), 0.84 (t, 3H, J = 5.9 Hz). M- (APCI): 489.2 (M-CO2). HPLC (Condition A), Tr: 6.44 min (HPLC purity: 97.4%).
Example 229: [{4 - [(dodecylamino) carbonyl] benzyl} (2-methoxyphenyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2-methoxyaniline in step c provided the title compound as a yellow oil (1.9 mg). M- (LC / MS (ESI)): 495.2; M + (LC / MS (ESI)): 497.2 HPLC (Condition A), Tr: 6.00 min (HPLC purity: 90.2%).
Example 230: ((1,2-diphenylethyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 1,2-diphenylethylamine in step c provided the title compound as a colorless oil (6.3 mg) . M- (LC / MS (ESI)): 570.5; M + (LC / MS (ESI)): 571.0. HPLC (Condition A), Tr: 6.60 min (HPLC purity: 94.4%).
Example 231: N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benzyl} -L-phenylalanine
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and t-butyl ester hydrochloride of L-phenylalanine in step c provided the title compound as a yellow oil ( 8.0 mg). M- (LC / MS (ESI)): 537.0; M + (LC / MS (ESI)): 539.2. HPLC (Condition A), Tr: 5.82 min (HPLC purity: 89.2%).
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3-phenoxyaniline in step c provided the title compound as a yellow oil (2.4 mg). M + (LC / MS (ESI)): 559.2. HPLC (Condition A), Tr: 6.50 min (HPLC purity: 89.9%).
Example 233: [{4 - [(dodecylamino) carbonyl] benzyl} (2-isopropoxyphenyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2-isopropoxy aniline in step c provided the title compound as a colorless oil (6.7 mg). M- (LC / MS (ESI)): 523.2; M + (LC / MS (ESI)): 524.2. HPLC (Condition A), Tr: 6.33 min (HPLC purity: 91.7%).
Example 234: [{4 - [(dodecylamino) carbonyl] benzyl} (4-iodophenyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 4-iodoaniline in step c provided the title compound as a colorless oil (7.2 mg). M + (LC / MS (ESI)): 592.7. HPLC (Condition A), Tr: 6.34 min (HPLC purity: 81.9%).
Example 235: {{4 - [(dodecylamino) carbonyl] benzyl} [3-fluoro-4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3-fluoro-4- (trifluoromethyl) benzylamine in step c provided the title compound as a colorless oil ( 2.7 mg). M- (LC / MS (ESI)): 564.9; M + (LC / MS (ESI)): 566.9. HPLC (Condition A), Tr: 6.58 min (HPLC purity: 88.5%).
Example 236: ((3-Chloro-2-methylphenyl) {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3-chloro-2-methylaniline in step c provided the title compound as a colorless oil (3.3 mg) M + (LC / MS (ESI)): 515.5. HPLC (Condition A), Tr: 6.38 min (HPLC purity: 92.9%).
Example 237: 4 '- ((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) -1,1'-biphenyl-2-carboxylic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 4- (2-methoxycarbonylphenyl) aniline in step c provided the title compound as a white solid (3, 9 mg) M- (LC / MS (ESI)): 585.5; M + (LC / MS (ESI)): 586.9. HPLC (Condition A), Tr: 5.96 min (HPLC purity: 67.6%).
Example 238: ((2,4-dichlorobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2,4-dichlorobenzylamine in step c provided the title compound as a colorless oil (7.1 mg) . M- (LC / MS (ESI)): 546.9; M + (LC / MS (ESI)): 549. HPLC (Condition A), Tr: 6.70 min (HPLC purity: 92.1%).
Example 239: [{4 - [(dodecylamino) carbonyl] benzyl} (1-phenylpropyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 1-phenyl-propylamine in step c provided the title compound as a colorless oil (3.6 mg) . M- (LC / MS (ESI)): 507.1; M + (LC / MS (ESI)): 509.2. HPLC (Condition A), Tr: 6.41 min (HPLC purity: 95.2%).
Example 240: ([2- (4-chlorophenyl) propyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2- (4-chloro-phenyl) -propylamine hydrochloride in step c provided the title compound as a colorless oil (8.1 mg). M- (LC / MS (ESI)): 541.0; M + (LC / MS (ESI)): 543.0. HPLC (Condition A), Tr: 6.67 min (HPLC purity: 86.2%).
Example 241: [{4 - [(dodecylamino) carbonyl] benzyl} (4-isopropoxyphenyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 4-isopropoxyaniline in step c provided the title compound as a colorless oil (5.8 mg). M + (LC / MS (ESI)): 525.2. HPLC (Condition A), Tr: 6.36 min (HPLC purity: 77.3%).
Example 242: ([4- (benzyloxy) phenyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 4-benzyloxyaniline hydrochloride in step c provided the title compound Example 243: acid {{4 - [( dodecylamino) carbonyl] benzyl} [2- (trifluoromethyl) benzyl] amino} - (oxo) acetic
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2- (trifluoromethyl) benzylamine in step c provided the title compound as a white solid (4.7 mg ). M- (LC / MS (ESI)): 547.2; M + (LC / MS (ESI)): 549.2. HPLC (Condition A), Tr: 6.52 min (HPLC purity: 94.8%).
Example 244: [{4 - [(dodecylamino) carbonyl) benzyl} (2-methoxybenzyl) amino (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2-methoxybenzylamine in step c provided the title compound as a colorless oil (3.9 mg). M- (LC / MS (ESI)): 509.1; M + (LC / MS (ESI)): 511.0. HPLC (Condition A), Tr: 6.20 min (HPLC purity: 78.4%).
Example 245: ([(1R) -1- (4-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b (1R) -1- (4-chlorophenyl) ethanamine in step c provided the title compound as an oil colorless (3.0 mg). M- (LC / MS (ESI)): 527.0; M + (LC / MS (ESI)): 529. HPLC (Condition A), Tr: 6.50 min (HPLC purity: 93.4%).
Example 246: ((3,4-dichlorobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3,4-dichlorobenzylamine in step c provided the title compound as a colorless oil (8.6 mg) . M- (LC / MS (ESI)): 546.9; M + (LC / MS (ESI)): 550.7. HPLC (Condition A), Tr: 6.65 min (HPLC purity: 91.6%).
Example 247: ((1-benzothien-3-ylmethyl) {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and benzo [b] thiophene-3-ylmethylamine in step c provided the title compound as a colorless oil (5 , 3 mg). M- (LC / MS (ESI)): 535.0; M + ILC / MS (ESI)): 536.9. HPLC (Condition A), Tr: 6.48 min (HPLC purity: 87.9%).
Example 248: ([2- (2,6-Dichlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] -benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2,6-dichlorophenethylamine in step c provided the title compound as a colorless oil (5.1 mg) . M- (LC / MS (ESI)): 560.9; M + (LC / MS (ESI)): 565.0. HPLC (Condition A), Tr: 6.52 min (HPLC purity: 87.0%).
Example 249: ({4 - [(dodecylamino) carbonyl] benzyl} {2- [3- (trifluoromethyl) phenyl] -ethyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 2- (3-trifluoromethylphenyl) -ethylamine in step c provided the title compound as a yellow oil (6 , 1 mg). M- (LC / MS (ESI)): 561.0; M + (LC / MS (ESI)): 563.7. HPLC (Condition A), Tr: 6.59 min (HPLC purity: 83.9%).
Example 250: {{(4 - [(dodecylamino) carbonyl] benzyl} [2- (3-fluorophenyl) ethyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3-fluorophenethylamine in step c provided the title compound as a white solid (4.1 mg). M- (LC / MS (ESI)): 511.0; M + (LC / MS (ESI)): 513. HPLC (Condition A), Tr: 6.30 min (HPLC purity: 84.2%).
Example 251: ([(1S) -1- (4-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] -benzyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b (1 S) -1- (4-chlorophenyl) ethanamine in step c provided the title compound as an oil colorless (12 mg). M- (LC / MS (ESI)): 527.0; M + (LC / MS (ESI)): 529. HPLC (Condition A), Tr: 6.50 min (HPLC purity: 93.0%).
Example 252: {{4 - [(dodecylamino) carbonyl] benzyl} [(1S) -1-phenylethyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b (1 S) -1-phenylethanamine in step c provided the title compound as an Example 253: acid {{ 4 - [(dodecylamino) carbonyl] benzyl} [(1R) -1-phenylethyl] amino} (oxo) acetic
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b (1R) -1-phenylethanamine in step c provided the title compound as a light yellow oil (43 mg ). M- (LC / MS (ESI)): 493.0; M + (LC / MS (ESI)): 495.2. HPLC (Condition A), Tr: 6.26 min (HPLC purity: 91.3%).
Example 254: ([3- (benzyloxy) phenyl] {4 - [(dodecylamino) carbonyl] benzyl} -amino (oxo) acetic acid
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and 3- (benzyloxy) aniline in step c provided the title compound as a white solid (10.4 mg ). M + (LC / MS (ESI)): 572.9. HPLC (Condition A), Tr: 6.53 min (HPLC purity: 89.2%).
Example 255: N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benzyl} -D-phenylalanine
The same procedure used in the preparation of Example 28 using dodecylamine in step a, 4-chloromethylbenzoyl chloride in step b and t-butyl ester hydrochloride of D-phenylalanine in step c provided the title compound as a colorless solid ( 8.0 mg). M- (LC / MS (ESI)): 537.0; M + (LC / MS (ESI)): 539.0. HPLC (Condition A), Tr: 5.83 min (HPLC purity: 80.3%).
Example 256: {{4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Step a) Preparation of N-dodecyl-4 - {[4- (trifluoromethyl) benzyl] amino} benzamide
The same procedure used in the preparation of Example 228 (step a) using 4-amino-Ndodecylbenzamide (Example 150, step b) and 4- (trifluoromethyl) benzaldehyde provided the title compound as a colorless oil (74%). 1H NMR (DMSO-d6, 300 MHz) δ 7.68 (d, 2H, J = 8.3 Hz), 7.47-7.60 (m, 4H), 6.53 (d, 2H, J = 8.6 Hz), 4.41 (s, 2H), 3.31 (s, 2H), 3.14 (t, 2H, J = 6.8 Hz), 1.35-1.51 (m, 2H), 1.11-1.32 (m, 18H), 0.83 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 7.00 min (HPLC purity: 91.2%).
Step b) Preparation of ethyl {{4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 1 (step b) using N-dodecyl-4 - {[4 (trifluoromethyl) benzyl] amino} benzamide provided the title compound as a colorless oil (93%).
Step c) Preparation of {{4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl {{4 [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (96%). 1H NMR (DMSO-d6, 300 MHz) δ 8.5 (br s, 1H), 7.78 (d, 2H, J = 8.3 Hz), 7.68 (d, 2H, J = 7.9 Hz), 7.42 (d, 2H, J = 7.9 Hz), 7.31 (d, 2H, J = 8.3 Hz), 5.08 (s, 2H), 3.15-3, 22 (m, 2H), 1.37-1.52 (m, 2H), 1.11-1.32 (m, 18H), 0.83 (t, 3H, J = 6.7 Hz). M + (LC / MS (ESI)): 535.0. HPLC (Condition A), Tr: 6.73 min (HPLC purity: 100%).
Example 257: {{4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- (methylamino) ) glucitol)
The same procedure used in the preparation of Example 2 using {{4 - [(dodecylamino) carbonyl] phenyl} [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white powder (97%). M + (LC / MS (ESI)): 535.4. HPLC (Condition A), Tr: 6.30 min (HPLC purity: 98.9%). Analysis calculated for C29H37F3N2O4.C7H17NO5 = 1 H2O: C, 57.82; H, 7.55; N, 5.62%. Found: C, 57.87; H, 7.58; N, 5.62%
Example 258: oxo {{1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Step a) Preparation of tert-butyl 4 - ({[(1-aminododecylidene) amino] oxy} carbonyl) benzylcarbamate
At 0 ° C, to a solution of boc- (4-aminomethyl) -benzoic acid (5,000 g, 19.9 mmol), NMM (2,214 g, 21.89 mmol) in anhydrous THF (50 mL) was added drip isobutyl chloroformate (2,853 g, 20.89 mmol). The resulting mixture was stirred for 10 min, then N-hydroxidedecanimidamide was added once (Example 23, step a) (6.398 g, 29.85 mmol). After 1h the ice-water bath was removed and the mixture was stirred for 14 h at RT. An aqueous solution of HCl (1N, 50 mL) was added and the mixture was extracted with AcOEt (3x 70 mL). The combined organic layers were washed with water (150 mL), dried over MgSO4 and evaporated to provide a white solid (9.2 g). This crude product was purified by flash chromatography on silica gel (c-Hex / AcOEt 4/1) to give the title compound as a white solid (7.91 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, 2H, J = 8.0 Hz), 7.50 (t, 1H, J = 5.7 Hz) 7.32 (d, 2H, J = 8.0 Hz), 6.42 (br s, 1H), 6.27 (br s, 1H), 4.20 (s, 1H), 4.18 (s, 1H), 1.91-2, 15 (m, 2H), 1.08-1.66 (m, 27H), 0.86 (t, 3H, J = 6.9 Hz). M + (LC / MS (ESI)): 448.4; M- (LC / MS (ESI)): 446.3.
Stage b) Preparation of tert-butyl 4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzylcarbamate
The same procedure used in the preparation of Example 23 (step e) using tert-butyl 4 - ({[(1aminododecylidene) amino] oxy} carbonyl) benzylcarbamate provided the title compound as a colorless oil (78%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, 2H, J = 7.9 Hz), 7.44 (d, 2H, J = 7.9 Hz), 4.97 (br s, 1H) , 4.41 (s, 2H), 2.81 (t, 2H, J = 7.7 Hz), 1.71-1.91 (m, 27H), 0.89 (t, 3H, J = 6 , 8 Hz). HPLC (Condition A), Tr: 7.06 min (HPLC purity: 99.4%).
Step c) Preparation of 1- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) phenyl] methanamine
The same procedure used in the preparation of Example 23 (step f) using tert-butyl 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzylcarbamate provided the hydrochloride salt of the title compound as a white solid (98 %). A suspension of this solid (2,085 g, 5.70 mmol) in AcOEt (100 mL) was washed twice with a saturated aqueous solution of NaHCO3 (50 mL). The organic layer was dried over MgSO4 and evaporated to give the title compound as a white solid (1.878 g). 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 2H, J = 8.3 Hz), 7.56 (d, 2H, J = 8.3 Hz), 3.79 (s, 2H ), 2.72 (t, 2H, J = 7.3 Hz), 1.60-1.76 (m, 2H), 1.10-1.40 (m, 18H), 0.83 (t, 3H, J = 7.0 Hz). M + (LC / MS (ESI)): 330.3. HPLC (Condition A), Tr: 4.55 min (HPLC purity: 99.8%).
Step d) Preparation of N- {1- [4- (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 223 (step b) using 1- [4- (3-undecyl-1,2,4oxadiazol-5-yl) phenyl] methanamine provided the title compound as a white solid (84% ). 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, 2H, J = 8.3 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 8.0 Hz), 3.90 (q, 1H, J-6.7 Hz), 3.72 (s, 1H), 3, 70 (s, 1H), 2.81 (t, 2H, J = 7.7 Hz), 1.75-1.90 (m, 2H), 1.19-1.49 (m, 19H), 0 , 89 (t, 3H, J = 6.8 Hz) HPLC (Condition A), Tr: 5.42 min (HPLC purity: 93.2%).
Step e) Preparation of ethyl oxo {{1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure as used for the preparation of Example 1 (step b) using N- {1- [4 (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-l, 2,4-oxadiazole -5-yl) benzyl] amine gave the title compound as a colorless oil (93%). HPLC (Condition A), Tr: 7.84 min (HPLC purity: 99.9%).
Step f) Preparation of oxo {{1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) using ethyl oxo {{1- [4 (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate provided the title compound as a white solid (91%). 1H NMR ((DMSO-d6, 300 MHz) δ 7.97-7.11 (m, 8H), 5.56 (q, 0.35H, J = 7.1 Hz), 5.15 (q, 0 , 65H, J = 6.8 Hz), 4.31-4.71 (m, 2H), 2.65-2.79 (m, 2H), 1.43-1.77 (m, 5H), 1.06-1.38 (m, 16H), 0.83 (t, 3H, J = 6.8 Hz) .M- (LC / MS (ESI)): 571.9. HPLC (Condition A), Tr: 6.93 (HPLC purity: 99.9%)
Example 259: oxo {{1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino) acetic acid, Nmethyl-D salt -glucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 using oxo {{1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino Acetic and N-methyl-D-glucamine provided the title compound as a white powder (99%). M- (LC / MS (ESI)): 572.5. HPLC (Condition A), Tr: 6.90 min (HPLC purity: 99.4%).
Example 260: ([(2-Butyl-1-benzofuran-3-yl) methyl] {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid
Stage a) Formation of 2-butyl-1-benzofuran-3-carbaldehyde
To a solution of DMF (59 g, 0.805 mol) in anhydrous DCM (300 mL) was added slowly at 0 ° C under an atmosphere of N2 phosphorus oxychloride (123 g, 0.84 mol). The mixture was stirred at RT for 2 h. To this, 2-butyl-benzofuran (35 g, 0.21 mol) in anhydrous DCM (100 mL) was added slowly. The reaction mixture was slowly heated to 60 ° C for 72 h, cooled to RT and poured on ice and extracted with EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (Pet / EtOAc ether) to provide 2-butyl-1-benzofuran-3-carbaldehyde (30 g, 74%) as a light brown liquid. .
Stage b) Formation of 2-butyl-1-benzofuran-3-carbaldehyde oxime
To a mixture of 2-butyl-1-benzofuran-3-carbaldehyde (25 g, 0.124 mol) and sodium acetate (12.2 g, 0.124 mol) in methanol (100 mL) was added hydroxylamine hydrochloride (10.3 g, 0.149 mol) in water (25 mL) at 0 ° C. The mixture was stirred at RT for 2 h. Water (300 mL) was added to the reaction mixture and the product was extracted with EtOAc. The
Stage c) Formation of (2-butyl-1-benzofuran-3-yl) methylamine hydrochloride
To a suspension of LiAlH4 (6.6 g, 0.173 mol) in anhydrous THF (400 mL) was added a solution of oxime of 2-butyl-benzofuran-3-carbaldehyde (25 g, 0.11 mol) in dry THF ( 100 mL) drip at 0 ° C under N2. The reaction mixture was stirred at RT for 18 h and then quenched with an aqueous solution of NaOH (30 mL, 10%) at -15 ° C. The solid was removed by filtration, washed with THF and the filtrates were concentrated. The residue was dissolved in DCM (100 mL), washed with water, brine and dried over MgSO4. The solvent was removed and the resulting crude product was dissolved in Et2O. A saturated solution of ether HCl was added while a white solid precipitated. The white solid was filtered, washed with EtOAc to provide the title compound as a white solid (15 g, 54%). 1H NMR (DMSO-d6, 300 MHz) δ 8.45 (br s, 3H), 7.82 (m, 1H), 7.52 (m, 1H), 7.27 (m, 2H), 2, 85 (t, 2H, J = 7.5 Hz), 1,721.50 (m, 2H), 1.81-1.51 (m, 2H), 1.43-1.29 (m, 2H), 0 , 83 (t, 3H, J = 7.3 Hz)
Step d) Formation of 4 - ({[(2-butyl-1-benzofuran-3-yl) methyl] amino} methyl) -N-dodecylbenzamide
The same procedure used in the preparation of Example 1 (step a) but using (2-butyl-1-benzofuran-3-yl) methylamine hydrochloride, triethylamine and N-dodecyl-4-formylbenzamide provided the title compound as a colorless oil ( 59%) 1H NMR (CDCl3, 300 MHz) δ 7.76 (m, 2H), 7.58 (m, 1H), 7.42 (m, 3H), 7.29-7.18 (m, 2H), 6 , 23 (m, 1H), 3.87 (m, 4H), 3.46 (m, 2H), 2.75 (t, 2H, J = 7.5 Hz), 1.77-1.56 ( m, 5H), 1.45-1.23 (m, 20H), 0.98-0.86 (m, 6H). HPLC (Condition A), Tr: 5.49 min (HPLC purity: 97.4%).
Step e) Formation of ethyl ([(2-butyl-1-benzofuran-3-yl) methyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using 4 - ({[(2-butyl-1benzofuran-3-yl) methyl] amino} methyl) -N-dodecylbenzamide gave the compound title as a colorless oil (83%). 1H NMR (CDCl3, 300 MHz) δ 7.71 (d, 1.3H, J = 8.1 Hz), 7.62 (d, 0.7H, J = 8.1 Hz), 7.48-7 , 30 (m, 2H), 7,247.07 (m, 4H), 6.18 (m, 1H), 4.55 (s, 1.3H), 4.45 (s, 0.7H), 4, 40-4.18 (m, 4H), 3.37 (m, 2H), 2.48-2.5 (m, 2H), 1,611.45 (m, 4H), 1.35-1.10 ( m, 23H), 0.88-0.72 (m, 6H). HPLC (Condition A), Tr: 7.34 min (HPLC purity: 99.7%).
Step f) Formation of ([(2-butyl-1-benzofuran-3-yl) methyl] {4 - [(dodecylamino) carbonyl] -benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ([(2-butyl-1benzofuran-3-yl) methyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetate provided the title compound as a white solid (99%). 1H NMR (CDCl3, 300 MHz) δ 10.6 (m, 1H), 7.58 (t, 2H, J = 8.0 Hz), 7.40-7.30 (m, 2H), 7.186.95 (m, 4H), 6.65 (m, 0.7H), 6.50 (m, 0.3H), 4.60-4.46 (m, 2H), 4.38-4.21 (m , 2H), 3.36 (m, 2H), 2.39 (m, 2H), 1.54 (m, 4H), 1.17 (m, 20H), 0.80 (m, 6H) M- (LC / MS (ESI)): 575.2. HPLC (Condition A), Tr: 7.22 min (HPLC purity: 99.7%).
Example 261: {(1- {4 - [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of 4-acetyl-N-dodecylbenzamide
The same procedure used in the preparation of Example 10 (step a) but using 4-acetylbenzoic acid and dodecylamine gave the title compound as a white solid (54%). 1H NMR (CDCl3, 300 MHz) δ 8.007.90 (m, 2H), 7.85-7.71 (m, 2H), 6.05 (br s, 1H), 3.41-3.30 (m , 2H), 2.56 (s, 1.5H), 2.54 (s, 1.5H), 1.63-1.73 (m, 2H), 1.72-1.05 (m, 18H ), 0.78 (m, 3H). M- (LC / MS (ESI)): 330.4; M + (LC / MS (ESI)): 332.4. HPLC (Condition A), Tr: 5.87 min (HPLC purity: 99.7%).
Stage b) Formation of N-dodecyl-4- (1 - {[4- (trifluoromethyl) benzyl] amino} ethyl) benzamide
The same procedure used in the preparation of Example 223 (step b) but using 4-acetyl-Ndodecylbenzamide and 4- (trifluoromethyl) benzylamine provided the title compound as a colorless oil (71%). M- (LC / MS (ESI)): 489.1; M + (LC / MS (ESI)): 491.5. HPLC (Condition A), Tr: 5.51 min (HPLC purity: 50.0%).
Step c) Formation of ethyl {(1- {4 - [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N-dodecyl-4- (l - {[4 (trifluoromethyl) benzyl] amino} ethyl) benzamide provided the title compound as a white foam (54% ). 1H NMR (CDCl3, 300 MHz) δ 7.70 (m, 2H), 7.64-7.41 (m, 2H), 7.39-7.30 (m, 2H), 7.28-7, 12 (m, 2H), 6.09-5.90 (m, 1H), 4.67-4.37 (m, 2H), 4.30-4.08 (m, 2H), 3.50- 3.38 (m, 2H), 1.68-1.48 (m, 6H), 1.43-1.10 (m, 21H), 0.88 (m, 3H). M + (LC / MS (ESI)): 591.7. HPLC (Condition A), Tr: 7.24 min (HPLC purity: 99.6%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1- {4 [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of the title as a white solid (91%). 1H NMR (CD3OD, 300 MHz) δ 7.75 (t, 2H, J = 7.5 Hz), 7.48-7.19 (m, 6H), 5.75 (m, 0.3H), 5 , 28 (m, 0.7H), 4.60-4.31 (m, 2H), 3.38 (t, 2H, J = 7.1 Hz), 1.66-1.56 (m, 5H ), 1.36 (m, 18H), 0.90 (m, 3H). M (LC / MS (ESI)): 562.6; M + (LC / MS (ESI)): 563.7. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 98.7%).
Example 262: {(1- {4 - [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid, Nmethyl-D-glucamine salt (ie 1- deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {(l- {4 [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acid acetic gave the title compound as a white solid (82%). M- (LC / MS (ESI)): 562.5; M + (LC / MS (ESI)): 564.1. HPLC (Condition A), Tr: 6.27
min (HPLC purity: 99.0%). Analysis calculated for C31H41F3N2O4.C7H17NO5 = 1.0 H2O: C, 58.82; H, 7.79; N, 5.42%. Found: C, 58.92; H, 7.96; N, 5.35%
Example 263: {(4 - {[(4-octylphenyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Step a) Formation of ethyl {(4 - {[(4-octylphenyl) amino] carbonyl} benzyl) [4- (trifluoro-methyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 10 (step a) but using 4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid and 4-octylaniline gave the title compound as a colorless oil (22%). 1H NMR (CDCl3, 300 MHz) δ 7.89-6.60 (m, 12H), 4.48 (s, 2H), 4.44-4.21 (m, 4H), 2.65-2, 36 (m, 2H), 1.68-1.40 (m, 3H), 1.38-1.08 (m, 13H), 0.81 (t, J = 6.9 Hz, 3H). M + (LC / MS (ESI)): 597.7. HPLC (Condition A), Tr: 6.75 min (HPLC purity: 98.9%).
Step b) Formation of {(4 - {[(4-octylphenyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4 - {[(4octylphenyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of title as a brown oil (95%). 1HNMR (CDCl3, 300 MHz) δ 8.30 (m, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.46 (m, 3H), 7.277.04 (m, 6H), 4.62-4.46 (m, 4H), 2.55 (t, 2H, J = 7.5 Hz), 1.56 (m, 2H), 1.25 (m, 10H), 0.86 (t, 3H, J = 6.5 Hz). M (LC / MS (ESI)): 567.2; M + (LC / MS (ESI)): 569.6. HPLC (Condition A), Tr: 6.24 min (HPLC purity: 97.0%).
Example 264: {(3-Chlorobenzyl) [4- (3-undecyl-l, 2,3-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N- (3-chlorobenzyl) -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 1- [4- (3-undecyl-1,2,4oxadiazol-5-yl) phenyl] methanamine and 3-chlorobenzaldehyde provided the title compound as a colorless oil (86%). 1H NMR (DMSO-d6, 300 MHz) δ 8.03 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.43 (s, 1H ), 7.65-7.23 (m, 3H), 3.77 (s, 2H), 3.70 (s, 2H), 3.30 (s, 1H), 2.75 (t, J = 7.2 Hz, 2H), 1.79-1.65 (m, 2H), 1.41-1.16 (m, 16H), 0.84 (t, J = 7.0 Hz, 3H). HPLC (Condition A), Tr: 5.19 min (HPLC purity: 98.4%).
Stage b) Formation of ethyl {(3-chlorobenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (3-chlorobenzyl) -N- [4 (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as a yellow oil (95%). 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.55-7.13 (m, 6H), 4.60 (d, 2H), 4.51 (d, 2H), 4.34-4.21 (m, 2H), 2.75 (m, 2H), 1.79- 1.62 (m, 2H), 1.41-1.11 (m, 19H), 0.84 (t, J = 6.8 Hz, 3H). HPLC (Condition A), Tr: 7.72 min (HPLC purity: 99.9%).
Step c) Formation of {(3-chlorobenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(3-chlorobenzyl) [4- (3 undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (91%). 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.29-6.97 (m, 4H), 4.48-4.23 (m, 4H), 2.60 (t, J = 7.3 Hz, 2H) , 1.64-1.47 (m, 2H), 1.25-0.95 (m, 16H), 0.67 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 524.2. HPLC (Condition A), Tr: 7.23 min (HPLC purity: 100%).
Example 265: {(3-Chlorobenzyl) [4- (3-undecyl-l, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {(3-chlorobenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetic gave the title compound as a white powder (93%). M- (LC / MS (ESI)): 523.9. HPLC (Condition A), Tr: 7.24 min (HPLC purity: 99.9%). Analysis Example 266: {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoylamino) -benzyl] amino} (oxo) acetic acid
Step a) Preparation of N-methoxy-N-methyl-4- (trifluoromethyl) benzamide
To a cold solution (0 ° C) of N, O-dimethylhydroxylamine hydrochloride (2.5 g, 25.6 mmol) and 4 (trifluoromethyl) benzoyl chloride (prepared by refluxing a solution of 4- (trifluoromethyl) benzoic acid in SOCl2, 4.86 g, 23.3 mmol) in DCM (50 mL) was added drip pyridine (4.06 g, 51.26 mmol). The reaction mixture was stirred overnight and evaporated. The residue was dissolved in a mixture of DCM / Et2O (1/1) (45 mL) and brine (45 mL) was added. The aqueous layer was separated and extracted twice with DCM / Et2O (1/1) (45 mL). The combined organic layers were washed with brine (45 mL), dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil (4.88 g, 90%). 1H NMR (CDCl3, 300 MHz) δ 7.90-7.70 (m, 2H), 7.76-7.60 (m, 2H), 3.65-3.45 (m, 3H), 3, 43-3.33 (m, 3H). HPLC (Condition A), Tr: 3.41 min (HPLC purity: 98.0%).
Stage b) Preparation of cyclopentyl [4- (trifluoromethyl) phenyl] methanone
To a cold solution (0 ° C) of N-methoxy-N-methyl-4- (trifluoromethyl) benzamide (3.44 g, 14.75 mmol) in anhydrous THF (70 mL) was added dropwise over a period of 30 minutes a solution of cyclopentylmagnesium bromide (2M in diethyl ether, 29.5 mmol, 14.75 mL) under an inert atmosphere of N2. The reaction mixture was allowed to warm slowly until RT was reached overnight. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over MgSO4, filtered and evaporated in vacuo to provide a brown oil (3.0 g). Purification by chromatography (SiO2, DCM / c-Hex 1/3) provided the title compound as a colorless oil (610 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 8.24 (d, J = 8.1Hz, 2H), 7.90 (d, J = 8.1 Hz, 2H), 3,963.79 (m, 1H), 2 , 21, 2.00 (m, 4H), 2.01-1.71 (m, 4H). HPLC (Condition A), Tr: 5.22 min (HPLC purity: 98.6%).
Stage c) Formation of N- {cyclopentyl [4- (trifluoromethyl) phenyl] methyl} -N- (4-nitrobenzyl) -amine
The same procedure used in the preparation of Example 223 (step b) but using cyclopentyl [4 (trifluoromethyl) phenyl] methanone and 4-nitrobenzylamine gave the title compound as an oil (67%). M (LC / MS (ESI)): 377.2; M + (LC / MS (ESI)): 379.2
Stage d) Formation of ethyl [{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} (4-nitrobenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- {cyclopentyl [4 (trifluoromethyl) phenyl] methyl} -N- (4-nitrobenzyl) amine gave the title compound as a colorless oil (68% ) .1H NMR (CDCl3, 300 MHz) δ 8.02-7.90 (m, 2H), 7.55-7.38 (m, 4H), 7.11-6.99 (m, 2H), 4.60-4.30 (m, 4H), 4.20-4.02 (m, 1H), 2.78-2.61 (m, 1H), 1.78-1.38 (m, 7H ), 1.30-0.91 (m, 4H). M- (LC / MS (ESI)): 477.8; M + (LC / MS (ESI)): 479.1 HPLC (Condition A), Tr: 5.72 min (HPLC purity: 98.4%).
Stage e) Formation of ethyl ((4-aminobenzyl) {cyclopentyl [4- (trifluoromethyl) phenyl] -methyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 1 (step c) but using ethyl [{cyclopentyl [4 (trifluoromethyl) phenyl] methyl} (4-nitrobenzyl) amino] (oxo) acetate and provided the title compound as a brown oil (36%). M + (LC / MS (ESI)): 449.1. HPLC (Condition A), Tr: 4.0 min (HPLC purity: 88.2%).
Step f) Formation of ethyl {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoyl-amino) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step d) but using ethyl ((4-aminobenzyl) {cyclopentyl [4- (trifluoromethyl) phenyl] methyl} amino) (oxo) acetate and tridecanoyl chloride provided the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.21 (m, 6H), 6.95 (d, 1H, J = 8.5 Hz) 6.8 (d, 1H, J = 8.5 Hz), 5.30 (m, 1H), 4.47-4.05 (m, 4H), 2.85-2.60 (m, 1H), 2.45-2.26 (m, 2H) , 1.80-1.10 (m, 31H), 1.05-0.86 (m, 4H). M- (LC / MS (ESI)): 643.9; M + (LC / MS (ESI)): 645.2. HPLC (Condition A), Tr: 6.85 min (HPLC purity: 98.0%).
Step g) Formation of {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{cyclopentyl [4 (trifluoromethyl) phenyl] methyl} [4- (tridecanoylamino) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (94%). 1H NMR (CDCl3, 300 MHz) δ 7.85-7.24 (m, 6H), 6.85 (m, 2H), 5.30 (m, 0.6H), 4.62-4.32 ( m, 1.4H), 2.74-2.65 (m, 0.6H), 2.31-2.21 (m, 1.4H), 1.68-1.45 (m, 8H), 1.24 (m, 22H), 1.05-0.86 (m, 4H). M (LC / MS (ESI)): 615.1; M + (LC / MS (ESI)): 617.3. HPLC (Condition A), Tr: 6.30 min (HPLC purity: 97.0%).
Stage a) Preparation of methyl 4-methyl-1-naphthoate
To a stirred solution of 4-methyl-1-naphthoic acid (25 g, 0.13 mol) in methanol (350 mL), thionyl chloride (39g, 0.33 mol) was added and the reaction mixture was subjected to reflux for 15 h. The excess thionyl chloride and methanol was removed by distillation. The residue was taken up in DCM (400 mL), washed with an aqueous solution of NaHCO3 (10%), water, brine and dried over MgSO4. The solvent was removed in vacuo to provide 4-methyl-1-naphthoic acid methyl ester (22.5 g, 83%) as a light yellow solid.
Stage b) Preparation of methyl 4- (bromomethyl) -1-naphthoate
To a stirred solution of methyl 4-methyl-1-naphthoate (22.5 g, 0.121 mol) in CC14 (500 mL) was added NBS (22 g, 0.123 mol) and benzoyl peroxide (10% w / w). The reaction mixture was left until refluxing at 80 ° C for 7 h. The reaction mixture was cooled to RT and filtered off. The solid was concentrated in vacuo and the crude product obtained (30 g) was used for further reaction.
Stage c) Preparation of methyl 4- (azidomethyl) -1-naphthoate
To a solution of methyl 4- (bromomethyl) -1-naphthoate (30 g, 0.107 mol) in anhydrous DMSO (300 mL) NaN3 was added portionwise (14g, 0.215 mol) at 0 ° C and stirred at RT for 16 h. Then the reaction mixture was diluted with water (500 mL), extracted with EtOAc (2x 250 mL), washed with water, brine and dried over MgSO4. The solvent was removed in vacuo to provide methyl 4- (azidomethyl) -1-naphthoate (20 g, 77%).
Stage d) Preparation of methyl 4- (aminomethyl) -1-naphthoate hydrochloride
To a mixture of methyl 4- (azidomethyl) -1-naphthoate (17 g, 0.078 mol) in THF (400 mL) and water (210 mL), triphenylphosphine (31 g, 0.118 mol) was added. The reaction mixture was stirred at RT for 4 h then concentrated in vacuo, extracted with EtOAc (350 mL). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The resulting residue was taken up in an aqueous solution of HCl (75 mL, 2N), washed with diethyl ether (2x 150 mL). The aqueous layer was treated with an aqueous solution of NaHCO3 (10%) until pH 7. The mixture was then extracted with ethyl acetate (2x 150 mL), washed with brine, dried over MgSO4 and concentrated. The product was slowly added to a saturated solution of HCl (g) in diethyl ether (75 mL) and the solid hydrochloride product was filtered off. The product was washed with dry ether (2x 100 mL) to provide methyl-4- (aminomethyl) -1-naphthoate hydrochloride (5.5 g). M + (LC / MS (ESI)): 216.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.75 (m, 1H), 8.25 (m, 1H), 8.12 (d, 1H, J = 7.5 Hz), 7.74 (m , 3H), 4.60 (s, 2H), 3.93 (s, 3H).
Step e) Preparation of methyl 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) -1-naphthoate
