Heterocyclic phenyl carbamates as novel FAAH-inhibitors

Field of the invention

The present invention relates to inhibitors of fatty acid amide hydrolase and/or monoglycehde lipase. More particularly, the invention relates to inhibitors of fatty acid amide hydrolase employing a heterocyclic phenyl carbamate pharmacophore.

Background

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of endocannabinoid N-arachidonoyl- ethanolamide (AEA) to arachidonic acid and ethanolamine. FAAH is also able to hydrolyze another endocannabinoid, 2-arachidonoylglycerol (2-AG), and a sleep-inducing endogenous lipid, oleamide. However, the enzymatic hydrolysis of 2-AG has been assumed to occur in vivo by monoglyceride lipase (MGL). Inhibition of FAAH or MGL prevents degradation of endo- cannabinoids (AEA, 2-AG and oleamide) which activate the cannabinoid receptors and therefore causes beneficial effects in many physiological disorders such as pain, inflammation, anxiety, epilepsy, depression, appetite disorders, glaucoma and insomnia.

Introduction

Arachidonoylethanolamide and 2-arachidonoylglycerol are endogenous compounds called endocannabinoids and they are considered to be the most important endogenous agonists for the G protein-coupled cannabinoid receptors, CB1 and CB2. (Lambert J. Med. Chem. 2005, 48, 5059-5087). CB1 receptors are predominantly located on presynaptic terminals in the central nervous system (CNS), whereas CB2 receptors are located mainly

in peripheral tissues (Facci, Proc. Natl. Acad. Sci. USA 1995, 92, 3376- 3380; Galiegue, Eur. J. Biochem. 1995, 232, 54-61 ; Ishac, Br. J. Pharmacol. 1996, 118, 2023-2028). However, very recently it has been reported that CB2 receptors are also expressed in CNS (Gong, Brain Res. 2006, 1071, 10-23). The endocannabinoids are inactivated rapidly by cellular reuptake followed by the intracellular hydrolysis by specific enzymes (Goparaju, Biochem. Pharmacol. 1999, 57, 417-423; Schmid, J. Biol. Chem. 1985, 260, 14145-14149). AEA is assumed to be transported into a cell by a specific transporter and rapidly hydrolyzed by the enzyme fatty acid am- ide hydrolase (FAAH) (Fowler, Leukotrienes Essent. Fatty Acids, 2002, 66, 193-200). Also, like AEA, 2-AG is thought to be removed from its sites of action by cellular uptake and then hydrolyzed enzymatically. Although 2- AG can be hydrolyzed by FAAH (Ueda, Chem. Phys. Lipids 2000, 108, 107-121 ), the main enzyme responsible for 2-AG hydrolysis in vivo is probably monoacyl glycerol lipase (MGL; EC 3.1.1.23) or MGL-like enzyme (Dinh, Proc. Natl. Acad. Sci. USA 2002, 99, 10819-10824; Saario, Biochem. Pharmacol. 2004, 67, 1381 -1387).

The cannabimimetic effects of the endocannabinoids remain very weak in vivo due to their rapid enzymatic inactivation. The increase in the concentration of the endocannabinoids in the extracellular space can lead to several beneficial therapeutic effects such as relief of pain and anxiety, reduction of intraocular pressure as well as increase of appetite. (Pertwee, Prostaglandins, Leukotrienes Essent. Fatty Acids, 2002, 66, 101 -121 ;Walker, Proc. Natl. Acad. Soc. USA 1999, 96, 12198-12203; Kathuria, Nat. Med. 2003, 9, 76-81 ; Jarvinen, Pharm. Ther. 2002, 95, 203-220; Di Marzo, Natu- re, 2001 , 470, 822-825).

The enzyme inhibition could be a convenient way to elevate endocannabi- noid levels and thus increase the receptor activity (Cravatt, Curr. Opin.

Chem. Biol. 2003, 7, 469-475). Endocannabinoids are biosynthesized upon demand and removed from their sites of action by cellular uptake and intracellular enzymatic hydrolysis. By inhibiting FAAH or MGL, it is possible to potentiate the actions of endocannabinoids at their site of biosynthesis.

Boger and co-workers at the Scripps Research Institute have reported a class of reversible alpha-ketoheterocycle inhibitors of FAAH (US patent 6462054, WO 2004/033652, WO 04/033652, WO 2006/04461 , WO 2007/098142, WO 2008/030532, Proc. Natl. Acad. Sci. USA 2000, 97(10), 5044-5049; J. Med. Chem. 2005, 48 (6), 1849-1856, Bioorg. Med. Chem. Lett. 2005, 15, 1423-1428, J. Med. Chem. 2007, 50(14), 3359-3368, J. Med. Chem. 2007, 50(5), 1058-1068, J. Med. Chem. 2008, 51 (4), 937-947). Additionally, the series of carbamates including highly active compound URB597 with promising pharmacological features have been developed (WO 2004/033422, WO 2005/090322, WO2005/089759, WO

2005/090347, WO 2005/090292, WO 2005/077898, WO 2006/088075, WO 2007/079180, WO 2008/024139). Certain oxazolyl piperidines (WO 2007/140005), piperazinyl and piperidinyl ureas (WO 2007/005510, WO 2006/074025) have been also reported as inhibitors of FAAH. Further, Saario et al (J. Med. Chem. 2006, 49, 4650-4656) have performed virtual screening of MGL inhibitors and found five compounds inhibiting FAAH. The most potent FAAH inhibitor found by Saario and co-workers was a 4- substituted dihydrothiazolylphenyl N-butyl carbamate which, however, had an IC ₅₀ value of only 0.52 μM. Consequently, there still exists a need for potential effective inhibitors of the fatty acid amide hydrolase enzyme.

Summary of the invention

The invention relates to novel heterocyclic phenyl carbamates and hetero- cyclic carbonyl phenyl carbamates represented by the formula I:

wherein Z is CH or N,

R' is selected from the group consisting of H, substituted or unsubstituted alkyl of 1 to 24 carbon atoms, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and

R is a cyano, carboxyl, (C1 -4 alkoxy)carbonyl, mono-C1 -4 aliphatic amino- carbonyl, di-C1 -4 aliphatic aminocarbonyl, N-hydroxycarbamimidoyl, N- alkoxycarbamimidoyl, acyloxycarbamimidoyl, a heterocyclic moiety or heterocyclic carbonyl moiety. The novel compounds of formula I are useful as inhibitors of fatty acid amide hydrolase and/or monoglyceride lipase.

The heterocyclic moiety R in the novel compounds of formula I is represented by the following structures:

wherein X is O, S, NH or NCH ₃ , and

R1 , R2, R3, R4 are individually H, halogen, alkyl, cycloalkyl, alkylene, acyl, aroyl, aryl, phenoxy, alkoxy, alkoxyalkyl, alkylthio, hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, acyloxy, acylamino, acyloxyalkyl, acylaminoalkyl, hydroxyacyl, sulfonate, alkylsulfonyl, arylsulfonyl, nitro, cyano, amino, - NR5R6, aminoalkyl, -(CH ₂ ) _n -NR5R6, aminoacyl, -CO-(CH ₂ ) _n -NR5R6, carbamoyl, -CO-NR5R6, carbamoyloxy, -O-CO-NR5R6, sulfonamide - SO ₂ NR5R6, wherein n represents an integer from 1 to 4 and wherein R5 and R6 are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and wherein optionally R5 and R6 together with the N atom to which they are attached form a 5-7 membered cyclic ring.

The invention also relates to pharmaceutical compositions which contain a compound of the formula I, and to the use of the compounds of the formula I for the therapeutic treatment of a human or animal body or for the preparation of pharmaceutical compositions.

A further object of the invention is a method of inhibiting fatty acid amid hydrolase and/or monoglyceride lipase in a mammal, said method comprising administering an effective amount of a compound of the formula I to a subject in need of inhibition of FAAH or MGL.

A still further object of the invention is a method of treating pain, inflammation, anxiety, epilepsy, depression, appetite disorders, glaucoma, insomnia or other disease states, disorders and conditions mediated by fatty acid amide hydrolase activity in a mammal, said method comprising administering an effective amount of a compound of the formula I to a subject in need of such treatment.

Detailed Description of the Invention

In the context of the present application, the general terms used above and below preferably have the following meanings:

Alkyl is a saturated hydrocarbon radical containing 1 -24, preferably 3-12 carbon atoms. It is for example ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, octenyl, octadecenyl, etc preferably pro- pyl, butyl, pentyl, hexyl, octyl, decyl or dodecyl. Substituted alkyl is preferably chloroalkyl or fluoroalkyl.

In the meaning of the group R1 , R2, R3 and R4 alkyl preferably contains 1 - 6 carbon atoms, preferably 1 -4 carbon atoms. It is for example ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

Cycloalkyl contains 3-8, preferably 5 or 6 atoms. It is for example cyclopro- pyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopen- tyl or cyclohexyl.

Heteroalkyl means a straight or branched chain hydrocarbon radical, containing 1 -22, preferably 3-12 carbon atoms and at least one heteroatom selected from the group consisting of O, N and S. Examples of heteroalkyl include, but are not limited to hydroxyalkyl (e.g., 2-hydroxyethyl, 2- hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl), alkoxyalkyl (e.g., meth- oxyalkyl, ethoxyalkyl, propoxyalkyl, butoxyalkyl, pentoxyalkyl), acyloxyalkyl (e.g., acetoxyalkyl, propionyloxyalkyl, benzoyloxyalkyl), mercaptoalkyl, al- kylthioalkyl, acylthioalkyl, aminoalkyl (e.g., amino, mono- and di-d-C ₃ al- kanylaminoalkyl).

Aryl means a polyunsaturated, aromatic hydrocarbon substituent. Het- eroaryl refers to aryl groups that contain from one to four heteroatoms selected from N, O and S. Non-limiting examples of aryl and heteroaryl include phenyl, benzyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thi- azolyl, furyl, thienyl, pyridyl or pyrimidyl. Preferred aryls are substituted or unsubstituted phenyl or benzyl, especially substituted benzyl.

When the group R' is a substituted group as defined, especially a substituted cycloalkyl, aryl or heteroaryl group, suitable substituents include those defined for R1 , R2, R3 and R4, in particular alkyl, alkoxy, halogen, alkylthio, hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, acyloxy, acylamino, aminoalkyl, aminoacyl, carbamoyl, carbamoyloxy or sulfonamide

Preferred substituents of a substituted benzyl are e.g. 2-methyl and 3- methyl.

If heteroaryl is substituted, preferred substituents are e.g. methyl, ethyl, and acetyl.

Halogen is chlorine, bromine, fluorine or iodine.

In this description alkylene contains 2-24, preferably 2-8 carbon atoms. It is for example ethylene, methylene, thmethylene, tetramethylene or pentame- thylene.

In this description alkoxy contains 1 -6, preferably 1 -2 carbon atoms. It is for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy or ethyloxy, preferably methoxy.

In this description acyl contains 1 -6, preferably 1 -2 carbon atoms. It is, for example, formyl, acetyl, propionyl or pivaloyl.