The same procedure used in the preparation of example 226 (step a) provided the title compound (74%). 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (m, 1H), 8.24 (m, 1H), 8.09 (d, 1H, J = 7.5 Hz), 7.71-7 , 57 (m, 7H), 4.20 (s, 2H), 3.93 (s, 3H), 3.90 (s, 2H). M + (LC / MS (ESI)): 374.2
Step f) Preparation of 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) -1-naphthoic acid
The same procedure used in the preparation of example 1 (step e) but using 4 - ({[4 (trifluoromethyl) benzyl] amino} methyl) -1-naphthoic acid gave the title compound (74%). M + (LC / MS (ESI)): 360.2; M (LC / MS (ESI)): 358.3. 1H NMR (DMSO-d6, 300 MHz) δ 13.3 (m, 1H), 9.90 (m, 1H), 8.91-8.84 (m, 1H), 8.28-8.22 ( m, 1H), 8.12 (d, 1H, J = 7.5 Hz), 7.98-7.89 (m, 5H), 7.76-7.65 (m, 2H), 4.76 (s, 2H), 4.47 (s, 2H).
Step g) Formation of 4 - ({(tert-butoxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) -1-naphthoic acid
The same procedure used in the preparation of Example 23 (step b) but using 4 - ({[4 (trifluoromethyl) benzyl] amino} methyl) -1-naphthoic acid gave the title compound as a white foam (55%). 1H NMR (DMSO-d6, 300 MHz) δ 8.89 (m, 1H), 8.22-8.06 (m, 2H), 7.69-7.56 (m, 4H), 7.45- 7.31 (m, 3H), 4.97 (s, 2H), 4.55-4.41 (m, 2H), 1.40-1.35 (m, 9H). M- (LC / MS (ESI)): 458.3. HPLC (Condition A), Tr: 5.72 min (HPLC purity: 100%).
Step h) Formation of tert-butyl 4- (trifluoromethyl) benzyl {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1-naphthyl] methyl} carbamate
The same procedure used in the preparation of Example 258 (step a and b) but using 4 - ({(tert-butoxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) -1-naphthoic acid and provided the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 9.15 (d, 1H, J = 8.7 Hz), 8.30-7.76 (m, 2H), 7.70 (m, 1H), 7.64 -7.50 (m, 3H), 7.37 (d, 1H, J = 8.7 Hz), 7.33-7.18 (m, 2H), 5.02-4.87 (m, 2H ), 4.55-4.33 (m, 2H), 2.88 (t, 2H, J = 7.5 Hz), 1,931.82 (m, 2H), 1.50 (m, 9H), 1 , 46-1.22 (m, 16H), 0.86 (m, 3H). HPLC (Condition A), Tr: 7.84 min (HPLC purity: 100%).
Stage i) Formation of N- [4- (trifluoromethyl) benzyl] -N - {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1-naphthyl] methyl} amine hydrochloride
Step j) Formation of ethyl oxo ([4- (trifluoromethyl) benzyl] {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1-naphthyl] methyl} amino) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4 (trifluoromethyl) benzyl] -N - {[4- (3-undecyl-1,2,4-oxadiazol-5-yl hydrochloride) ) -1-naphthyl] methyl} amine provided the title compound as a colorless oil (87%). 1H NMR (CDCl3, 300 MHz) δ 9.17 (m, 1H), 8.30 (d, 0.4H, J = 7.5 Hz), 8.22 (d, 0.6H, J = 7, 5 Hz), 8.05 (m, 0.6H), 7.95 (m, 0.4H), 7.76-7.46 (m, 4H), 7.33-7.24 (m, 3H ), 5.08 (s, 1.2H), 4.88 (s, 0.8H), 4.65 (s, 0.8H), 4.37 (s, 1.2H), 4.36- 4.24 (m, 2H), 2.89 (m, 2H), 1.88 (m, 2H), 1.50-1.20 (m, 19H), 0.88 (m, 3H). HPLC (Condition A), Tr: 7.17 min (HPLC purity: 100%).
Step k) Formation of oxo ([4- (trifluoromethyl) benzyl] {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1-naphthyl] methyl} amino) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo ([4 (trifluoromethyl) benzyl] {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1- naphthyl] methyl} amino) acetate provided the title compound as a colorless oil (35%). 1H NMR (DMSO-d6, 300 MHz) δ 9.03 (d, J = 8.3 Hz, 1H), 8.32-8.15 (m, 2H), 7.80-7.30 (m, 7H), 5.17 (s, 1H), 5.07 (s, 1H), 4.68 (s, 1H), 4.62 (s, 1H), 2.86 (t, J = 7.2 Hz, 2H), 1.83-1.69 (m, 2H), 1.45-1.05 (m, 16H), 0.83 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 608.1. HPLC (Condition A), Tr: 6.51 min (HPLC purity: 100%).
Example 268: oxo ([4- (trifluoromethyl) benzyl] {[4- (3-undecyl-1,2,4-oxadiazol-5-yl) -1-naphthyl] methyl} amino) acetic acid, N- salt methyl-D-glucamine (i.e. 1-deoxy-1- (methylamino) -glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo ([4- (trifluoromethyl) benzyl] {[4- (3-undecyl-1,2,4-oxadiazol-5- il) -1-naphthyl] methyl} amino) acetic gave the title compound as a white powder (87%). M- (LC / MS (ESI)): 608.1. HPLC (Condition A), Tr: 6.45 min (HPLC purity: 98.5%). Analysis calculated for C34H38F3N3O4.C7H17NO5: C, 61.18; H, 6.89; N, 6.96%. Found: C, 57.94; H, 6.90; N, 6.58%
Example 269: {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- {cyclopentyl [4- (trifluoromethyl) phenyl] methyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 223 (step b) but using cyclopentyl [4 (trifluoromethyl) phenyl] methanone and 4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzylamine provided the compound of title as a colorless oil (55%). 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 2H), 7.64 (m, 2H), 7.50 (m, 4H), 3.62-3.34 (m, 2H) , 2.74 (m, 2H), 2.12-1.85 (m, 2H), 1.70 (m, 2H), 1.60-0.92 (m, 25H), 0.83 (m , 3H). HPLC (Condition A), Tr: 5.42 min (HPLC purity: 98.3%).
Stage b) Formation of ethyl {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- {cyclopentyl [4 (trifluoromethyl) phenyl] methyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.89 (m, 2H), 7.62-7.41 (m, 5H), 7.15-7.04 (m, 2H), 4.57-4, 31 (m, 5H), 2.81-2.63 (m, 3H), 1.83-1.13 (m, 28H), 0.88 (m, 3H). HPLC (Condition A), Tr: 7.09 min (HPLC purity: 99.3%).
Step c) Formation of {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{cyclopentyl [4 (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl ] amino} (oxo) acetate provided the title compound as a colorless oil (92%). 1H NMR (DMSO-d6, 300 MHz) δ 7.87-7.68 (m, 2H), 7.63 (d, J-7.9 Hz, 2H), 7.51 (d, J = 8, 2 Hz, 2H), 7.02 (d, J = 8.3 Hz, 3H), 4.72-4.43 (m, 3H), 3.19-2.85 (m, 2H), 2, 72 (t, J = 7.0 Hz, 2H), 1.76-1.37 (m, 8H), 1.26-1.10 (m, 16H), 0.84 (t, J = 6, 9 Hz, 3H). M- (LC / MS (ESI)): 626.2. HPLC (Condition A), Tr: 6.56 min (HPLC purity: 99.1%).
Example 270: {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino (oxo) acetic acid, N-methyl salt -D-glucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazole-) 5-yl) benzyl] amino} (oxo) acetic gave the title compound as a white powder (90%). M- (LC / MS (ESI)): 626.9. HPLC (Condition A), Tr: 6.52 min (purity Example 271: {(4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetic acid
Stage a) Formation of 4- (4-nitrophenyl) dibenzo [b, d] furan
To a mixture of dibenzofuran-4-boronic acid (30 g, 0.14 mol), 4-bromonitrobenzene (25.7 g, 0.127 mol), sodium carbonate (150 g) in toluene / water (500 mL / 500 mL ) tetrakis (triphenylphosphine) palladium (0) (8.2 g, 0.7 mol%) was added and the resulting reaction mixture was refluxed for 20h under N2 atmosphere. The toluene layer was separated and concentrated to 200 mL. The concentrated solution was cooled to 0 ° C and filtered off. The collected solid was dried and dissolved in chloroform and the solution obtained was filtered through a bed of celite to remove insoluble materials. The filtrate was concentrated in vacuo to provide the title compound (23 g, 58%).
Stage b) Formation of 4-dibenzo [b, d] furan-4-ilanilina
A solution of 4- (4-nitrophenyl) dibenzo [b, d] furan (22 g) in EtOAc (800 mL) was hydrogenated in the presence of Pd / C (10%, 4.2 g) for 12 h at RT under 2 Kg of pressure The reaction mixture was filtered and the filtrates were concentrated. The residue was crystallized from Pet's chloroform / ether (6/4) to provide the title compound (16 g, 84%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, 1H, J = 7.6 Hz), 7.97 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H , J = 8.1 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.57 (d, 1H, J = 8.6 Hz), 7.50 (m, 1H), 7.38 (m, 2H), 6.72 (d, 2H, J = 8.4 Hz), 7.35 (s, 2H). M + ILC / MS (ESI)): 260.2
Stage c) Formation of N- (4-dibenzo [b, d] furan-4-ylphenyl) -N- [4- (trifluoromethyl) -benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4-dibenzo [b, d] furan-4ilaniline and 4- (trifluoromethyl) benzaldehyde provided the title compound as a colorless oil (78%). 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, 1H, J = 7.1 Hz), 8.01 (m, 1H), 7.75-48 (m, 9H), 7.44 -7.37 (m, 2H), 6.74 (m, 3H), 4.47 (m, 2H). M- (LC / MS (ESI)): 416.2; M + (LC / MS (ESI)): 418.2. HPLC (Condition A), Tr: 5.72 min (HPLC purity: 99.3%).
Stage d) Formation of ethyl {(4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) -benzyl] amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-dibenzo [b, d] furan4-ylphenyl) -N- [4- (trifluoromethyl) benzyl] amine gave the title compound as a colorless oil (89%). 1H NMR (CDCl3, 300 MHz) δ 8.26-8.11 (m, 4H), 7.87-7.77 (m, 4H), 7.75-7.58 (m, 5H), 7, 52-7.45 (m, 2H), 5.31 (s, 2H), 4.32 (q, 2H, J = 7.2 Hz), 1.27 (t, 3H, J = 7.2 Hz ). M + (LC / MS (ESI)): 518.2. HPLC (Condition A), Tr: 5.78 min (HPLC purity: 99.4%).
Stage e) Formation of {(4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dibenzo [b, d] furan4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a colorless oil (95%). 1H NMR (DMSO-d6, 300 MHz) δ 8.04 (t, J = 7.6 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.65-7.51 (m, 4H), 7.46-7.22 (m, 7H), 5.00 (s, 2H). M- (LC / MS (ESI)): 416.3 (M-CO-CO2); M + (LC / MS (ESI)): 489.9. HPLC (Condition A), Tr: 5.07 min (HPLC purity: 99.1%).
Example 272: {(4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} (oxo) -acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy- 1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {(4dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided the title compound as a white powder (96%). M + (LC / MS (ESI)): 490.2. HPLC (Condition A), Tr: 5.03 min (HPLC purity: 98.4%). Analysis calculated for C28H18F3NO4.C7H17NO5 = 1.5 H2O: C, 59.07; H, 5.38; N, 3.94%. Found: C, 59.26; H, 5.39; N, 3.91%
Stage a) Formation of N- [4- (octyloxy) benzyl] -N- [4- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4 (octyloxy) benzaldehyde and 4- (trifluoromethyl) benzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.57 (d, 2H, J = 7.9 Hz), 7.45 (d, 2H, J = 7.9 Hz), 7.22 (m, 2H), 6.85 (m, 2H), 3.93 (t, 2H, J = 6.5 Hz), 3.84 (s, 2H), 3.72 (s, 2H), 1.82-1.70 (m, 2H), 1.50-1.23 (m, 10H), 0.89 (m, 3H). M (LC / MS (ESI)): 406.3 HPLC (Condition A), Tr: 4.42 min (HPLC purity: 98.7%).
Stage b) Formation of ethyl {[4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) -acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4- (octyloxy) benzyl] -N [4- (trifluoromethyl) benzyl] amine gave the title compound as a colorless oil (79%) . 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.36 (d, 1H, J = 7.9 Hz), 7.31 (d, 1H, J = 7.9 Hz), 7.17-7.07 (m, 2H), 6.89-6.81 (m, 2H), 4.50 (s, 1H), 4.43 (s, 1H), 4.41-4, 24 (m, 4H), 3.93 (m, 2H), 1.77 (m, 2H), 1.51-1.24 (m, 13H), 0.89 (m, 3H). M + (LC / MS (ESI)): 494.2. HPLC (Condition A), Tr: 6.22 min (HPLC purity: 99.4%).
Step c) Formation of {[4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[4- (octyloxy) benzyl] [4 (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a white solid (51 %). 1H NMR (CD3OD, 300 MHz) δ 7.64 (m, 2H), 7.48 (d, 0.8H, J = 8.3 Hz), 7.37 (d, 1.2H, J = 8, 3 Hz), 7.23 (d, 1.2H, J = 8.3 Hz), 7.21 (d, 0.8H, J = 8.5 Hz), 6.95-6.80 (m, 2H), 4.55 (s, 2H), 4.45 (s, 2H), 3.96 (t, 2H, J = 6.4 Hz), 1.85-1.70 (m, 2H), 1.55-1.30 (m, 10H), 0.91 (m, 3H). M- (LC / MS (ESI)): 464.3. HPLC (Condition A), Tr: 5.57 min (HPLC purity: 96.8%). Analysis calculated for C25H30F3NO4 = 0.9 H2O: C, 62.33; H, 6.65; N, 2.91%. Found: C, 62.09; H, 6.28; N, 2.78%
Example 274: {[4- (octyloxy) benzyl] [4- (trifluoromethyl] benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol )
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {[4 (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided the title compound as a white solid (82%). M- (LC / MS (ESI)): 464.3. HPLC (Condition A), Tr: 5.57 min (HPLC purity: 100%). Analysis calculated for C25H30F3NO4.C7H17NO5 = 2.0 H2O: C, 55.16; H, 7.38; N, 4.02%. Found: C, 55.21; H, 7.18; N, 4.02%
Example 275: [[2- (3-chlorophenyl) ethyl] (4-dec-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of 4-dec-1-inylbenzaldehyde
To a solution of 4-bromobenzaldehyde (30.0 g, 162.2 mmol), 1-decino (26.9 g, 35 mL, 194.6 mmol), CuI (309 mg, 1.62 mmol) and Et3N (68 mL) in anhydrous THF (450 mL) PPh3 (1.7 g, 6.49 mmol) and Pd (OAc) 2 (728 mg) were added. The reaction mixture was refluxed under argon for 1 hour. After cooling to RT, the solution was concentrated under reduced pressure and the residual oil was dissolved in hexane (480 mL). The solution was washed with an aqueous solution of HCl (0.1N, 1x), brine (2x), water (2x), dried over MgSO4, filtered and concentrated under reduced pressure to provide a brown oil. Purification by silica gel chromatography (c-Hex / EtOAc 20/1) provided the title compound as a yellow solid (34.7 g, 88%). 1H NMR (CDCl3, 300 MHz) δ 9.97 (s, 1H), 7.78 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H, J = 8.3 Hz), 2.42 (t, 2H, J = 7.0 Hz), 1.67-1.55 (m, 2H), 1.50-1.38 (m, 2H), 1.36-1.21 ( m, 8H), 0.87 (m, 3H). HPLC (Condition A), Tr: 5.50 min (HPLC purity: 93.2%).
Stage b) Formation of N- [2- (3-chlorophenyl) ethyl] -N- (4-dec-1-inylbenzyl) amine and N- [2- (3-chlorophenyl) ethyl] -N- {4- [ (1Z) -dec-1enyl] benzyl} amine in relation to hplc (74.3 / 24.3)
The same procedure used in the preparation of Example 226 (step a) but using 4-dec-1-benzylbenzaldehyde and [2- (3-chlorophenyl) ethyl] amine gave the title compounds as a colorless oil (53%). M + (LC / MS (ESI)): 382.4. HPLC (Condition A), Tr: 4.65 (alkyne) and 4.73 (alkene) min (HPLC purity: 74.3 (alkyne) and 24.3 (alkene)%).
Step c) Formation of ethyl [[2- (3-chlorophenyl) ethyl] (4-dec-1-inylbenzyl) amino] - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N (4-dec-1-inylbenzyl) amine and N- [2- (3-chlorophenyl) ) ethyl] -N- {4 - [(1Z) -dec-1-enyl] benzyl} amine in relation to hplc (74.3 / 24.3) provided (after chromatography) the title compound as a colorless oil (2%). 1H NMR (CDCl3, 300 MHz) δ 7.37 (d, 2H, J = 7.9 Hz), 7.24-6.91 (m, 6H), 4.57 (s, 1H), 4.38 -4.23 (m, 3H), 3.50-3.34 (m, 2H), 2.84-2.76 (m, 2H), 2.38 (t, 2H, J = 6.9 Hz ), 1.65-1.53 (m, 2H), 1.47-1.22 (m, 13H), 0.89 (m, 3H) M + (LC / MS (ESI)): 482.4. HPLC (Condition A), Tr: 6.40 min (HPLC purity: 98.5%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl [[2- (3-chlorophenyl) ethyl] (4dec-1-inylbenzyl) amino] (oxo) acetate gave the title compound as a colorless oil (32%) 1H NMR (CDCl3, 300 MHz) δ 7.38 (m, 2H), 7.25-6.93 (m, 6H), 4.95 (s, 0.8H), 4.59 (s, 1, 2H), 3.95 (m, 1H), 3.53 (m, 1H), 2,902.73 (m, 2H), 2.39 (t, 2H, J = 6.9 Hz), 1.65- 1.52 (m, 2H), 1.48-1.37 (m, 2H), 1.34-1.20 (m, 8H), 0.85 (m, 3H). M (LC / MS (ESI)): 452.2; M + (LC / MS (ESI)): 455.3. HPLC (Condition A), Tr: 5.85 min (HPLC purity: 97.4%). Analysis calculated for C27H32ClNO3 = 0.5 H2O: C, 70.04; H, 7.18; N, 3.03%. Found: C, 70.39; H, 7.12; N, 2.96%
Example 276: ([2- (3-chlorophenyl) ethyl] {4 - [(1Z) -dec-1-enyl] benzyl} amino (oxo) acetic acid
Stage a) Formation of ethyl ([2- (3-chlorophenyl) ethyl] {4 - [(1Z) -dec-1-enyl] benzyl} amino) - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N (4-dec-1-inylbenzyl) amine and N- [2- (3-chlorophenyl) ) ethyl] -N- {4 - [(1Z) -dec-1-enyl] benzyl} amine in relation to hplc (74.3 / 24.3) provided (after chromatography) the title compound as a colorless oil (2%). 1H NMR (CDCl3, 300 MHz) δ 7.32-6.96 (m, 8H), 6.39 (d, 1H, J = 11.7 Hz), 5.70 (m, 1H), 4.61 (s, 1H), 4.36 (q, 2H, J = 7.1 Hz), 4.30 (s, 1H), 3.54-3.38 (m, 2H), 2.90-2, 76 (m, 2H), 2.32 (m, 2H), 1.52-1.22 (m, 13H), 0.89 (m, 3H) M + (LC / MS (EST)): 484.3 . HPLC (Condition A), Tr: 6.55 min (HPLC purity: 96.6%).
Stage b) Formation of ([2- (3-chlorophenyl) ethyl] {4 - [(1Z) -dec-1-enyl] benzyl} amino) (oxo) -acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ([2- (3-chlorophenyl) ethyl] {4 [(1Z) -dec-1-enyl] benzyl} amino) (oxo) acetate provided the title compound as a colorless oil (69%). 1H NMR (CDCl3, 300 MHz) δ 7.29-6.99 (m, 8H), 6.37 (d, 1H, J = 6.7 Hz), 5.68 (m, 1H), 4.93 (s, 1H), 4.92 (s, 1H), 3.92 (m, 1H), 3.54 (m, 1H), 2.88 (m, 1H), 2.78 (m, 1H) , 2.29 (m, 2H), 1.49-1.37 (m, 2H), 1.33-1.18 (m, 10H), 0.86 (m, 3H) M- (LC / MS (ESI)): 454.2. HPLC (Condition A), Tr: 5.96 min (HPLC purity: 95.9%).
Example 277: {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of 4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzaldehyde
To a solution of 4-carboxybenzaldehyde (20.0 g, 133.2 mmol) in anhydrous DCM (500 mL) was added DIC (18.42g, 146.5 mmol). The mixture was stirred at RT for 30 min, then a solution of N-hydroxidedecanimidamide (31.41 g, 146.5 mmol) in anhydrous DCM (500 mL) was added in one portion. The resulting reaction mixture was stirred overnight at RT. The reaction was filtered, the collected solid was washed with DCM and the solvent was concentrated in vacuo. The residue was heated at 115 ° C for 5 h in a mixture of toluene (285 mL) and pyridine (115 mL). The solvents were removed by evaporation and the resulting residue was purified on a column (SiO2, c-Hex / EtOAc 20/1) to provide the title compound as a white solid (24.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.18 (d, 2H, J = 8.3 Hz), 7.94 (d, 2H, J = 8.3 Hz), 2.33 (t, 2H, J = 7.4 Hz), 1.74-1.58 (m, 2H), 1.43-1.18 (m, 16H), 0.87 (m, 3H) . HPLC (Condition A), Tr: 5.83 min (HPLC purity: 99.6%).
Stage b) Formation of N- [2- (3-chlorophenyl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and [2- (3-chlorophenyl) ethyl] amine provided the compound of title as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.21-6.96 (m , 4H), 3.80 (s, 2H), 2.87-2.78 (m, 2H), 2.77-2.66 (m, 4H), 1.80-1.66 (m, 2H ), 1.40-1.10 (m, 16H), 0.80 (t, J = 7.2 Hz, 3H). M + (LC / MS (ESI)): 468.4. HPLC (Condition A), Tr: 5.1 min (HPLC purity: 99.1%).
Step c) Formation of ethyl {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N [4- (3-undecyl-1,2,4-oxadiazol-5-yl) Benzyl] amine provided the title compound as a colorless oil (99%). 1H NMR (CDCl3, 300 MHz) δ 8.13 (dd, J1 = 1.7 Hz, J2 = 8.5 Hz, 2H), 7.46-7.37 (m, 2H), 7.26-7 , 20 (m, 2H), 7.18-6.95 (m, 2H), 4.67 (s, 1H), 4.42-. 4.30 (m, 3H), 3.57-3.44 (m, 2H), 2.92-2.76 (m, 4H), 1.89-1.75 (m, 2H), 1, 49-1.19 (m, 19H), 0.89 (t, J = 7.0 Hz, 3H). M + (LC / MS (ESI)): 568.2. HPLC (Condition A), Tr: 6.78 min (HPLC purity: 99.8%).
Step d) Formation of {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3-chlorophenyl) ethyl] [4 (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino } (oxo) acetate provided the title compound as a white powder (85%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, J = 8.1 Hz, 2H), 7.94 (br s, 1H), 7.36-7.26 (m, 2H), 7, 20-6.91 (m, 4H), 4.86 (s, 1H), 4.61 (s, 1H), 3.84 (t, J = 7.6 Hz, 1H), 3.51 (t , J = 7.6 Hz, 1H), 2.91-2.67 (m, 4H), 1.80-1.65 (m, 2H), 1,411.09 (m, 16H), 0.80 ( t, J = 6.8 Hz, 3H). M- (LC / MS (ESI)): 538.0. HPLC (Condition A), Tr: 6.21 min (HPLC purity: 98.4%). Analysis calculated for C30H38ClN3O4 = 0.2 H2O: C, 66.27; H, 7.12; N, 7.73%. Found: C, 66.10; H, 7.16; N, 7.64%
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic gave the title compound as a white solid (84%). M- (LC / MS (ESI)): 538.4. HPLC (Condition A), Tr: 6.17 min (HPLC purity: 99.8%). Analysis calculated for C30H38ClN3O4.C7H17NO5 = 0.3 H2O: C, 60.00; H, 7.57; N, 7.56%. Found: C, 59.84; H, 7.70; N, 7.48%
Example 279: oxo {{(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N - {(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and (1R) -1- [4- (trifluoromethyl) phenyl] ethylamine provided the title compound as a colorless oil (71%). M + (LC / MS (ESI)): 502.4. HPLC (Condition A), Tr: 5.04 min (HPLC purity: 99.6%).
Stage b) Formation of ethyl oxo {{(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15 (step b) but using N - {(1R) -1- [4 (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4 -oxadiazol-5-yl) benzyl] amine provided the title compound as a colorless oil (89%). 1H NMR (CDCl3, 300 MHz) δ 8.04 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.64-7.55 (m , 2H), 7.50-7.38 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5 , 94 (q, J = 7.2 Hz, 0.5H), 5.12 (q, J = 7.0 Hz, 0.5H), 4.80-4.06 (m, 4H), 2, 86-2.73 (m, 2H), 1.86-1.73 (m, 2H), 1.60 (d, J = 7.2 Hz, 1.5H), 1.54 (d, J = 7.3 Hz, 1.5H), 1.49-1.13 (m, 19H), 0.89 (t, J = 6.9 Hz, 3H). M- (LC / MS (ESI)): 600.1; M + (LC / MS (ESI)): 602.5. HPLC (Condition A), Tr: 6.75 min (HPLC purity: 100%).
Step c) Formation of oxo {{(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{(1R) -1- [4 (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazole -5-yl) benzyl] amino} acetate provided the title compound as a white powder (88%). 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J = 7.0 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.567.44 (m, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.18 (d, 8.1 Hz, 1H), 7.10 ( d, J = 8.1 Hz, 1H), 6.02 (q, J = 6.5 Hz, 0.5H), 5.75 (q, J = 6.5 Hz, 0.5H), 4, 99 (d, J = 17 Hz, 0.5H), 4.67-4.49 (m, 1H), 4.14 (d, J = 17 Hz, 0.5H), 2.78-2.64 (m, 2H), 1.81-1.63 (m, 2H), 1.55 (d, J = 6.4 Hz, 1.5H), 1.45 (d, J = 6.5 Hz, 1.5H), 1.40-1.07 (m, 16H), 0.80 (t, J = 6.8 Hz, 3H). M- (LC / MS (ESI)): 572.3. HPLC (Condition A), Tr: 6.21 min (HPLC purity: 97.9%).
Example 280: oxo {{(1R) -l- [4- (trifluoromethyl] phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl] benzyl] amino} acetic acid, salt of N-methyl-D-glucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo {{(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-Oxadiazol-5-yl) benzyl] amino} acetic acid provided the title compound as a white powder (86%). M- (LC / MS (ESI)): 572.4. HPLC (Condition A), Tr: 6.18 min (HPLC purity: 99.2%). Analysis calculated for C31H38F3N3O4.C7H17NO5 = 0.5 H2O: C, 58.67; H, 7.26; N, 7.20%. Found: C, 58.58; H, 7.31; N, 7.12%
Example 281: oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} acetic acid
Stage a) Formation of N- [4- (trifluoromethyl) phenyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 4- (trifluoromethyl) aniline provided the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8 , 3 Hz, 2H), 6.54 (d, J = 8.3 Hz, 2H), 4.40 (s, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1, 80-1.65 (m, 2H), 1.40-1.07 (m, 16H), 0.80 (t, J = 6.8 Hz, 3H). M- (LC / MS (ESI)): 472.5; M + (LC / MS (ESI)): 474.2. HPLC (Condition A), Tr: 6.78 min (HPLC purity: 97.5%).
Stage b) Formation of ethyl oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4- (trifluoromethyl) phenyl] N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as a colorless oil (95%). 1 H NMR (CDCl 3, 300 MHz) δ 8.09 (d, J = 8.3 Hz, 2 H), 7.61 (d, J = 8, 3 Hz, 2H), 7.4 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 5.07 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.9 Hz, 2H), 1.88-1.72 (m, 2H), 1.51-1.17 ( m, 16H), 1.04 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). M- (LC / MS (ESI)): 572.3; M + (LC / MS (ESI)): 574.4. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 99.4%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[4 (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a white powder (54%). 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8 , 0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.97 (s, 2H), 2.70 (t, J = 7.53 Hz, 2H), 1, 76-1.61 (m, 2H), 1.39-1.09 (m, 16H), 0.8 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 472.5 (M-CO-CO2); M + (LC / MS (ESI)): 546.4. HPLC (Condition A), Tr: 6.12 min (HPLC purity: 97.5%). Analysis calculated for C29H34F3N3O4: C, 63.84; H, 6.28; N, 7.70%. Found: C, 63.77; H, 6.32; N, 7.60%
Example 282: oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid, N-methylD-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl ) benzyl] amino} acetic acid provided the title compound as a white powder (89%). M- (LC / MS (ESI)): 472.5 (M-CO-CO2). HPLC (Condition A), Tr: 6.09 min (HPLC purity: 100%). Analysis calculated for C29H34F3N3O4.C7H17NO5 = 0.5 H2O: C, 57.67; H, 6.99; N, 7.47%. Found: C, 57.40; H, 7.13; N, 7.36%
Example 283: oxo {{(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of benzyl 4 - [({(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} amino) -methyl] benzoate
The same procedure used in the preparation of Example 226 (step a) but using benzyl 4-formylbenzoate and (1S) -1- [4- (trifluoromethyl) phenyl] ethylamine provided the title compound as a light yellow oil (83%) . M + (LC / MS (ESI)): 414.3. HPLC (Condition A), Tr: 3.77 min (HPLC purity: 99.1%).
Stage b) Formation of benzyl 4 - [((tert-butoxycarbonyl) {(1S) -1- [4- (trifluoromethyl) phenyl] -ethyl} amino) methyl] benzoate
The same procedure used in the preparation of Example 23 (step b) but using benzyl 4 - [({(1S) -1- [4 (trifluoromethyl) phenyl] ethyl} amino) methyl] benzoate gave the title compound as an oil colorless (90%). HPLC (Condition A), Tr: 6.48 min (HPLC purity: 66.5%).
Step c) Formation of tert-butyl (1S) -1- [4- (trifluoromethyl) phenyl] ethyl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] carbamate
The same procedure used in the preparation of Example 258 (step a and b) but using benzyl 4 - [((tert-butoxycarbonyl) {(1 S) -1- [4- (trifluoromethyl) phenyl] ethyl} amino) methyl] benzoate and N-hydroxidedecanimidamide provided the title compound as a colorless oil (85%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.34-7.17 (m , 4H), 4.47 (br s, 1H), 4.35 (br s, 1H), 2.75 (t, J = 7.5 Hz, 2H), 1.83-1.69 (m, 2H), 1,601.14 (m, 29H), 0.90 (t, J = 7.0 Hz, 3H). HPLC (Condition A), Tr: 8.02 min (HPLC purity: 95.7%).
Stage d) Formation of N - {(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 23 (step f) but using tert-butyl (1S) -1- [4 (trifluoromethyl) phenyl] ethyl [4- (3-undecyl-1,2,4-oxadiazol-5 -yl) benzyl] carbamate and provided the hydrochloride salt of the title compound. The salt was poured into DCM and the resulting solution was washed with an aqueous solution of NaOH (1N). The solvent was dried over MgSO4, filtered and evaporated to give the title compound as a colorless oil (98%). 1H NMR (DMSO-d6, 300 MHz) δ 10.18 (br s, 0.5H), 9.76 (br s, 0.5H), 8.1 (d, J = 8.3 Hz, 2H) , 7.90-7.79 (m, 4H), 7.75 (d, J = 8.3 Hz, 2H), 4.63-4.48 (m, 1H), 4.30-5.16 (m, 1H), 4.04-3.90 (m, 1H), 3.00 (t, J = 7.5 Hz, 2H), 1.78-1.63 (m, 5H), 1, 41-1.24 (m, 16H), 0.84 (t, J = 7.3 Hz, 3H). HPLC (Condition A), Tr: 5.59 min (HPLC purity: 99.5%).
Step e) Formation of ethyl oxo {{(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15 (step b) but using N - {(1S) -1- [4 (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4 -oxadiazol-5-yl) benzyl] amine gave the title compound as a colorless oil (93%).
Step f) Formation of oxo {{(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{(1S) -1- [4 (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazole -5-yl) benzyl] amino} acetate provided the title compound as a colorless oil (93%). 1H NMR (DMSO-d6, 300 MHz) δ 7.80-7.60 (m, 2H), 7.45-7.16 (m, 6H), 7.02 (d, J = 8.3 Hz, 2H), 5.36 (m, 0.3H), 4.95 (m, 0.7H), 4.55-4.23 (m, 2H), 2.59-2.48 (m, 2H) , 1.40 (d, J = 6.5 Hz, 2.1H), 1.35 (d, J = 6.5 Hz, 0.9H), 1.19-0.90 (m, 16H), 0.65 (t, J = 6.9 Hz, 3H). M- (LC / MS (ESI)): 572.3; M + (LC / MS (ESI)): 573.9. HPLC (Condition A), Tr: 7.29 min (HPLC purity: 100%).
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and oxo {{(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-Oxadiazol-5-yl) benzyl] amino} acetic acid gave the title compound as a white solid (92%). M- (LC / MS (ESI)): 572.3; M + (LC / MS (ESI)): 574.3. HPLC (Condition A), Tr: 7.32 min (HPLC purity: 98.7%). Analysis calculated for C31H38F3N3O4.C7H17NO5 = 0.9 H2O: C, 58.14; H, 7.29; N, 7.14%. Found: C, 58.18; H, 7.27; N, 7.19%
Example 285: [(3-Chlorobenzyl) (4-dec-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of N- (3-chlorobenzyl) -N- (4-dec-1-inylbenzyl) amine
The same procedure used in the preparation of Example 226 (step a) but using 4-dec-1-benzylbenzaldehyde and 3-chlorobenzylamine gave the title compound as a colorless oil (60%). 1H NMR (CDCl3, 300 MHz) δ 7.37-7.19 (m, 8H), 3.75 (s, 2H), 3.74 (s, 2H), 2.37 (t, J = 7, 2 Hz, 2H), 1.64-1.52 (m, 2H), 1,481.37 (m, 2H), 1.36-1.19 (m, 8H), 0.91-0.81 (m , 3H). M + (LC / MS (ESI)): 368.4. HPLC (Condition A), Tr: 4.60 min (HPLC purity: 84.1%).
Stage b) Formation of ethyl [(3-chlorobenzyl) (4-dec-1-inylbenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (3-chlorobenzyl) -N- (4dec-1-inylbenzyl) amine gave the title compound as a colorless oil (52%). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.12 (m, 2H), 7.11-7.00 (m, 3H), 6.99-6.84 (m, 3H), 4, 25 (s, 1H), 4.22 (s, 1H), 4.18-4.04 (m, 4H), 2.19 (t, 2H), 1.52-0.95 (m, 15H) , 0.69 (t, J = 6.9 Hz, 3H). HPLC (Condition A), Tr: 6.35 min (HPLC purity: 95.4%).
Stage c) Formation of [(3-chlorobenzyl) (4-dec-1-inylbenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl [(3-chlorobenzyl) (4-dec1-inylbenzyl) amino] (oxo) acetate gave the title compound as a colorless oil (92%). 1H NMR (CD3OD, 300 MHz) δ 7.49-7.04 (m, 8H), 4.50 (s, 4H), 2.43 (t, J = 6.8 Hz, 2H), 1.71 -1.25 (m, 12H), 0.94 (t, J = 7.0 Hz, 3H). M (LC / MS (ESI)): 438.1 HPLC (Condition A), Tr: 5.73 min (HPLC purity: 96.1%). Analysis calculated for C26H30ClNO3 = 0.3 H2O: C, 70.12; H, 6.92; N, 3.14%. Found: C, 69.95; H, 6.73; N, 3.01%
Example 286: [(3-Chlorobenzyl) (4-dec-1-inylbenzyl) amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and [(3-chlorobenzyl) (4-dec-1-inylbenzyl) amino] (oxo) acetic acid gave the title compound as a white powder ( 78%) M- (ESI): 438.0; M + (ESI): 440.2. HPLC (Condition A), Tr: 5.70 min (HPLC purity: 98.3%). Analysis calculated for C26H30ClNO3.C7H17NO5 = 0.3 H2O: C, 61.87; H, 7.49; N, 4.37%. Found: C, 61.59; H, 7.48; N, 4.29%
Example 287: [[2- (3-chlorophenyl) ethyl] (4-oct-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of 4-oct-1-inylbenzaldehyde
The same procedure used in the preparation of Example 275 (step a) but using 4-bromobenzaldehyde and 1-octino gave the title compound as a yellow oil (84%). 1H NMR (CDCl3, 300 MHz) δ 9.97 (s, 1H), 7.78 (d, 2H, J = 8.3 Hz), 7.51 (d, 2H, J = 8.3 Hz), 2.42 (t, 2H, J = 7.0 Hz), 1.67-1.54 (m, 2H), 1.50-1.24 (m, 6H), 0.89 (m, 3H) . M + (LC / MS (ESI)): 215.4. HPLC (Condition A), Tr: 5.17 min (HPLC purity: 78.6%).
Stage b) Formation of N- [2- (3-chlorophenyl) ethyl] -N- (4-oct-1-inylbenzyl) amine
The same procedure used in the preparation of Example 1 (step a) but using 4-oct-1-inylbenzaldehyde and [2- (3-chlorophenyl) ethyl] amine gave the title compound as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.26 (d, J = 8.3 Hz, 2H), 7.19-7.08 (m, 5H), 7.03-6.96 (m, 1H) , 3.71 (s, 2H), 2.83-2.67 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.63-1.44 (m, 2H ), 1.44-1.31 (m, 2H), 1.31-1.15 (m, 6H), 0.83 (t, J = 8.3 Hz, 3H). M + (LC / MS (ESI)): 354.4. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 97.5%).
Stage c) Formation of ethyl [[2- (3-chlorophenyl) ethyl] (4-oct-1-inylbenzyl) amino] (oxo) -acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N (4-oct-1-inylbenzyl) amine gave the title compound as a colorless oil ( 81%) 1H NMR (CDCl3, 300 MHz) δ 7.39 (d, J = 7.7 Hz, 2H), 7.29-6.91 (m, 6H), 4.59 (s, 1H), 4.41 -4.25 (m, 3H), 3.53-3.35 (m, 2H), 2.82 (q, J = 7.3 Hz, 2H), 2.41 (t, J = 7.0 Hz, 2H), 1.69-1.55 (m, 2H), 1.54-1.25 (m, 9H), 0.90 (t, J = 6.9 Hz, 3H). M + (LC / MS (ESI)): 454.3 HPLC (Condition A), Tr: 5.92 min (HPLC purity: 99.8%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl [[2- (3-chlorophenyl) ethyl] (4oct-1-inylbenzyl) amino] (oxo) acetate provided the title compound as a colorless oil (96%). 1H NMR (CD3OD, 300 MHz) δ 7.39-6.85 (m, 8H), 4.49 (s, 1H), 4.32 (s, 1H), 3.48-3.28 (m, 2H), 2.78 (t, J = 7.6 Hz, 1H), 2.66 (t, J = 7.5 Hz, 1H), 2.30 (t, J = 6.4 Hz, 2H) , 1.59-1.10 (m, 8H), 0.80 (t, J = 6.9 Hz, 3H). M- (LC / MS (ESI)): 424.2. HPLC (Condition A), Tr: 5.31 min (HPLC purity: 99.7%). Analysis calculated for C25H28ClNO3 = 0.1 H2O: C, 70.20; H, 6.64; N, 3.27%. Found: C, 69.97; H, 6.76; N, 3.20%
Example 288: [[2- (3-Chlorophenyl) ethyl] (4-oct-1-inylbenzyl) amino] (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and [[2- (3-chlorophenyl) ethyl] (4-oct-1-inylbenzyl) amino] (oxo) acetic acid gave the title compound as a white solid (92%). M- (LC / MS (ESI)): 424.3. HPLC (Condition A), Tr: 5.32 min (HPLC purity: 99.7%). Analysis calculated for C25H28ClNO3.C7H17NO5 = 0.5 H2O: C, 60.99; H, 7.36; N, 4.45%. Found: C, 60.98; H, 7.46; N, 4.40%
Example 289: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- [4- (trifluoromethyl) phenyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4-dec-1-benzylbenzaldehyde and 4- (trifluoromethyl) aniline provided the title compound as a colorless oil (50%). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.21-7.13 (m , 2H), 6.50 (d, J = 8.7 Hz, 2H), 4.28 (s, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.60-1 , 43 (m, 2H), 1.43-1.31 (m, 2H), 1.30-1.11 (m, 8H), 0.87-0.75 (m, 3H). M- (LC / MS (ESI)): 386.4. HPLC (Condition A), Tr: 6.43 min (HPLC purity: 82.6%).
Stage b) Formation of tert-butyl {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-dec-1-inylbenzyl) -N [4- (trifluoromethyl) phenyl] amine and tert-butyl chloro (oxo) acetate provided the compound of the title as a colorless oil (27%). 1H NMR (CDCl3, 300 MHz) δ 7.58 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8 , 3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 5.01 (s, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1, 65-1.69 (m, 2H), 1.49-1.37 (m, 2H), 1.37-1.22 (m, 8H), 1.17 (s, 9H), 0.87 ( t, J = 6.8 Hz, 3H). M + (LC / MS (ESI)): 460.1 (Mt-Bu). HPLC (Condition A), Tr: 6.52 min (HPLC purity: 97.1%).
Step c) Formation of {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 15 (step c) but using tert-butyl {(4-dec-1-ylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetate provided the title compound as a yellow foam (60%) 1H NMR (CDCl3, 300 MHz) δ 7.65 (m, 2H), 7.43 (m, 2H), 7.27 (m, 2H), 5.76 (s, 1H), 4.96 (s , 2H), 2.38 (t, 2H), 1.59-1.45 (m, 2H), 1.44-1.15 (m, 12H), 0.84 (t, J = 6.7 Hz, 3H). M- (ESI): 458. HPLC (Condition A), Tr: 5.70 min (HPLC purity: 94.6%).
Example 290: ((4-dec-1-inylbenzyl) {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- {1- [4- (trifluoromethyl) phenyl] ethyl} amine
The same procedure used in the preparation of Example 226 (step a) but using 4-dec-1-benzylbenzaldehyde and l- [4- (trifluoromethyl) phenyl] ethanamine gave the title compound as a colorless oil (54%). M + (ESI): 416.2. HPLC (Condition A), Tr: 4.67 min (HPLC purity: 87.6%).
Stage b) Formation of ethyl ((4-dec-1-inylbenzyl) {1- [4- (trifluoromethyl) phenyl] ethyl} -amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-dec-1-inylbenzyl) -N {1- [4- (trifluoromethyl) phenyl] ethyl} amine gave the title compound as a colorless oil (60%). 1H NMR (CDCl3, 300 MHz) δ 7.63-7.52 (m, 2H), 7.43-7.34 (m, 2H), 7.32-7.20 (m, 2H), 7, 07-6.95 (m, 2H), 5.81 (m, 0.5H), 5.03 (m, 0.5H), 4.77-3.86 (m, 4H), 2.38 ( t, J = 7.2 Hz, 2H), 1.66-1.21 (m, 18H), 0.88 (t, J = 7.1 Hz, 3H). M + (ESI): 516.2. HPLC (Condition A), Tr: 6.38 min (HPLC purity: 98.2%).
Step c) Formation of ((4-dec-1-inylbenzyl) {1- [4- (trifluoromethyl) phenyl] ethyl} amino) - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ((4-dec-1-inylbenzyl) {1 [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetate gave the title compound as a colorless oil (85%). 1H NMR (DMSO-d6, 300 MHz) δ 7.53-7.39 (m, 2H), 7.38-7.18 (m, 2H), 7.10-6.70 (m, 3H), 6.78 (d, J = 8.3 Hz, 1H), 5.24 (q, J = 7.2 Hz, 0.4H), 4.93 (q, J = 7.2 Hz, 0.6H ), 4.39-4.15 (m, 1.4H), 4.00-3.89 (m, 0.6H), 2.20-2.13 (m, 2H), 1,410.96 (m , 15H), 0.66 (t, J = 7.1 Hz, 3H). M- (LC / MS (ESI)): 486.3. HPLC (Condition A), Tr: 5.76 min (HPLC purity: 98.2%). Analysis calculated for C28H32F3NO3 = 1.0 H2O: C, 66.52; H, 6.78; N, 2.77%. Found: C, 66.73; H, 6.82; N, 2.72%
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and ((4dec-1-inylbenzyl) {1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) -acetic acid provided the title compound as a solid
5 white (84%). M- (LC / MS (ESI)): 486.1. HPLC (Condition A), Tr: 5.79 min (HPLC purity: 98.3%). Analysis calculated for C28H32F3NO3.C7H17NO5 = 1.0 H2O: C, 59.99; H, 7.33; N, 4.00%. Found: C, 60.22; H, 7.37; N, 3.96%
Example 292: {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} acetamide
To a cold solution (0 ° C) H2SO4 (2.68 g, 27.3 mmol) in CH3CN (91 mL) was added dropwise a solution of 2- (4 (trifluoromethyl) -phenyl) -2-propanol (1, 86 g, 9.1 mmol) in CH3CN (9.1 mL). The resulting reaction mixture was stirred at 0 ° C for 1 h then at RT for 23 h. The solvent was evaporated in vacuo and H2O (20 mL) was added. The mixture was extracted with Et2O (2x 50mL) and the combined organic layers were washed with H2O (2x 20 mL), an aqueous solution of NaOH (1N) (2x 20 mL), dried over MgSO4, filtered and evaporated to provide the compound of
15 title as a white solid (2.00 g, 90%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 2.10 (s, 3H), 1.79 (s, 6H). HPLC (Condition A), Tr: 3.18 min (HPLC purity: 97.2%).
Stage b) Formation of 1-methyl-1- [4- (trifluoromethyl) phenyl] ethylamine
To a solution N- {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} acetamide (2.0 g, 8.16 mmol) in ethylene glycol (5 mL) was added KOH (3.66 g, 8 , 16 mmol) and the resulting mixture was heated for 48 h at 170 ° C. After cooling to 20 RT, the reaction mixture was extracted with Et2O (3 x 20 mL). The combined organic layers were washed with water (4x), dried over MgSO4, filtered and evaporated to give a colorless oil. This oil was dissolved in Et2O (30 mL) and a saturated solution of HCl in Et2O (10 mL) was added. The white precipitate was collected, washed with Et2O (3 x 10 mL) and dried in vacuo. This solid was then poured into Et2O (50 mL) and a 1N aqueous solution of NaOH (20 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et2O. Layers
The combined organics were washed with water (2 x 20 mL), dried over MgSO4, filtered and evaporated to give the title compound as a colorless oil (1.2 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.60-7.46 (m, 4H), 1.53 (br s, 2H), 1.43 (s, 6H). HPLC (Condition A), Tr: 1.73 min (HPLC purity: 94.0%).
Step c) Formation of N- {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (3-undecyl-1,2,4
Oxadiazol-5-yl) benzaldehyde and 1-methyl-1- [4- (trifluoromethyl) phenyl] ethylamine gave the title compound as a colorless oil (78%). 1H NMR (CDCl3, 300 MHz) δ 8.07 (d, J = 7.9 Hz, 2H), 7.73-7.59 (m, 4H), 7.49 (d, J = 8.3 Hz , 2H), 3.57 (s, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.89-1.74 (m, 2H), 1.57 (s, 3H) , 1.47-1.17 (m, 19H), 0.88 (t, J = 7.0 Hz, 3H). M + (LC / MS (ESI)): 516.3. HPLC (Condition A), Tr: 5.02 min (HPLC purity: 98.2%).
Step d) Formation of ethyl {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-535 yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- {1-methyl-1- [4 (trifluoromethyl) phenyl] ethyl} -N- [4- (3-undecyl-1,2,4 -oxadiazol-5-yl) benzyl] amine gave the title compound as a yellow oil (87%). 1H NMR (CDCl3, 300 MHz) δ 8.15 (d, J = 8.3 Hz, 2H), 7.70-7.50 (m, 4H), 7.42 (d, J = 8.3 Hz , 2H), 4.92-4.75 (m, 2H), 4.31-4.18 (m, 1.3H), 3.65-3.52 (m, 0.7H), 2.79 (t, J = 7.2 Hz, 2H), 1.91-1.75 (m, 2H), 1.75
40 1.60 (m, 3H), 1.54 (s, 3H), 1.48-1.00 (m, 19H), 0.87 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 614.2; M + (LC / MS (ESI)): 616.4. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 99.7%).
Step e) Formation of {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{1-methyl-1- [4
45 (Trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless foam (94%). 1H NMR (CD3OD, 300 MHz) δ 8.08 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8 , 3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 5.03 (s, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1, 82-1.48 (m, 8H), 1.40-1.10 (m, 16H), 0.89 (t, J = 7.0Hz, 3H). M- (LC / MS (ESI)): 586.2. HPLC (Condition A), Tr: 6.21 min (HPLC purity: 99.6%). Analysis calculated for C32H40F3N3O4 = 0.2 H2O: C, 65.00; H, 6.89; N, 7.11%. Found: C, 64.64; H, 6.69; 50 N, 6.84%
Example 293: {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid , N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4 -oxadiazol-5-yl) benzyl] amino} (oxo) acetic gave the title compound as a white powder (95%). M- (LC / MS (ESI)): 586.3. HPLC (Condition A), Tr: 6.22 min (HPLC purity: 99.9%). Analysis calculated for C32H40F3N3O4.C7H17NO5 = 1.5 H2O: C, 57.84; H, 7.47; N, 6.92%. Found: C, 57.79; H, 7.46; N, 6.88%
Example 294: {[2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} - (oxo) acetic acid
Stage a) Formation of 4- (3-octyl-1,2,4-oxadiazol-5-yl) benzaldehyde
The same procedure used in the preparation of Example 277 (step a) but using 4-carboxybenzaldehyde and N-hydroxynimanimidamide provided the title compound as a beige solid (34%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.29 (d, 2H, J = 8.3 Hz), 8.03 (d, 2H, J = 8.3 Hz), 2.81 (t, 2H, J = 7.4 Hz), 1.86-1.75 (m, 2H), 1.46-1.21 (m, 10H), 0.87 (m, 3H) . HPLC (Condition A), Tr: 5.16 min (HPLC purity: 95.4%).
Stage b) Formation of N- [2- (3-chlorophenyl) ethyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and [2- (3-chlorophenyl) ethyl] amine provided the compound of title as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.23-7.00 (m , 4H), 3.88 (s, 2H), 2.95-2.68 (m, 6H), 1.75-1.65 (m, 2H), 1.41-1.20 (m, 10H ), 0.87 (t, J = 7.1 Hz, 3H). M + (LC / MS (ESI)): 426.4. HPLC (Condition A), Tr: 4.35 min (HPLC purity: 99.6%).
Step c) Formation of ethyl {[2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N [4- (3-octyl-1,2,4-oxadiazol-5-yl) Benzyl] amine provided the title compound as a colorless oil (59%). 1H NMR (CDCl3, 300 MHz) δ 8.05 (dd, J = 8.3 Hz, J2 = 1.5 Hz, 2H), 7.37-7.39 (m, 2H), 7.18-7 , 12 (m, 2H), 7.09-6.87 (m, 2H), 4.59 (s, 1H), 4.43-4.22 (m, 3H), 3.48-3.35 (m, 2H), 2.84-2.68 (m, 4H), 1.80-1.68 (m, 2H), 1.38-1.14 (m, 13H), 0.87 (t , J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 524.4; M + (LC / MS (ESI)): 526.4. HPLC (Condition A), Tr: 6.06 min (HPLC purity: 99.8%).
Step d) Formation of {[2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3-chlorophenyl) ethyl] [4 (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino } (oxo) acetate provided the title compound as a colorless oil (79%). 1H NMR (CD3OD, 300 MHz) δ 8.14 (d, J = 8.3 Hz, 2H), 7.60-7.49 (m, 2H), 7.34-7.09 (m, 4H) , 4.72 (s, 1.2H), 4.57 (s, 0.8H), 3.67-3.49 (m, 2H), 3.03-2.76 (m, 4H), 1 , 90-1.75 (m, 2H), 1.51-1.24 (m, 10H), 0.89 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 496.3. HPLC (Condition A), Tr: 5.48 min (HPLC purity: 100%). Analysis calculated for C27H32ClN3O4 = 0.5 H2O: C, 63.96; H, 6.56; N, 8.29%. Found: C, 63.96; H, 6.59; N, 8.20%
Example 295: {[2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid, N-methyl salt -Dglucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {[2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic gave the title compound as a white solid (68%). M- (LC / MS (ESI)): 496.2. HPLC (Condition A), Tr: 5.51 min (HPLC purity: 99.4%). Analysis calculated for C27H32ClN3O4.C7H17NO5 = 1.5 H2O: C, 56.70; H, 7.28; N, 7.78%. Found: C, 56.83; H, 7.48; N, 7.77%
Example 296: {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -N- [4- (trifluoromethyl) -benzyl] amine
The same procedure used in the preparation of Example 223 (step b) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 4- (trifluoromethyl) benzylamine provided the title compound as a colorless oil (49%). M + (LC / MS (ESI)): 446.4.
Stage b) Formation of ethyl {[4- (3-octyl-l, 2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4- (3-octyl-1,2,4oxadiazol-5-yl) benzyl] -N- [4- (trifluoromethyl) benzyl] amine provided the title compound as a colorless oil (89%). 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.60-7.49 (m , 2H), 7.39-7.22 (m, 4H), 4.50 (s, 2H), 4.37 (s, 2H), 4.34-4.23 (m, 2H), 2, 78-2.67 (m, 2H), 1.82-1.66 (m, 2H), 1.42-1.11 (m, 13H), 0.81 (t, J = 7.2 Hz, 3H). M- (LC / MS (ESI)): 544.3; M + (LC / MS (ESI)): 546.2. HPLC (Condition A), Tr: 5.98 min (HPLC purity: 98.5%).
Step c) Formation of {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[4- (3-octyl-1,2,4oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo ) acetate provided the title compound as a colorless oil (90%). 1H NMR (CD3OD, 300 MHz) δ 8.16-8.04 (m, 2H), 7.71-7.38 (m, 6H), 4.66 (s, 2H), 4.64 (s, 2H), 2.80 (m, 2H), 1.91-1.76 (m, 2H), 1.52-1.25 (m, 10H), 0.91 (t, J = 7.0 Hz , 3H). M- (LC / MS (ESI)): 516.2. HPLC (Condition A), Tr: 5.45 min (HPLC purity: 98.3%). Analysis calculated for C27H30F3N3O4 = 0.2 H2O: C, 62.23; H, 5.88; N, 8.06%. Found: C, 62.10; H, 6.04; N, 7.87%
Example 297: {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methylD-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {[4- (3octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic gave the title compound as a white solid (82%). M- (LC / MS (ESI)): 516.3. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 98.6%). Analysis calculated for C27H30F3N3O4.C7H17NO5 = 1.0 H2O: C, 55.88; H, 6.76; N, 7.67%. Found: C, 55.54; H, 6.79; N, 7.55%
Example 298: {{[4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of 4- (dodecyloxy) -1-naphthaldehyde
To a solution of 1-bromodecane (10.0 g, 40.12 mmol) and 4-hydroxy-1-naphthaldehyde (6.29 g, 36.5 mmol) in anhydrous DMF (150 mL) was added NaOMe (2, 38 g, 44.1 mmol). The mixture was stirred at 50 ° C for 5 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was dissolved in EtOAc and washed with brine (3x), dried over MgSO4, filtered and concentrated under reduced pressure to provide an orange solid. Purification by chromatography (SiO2, c-Hex / EtOAc 9/1) provided the title product as a beige powder (11.12 g, 81%). 1H NMR (CDCl3, 300 MHz) δ 10.2 (s, 1H), 9.29 (d, 1H, J = 8.7 Hz), 8.35 (d, 1H, J = 8.7 Hz), 7.90 (d, 1H, J = 8.3 Hz), 7.69 (m, 1H), 7.57 (m, 1H), 6.90 (d, 1H, J = 7.9 Hz), 4.23 (t, 2H, J = 6.4 Hz), 2.01-1.79 (m, 2H), 1,681.48 (m, 2H), 1.45-1.20 (m, 16H) , 0.87 (m, 3H). HPLC (Condition A), Tr: 6.61 min (HPLC purity: 85.8%).
Stage b) Formation of N - {[4- (dodecyloxy) -1-naphthyl] methyl} -N- [4- (trifluoromethyl) -benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (dodecyloxy) -1 naphthalene and 4- (trifluoromethyl) benzylamine gave the title compound as a colorless oil (66%). 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.76-7.41 (m , 6H), 7.32 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 4.19-4.11 (m, 4H), 3 , 63 (s, 2H), 1.96-1.84 (m, 2H), 1.63-1.47 (m, 2H), 1.45-1.20 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H). HPLC (Condition A), Tr: 5.41 min (HPLC purity: 100%).
Step c) Formation of ethyl {{[4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N - {[4- (dodecyloxy) -1 naphthyl] methyl} -N- [4- (trifluoromethyl) benzyl] amine gave the title compound as an oil colorless (88%). 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 0.5H), 7.76 (m, 0 , 5H), 7.60-7.44 (m, 4H), 7.28 (m, 1.5H), 7.19 (t, J = 8.3 Hz, 1H), 7.02 (d, J = 7.9 Hz, 0.5H), 6.72 (d, J = 7.9 Hz, 0.5H), 6.68 (d, J = 7.9 Hz, 0.5H), 4, 93 (s, 1H), 4.79 (s, 1H), 4.52 (s, 1H), 4.40-4.23 (m, 3H), 4.11 (m, 2H), 1.93 (m, 2H), 1.40-1.15 (m, 21H), 0.87 (t, J = 6.9 Hz, 3H). HPLC (Condition A), Tr: 6.98 min (HPLC purity: 96.6%).
Step d) Formation of {{[4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{[4- (dodecyloxy) -1 naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a white powder (67%). 1H NMR (CD3OD, 300 MHz) δ 8.30-8.19 (m, 1H), 8.00-7.91 (m, 1H), 7.61-7.26 (m, 6H), 7, 21-7.09 (s, 1H), 4.98 (s, 2H), 4.54 (s, 1H), 4.46 (s, 1H), 4.17 (m, 2H), 2.05 -1.88 (m, 2H), 1.71-1.55 (m, 2H), 1.55-1.21 (m, 16H), 0.91 (t, J = 6.8 Hz, 3H ). M- (LC / MS (ESI)): 570.2. HPLC (Condition A), Tr: 6.44 min (HPLC purity: 100%).
Example 299: {{[4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1 - (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and {{[4 (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided the title compound as a pink solid (68%). M- (LC / MS (ESI)): 570.3. HPLC (Condition A), Tr: 6.45 min (HPLC purity: 99.7%). Analysis calculated for C33H40F3NO4.C7H17NO5 = 1.5 H2O: C, 60.52; H, 7.62; N, 3.53%. Found: C, 60.71; H, 7.50; N, 3.56%
Stage a) Formation of N- (4-bromobenzyl) -N- (4-oct-1-inylbenzyl) amine
The same procedure used in the preparation of Example 226 (step a) but using 4-oct-1-benzylbenzaldehyde and 4-bromobenzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.30-7.19 (m , 4H), 3.78 (s, 2H), 3.75 (s, 2H), 2.42 (t, J = 6.8 Hz, 2H), 1.69-1.55 (m, 2H) , 1.54-1.42 (m, 2H), 1.42-1.27 (m, 4H), 0.93 (t, J = 6.8 Hz, 3H). M + (LC / MS (ESI)): 384.4 HPLC (Condition A), Tr: 4.18 min (HPLC purity: 97.6%).
Stage b) Formation of ethyl [(4-bromobenzyl) (4-oct-1-inylbenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-bromobenzyl) -N- (4oct-1-inylbenzyl) amine gave the title compound as a yellow oil (93%). 1H NMR (CDCl3, 300 MHz) δ 7.56-7.44 (m, 2H), 7.45-7.34 (m, 2H), 7.22-7.06 (m, 4H), 4, 51-4.23 (m, 6H), 2.49-2.37 (m, 2H), 1.75-1.56 (m, 2H), 1.54-1.24 (m, 9H), 0.92 (t, J = 7.0 Hz, 3H). HPLC (Condition A), Tr: 98.9 min (HPLC purity: 95.2%).
Stage c) Formation of [(4-bromobenzyl) (4-oct-1-inylbenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl [(4-bromobenzyl) (4oct-1-inylbenzyl) amino] (oxo) acetate gave the title compound as a colorless oil (87%). 1H NMR (CD3OD, 300 MHz) δ 7.57-7.47 (m, 2H), 7.39-7.31 (m, 2H), 7.29-7.22 (m, 2H), 7, 18-7.11 (m, 2H), 4.47 (s, 2H), 4.45 (s, 2H), 2.42 (t, J = 6.8 Hz, 2H), 1.69-1 , 30 (m, 8H), 0.96 (t, J = 7.0 Hz, 3H). M- (LC / MS (ESI)): 455.8. HPLC (Condition A), Tr: 5.28 min (HPLC purity: 98.7%).
Example 301: [{4 - [(dodecylamino) carbonyl] benzyl} (2-hydroxy-1-phenylethyl) amino] - (oxo) acetic acid
Stage a) Formation of N-dodecyl-4 - {[(2-hydroxy-1-phenylethyl) amino] methyl} benzamide
The same procedure used in the preparation of Example 226 (step a) but using N-dodecyl-4formylbenzamide and 2-amino-2-phenylethanol provided the title compound as a white powder (83%). 1H NMR (CD3OD, 300 MHz) δ 7.79 (d, J = 8.3 Hz, 2H), 7.44-7.26 (m, 7H), 3.85-3.56 (m, 5H) , 3.39 (t, J = 7.2 Hz, 2H), 1,711.58 (m, 2H), 1.47-1.25 (m, 18H), 0.92 (t, J = 6.8 Hz, 3H) M- (LC / MS (ESI)): 437.5; M + (LC / MS (ESI)): 439.6 HPLC (Condition A), Tr: 4.26 min (HPLC purity: 98.8%).
Stage b) Formation of 4 - [(2,3-dioxo-5-phenylmorpholin-4-yl) methyl] -N-dodecylbenzamide
The same procedure used in the preparation of Example 15 (step b) but using N-dodecyl-4 - {[(2-hydroxy1-phenylethyl) amino] methyl} benzamide gave the title compound as a colorless oil (39%). 1H NMR (CDCl3, 300 MHz) δ 7.66 (d, J = 8.3 Hz, 2H), 7.41-7.31 (m, 3H), 7.19 (d, J = 8.3 Hz , 2H), 7.15-7.05 (m, 2H), 6.17 (t, J = 6.0 Hz, 1H), 5.43 (s, 0.5H), 5.38 (s, 0.5H), 4.64-4.47 (m, 2H), 4.41-4.31 (m, 1H), 3.77 (s, 0.5H), 3.72 (s, 0, 5H), 3.37 (m, 2H), 1.61-1.48 (m, 2H), 1.38-1.09 (m, 18H), 0.81 (t, J = 7.1 Hz , 3H). M- (LC / MS (ESI)): 491.4; M + (LC / MS (ESI)): 493.4. HPLC (Condition A), Tr: 5.48 min (HPLC purity: 98.8%).
Step c) Formation of [{4 - [(dodecylamino) carbonyl] benzyl} (2-hydroxy-1-phenylethyl) -amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using 4 - [(2,3-dioxo-5-phenylmorpholin-4-yl) methyl] -N-dodecylbenzamide provided the title compound as a colorless oil (87% ). 1H NMR (CDCl3, 300 MHz) δ 7.54 (m, 2H), 7.31-7.20 (m, 3H), 7.15-6.91 (m, 4H), 6.02 (br s , 1H), 5.30 (d, J = 14.6 Hz, 1H), 4.56-4.20 (m, 3H), 3.63 (d, J = 14.6 Hz, 1H), 3 , 26 (m, 2H), 1.51-1.35 (m, 2H), 1.32-0.97 (m, 18H), 0.70 (t, J = 6.9 Hz, 3H). M- (LC / MS (ESI)): 509.4; M + (LC / MS (ESI): 511.4. HPLC (Condition A), Tr: 5.47 min (HPLC purity: 90.2%).
Example 302: ((4-dec-1-inylbenzyl) {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} -amino) (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- {1-methyl-1- [4- (trifluoromethyl) phenyl] -ethyl} amine
The same procedure used in the preparation of Example 226 (step a) but using 4-dec-1-benzylbenzaldehyde and 1-methyl-1- [4- (trifluoromethyl) phenyl] ethylamine gave the title compound as a colorless oil (79%) . 1H NMR (CDCl3, 300 MHz) δ 7.74-7.57 (m, 4H), 7.36 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.3 Hz , 2H), 3.48 (s, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.73-1.22 (m, 18H), 0.91 (t, J = 7.0 Hz, 3H). M + (LC / MS (ESI)): 430.4. HPLC (Condition A), Tr: 4.69 min (HPLC purity: 99.8%).
Stage b) Formation of ethyl ((4-dec-1-inylbenzyl) {1-methyl-1- [4- (trifluoromethyl) phenyl] -ethyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-dec-1-inylbenzyl) -N {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} amine provided the compound of the title as a colorless oil (91%). 1H NMR (CDCl3, 300 MHz) δ 7.58 (d, J = 8.1 Hz, 2H), 7.51-7.25 (m, 6H), 4.90-4.71 (m, 2H) , 4.33-4.17 (m, 1.5H), 3.663.46 (m, 0.5H), 2.43 (t, J = 7.2 Hz, 2H), 1.77-1.54 (m, 8H), 1.53-1.18 (m, 13H), 0.91 (t, J = 7.0 Hz, 3H)
Step c) Formation of ((4-dec-1-inylbenzyl) {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} -amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ((4-dec-1-inylbenzyl) {1methyl-1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetate provided the title compound as a colorless oil (95%). 1H NMR (CD3OD, 300 MHz) δ 7.60-7.04 (m, 8H), 4.80 (s, 2H), 2.31 (t, J = 6.8 Hz, 2H), 1.70 -1.10 (m, 18H), 0.80 (t, J = 6.9 Hz, 3H). M- (LC / MS (ESI)): 500.2. HPLC (Condition A), Tr: 5.84 min (HPLC purity: 99.8%). Analysis calculated for C29H34F3NO3: C, 69.44; H, 6.83; N, 2.79%. Found: C, 69.55; H, 7.07; N, 2.77%
Example 303: ((4-dec-1-inylbenzyl) {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} amino) - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1 -deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using N-methyl-D-glucamine and acid ((4dec-1-inylbenzyl) {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} -amino) ( oxo) acetic gave the title compound as a white solid (80%). M- (LC / MS (ESI)): 500.2. HPLC (Condition A), Tr: 5.89 min (HPLC purity: 98.6%). Analysis calculated for C29H34F3NO3.C7H17NO5 = 1.0 H2O: C, 60.49; H, 7.47; N, 3.92%. Found: C, 60.75; H, 7.76; N, 3.89%
Example 304: oxo {{4 - [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic acid
Stage a) Formation of ethyl oxo {{4 - [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} acetate
To a cold solution (0 ° C) of ethyl {(4-aminobenzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetate (140 mg, 0.37 mmol) in anhydrous pyridine (2 mL) was added (9Z) -tetradec-9-enoyl (100 mg, 0.40 mmol) under an inert atmosphere. The resulting reaction mixture was stirred for 1 h at 0 ° C. A 5 N aqueous solution of HCl (10 mL) was added and the mixture was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide a yellow oil. This crude product was purified by SPE (Isolute NH2 column) to provide the title compound as a light yellow oil (191 mg, 88%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.52 (m, 2H), 7.39 (d, 1H, J = 8.0 Hz), 7.33 (d, 1H , J = 7.9 Hz), 7.20 (m, 3H), 5.36 (m, 2H), 4.52 (s, 1H), 4.46 (s, 1H), 4.42-4 , 30 (m, 4H), 2.37 (t, 2H, J = 7.5 Hz), 2.03 (m, 4H), 1.74 (m, 2H), 1.39-1.29 ( m, 15H), 0.90 (t, 3H, J = 6.9 Hz). M- (LC / MS (ESI)): 587; M + (LC / MS (ESI)): 589. HPLC (Condition A), Tr: 7.24 min (HPLC purity: 97.3%).
Stage b) Formation of oxo {{4 - [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 - [(9Z) -tetradec9-enoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} acetate gave the title compound as a yellow oil (84%). 1H NMR (CD3OD, 300 MHz) δ 7.64 (m, 2H), 7.50 (m, 3H), 7.36 (d, 1H, J = 8.18 Hz), 7.25 (d, 1H , J = 8.67 Hz), 7.15 (d, 1H, J = 8.67 Hz), 5.35 (m, 2H), 4.55 (s, 2H), 4.47 (s, 2H ), 2.36 (t, 2H, J = 7.2 Hz), 2.03 (m, 4H), 1.33 (m, 14H), 0.91 (m, 3H). M- (LC / MS (ESI)): 559; M + (LC / MS (ESI)): 561. HPLC (Condition A), Tr: 6.25 min (HPLC purity: 99.1%).
Example 305: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of ethyl {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] -amino} - (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-decino gave the title compound as a yellow oil (58%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.36 (m, 4H), 7.15 (m, 2H), 4.50 (m, 2H), 4.35 (m , 4H), 2.42 (dt, 2H, J = 7.0, 1.5 Hz), 1.62 (m, 2H), 1.47 (m, 2H), 1.34 (m, 11H) , 0.90 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 7.16 min (HPLC purity: 99.5%).
Stage b) Formation of {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a yellow oil ( 91%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 3H), 7.34 (m, 4H), 7.12 (m, 2H), 6.28 (br s, 1H), 4.89 ( s, 1H), 4.82 (s, 1H), 4.55 (s, 1H), 4.52 (s, 1H), 2.38 (t, 2H, J = 6.7 Hz), 1, 58 (m, 2H), 1.41 (m, 2H), 1.27 (br s, 8H), 0.87 (m, 3H) M- (LC / MS (ESI)): 472. HPLC (Condition A), Tr: 6.57 min (HPLC purity: 98.5%).
Example 306: oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} acetic acid
Stage a) Formation of 3 - ({[4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid
The same procedure used in the preparation of Example 226 (step a) but using 3-formylbenzoic acid gave the title compound as a white solid (72%). 1H NMR (CD3OD, 300 MHz) δ 8.20 (br s, 1H), 8.11 (d, 1H, J = 7.9 Hz), 7.80-7.70 (m, 4H), 7, 59 (m, 2H), 4.38 (m, 4H). M- (LC / MS (ESI)): 308; M + (LC / MS (ESI)): 310. HPLC (Condition A), Tr: 2.60 min (HPLC purity: 78.7%).
To a solution of 3 - ({[4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid hydrochloride (4.00 g, 11.6 mmol) and a 1N aqueous solution of NaOH (25 mL) in dioxane (25 mL) at 0 ° C di-tert-butyl dicarbonate (2.78 g, 12.7 mmol) was added and the resulting reaction mixture was stirred at 0 ° C for 30 min. The solvents were removed by evaporation. The residue was diluted with a 1N aqueous solution of HCl (35 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM / MeOH 95/5) to provide the title compound as a yellow oil (3.05 g, 64%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, 1H, J = 7.1 Hz), 7.94 (br s, 1H), 7.59 (d, 2H, J = 7.9 Hz) , 7.45 (m, 2H), 7.33 (m, 2H), 4.50 (br s, 2H), 4.42 (br s, 2H), 1.50 (s, 9H). M (LC / MS (ESI)): 408 HPLC (Condition A), Tr: 5.41 min (HPLC purity: 98.2%).
Step c) Formation of tert-butyl 3 - {[(dodecanimidoylamino) oxy] carbonyl} benzyl [4- (trifluoromethyl) benzyl] carbamate
The same procedure used in the preparation of Example 10 (step a) but using 3 - ({(tert-butoxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid and N-hydroxidedecanimidamide provided the title compound as a yellow oil clear (99%). 1H NMR (CDCl3, 300 MHz) δ 7.91 (m, 2H), 7.59 (m, 2H), 7.36 (m, 4H), 4.78 (br s, 2H), 4.48 ( br s, 2H), 4.41 (br s, 2H), 2.34 (m, 2H), 1.65 (m, 2H), 1.50 (s, 9H), 1.26 (br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Tr: 7.34 min (HPLC purity: 95.6%).
Stage d) Formation of tert-butyl 4- (trifluoromethyl) benzyl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] carbamate
The same procedure used in the preparation of Example 23 (step e) but using tert-butyl 3 {[(dodecanimidoylamino) oxy] carbonyl} benzyl [4- (trifluoromethyl) benzyl] carbamate provided the title compound as a yellow oil (54 %). 1H NMR (CDCl3, 300 MHz) δ 8.04 (d, 1H, J = 7.1 Hz), 7.95 (br s, 1H), 7.59 (d, 2H, J = 8.3 Hz) , 7.48 (m, 2H), 7.32 (m, 2H), 4.51 (br s, 2H), 4.44 (br s, 2H), 2.80 (t, 2H, J = 7 , 5 Hz), 1.80 (m, 2H), 1.51 (s, 9H), 1.43-1.27 (m, 16H), 0.88 (m, 3H). HPLC (Condition A), Tr: 8.35 min (HPLC purity: 96.4%).
Stage e) Formation of N- [4- (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine hydrochloride
The same procedure used in the preparation of Example 23 (step f) but using tert-butyl 4 (trifluoromethyl) benzyl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] carbamate provided the compound of the title as a white solid (90%). 1H NMR (CD3OD, 300 MHz) δ 8.31 (br s, 1H), 8.23 (d, 1H, J = 7.9 Hz), 7.80 (m, 3H), 7.71 (m, 3H), 4.43 (s, 2H), 4.41 (s, 2H), 2.80 (t, 2H, J = 7.5 Hz), 1.80 (m, 2H), 1.33 ( m, 16H), 0.89 (t, 3H, J = 6.6 Hz). HPLC (Condition A), Tr: 5.4 min (HPLC purity: 99.7%).
Step f) Formation of ethyl oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4 (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) hydrochloride) benzyl] amine provided the title compound as a light yellow oil (89%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 1H), 7.98 (br s, 0.5H), 7.88 (br s, 0.5H), 7.61 (m, 2H) , 7.52 (m, 2H), 7.39 (d3 1H, J = 7.9 Hz), 7.34 (d, 1H, J = 7.9 Hz), 4.58 (m, 2H), 4.46 (m, 2H), 4.36 (m, 2H), 2.79 (m, 2H), 1.81 (m, 2H), 1.42-1.23 (m, 19H), 0 , 87 (t, 3H, J = 6.6 Hz). HPLC (Condition A), Tr: 7.43 min (HPLC purity: 99.4%).
Step g) Formation of oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[4 (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a yellow oil (77%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (br s, 1H), 7.96 (m, 1H), 7.61-7.33 (m, 6H), 4.98 (m, 2H), 4.64 (br s, 2H), 2.80 (m, 2H), 1.79 (m, 2H), 1.25 (br s, 16H), 0.87 (m, 3H). M- (LC / MS (ESI)): 558; M + (LC / MS (ESI)):
560. HPLC (Condition A), Tr: 6.87 min (HPLC purity: 99.3%). Analysis calculated for C30H36F3N3O4 = 0.2 H2O: C, 63.98; H, 6.51; N, 7.46%. Found: C, 63.90; H, 6.59; N, 7.46%
Example 307: oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid, N-methylD-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using oxo {[4 (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid and N- methyl-D-glucamine provided the title compound as a white powder (98%). M- (LC / MS (ESI)): 558. HPLC (Condition A), Tr: 6.85 min (HPLC purity: 99.2%). Analysis calculated for C30H36F3N3O4.C7H17NO5 = 1.5 H2O: C, 56.84; H, 7.22; N, 7.17%. Found: C, 56.88; H, 7.13; N, 7.10%
Example 308: {(4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino (oxo) acetic acid
Stage a) Formation of ethyl {(4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetate
The same procedure used in the preparation of Example 1 (step c) but using ethyl {(4-dodec-1inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate in EtOAc provided the title compound as a colorless oil (95%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, 0.7H, J = 8.2 Hz), 7.60 (d, 1.3H, J = 8.1 Hz), 7.39 (d , 0.7H, J = 8.2 Hz), 7.33 (d, 1.3H, J = 8.1 Hz), 7.15 (m, 4H), 4.54 (s, 1.3H) , 4.48 (s, 0.7H), 4.41-4.30 (m, 4H), 2.61 (m, 2H), 1.61 (m, 2H), 1.38-1.27 (m, 21H), 0.89 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 7.24 min (HPLC purity: 99.5%).
Stage b) Formation of {(4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dodecylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a colorless oil (95%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.35 (m, 2H), 7.16 (m, 4H), 5.06 (s, 1H), 4.97 (s , 1H), 4.61 (s, 1H), 4.56 (s, 1H), 2.61 (t, 2H, J = 7.7 Hz), 1.61 (m, 2H), 1.29 (m, 18H), 0.89 (t, 3H, J = 6.6 Hz). M- (LC / MS (ESI)): 504. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 99.6%). Analysis calculated for C29H38F3NO3: C, 68.89; H, 7.57; N, 2.77%. Found: C, 68.72; H, 7.52; N, 2.66%
Example 309: {(4-Dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {(4-dodecylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine gave the title compound as a white powder ( 94%). M- (LC / MS (ESI)): 504 HPLC (Condition A), Tr: 6.58 min (HPLC purity: 99.9%). Analysis calculated for C29H38F3NO3.C7H17NO5: C, 61.70; H, 7.91; N, 4.00%. Found: C, 61.32; H, 7.97; N, 3.91%