In this description alkyne preferably contains 2-6 carbon atoms. It is for ex- ample acetylene, propyne or 1 - or 2-butyne.

If R5 and R6 together with the N atom to which they are attached form a 5- 7 membered cyclic ring, said ring is for example, but not limited to, pyrrolid- inyl, piperidyl, or morpholinyl.

The compounds of the invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enanti- omers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the inventive compounds.

The compounds of the invention include the diastereoisomers of pairs of enantiomers. Diastereomers, for example, can be obtained by fractional crystallization from a suitable solvent, for example methanol or ethyl ace- tate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.

Alternatively, any enantiomer of such a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.

In the compounds of formula I, the substituent R' is preferably H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substi- tuted or unsubstituted phenyl, or substituted or unsubstituted benzyl. More preferably R' is substituted or unsubstituted alkyl (preferably an unsubsti-

tuted alkyl of 5 to 12 carbon atoms), cycloalkyl (preferably cyclopentyl or cyclohexyl), or substituted or unsubstituted benzyl. Preferred substituents are e.g. H and methyl.

In one embodiment, R' is selected from the group consisting of unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted aryl or unsubstituted heteroaryl.

The substituent Z is preferably CH.

The substituent R is preferably selected from the group consisting of cyano, carboxyl, (C1 -4 alkoxy)carbonyl, N-hydroxycarbamimidoyl, N- alkoxycarbamimidoyl, acyloxycarbamimidoyl, a heterocyclic moiety or heterocyclic carbonyl moiety, wherein the heterocyclic moiety is selected from the group represented by the following structures

wherein X is O, S, NH or NCH ₃ , and

R1 , R2, R3, R4 are individually H, halogen, alkyl, cycloalkyl, alkylene, acyl, aroyl, aryl, phenoxy, alkoxy, alkoxyalkyl, alkylthio, hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, acyloxy, acylamino, acyloxyalkyl, acylaminoalkyl, hydroxyacyl, sulfonate, alkylsulfonyl, arylsulfonyl, nitro, cyano, amino - NR5R6, aminoalkyl -(CH ₂ ) _n -NR5R6, aminoacyl -CO-(CH ₂ ) _n -NR5R6, carbamoyl -CO-NR5R6, carbamoyloxy -O-CO-NR5R6, sulfonamido - SO ₂ NR5R6, wherein n represents an integer from 1 to 4 and wherein R5 and R6 are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and wherein optionally R5 and R6 together with the N atom to which they are attached form a 5-7 membered cyclic ring.

Even more preferably the substituent R is selected from the group consisting of

wherein

R1 , R2, R3 and R4 are independently of each other hydrogen, alkyl, aryl, acyl, alkoxycarbonyl, aminoacyl, or dialkylaminoacyl.

Most preferably, R1 , R2, R3 and R4 are independently of each other hydrogen, alkyl (especially methyl), acetyl or ethoxycarbonyl.

The substituent R is even more preferably methoxycarbonyl, oxazolyl, tetrazolyl, thiadiazolyl, benzoxazole-carbonyl or benzothiazolecarbonyl.

The invention relates particularly to the compounds of the formula I

wherein Z is CH or N, preferably CH,

R' is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl, and

R is selected from the group consisting of the following structures:

wherein

R1 , R2, R3 and R4 are individually hydrogen, alkyl, aryl, acyl, alkoxycar- bonyl, aminoacyl, or dialkylaminoacyl, preferably hydrogen, alkyl, acyl, acetyl or ethoxycarbonyl.

In a further, preferred embodiment the invention relates to the compounds of the following formula

wherein Z is CH or N, preferably CH,

R' is substituted or unsubstituted alkyl (preferably an unsubstituted alkyl of

5 to 12 carbon atoms), cycloalkyl (preferably cyclopentyl or cyclohexyl), or substituted or unsubstituted benzyl,

R is methoxycarbonyl, oxazolyl, tetrazolyl, thiadiazolyl, benzoxazole- carbonyl or benzothiazolecarbonyl.

The instant compounds may be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Such acids may include hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, suc- cinic, malonic and the like. In addition, certain compounds containing an acidic function can be in the form of their inorganic salt in which the counte- rion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic proc- esses before becoming active pharmacological substances. In general, such prodrugs will be derivatives of the present compounds that are readily convertible in vivo into a functional compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bund- gaard, Elsevier, 1985. The invention also encompasses active metabolites of the present compounds.

The invention also relates to pharmaceutical compositions which contain a compound of formula I or a pharmaceutically acceptable salt thereof as ac- tive ingredient. The pharmaceutical compositions usually contain the pharmacologically active ingredient together with customary pharmaceutical excipients and optionally with other therapeutical ingredients.

The pharmaceutical compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, subdermal, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inha-

lation), or nasal administration. In some embodiments, administration is transdermal. The most suitable route in any given case will depend in part on the nature and severity of the conditions being treated and on the nature of the active ingredient. An exemplary route of administration is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharma- ceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations can contain at least 0.1 percent of the active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such

therapeutically useful compositions is such that a therapeutically effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dical- cium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shel- lac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. To prevent breakdown during transit through the upper portion of the Gl tract, the composition may be an enteric coated formulation.

Although the preferred route of administration is the oral route, the compounds of the invention may also be administered for example parenterally. Solutions or suspensions of the active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Disper- sions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous

preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The dose of the active ingredient can depend on various factors, such as the efficacy of the active ingredient, severity of the disease to be treated or its symptoms, administration procedure, sex, age, weight and/or individual condition of the subject in need of the treatment. In a normal case, for a human adult, one daily dose of about 1 mg to about 500 mg, in particular from about 5 mg to about 200 mg, or from about 1 to 100 mg is to be estimated. Doses of from about 0.05 to about 100 mg, and more preferably from about 0.1 to about 100 mg, per day may be used. This can be administered as a single dose or in several sub-doses.

Generally, the compounds of the present invention can be dispensed in unit dosage form comprising preferably from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage. Usually dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent. For storage and use, these preparations preferably contain a preservative to prevent the growth of microorganisms.

Formulations suitable for oral administration can consist of (i) liquid solutions, such as an effective amount of the active ingredient suspended in

diluents, such as water, saline or PEG 400; (ii) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (iii) suspensions in an appropriate liquid; and (iv) suitable emulsions. Tablet forms can include one or more of lac- tose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents; and pharmaceutically compati- ble carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g. sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like, containing, in addition to the active ingredient, carriers known in the art.

Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Formulations suitable for parenteral administration, such as, for example, by intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preserva- tives.

With respect to transdermal routes of administration, methods for transdermal administration of drugs are disclosed in Remington's Pharmaceutical Sciences, Gennaro A R ed. 20 th edition, 2000, USA. Dermal or skin patches are one means for transdermal delivery of the compounds of the invention.

Preferred patches include those that control the rate of drug delivery to the skin. Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin.

The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.

Compounds of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in the treatment, prevention or suppression of a neurological or psychological disorder. In one embodiment, the second drug is not a FAAH inhibitor and is directed toward the same disorder as the fatty acid amide inhibitor. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound is preferred. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain

one or more other active ingredients, in addition to the compounds disclosed above. For example, a FAAH inhibitor according to formula I may be formulated with an anxiolytic agent which is not a FAAH inhibitor. For example, a FAAH inhibitor according to formula I may be formulated with an antidepressant. Further, a FAAH inhibitor according to formula I may be used in a combination with an analgetic drug/compound. A further embodiment is to formulate a FAAH inhibitor according to formula I with an immunosuppressant drug/compound.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, by itself or in association with another active principle, can be administered to animals and humans in unit forms of administration mixed with conventional pharmaceutical carri- ers. The appropriate unit forms of administration include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

When used to treat e.g. glaucoma, direct application to the eye is preferred. Ocular carrier formulations for such ocular application are taught in Remington's Pharmaceutical Sciences, ed. Gennaro A.R., 20 ^th edition, 2000.

The invention also provides a method of inhibiting fatty acid amid hydrolase in a mammal, said method comprising administering an effective amount of a compound of the formula I to a subject in need of inhibition of FAAH.

The invention also provides a method for inhibiting monoglyceride lipase in a mammal, said method comprising administering an effective amount of a compound of the formula I to a subject in need of inhibition of MGL.

A still further object of the invention is a method of treating, preventing or ameliorating pain, inflammation, anxiety, epilepsy, depression, appetite disorders, glaucoma, insomnia or other disease states, disorders and conditions mediated by fatty acid amide hydrolase activity in a mammal, said method comprising administering an effective amount of a compound of the formula I to a subject in need of such treatment.

The invention further relates to the use of compounds of the formula I for the preparation of medicaments for the treatment, prevention or amelioration of disease states, disorders, and conditions mediated by fatty acid amide hydrolase activity and/or monoglyceride lipase activity of a human or animal body. Among such disease states, disorders and conditions may be mentioned for example anxiety, epilepsy, depression, pain, inflammation, appetite disorders, glaucoma and insomnia. More specifically, among such diseases, disorders or conditions may be mentioned pain, nociceptive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, pain associated with the herpes virus, pain associated with diabetes, peripheral neuropathic pain, central pain, deafferentiation pain, chronic nociceptive pain, stimulus of nociceptive receptors, phantom and transient acute pain, diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, neuralgia, pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions, Parkinson's disease, muscle spasticity, epilepsy, obesity, hyperlipidemia, insulin resistance syndrome, fatty liver disease, atherosclerosis, arteriosclerosis, metabolic disorders, feeding and fasting, alteration of appetite, hypertension, septic shock, cardiogenic shock, intestinal inflammation and motility, irritable bowel syndrome, colitis,

diarrhea, ileitis, ischemia, cerebral ischemia, hepatic ischemia, myocardial infarction, arthritis, rheumatoid arthritis, spondylitis, shoulder tendonitis or bursitits, gouty arthritis, aolymyalgia rheumratica, thyroiditis, hepatitis, inflammatory bowel diseases, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and cardiovascular diseases.

Preferred examples of compounds of the present invention are selected from the group consisting of:

More preferred compounds of the invention are selected from the group consisting of:

3-(Oxazol-2-yl)phenyl cyclopentylcarbamate;

3-(Oxazol-2-yl)phenyl cyclohexylcarbamate;

3-(2-Methyl-2H-tetrazol-5-yl)phenyl cyclopentylcarbamate;

Methyl 3-(cyclohexylcarbamoyloxy)benzoate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl cyclohexylcarbamate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl cyclopentylcarbamate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl benzylcarbamate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl dodecylcarbamate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl hexylcarbamate;

3-(1 ,2,3-Thiadiazol-4-yl)phenyl (4-phenyl-butyl)carbamate; and

3-(Thiazol-2-yl)phenyl cyclohexylcarbamate.

The compounds of the formula I can be prepared as described below, using commercially available starting materials and following the methods described in the literature.