Example

310: {[4 - ({[(2-butyl-1-benzofuran-3-yl) methyl] amino} carbonyl) benzyl] [4

(trifluoromethyl) ben

cil] amino} (oxo) ethical ac

Stage

a) Formation of ethyl {[4 - ({[(2-butyl-1-benzofuran-3-yl) methyl] amino} carbonyl) -benzyl] [4

(trifluoromethyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 1 (step d) but using 4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) benzoic acid and [(2-butyl-1 hydrochloride] -benzofuran-3-yl) methyl] amine, HOBT and TEA in DCM provided the title compound as a white solid (33%). 1H NMR (CDCl3, 300 MHz) δ 7.66 (m, 2H), 7.51 (m, 3H), 7.35-7.18 (m, 7H), 6.05 (br s, 1H), 4.64 (s, 2H), 4.44 (s, 2H), 4.29 (m, 4H), 2.78 (m, 2H), 1.66 (m, 2H), 1.46 (m , 2H), 1.24 (m, 3H), 0.88 (m, 3H). M- (LC / MS (ESI)): 593; M + (LC / MS (ESI)): 595. HPLC (Condition A), Tr: 6.38 min (HPLC purity: 99.6%).
Step b) Formation of {[4 - ({[(2-butyl-1-benzofuran-3-yl) methyl] amino} carbonyl) benzyl] [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[4 - ({[(2-butyl-1benzofuran-3-yl) methyl] amino} carbonyl) benzyl] [4- (trifluoromethyl) - benzyl] amino} (oxo) acetate provided the title compound as a white powder (93%). 1H NMR (CDCl3, 300 MHz) δ 7.71-7.26 (m, 12H), 6.22 (br s, 1H), 4.89 (s, 1H), 4.74 (br s, 3H) , 4.55 (s, 2H), 2.86 (m, 2H), 2.10-1.27 (m, 4H), 0.95 (m, 3H). M- (LC / MS (ESI)): 565; M + (LC / MS (ESI)):
567. HPLC (Condition A), Tr: 5.71 min (HPLC purity: 99.8%).
Example 311: {(4 - {[4- (benzyloxy) benzoyl] amino} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Step a) Formation of ethyl {(4 - {[4- (benzyloxy) benzoyl] amino} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate
To a solution of 4- (benzyloxy) benzoic acid (180 mg, 0.79 mmol) in anhydrous pyridine (3 mL) at RT was added dropwise isobutyl chloroformate (0.100 mL, 0.79 mmol) under an inert atmosphere. After 30 min, a solution of ethyl {(4-aminobenzyl) [4-trifluoromethyl) benzyl] amino} (oxo) acetate (100 mg, 0.26 mmol) in anhydrous pyridine (1 mL) was added dropwise and The resulting mixture was heated at 70 ° C for 30 min. The reaction mixture was diluted with a 5N aqueous solution of HCl (11 mL) and extracted with Et2O (2 x 5 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. This residue was purified by flash chromatography on silica gel (Et2O / c-Hex 1/1 to Et2O) to give the title compound as a colorless oil (125 mg, 79%). 1H NMR (CDCl3, 300 MHz) δ 7.86 (m, 2H), 7.77 (br s, 1H), 7.63 (m, 4H), 7.44-7.21, (m, 9H) , 7.08 (m, 2H), 5.16 (s, 2H), 4.54-4.33 (m, 6H), 1.35 (m, 3H). M- (LC / MS (ESI)): 589; M + (LC / MS (ESI)): 591. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 99.7%).
Stage b) Formation of {(4 - {[4- (benzyloxy) benzoyl] amino} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4 - {[4 (benzyloxy) benzoyl] amino} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of the title as a beige solid (48%). 1H NMR (CD3OD, 300 MHz) δ 7.96 (d, 2H, J = 8.7 Hz), 7.69 (m, 4H), 7.55-7.33 (m, 8H), 7.25 (d, 1H, J = 8.3 Hz), 7.16 (d, 2H, J = 8.7 Hz), 5.22 (s, 2H), 4.62 (s, 2H), 4.54 (s, 2H). M- (LC / MS (ESI)): 561; M + (LC / MS (ESI)): 563. HPLC (Condition A), Tr: 5.35 min (HPLC purity: 97.0%).
Stage a) Formation of (3,5-dichlorobenzyl) (4-nitrobenzyl) amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using 3,5-dichlorobenzylamine and 4-nitrobenzaldehyde provided the title compound as a yellow powder (71%). 1H NMR (CD3OD, 300 MHz) δ 8.37 (d, 2H, J = 8.8 Hz), 7.83 (d, 2H, J = 8.8 Hz), 7.61 (br s, 3H) , 4.48 (s, 2H), 4.38 (s, 2H). M- (LC / MS (ESI)): 309; M + (LC / MS (ESI)): 311 HPLC (Condition A), Tr: 2.78 min (HPLC purity: 93.0%).
Stage b) Formation of ethyl [(3,5-dichlorobenzyl) (4-nitrobenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using (3,5-dichlorobenzyl) (4-nitrobenzyl) amine hydrochloride gave the title compound as a yellow powder (77%). 1H NMR (CDCl3, 300 MHz) δ 8.22 (m, 2H), 7.46-7.30 (m, 3H), 7.13 (br s, 1H), 7.06 (br s, 1H) , 4.60 (s, 1H), 4.51 (s, 1H), 4.45 (s, 1H), 4.37 (m, 3H), 1.35 (m, 3H). M- (LC / MS (ESI)): 409. HPLC (Condition A), Tr: 5.57 min (HPLC purity: 97.7%).
Step c) Formation of ethyl [(4-aminobenzyl) (3,5-dichlorobenzyl) amino] (oxo) acetate
A suspension of PtO2 (250 mg) in EtOAc (5 mL) was added to a solution of ethyl [(3,5-dichlorobenzyl) (4-nitrobenzyl) amino] (oxo) acetate (2.00 g, 4.86 mmol) in EtOH / EtOAc (2/1, 90 mL) under H2 (1 atm). The reaction mixture was vigorously stirred at RT for 30 min. The reaction mixture was filtered through a pad of Celite and silica gel to remove the catalyst. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel (c-Hex / EtOAc 2/1) to provide the title compound as a light yellow oil (1.21 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.05 (m, 5H), 6.71 (m, 2H), 4.39 (m, 4H), 4.25 (br s, 2H), 1.36 (m, 3 H). HPLC (Condition A), Tr: 3.4 min (HPLC purity: 94.1%).
Stage d) Formation of ethyl {(3,5-dichlorobenzyl) [4- (tridecanoylamino) -benzyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 15 (step d) but using ethyl [(4-aminobenzyl) (3,5-dichlorobenzyl) amino] (oxo) acetate gave the title compound as a light yellow oil (59%). 1H NMR (CDCl3, 300 MHz) δ 7.52 (m, 2H), 7.32-7.05 (m, 6H), 4.47-4.27 (m, 6H), 2.37 (t, 2H, J = 7.5 Hz), 1.73 (m, 2H), 1,381.26 (m, 21H), 0.88 (t, 3H, J = 6.6 Hz). HPLC (Condition A), Tr: 7.52 min (HPLC purity: 99.0%).
Step e) Formation of {(3,5-dichlorobenzyl) [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(3,5-dichlorobenzyl) [4 (tridecanoylamino) benzyl] amino} (oxo) acetate provided the title compound as a white powder (81% ). 1H NMR (CDCl3, 300 MHz) δ 7.50 (br s, 2H), 7.30-7.06 (m, 6H), 4.91 (s, 2H), 4.50 (m, 2H), 2.36 (m, 2H), 1.72 (m, 2H), 1.25 (br s, 18H), 0.88 (br s, 3H). M- (LC / MS (ESI)): 547; M + (LC / MS (ESI)): 549. HPLC (Condition A), Tr: 6.46 min (HPLC purity: 99.5%).
Example 313: {(3,5-Dichlorobenzyl) [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {(3,5-dichlorobenzyl) [4 (tridecanoylamino) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a powder white (88%). M- (LC / MS (ESI)): 547; M + (LC / MS (ESI)): 549. HPLC (Condition A), Tr: 6.48 min (HPLC purity: 99.5%). Analysis calculated for C29H38Cl2N2O4.C7H17NO5 = 1.1 H2O: C, 56.55; H, 7.54; N, 5.50%. Found: C, 56.52; H, 7.50; N, 5.47%
Example 314: {{4 - [(4-octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of ethyl {{4 - [(4-octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-ethynyl-4-octylbenzene under microwave conditions (300W, 120 ° C, 5 min) provided the title compound as a light yellow oil (37%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.54-7.33 (m, 6H), 7.21 (m, 4H), 4.55 (s, 1H), 4 , 52 (s, 1H), 4.36 (m, 4H), 2.62 (m, 2H), 1.62 (m, 2H), 1.32 (m, 13H), 0.89 (m, 3H). HPLC (Condition A), Tr: 7.91 min (HPLC purity: 97.2%).
Stage b) Formation of {{4 - [(4-octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4 - [(4octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a light yellow oil (89%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (m, 2H), 7.50 (m, 4H), 7.36 (m, 2H), 7.19 (m, 4H), 5.04 (s , 1H), 4.98 (s, 1H), 4.62 (s, 1H), 4.59 (s, 1H), 2.62 (m, 2H), 1.62 (m, 2H), 1 , 27 (br s, 10H), 0.89 (m, 3H). M (LC / MS (ESI)): 548. HPLC (Condition A), Tr: 7.53 min (HPLC purity: 98.5%).
Stage a) Formation of tert-butyl 4- (trifluoromethyl) benzyl [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] carbamate
The same procedure used in the preparation of Example 23 (step e) but using tert-butyl 4 [[((dodecanoyloxy) amino] (imino) methyl] benzyl [4- (trifluoromethyl) benzyl] carbamate gave the title compound as an oil colorless (71%). 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, 2H, J = 8.1 Hz), 7.60 (d, 2H, J = 7.9 Hz), 7.31 (m, 4H), 4.45 (m, 4H), 2.95 (t, 2H, J = 7.5 Hz), 1.88 (m, 2H), 1.50 (s, 9H), 1.27 (br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Tr: 7.93 min (HPLC purity: 99.9%).
Stage b) Formation of tert-butyl 4 - [[(dodecanoyloxy) amino] (imino) methyl] benzyl [4- (trifluoromethyl) benzyl] carbamate
The same procedure used in the preparation of Example 10 (step a) but using tert-butyl 4 [(hydroxyamino) (imino) methyl] benzyl [4- (trifluoromethyl) benzyl] carbamate and dodecanoic acid provided the title compound as an oil colorless (95%). 1H NMR (CD3OD, 300 MHz) δ 7.68 (d, 2H, J = 7.9 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.27 (m, 4H), 5.08 (br s, 2H), 4.42 (m, 4H), 2.49 (m, 2H), 1.72 (m, 2H), 1.49 (s, 9H), 1.27 ( br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Tr: 7.06 min (HPLC purity: 86.0%).
Step c) Formation of tert-butyl 4 - [(hydroxyamino) (imino) methyl] benzyl [4- (trifluoromethyl) benzyl] carbamate
The same procedure used in the preparation of Example 23 (step a) but using tert-butyl 4cianobenzyl [4- (trifluoromethyl) benzyl] carbamate provided the title compound as a white foam (88%). 1 H NMR (CDCl 3, 300 MHz ) δ 7.60 (m, 4H), 7.28 (m, 4H), 5.05 (br s, 3H), 4.43 (m, 4H), 1.49 (s, 9H). M- (LC / MS (ESI)): 422; M + (LC / MS (ESI)): 424. HPLC (Condition A), Tr: 3.67 min (HPLC purity: 96.1%).
Stage d) Formation of tert-butyl 4-cyanobenzyl [4- (trifluoromethyl) benzyl] carbamate
The same procedure used in the preparation of Example 23 (step b) but using 4- ({[4 (trifluoromethyl) benzyl] amino} methyl) benzonitrile hydrochloride and DIEA gave the title compound as a colorless oil (92%); 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 4H), 7.30 (m, 4H), 4.44 (m, 4H), 1.48 (s, 9H). M- (LC / MS (ESI)): 389. HPLC (Condition A), Tr: 6.02 min (HPLC purity: 99.8%).
Step e) Formation of 4 - ({[4- (trifluoromethyl) benzyl] amino} methyl) benzonitrile hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using 4-cyanobenzaldehyde gave the title compound as a white solid (83%). 1H NMR (DMSO-d6, 300 MHz) δ 10.01 (br s, 2H), 7.92 (d, 2H, J = 8.4 Hz), 7.80 (s, 4H), 7.77 ( d, 2H, J = 8.4 Hz), 4.28 (s, 4H). HPLC (Condition A), Tr: 2.59 min (HPLC purity: 98.3%).
Step f) Formation of N- [4- (trifluoromethyl) benzyl] -N- [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amine hydrochloride
The same procedure used in the preparation of Example 23 (step f) but using tert-butyl 4 (trifluoromethyl) benzyl [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] carbamate provided the compound of the title as a white powder (94%). 1H NMR (DMSO-d6, 300 MHz) δ 9.64 (br s, 2H), 8.05 (m, 2H), 7.76 (m, 6H), 4.30 (br s, 4H), 2 , 99 (m, 2H), 1.77 (m, 2H), 1.23 (br s, 16H), 0.84 (m, 3H). HPLC (Condition A), Tr: 5.35 min (HPLC purity: 99.9%).
Stage g) Formation of ethyl oxo {[4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4 (trifluoromethyl) benzyl] -N- [4- (5-undecyl-1,2,4-oxadiazol-3-yl) hydrochloride Benzyl] amine provided the title compound as a colorless oil (96%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 2H), 7.63 (m, 2H), 7.36 (m, 4H), 4.57 (s, 2H), 4.42 (s , 2H), 4.39 (m, 2H), 2.96 (m, 2H), 1.88 (m, 2H), 1.43-1.27 (m, 19H), 0.89 (m, 3H). HPLC (Condition A), Tr: 7.36 min (HPLC purity: 99.9%).
Step h) Formation of oxo {[4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[4 (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino} Acetate provided the title compound as a colorless oil (90%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 2H), 7.64 (m, 2H), 7.35 (m, 4H), 5.04 (m, 2H), 4.64 (s , 2H), 2.96 (m, 2H), 1.88 (m, 2H), 1.50-1.15 (m, 16H), 0.88 (m, 3H). M- (LC / MS (ESI)): 558. HPLC (Condition A), Tr: 6.85 min (HPLC purity: 99.9%). Analysis calculated for C30H36F3N3O4 = 0.2 H2O: C, 63.98; H, 6.51; N, 7.46%. Found: C, 63.93; H, 6.56; N, 7.44%
Example 316: oxo {[4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino} acetic acid, N-methylD-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using oxo {[4 (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino} acetic acid and N- methyl-D-glucamine provided the title compound as a white powder (79%). M- (LC / MS (ESI)): 558. HPLC (Condition A), Tr: 6.85 min (purity Example 317: {{4- [2- (4-octylphenyl) ethyl] benzyl} (4- (trifluoromethyl) benzyl] amino} - (oxo) acetic
The same procedure used in the preparation of Example 1 (step c) but using {{4 - [(4octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid in EtOAc provided the title compound as a colorless oil (54%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.34 (m, 2H), 7.13 (m, 8H), 5.42 (br s, 1H), 4.97 ( s, 1H), 4.87 (s, 1H), 4.59 (s, 1H), 4.55 (s, 1H), 2.89 (br s, 4H), 2.57 (m, 2H) , 1.59 (m, 2H), 1.27 (br s, 10H), 0.89 (m, 3H). M- (LC / MS (ESI)): 552; M + (LC / MS (ESI)): 554. HPLC (Condition A), Tr: 7.13 min (HPLC purity: 98.5%).
Example 318: {(4 - {[4- (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of ethyl {(4 - {[4- (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-ethynyl-4 (heptyloxy) benzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a light yellow oil (43% ). HPLC (Condition A), Tr: 7.57 min (HPLC purity: 94.2%).
Stage b) Formation of {(4 - {[4- (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4 - {[4 (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of the title as a light yellow oil (90%). M- (LC / MS (ESI)): 550. HPLC (Condition A), Tr: 6.71 min (HPLC purity: 94.6%).
Example 319: {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of ethyl {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-butyl-4-ethynylbenzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a light yellow oil (50%). HPLC (Condition A), Tr: 7.24 min (HPLC purity: 96.8%).
Stage b) Formation of {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a light yellow oil (92%). M- (LC / MS (ESI)): 492. HPLC (Condition A), Tr: 6.25 min (HPLC purity: 96.2%).
Example 320: {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of 4 - [(4-hexylphenyl) ethynyl] benzaldehyde
A mixture of 4-bromobenzaldehyde (5.00 g, 27.0 mmol), 1-ethynyl-4-hexylbenzene (6.29 g, 33.4 mmol), Et3N (4.70 mL, 33.4 mmol) was stirred ), bis (triphenylphosphine) palladium chloride (950 mg, 1.35 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in anhydrous THF (100 mL) at RT for 30 min under an inert atmosphere. Then copper (I) bromide (82 mg, 0.43 mmol) was added and the resulting mixture was stirred overnight at RT. The solvent was removed by evaporation. The residue was dissolved in Et2O (100 mL), washed with water (50 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The resulting brown solid was triturated in hexane (25 mL), filtered off and washed with hexane to give the title compound as a beige solid (7.73 g, 91%). HPLC (Condition A), Tr: 5.88 min (HPLC purity: 91.9%).
Stage b) Formation of N- {4 - [(4-hexylphenyl) ethynyl] benzyl} -N- [4- (trifluoromethyl) benzyl] -amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using 4 (trifluoromethyl) benzylamine and 4 - [(4-hexylphenyl) ethynyl] benzaldehyde gave the title compound as a beige solid (68%). 1H NMR (DMSO-d6, 300 MHz) δ 9.74 (br s, 2H), 7.83 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.59 (m, 4H), 7.46 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz), 4.28 (s, 2H), 4.22 (s, 2H), 2.59 (t, 2H, J = 7.5 Hz), 1.56 (m, 2H), 1.27 (br s, 6H), 0.84 (t, 3H, J = 6.7 Hz). M + (LC / MS (ESI)): 450. HPLC (Condition A), Tr: 4.87 min (HPLC purity: 99.6%).
Step c) Formation of ethyl {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- {4 - [(4hexylphenyl) ethynyl] benzyl} -N- [4- (trifluoromethyl) benzyl] amine hydrochloride provided the title compound as a light yellow oil (96%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.52 (m, 2H), 7.46 (m, 2H), 7.37 (m, 2H), 7.21 (m , 4H), 4.55 (s, 1H), 4.52 (s, 1H), 4.37 (m, 4H), 2.63 (t, 2H, J = 7.7 Hz), 1.62 (m, 2H), 1.35 (m, 9H), 0.89 (t, 3H, J = 6.7 Hz). HPLC (Condition A), Tr: 6.50 min (HPLC purity: 99.2%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a light yellow gummy solid (90%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (m, 2H), 7.52 (m, 2H), 7.46 (m, 2H), 7.37 (m, 2H), 7.21 (m , 4H), 6.12 (br s, 1H), 4.95 (s, 1H), 4.89 (s, 1H), 4.61 (s, 1H), 4.58 (s, 1H), 2.63 (t, 2H, J = 7.8 Hz), 1.63 (m, 2H), 1.32 (m, 6H), 0.90 (t, 3H, J = 6.8 Hz). M '(LC / MS (ESI)): 520. HPLC (Condition A), Tr: 5.94 min (HPLC purity: 99.1%).
Example 321: {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl) amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the compound of the title as a white powder (94%). M- (LC / MS (ESI)): 520. HPLC (Condition A), Tr: 5.94 min (HPLC purity: 99.6%). Analysis calculated for C31H30F3NO3.C7H17NO5 = 1.3 H2O: C, 61.66; H, 6.75; N, 3.78%. Found: C, 61.63; H, 6.63; N, 3.70%
Example 322: oxo {(4 - {[4- (pentyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} acetic acid
Stage a) Formation of ethyl oxo {(4 - {[4- (pentyloxy) phenyl] ethynyl} benzyl) [4- (trifluoro-methyl) benzyl] amino} acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-ethynyl-4 (pentyloxy) benzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a light yellow oil (33% ). HPLC (Condition A), Tr: 6.80 min (HPLC purity: 74.0%).
Stage b) Formation of oxo {(4 - {[4- (pentyloxy) phenyl] ethynyl) benzyl) [4- (trifluoromethyl) -benzyl] amino) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {(4 - {[4 (pentyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] amino} acetate gave the title compound as a light yellow oil (79%). M- (LC / MS (ESI)): 522. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 74.9%).
Example 323: oxo {{4 - [(4-propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic acid
Stage a) Formation of ethyl oxo {{4 - [(4-propylphenyl) ethynyl] benzyl) [4- (trifluoromethyl) -benzyl] amino} acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-ethynyl-4-propylbenzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a light yellow oil (45%). HPLC (Condition A), Tr: 6.65 min (HPLC purity: 97.5%).
Stage b) Formation of oxo {{4 - [(4-propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 - [(4propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} acetate gave the title compound as a yellow oil clear (80%). M- (LC / MS (ESI)): 478. HPLC (Condition A), Tr: 6.44 min (HPLC purity: 96.9%).
Example 324: [[2- (3-chlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of 4-dodec-1-inyl benzaldehyde
The same procedure used in the preparation of Example 275 (step a) but using 1-dodecin provided the title compound as a yellow oil (77%). 1H NMR (CDCl3, 300 MHz) δ 9.97 (s, 1H), 7.78 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz), 2.43 (t, 2H, J = 7.0 Hz), 1.66-1.55 (m, 2H), 1.50-1.38 (m, 2H), 1.36-1.21 ( m, 12H), 0.87 (t, 3H, J = 6.9 Hz). HPLC (Condition A), Tr: 5.92 min (HPLC purity: 89.4%).
Stage b) Formation of N- [2- (3-chlorophenyl) ethyl] -N- (4-dodec-1-inylbenzyl) amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using [2- (3-chlorophenyl) ethyl] amine and 4-dodec-1-inylbenzaldehyde gave the title compound as a white powder (50%). 1 H NMR ( DMSO-d6, 300 MHz) δ 9.27 (br s, 1H), 7.51-7.24 (m, 8H), 4.15 (br s, 2H), 3.14 (br s, 2H) , 2.98 (m, 2H), 1.99 (m, 2H), 1.55-1.40 (m, 16H), 0.85 (t, 3H, J = 6.6 Hz). M- (LC / MS (ESI)): 411. HPLC (Condition A), Tr: 5.30 min (HPLC purity: 99.9%).
Step c) Formation of ethyl [[2- (3-chlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [2- (3-chlorophenyl) ethyl] -N- (4-dodec-1-inylbenzyl) amine hydrochloride gave the title compound as a yellow oil clear (80%). 1H NMR (CDCl3, 300 MHz) δ 7.37-6.93 (m, 8H), 4.30 (m, 2H), 4.43-4.07 (m, 4H), 3.40 (m, 2H), 2.77 (m, 2H), 2.39 (m, 2H), 1.53-1.30 (m, 16H), 0.87 (t, 3H, J = 6.6 Hz). M + (LC / MS (ESI)): 511. HPLC (Condition A), Tr: 7.04 min (HPLC purity: 99.6%).
The same procedure used in the preparation of Example 1 (step e) but using ethyl [[2- (3-chlorophenyl) ethyl] (4dodec-1-inylbenzyl) amino] (oxo) acetate provided the title compound as a white foam (87%). 1H NMR (DMSO-d6, 300 MHz) δ 7.39-7.22 (m, 6H), 7.11 (m, 2H), 4.56 (s, 1H), 4.43 (s, 1H) , 3.32 (br s, 2H), 2.84 (m, 1H), 2.72 (m, 1H), 2.39 (m, 2H), 1.54-1.23 (m, 16H) , 0.88 (t, 3H, J = 6.6 Hz). M- (LC / MS (ESI)): 480. HPLC (Condition A), Tr: 6.44 min (HPLC purity: 99.8%).
Example 325: [[2- (3-chlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- ( methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using [[2- (3-chlorophenyl) ethyl] (4-dodec1-inylbenzyl) amino] (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white powder (90%). M + (LC / MS (ESI)): 481. HPLC (Condition A), Tr: 6.33 min (HPLC purity: 99.1%).
Example 326: {(4-oct-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic
Stage a) Formation of ethyl {(4-oct-1-inylbenzyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1-octino provided the title compound as a light yellow oil (9%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.36 (m, 4H), 7.15 (m, 2H), 4.52 (s, 1H), 4.48 (s , 1H), 4.35 (m, 4H), 2.42 (dt, 2H, J = 6.9, 1.4 Hz), 1.62 (m, 2H), 1.46 (m, 2H) , 1.34 (m, 7H), 0.92 (t, 3H, J = 6.7 Hz) M + (LC / MS (ESI)): 474. HPLC (Condition A), Tr: 6.10 min ( HPLC purity: 99.1%).
Stage b) Formation of {(4-oct-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-oct-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a yellow oil ( 92%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.37 (m, 4H), 7.15 (m, 2H), 6.11 (br s, 1H), 4.89 ( s, 1H), 4.82 (s, 1H), 4.58 (s, 1H), 4.54 (s, 1H), 2.42 (t, 2H, J = 7.0 Hz), 1, 62 (m, 2H), 1.48 (m, 2H), 1.34 (m, 4H), 0.92 (t, 3H, J = 6.8 Hz). M (LC / MS (ESI)): 444. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 94.8%).
Example 327: {[4- (11-hydroxyundec-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of ethyl {[4- (11-hydroxyundec-1-inyl) benzyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 10-undecin-1-ol gave the title compound as a yellow oil (30%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.36 (m, 4H), 7.15 (m, 2H), 4.53 (s, 1H), 4.48 (s , 1H), 4.35 (m, 4H), 3.65 (t, 2H, J = 6.6 Hz), 2.42 (dt, 2H, J = 7.0.1.4 Hz), 1 , 64-1,30 (m, 17H). M + (LC / MS (ESI)): 532. HPLC (Condition A), Tr: 5.61 min (HPLC purity: 98.2%).
Stage b) Formation of {[4- (11-hydroxyundec-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[4- (11-hydroxyundec1-inyl) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a yellow oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.36 (m, 4H), 7.15 (m, 2H), 4.85 (s, 1H), 4.75 (s , 1H), 4.69 (br s, 2H), 4.58 (s, 1H), 4.52 (s, 1H), 3.66 (m, 2H), 2.42 (t, 2H, J = 6.8 Hz), 1.64-1.24 (m, 14H). M- (LC / MS (ESI)): 502; M + (LC / MS (ESI)): 504. HPLC (Condition A), Tr: 4.93 min (HPLC purity: 91.7%).
Example 328: {[4- (11-methoxy-11-oxoundec-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of methyl 11- [4 - ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino-} methyl) phenyl] undec-10-inoate
The same procedure used in the preparation of Example 226 (step c) but using methyl 10-undecinate provided the title compound as a colorless oil (20%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.36 (m, 4H), 7.15 (m, 2H), 4.51 (m, 2H), 4.36 (m , 4H), 3.68 (s, 3H), 2.42 (dt, 2H, J = 6.9, 1.4 Hz), 2.32 (t, 2H, J = 7.5 Hz), 1 , 63 (m, 4H), 1.47-1.24 (m, 11H). M- (LC / MS (ESI)): 558; M + (LC / MS (ESI)): 560. HPLC (Condition A), Tr: 5.98 min (HPLC purity: 97.3%).
Stage b) Formation of {[4- (11-methoxy-11-oxoundec-1-inyl) benzyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using methyl 11- [4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) phenyl] undec-10-inoate and placating after one minute provided the title compound as a colorless oil (61%). M- (LC / MS (ESI)): 530. HPLC (Condition A), Tr: 5.35 min (HPLC purity: 83.6%).
The same procedure used in the preparation of Example 1 (step e) but using methyl 11- [4 ({[ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} methyl) phenyl] undec-10-inoate provided the title compound as a light yellow oil (84%). 1H NMR (CDCl3, 300 MHz) δ 8.60 (br s, 2H), 7.62 (m, 2H), 7.35 (m, 4H), 7.14 (m, 2H), 4.77 ( s, 1H), 4.68 (s, 1H), 4.57 (s, 1H), 4.51 (s, 1H), 2.39 (m, 4H), 1.64-1.24 (m , 12H). M- (LC / MS (ESI)): 516. HPLC (Condition A), Tr: 4.78 min (HPLC purity: 95.7%).
Example 330: {(4 - {[4- (benzyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of ethyl {(4 - {[4- (benzyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using 1- (benzyloxy) -4ethynylbenzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a light yellow solid (28%). HPLC (Condition A), Tr: 6.36 min (HPLC purity: 95.9%).
Stage b) Formation of {(4 - {[4- (benzyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4 - {[4 (benzyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of the title as a light yellow oil (86%). M- (LC / MS (ESI)): 542. HPLC (Condition A), Tr: 6.21 min (HPLC purity: 96.5%).
Example 331: {(4- {2- [4- (heptyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step c) but using {(4 - {[4 (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid provided in EtOAc provided the title compound as a colorless oil (54%). M- (LC / MS (ESI)): 554. HPLC (Condition A), Tr: 5.95 min (HPLC purity: 95.1%).
Example 332: {{4- [2- (4-Butylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step c) but using {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid in EtOAc gave the title compound as a colorless oil (38%). M- (LC / MS (ESI)): 496. HPLC (Condition A), Tr: 5.62 min (HPLC purity: 95.5%).
Example 333: {{4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of ethyl {{4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 1 (step c) but using ethyl {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate in EtOAc gave the title compound as a colorless oil (94%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 0.8H, J = 8.1 Hz), 7.60 (d, 1.2H, J = 8.1 Hz), 7.39 (d , 0.8H, J = 8.1 Hz), 7.33 (d, 1.2H, J = 8.1 Hz), 7.18 (m, 4H), 7.11 (s, 4H), 4 , 54 (s, 1.2H), 4.49 (s, 0.8H), 4.42-4.30 (m, 4H), 2.90 (m, 4H), 2.59 (t, 2H , J = 7.8 Hz), 1.61 (m, 2H), 1.39-1.30 (m, 9H), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 552; M + (LC / MS (ESI)): 554. HPLC (Condition A), Tr: 6.46 min (HPLC purity: 99.2%).
Stage b) Formation of {{4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a colorless oil (95%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.35 (m, 2H), 7.19 (m, 4H), 7.11 (s, 4H), 5.03 (s , 1H), 4.93 (s, 1H), 4.61 (s, 1H), 4.56 (s, 1H), 2.90 (m, 4H), 2.59 (t, 2H, J = 7.8 Hz), 1.61 (m, 2H), 1.32 (m, 6H), 0.89 (t, 3H, J = 6.8 Hz). M-LC / MS (ESI)): 524; M + (LC / MS (ESI)): 526. HPLC (Condition A), Tr: 5.95 min (HPLC purity: 99.5%). Analysis calculated for C31H34F3NO3 = 0.2 H2O: C, 70.36; H, 6.55; N, 2.65%. Found: C, 70.32; H, 6.56; N, 2.57%
Example 334: {{4- [2- (4-Hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl] benzyl) amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy- 1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {{4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white powder (92%). M- (LC / MS (ESI)): 524; M + (LC / MS (ESI)): 526. HPLC (Condition A), Tr: 5.90 min (HPLC purity: 99.5%). Analysis calculated for C31H34F3NO3.C7H17NO5 = 0.4 H2O: C, 62.69; H, 7.17; N, 3.85%. Found: C, 62.63; H, 7.25; N, 3.83%
Example 335: oxo {(4- {2- [4- (pentyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} acetic acid
The same procedure used in the preparation of Example 1 (step c) but using oxo {(4 - {[4 (pentyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] amino} acetic acid in EtOAc provided the compound of the title as a yellow oil (49%). M- (LC / MS (ESI)): 526. HPLC (Condition A), Tr: 5.62 min (HPLC purity: 74.1%).
The same procedure used in the preparation of Example 1 (step c) but using oxo {{4 - [(4propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid in EtOAc provided the title compound as a colorless oil (51%). M- (LC / MS (ESI)): 482. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 89.2%).
Example 337: 11- [4 - ({(carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino} -methyl) -phenyl] undecanoic acid
The same procedure used in the preparation of Example 1 (step c) but using 11- [4 ({(carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino} methyl) phenyl] undec-10-inoic acid in EtOAc provided the compound of the title as a colorless oil (20%). M- (LC / MS (ESI)): 520. HPLC (Condition A), Tr: 5.03 min (HPLC purity: 96.1%).
Example 338: {[4-11-hydroxyundecyl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step c) but using {[4- (11-hydroxyundec-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid gave the title compound as a colorless oil (45%). M- (LC / MS (ESI)): 506; M + (LC / MS (ESI)): 508. HPLC (Condition A), Tr: 5.19 min (HPLC purity: 86.3%).
Example 339: {(4-dodec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dodec-1-inylbenzyl) -N- [4- (trifluoromethyl) phenyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (trifluoromethyl) aniline and 4-dodec-1-inylbenzaldehyde provided the title compound as a light yellow oil (42%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.23 (m, 8H), 4.35 (s, 2H), 2.40 (m, 2H), 1.62-1.27 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). HPLC (Condition A), Tr: 7.0 min (HPLC purity: 99.4%).
Stage b) Formation of ethyl {(4-dodec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-dodec-1-inylbenzyl) N- [4- (trifluoromethyl) phenyl] amine gave the title compound as a colorless oil (81% ). 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.33 (m, 2H), 7.20 (m, 4H), 4.94 (s, 2H), 4.04 (q , 2H, J = 7.14 Hz), 2.39 (m, 2H), 1.58 (m, 2H), 1.43 (m, 2H), 1.26 (m, 12H), 0.99 (m, 3H), 0.88 (t, 3H, J = 6.8 Hz). M + (LC / MS (ESI)): 516. HPLC (Condition A), Tr: 6.81 min (HPLC purity: 91.8%).
Step c) Formation of {(4-dodec-1-inylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dodec-1inylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetate provided the title compound as a colorless oil (95 %). 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, 2H, J = 8.31 Hz), 7.32 (d, 2H, J = 8.28 Hz), 7.09 (m, 4H), 5.03 (s, 1H), 4.93 (s, 1H), 2.39 (m, 2H), 1.60 (m, 2H), 1.42 (m, 2H), 1.27 (br s, 12H), 0.87 (m, 3H). HPLC (Condition A), Tr: 6.22 min (HPLC purity: 97.1%).
Example 340: {(4-dodec-1-inyl] benzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie 1-deoxy-1- ( methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {(4-dodec-1-inylbenzyl) [4 (trifluoromethyl) phenyl] amino} (oxo) acetic acid and N-methyl-D-glucamine gave the title compound as a white powder (99%). HPLC (Condition A), Tr: 6.07 min (HPLC purity: 96.7%).
Example 341: oxo ([4- (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) -ethyl) benzyl} amino) acetic acid
Step a) Formation of tert-butyl 4- {3 - [(dodecanimidoylamino) oxy] -3-oxopropyl} benzylcarbamate
The same procedure used in the preparation of Example 10 (step a) but using 3- (4 - {[(tert-butoxycarbonyl) amino] methyl} phenyl) propanoic acid gave the title compound as a light yellow solid (99%). NMR (CDCl3, 300 MHz) δ 7.21 (s, 4H), 5.03-4.58 (m, 3H), 4.27 (d, 2H, J = 5.6 Hz), 3.01 ( t, 2H, J = 7.4 Hz), 2.75 (t, 2H, J = 7.4 Hz), 2.23 (t, 2H, J = 7.9 Hz), 1.57 (m, 2H), 1.46 (s, 9H), 1.25 (br s, 16H), 0.89 (t, 3H, J = 6.6 Hz). M (LC / MS (ESI)): 474; M + (LC / MS (ESI)): 476. HPLC (Condition A), Tr: 5.29 min (HPLC purity: 99.0%).
Stage b) Formation of tert-butyl 4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl] -benzyl-carbamate
The same procedure used in the preparation of Example 23 (step e) but using tert-butyl 4- {3 [(dodecanimidoylamino) oxy] -3-oxopropyl} benzylcarbamate provided the title compound as a light yellow solid (71%). 1H NMR (CDCl3, 300 MHz) δ 7.22 (d, 2H, J = 8.3 Hz), 7.16 (d, 2H, J = 8.3 Hz), 4.80 (br s, 1H) , 4.27 (m, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J = 7.5 Hz), 1.73 (m, 2H), 1.46 (s, 9H), 1.29 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). HPLC (Condition A), Tr: 6.07 min (HPLC purity: 98.0%).
The same procedure used in the preparation of Example 23 (step f) but using tert-butyl 4- [2- (3-undecyl 1,2,2-oxadiazol-5-yl) ethyl] benzylcarbamate provided the title compound as a solid white (82%). 1H NMR (CDCl3, 300 MHz) δ 7.25 (d, 2H, J = 8.3 Hz), 7.17 (d, 2H, J = 8.3 Hz), 3.85 (s, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J = 7.7 Hz), 1.97 (br s, 2H), 1.73 (m, 2H), 1.30 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). M + (LC / MS (ESI)): 358. HPLC (Condition A), Tr: 4.17 min (HPLC purity: 98.0%).
Stage d) Formation of N- [4- (trifluoromethyl) benzyl] -N- {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} amine
The same procedure used in the preparation of Example 226 (step a) but using 4- [2- (3-undecyl-1,2,4oxadiazol-5-yl) ethyl] benzylamine and 4- (trifluoromethyl) benzaldehyde provided the compound of title as a light yellow oil (68%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, 2H, J = 8.1 Hz), 7.53 (d, 2H, J = 8.1 Hz), 7.33 (d, 2H, J = 7.9 Hz), 7.19 (d, 2H, J = 7.9 Hz), 3.86 (s, 2H), 3.79 (s, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J = 7.7 Hz), 1.72 (m, 2H), 1.29 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). M + (LC / MS (ESI)): 516. HPLC (Condition A), Tr: 4.83 min (HPLC purity: 93.5%).
Step e) Formation of ethyl oxo ([4- (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxa-diazol-5-yl) ethyl] benzyl} amino) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [4 (trifluoromethyl) benzyl] -N- {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl ) ethyl] benzyl} amine provided the title compound as a colorless oil (67%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.37 (d, 1H, J = 8.3 Hz), 7.32 (d, 1H, J = 8.3 Hz), 7.17 (m, 4H), 4.52 (s, 1H), 4.47 (s, 1H), 4.35 (m, 4H), 3.15 (br s, 4H), 2.71 ( t, 2H, J = 7.7 Hz), 1.73 (m, 2H), 1.37-1.25 (m, 19H), 0.88 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 614; M + (LC / MS (ESI)): 616. HPLC (Condition A), Tr: 6.37 min (HPLC purity: 97.3%).
Step f) Formation of oxo ([4- (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} amino) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo ([4 (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl ] benzyl} amino) acetate provided the title compound as a colorless oil (92%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.35 (m, 2H), 7.19 (m, 4H), 5.03 (s, 1H), 4.91 (s , 1H), 4.61 (s, 1H), 4.55 (s, 1H), 3.14 (br s, 4H), 2.70 (m, 2H), 1.71 (m, 2H), 1.32 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 586. HPLC (Condition A), Tr: 5.87 min (HPLC purity: 99.9%). Analysis calculated for C32H40F3N3O4 = 0.5 H2O C, 64.41; H, 6.93; N, 7.04%. Found: C, 64.31; H, 6.93; N, 6.97%.
Example 342: oxo ([4- (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} amino) acetic acid, N-methyl salt -D-glucamine (i.e. 1-deoxy-1- (methylamino) -glucitol)
The same procedure used in the preparation of Example 2 but using oxo ([4 (trifluoromethyl) benzyl] {4- [2- (3-undecyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} amino acid ) acetic and N-methyl-D-glucamine provided the title compound as a colorless oil (97%). M- (LC / MS (ESI)): 586; M + (LC / MS (ESI)): 588. HPLC (Condition A), Tr: 5.88 min (HPLC purity: 99.5%).
Example 343: {{4- [2- (3-Octyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
Step a) Formation of tert-butyl 4- {3 - [(nonanimidoylamino) oxy] -3-oxopropyl} -benzyl-carbamate
The same procedure used in the preparation of Example 10 (step a) but using 3- (4 - {[(tert-butoxycarbonyl) amino] methyl} phenyl) propanoic acid gave the title compound as a light yellow solid (99%). NMR (CDCl3, 300 MHz) δ 7.21 (s, 4H), 5.00-4.50 (m, 3H), 4.27 (d, 2H, J = 5.6 Hz), 3.00 ( t, 2H, J = 7.3 Hz), 2.73 (t, 2H, J = 7.3 Hz), 2.19 (t, 2H, J = 7.5 Hz), 1.56 (m, 2H), 1.46 (s, 9H), 1.26 (br s, 10H), 0.88 (t, 3H, J = 6.8 Hz). M (LC / MS (ESI)): 432; M + (LC / MS (ESI)): 434. HPLC (Condition A), Tr: 4.70 min (HPLC purity: 97.8%).
Stage b) Formation of tert-butyl 4- [2- (3-octyl-1,2,4-oxadiazol-5-yl) ethyl] benzylcarbamate
The same procedure used in the preparation of Example 23 (step e) but using tert-butyl 4- {3 [(nonanimidoylamino) oxy] -3-oxopropyl} benzylcarbamate provided the title compound as a light yellow solid (76%).
Stage c) Formation of 4- [2- (3-octyl-1,2,4-oxadiazol-5-yl) ethyl] benzylamine
The same procedure used in the preparation of Example 23 (step f) but using 4- [2- (3-octyl-1,2,4oxadiazol-5-yl) ethyl] benzylamine gave the title compound as a white solid (87 %). 1H NMR (CDCl3, 300 MHz) δ 7.25 (d, 2H, J = 7.7 Hz), 7.17 (d, 2H, J = 7.7 Hz), 3.84 (s, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J = 7.7 Hz), 1.78 (br s, 2H), 1.73 (m, 2H), 1.30 (m, 10H), 0.88 (t, 3H, J = 6.8 Hz). M + (LC / MS (ESI)): 316. HPLC (Condition A), Tr: 3.51 min (HPLC purity: 98.0%).
The same procedure used in the preparation of Example 226 (step a) but using 4- [2- (3-octyl-1,2,4oxadiazol-5-yl) ethyl] benzylamine and 4- (trifluoromethyl) benzaldehyde provided the compound of title as a light yellow oil (65%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, 2H, J = 8.3 Hz), 7.51 (d, 2H, J = 8.3 Hz), 7.30 (d, 2H, J = 7.9 Hz), 7.18 (d, 2H, J = 7.9 Hz), 3.86 (s, 2H), 3.78 (s, 2H), 3.12 (m, 4H), 2.70 (t, 2H, J = 7.7 Hz), 1.73 (m, 2H), 1.28 (m, 10H), 0.88 (t, 3H, J = 6.6 Hz). M + (LC / MS (ESI)): 474. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 97.9%).