Synthesis

The carbamic acid esters (1e, 2-8, 9c, 10-16, 17b, 18, 19c, 20-22, 23, 26- 35, 36c, 37-44, 45f, 46d, 47d, 48c, 49-54, 56, 57b) were obtained by treatment of heterocyclic phenol (examples 1d, 9b, 17a, 19b, 36b, 45e, 46c, 47c, 48b, 49a, 50b, 51b, 52b, 53b, 54a, 55, 57a) and commercial substances) with a suitable isocyanate in the presence of a catalytic amount of triethylamine in toluene at rt or heating up to 93°C (Scheme 1 ). Scheme 1

1 d, 2-8, 9c, 10-16, 17b, 18, 19c, 20-23, 26-35, 36c, 37-44, 45f, 46d, 47d, 49b, 50c, 51c, 52c, 53c, 54b, 55, 56, 57b

The synthesis of carbamate derivatives of 2-benzoxazolyl- and 2- benzothiazolyl-(3-hydroxyphenyl)-methanones (examples 1e, 2-8, 9c, 10- 16) were started from 3-hydroxybenzoic acid (Scheme 2). The phenol func- tionality was protected as benzyl ether and then the acids were converted to acid chlorides. The acid chlorides were then coupled with benzoxazole following the method described by Harn et al. (Tetrahedron Lett. 1995, 36; 9453-9456). The benzothiazole was coupled with 3-benzyloxybenzoic acid chloride in a similar way. Deprotection of phenolic hydroxyl was first at- tempted with hydrogenation catalyzed by Pd/C. Unfortunately in these conditions the methanone was reduced to alcohol before the cleavage of ben-

zyl group. Although the alcohols were easily oxidized back to ketone with IBX or DDQ, another method was needed to avoid the extra step. Finally the removal of the benzyl protecting group without reducing the ketone was carried out using BF ₄ Et ₂ O and Me ₂ S (Fuji, K.; Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980, 28, 3662-3664). Later an even more efficient method for removal of the benzyl protecting group utilizing ionic liquid (λ/-1 - butylpyridinium bromide) and microwave irradiation was used (Chauhan, S. M. S.; Jain N. J. Chem. Res. 2004, 693-4). The aromatic alcohols were then coupled with isocyanates in a usual way (Scheme 1 ).

Scheme 2

1b 1c/9a/

1d/9b

Scheme 2. Reagents and conditions for the preparation of compounds 1d and 9b: a) NaOH, BnBr, THF, reflux, 65%; b) SOCI ₂ , reflux, 98%; c) benzo[c/]oxazole (X=O) or benzo[c/]thiazole (X=S), n-BuLi, 1 M ZnCI ₂ /Et ₂ O, CuI, THF, -75 ⁰ C -> 0 ⁰ C, 54-55%; d) BF ₃ Et ₂ O, Me ₂ S, CH ₂ CI ₂ , rt, 84-91 % or /V-1 -BuPyrBr, MW, 30 sec, 90%

Oxazoline containing phenol 17a for the preparation of compounds 17b and 18 were prepared in a method described by Vorbrϋggen et al. (Tetrahedron 1993, 49, 9353-72) (Scheme 3).

17a

Scheme 3. Reagents and conditions for the preparation of compound 17a: PPh ₃ , 2-aminoethanol, Et ₃ N, CCI ₄ , pyridine, acetonitrile, rt, 18 hrs, 29%.

2-Oxazole and 2-thiazole containing phenols for the preparation of carbamate derivatives 19c, 20-22, 51c were prepared from 3- methoxybenzamide or 3-methoxybenzothioamide and bromoacetaldehyde diethyl acetal under microwave conditions (Scheme 4, step a). The depro- tection of phenol was carried out via method described by Chauhan and Jain {J. Chem. Res. 2004, 693-4) (Scheme 4, step b).

19a, 51a 19b, 51b

Scheme 4. Reagents and conditions for preparation of compounds 19b, and 51b: X= O or S; a) 2-Bromoacetaldehyde diethyl acetal, THF or no solvent, MW-irradiation, 5 min, 45-90%; b) 1 -Butyl-3-methylimidazolium bromide or /V-butylpyridinium bromide, MW-irradiation, 4x20 sec, 60-65%.

3-(2H-tetrazol-5-yl)phenol, methyl 3-hydroxybenzoate, 3-cyanophenol and methyl 4-hydroxybenzoate were used as starting materials in preparation of carbamates 23 and 26-28 in a usual way (Scheme 1 ).

In examples 24 and 25 3-(2H-tetrazol-5-yl)phenol was first converted to its cyclopentylcarbamate in a usual way (Scheme 5, step a). The proton of the tetrazole group was then substituted with either methyl or benzyl group (Scheme 5, step b).

2 ³ 24, 25

Scheme 5. Reagents and conditions for the preparation of compounds 23- 25: a) Et ₃ N, RNCO, toluene, reflux, 65%; b) MeI, Et ₃ N, acetone, 2 ⁰ C, 44% or BnBr, Kl, Et ₃ N, acetone, 2 ⁰ C, 60%.

In examples 29a-35a oxazolines were prepared from aminoalcohols and 3- hydroxynitrile (Scheme 6) via a method described by BoIm et al. (Chem. Ber. 1991 , 124, 1173-1180) and used as starting materials for the preparation of carbamate derivatives 29b-35b (Scheme 1 ).

29a-35a

Scheme 6. Reagents and conditions for the the preparation of compounds 29a-35a: ZnCI ₂ , PhCI, reflux, 24 h, 70%.

The 3-(1 ,2,3-thiadiazol-4-yl)-phenol (36b) was prepared from the 3- hydroxyphenylketone by the Hurd-Mori reaction via the corresponding hy- drazone as has been previously described in the literature (Molecules 2004, 9, 957) (Scheme 7). The carbamic acid esters of 3-(1 ,2,3-thiadiazol- 4-yl)-phenol were obtained by treatment of heterocyclic phenol with suitable isocyanate (Scheme 1 ).

36a 36b

Scheme 7. Reagents and conditions for the preparation of compound 36b: a)_ethylcarbazate, p-TsOH, toluene, reflux, 69 %; b) SOCI ₂ , rt, 71 %.

1 ,2,4-oxadiazole containing phenols 45e and 46c-47c for the preparation of carbamate derivatives 45f and 46d-47d were prepared starting from 3- cyanophenol (Scheme 8).

First the phenol functionality was protected as MEM-ether and then the cyano group was converted to amidoxime. Amidoxime was converted to various acyl amidoximes following the method described by Unangst et al. (J. Med. Chem. 1992, 35, 3691 -3698). The cyclization of acyl amidoximes to 3,5-disubstituted-1 ,2,4-oxadiazoles was performed in the presence of catalytic amount of TBAF (A. R. Gangloff et al. Tetrahedron Lett. 2001 , 42, 1441 -1443). Deprotection of phenolic hydroxyl was carried out by using ZnBr ₂ (Unangst et al. J. Med. Chem. 1992, 35, 3691 -3698). The 1 ,2,4- oxadiazole containing phenol 48b was prepared in a similar manner, but without the treatment with TBAF (Scheme 9). The resulting aromatic alcohols were then coupled with isocyanates in a usual way (Scheme 1 ).

15a 45b 45c , 46a, 47a

47d, 46b, 47b 45e, 46c, 47c

Scheme 8. Reagents and conditions for the preparation of compounds 45e, 46c, and 47c: a) Methoxyethoxymethyl chloride, triethyl amine, THF, reflux, 88 %; b) Hydroxylamine hydrochloride, triethyl amine, EtOH, rt, 77 %; c) Acetyl chloride/cyclopentylpropionyl chloride/trimethylacetyl chloride, triethylamine, CHCI ₃ , rt, 30-68 %; d) TBAF, THF, rt, 81 -100 %; e) ZnBr ₂ , CH ₂ CI ₂ , rt, 24-49 %.

45b 48a 48b

Scheme 9. Reagents and conditions for the preparation of compound 48b: a) Ethyl chlorooxoacetate, triethylamine, CHCI ₃ , rt, 20 %; b) ZnBr ₂ , CH ₂ CI ₂ , rt, 68 %.

3-Cyanophenol was oxidized to amide 49a via a method described by McKillop and Kemp (Tetrahedron, 1989, 47, 3299-3306). Scheme 10.

49a

Scheme 10. Reagents and conditions for the preparation of phenol 49a: a) NaBO ₃ - 4 H ₂ O, H ₂ O, MeOH, 54%.

4-Oxazole and 4-imidazole containing phenols for the preparation of carbamate derivatives 50c and 52c were prepared from 2-bromo-1 -(3- methoxyphenyl)-ethanone and formamide either by MW-irradiated reaction or by oil-bath heated reaction (Scheme 1 1 steps a and b). The deprotec- tion of phenol was carried out either via a method described by Chauhan and Jain (J. Chem. Res. 2004, 693-4) or via treatment with BBr ₃ . (McOmie J. F. W.; and West, D. E. Org. Synth. 1973, Coll. Vol. 5, 412-414). Scheme 11.

52a 52b Scheme 11. Reagents and conditions for the preparation of compounds 50b and 52b: a) Formamide, MW, 100 ⁰ C, 51 %; b) Formamide, 165 ⁰ C, 85%; c) N- butylpyridinimum bromide, MW, 100 ⁰ C, 56%; d) BBr ₃ , CH ₂ CI ₂ , - 78 °C-rt, 59%.

2-Oxazolines 53b and 54a were prepared from 3-cyanophenol via imidate- intermediate 53a (Reider, P. J.; Conn, R. S. E.; Davis, P.; Grenda, V. J.; Zambito, A, J.; Grabowski, E. J. J. J. Org. Chem. 1987,52, 3326-3334) us-

ing (S)- or (R)- serine as an amino alcohol (Huang, J.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 1997, 62, 372-376). (Scheme 12).

63a 63b, 54a

Scheme 12. Reagents and conditions for the preparation of compounds 53b (R= CO ₂ Me, R'= H) and 54a (R= H, R'= CO ₂ Me): a) MeOH, HCI (gas), CH ₂ CI ₂ , 2 ⁰ C, 92%; b) Et ₃ N, CH ₂ CI ₂ , reflux, 68%.

3-(λ/-hydroxycarbamimidoyl)phenyl cyclohexylcarbamate (56) was prepared from 3-cyanophenyl cyclohexylcarbamate (28) by converting the cyano group to amidoxime (Scheme 13).

28 56

Scheme 13. Reagents and conditions for the preparation of compound 56: a) Hydroxylamine hydrochloride, thethyl amine, EtOH, rt, 29 %.

2-Hydroxyisonicotinic acid methyl ester 57a for the preparation of carbamate derivative 57b was prepared from 2-hydroxyisonicotinic acid (Scheme 14).

5 ^7a

Scheme 14. Reagents and conditions for the preparation of phenol 57a: a) MeOH, cone. H ₂ SO ₄ , 82 %.

The following examples further illustrate the invention described above.

Examples

Methods employed in the characterization of examples

Analytical thin-layer chromatography was carried out on Merck silica gel F ₂ 5 ₄ (60 A, 40-63 μm, 230-400 mesh) pre-coated aluminum sheets and detected under UV-light. Melting points (mp) were determined in open capillaries using a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) spectra were recorded on a Bruker Avance DPX 400 (or Bruker Avance 500) spectrometer operating at 400 MHz (500.1 MHz) for ¹ H and 100 MHz (125.8 MHz) for ¹³ C. Chemical shifts are reported in ppm on the δ scale from an internal standard of residual solvent (CDCI ₃ 7.26 and 77.0 ppm; DMSO-c/ ₆ 2.50 and 39.52 ppm). Infrared (IR) spectra were recorded using a Perkin-Elmer Spectrum One FT-IR spectrometer, and values are reported as frequency (v) and expressed in cm ^"1 . Elemental analyses were recorded on a Perkin Elmer 2400 CHN or a ThermoQuest CE Instruments EA1110-CHNS-O elemental analysator. HRMS spectra were measured with a Jeol JMS-DX 303 and Micromass LCT or Waters Micromass LCT Premier (ESI / TOF) HRMS -spectrometer. ESI-MS spectra were acquired using A Finnigan LTQ quadrupole ion trap mass spectrometer (Thermo Electron Corporation, San Jose, CA, USA), equipped with an electrospray ion source.

Example 1

3-Benzyloxy benzoic acid (1a). 3-Hydroxy-benzoic acid (22.0 g, 159 mmol, 100 mol-%) in THF (100 mL) was treated with 1 M aq. NaOH (200 mL, 400 mmol, 250 mol-%) during 30 min followed by dropwise addition of

BnBr (24 ml_, 202 mmol, 127 mol-%) in THF (100 ml_) at 1 O ⁰ C. The mixture was refluxed for 48 h and then cooled to rt. The mixture was acidified with 1 M HCI (400 ml_) and extracted with EA (3 x 150 ml_). The combined organic phases were washed with water (150 ml_) and brine (150 ml_), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield the crude product as a white solid which was recrystallized (AcOH) to yield 23.6 g (65%) of the title compound as a white solid: mp 137-139 ⁰ C (lit. 135.5-136 ⁰ C ³³ ), Rf (5% MeOH in CH ₂ CI ₂ ) 0.22; ¹ H NMR (CDCI ₃ ) 7.74-7.72 (m, 2 H), 7.46-7.32 (m, 6 H), 7.24-7.21 (m, 1 H), 5.13 (s, 2 H). CAS number: 69026-14-8. 3-Benzyloxy benzoyl chloride (1b). 3-Benzyloxy benzoic acid (1a, 550 mg, 2.4 mmol, 100 mol-%) was refluxed in SOCI ₂ (3 ml_, 41 mmol, 1700 mol-%) for 3 h and evaporated to dryness. The crude product was twice diluted to benzene (20 ml_) and evaporated to yield 580 mg (98%) of the title compound as a colourless oil: Rf (5% MeOH in CH ₂ CI ₂ ) 0.88; ¹ H NMR (CDCI ₃ ) 7.63 (ddd, 1 H, J = 7.7, 1.6, 1.0 Hz), 7.58 (dd, 1 H, J = 2.5, 1.7 Hz), 7.35-7.23 (m, 6 H), 5.00 (s, 2 H) ¹³ C NMR (CDCI ₃ ) 168.1 , 158.9, 136.0, 134.4, 129.9, 128.7, 128.3, 127.5, 124.2, 122.5, 116.5, 70.3. CAS number: 61535-46-4. Benzo[cfloxazol-2-yl(3-benzyloxyphenyl)methanone (1c). To a mixture of benzo[c/]oxazole (727 mg, 6.1 mmol, 100 mol-%) in THF (35 ml_) was added n-BuLi (1.8 M in hex, 3.7 ml_, 6.7 mmol, 110 mol%) at -75 ⁰ C drop- wise during 10 min After 30 min ZnCI ₂ (1.66 g, 12.2 mmol, 200 mol-%) in Et ₂ O (20 ml_) was added. The mixture was warmed to 0 ⁰ C and after 45 min CuI (1.16 mg, 6.1 mmol, 100 mol-%) was added. Then after 10 min 3- benzyloxy benzoyl chloride (1b, 1.5 g, 6.1 mmol, 100 mol-%) in THF (10 ml_) was added. The mixture was stirred at 0 ⁰ C for another 45 min and quenched by diluting with EtOAc (400 ml_) and washing with 1 :1 H ₂ O: 25% aq. ammonia (100 ml_), H ₂ O (100 ml_) and brine (100 ml_). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield the crude product as tan solid which was purified with flash chromatography (5% EtOAc in Hex) and recrystallized (EtOAc/Hex) to give 1.08 g (54%)

of the title compound as a yellow solid: mp 95-97 ⁰ C, Rf (20% EtOAc in Hex) 0.50; ¹ H NMR (CDCI ₃ ) 8.22 (d, 1 H ₁ J = 7.7Hz), 8.13 (dd, 1 H ₁ J = 2.4, 1 .6 Hz), 7.93 (dd, 1 H ₁ J = 7.9 Hz), 7.70 (d, 1 H, J = 8.2 Hz), 7.54 (td, 1 H, J = 7.8, 1 .0 Hz), 7.49-7.44 (m, 4 H), 7.41 -7.28 (m, 4 H), 5.17 (s, 2 H); ¹³ C NMR (CDCI ₃ ) 180.1 , 158.8, 157.1 , 150.4, 140.7, 136.4, 136.2, 129.7, 128.6, 128.4, 128.1 , 127.6, 125.7 , 124.1 , 122.4, 121 .7, 1 16.0, 1 1 1 .8, 70.3; IR (KBr) 1648, 1604, 1577, 1443 cm ^"1 ; Anal, calcd for C ₂ iH ₁₅ NO ₃ ; C, 76.58; H, 4.59; N, 4.25; Found C, 76.26; H, 4.24; N, 4.58. Benzo[cfloxazol-2-yl(3-hydroxyphenyl)methanone (1 d). 2-Benzoxazole- (3-benzyloxyphenyl)methanone (1c, 5.0 g, 15.2 mmol, 100 mol-%) was stirred in a solution of boron trifluoride diethyletherate (6.9 ml_, 55 mmol, 360 mol-%) and dimethylsulfide (10 ml_, 136 mmol, 900 mol-%) in dry CH ₂ CI ₂ (100 ml_) at rt for 72 h. The mixture was then quenched with H ₂ O (120 ml_) and diluted with CH ₂ CI ₂ (300 ml_) and EtOAc (50 ml_). The or- ganic phase was washed with brine (2 x 100 ml_), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to yield a crude product as a red solid which was recrystallized (EtOAc/Hex) to yield 3.06 g (84%) of title compound as light yellow crystals; mp 125-128 ⁰ C, Rf (50% EtOAc/Hex) 0.61 ; ¹ H NMR (CDCI ₃ ) 8.17 (ddd, 1 H, J = 7.8, 1.6, 1.0 Hz), 8.04 (dd, 1 H, J = 2.4, 1.6 Hz), 7.94 (ddd, 1 H, J = 8.0, 1.3, 0.7), 7.69 (dt, 1 H, J = 8.2, 0.9), 7.57- 7.52 (m, 1 H), 7.48-7.41 (m, 2 H), 7.19 (ddd, 1 H, J= 8.1 , 2.7, 0.9 Hz), 5.74 (s, 1 H); ¹³ C NMR (CDCI ₃ ) 180.2, 157.1 , 156.0, 150.4, 140.6, 136.2, 130.0, 128.5, 125.8, 123.7, 122.3, 121.9, 117.2, 111.9; IR (KBr) 3463, 1651 , 1593, 1525, 1450 cm ^"1 ; Elem. anal. calc. for Ci ₄ H ₉ NO ₃ ; C, 70.29; H, 3.79; N, 5.86; Found C, 70.24; H, 3.56; N, 5.76.

3-(Benzo[d]oxazole-2-carbonyl)phenyl ethyl carbamate ester (1e). 2- Benzoxazole-(3-hydroxy-phenyl)-methanone (1d, 100 mg, 0.42 mmol, 100 mol-%) was dissolved in dry toluene (4 ml_) followed by addition of TEA (60 μl_, 0.42 mmol, 100 mol-%) and ethyl isocyanate (166 μl_, 2.1 mmol, 500 mol-%). The mixture was stirred at rt for 12 h and monitored by TLC (5% Et ₂ O in CH ₂ CI ₂ ). After the reaction was complete the mixture was diluted

with EtOAc (8 ml_), filtered through a pad of silica gel and evaporated to dryness. Recrystallization from EtOAc/Hex gave 121 mg (93%) of compound 1e as a white cotton-like solid: mp 141 -142 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.70; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.7 Hz), 8.32 (s, 1 H), 7.94 (d, 1 H, J = 8.1 Hz), 7.70 (d, 1 H, J = 8.2 Hz), 7.57-7.45 (m, 4 H), 5.19 (br s, 1 H, NH), 3.33 (qui, 2 H, J = 6.8 Hz), 1.23 (t, 3 H, J = 7.2 Hz); ¹³ C NMR (CDCI3) 179.4, 156.9, 154.0, 151.2, 150.4, 140.7, 136.0, 129.4, 128.5, 127.9 , 127.8, 125.7, 123.9, 122.4, 111.8, 36.2, 15.0; IR (KBr) 3345, 2976, 1712, 1662, 1527 cm ^"1 ; Anal, calcd for Ci ₇ H ₁₄ N ₂ O ₄ ; C, 65.80; H, 4.55; N, 9.03; Found C, 65.69; H, 4.21 ; N, 8.98.

Example 2

3-(Benzo[d]oxazole-2-carbonyl)phenyl propyl carbamate ester (2). This compound was synthesized and worked up as described for 1e using pro- pyl isocyanate (86 μl_, 0.90 mmol, 750 mol-%) as starting material. Recrystallization from EtOAc/Hex gave 38 mg (97%) of compound 2 as a white solid: mp 121 -122 ⁰ C, Rf (50% EtOAc in Hex) 0.53; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.5 Hz), 8.33 (s, 1 H), 7.96 (d, 1 H, J = 8.1 Hz ), 7.72 (d, 1 H, J = 8.1 Hz), 7.58-7.54 (m, 2 H), 7.51 -7.46 (m, 2 H), 5.10 (s, 1 H, NH), 3.27 (q, 2 H, J = 6.6 Hz), 1.63 (sext, 2 H, J = 7.2 Hz), 0.99 (t, 3 H, J = 7.4 Hz); ¹³ C NMR (CDCI ₃ ) 179.5, 157.0, 154.2, 151.3, 150.5, 140.8, 136.1 , 129.5, 128.5, 128.0, 127.8, 125.8, 124.0, 122.5, 111.9, 43.1 , 23.1 , 11.2; IR (KBr) 3306, 2957, 1732, 1708, 1647, 1536 cm-1 ; Anal, calcd for C ₁₈ H ₁₆ N ₂ O ₄ ; C, 66.66; H, 4.97; N, 8.64; Found C, 66.64, H, 4.76, N, 8.49.