Step e) Formation of ethyl {{4- [2- (3-octyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoro-methyl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- {4- [2- (3-octyl-1,2,4oxadiazol-5-yl) ethyl] benzyl} -N- [4- ( Trifluoromethyl) benzyl] amine gave the title compound as a colorless oil (74%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.37 (d, 1H, J = 7.9 Hz), 7.31 (d, 1H, J = 7.9 Hz), 7.17 (m, 4H), 4.52 (s, 1H), 4.46 (s, 1H), 4.35 (m, 4H), 3.14 (m, 4H), 2.71 (t , 2H, J = 7.5 Hz), 1.73 (m, 2H), 1.37-1.23 (m, 13H), 0.87 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 572; M + (LC / MS (ESI)): 574. HPLC (Condition A), Tr: 5.92 min (HPLC purity: 99.9%).
Step f) Formation of {{4- [2- (3-octyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) -benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4- [2- (3-octyl-1,2,4oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) benzyl ] amino} (oxo) acetate provided the title compound as a colorless oil (91%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (m, 2H), 7.37 (m, 2H), 7.19 (m, 4H), 5.04 (s, 1H), 4.93 (s , 1H), 4.63 (s, 1H), 4.56 (s, 1H), 3.17 (m, 4H), 2.73 (t, 2H, J = 7.7 Hz), 1.75 (m, 2H), 1.31 (m, 10H), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 544; M + (LC / MS (ESI)): 546 HPLC (Condition A), Tr: 5.38 min (HPLC purity: 99.2%).
Example 344: {{4- [2- (3-Octyl-1,2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl] -benzyl] amino} (oxo) acetic acid, salt of Nmethyl-D-glucamine (i.e. 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {{4- [2- (3-octyl-l, 2,4-oxadiazol5-yl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} ( oxo) acetic acid and N-methyl-D-glucamine provided the title compound as a white gummy solid (96%). M- (LC / MS (ESI)): 544; M + (LC / MS (ESI)): 546. HPLC (Condition A), Tr: 5.37 min (HPLC purity: 99.0%).
Example 345: {{4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] -amino} - (oxo) acetic acid
Step a) Formation of ethyl {{4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 311 (step a) but using 4-octylbenzoic acid gave the title compound as a colorless oil (93%). 1HNMR (CDCl3, 300 MHz) δ 7.81 (m, 3H), 7.63 (m, 4H), 7.42-7.21 (m, 6H), 4.54 (s, 1H), 4, 49 (s, 1H), 4.37 (m, 4H), 2.68 (m, 2H), 1.64 (m, 2H), 1.28 (m, 13H), 0.89 (m, 3H ). M- (LC / MS (ESI)): 595; M + (LC / MS (ESI)): 597. HPLC (Condition A), Tr: 7.19 min (HPLC purity: 99.2%).
Stage b) Formation of {{4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{4 - [(4octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a white solid (93%). 1H NMR (CDCl3, 300 MHz) δ 7.95 (m, 1H), 7.80 (m, 2H), 7.61 (m, 4H), 7.39-7.23 (m, 6H), 5 , 13 (br s, 1H), 4.91 (s, 1H), 4.77 (s, 1H), 4.58 (s, 1H), 4.53 (s, 1H), 2.68 (m , 2H), 1.63 (m, 2H), 1.28 (br s, 10H), 0.89 (m, 3H). M- (LC / MS (ESI)): 567; M + (LC / MS (ESI)): 569. HPLC (Condition A), Tr: 6.64 min (HPLC purity: 99.5%). Analysis calculated for C32H35F3N2O4: C, 67.59; H, 6.20; N, 4.93%. Found: C, 67.32; H, 6.21; N, 4.86%
Example 346: {{4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid, N-methyl-Dglucamine salt (ie 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {{4 - [(4octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl-D-glucamine provided the compound of the title as a white powder (92%). M- (LC / MS (ESI)): 567; M + (LC / MS (ESI)): 569. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 99.4%). Analysis calculated for C32H35F3N2O4.C7H17NO5 = 0.6 H2O: C, 60.47; H, 6.92; N, 5.42%. Found: C, 60.48; H, 7.11; N, 5.41%
Example 347: oxo {[(1-tridecanoylpiperidin-4-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} acetic acid
Step a) Formation of tert-butyl hydrochloride 4- (2 - {[4-trifluoromethylbenzyl] amino} methyl) piperidine-1-carboxylate
The same procedure used in the preparation of Example 226 (step a) but using tert-butyl 4 (aminomethyl) piperidine-1-carboxylate and 4- (trifluoromethyl) benzaldehyde gave the title compound as a white solid (65%). 1H NMR (DMSO-d6, 300 MHz) δ 9.16 (br s, 1H), 7.84 (d, 2H, J = 8.3 Hz), 7.77 (d, 2H, J = 8.3 Hz), 4.25 (br s, 2H), 3.92 (m, 2H), 2.84 (m, 2H), 2.70 (br s, 2H), 1.89 (br s, 1H) , 1.72 (br s, 2H), 1.39 (br s, 9H), 1.05 (m, 2H).
Step b) Formation of tert-butyl 4- (2- {ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} -methyl) piperidine-1-carboxylate.
The same procedure used in the preparation of Example 15 (step b) but using tert-butyl 4- (2 - {[4-trifluoromethylbenzyl] amino} methyl) piperidine-1-carboxylate hydrochloride gave the title compound as a colorless oil (94%). M- (LC / MS (ESI)): 471. HPLC, RT: 5.78 min (HPLC purity: 99.9%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.39 (m, 2H), 4.68 (s, 1H), 4.54 (s, 1H), 4.45-4 , 20 (m, 2H), 4.19-4.00 (m, 2H), 3.19 (d, 1H, J = 7.2 Hz), 3.12 (d, 1H, J = 7.2 Hz), 2.63 (m, 2H), 1.81 (m, 1H), 1.59 (m, 2H), 1.48-0.95 (m, 14H).
Step c) Formation of ethyl oxo hydrochloride - {(2-piperidin-4-ylmethyl) [4- (trifluoromethylbenzyl] amino} -acetate.
The same procedure used in the preparation of Example 23 (step f) but using tert-butyl 4- (2 {ethoxy (oxo) acetyl] [4- (trifluoromethyl) benzyl] amino} -methyl) piperidine-1-carboxylate provided the title compound as a colorless gummy solid (99%). HPLC, RT: 3.12 min (HPLC purity: 99.5%).
Step d) Formation of ethyl oxo {[(1-tridecanoylpiperidin-4-yl) methyl] [4-trifluoromethyl) -benzyl] amino} acetate.
The same procedure used in the preparation of Example 1 (step d) but using ethyl oxo hydrochloride - {(2piperidin-4-ylmethyl) [4- (trifluoromethylbenzyl] amino} acetate, tridecanoic acid, HOBT and TEA in DCM provided the compound of the title as a yellow oil (66%). M- (LC / MS (ESI)): 567; M + (LC / MS (ESI)): 569. HPLC (Condition A), Tr: 7.24 min (purity HPLC: 99.4%).
Step e) Formation of oxo {[(1-tridecanoylpiperidin-4-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[(1tridecanoylpiperidin-4-yl) methyl] [4-trifluoromethyl) benzyl] amino} acetate gave the title compound as an orange gummy solid ( 58%). 1H NMR (DMSO-d6, 300 MHz) δ 7.75 (m, 2H), 7.50 (m, 2H), 4.63 (m, 2H), 4.35 (br t, 1H), 3, 83 (br d, 1H), 3.20-2.80 (m, 3H), 2.41 (br q, 1H), 2.24 (t, 2H, J = 7.4 Hz), 1.90 (br s, 1H), 1.65-1.35 (m, 4H), 1.23 (br s, 18H), 1.15-0.70 (m, 5H). M- (LC / MS (ESI)): 539. HPLC (Condition A), Tr: 6.68 min (HPLC purity: 98.3%).
Step a) Formation of ethyl {{[1- (4-octylbenzoyl) piperidin-4-yl] methyl} [4-trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 1 (step d) but using ethyl oxo - {(2piperidin-4-ylmethyl) [4- (trifluoromethylbenzyl] amino} acetate, 4-n-octylbenzoic acid, HOBT and TEA hydrochloride in DCM provided the title compound as a colorless oil (84%). 1 H NMR (CDCl 3, 300 MHz) δ 7.63 (m, 2H), 7.40 (m, 2H), 7.327.17 (m, 4H) , 4.70 (s, 1H), 4.55 (s, 1H), 4.40 (q, 2H, J = 7.2 Hz), 4.20 (q, 2H, J = 7.2 Hz) , 3.4-3.1 (m, 2H), 2.85 (br s, 2H), 2.6 (m, 2H), 1.95 (br s, 1H), 1.6 (m, 4H ), 1.47-1.1 (m, 17H), 0.88 (m, 3H) .M- (LC / MS (ESI)): 587. HPLC (Condition A), Tr: 6.26 min ( HPLC purity: 99.2%).
Stage b) Formation of {{[1- (4-octylbenzoyl) piperidin-4-yl] methyl) [4- (trifluoromethyl) -benzyl] amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{[1- (4octylbenzoyl) piperidin-4-yl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of the title as a white foam (67%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (m, 2H), 7.39 (m, 2H), 7.31 (m, 2H), 7.22 (m, 2H), 4.80 (m , 3H), 3.86 (m, 1H), 3.49 (br s, 1H), 3.25 (br s, 1H), 2.94 (m, 2H), 2.60 (t, 2H, J = 7.5 Hz), 2.15-1.45 (m, 4H), 1.28 (m, 13H), 0.88 (t, 3H, J = 6.6 Hz). M- (LC / MS (ESI)): 559; M + (LC / MS (ESI)): 561. HPLC (Condition A), Tr: 5.68 min (HPLC purity: 99.5%).
Example 349: {{[1- (4-octylbenzoyl) piperidin-4-yl] methyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid, N-methylD-glucamine salt (ie 1- deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using {{[1- (4-octyl-benzoyl) piperidin4-yl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid and N-methyl- D-glucamine provided the title compound as a white powder (90%). M- (LC / MS (ESI)): 559; M + (LC / MS (ESI)): 561. HPLC (Condition A), Tr: 5.56 min (HPLC purity: 97.1%). Analysis calculated for C31H39F3N2O4.C7H17NO5 = 3.5 H2O: C, 55.73; H, 7.75; N, 5.13%. Found: C, 55.68; H, 7.56; N, 5.17%
Example 350: {[(3-dec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of 3-bromo-1-benzofuran-5-carbaldehyde
To a solution of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (10 g) in dry ethanol (25 mL) was added a solution of KOH in dry ethanol (14 mL) and subjected at reflux 70 ° C for 2h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3x 50 mL). The organic layer was washed with water, brine and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (pet / EtOAc Ether 99.5 / 0.5) to give the title compound as a light yellow solid (3.3 g, 45%).
1H NMR (DMSO-d6, 300 MHz) δ 10.12 (s, 1H), 8.47 (s, 1H), 8.14 (d, 1H, J = 1.5 Hz), 7.97 (dd , 1H, J = 8.6, 1.5 Hz), 7.87 (d, 1H, J = 8.6 Hz).
Stage b) Formation of N - [(3-bromo-1-benzofuran-5-yl) methyl] -N- [4- (trifluoromethyl) -benzyl] amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using 3-bromo-1-benzofuran5-carbaldehyde gave the title compound as a beige solid (77%). 1H NMR (DMSO-d6, 300 MHz) δ 10.00 (br s, 2H), 8.35 (s, 1H), 7.81-7.64 (m, 7H), 4.32 (s, 2H ), 4.26 (s, 2H). M + (LC / MS (ESI)): 386.1. HPLC (Condition A), Tr: 3.11 min (HPLC purity: 96.4%).
Step c) Formation of ethyl {[(3-bromo-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N - [(3bromo-1-benzofuran-5-yl) methyl] -N- [4- (trifluoromethyl) benzyl] amine hydrochloride provided the compound of title as a colorless oil (84%). 1H NMR (CDCl3, 300 MHz) δ 7.71 (s, 0.5H), 7.69 (s, 0.5H), 7.65 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J = 8.1 Hz), 7.50 (d, 0.5H, J = 8.4 Hz), 7.48 (d, 0.5H, J = 8.5 Hz), 7 , 41-7.25 (m, 4H), 4.64 (s, 1H), 4.56 (s, 1H), 4.49 (s, 1H), 4.43 (s, 1H), 4, 40 (q, 1H, J = 7.2 Hz), 4.35 (q, 1H, J = 7.2 Hz), 1.38 (t, 1.5H, J = 7.2 Hz), 1, 33 (t, 1.5H, J = 7.2 Hz). M + (LC / MS (ESI)): 484.0. HPLC (Condition A), Tr: 4.95 min (HPLC purity: 99.0%).
Step d) Formation of ethyl {[(3-dec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl {[(3-bromo-1benzoforan-5-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate and 1-decino provided the title compound as a yellow oil (40%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 0.5H), 7.76 (s, 0.5H), 7.65 (d, 1H, J = 7.9 Hz), 7.61 (d, 1H, J = 7.9 Hz), 7.52-7.33 (m, 4H), 7.22 (m, 1H), 4.64 (s, 1H), 4.56 (s, 1H), 4.47 (s, 1H), 4.41 (s, 1H), 4.39 (q, 1H, J = 7.2
Hz), 4.34 (q, 1H, J = 7.2 Hz), 2.49 (m, 2H), 1.66 (m, 2H), 1.49 (m, 2H), 1.40- 1.26 (m, 11H), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 540.5; M + (LC / MS (ESI)): 542.7. HPLC (Condition A), Tr: 6.07 min (HPLC purity: 98.0%).
Step e) Formation of {[(3-dec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[(3-dec-1-inyl-1benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) Acetate provided the title compound as a yellow oil (91%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 0.5H), 7.77 (s, 0.5H), 7.63 (m, 2H), 7.47 (m, 2H), 7 , 36 (m, 2H), 7.22 (m, 1H), 5.07 (s, 1H), 5.03 (s, 1H), 4.71 (s, 1H), 4.62 (s, 1H), 2.49 (t, 2H, J = 7.0 Hz), 1.67 (m, 2H), 1.49 (m, 2H), 1.30 (m, 8H), 0.89 ( t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 512.4. HPLC (Condition A), Tr: 5.54 min (HPLC purity: 92.4%).
Example 351: {[(3-dodec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of ethyl {[(3-dodec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino) (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl {[(3-bromo-1benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate and 1-dodecin provided the title compound as a yellow oil (34%). HPLC (Condition A), Tr: 6.39 min (HPLC purity: 99.2%).
Stage b) Formation of {[(3-dodec-1-inyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[(3-dodec-1-inyl-1benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) Acetate provided the title compound as a yellow oil (86%). M- (LC / MS (ESI)): 540.4. HPLC (Condition A), Tr: 5.91 min (HPLC purity: 96.3%).
Example 352: oxo {({3 - [(4-propylphenyl) ethynyl] -1-benzofuran-5-yl} methyl) [4- (trifluoro-methyl) benzyl] amino} acetic acid
Stage a) Formation of ethyl ({3 - [(4-propylphenyl) ethynyl] -1-benzofuran-5-yl} methyl) [4- (trifluoromethyl) benzyl] amino} acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl {[(3-bromo-1benzofuran-5-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate and 1-ethynyl -4-propylbenzene under microwave conditions (300W, 120 ° C, 10 min) provided the title compound as a yellow oil (5%). M (LC / MS (ESI)): 545.8; M + (LC / MS (ESI)): 548.2 HPLC (Condition A), Tr: 5.85 min (HPLC purity: 92.4%).
The same procedure used in the preparation of Example 1 (step e) but using ethyloxo {({3 - [(4-propylphenyl) ethynyl] -1-benzofuran-5-yl} methyl) [4- (trifluoromethyl) benzyl] amino } acetate provided the title compound as a light yellow foam (75%). M- (LC / MS (ESI)): 518.2; M + (LC / MS (ESI)): 520.0. HPLC (Condition A), Tr: 5.30 min (HPLC purity: 84.0%).
Example 353: [(4-dodec-1-inylbenzyl) (4-fluorobenzyl) amino] (oxo) acetic acid
Stage a) Formation of N- (4-bromobenzyl) -N- (4-fluorobenzyl) amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using 4-fluorobenzylamine gave the title compound as a white solid (98%). 1H NMR (CD3OD, 300 MHz) δ 7.65 (m, 2H), 7.57 (m, 2H), 7.47 (m, 2H), 7.22 (m, 2H), 4.22 (s , 2H), 4.20 (s, 2H). HPLC (Condition A), Tr: 2.23 min (HPLC purity: 97.4%).
Stage b) Formation of ethyl [(4-bromobenzyl) (4-fluorobenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (4-bromobenzyl) -N- (4-fluorobenzyl) amine hydrochloride provided the title compound as a light yellow oil (87%). 1H NMR (CDCl3, 300 MHz) δ 7.51 (d, 1H, J = 8.2 Hz), 7.48 (d, 1H, J = 8.3 Hz), 7.24-7.00 (m , 6H), 4.45 (s, 1H), 4.43 (s, 1H), 4.37 (q, 1H, J = 7.2 Hz), 4.35 (q, 1H, J = 7, 2 Hz), 4.30 (s, 1H), 4.28 (s, 1H), 1.36 (t, 1.5H, J = 7.2 Hz), 1.35 (t, 1.5H, J = 7.2 Hz). M + (LC / MS (ESI)): 394.0. HPLC (Condition A), Tr: 4.58 min (HPLC purity: 95.3%).
Stage c) Formation of ethyl [(4-dodec-1-inylbenzyl) (4-fluorobenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl [(4-bromobenzyl) (4fluorobenzyl) amino] (oxo) acetate and 1-dodecin provided the title compound as a light yellow oil (23%) . 1H NMR (CDCl3, 300 MHz) δ 7.39 (m, 2H), 7.25-7.00 (m, 6H), 4.45 (s, 1H), 4.44 (s, 1H), 4 , 36 (m, 2H), 4.30 (s, 1H), 4.28 (s, 1H), 2.42 (t, 2H, J = 7.1 Hz), 1.62 (m, 2H) , 1.46 (m, 2H), 1.37-1.25 (m, 15H), 0.89 (t, 3H, J = 6.6 Hz). M + (LC / MS (ESI)): 480.3. HPLC (Condition A), Tr: 6.28 min (HPLC purity: 99.8%).
Stage d) Formation of [(4-dodec-1-inylbenzyl) (4-fluorobenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl [(4-dodec-1inylbenzyl) (4-fluorobenzyl) amino] (oxo) acetate gave the title compound as a yellow oil (87%). 1H NMR (CDCl3, 300 MHz) δ 7.40 (m, 2H), 7.25-7.02 (m, 6H), 4.95 (s, 1H), 4.93 (s, 1H), 4 , 53 (s, 1H), 4.51 (s, 1H), 2.41 (t, 2H, J = 6.8 Hz), 1.62 (m, 2H), 1.45 (m, 2H) , 1.28 (br s, 12H), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 450.2. HPLC (Condition A), Tr: 5.75 min (HPLC purity: 99.0%).
Example 354: [bis (4-oct-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of ethyl [bis (4-oct-1-inylbenzyl) amino] (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl [(4-bromobenzyl) (4oct-1-inylbenzyl) amino] (oxo) acetate and 1-octino gave the title compound as a light yellow oil (32%) 1H NMR (CDCl3, 300 MHz) δ 7.38 (m, 4H), 7.16 (d, 2H, J = 8.3 Hz), 7.12 (d, 2H, J = 7.9 Hz), 4.45 (s, 2H), 4.35 (q, 2H, J = 7.2 Hz), 4.28 (s, 2H), 2.42 (t, 4H, J = 7.1 Hz), 1.62 (m, 4H), 1.47 (m, 4H), 1.33 (m, 11H), 0.92 (t, 6H, J = 6.8 Hz). M + (LC / MS (ESI)): 514.0. HPLC (Condition A), Tr: 6.54 min (HPLC purity: 99.3%).
Stage b) Formation of [bis (4-oct-1-inylbenzyl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl [bis (4-oct-1-ylbenzyl) amino] (oxo) acetate gave the title compound as a yellow oil (94%). 1H NMR (CDCl3, 300 MHz) δ 7.39 (m, 4H), 7.14 (m, 4H), 4.93 (s, 2H), 4.52 (s, 2H), 2.42 (t , 4H, J = 7.0 Hz), 1.62 (m, 4H), 1.47 (m, 4H), 1.34 (m, 8H), 0.92 (t, 6H, J = 6, 8 Hz) M- (LC / MS (ESI)): 484.3. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 98.7%).
Example 355: {[(6-dodec-1-inylpyridin-3-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of 6-dodec-1-inilnicotinaldehyde
A mixture of 6-bromonicotinaldehyde (500 mg, 2.69 mmol), 1-dodecino (680 mg, 4.09 mmol), triphenylphosphine (23 mg, 0.09 mmol), triethylamine (470 ml, 3.38 mmol) and bis (triphenylphosphine) palladium (II) chloride (94 mg, 0.13 mmol) in THF (10 mL) was stirred under argon at RT for 30 min. Copper (I) iodide (21 mg, 0.11 mmol) was added and the mixture was stirred for 21 hours at RT. The solvent was removed under reduced pressure. The residue was diluted with a saturated aqueous solution of NH4CI (20 mL) and extracted with Et2O (50 ml + 2x 20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (c-Hex / EtOAc 4/1) to provide the title compound as a yellow oil (218 mg, 29%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 9.00 (s, 1H), 8.11 (d, 1H, J = 8.1 Hz), 7.52 (d, 1H , J = 8.1 Hz), 2.49 (t, 2H, J = 7.1 Hz), 1.67 (m, 2H), 1.47 (m, 2H), 1.28 (m, 12H ), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 270.3; M + (LC / MS (ESI)): 272.4. HPLC (Condition A), Tr: 5.23 min (HPLC purity: 98.3%).
Stage b) Formation of N - [(6-dodec-1-inylpyridin-3-yl) methyl] -N- [4- (trifluoromethyl) -benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 6-dodec-1-butylnicotinaldehyde gave the title compound as a light yellow solid (54%). M + (LC / MS (ESI)): 431.4. HPLC (Condition A), Tr: 4.47 min (HPLC purity: 98.8%).
Step c) Formation of ethyl {[(6-dodec-1-inylpyridin-3-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N - [(6-dodec-1-inylpyridin-3-yl) methyl] -N- [4- (trifluoromethyl) benzyl] amine gave the title compound as a colorless oil (93%). 1H NMR (CDCl3, 300 MHz) δ 8.38 (d, 0.5H, J = 2.0 Hz), 8.34 (d, 0.5H, J = 2.0 Hz), 7.64 (m , 2.5H), 7.56 (dd, 0.5H, J = 7.9.2.0 Hz), 7.41-7.31 (m, 3H), 4.54 (s, 1H), 4.49 (s, 1H), 4.42-4.32 (m, 4H), 2.46 (m, 2H), 1.65 (m, 2H), 1.46 (m, 2H), 1 , 39-1.28 (m, 15H), 0.89 (t, 3H, J = 6.8 Hz). M- (LC / MS (ESI)): 529.3; M + (LC / MS (ESI)): 531.4. HPLC (Condition A), Tr: 5.60 min (HPLC purity: 100%).
Stage d) Formation of {[(6-dodec-1-inylpyridin-3-yl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[(6-dodec-1-inylpyridin-3-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of title as a white foam (90%). 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 0.5H), 8.58 (s, 0.5H), 7.84 (d, 0.5H, J = 8.3 Hz), 7 , 69 (d, 0.5H, J = 8.2 Hz), 7.58 (m, 2H), 7.45 (m, 2H), 7.35 (d, 1H, J = 7.9 Hz) , 5.38 (br s, 1H), 4.72 (s, 1H), 4.70 (s, 1H), 4.60 (s, 1H), 4.50 (s, 1H), 2.45 (t, 2H, J = 7.0 Hz), 1.63 (m, 2H), 1.42 (m, 2H), 1.27 (br s, 12H), 0.88 (t, 3H, J = 6.6 Hz). M- (LC / MS (ESI)): 501.2; M + (LC / MS (ESI)): 503.0. HPLC (Condition A), Tr: 4.76 min (HPLC purity: 99.5%).
Example 356: {(3-dodec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of 3-dodec-1-inylbenzaldehyde
The same procedure used in the preparation of Example 226 (step c) but using 3-bromobenzaldehyde gave the title compound (59%).
Stage b) Formation of N- (3-dodec-1-inylbenzyl) -N- [4- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 3-dodec-1-ylbenzaldehyde and 4- (trifluoromethyl) benzylamine gave the title compound (37%). M + (LC / MS (ESI)): 430.5. HPLC (Condition A), Tr: 4.82 min (HPLC purity: 94.7%).
Step c) Formation of ethyl {(3-dodec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- (3-dodec-1-inylbenzyl) N- [4- (trifluoromethyl) benzyl] amine gave the title compound (99%). HPLC (Condition A), Tr: 6.48 min (HPLC purity: 100%).
Step d) Formation of {(3-dodec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino) (oxo acetic acid)
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(3-dodec-1inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as a colorless oil (95 %). 1H NMR (CD3OD, 300 MHz) δ 7.71-7.61 (m, 2H), 7.52 (d, 1H, J = 7.9 Hz), 7.41 (d, 1H, J = 8, 3Hz), 7.34-7.14 (m, 4H), 4.62 (m, 2H), 4.54 (m, 2H), 2.45 (t, 2H, J = 6.8 Hz), 1.70-1.58 (m, 2H), 1.57-1.46 (m, 2H), 1.45-1.28 (m, 12H), 0.92 (m, 3H). M- (LC / MS (ESI)): 500.4. HPLC (Condition A), Tr: 5.94 min (HPLC purity: 98.4%).
Example 357: {[2- (2-fluorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl] benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- [2- (2-fluorophenyl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
To a solution of 4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzaldehyde (32.8 mg, 0.1 mmol) in anhydrous THF (0.6 mL) was added 2- ( 2-fluorophenyl) ethylamine (11.8 mg, 0.1 mmol) and Ti (iPrO) 4 (0.035 mL, 0.12 mmol). The mixture was stirred for 3 h at 60 ° C then sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added and the reaction mixture was stirred overnight at RT. THF (0.75 mL) was added followed by PS-DEAM resin (Argonaut, 148 mg, 1.68 mmol / g) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrates were eluted through a SCX column (Isolute, 1 g) with DCM (6 mL), then NH3 (2M in MeOH, 4 mL). The desired fractions (TLC monitoring) were concentrated in vacuo to provide the title product.
To a solution of N- [2- (2-fluorophenyl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine (45.1 mg, 0, 1 mmol) in anhydrous DCM (0.6 mL) the morpholinomethyl polystyrene resin (Novabiochem, HL, 39.5 mg, 0.15 mmol, 3.8 mmol / g) was added and the resulting mixture was cooled to 0 ° C. Oxalyl ethylchloride (4.7 mg, 0.13 mmol) in anhydrous DCM (0.4 mL) was added. The reaction mixture was stirred for 2 h at RT, then PL-AMS-Resin (Polymer Laboratories, 52 mg, 0.1 mmol, 1.93 mmol / g) was added and the mixture was stirred for 1.5 h. The resins were filtered off, washed with DCM and the filtrates concentrated in vacuo to provide the title compound as an oil.
Step c) Formation of {[2- (2-fluorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (2fluorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (26% (general yield from step a)). M- (LC / MS (ESI)): 522.3. HPLC (Condition A), Tr: 5.76 min (HPLC purity: 98.9%).
Example 358: {[2- (2-fluorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- [2- (2-fluorophenyl) ethyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (2-fluorophenyl) ethylamine gave the title compound as a oil.
Stage b) Formation of ethyl {[2- (2-fluorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (2-fluorophenyl) ethyl] N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as an oil. M + (LC / MS (ESI)): 552.5. HPLC (Condition A), Tr: 6.31 min (HPLC purity: 91.2%).
Step c) Formation of {[2- (2-fluorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (2-fluorophenyl) ethyl] [3 (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino } (oxo) acetate provided the title compound as a yellow oil (24% (general yield from step a)). M- (LC / MS (ESI)): 522.4; M + (LC / MS (ESI)): 524.2. HPLC (Condition A), Tr: 5.76 min (HPLC purity: 98.5%).
Example 359: {[2- (2-fluorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl] benzyl) amino} - (oxo) acetic acid
Stage a) Formation of N- [2- (2-fluorophenyl) ethyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (2-fluorophenyl) ethylamine gave the title compound as a oil.
Stage b) Formation of ethyl {[2- (2-fluorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (2-fluorophenyl) ethyl] N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {[2- (2-fluorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (2-fluorophenyl) ethyl] [4 (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino } (oxo) acetate provided the title compound as a yellow oil (29% (general yield from step a)). M- (LC / MS (ESI)): 480.2. HPLC (Condition A), Tr: 5.21 min (HPLC purity: 98.4%).
Example 360: {[2- (3,4-Dichlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl] benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound Like an oil
Stage b) Formation of ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil.
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (23% (general yield from step a)). M- (LC / MS (ESI)): 572.2. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 99.2%).
Example 361: {[2- (3,4-Dichlorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound Like an oil
Stage b) Formation of ethyl {[2- (3,4-dichlorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil.
Step c) Formation of {[2- (3,4-dichlorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3,4-dichlorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (18% (general yield from step a)). M- (LC / MS (ESI)): 572.3; M + (LC / MS (ESI)): 574.0. HPLC (Condition A), Tr: 6.04 min (HPLC purity: 97.9%).
Example 362: {[2- (3,4-Dichlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl] benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound Like an oil
Stage b) Formation of ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil. M (LC / MS (ESI)): 558.5; M + (LC / MS (ESI)): 560.1. HPLC (Condition A), Tr: 6.07 min (HPLC purity: 78.5%).
Step c) Formation of {[2- (3,4-dichlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (14% (general yield from step a)). M- (LC / MS (ESI)): 532.0. HPLC (Condition A), Tr: 5.52 min (HPLC purity: 89.6%).
Example 363: {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- [2- (1,1'-biphenyl-4-yl) ethyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (1,1'-biphenyl-4-yl) ethylamine provided the title compound as an oil.
Stage b) Formation of ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (1,1'-biphenyl-4-yl) ethyl] -N- [4- (3-undecyl-1,2,4- oxadiazol-5-yl) benzyl] amine provided the title compound as an oil. M + (LC / MS (ESI)): 610.3. HPLC (Condition A), Tr: 6.60 min (HPLC purity: 77.8%).
Step c) Formation of {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetic
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5 -il) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (4% (general yield from step a)). M- (LC / MS (ESI)): 580.3. HPLC (Condition A), Tr: 6.10 min (HPLC purity: 95.3%).
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (1,1'-biphenyl-4-yl) ethylamine provided the title compound as an oil.
Stage b) Formation of ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (1,1'-biphenyl-4-yl) ethyl] -N- [3- (3-undecyl-1,2,4- oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {[2- (1,1'-biphenyl-4-yl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetic
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5 -il) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (24% (general yield from step a)). M- (LC / MS (ESI)): 580.1; M + (LC / MS (ESI)): 582.3. HPLC (Condition A), Tr: 6.10 min (HPLC purity: 97.8%).
Example 365: {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic
Stage a) Formation of N- [2- (1,1'-biphenyl-4-yl) ethyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (1,1'-biphenyl-4-yl) ethylamine provided the title compound as an oil.
Stage b) Formation of ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-octyl-l, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (1,1'-biphenyl-4-yl) ethyl] -N- [4- (3-octyl-1,2,4- oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo )acetic
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (1,1'-biphenyl-4-yl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5 -il) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (13% (general yield from step a)). M- (LC / MS (ESI)): 538.3. HPLC (Condition A), Tr: 5.63 min (HPLC purity: 97.8%).
Example 366: oxo {5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine provided the title compound as an oil. M + (LC / MS (ESI)): 460.4. HPLC (Condition A), Tr: 6.36 min (HPLC purity: 73.3%).
Stage b) Formation of ethyl oxo {5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [4- (3-undecyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil.
Step c) Formation of oxo {5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {5,6,7,8tetrahydronaphthalen-1-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate provided the title compound as a white powder (23% (general yield from step a)). M- (LC / MS (ESI)): 530.3. HPLC (Condition A), Tr: 5.95 min (HPLC purity: 94.7%).
Example 367: oxo {5,6,7,8-tetrahydronaphthalen-1-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [3- (3-undecyl-1,2,4-oxa-diazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine provided the title compound as an oil. M + (LC / MS (ESI)): 460.4. HPLC (Condition A), Tr: 6.32 min (HPLC purity: 68.9%).
The same procedure used in the preparation of Example 357 (step b) but using N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [3- (3-undecyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil. M + (LC / MS (ESI)): 560.4. HPLC (Condition A), Tr: 6.52 min (HPLC purity: 73.3%).
Step c) Formation of oxo {5,6,7,8-tetrahydronaphthalen-1-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {5,6,7,8tetrahydronaphthalen-1-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate provided the title compound as a yellow solid (7% (general yield from step a)). M- (LC / MS (ESI)): 530.2; M + (LC / MS (ESI)): 532.3. HPLC (Condition A), Tr: 5.94 min (HPLC purity: 90.3%).
Example 368: [[4- (3-Octyl-1,2,4-oxadiazol-5-yl) benzyl] (5,6,7,8-tetrahydronaphthalen-1-yl) amino] (oxo) acetic acid
Stage a) Formation of N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine provided the title compound as an oil. M + (LC / MS (ESI)): 418.4. HPLC (Condition A), Tr: 5.83 min (HPLC purity: 82.3%).
Stage b) Formation of ethyl oxo {5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N-5,6,7,8-tetrahydronaphthalen-1-yl-N- [4- (3-octyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil.
Step c) Formation of [[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] (5,6,7,8-tetrahydronaphthalen-1-yl) amino] (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {5,6,7,8tetrahydronaphthalen-1-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate provided the title compound as a white solid (11% (general yield from step a)). M- (LC / MS (ESI)): 488.2. HPLC (Condition A), Tr: 5.43 min (HPLC purity: 95.6%).
Example 369: {(1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- (1,1'-biphenyl-3-ylmethyl) -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1,1'-biphenyl-3-ylmethylamine hydrobromide provided the compound of the title as an oil. M + (LC / MS (ESI)): 496.5. HPLC (Condition A), Tr: 4.99 min (HPLC purity: 90.9%).
Stage b) Formation of ethyl {(1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1,1'-biphenyl-3-ylmethyl) N- [4- (3-undecyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil. M + (LC / MS (ESI)): 596.1. HPLC (Condition A), Tr: 6.51 min (HPLC purity: 91.8%).
Step c) Formation of {(1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1,1'-biphenyl-3-methyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (6% (general yield from step a)). M- (LC / MS (ESI)): 566.3. HPLC (Condition A), Tr: 6.06 min (HPLC purity: 99.5%).
Example 370: {(1,1'-biphenyl-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- (1,1'-biphenyl-3-ylmethyl) -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1,1'-biphenyl-3-ylmethylamine hydrobromide provided the compound of the title as an oil. M + (LC / MS (ESI)): 496.5. HPLC (Condition A), Tr: 4.99 min (HPLC purity: 87.7%).
Stage b) Formation of ethyl {(1,1'-biphenyl-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1,1'-biphenyl-3-ylmethyl) N- [3- (3-undecyl-1,2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil.
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1,1'-biphenyl-3-methyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (17% (general yield from step a)). M- (LC / MS (ESI)): 566.1; M + (LC / MS (ESI)): 568.2. HPLC (Condition A), Tr: 5.99 min (HPLC purity: 94.5%).
Example 371: {(1,1'-biphenyl-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- (1,1'-biphenyl-3-ylmethyl) -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1,1'-biphenyl-3-ylmethylamine hydrobromide provided the compound of the title as an oil. M + (LC / MS (ESI)): 454.6. HPLC (Condition A), Tr: 4.52 min (HPLC purity: 81%).
Stage b) Formation of ethyl {(1,1'-biphenyl-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1,1'-biphenyl-3-ylmethyl) N- [4- (3-octyl-l, 2,4-oxadiazol-5- il) benzyl] amine provided the title compound as an oil.
Step c) Formation of {(1,1'-biphenyl-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1,1'-biphenyl-3-methyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (4% (general yield from step a)). M- (LC / MS (ESI)): 524.2. HPLC (Condition A), Tr: 5.51 min (HPLC purity: 90.8%).
Example 372: {(1-benzothien-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- (1-benzothien-3-ylmethyl) -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1-benzothien-3-ylmethylamine provided the title compound as an oil . M + (LC / MS (ESI)): 476.4. HPLC (Condition A), Tr: 4.82 min (HPLC purity: 77.5%).
Stage b) Formation of ethyl {(1-benzothien-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1-benzothien-3-methylmethyl) -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of {(1-benzothien-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1-benzothien-3-methylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a colorless oil (15% (general yield from step a)). M- (LC / MS (ESI)): 546.2. HPLC (Condition A), Tr: 5.88 min (HPLC purity: 98.3%).
Example 373: {(1-benzothien-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- (1-benzothien-3-ylmethyl) -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1-benzothien-3-ylmethylamine provided the title compound as an oil . M + (LC / MS (ESI)): 476.3. HPLC (Condition A), Tr: 4.79 min (HPLC purity: 86.7%).
Stage b) Formation of ethyl {(1-benzothien-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1-benzothien-3-methylmethyl) -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil. M + (LC / MS (ESI)): 576.7. HPLC (Condition A), Tr: 6.37 min (HPLC purity: 87.9%).
Step c) Formation of {(1-benzothien-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1-benzothien-3ylmethyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a colorless oil (23% (general yield from step a)). M- (LC / MS (ESI)): 546.1. HPLC (Condition A), Tr: 5.84 min (HPLC purity: 98.0%).
Stage a) Formation of N- (1-benzothien-3-ylmethyl) -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) -benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil . M + (LC / MS (ESI)): 434.3. HPLC (Condition A), Tr: 4.30 min (HPLC purity: 89.9%).
Stage b) Formation of ethyl {(1-benzothien-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (1-benzothien-3-methylmethyl) -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of {(1-benzothien-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(1-benzothien-3-methylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a yellow oil (9% (general yield from step a)). M- (LC / MS (ESI)): 504.1. HPLC (Condition A), Tr: 5.34 min (HPLC purity: 88.7%).
Example 375: oxo {[2- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} acetic acid
Stage a) Formation of N- [2- (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 488.5. HPLC (Condition A), Tr: 4.78 min (HPLC purity: 95.4%).
Stage b) Formation of ethyl oxo {[2- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2 (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of oxo {[2- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) -benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[2 (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a colorless oil (38% (general yield from step a)). M- (LC / MS (ESI)): 558.1. HPLC (Condition A), Tr: 5.94 min (HPLC purity: 98.7%).
Example 376: oxo {[2- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N- [2- (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 488.4. HPLC (Condition A), Tr: 4.78 min (HPLC purity: 95.4%).
Stage b) Formation of ethyl oxo {[2- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2 (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of oxo {[2- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[2 (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a colorless oil (13% (general yield from step a)). M- (LC / MS (ESI)): 558.2. HPLC (Condition A), Tr: 5.87 min (HPLC purity: 97.8%).
Example 377: {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [2- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N- [2- (trifluoromethyl) benzyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 446.4. HPLC (Condition A), Tr: 4.23 min (HPLC purity: 96.5%).
The same procedure used in the preparation of Example 357 (step b) but using N- [2 (trifluoromethyl) benzyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil. M- (LC / MS (ESI)): 544.2; M + (LC / MS (ESI)): 546.1. HPLC (Condition A), Tr: 5.95 min (HPLC purity: 92.7%).
Step c) Formation of {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[2 (trifluoromethyl) benzyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a colorless oil (18% (general yield from step a)). M- (LC / MS (ESI)): 516.2. HPLC (Condition A), Tr: 5.35 min (HPLC purity: 99.0%).
Example 378: oxo {[3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N- [3- (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 3- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 488.4. HPLC (Condition A), Tr: 4.84 min (HPLC purity: 64.4%).