Example 3

3-(Benzo[d]oxazole-2-carbonyl)phenyl butyl carbamate ester (3). This compound was synthesized and worked up as described for 1e using butyl isocyanate (240 μl_, 2.1 mmol, 500 mol-%) as starting material. Recrystalli- zation from EtOAc/Hex yielded 140 mg (99%) of the title compound as a white solid: mp 144-145 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.71 ; ¹ H NMR (CDCI ₃ )

8.46 (d, 1 H ₁ J = 7.7 Hz), 8.32 (s, 1 H), 7.95 (d, 1 H ₁ J = 7.9 Hz), 7.71 (d, 1 H ₁ J = 8.2 Hz), 7.58-7.46 (m, 4 H), 5.11 (br s, 1 H, NH), 3.30 (q, 2 H, J = 6.7 Hz), 1.58 (qui, 2 H, J = 7.3 Hz), 1.41 (sext, 2 H, J = 7.4 Hz), 0.96 (t, 3 H, J = 7.3 Hz); ¹³ C NMR (CDCI ₃ ) 179.4, 156.9, 154.1 , 151.2, 150.4, 140.7, 136.0, 129.4, 128.5, 127.9, 127.8, 125.7, 123.9, 122.4, 111.8, 41.0, 31.8, 19.9, 13.6; IR (KBr) 3356, 2953, 1710, 1663, 1529 cm ^"1 ; Anal, calcd for C ₁₉ H ₁₈ N ₂ O ₄ ; C, 67.44; H, 5.36; N, 8.28; Found C, 67.51 ; H, 5.15; N, 8.20.

Example 4 3-(Benzo[d]oxazole-2-carbonyl)phenyl cyclopentyl carbamate ester (4). This compound was synthesized and worked up as described for 1e using cyclopentyl isocyanate (240 μl_, 2.1 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 142 mg (96%) of the title compound as a white solid: mp 156-157 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.70; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.5 Hz), 8.32 (s, 1 H), 7.95 (d, 1 H, J = 7.9 Hz), 7.71 (d, 1 H, J = 8.2 Hz), 7.57-7.45 (m, 4 H), 5.11 (br d, 1 H, NH), 4.07 (sext, 1 H, J = 6.8 Hz), 2.10-2.00 (m, 2 H), 1.75-1.46 (m, 6 H); ¹³ C NMR (CDCI ₃ ) 179.4, 156.9, 153.5, 151.2, 150.4, 140.7, 136.1 , 129.4, 128.5, 127.9, 127.8, 125.7, 123.9, 122.4, 111.8, 53.1 , 33.1 , 23.5; IR (KBr) 3352, 2954, 1716, 1659, 1520 cm ^"1 ; Anal, calcd for C ₂₀ H ₁₈ N ₂ O ₄ ; C, 68.56; H, 5.18; N, 8.00; Found C, 68.54; H, 5.02; N, 7.90.

Example 5

3-(Benzo[d]oxazole-2-carbonyl)phenyl cyclohexyl carbamate ester (5). This compound was synthesized and worked up as described for 1e but using cyclohexyl isocyanate (270 μl_, 2.1 mmol, 500 mol-%) as a starting material. Recrystallization from EtOAc/Hex gave 122 mg (80%) of the title compound as a white solid: mp 172-173 ⁰ C, Rf (20% EtOAc/Hex) 0.4; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.7 Hz), 8.32 (t, 1 H, J = 1.9 Hz), 7.96 (d, 1 H, J = 7.9 Hz), 7.71 (d, 1 H, J = 8.2 Hz), 7.58-7.54 (m, 2 H), 7.51 -7.46 (m, 2 H), 4.98 (d, 1 H, J = 7.5 Hz), 3.62-3.55 (m, 1 H), 2.05-2.03 (m, 2 H), 1.77-

1 .74 (m, 2 H), 1 .65-1 .61 (m, 1 H), 1 .44-1 .34 (m, 2 H), 1 .30-1 .20 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 179.5, 156.9, 153.2, 151 .3, 150.5, 140.8, 136.1 , 129.5, 128.5, 127.9, 127.88, 125.7, 123.9, 122.5, 1 1 1 .9, 50.3, 33.2, 25.4, 24.7; IR (KBr) 3352, 2954, 1716, 1659, 1520 cm ^"1 ; Anal, calcd for C ₂ IH ₂₀ N ₂ O ₄ ; C, 69.22; H, 5.53; N, 7.69; Found C, 68.78; H, 5.38; N, 7.62.

Example 6

3-(Benzo[d]oxazole-2-carbonyl)phenyl benzyl carbamate ester (6). This compound was synthesized and worked up as described for 1e using ben- zyl isocyanate (260 μl_, 2.1 mmol, 500 mol-%) as starting material. Recrys- tallization from EtOAc/Hex yielded 156 mg (97%) of the title compound as a white solid: mp 165-166 ⁰ C, Rf (50% EtOAc in Hex) 0.52; ¹ H NMR (CDCI ₃ ) 8.47 (d, 1 H, J = 7.5 Hz), 8.35 (s, 1 H), 7.95 (d, 1 H, J = 8.1 Hz ), 7.71 (d, 1 H, J = 8.2 Hz), 7.58-7.46 (m, 4 H), 7.37-7.36 (m, 4 H), 7.33-7.31 (m, 1 H), 5.44 (s, 1 H), 4.48 (d, 2 H, J = 6.0 Hz); ¹³ C NMR (CDCI3) 179.4, 156.9, 154.2, 151 .2, 150.5, 140.8, 137.8, 136.1 , 129.5, 128.8, 128.5, 128.1 , 127.83, 127.77, 125.8, 124.0, 122.5, 1 1 1 .9, 45.4; IR (KBr) 3306, 3034, 1701 , 1659, 1531 cm ^"1 ; Anal. calc. for C ₂₂ H ₁₆ N ₂ O ₄ ; C, 70.96; H, 4.33; N, 7.52; found C, 70.75, H, 4.07, N, 7.30.

Example 7

3-(Benzo[d]oxazole-2-carbonyl)phenyl 4-methoxy-benzyl carbamate ester (7). This compound was synthesized and worked up as described for 1e using 4-methoxyphenyl isocyanate (180 μl_, 1.2 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 64 mg (69%) of the title compound as a white solid: mp 155-157 ⁰ C, Rf (50% EtOAc in Hex) 0.44; ¹ H NMR (CDCI ₃ ) 8.48 (d, 1 H, J = 7.5 Hz), 8.40 (s, 1 H), 7.94 (d, 1 H, J = 8.1 Hz ), 7.70 (d, 1 H, J = 8.2 Hz), 7.59-7.52 (m, 3 H), 7.48-7.44 (m, 1 H), 7.35 (d, 2 H, J = 8.6), 7.08 (s, 1 H, NH), 6.86 (d, 2 H, J = 9.0 Hz), 3.77 (s, 3 H, -OCH3); ¹³ C NMR (CDCI ₃ ) 179.3, 156.8, 156.4, 151 .5, 150.8, 150.4, 140.7, 136.1 , 130.1 , 129.6, 128.5, 128.2, 127.7, 125.7, 124.1 , 122.4, 120.8,

114.4, 111.8, 55.5; IR (KBr) 3285, 3097, 1707, 1660, 1543 cm ^"1 ; Anal. calc. for C ₂₂ H ₁₆ N ₂ O ₅ ; C, 68.04; H, 4.15; N, 7.21 ; found C, 67.76; H, 4.09; N, 7.05.

Example 8 3-(Benzo[d]oxazole-2-carbonyl)phenyl 3-methyl-benzyl carbamate ester (8). This compound was synthesized and worked up as described for 1e using 3-methyl-benzyl isocyanate (290 μl_, 2.1 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 160 mg (97%) of the title compound as a white solid: mp 154-155 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.71 ; ¹ H NMR (CDCI ₃ ) 8.47 (d, 1 H, J = 7.7 Hz), 8.35 (s, 1 H), 7.95 (d, 1 H, J = 7.7 Hz), 7.70 (d, 1 H, J = 8.1 Hz), 7.58-7.45 (m, 4 H), 7.27-7.11 (m, 4 H), 5.45 (m, 1 H, NH), 4.43 (d, 2 H, J = 5.7 Hz), 2.36 (s, 3 H); ¹³ C NMR (CDCI ₃ ) 179.4, 156.9, 154.1 , 151.2, 150.4, 140.7, 138.5, 137.7, 136.1 , 129.5, 128.7, 128.5, 128.0, 127.7, 125.7, 124.7, 123.9, 122.4, 111.8, 45.4, 21.3; IR (KBr) 3297, 3042, 1702, 1660, 1530 cm ^"1 ; Anal, calcd for C ₂₃ H ₁₈ N ₂ O ₄ ; C, 71.49; H, 4.70; N, 7.25; found C, 71.41 ; H, 4.41 ; N, 7.14;.

Example 9

Benzo[c/]thiazol-2-yl(3-benzyloxyphenyl)methanone (9a). This com- pound was synthesized and worked up as described for 1c but using benzo[c/]thiazole (2.6 ml_, 23.9 mmol, 100 mol-%) as starting material instead of benzo[c/]oxazole. Purification with flash chromatography (8% EtOAc in Hex) and recrystallization (EtOAc/Hex) yielded 4.56 g (55%) of the the title compound as a light yellow solid: mp 98-100 ⁰ C, Rf (20% EA in Hex) 0.47. ¹ H NMR (CDCI ₃ ) 8.22 (d, 2 H, J = 8.1 Hz), 8.16 (dd, 1 H, J = 2.6, 1.6 Hz), 8.01 -7.99 (m, 1 H), 7.60-7.24 (m, 9 H), 5.17 (s, 2 H); ¹³ C NMR (CDCI ₃ ) 184.9, 167.1 , 158.8, 153.9, 137.0, 136.6, 136.2, 129.6, 128.6, 128.1 , 127.6, 126.9, 125.8, 124.4, 122.12, 121.4, 116.4, 70.3; IR (KBr) 1633, 1588, 1491 cm ^"1 ; Anal, calcd for C ₂₁ H ₁₅ NO ₂ S; C, 73.02; H, 4.38; N, 4.06; Found C, 72.46; H, 4.25; N, 3.96.

Benzo[cflthiazol-2-yl(3-hydroxyphenyl)methanone (9b). This compound was synthesized and worked up as described for 1d using benzo[c/]thiazol- 2-yl(3-hydroxy-phenyl)methanone (9a, 4.33 g, 12.5 mmol, 100 mol-%) as starting material. Purification with flash chromatography (25% EtOAc in Hex) and recrystallization from EtOAc/Hex gave 2.92 g (91 %) of the the title compound as a yellow solid: mp 146-147 ⁰ C, Rf (50% EtOAc in Hex) 0.50; ¹ H NMR (DMSO-CZ ₆ ) 9.95 (s, 1 H), 8.27-8.22 (m, 2 H), 7.94 (app d, 1 H ₁ J = 7.9 Hz), 7.85 (t, 1 H, J = 1.9 Hz), 7.67-7.60 (m, 2 H), 7.43 (t, 1 H, J = 8.0 Hz), 7.16 (ddd, 1 H, J = 8.1 , 2.4, 0.9 Hz); ¹³ C NMR (DMSO) 184.7, 166.8, 157.4, 153.3, 136.2, 135.6, 129.7, 127.9, 127.3, 125.3, 122.8, 121.9, 121.4, 117.0; IR (KBr) 3466, 1634, 1590, 1489, 1446 cm ^"1 ; Anal, calcd for C ₁₄ H ₁₁ NO ₂ S; C, 65.87; H, 3.55; N, 5.49; Found C, 66.01 ; H, 3.35; N, 5.32. 3-(Benzo[d]thiazole-2-carbonyl)phenyl ethyl carbamate ester (9c). This compound was synthesized and worked up as described for 1e using the compound 9b (100 mg, 0.39 mmol, 100 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 101 mg (79%) of the title compound as a white solid: mp 97-99 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.61 ; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.7 Hz), 8.32 (s, 1 H), 8.24 (app. dd, 1 H, J = 7.6, 1.2 Hz), 8.01 -7.99 (m, 1 H), 7.60-7.46 (m, 4 H), 5.15 (m, 1 H, NH), 3.33 (qui, 2 H, J = 6.8 Hz), 1.22 (t, 3 H, J = 7.2 Hz); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 154.0, 153.8, 151.1 , 137.0, 136.0, 129.3, 128.2, 127.7, 127.4, 126.9, 125.8, 124.2, 122.1 , 36.2, 15.1 ; IR (KBr) 3335, 2975, 1712, 1643, 1531 cm ^{" 1} ; Anal, calcd for C ₁₇ H ₁₄ N ₂ O ₃ S; C, 62.56; H, 4.32; N, 8.58; found C, 62.50; H, 4.40; N, 8.50.

Example 10

3-(Benzo[d]thiazole-2-carbonyl)phenyl propyl carbamate ester (10).

This compound was synthesized and worked up as described for 9c (except that the mixture was stirred at 64 ⁰ C for 16 h) using propyl isocyanate (160 μl_, 2.0 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 126 mg (95%) of the title compound as a white solid:

mp. 98-100 ⁰ C, Rf (CHCI ₃ ) 0.50; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.7 Hz), 8.32 (s, 1 H), 8.24 (dd, 1 H ₁ J = 7.3, 1.3 Hz ), 8.02-8.00 (m, 1 H), 7.60-7.46 (m, 4 H), 5.15 (s, 1 H, -NH), 3.26 (q, 2 H, J = 6.7 Hz), 1.62 (sext, 2 H, J = 7.3 Hz), 0.98 (t, 3 H, J = 7.3 Hz); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 154.2, 153.9, 151.1 , 137.0, 136.1 , 129.3, 128.2, 127.7, 127.4, 126.9, 125.8, 124.2, 122.1 , 43.0, 23.0, 11.2; IR (KBr) 3306, 2957, 1732, 1708, 1647, 1536 cm ^"1 ; Anal, calcd for C ₁₈ H ₁₆ N ₂ O ₃ S; C, 63.51 ; H, 4.74; N, 8.23; found C, 63.61 ; H, 4.49; N, 8.14.

Example 11

3-(Benzo[d]thiazole-2-carbonyl)phenyl butyl carbamate ester (11). This compound was synthesized and worked up as described for 9c using butyl isocyanate (225 μl_, 2.0 mmol, 500 mol-%) as starting material. Recrystalli- zation from EtOAc/Hex yielded 128 mg (90%) of the title compound as a white solid: mp 120-121 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.62; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.7 Hz), 8.32 (s, 1 H), 8.24 (app. d, 1 H, J = 7.7 Hz), 8.00 (app. dd, 1 H, J = 7.7, 0.9 Hz), 7.60-7.46 (m, 4 H), 7.27-7.11 (m, 4 H), 5.12 (br s, 1 H, NH), 3.29 (q, 2 H, J = 6.7 Hz), 1.57 (qui, 2 H, J = 7.4 Hz), 1.41 (sext, 2 H, J = 7.6 Hz), 0.96 (t, 3 H, J = 7.3 Hz); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 154.2, 153.9, 151.1 , 137.0, 136.1 , 129.3, 128.2, 127.7, 127.4, 126.9, 125.8, 124.2, 122.1 , 41.0, 31.9, 19.9, 13.7; IR (KBr) 3327, 2961 , 1715, 1646, 1536, 1489 cm ^"1 ; Anal, calcd for C ₁₉ H ₁₈ N ₂ O ₃ S; C, 64.39; H, 5.12; N, 7.90; found C, 64.56; H, 4.91 ; N, 7.84.

Example 12

3-(Benzo[d]thiazole-2-carbonyl)phenyl cyclopentyl carbamate ester (12). This compound was synthesized and worked up as described for 9c using cyclopentyl isocyanate (225 μl_, 2.0 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 120 mg (84%) of the title compound as a white solid: mp 121 -123 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.60; ¹ H NMR (CDCI ₃ ) 8.45 (d, 1 H, J = 7.7 Hz), 8.32 (s, 1 H), 8.25-8.23 (m,

1 H), 8.01 -7.99 (m, 1 H), 7.60-7.46 (m, 4 H), 5.12 (br d, 1 H, J = 6.4 Hz, NH), 4.07 (sext, 1 H, J = 6.8 Hz), 2.17-1.98 (m, 2 H), 1.75-1.45 (m, 6 H); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 153.8, 153.6, 151.1 , 137.0, 136.0, 129.3, 128.1 , 127.6, 127.4, 126.9, 125.8, 124.2, 122.1 , 53.1 , 33.1 , 23.5; IR (KBr) 3339, 2966, 1706, 1646, 1521 , 1489 cm ^"1 ; Anal, calcd for C ₂₀ H ₁₈ N ₂ O ₃ S; C, 65.55; H, 4.95; N, 7.64; found C, 65.49; H, 4.94; N, 7.46.

Example 13

3-(Benzo[d]thiazole-2-carbonyl)phenyl cyclohexyl carbamate ester (13). This compound was synthesized and worked up as described for 9c (except that mixture was refluxed for 17 hrs) using cyclohexyl isocyanate (278 μl_, 1.95 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 132 mg (89%) of the title compound as white solid: mp 151 -152 ⁰ C, Rf (30% EtOAc/Hex) 0.50; ¹ H NMR (CDCI ₃ ) 8.45 (d, 1 H, J = 7.7 Hz), 8.32 (t, 1 H, J = 1.7 Hz), 8.24-8.22 (m, 1 H), 8.00-7.98 (m, 1 H), 7.59-7.46 (m, 4 H), 5.10 (d, 1 H, J = 7.7 Hz), 3.62-3.53 (m, 1 H), 2.04-2.00 (m, 2 H), 1.75-1.72 (m, 2 H), 1.64-1.60 (m, 1 H), 1.42-1.32 (m, 2 H), 1.28- 1.14 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 153.8, 153.2, 151.1 , 137.0, 136.0, 129.2, 128.1 , 127.6, 127.4, 126.9, 125.7, 124.1 , 122.1 , 50.2, 33.1 , 25.4, 24.7; IR (KBr) 3351 , 2935, 1707, 1642, 1523 cm ^"1 ; Anal, calcd for C ₂ IH ₂₀ N ₂ O ₃ S; C, 66.29; H, 5.30; N, 7.36; Found C, 66.21 ; H, 5.30; N, 7.24.

Example 14

3-(Benzo[d]thiazole-2-carbonyl)phenyl benzyl carbamate ester (14).

This compound was synthesized and worked up as described for 9c (except that the mixture was stirred at 92 ⁰ C for 14 h) using benzyl isocyanate (240 μl_, 1.95 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 127 mg (84%) of the title compound as a white solid: mp 157-159 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.61 ; ¹ H NMR (CDCI ₃ ) 8.47 (d, 1 H,

J = 7.7 Hz), 8.35 (s, 1 H), 8.24 (d, 1 H, J = 7.7 Hz), 8.02-8.00 (m, 1 H), 7.60-7.48 (m, 4 H), 7.37-7.31 (m, 5 H), 5.45 (br s, 1 H, NH), 4.47 (d, 2 H, J = 5.9 Hz); ¹³ C NMR (DMSO-c/ ₆ ) 184.0, 166.5, 154.3, 153.2, 151.0, 139.1 , 136.3, 135.6, 129.6, 128.3, 128.1 , 127.6, 127.6, 127.4, 127.1 , 127.0, 125.4, 123.6, 122.9, 44.1 ; IR (KBr) 3351 , 1710, 1649, 1519, 1491 cm ^"1 ; Anal, calcd for C ₂₂ H ₁₆ N ₂ O ₃ S; C, 68.02; H, 4.15; N, 7.21 ; found C, 68.21 ; H, 3.88; N, 7.20.

Example 15 3-(Benzo[d]thiazole-2-carbonyl)phenyl 4-methoxy-benzyl carbamate ester (15). This compound was synthesized and worked up as described for 9c using 4-methoxy-benzyl isocyanate (280 μl_, 2.0 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 62 mg (41 %) of the title compound as white needles: mp 168-170 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.61 ; ¹ H NMR (CDCI ₃ ) 8.49 (d, 1 H, J = 7.7 Hz), 8.41 (s, 1 H), 8.26- 8.24 (m, 1 H), 8.02-8.00 (m, 1 H), 7.60-7.51 (m, 4 H), 7.37 (d, 2 H, J = 8.8 Hz), 6.95 (br s, 1 H, NH), 6.88 (d, 2 H, J = 9.0 Hz), 3.79 (s, 3 H); ¹³ C NMR (CDCI ₃ ) 184.1 , 166.8, 153.9, 150.7, 137.1 , 136.2, 130.2, 129.5, 128.6, 127.7, 127.3, 127.0, 125.8, 124.3, 122.2, 120.9, 120.8, 120.8, 114.4, 55.5; IR (KBr) 3302, 1706, 1643, 1526, 1495 cm ^"1 ; Anal, calcd for C ₂₂ H ₁₆ N ₂ O ₄ S; C, 65.33; H, 3.99; N, 6.93; found C, 65.11 ; H, 3.70; N, 6.73.

Example 16

3-(Benzo[d]thiazole-2-carbonyl)phenyl 3-methyl-benzyl carbamate es- ter (16). This compound was synthesized and worked up as described for 9c using 3-methyl-benzyl isocyanate (280 μl_, 2.0 mmol, 500 mol-%) as starting material. Recrystallization from EtOAc/Hex yielded 135 mg (86%) of the title compound as a white solid: mp 131 -132 ⁰ C, Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.59; ¹ H NMR (CDCI ₃ ) 8.46 (d, 1 H, J = 7.5 Hz), 8.35 (s, 1 H), 8.25- 8.22 (m, 1 H), 8.01 -7.99 (m, 1 H), 7.60-7.48 (m, 4 H), 7.27-7.23 (m, 1 H); ¹³ C NMR (CDCI ₃ ) 184.2, 166.8, 154.2, 154.0, 153.8, 151.1 , 138.5, 137.7,

137.0, 136.1 , 129.3, 128.7, 128.5, 128.3, 127.7, 127.3, 126.9, 125.8, 124.7, 124.2, 122.1 , 45.6, 21.3; IR (KBr) 3339, 3019, 1717, 1645, 1520, 1492 cm ^{" 1} ; Anal, calcd for C ₂₃ H ₁₈ N ₂ O ₃ S; C, 68.64; H, 4.51 ; N, 6.96; found C, 68.45; H, 4.34; N, 6.92.