Stage b) Formation of ethyl oxo {[3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [3 (trifluoromethyl) benzyl] -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of oxo {[3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[3 (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a yellow oil (14% (general yield from step a)). M- (LC / MS (ESI)): 558.3. HPLC (Condition A), Tr: 5.85 min (HPLC purity: 97.8%).
Example 379: oxo {[3- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N- [3- (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 3- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 488.5. HPLC (Condition A), Tr: 4.86 min (HPLC purity: 66.8%).
Stage b) Formation of ethyl oxo {[3- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [3 (trifluoromethyl) benzyl] -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of oxo {[3- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[3 (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a yellow oil (44% (general yield from step a)). M- (LC / MS (ESI)): 558.1; M + (LC / MS (ESI)): 560.2. HPLC (Condition A), Tr: 5.84 min (HPLC purity: 97.3%).
Example 380: {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [3- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
Stage a) Formation of N- [3- (trifluoromethyl) benzyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 3- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 446.4. HPLC (Condition A), Tr: 4.31 min (HPLC purity: 73.9%).
Stage b) Formation of ethyl oxo {[3- (trifluoromethyl) benzyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [3 (trifluoromethyl) benzyl] -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {[3 (trifluoromethyl) benzyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} Acetate provided the title compound as a yellow oil (20% (general yield from step a)). M- (LC / MS (ESI)): 516.1. HPLC (Condition A), Tr: 97.9 min (HPLC purity: 97.9%).
Example 381: {(2-methoxybenzyl) [4- (3-undecyl-l, 2,4-oxadiazol-5-yl) benzyl] -amino} - (oxo) acetic acid
Stage a) Formation of N- (2-methoxybenzyl) -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzaldehyde and 2-methoxybenzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 450.5. HPLC (Condition A), Tr: 4.70 min (HPLC purity: 92.7%).
Stage b) Formation of ethyl {(2-methoxybenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (2-methoxybenzyl) -N [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {(2-methoxybenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(2-methoxybenzyl) [4- (3undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a colorless oil (43% (general yield of step a)). M- (LC / MS (ESI)): 520.3; M + (LC / MS (ESI)): 522.4. HPLC (Condition A), Tr: 5.76 min (HPLC purity: 98.6%).
Example 382: {(2-Methoxybenzyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N- (2-methoxybenzyl) -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzaldehyde and 2-methoxybenzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 450.5. HPLC (Condition A), Tr: 4.72 min (HPLC purity: 92.6%).
Stage b) Formation of ethyl {(2-methoxybenzyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (2-methoxybenzyl) -N [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {(2-methoxybenzyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(2-methoxybenzyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a white solid (17% (general yield of step a)). M- (LC / MS (ESI)): 520.3; M + (LC / MS (ESI)): 522.3. HPLC (Condition A), Tr: 5.70 min (HPLC purity: 98.9%).
Example 383: {(2-methoxybenzyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N- (2-methoxybenzyl) -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 2-methoxybenzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 408.4. HPLC (Condition A), Tr: 4.12 min (HPLC purity: 91.9%).
Stage b) Formation of ethyl {(2-methoxybenzyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (2-methoxybenzyl) -N [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine provided the title compound as an oil.
Step c) Formation of {(2-methoxybenzyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(2-methoxybenzyl) [4- (3octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (33% (general yield of step a)). M- (LC / MS (ESI)): 478.2. HPLC (Condition A), Tr: 5.15 min (HPLC purity: 98.0%).
Stage a) Formation of N- {4 - [(trifluoromethyl) sulfonyl] benzyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 4 - [(trifluoromethyl) sulfonyl] benzylamine hydrochloride provided the compound of Title as an oil. M + (LC / MS (ESI)): 552.7. HPLC (Condition A), Tr: 4.85 min (HPLC purity: 36%).
Stage b) Formation of ethyl oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- {4 [(trifluoromethyl) sulfonyl] benzyl} -N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil.
Step c) Formation of oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl ] amino} acetate provided the title compound as a yellow oil (15% (general yield from step a)). M- (LC / MS (ESI)): 622.1; M + (LC / MS (ESI)): 624.1. HPLC (Condition A), Tr: 5.80 min (HPLC purity: 79.4%).
Example 385: oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid
Stage a) Formation of N- {4 - [(trifluoromethyl) sulfonyl] benzyl} -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 4 - [(trifluoromethyl) sulfonyl] benzylamine hydrochloride provided the compound of Title as an oil. M + (LC / MS (ESI)): 552.5. HPLC (Condition A), Tr: 4.85 min (HPLC purity: 62.0%).
Stage b) Formation of ethyl oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- {4 [(trifluoromethyl) sulfonyl] benzyl} -N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil.
Step c) Formation of oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1,2,4-oxadiazol-5yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl ] amino} acetate provided the title compound as a yellow oil (37% (general yield from step a)). M- (LC / MS (ESI)): 622.1; M + (LC / MS (ESI)): 624.0. HPLC (Condition A), Tr: 5.79 min (HPLC purity: 81.4%).
Example 386: ([4- (3-Octyl-1,2,4-oxadiazol-5-yl) benzyl] {4 - [(trifluoromethyl) sulfonyl] -benzyl} amino} (oxo) acetic acid
Stage a) Formation of N- {4 - [(trifluoromethyl) sulfonyl] benzyl} -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 4 - [(trifluoromethyl) sulfonyl] benzylamine hydrochloride provided the compound of Title as an oil. HPLC (Condition A), Tr: 4.36 min (HPLC purity: 43.4%).
Stage b) Formation of ethyl oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 357 (step b) but using N- {4 [(trifluoromethyl) sulfonyl] benzyl} -N- [4- (3-octyl-1,2,4-oxadiazol-5-yl ) benzyl] amine provided the title compound as an oil.
Step c) Formation of ([4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] {4 - [(trifluoromethyl) sulfonyl] benzyl} amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl oxo {{4 [(trifluoromethyl) sulfonyl] benzyl} [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl ] amino} acetate provided the title compound as a yellow oil (24% (general yield from step a)). M- (LC / MS (ESI)): 580.1; M + (LC / MS (ESI)): 582.1. HPLC (Condition A), Tr: 5.26 min (HPLC purity: 81.1%).
Stage a) Formation of N-1,3-benzodioxol-5-yl-N- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and l, 3-benzodioxol-5-ylamine provided the title compound as a oil. HPLC (Condition A), Tr: 5.15 min (HPLC purity: 97.2%).
Stage b) Formation of ethyl {1,3-benzodioxol-5-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N-1,3-benzodioxol-5-yl- [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of {1,3-benzodioxol-5-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {1,3-benzodioxol-5il [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a brown oil (46% (general yield from step a)). M + (LC / MS (ESI)): 478.2 (-C02). HPLC (Condition A), Tr: 5.55 min (HPLC purity: 96.4%).
Example 388: {1,3-benzodioxol-5-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} - (oxo) acetic acid
Stage a) Formation of N-1,3-benzodioxol-5-yl-N- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 3- (3-undecyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1,3-benzodioxol-5-ylamine provided the title compound as an oil. M + (LC / MS (ESI)): 450.4. HPLC (Condition A), Tr: 5.12 min (HPLC purity: 95.4%).
Stage b) Formation of ethyl {1,3-benzodioxol-5-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N-1,3-benzodioxol-5-yl- [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of {1,3-benzodioxol-5-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {1,3-benzodioxol-5il [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a brown oil (56% (general yield from step a)). M + (LC / MS (ESI)): 522.1. HPLC (Condition A), Tr: 5.55 min (HPLC purity: 94.7%).
Example 389: {1,3-benzodioxol-5-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N-1,3-benzodioxol-5-yl-N- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amine
The same procedure used in the preparation of Example 357 (step a) but using 4- (3-octyl-1,2,4oxadiazol-5-yl) benzaldehyde and 1,3-benzodioxol-5-ylamine provided the title compound as an oil. M + (LC / MS (ESI)): 408.4. HPLC (Condition A), Tr: 4.54 min (HPLC purity: 85.5%).
Stage b) Formation of ethyl {1,3-benzodioxol-5-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N-1,3-benzodioxol-5-yl- [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] Amine provided the title compound as an oil.
Step c) Formation of {1,3-benzodioxol-5-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {1,3-benzodioxol-5il [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetate provided the title compound as a brown oil (48% (general yield from step a)). M + (LC / MS (ESI)): 478.2 (-CO2). HPLC (Condition A), Tr: 4.91 min (HPLC purity: 97.5%).
Example 390: {[(4-dodec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of (4-bromo-1-naphthyl) methylamine hydrochloride
A mixture of 1-bromo-4-methylnaphthalene (25 g, 0.113 mol), NBS (22.2 g, 0.123 mol) and benzoyl peroxide (5 g) in CCl4 (750 mL) was refluxed for 5 h. The reaction mixture was cooled, the succinimide was filtered off and concentrated to provide crude bromide (34 g) and was used for the next reaction without any purification. To a cold solution (-40 ° C) of liquid ammonia (2 L) was added 1-bromo-4-bromomethyl naphthalene (crude, 34 g) dissolved in 200 ml of CH2Cl2 over a period of 45 min. The reaction mixture was then stirred at -40 ° C for 18h. The reaction mixture was then allowed to stir at RT and concentrated in vacuo to provide a yellow residue.
The residue was then treated with 3N HCl (250 mL), the solid obtained was filtered off and washed with CH2Cl2 (2x 250 mL). The solid was dried under vacuum to provide (4-bromo-1-naphthyl) methylamine hydrochloride (25 g, 80%). HPLC purity: 96.6%
Stage b) Formation of N - [(4-bromo-1-naphthyl) methyl] -N- [4- (trifluoromethyl) benzyl] amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using (4-bromo-1-naphthyl) methylamine and 4- (trifluoromethyl) benzaldehyde provided the title compound as a brown oil (58%). HPLC (Condition A), Tr: 3.40 min (HPLC purity: 98.4%).
Stage c) Formation of ethyl {[(4-bromo-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N - [(4bromo-1-naphthyl) methyl] -N- [4- (trifluoromethyl) benzyl] amine hydrochloride gave the title compound (98% ). M- (LC / MS (ESI)): 491.4; M + (LC / MS (ESI)): 496.1. HPLC (Condition A), Tr: 5.25 min (HPLC purity: 97.9%).
Stage d) Formation of ethyl {[(4-dodec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl {[(4-bromo-1naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided
the title compound as a yellow oil (74%). HPLC (Condition A), Tr: 6.64 min (HPLC purity: 100%).
Step e) Formation of {[(4-dodec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[(4-dodec-1-inyl-1naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of title as a yellow oil (48% (general yield of stage a)). M- (LC / MS (ESI)): 550.2. HPLC (Condition A), Tr: 6.15 min (HPLC purity: 99.3%). Analysis calculated for C33H36F3NO3 = 0.5 H2O: C, 70.70; H, 6.65; N, 2.50%. Found: C, 70.44; H, 6.72; N, 2.29%
Example 391: {[(4-dec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N - [(4-bromo-1-naphthyl) methyl] -N- [4- (trifluoromethyl) benzyl] amine hydrochloride
The same procedure used in the preparation of Example 226 (step a) but using (4-bromo-1-naphthyl) methylamine and 4- (trifluoromethyl) benzaldehyde provided the title compound as a brown oil (58%). HPLC (Condition A), Tr: 3.40 min (HPLC purity: 98.4%).
Stage b) Formation of ethyl {[(4-bromo-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N - [(4bromo-1-naphthyl) methyl] -N- [4- (trifluoromethyl) benzyl] amine hydrochloride provided the title compound as an oil colorless (98%).
Step c) Formation of ethyl {[(4-dec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 226 (step c) but using ethyl {[(4-bromo-1naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided
the title compound as a yellow oil (87%). M- (LC / MS (ESI)): 550.1; M + (LC / MS (ESI)): 552.5. HPLC (Condition A), Tr: 6.36 min (HPLC purity: 96.4%).
Step d) Formation of {[(4-dec-1-inyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[(4-dec-1-inyl-1naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetate provided the compound of title as a brown oil (91%). 1H NMR (CDCl3, 300 MHz) δ 8.43-8.37 (m, 1H), 7.90-7.76 (m, 1H), 7.61-7.48 (m, 5H), 7, 28-7.08 (m, 3H), 5.37 (s, 0.7H), 5.05 (s, 1.3H), 4.79 (s, 1.3H), 4.61 (s, 0.7H), 2.57 (t, 2H, J = 7.0Hz), 1.77-1.65 (m, 2H), 1.59-1.48 (m, 2H), 1.42- 1.25 (m, 8H), 0.89 (m, 3H). M- (LC / MS (ESI)): 522.3. HPLC (Condition A), Tr: 5.83 min (HPLC purity: 97.7%).
Stage a) Formation of N- [1- (3-chlorophenyl) -1-methylethyl] -N- {4 - [(4-hexylphenyl) -ethylyl] benzyl} amine
The same procedure used in the preparation of Example 226 (step a) but using 4 - [(4-hexylphenyl) ethynyl] benzaldehyde and l- (3-chlorophenyl) -1-methylethylamine gave the title compound as a brown oil (80%) . HPLC (Condition A), Tr: 4.73 min (HPLC purity: 98.7%).
5 Stage b) Formation of ethyl ([1- (3-chlorophenyl) -1-methyl ethyl] {4 - [(4-hexylphenyl) ethynyl] -benzyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 15 (step b) but using N- [1- (3-chlorophenyl) -1-methyl ethyl] -N- {4 - [(4-hexylphenyl) ethynyl] benzyl} amine provided the compound of title as a brown oil (95%). HPLC (Condition A), Tr: 6.26 min (HPLC purity: 99.3%).
Step c) Formation of ([1- (3-chlorophenyl) -1-methyl ethyl] {4 - [(4-hexylphenyl) ethynyl] -benzyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ([1- (3-chlorophenyl) -1-methyl ethyl] {4 - [(4-hexylphenyl) ethynyl] benzyl} -amino) (oxo) acetate provided the title compound as a yellow powder (89%). M- (LC / MS (ESI)): 514.1. HPLC (Condition A), Tr: 5.84 min (HPLC purity: 99.1%).
Step d) Formation of ([1- (3-chlorophenyl) -1-methyl ethyl] {4 - [(4-hexylphenyl) ethynyl] -benzyl} amino) (oxo) acetic acid, Nmethyl-D-glucamine salt (es say 1-deoxy-1- (methylamino) glucitol)
The same procedure used in the preparation of Example 2 but using ([1- (3-chlorophenyl) -1-methyl ethyl] {4 [(4-hexylphenyl) ethynyl] benzyl} amino) (oxo) acetic acid provided the compound of title as a white powder (94%). M (LC / MS (ESI)): 514.7. HPLC (Condition A), Tr: 5.81 min (HPLC purity: 99.4%). Analysis calculated for C32H34ClNO3.C7H17NO5 = 0.8 H2O: C, 64.55; H, 7.31; N, 3.86%. Found: C, 64.6; H, 7.43; N, 3.87%
Example 393: oxo {[4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetic acid
20 Stage a) Formation of 4- (1,3-dioxolan-2-yl) benzonitrile
To a solution of 4-cyanobenzaldehyde (25 g, 0.190 mol) in dry toluene (300 mL) was added ethylene glycol (15 g, 0.228 mol) and PTSA (0.5 g) and allowed to reach reflux at 130 ° C with azeotropic removal of water for 12h. The reaction mixture was cooled, washed with 10% aqueous NaHCO3 (100 mL), dried and concentrated in vacuo. The crude solid was recrystallized from pet / EtOAc Ether to provide 4- (1,3-dioxolan-2-yl) benzonitrile (17 g,
25 51%) as a white solid. TLC (pet ether / EtOAc 4/1), Rf = 0.6
Stage b) Formation of 4- (1,3-dioxolan-2-yl) benzenecarbotioamide
To a solution of 4- (1,3-dioxolan-2il) benzonitrile (2 g, 0.01 1mol) in dry pyridine (50 mL)
and TEA (5.75 g, 0.057 mol) was passed H2S gas (recently generated) for 1h with stirring to
TA The reaction mixture was diluted with water (100 mL), extracted with diethyl ether (100 mL), washed with brine
30 (50 mL) and dried. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (pet / EtOAc Ether, 3/7) to provide 4- (1,3-dioxolan-2-yl) benzenecarbotioamide (1, 9 g, 86%) as a yellow solid. TLC (pet ether / EtOAc 3/7), Rf = 0.35
Stage c) Formation of 1-bromotridecan-2-one
To a solution of lauric acid chloride (10.0 g, 45.7 mmol) in anhydrous THF (91 mL) at 0 ° C was added dropwise
35 a solution of trimethylsilyldiazomethane (2M in ether, 45.7 mL, 91.4 mmol). The mixture was stirred 1 h at 0 ° C then overnight at RT. The solvents were evaporated in vacuo to provide a yellow oil. This crude product was dissolved in DCM (50 mL) and stirred in the presence of PL-AMS-Resin (Polymer Laboratories, 1.54 mmol / g, 5 g) for 5 h at RT. The resin was removed by filtration and washed with DCM. The combined filtrates were evaporated to provide a yellow oil. This crude product was dissolved in Et2O, cooled to 0 ° C and
40 added a concentrated aqueous solution of HBr (48%, 10 mL) by dripping carefully. After 1 h of reaction, the mixture was decanted and the organic layer was dried over MgSO4, filtered and evaporated to give the title product as a beige solid (8.32 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 3.87 (s, 2H), 2.63 (t, 2H, J = 7.5Hz), 1.67-1.54 (m, 2H), 1.30- 1.21 (m, 16H), 0.87 (m, 3H)
Stage d) Formation of 4- (4-undecyl-1,3-thiazol-2-yl) benzaldehyde
A solution of 1-bromotridecan-2-one (5.54 g, 20 mmol) and 4- (1,3-dioxolan-2-yl) benzenecarbotioamide (4.19 g, 20 mmol) in EtOH (50 mL) underwent reflux overnight. After evaporation of the solvent, the residue was taken up in ether, washed with water, brine, dried over MgSO4 and filtered. The solvents were evaporated in vacuo to provide a yellow oil. Purification by silica gel gave the title product as a yellow solid (4.05 g, 59%). 1H NMR (CDCl3, 300 MHz) δ 10.0 (s, 1H), 8.11 (d, 2H, J = 8.3 Hz), 7.93 (d, 2H, J = 8.6 Hz), 6.98 (s, 1H), 2.84 (t, 2H, J = 7.2 Hz), 1.78-1.72 (m, 2H), 1.50-1.20 (m, 16H) , 0.87 (t, 3H, J = 6.8 Hz). M + (LC / MS (ESI)): 344.3
Stage e) Formation of N- [4- (trifluoromethyl) benzyl] -N- [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amine
The same procedure used in the preparation of Example 226 (step a) but using 4- (4-undecyl-1,3-thiazol2-yl) benzaldehyde and 4- (trifluoromethyl) benzylamine gave the title compound as a colorless oil (90 %). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, 2H, J = 8.3 Hz), 7.45 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.25 (d, 2H, J = 8.3 Hz), 6.72 (s, 1H), 3.689 (s, 2H, J-7.3 Hz), 3 , 74 (s, 2H), 2.67 (t, J = 2H, 7.7 Hz), 1.95-1.72 (m, 1H), 1.62-1.55 (m, 2H), 1.37-1.05 (m, 16H), 0.74 (t, 3H, J = 6.7 Hz). M + (LC / MS (ESI)): 503.4. HPLC (Condition A), Tr: 4.99 min (HPLC purity: 91.2%).
Step f) Formation of ethyl ethyl {[4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetate
The same procedure used in the preparation of Example 15 (step b) but using 4- (4-undecyl-1,3-thiazol-2-yl) benzaldehyde provided the title compound as a colorless oil (93%). 1H NMR (CDCl3, 300 MHz) δ 7.98-7.88 (m, 2H), 7.65-7.56 (m, 2H), 7.40-7.23 (m, 4H), 6, 89 (d, 1H, J = 3.8Hz), 4.54 (d, 2H, J = 4.5Hz), 4.41-4.29 (m, 4H), 2.82 (t, 2H, J = 7.7 Hz), 1.81-1.70 (m, 2H), 1.40-1.21 (m, 19H), 0.87 (m, 3H). HPLC (Condition A), Tr: 6.52 min (HPLC purity: 98.9%).
Stage g) Formation of oxo {[4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyloxo {[4 (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetate provided the title compound as a colorless oil (95%). M- (LC / MS (ESI)): 573.3; M + (LC / MS (ESI)): 575.1. HPLC (Condition A), Tr: 5.98 min (HPLC purity: 98.6%).
Step h) Formation of oxo {[4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetic acid
The same procedure used in the preparation of Example 1 (step e) but using oxo {[4 (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) benzyl] amino} acetic acid provided the title compound as a white powder (93%). M- (LC / MS (ESI)): 573.4; M + (LC / MS (ESI)): 575.3. HPLC (Condition A), Tr: 5.99 min (HPLC purity: 99.3%). Analysis calculated for C31H37F3N2O3S.C7H17NO5 = 0.1H2O: C, 59.14; H, 7.08; N, 5.45%. Found: C, 58.87; H, 6.96; N, 5.38%
Example 394: {(-dec-1-inylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- [2- (2-fluorophenyl) ethyl] amine
To a solution of 4-dec-1-inylbenzaldehyde (24.2 mg, 0.1 mmol) in anhydrous THF (0.6 mL) was added 2- (2fluorophenyl) ethylamine (13.9 mg, 0.1 mmol ) and anhydrous MgSO4 (50 mg). The mixture was stirred overnight at RT. The reaction mixture was filtered and evaporated to provide an oily residue. This crude product was taken up in MeOH (0.5 mL) then sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added and the reaction mixture was stirred overnight at RT. The solvents were evaporated in vacuo to provide a solid. This solid was suspended in DCM (0.75 mL) and eluted through a SCX column (Isolute, 1 g) with DCM (6 mL), then NH3 (2M in MeOH, 4 mL). The desired fractions (TLC monitoring) were concentrated in vacuo to provide the title product as a yellow oil. M + (LC / MS (ESI)): 366.3. HPLC (Condition A), Tr: 4.64 min (HPLC purity: 80.5%).
Stage b) Formation of ethyl {(4-dec-1-inylbenzyl) [2- (2-fluorophenyl) ethyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (4-dec-1-inylbenzyl) N- [2- (2-fluorophenyl) ethyl] amine gave the title compound as an oil. HPLC (Condition A), Tr: 6.18 min (HPLC purity: 65.5%).
Step c) Formation of {(4-dec-1-inylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dec-1-inylbenzyl) [2 (2-fluorophenyl) ethyl] amino} (oxo) acetate provided the title compound as an oil orange (5% (overall yield of stage a)). M- (LC / MS (ESI)): 436.3. HPLC (Condition A), Tr: 5.45 min (HPLC purity: 87.5%).
Example 395: {(4-dodec-1-inyl] benzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dodec-1-inylbenzyl) -N- [2- (2-fluorophenyl) ethyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4-dodec-1-ylbenzaldehyde and 2- (2-fluorophenyl) ethylamine gave the title compound as an oil. M + (LC / MS (ESI)): 394.4. HPLC (Condition A), Tr: 5.00 min (HPLC purity: 93.6%).
The same procedure used in the preparation of Example 357 (step b) but using N- (4-dodec-1-ylbenzyl) -N- [2- (2-fluorophenyl) ethyl] amine gave the title compound as an oil.
Step c) Formation of {(4-dodec-1-inylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dodec-1inylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetate provided the title compound as an orange oil (21% (overall performance of stage a)). HPLC (Condition A), Tr: 5.78 min (HPLC purity: 82.2%).
Example 396: {{[4- (dodecyloxy) -1-naphthyl] methyl} [2- (2-fluorophenyl) ethyl] amino} - (oxo) acetic acid
Stage a) Formation of N - {[4- (dodecyloxy) -1-naphthyl] methyl} -N- [2- (2-fluorophenyl) -ethyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4- (dodecyloxy) -1 naphthalene and 2- (2-fluorophenyl) ethylamine gave the title compound as an oil. HPLC (Condition A), Tr: 5.48 min (HPLC purity: 86.4%).
Stage b) Formation of ethyl {{[4- (dodecyloxy) -1-naphthyl] methyl} [2- (2-fluorophenyl) ethyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N - {[4- (dodecyloxy) -1 naphthyl] methyl} -N- [2- (2-fluorophenyl) ethyl] amine gave the title compound as an oil.
Step c) Formation of {{[4- (dodecyloxy) -1-naphthyl] methyl} [2- (2-fluorophenyl) ethyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{[4- (dodecyloxy) -1 naphthyl] methyl} [2- (2-fluorophenyl) ethyl] amino} (oxo) acetate provided the compound of title as an orange oil (7% (general yield of stage a)). M- (LC / MS (ESI)): 534.3. HPLC (Condition A), Tr: 6.25 min (HPLC purity: 92.8%).
Example 397: {[2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- [2- (2-fluorophenyl) ethyl] -N- [4- (octyloxy) benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4 (octyloxy) benzaldehyde and 2- (2-fluorophenyl) ethylamine gave the title compound as an oil. HPLC (Condition A), Tr: 4.37 min (HPLC purity: 76.0%).
Stage b) Formation of ethyl {[2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (2-fluorophenyl) ethyl] N- [4- (octyloxy) benzyl] amine gave the title compound as an oil.
Step c) Formation of {[2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetate provided the title compound as a white solid ( 22% (overall performance of stage a)). M- (LC / MS (ESI)): 428.3. HPLC (Condition A), Tr: 5.19 min (HPLC purity: 64.2%).
Example 398: {(4-dec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- [2- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4-dec-1-benzylbenzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 402.3. HPLC (Condition A), Tr: 4.71 min (HPLC purity: 86.5%).
Stage b) Formation of ethyl {(4-dec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] -amino} - (oxo) -acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (4-dec-1-inylbenzyl) N- [2- (trifluoromethyl) benzyl] amine gave the title compound as an oil. HPLC (Condition A), Tr: 6.31 min (HPLC purity: 80.7%).
Step c) Formation of {(4-dec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dec-1-inylbenzyl) [2 (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as an orange oil ( 7% Example 399: {(4-dodec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dodec-1-inylbenzyl) -N- [2- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4-dodec-1-ylbenzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. M + (LC / MS (ESI)): 430.4. HPLC (Condition A), Tr: 5.05 min (HPLC purity: 96.9%).
Stage b) Formation of ethyl {(4-dodec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] -amino} - (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- (4-dodec-1inylbenzyl) -N- [2- (trifluoromethyl) benzyl] amine gave the title compound as an oil.
Step c) Formation of {(4-dodec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dodec-1inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as an orange oil (17 % (general performance of stage a)). M- (LC / MS (ESI)): 500.2. HPLC (Condition A), Tr: 5.92 min (HPLC purity: 82.5%).
Example 400: {{4- (dodecyloxy) -1-naphthyl] methyl} [2- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid
Stage a) Formation of N - {[4- (dodecyloxy) -1-naphthyl] methyl} -N- [2- (trifluoromethyl) -benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4- (dodecyloxy) -1 naphthalene and 2- (trifluoromethyl) benzylamine gave the title compound as an oil. HPLC (Condition A), Tr: 5.54 min (HPLC purity: 98.0%).
Stage b) Formation of ethyl {{[4- (dodecyloxy) -1-naphthyl] methyl} [2- (trifluoromethyl) -benzyl] amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N - {[4- (dodecyloxy) -1 naphthyl] methyl} -N- [2- (trifluoromethyl) benzyl] amine gave the title compound as an oil .
Step c) Formation of {{[4- (dodecyloxy) -1-naphthyl] methyl} [2- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {{[4- (dodecyloxy) -1 naphthyl] methyl} [2- (trifluoromethyl) benzyl] amino} (oxo) acetate gave the title compound as an orange oil (8% (general yield of stage a)). M- (LC / MS (ESI)): 570.4. HPLC (Condition A), Tr: 6.30 min (HPLC purity: 79.2%).
Example 401: {[4- (octyloxy) benzyl] [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- [4- (octyloxy) benzyl] -N- [2- (trifluoromethyl) benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4 (octyloxy) benzaldehyde and 2- (trifluoromethyl) benzylamine provided the title compound as an oil. HPLC (Condition A), Tr: 4.24 min (HPLC purity: 91.0%).
Stage b) Formation of ethyl {[4- (octyloxy) benzyl] [2- (trifluoromethyl) benzyl] -amino} (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [4- (octyloxy) benzyl] -N [2- (trifluoromethyl) benzyl] amine gave the title compound as an oil.
Step c) Formation of {[4- (octyloxy) benzyl] [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[4- (octyloxy) benzyl] [2 (trifluoromethyl) benzyl] amino} (oxo) acetate provided the title compound as a yellow oil (13 % (general performance of stage a)). M- (LC / MS (ESI)): 464.3. HPLC (Condition A), Tr: 5.33 min (HPLC purity: 92.2%).
Example 402: {(4-dec-1-inylbenzyl) [2- (3,4-dichlorophenyl) ethyl] amino} (oxo) acetic acid
Stage a) Formation of N- (4-dec-1-inylbenzyl) -N- [2- (3,4-dichlorophenyl) ethyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4-dec-1-benzylbenzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound as an oil. M + (LC / MS (ESI)): 416.3. HPLC (Condition A), Tr: 4.91 min (HPLC purity: 72.4%).
The same procedure used in the preparation of Example 357 (step b) but using N- (4-dec-1-inylbenzyl) N- [2- (3,4-dichlorophenyl) ethyl] amine gave the title compound as an oil . HPLC (Condition A), Tr: 6.45 min (HPLC purity: 62.5%).
Step c) Formation of {(4-dec-1-inylbenzyl) [2- (3,4-dichlorophenyl) ethyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {(4-dec-1-inylbenzyl) [2 (3,4-dichlorophenyl) ethyl] amino} (oxo) acetate gave the title compound as an orange oil (11% (general yield of stage a)). M- (LC / MS (ESI)): 486.1. HPLC (Condition A), Tr: 5.76 min (HPLC purity: 89.8%).
Example 403: [[2- (3,4-dichlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N- (4-dodec-1-inylbenzyl) amine
The same procedure used in the preparation of Example 394 (step b) but using 4-dodec-1-ylbenzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound as an oil. M + (LC / MS (ESI)): 444.4. HPLC (Condition A), Tr: 5.27 min (HPLC purity: 83.9%).
Stage b) Formation of ethyl [[2- (3,4-dichlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] - (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N- (4-dodec-1-inylbenzyl) amine gave the title compound as an oil.
Step c) Formation of [[2- (3,4-dichlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] - (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl [[2- (3,4-dichlorophenyl) ethyl] (4-dodec-1-inylbenzyl) amino] (oxo) acetate gave the title compound as a yellow oil (4% (general yield of stage a)). M- (LC / MS (ESI)): 514.1. HPLC (Condition A), Tr: 6.08 min (HPLC purity: 96.1%).
Example 404: ([2- (3,4-dichlorophenyl) ethyl] {[4- (dodecyloxy) -1-naphthyl] methyl} amino) - (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N - {[4- (dodecyloxy) -1-naphthyl] methyl} amine
The same procedure used in the preparation of Example 394 (step b) but using 4- (dodecyloxy) -1 naphthalene and 2- (3,4-dichlorophenyl) ethylamine gave the title compound as an oil. HPLC (Condition A), Tr: 5.72 min (HPLC purity: 82.0%).
Stage b) Formation of ethyl ([2- (3,4-dichlorophenyl) ethyl] {[4- (dodecyloxy) -1-naphthyl] -methyl} amino) (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N - {[4- (dodecyloxy) -1-naphthyl] methyl} amine provided the compound of Title as an oil.
Step c) Formation of ([2- (3,4-dichlorophenyl) ethyl] {[4- (dodecyloxy) -1-naphthyl] methyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl ([2- (3,4-dichlorophenyl) ethyl] {[4- (dodecyloxy) -1-naphthyl] methyl} amino) (oxo) acetate provided the title compound as a yellow oil (6% (general yield of step a)). M- (LC / MS (ESI)): 584.0. HPLC (Condition A), Tr: 6.50 min (HPLC purity: 63.7%).
Example 405: {[2- (3,4-dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic acid
Stage a) Formation of N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (octyloxy) benzyl] amine
The same procedure used in the preparation of Example 394 (step b) but using 4 (octyloxy) benzaldehyde and 2- (3,4-dichlorophenyl) ethylamine gave the title compound as an oil. HPLC (Condition A), Tr: 4.69 min (HPLC purity: 71.8%).
Stage b) Formation of ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} - (oxo) acetate
The same procedure used in the preparation of Example 357 (step b) but using N- [2- (3,4-dichlorophenyl) ethyl] -N- [4- (octyloxy) benzyl] amine gave the title compound as an oil.
Step c) Formation of {[2- (3,4-dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 1 (step e) but using ethyl {[2- (3,4-dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetate provided the title compound as an oil yellow (6% Example 406: ({4 - [(4-hexylphenyl) ethynyl] benzyl} {1-methyl-1- [4- (trifluoromethyl) -phenyl] ethyl} amino) (oxo) acetic acid
The same procedure used in the preparation of Example 392 but using 1-methyl-1- [4 (trifluoromethyl) phenyl] ethylamine and 4 - [(4-hexylphenyl) ethynyl] benzaldehyde (step a) provided the title compound as a white powder M- (LC / MS (ESI)): 548.1. HPLC (Condition A), Tr: 5.89 min (HPLC purity: 98.7%).
Example 407: {[4- (5-cyclohexylpent-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 226 (step c) but using pent-4-inylcyclohexane gave the title compound as a yellow oil. M- (LC / MS (ESI)): 484.2. HPLC (Condition A), Tr: 5.53 min (HPLC purity: 98.8%).
Example 408: {{3 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 226 (step c) but using 1-ethynyl-4-hexylbenzene gave the title compound as a white powder. M- (LC / MS (ESI)): 520.0. HPLC (Condition A), Tr: 5.68 min (HPLC purity: 99.9%).
Example 409: {[4- (4-ethyl-3-hydroxioct-1-inyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid
The same procedure used in the preparation of Example 226 (step c) but using 4-ethyl-1-in-3-ol gave the title compound as a yellow foam. M- (LC / MS (ESI)): 488.2. HPLC (Condition A), Tr: 4.79 min (HPLC purity: 98.9%).
Example 410: {(2-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid
The same procedure used in the preparation of Example 226 (step c) but using ethyl {(2-bromobenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetate and dec-1-ino provided the title compound as an oil light yellow. M- (LC / MS (ESI)): 472.0. HPLC (Condition A), Tr: 5.51 min (HPLC purity: 99.6%).
Example 411: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid, L-lysine salt
The same procedure used in the preparation of Example 2 but using {(4-dec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and L-lysine provided the title compound as a white powder. M (LC / MS (ESI)): 472.3. HPLC (Condition A), Tr: 5.59 min (HPLC purity: 99.4%).
Example 412: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid, tromethamine salt (ie (2 amino-2- hydroxymethyl) -1,3-propanediol)
The same procedure used in the preparation of Example 2 but using {(4-dec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and tris (hydroxymethyl) amino methane gave the title compound as a white solid M- (LC / MS (ESI)): 472.3. HPLC (Condition A), Tr: 5.58 min (HPLC purity: 99.5%).
Example 413: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid, L-arginine salt
The same procedure used in the preparation of Example 2 but using {(4-dec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and L-arginine provided the title compound as a white powder. M (LC / MS (ESI)): 472.4. HPLC (Condition A), Tr: 5.55 min (HPLC purity: 99.6%).
Example 414: {(4-dec-1-inylbenzyl) [4- (trifluoromethyl) benzyl] -amino} - (oxo) sodium acetate
The same procedure used in the preparation of Example 2 but using {(4-dec-1-inylbenzyl) [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid and sodium hydroxide gave the title compound as a white solid. M- (LC / MS (ESI)): 472.2. HPLC (Condition A), Tr: 5.54 min (HPLC purity: 99.6%).
Example 415: Preparation of a pharmaceutical formulation
Pharmaceutical formulations using the compounds of formula (I) can be prepared according to conventional procedures known to those skilled in the art.
The following examples of formulations illustrate representative pharmaceutical compositions using compounds of formula (I), although it is stressed that the present invention should not be construed as limited to said formulations, which are set forth below.
A substituted methyleneamide derivative of formula (I) is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed in 240-270 mg tablets (80-90 mg of active substituted methylenamide derivative per tablet) in a tablet press.
Formulation 2 - Capsules
A substituted methyleneamide derivative of formula (I) is mixed as a dry powder with a starch diluent in an approximate weight ratio of 1: 1. The mixture is placed in 250 mg capsules (125 mg of methylenamide derivative substituted with capsule).
Formulation 3 - Liquid
A substituted methyleneamide derivative of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are combined, passed through a US sieve with No. 10 mesh and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then enough water is added.
Formulation 4 - Tablets
A substituted methyleneamide derivative of formula (I) is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed in 300-600 mg tablets (150-300 mg of active substituted methyleneamide derivative) in a tablet press.
Formulation 5 - Injection
A substituted methyleneamide derivative of formula (I) is dissolved in an aqueous medium of injectable sterile buffered saline to a concentration of approximately 5 mg / ml.
Example 416: Biological tests
The compounds of formula (I) may be subjected to the following tests:

(one)

The PTP Enzymatic Assay

(2)

The in vivo assay in db / db mice

(1) PTP enzyme assay (in vitro assay)

Assays for the determination of PTP inhibitory activity of test compounds are known to those skilled in the art. An example of such an assay is described below:

The enzymatic PTP assay is intended to determine the extent of PTP inhibition, for example, of PTP1B, SHP-1, SHP-2 or GLEPP-1 in the presence of a test compound of formula (I). The inhibition is illustrated by IC50 values denoting the concentration of the test compound necessary to achieve 50% inhibition of said PTP using the following concentration of DiFMUP PTP substrate:

5 µM DiFMUP for PTP1b;

20 µM DiFMUP for SHP-1 and SHP-2;

30 µM DiFMUP for GLEPP-1.

a) PTP cloning

The cloning and expression of the catalytic domain of PTP1B can be carried out as described in J. Biol. Chem. 2000,275 (13), pp. 9792-9796.

b) Materials and Methods

The DiFMUP test allows to follow the dephosphorylation of DiFMUP (6,8-DiFluoro-4-Methyl Umbeliferyl Phosphate) - which is the PTP substrate - mediated by PTP in its stable hydrolysis product, that is, DiFMU (6,8-difluoro -7-hydroxy coumarin). Due to its quite low pKa and its high quantum yield, DiFMU allows to measure the activities of acid and alkaline phosphatase with great sensitivity.