Example 17

3-(4,5-dihydrooxazol-2-yl)phenol (17a). 3-Hydroxy-benzoic acid (1.38 g, 10 mmol, 100 mol-%), 2-aminoethanol (4a, 610 μl_, 10 mmol, 100 mol-%) and TEA (4.2 ml_, 30 mmol, 300 mol-%) were stirred in pyridine (20 ml_) and MeCN (30 ml_) at 22 ⁰ C for 40 min. CCI ₄ (6.15 g, 40 mmol, 400 mol-%) was added followed by dropwise admission of PPh ₃ in pyridine-MeCN (1 :1 , 80 ml_) during 2 hrs keeping the temperature of the mixture between 22-24 ⁰ C with water bath. The mixture was stirred for 18 hrs and mixture was concentrated with rotavapor to ca. 40 ml. The mixture was diluted with aq. am- monia (25%, 100 ml) and extracted with EtOAc (3x100 ml). Combined organic phases were washed with sat. aq. CuSO ₄ (100 ml), water (100 ml) and brine (100 ml), dried with Na ₂ SO ₄ , filtered and evaporated. The crude product was a red solid which was purified with flash chromatography (0-4 % MeOH in CH ₂ CI ₂ ) to yield 479 mg (29%) of the compound 17a as white solid: mp 188-189 ⁰ C, Rf (EtOAc) 0.5; ¹ H NMR (DMSO-c/ ₆ , 400 MHz) 9.70 (s, 1 H), 7.30-7.23 (m, 3 H), 6.91 (d, 1 H, J = 8.1 Hz), 4.36 (t, 2 H, J = 9.5 Hz), 3.92 (t, 2 H, J = 9.5 Hz); ¹³ C NMR (DMSO-c/ ₆ , 400 MHz) 163.0, 157.3, 129.7, 128.7, 118.5, 118.4, 114.3, 67.2, 54.4. 3-(4,5-Dihydrooxazol-2-yl)phenyl n-propylcarbamate (17b). This com- pound was synthesized and worked up as described for 1e using 17a (65 mg, 0.4 mmol, 100 mol-%) and n-propyl isocyanate (170 μl_, 2.0 mmol, 500 mol-%) as starting materials. Recrystallization from EtOAc/Hex gave the title compound as white white crystals: mp 94-95 ⁰ C, Rf (EtOAc) 0.5; ¹ H NMR (CDCI ₃ , 400 MHz) 7.78 (d, 1 H, J = 7.8 Hz), 7.70 (s, 1 H), 7.39 (t, 1 H, J = 8.0 Hz), 7.29-7.24 (m, 1 H), 5.05 (br s, 1 H), 4.43 (app t, 2 H, J = 9.5 Hz), 4.06 (app t, 2 H, J = 9.5 Hz), 3.24 (q, 2 H, J = 6.7 Hz), 1.60 (sext, 2 H,

J = 7.3 Hz), 0.97 (t, 3 H, J = 7.4 Hz); ¹³ C NMR (CDCI ₃ , 400 MHz) 163.9, 150.9, 129.1 , 128.9, 124.9, 124.6, 121.4, 67.6, 54.8, 42.9, 23.0, 11.1 ; Anal, calcd for C ₁₃ H ₁₆ N ₂ O ₃ ; C, 62.89; H, 6.50; N, 11.28; Found C, 62.77; H, 6.26; N, 11.15.

Example 18

3-(4,5-Dihydrooxazol-2-yl)phenyl cyclopentylcarbamate (18). This compound was synthesized and worked up as described for 17b using cyclopentyl isocyanate (50 μl_, 0.5 mmol, 200 mol-%) as starting material. Recrystallization from EA:Hex (4:6 ml_) gave 48 mg (70%) of the compound 18 as white crystals: mp 166-168 ⁰ C; Rf (10% Et ₂ O in CH ₂ CI ₂ ) 0.40; ¹ H NMR (DMSO-c/e) 7.86 (d, 1 H, J = 7.1 Hz), 7.69 (d, 1 H, J = 7.7 Hz), 7.53 (s, 1 H), 7.47 (t, 1 H, J = 7.9 Hz), 7.28 (dd, 1 H, J = 1.5, 8.1 Hz), 4.41 (t, 2H, J = 9.5 Hz), 3.96 (t, 2H, J = 9.5 Hz), 3.88-3.79 (m, 1 H), 1.89-1.79 (m, 2H), 1.72- 1.61 (m, 2H), 1.57-1.44 (m, 4H); ¹³ C NMR (DMSO-c/ ₆ ) 162.3, 153.4, 151.0, 129.7, 128.6, 124.7, 124.1 , 120.9, 67.5, 54.4, 52.4, 32.2, 23.3; Anal, calcd for C ₁₅ H ₁₆ N ₂ O ₃ ; C, 66.68; H, 6.61 ; N, 10.21 ; Found C, 65.62; H, 6.91 ; N, 10.20.

Example 19

2-(3-Methoxy-phenyl)-oxazole (19a). 3-Methoxybenzamide (2,0 g, 13 mmol, 100 mol-%) and 2-bromoacetaldehyde diethyl acetal (5, 2.5 ml_, 16 mmol, 120 mol-%) were added to a flame dried 10 ml round bottomed flask and irradiated with CEM microwave apparatus for 5 min (power 300 W for 30 sec, then 50 W, air cooling, T _max = 100 ⁰ C ). The reaction mixture was dissolved to EtOAc (150 ml_), MeOH (10 ml_) and water (50 ml_). The organic phase was washed with NaHCO ₃ (100 ml_), water (50 ml_) and brine (50 ml_), dried over Na ₂ SO ₄ , filtered and evaporated. The tan oil was Kugel- rohr-distilled to yield 2.05 g of clear oil. The oil was diluted with hexane (5 ml_) and put to freezer overnight which caused crystallization. The solid was filtrated, washed with cold hex (20 ml_) and dried under reduced pres-

sure to yield 1 .01 g (45%) of the title compound as a white crystals: mp 23 ⁰ C, Rf (EtOAc) 0.62; ¹ H NMR (CDCI ₃ ) 7.69 (d, 1 H, J = 0.7 Hz ), 7.65-7.62 (app. ddd, 1 H ₁ J = 7.7, 1 .4, 0.9), 7.59 (dd, 1 H, J = 1 .4 Hz), 7.36 (t, 1 H ₁ J = 7.5 Hz), 7.23 (d, 1 H ₁ J = 0.7 Hz), 6.99, (ddd, 1 H, J = 8.3, 2.6, 0.9 Hz), 3.86 (s, 3 H), ¹³ C NMR (CDCI ₃ ) 161 .8, 159.8, 138.5, 129.8, 128.6, 128.3, 1 18.7, 1 16.9, 1 10.9, 55.3; Anal, calcd for C ₁₀ H ₉ NO ₂ , C, 68.56; H, 5.18; N, 8.00; Found C, 68.43; H, 4.84; N, 7.86.

2-(3-Hydroxy-phenyl)-oxazole (19b). 2-(3-Methoxy-phenyl)-oxazole (19a, 900 mg, 5.14 mmol, 100 mol-%) and 1 -butyl-3-methylimidazolium bromide (2.20 g, 10 mmol, 200 mol-%) were irradiated with CEM microwave apparatus in an open vessel for 4 x 20 sec (power 300 W, air cooling, T _max 200 ⁰ C). The reaction mixture was dissolved to EtOAc (200 ml_) and water (50 ml_). The organic phase was washed with water (50 ml_) and brine (50 ml_), dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified with flash chromatography (25% EtOAc in hex) to yield 500 mg (60%) of the compound 19b as a white solid: mp 130-131 ⁰ C, Rf (40% EA in hex) 0.5; ¹ H NMR (CDCI ₃ ) 9.81 (s, 1 H), 8.19 (d, 1 H, J = 0.8 Hz), 7.43-7.38 (m, 2 H), 7.36 (d, 1 H, J = 0.8 Hz), 7.33 (t, 1 H, J = 7.9 Hz), 6.91 (ddd, 1 H, J = 1.1 , 2.5, 8.1 Hz), 5.05 (br s, 1 H, NH), 4.43 (app t, 2 H, J = 9.5 Hz), 4.06 (app t, 2 H, J = 9.5 Hz), 3.24 (q, 2 H, J = 6.7 Hz), 1.60 (sext, 2 H, J = 7.3 Hz), 0.97 (t, 3 H, J = 7.4 Hz); ¹³ C NMR (CDCI ₃ ) 160.8, 157.8, 139.9, 130.3, 128.4, 128.1 , 117.7, 116.6, 112.4; CAS 35582-09-3.

3-(Oxazol-2-yl)phenyl cyclopentylcarbamate (19c). This compound was synthesized and worked up as described for 17b using compound 19b (64 mg, 0.40 mmol-%, 100 mol-%) and cyclopentyl isocyanate (150 μl_, 1.6 mmol, 400 mol-%) as starting materials. Recrystallization from EtOAc:hex (1 :10 ml_) gave 103 mg (94%) of compound 19c as white crystals: mp. 120- 122 ⁰ C; Rf (10% Et ₂ O in CH ₂ CI ₂ ) 0.50; ¹ H NMR (DMSO-c/ ₆ ) 8.25 (s, 1 H), 7.90 (d, 1 H, J = 7.1 Hz), 7.81 (d, 1 H, J = 7.8 Hz), 7.66 (s, 1 H), 7.54 (t, 1 H, J = 8.0 Hz), 7.41 (s, 1 H), 7.27 (dd, 1 H, J = 1.6, 8.1 Hz), 3.90-3.82 (m, 1 H), 1.80-1.90 (m, 2H), 1.61 -1.72 (m, 2H); 1.56-1.45 (m, 4H); ¹³ C NMR (DMSO-

Cf ₆ ) 160.1 , 153.4, 151.5, 140.4, 130.3, 128.6, 128.0, 123.9, 122.3, 119.0, 52.4, 32.2, 23.3; Anal, calcd for C ₁₅ H ₁₆ N ₂ O ₃ ; C, 66.16; H, 5.92; N, 10.29; Found C, 65.99; H, 5.81 ; N, 10.20.