The tests were carried out in a 96-well plate format, using the catalytic core of a recombinant human PTP as the enzyme and 6,8-DiFluoro-4-Methyl Umbeliferyl Phosphate (DiFMUP, Molecular Probes, D6567) as a substrate. The compounds to be tested were dissolved in 100% DMSO at a concentration of 2 mM. Subsequent dilutions of the test compounds (to provide a concentration of 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001 µM) were carried out at 100% of DMSO using a Tecan Stand Alone Workstation. 5 µl of diluted compound or vehicle (100% DMSO = control) was distributed in a black Costar 96-well plate. 25µl of diluted DiFMUP was added to the assay buffer solution (20mM Tris HCl pH 7.5, 0.01% IGEPAL CA-630, 0.1mM ethylenediaminetetraacetic acid, 1mM DL-Dithiothreitol), followed by 20µl of human PTP enzyme recombinant diluted in the buffer solution of the assay to initiate the enzymatic reaction. Alternatively, 20 µl of recombinant human PTP enzyme diluted in test buffer solution can be added to the dilutions of compound or vehicle (distributed on a black Costar 96-well plate), followed by 25 µl of DiFMUP diluted in the test buffer solution. The reaction was run for 30 minutes at room temperature before reading the fluorescence intensity (integral or intensity) on a PerKin-Elmer Victor 2 spectrofluorimeter (the excitation of 6,8-difluoro-7-hydroxy coumarin is at 355nm, the emission at 460 nm, for 0.1s). The percent inhibition is determined by measuring the absence of relative ion fluorescence of a test compound (PTP inhibitor), that is, with the solvent alone (5% DMSO). IC50 values for inhibition were determined in triplicate.

Test compounds according to formula (I) exhibit an inhibition (illustrated by IC50 values) with respect to PTP preferably less than 10 µM, more preferably less than 5 µM.

For example, the compound of example 10 exhibits an IC50 value of 2,224 µM with respect to PTP1B, an IC50 value of 1.40 with respect to GLEPP-1, an IC50 value of 2.40 and 2.70 with respect to to SHP-1 and SHP-2.

The compound of Example 4 exhibits an IC50 value of 0.916 µM with respect to PTP1B and an IC50 value of 0.50 with respect to GLEPP-1, an IC50 value of 1 and 1.4 with respect to SHP-1 and SHP-2

 (2) In vivo assay in db / db mice

The following test aims to determine the antidiabetic effect of the test compounds of formula (I) in a postprandial glycemia model in db / db mice in vivo.

The test was carried out as follows:

A total of 24 db / db mice (approximately 8-9 weeks; obtained from IFFACREDO, l'Arbreste, France) were fasted for 20 hours.

Four groups were formed, each with 6 animals:

Group 1: A dose of 10 mg / kg of vehicle was administered to the animals (orally).

Group 2: Animals were administered (orally) a dose of 20 mg / kg of test compound according to formula (I).

Group 3: Animals were administered (orally) a dose of 100 mg / kg of test compound according to formula (I).

Group 4: Animals were administered (orally) a dose of 200 mg / kg of test compound according to formula (I).

After oral administration of the compounds of formula (I) solubilized or suspended in Carboxymethyl Cellulose (0.5%), Tween 20 (0.25%) and water as a vehicle, the animals had access to commercial food (D04, UAR, Villemoisson / Orge, France) ad libitum. The diabetic state of the mice was verified by determining the level of blood glucose before drug administration. Blood glucose and serum insulin levels were then determined 4 hrs after drug administration.

The blood glucose level was determined using a glucometer (Precision Q.I.D., Medisense, Abbot, ref. 212.62.31).

Insulin level determination was carried out using an ELISA kit (Crystal CHEM, Ref. INSK R020).

Changes in blood glucose and serum insulin of the mice treated with the drug were expressed as a percentage of the control (group 1: mice treated with vehicle).

Treatment (orally) of the animals with substituted methyleneamide compounds of formula (I), at a dosage of 50 mg / kg, decreased the level of blood glucose induced by food intake by approximately 20-40%.

For example, after using the compound of example 10, that is, {4 - [(dodecylamino) carbonyl] -benzyl} [4 (trifluoromethyl) benzyl] amino} (oxo) acetic acid, the following decreases in level were determined of blood glucose as well as insulin level:

Group of animals

Decreased blood glucose ± EEM Serum insulin decrease in ± EEM

Group 2

17 6 -2 7

Group number 3

42 6 66 8

Group 4

48 4 89 2

(EEM = Standard error of the mean) Reference List: -American Journal of Medicine, 60, 80 (1976) of Reaven et al; -Metabolism, 34.7 (1985) of Stout et al .;

5 -Diabetes / Metabolism Reviews, 5, 547 (1989) of Pyorala et al; -European Journal of Endocrinology 138, 269-274 (1998) by A. Dunaif; -Endocrine Reviews 18 (6), 774-800 (1997); -Diabetes Care, 14, 173 (1991) of DeFronzo and Ferranninni; -J. Mol. Med. 78, 473-482 (2000) by A. Cheng et al .;

10 -Current Opinion in Drug Discovery & Development 3 (5), 527-540 (2000); -Molecular and Cellular Biology, 5479-5489 (2000) by Lori Klaman et al .; -Diabetes, 40, 939 (1991) by McGuire et al .; -J. Clinical Invest., 84, 976 (1989) of Meyerovitch et al; -Metabolism, 44, 1074, (1995) by Sredy et al .;

15 -Curr. Opin. Chem. Biol, 5 (4), 416-23 (2001) by Zhang et al .; -J. Biol. Chem., 275 (52), 41439-46 (2000) by Bjorge J.D et al .; -J. Neurosci. Res., 63 (2), 143-150 (2001) of Pathre et al .; -Mol. Brain Res., 28 (1), 110-16 (1995) of Shock L. P et al; -Biochemical Pharmacology, Vol. 60, 877-883, (2000) by Brian P. Kennedy et al .;

20 -Leptin. Annu Rev. Physiol. 62 p. 413-437 (2000) by Ahima R. S. et al; -Developmental Cell., Vol.2, p. 497-503 (2002).

Claims (16)

1. Substituted methylenamide derivative of Formula (I): image 1 as well as its geometric isomers, its optically active forms such as enantiomers, diastereomers and its 5 forms of racemate, as well as pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-C12) alkyl -aryl or (C1-C12) alkyl-heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl; R2a  and R2b are each independently selected from the other from the group comprising or consisting of H or 10 (C1-C12) alkyl; Cy is: a) a thienyl or phenyl group substituted with any of the following:  a phenyl  an oxadiazole group; 15  1 or 2 moieties selected from the group consisting of -NH-CO-R3, -SO2-NR3R3 'or -CO-NR3R3', in which R3, R3 'are independently selected from H and (C1-C15) alkyl ; b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl; c) when R2a and R2b are each H and R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2 or trifluoromethyl, A thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7-C15) alkyl; or d) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group, a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl.

2.

 Substituted methylenamide derivatives according to claim 1, wherein R2a and R2b are each H.

3.

 A substituted methyleneamide derivative according to claim 1, wherein R3 'is H and R3 is selected from the group consisting of dodecyl, octyl, pentadecyl, tridecyl or (2-ethyl) -hexyl.

Four.

 A substituted methyleneamide derivative according to any one of claims 1 to 3, wherein R 1 is 30 A, with A aryl, heteroaryl, heterocycloalkyl (3-8 members) or cycloalkyl (3-8 members).

5.

 A substituted methylenamide derivative according to any of the preceding claims is selected from the following group: (benzyl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid oxo {{4 - [(pentadecylamino) carbonyl acid ] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid (benzyl {4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) acetic acid (benzyl {4 - [(tridecylamino) carbonyl] benzyl} amino ) (oxo) acetic

[benzyl (4 - {[dodecyl (methyl) amino] carbonyl} benzyl) amino] (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid {benzyl [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid ({4- [(dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-pentylbenzyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl } (1-Phenylethyl) amino] (oxo) acetic acid (benzyl {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ((3-cyanobenzyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid {{3 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid [(3-cyanobenzyl) ({3 '- [(octylamino) carbonyl ] [1,1'-biphenyl] -4-yl} methyl) amino] - (oxo) acetic acid [(4-chlorobenzyl) ({3 '- [(octylamino) carbonyl] [1,1'-biphenyl] - 4-yl} methyl) amino] - (oxo) acetic acid {({3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-iI} methyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic acid [(3-cyanobenzyl) ({3 '- [(dodecylamino) carbonyl] [1 , 1'-biphenyl] -4-yl} methyl) -amino] - (oxo) acetic acid [(4-chlorobenzyl) ({3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4- il} methyl) -amino] - (oxo) acetic acid {({3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) [4- (trifiuoromethyl) -benzyl] amino } (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-methoxybenzyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (4-methoxybenzyl) amino] ( oxo) acetic acid {{3 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] amino} (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carboniI] benzyl} (3-thienylmethyl) amino] (oxo ) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (4-phenoxy benzyl) amino] (oxo) acetic acid ((1,3-benzodioxol-5-ylmethyl) {4 - [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) -acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (2-thienylmethyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (isopropyl) amino] (oxo) acetic acid ((3,5-dichlorobenzyl) {4 - [(dodecylamino ) carbonyl] benzyl} amino) (oxo) acetic acid (2,3-dihydro-1H-inden-1-yl {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid [{4 - [( dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (3-pyridinylmethyl) amino] (oxo) acetic acid ((4-cyanobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (1,3-thiazol-2-ylmethyl) amino] (oxo) acetic acid [{3- [(dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] (oxo) acetic acid [{3 - [(dodeciIamino) carbonyl] benzyl} (3-pyridiniImethyl) amino] (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (3-hydroxybenzyl) amino] (oxo) acetic acid (( 4-cyanobenzyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid [{3 - [(dodecylamino) carbonyl] benzyl} (1,3-thiazoI-2-ylmethyl) amino] (oxo) acetic acid ((1,3-benzodioxol-5-ylmethyl) {3 - [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl ) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) amino ] (oxo) acetic acid [cyclopentyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid [benzyl ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl ) amino] (oxo) acetic acid [({5 - [(dodecylamino) sulfonyl] -2-thieniI} methyl) (4-methoxybenzyl) amino] - (oxo) -acetic acid [({5 - [(dodecylamino) sulfonyl) ] -2-thienyl} methyl) (2-fluorobenzyl) amino] (oxo) acetic acid [({5 - [(do decylamino) sulfonyl] -2-thienyl} methyl) (4-phenoxybenzyl) amino] - (oxo) -acetic acid {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) [3- (trifluoromethyl) benzyl ] amino} - (oxo) acetic acid [(3-chlorobenzyl) ({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid {({4 '- [(dodecylamino) carbonyl ] -1,1'-biphenyl-4-yl} methyl) [2- (trifluoromethoxy benzyl] amino} (oxo) acetic acid [({4 '- [(dodecylamino) carbonyl] -1,1'-biphenyl-4 -yl} methyl) (3-phenoxybenzyl) -amino] (oxo) acetic acid {({4, - [(dodecylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic acid {({4 '- [(octylamino) carbonyl] -1,1'-biphenyl-4-yl} methyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (2-methoxyphenyl) amino] (oxo ) acetic acid N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benzyl} -L-phenylalanine acid [{4 - [(dodecylamino) carbonyl] benzyl} (3-phenoxyphenyl) am ino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-iodophenyl) amino] (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [3-fluoro-4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid ((2,4-dichlorobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl } (1-Phenylpropyl) amino] (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [2- (trifluoromethyl) benzyl] amino} (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (2-methoxybenzyl) amino] (oxo) acetic acid ([(1R) -1- (4-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid (( 3,4-Dichlorobenzyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ((1-benzothien-3-ylmethyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [(lS) -1-phenylethyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [(lR) -1-phenylethyl ] amino} (oxo) acetic acid N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benci l} -D-phenylalanine acid {{4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] phenyl} [4- ( trifluoromethyl) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie, 1-deoxy-1- (methylamino) glucitol) acid {(3,5-dichlorobenzyl) [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid {(3,5-dichlorobenzyl) [4- (tridecanoylamino) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol). 6. A substituted methyleneamide derivative selected from the following group: {(4 - {[dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid ([1- ( tert-butoxycarbonyl) -4-piperidinyl] {4 - [(dodecylamino) carbonyl] benzyl} -amino) - (oxo) acetic acid ({[1- (tert-butoxycarbonyl) -4-piperidinyl] methyl} {4- [ (dodecylamino) carbonyl] -benzyl} amino) (oxo) acetic acid oxo {[4- (tridecanoylamino) benzyl] [4- (trifluoromethyl) benzyl] amino} acetic acid [benzyl (4 - {[4- (hexyloxy) benzoyl) ] amino} benzyl) amino] (oxo) acetic acid oxo {[4- (trifluoromethyl) benzyl] [4- (10-undecenoylamino) benzyl] amino} acetic acid oxo {{4 - [(9E) -9-tetradecenoylamino] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid {{4 - [(2-hydroxydecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetic acid oxo {[4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} -acetic acid {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl ) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic [{4 - [(dodecylamino) carbonyl] benzyl} ({l - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl } (2-Carboxy-1-phenylethyl) amino] (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (2-methoxy-1-methylethyl) amino] (oxo) acetic acid (4-bromo { 4 - [(dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid ([2- (3-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid {{4- [(dodecylamino) carbonyl] benzyl} [2- (3-methoxyphenyl) ethyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [(d, l) -trans-2-phenylcyclopropyl] amino} - (oxo) acetic acid ([(d, l) -trans-2- (benzyloxy) cyclopentyl] {4 - [(dodecylamino) carbonyl] benzyl} -amino) - (oxo) acetic acid [{4- [ (dodecylamino) carbonyl] benzyl} (4-phenoxyanilino- (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (1,2,3,4-tetrahydro-l-naphthalenyl) amino] - (oxo) acetic acid ((1-benzyl-4-piperidinyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid {{4 - [(dodecyl mino) carbonyl] benzyl} [2- (4-phenoxyphenyl) ethyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [2- (2-phenoxyphenyl) ethyl] amino} (oxo) acetic acid ((2-, 1,1'-biphenyl] -4-ylethyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid (([1,1'-biphenyl] -3- Imethyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid (3- (benzyloxy) {4 - [(dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid ([4- (benzoylamino ) benzyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid N- (carboxycarbonyl) -N- {4 - [(dodecylamino) carbonyl] benzyl} -3-phenyl-beta-alanine acid { {4 - [(dodecylamino) carbonyl] benzyl} [4- (1,2,3-thiadiazol-4-yl) benzyl] amino} - (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [ 1- (1-Naphthyl) ethyl] amino} (oxo) acetic acid {{3 - [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] amino} (oxo) acetic acid {benzyl [(3'- {[(2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] -amino} (oxo) acetic acid {(3-cyanobenzyl) [(3 '- {[( 2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic acid {(4-chlorobenzyl) [(3 '- {[(2,2-diphenylethyl) amino] carbonyl} [1 , 1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic acid {[(3'- {[(2,2-diphenylethyl) amino] carbonyl} [1,1'-biphenyl] -4- il) methyl] [4- (trifluoro-methyl) benzyl] amino} (oxo) acetic acid oxo {{[3 '- ({[2- (4-phenoxyphenyl) ethyl] amino} carbonyl) [1,1'- biphenyl] -4-yl] methyl} - [4- (trifluoromethyl) benzyl] amino} acetic acid {(3-cyanobenzyl) [(3 '- {[(3-phenylpropyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] amino} (oxo ) acetic acid {benzyl [(3 '- {[(4-pentiIbenciI) amino] carbonyl} [1,1'-biphenyl] -4-iI) methy] amino} - (oxo) acetic acid {(3-cyanobenzyl) [(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) -methyl] amino} (oxo) acetic acid {(4-chlorobenzyl) [(3'- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) -methyl] amino} (oxo) acetic acid oxo {[(3 '- {[(4-pentylbenzyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] [4- (trifluoro-methyl) benzyl] amino} acetic acid oxo {[(3 '- {[(4-phenylbutyl) amino] carbonyl} [ 1,1'-biphenyl] -4-iI) methyl] [4- (trifluoro-methyl) benzyl] amino} acetic acid {(3-cyanobenzyl) [(3 '- {[(2-mesitylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) -methyl] amino} (oxo) acetic {(4-chlorobenzyl) [(3 '- {[(2-mesitylethyl) amino] carbonyl} [1,1'- biphenyl] -4-yl) -methyl] amino} (oxo) acetic acid {[(3 '- {[(2-mesitylethyl) amino] carbonyl} [1,1'-biphenyl] -4-yl) methyl] [ 4- (trif luoro-methyl) benzyl] amino} (oxo) acetic acid ((4-chlorobenzyl) {[3 '- ({[2- (4-methoxyphenyl) ethyl] amino} carbonyl) [1,1'-biphenyl] -4 -yl] methyl} amino) (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] amino} (oxo) acetic acid ({4 - [(dodecylamino) carbonyl] benzyl } {[6- (trifluoromethyl) -3-pyridinyl] methyl} -amino) (oxo) acetic acid 4 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) methyl] benzoic acid ({3 - [(dodecylamino) carbonyl] benzyl} {4- [hydroxy (oxido) amino] benzyl} -amino) (oxo) acetic acid ({3 - [(dodecylamino) carbonyl] benzyl} {[6- (trifluoromethyl) -3 -pyridinyl] methyl} -amino) (oxo) acetic acid 3 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} amino) methyl] benzoic acid 5 - [(((carboxycarbonyl) {3 - [(dodecylamino ) carbonyl] benzyl} amino) methyl] -2-thio-phenocarboxylic acid ({4 - [(dodecylamino) carbonyl] benzyl} {4- [hydroxy (oxido) amino] -benzyl} -amino) - (oxo) acetic acid 4 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] benzoic acid 5 - [((carb oxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) methyl] -2-thiophenecarboxylic acid ([4- (dimethylamino) benzyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ( {4 - [(dodecylamino) carbonyl] benzyl} {[2- (4-morpholinyl) -1,3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid ({3 - [(dodecylamino) carbonyl ] benzyl} {[2- (4-morpholinyl) -1,3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid 3 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl } amino) methyl] benzoic acid (({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) {3- [hydroxy (oxido) amino] -benzyl} -amino) (oxo) acetic acid {({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (methylsulfonyl) -benzyl] -amino} (oxo) acetic acid 4 - {[(carboxycarbonyl) ({5 - [(dodecylamino) sulfonyl] -2 -thienyl} methyl) -amino] -methyl} benzoic acid (({5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) {[6- (trifluoromethyl) -3-piidinyl] -methyl} amino) (oxo ) acetic acid (({1 - [(cyclohexylamino) carbonyl] -4-piperidinyl} methyl) {4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid ([(1- { [4- (dimethylamino) anilino] carbonyl} -4-piperidinyl) methyl] {4 - [(dodecyl amino) carbonyl] benzyl} amino) (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [(1-hexanoyl-4-piperidinyl) methyl] -amino} - (oxo) acetic acid ({4- [(dodecylamino) carbonyl] benzyl} {[1- (3-iodobenzoyl) -4-piperidinyl] methyl} -amino) (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [(1 - {( 2E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl} -4 piperidinyl) methyl] amino} (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] phenyl} [2- (methoxycarbonyl) benzyl] -amino} (oxo) acetic acid ((4-iodobenzyl) {[4'- ({[2- (4-Phenoxyphenyl) ethyl] amino} carbonyl) -1,1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid {({4 '- [(dodecylamino) carbonyl] - 1,1'-biphenyI-4-yl} methyl) [(4'-fluoro-1,1'-biphenyl-3-yl) methyl] amino} (oxo) acetic acid oxo [[(4 '- {[( 4-pentylbenzyl) amino] carboniI} -1,1'-biphenyI-4-iI) methy] (3-phenoxybenzyl) amino] acetic acid (({4 '- [(dodecyl amino) carbonyl] -1,1'-biphenyl -4-yl} methyl) {[2 '- (trifluoromethyl) -1,1'-biphenyl-1-4 il] metiI} amino) (oxo) acetic acid ({4 - [(dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) - (oxo) acetic acid ({4 - [( dodecylamino) carbonyl] benzyl} {1- [4- (trifluoromethyl) phenyl] ethyl} amino) - (oxo) acetic acid, N-methyl salt D-glucamine (ie, 1-deoxy-1- (methylamino) glucitol) ((1,2-diphenylethyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid [{4- [ (dodecylamino) carbonyl] benzyl} (2-isopropoxyphenyl) amino] (oxo) acetic acid ((3-chloro-2-methylphenyl) {4 - ((dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid 4'- ((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl} amino) -1,1'-biphenyl-2-carboxylic acid ([2- (4-chlorophenyl) propyl] {4 - [(dodecylamino) carbonyl] benzyl } amino) (oxo) acetic acid [{4 - [(dodecylamino) carbonyl] benzyl} (4-isopropoxyphenyl) amino] (oxo) acetic acid ([4- (benzyloxyphenyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ([2- (2,6-dichlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ({4 - [(dodecylamino) carbonyl) benzyl} {2- [3- (trifluoromethyl) phenyl] ethyl} -amino) - (oxo) acetic acid {{4 - [(dodecylamino) carbonyl] benzyl} [2- (3-fluorophenyl) ethyl] amino} (oxo) acetic acid ([(1S) -1- (4-chlorophenyl) ethyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) -acetic acid ([3- (benzyloxy) phenyl] {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid ([(2-butyl-1-benzofuran-3-yl) methyl] {4- [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid {(3-chlorobenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {(3-Chlorobenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoylamino) benzyl] -amino} (oxo) acetic acid {{cyclopentyl [4 - (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {{cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid, salt of N-methyl-D-glucamine (ie, 1-deoxy-1- (methyl-amino) glucitol) {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4 -oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid {[2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid, N-methyl-D salt glucamine (i.e. 1-deoxy-l- (methylamino) glucitol) oxo {{(1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4- oxadiazol-5-yl) benzyl] amino} acetic acid (1R) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} acetic acid, N-methyl-D salt glucamine (ie, 1-deoxy-1- (methylamino) -glucitol) oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} -acetic acid oxo {[4- (trifluoromethyl) phenyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} -acetic acid, N-methyl-D salt glucamine (i.e. 1-deoxy-1- (methylamino) glucitol) oxo {{(1S) -1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4- oxadiazol-5-yl) benzyl] amino} acetic acid {{1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {{ 1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid, N-methyl salt -D-glucamine (i.e. 1-deoxy-1- (methylamino) glucitol) {[2- (3-Chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {[2- (3-Chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid, N-methyl-D-glucamine salt (ie, 1-deoxy-1- (methylamino) glucitol) acid {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic acid {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) -acetic acid, N-methyl salt -D glucamine (i.e. 1-deoxy-1- (methylamino) glucitol) [{4 - [(dodecylamino) carbonyl] benzyl} (2-hydroxy-1-phenylethyl) amino] (oxo) acetic acid oxo {{4- [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifIuoromethyl) benzyl] amino} -acetic acid oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4- oxadiazol-5-yl) benzyl] -amino} acetic acid oxo {[4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} -acetic acid, N-methyl-D salt glucamine (i.e. 1-deoxy-1- (methylamino) glucitol) oxo {[4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino } -acetic acid oxo {[4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,2,4-oxadiazol-3-yl) benzyl] amino} -acetic acid, N-methyl salt D-glucamine (i.e. 1-deoxy-1- (methylamino) glucitol) {{4 - [(4-butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid {{ 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic acid {{4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino } (oxo) acetic acid, N-methyl-D-glucamine salt (es ie, 1-deoxy-1- (methylamino) glucitol) oxo {{4 - [(4-propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic acid {[2- (2-fluorophenyl) acid ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid {[2- (2-fluorophenyl) ethyl] [3- (3-undecyl -1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid {[2- (2-fluorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol- 5-yl) benzyl] amino} (oxo) acetic acid {[2- (3,4-dichlorophenyl) ethyl] [4- (3-undecyl-1,2,4-oxadiazoI-5-yl) benzyl] amino} - (oxo) acetic acid {[2- (3,4-dichlorophenyl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid { [2- (3,4-Dichlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {[2- (1,1 ' -biphenyl-4-yl) ethyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid {[2- (1,1'-biphenyl) -4-yl) ethyl] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid {[2- (1,1'-biphenyl-4 -yl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid ox or {5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} acetic acid oxo {5,6,7, 8-tetrahydronaphthalen-1-yl [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} acetic acid [4- (3-octyl-1,2,4-oxadiazole- 5-yl) benzyl] (5,6,7,8-tetrahydronaphthalen-1-yl) amino] - (oxo) acetic acid {(1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl- 1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic acid {(1,1'-biphenyl-3-ylmethyl) [3- (3-undecyl-1,2,4-oxadiazole -5-yl) benzyl] amino} - (oxo) acetic acid {(1,1'-biphenyl-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) -acetic acid {(1-benzothien-3-ylmethyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} - (oxo) -acetic acid {(1-benzothien-3-ylmethyl) [3- (3-undeciI-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid {(1-Benzothien-3-ylmethyl) [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid oxo {[2- (trifluoromethyl) benzyl ] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} -acetic acid oxo {[2- (trifluoromethyl) benzyl] [3- (3-undecyl-1,2, 4-oxadiazol-5-yl) benzyl] amino} acetic acid {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [2- (trifluoromethyl) benzyl] amino} (oxo) -acetic acid oxo {[3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} -acetic acid oxo {[3- (trifluoromethyl) benzyl ] [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} -acetic acid {[4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] [3- (trifluoromethyl) benzyl] amino} - (oxo) -acetic acid {(2-methoxybenzyl) [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} ( oxo) acetic acid {(2-methoxybenzyl) [3- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) -acetic acid {(2-methoxybenzyl) [4- ( 3-octyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid oxo {{4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1,2, 4-oxadiazol-5 -yl) -benzyl] amino} acetic acid oxo {{4 - [(trifluoromethyl) suIfonil] benzyl} [3- (3-undecyl-1,2,4-oxadiazoI-5-iI) -benzyl] amino} acetic acid ([4- (3-Octyl-1,2,4-oxadiazol-5-yl) benzyl] {4 - [(trifIuoromethyl) -sulfonyl] benzyl} -amino) (oxo) acetic acid {1,3-benzodioxol- 5-yl [4- (3-undecyl-1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {1,3-benzodioxol-5-yl [3- (3-undecyl- 1,2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic acid {1,3-benzodioxol-5-yl [4- (3-octyl-1,2,4-oxadiazol-5-yl ) benzyl] amino} (oxo) acetic acid ({4 - [(4-hexyIphenyl) ethynyl] benzyl} {1-methyl-1- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetic acid {{ 3 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic. 7. Substituted methylenamide derivative of Formula (I): image 1 as well as their geometric isomers, their optically active forms such as enantiomers, diastereomers and their racemate forms, as well as pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-C12) alkyl -aryl or (C1-C12) alkyl-heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl; R2a  and R2b are each independently selected from the other from the group comprising or consisting of H or (C1-C12) alkyl; Cy is: a) a thienyl or phenyl group substituted with any of the following:  a phenyl  an oxadiazole group;  1 or 2 moieties selected from the group consisting of -NH-CO-R3, -SO2-NR3R3 'or -CO-NR3R3', in which R3, R3 'are independently selected from H and (C1-C15) alkyl; b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl; a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7-C15) alkyl; or 5 d) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group, a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl, particularly alkyl (C8-C15) and more particularly, a dodecyl group; 10 or according to claim 6, for use as a medicament. 8. Use of a substituted methyleneamide derivative according to formula (I): image 1 as well as their geometric isomers, their optically active forms such as enantiomers, diastereomers and their racemate forms, as well as pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of H, (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8 membered), (C1-alkyl) -C12) -aryl or (C1-C12) alkyl-heteroaryl, (C2-C12) alkenyl or -heteroaryl, (C2-C12) alkynyl or -heteroaryl; R2a  and R2b are each independently selected from the other from the group comprising or consisting of H or (C1-C12) alkyl; Cy is: a) a thienyl or phenyl group substituted with any of the following:  a phenyl  an oxadiazole group;  1 or 2 moieties selected from the group consisting of -NH-CO-R3, -SO2-NR3R3 'or -CO-NR3R3', in which R3, R3 'are independently selected from H and (C1-C15) alkyl ; b) phenyl substituted with B-R4, wherein B is an ethynyl group and R4 is (C1-C12) alkyl phenyl; c) when R2a and R2b are each H and R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted with cyano, halogen, methoxy, hydroxy, phenoxy, -NO2 or trifluoromethyl, a thienyl, phenyl or biphenyl substituted with -SO2R3, -CO-NR3R3 'in which R3' is H and R3 is (C7-C12) alkyl or (C7-C15) alkyl; or d) when R2a and R2b are each H and R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted with a (C1-C6) alkyl group or a cycloalkyl group, a phenyl or biphenyl group substituted with a moiety selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl, particularly alkyl (C8-C15) and more particularly, a dodecyl group; or according to claim 6, for the preparation of a medicament for the treatment and / or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising type I and / or II diabetes, inadequate glucose tolerance, resistance to insulin, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS) or for appetite regulation.

Use of a substituted methyleneamide derivative according to claim 8 for the preparation of a pharmaceutical composition for the modulation of PTP activity.

10.

 Use according to claim 9, wherein PTP is PTP1B.

eleven.

 Use according to claim 9, wherein said modulation consists in the inhibition of PTP1B.

12.

 Use according to claim 11 for the treatment or prevention of disorders mediated by PTP1B.

13.

 A pharmaceutical composition containing at least one substituted methyleneamide derivative according to claims 1 to 6 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

14. A pharmaceutical composition according to claim 13 which also comprises at least one complementary drug selected from the group consisting of insulin, aldose reductase inhibitors, alpha-glucosidases inhibitors, sulfonylurea agents, biguanides (eg metformin) , thiazolidines, PPAR agonists, c-Jun Kinase or GSK-3 inhibitors.

15. A pharmaceutical composition according to claim 14, wherein said complementary drug is 10 selects from the group consisting of a fast-acting insulin, an intermediate-acting insulin, a long-acting insulin, a combination of intermediate and fast-acting insulins, Minalrestat, Tolrestat, Sorbinil, Metosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat , Ponalrestat, ONO-2235, GP-1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M-16209, NZ-314, M-79175, SPR-210, DNA 138, or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide or Glimepriride. 16. A method of preparing a substituted methyleneamide derivative according to any one of claims 1 to 5, comprising the step of coupling between the amine derivative of formula (III-0) and an ester of formula LG2-CO -CO-OR8 and subsequently a hydrolysis: image 1 wherein Cy, R1, R2a, R2b are as defined above, R8 is an alkyl or cycloalkyl (C1-C6) and LG2 is a leaving group selected from Cl, N-hydroxysuccinimide or benzotriazol-1-yl. 17. A method of preparing a substituted methyleneamide derivative according to any one of claims 1 to 6, comprising the step of providing the corresponding ester of formula (I-1): image 1 wherein X is -CO- or -SO2-, LG1 is Cl, OH, -Obn, O-Alkyl or O-Alkylaryl and LG2 is selected from Cl, Nhydroxysuccinimide or benzotriazol-1-yl, R8 is an alkyl or cycloalkyl ( C1-C6), P is H or a protective group selected from Boc or Fmoc, R1, R2a, R2b, R3 and R3 'are as defined above; and a subsequent hydrolysis step that provides the methyleneamide derivative of formula (I). 18. A method of preparing a methyleneamide derivative of formula (I) according to any of claims 1-6, wherein Cy has the same definition as in point (a), (b) or (d) of claim 1, comprising the step of providing the corresponding ester of formula (I-2): image 1 wherein LG1 is Cl, OH, OBn, O-Alkyl or O-Alkylaryl and LG2 is selected from Cl, N-hydroxysuccinimide or benzotriazol-1-yl, R8 is a C1-C6 alkyl or cycloalkyl, P is H or a group protector selected from Boc or Fmoc, R1, R2a, R2b, R3 and R3 'are as defined above, and a subsequent hydrolysis step, which provides the methyleneamide derivative of formula (I). 19. A method of preparing a substituted methyleneamide derivative according to any one of claims 1-6, wherein Cy has the same definition as in item (a) or (b) of claim 1, which comprises the step to provide the corresponding formula (I-4) ester: image 1 wherein X is a halogen atom selected from the group consisting of Br, I Cl or a leaving group such as - OSO2CF3, R8 is an alkyl group, LG2 is selected from Cl, N-hydroxysuccinimide or benzotriazol-1-yl, P it is H or a protective group selected from Boc or Fmoc, R1, R2a, R2b and R3 are as defined above; and a subsequent hydrolysis step, which provides the methyleneamide derivative of formula (I).