Example 20

3-(Oxazol-2-yl)phenyl cyclohexylcarbamate (20). This compound was synthesized and worked up as described for 19c using compound cyclo- hexyl isocyanate (190 μl_, 1.5 mmol, 300 mol-%) as starting material. Re- crystallization from EtOAc:hex gave 115 mg (80%) of compound 20 as white crystals: mp 142-143 ⁰ C; Rf (10% Et ₂ O in CH ₂ CI ₂ ) 0.30; ¹ H NMR (CDCI ₃ ) 7.88 (d, 1 H, J = 7.8 Hz), 7.82-7.80 (m, 1 H), 7.70-7.69 (m, 1 H), 7.44 (t, 1 H, J = 8.0 Hz), 7.25-7.21 (m, 2 H), 5.06 (br d, 1 H, J = 7.5 Hz), 3.66-3.51 (m, 1 H) 2.08-1.97 (m, 2 H), 1.79-1.69 (m, 2 H), 1.66-1.58 (m, 1 H), 1.43-1.31 (m, 2 H), 1.29-1.13 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 161.2, 153.3, 151.4, 138.7, 129.7, 128.6, 128.5, 123.6, 123.0, 119.7, 50.2, 33.2, 25.4, 24.7; Anal, calcd for C ₁₆ H ₁₈ N ₂ O ₃ ; C, 67.12; H, 6.34; N, 9.78; Found C, 66.72; H, 6.44; N, 9.74.

Example 21 3-(Oxazol-2-yl)phenyl 2-methyl-benzylcarbamate (21). This compound was synthesized and worked up as described for 20 using 2-methyl-benzyl isocyanate (165 μl_, 1.1 mmol, 200 mol-%) as starting material. Recrystalli- zation from EtOAc:hex gave compound 21 (154 mg, 89%) as white crystals: mp 120-121 ⁰ C; Rf, (5% Et ₂ O in CH ₂ CI ₂ ) 0.5; ¹ H NMR (DMSO-c/ ₆ ) 8.35 (t, 1 H ₁ J = 5.9 Hz), 8.24 (s, 1 H), 7.85-7.81 (m, 1 H), 7.70 (app. t, 1 H, J = 1.8 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.41 (s, 1 H), 7.33-7.27 (m, 2 H), 7.23-7.17 (m, 3 H), 4.29 (d, 1 H, J = 5.9 Hz), 2.32 (s, 3 H); ¹³ C NMR (DMSO-c/ ₆ ) 160.1 , 154.2, 151.5, 140.4, 136.7, 135.5, 130.4, 130.0, 128.6, 128.0, 127.4, 127.0, 125.9, 123.9, 122.5, 119.0, 42.1 , 18.6; Anal, calcd for C ₁₈ H ₁₆ N ₂ O ₃ ; C, 70.12; H, 5.23; N, 9.09; Found C, 69.78; H, 5.14; N, 9.02.

Example 22

3-(Oxazol-2-yl)phenyl phenethylcarbamate (22). This compound was synthesized and worked up as described for 21 using phenethyl isocyanate (110 μl_, 0.75 mmol, 200 mol-%) as starting material. Recrystallization from EtOAc:hex gave compound 22 as white crystals (83 mg, 73%): mp 112-113 ⁰ C; Rf (5% Et ₂ O in CH ₂ CI ₂ ) 0.5; ¹ H NMR (DMSO-c/ ₆ ) 8.25 (app. d, 1 H, J = 0.6 Hz), 7.96 (t, 1 H ₁ J = 5.6 Hz), 7.83-7.79 (m, 1 H), 7.64 (app. t, 1 H, J = 1.9 Hz), 7.54 (t, 1 H, J = 8.0 Hz), 7.41 (app. d, 1 H, J = 0.9 Hz), 7.35-7.20 (m, 6 H), 3.36-3.29 (m, 2 H), 2.82 (t, 2 H, J = 7.4 Hz); ¹³ C NMR (DMSO-c/ ₆ ) 160.1 , 154.0, 151.5, 140.4, 139.1 , 130.3, 128.7, 128.6, 128.3, 128.0, 126.2, 123.8, 122.4, 119.0, 42.0, 35.2, Anal, calcd for C ₁₈ H ₁₆ N ₂ O ₃ ; C, 70.12; H, 5.23; N, 9.09; Found C, 70.04; H, 5.09; N, 9.02.

Example 23 Cyclopentyl-carbamic acid 3-(2H-tetrazol-5-yl)-phenyl ester (23). 5-(3- Hydroxyphenyl)-tetrazole (98 mg, 0.6 mmol, 100 mol-%), cyclopentyl isocyanate (330 μl_, 3.0 mmol, 500 mol-%) and TEA (170 μl_, 1.2 mmol, 200 mol- %) were stirred in dry toluene (7 ml_) for 3 hrs at rt and refluxed for 6 hrs. The mixture was extracted with H ₂ O (3x20 ml_). The aqueous phase was acidified with 32% HCI (0.8 ml_) until white precipitate formed. Precipitate was filtered and recrystallized from MeOH:H ₂ O to give 48 mg (65%) of compound 23 as white crystals: mp 174-177 ⁰ C; Rf (8% MeOH, 2% AcOH in CHCI ₃ ) 0.40; ¹ H NMR (DMSO-c/ ₆ ) 7.94 (d, 1 H, J = 7.2 Hz), 7.89 (d, 1 H, J = 7.8 Hz), 7.77 (s, 1 H), 7.62 (t, 1 H, J= 8.0 Hz), 7.34 (dd, 1 H, J= 1.6, 8.1 Hz), 3.92-3-83 (m, 1 H), 1.91 -1.80 (m, 2H), 1.73-1.63 (m, 2H), 1.59-1.45 (m, 4H); ¹³ C NMR (DMSO-c/ ₆ ) 155.0, 153.4, 151.7, 130.6, 125.2, 124.7, 123.4, 120.3, 52.4, 32.2, 23.3; Anal, calcd for C ₁₃ H ₁₅ N ₅ O ₂ ; C, 57.13; H, 5.53; N, 25.63; Found C, 56.90; H, 5.30; N, 25.23.

Example 24

3-(2-Methyl-2H-tetrazol-5-yl)phenyl cyclopentylcarbamate (24). Compound 23 (123 mg, 0.45 mmol, 100 mol-%) in acetone (2.5 ml_) was cooled to 2 ⁰ C (Tbath)- Triethylamine (70 μL) was added followed by admission of MeI (160 mg, 1.1 mmol, 250 mol-%). After 2 hrs another portion of MeI (450 mg, 3.2 mmol, 700 mol-%) was added. The mixture was stirred for another 1 hrs at 2 ⁰ C and diluted with EtOAc (35 ml). The organic phase was washed with sat. NaHCO ₃ (2x10 ml_) and brine (10 ml_), dried over Na ₂ SO ₄ , filtered and evaporated resulting 100 mg (74%) of 4:1 mixture of 2- methylated and 1 -methylated tetrazoles. The isomers were separated by flash chromatography (0.5-1 % MeOH in CH ₂ CI ₂ ) and recrystallized (EtOAc:Hex) giving compound 24 as a white solid: mp 145-147 ⁰ C; Rf (3% MeOH in CH ₂ CI ₂ ) 0.7; ¹ H NMR (CDCI ₃ ) 7.97 (d, 1 H, J = 7.7 Hz), 7.91 (s, 1 H), 7.47 (t, 1 H, J = 7.9 Hz), 7.28-7.22 (m, 1 H), 5.05 (d, 1 H, J = 5.8 Hz), 4.39 (s, 3 H), 4.14-4.01 (m, 1 H), 2.10-1.98 (m, 2 H), 1.79-1.58 (m, 4 H), 1.56-1.46 (m, 2H); ¹³ C NMR (CDCI ₃ ) 164.6, 153.7, 151.5, 129.8, 128.5, 123.6, 123.5, 120.1 , 53.0, 39.5, 33.1 , 23.5; Anal, calcd for C ₁₄ H ₁₇ N ₅ O ₂ ; C, 58.52; H, 5.96; N, 24.37; Found C, 58.52; H, 5.85; N, 24.35.

Example 25 3-(2-Benzyl-2H-tetrazol-5-yl)phenyl cyclopentylcarbamate (25). Compound 23 (100 mg, 0.37 mmol, 100 mol-%) in acetone (2.5 ml_) was cooled to 2 ⁰ C (Tbath)- Triethylamine (60 μL) was added followed by admission of BnBr (50 μL, 0.41 mmol, 110 mol-%) and Kl (30 mg, 0.19 mmol- 50 mol-%). After 90 min the mixture was diluted with EtOAc (40 ml). The organic phase was washed with sat. NaHCO ₃ (2x10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , filtered and evaporated resulting 105 mg (78%) of 9:1 mixture of 2- benzylated and 1 -benzylated tetrazoles respectively. The isomers were separated by flash chromatography (CH ₂ CI ₂ ) and recrystallized (EtOAc:hex) giving compound 25 (81 mg, 60%) as a white solid: mp 129- 130 ⁰ C; Rf (3% MeOH in CH ₂ CI ₂ ) 0.9; ¹ H NMR (CDCI ₃ ) 7.97 (d, 1 H, J = 7.2 Hz), 7.90 (s, 1 H), 7.48-7.34 (m, 6 H), 7.26-7.20 (m, 1 H), 5.79 (s, 2 H),

5.02 (br s, 1 H), 4.11 -4.00 (m, 1 H), 2.08-1.96 (m, 2 H), 1.76-1.56 (m, 4 H), 1.54-1.46 (m, 2H); ¹³ C NMR (CDCI ₃ ) 164.8, 153.7, 151.4, 133.3, 129.8, 129.0, 128.9, 128.6, 128.3, 123.7, 123.6, 120.2, 56.8, 53.0, 33.1 , 23.5; Anal, calcd for C ₂₀ H ₂ IN ₅ O ₂ ; C, 66.10; H, 5.82; N, 19.27; Found C, 65.71 ; H, 5.85; N, 19.28.

Example 26

Methyl 3-(cyclopentylcarbamoyloxy)benzoate (26). This compound was synthesized and worked up as described for 1e using methyl 3- hydroxy benzoate (1.0 g, 6.6 mmol, 100 mol-%) and cyclopentyl isocyanate (900 μl_, 7.9 mmol, 120 mol-%) as starting materials. Purification by flash chromatography (30% EtOAc in hex) and recrystallization (EtOAc:hex) gave 26 (1.36 g, 79%) as colourless crystals: mp 112-114 ⁰ C; Rf (10% Et ₂ O in CH ₂ CI ₂ ) 0.5; ¹ H NMR (CDCI ₃ ) 7.85 (d ,1 H, J = 7.6 Hz), 7.78 (s, 1 H), 7.39 (t, 1 H, J = 7.9 Hz) 7.34-7.29 (m, 1 H), 5.53 (br d, 1 H, J = 7.0 Hz), 4.08- 3.97 (m, 1 H), 3.89 (s, 3 H), 2.01 -1.91 (m, 2 H), 1.72-1.40 (m, 6 H); ¹³ C NMR (CDCI ₃ ) 166.2, 153.6, 150.9, 131.1 , 128.9, 126.2, 126.0, 122.6, 52.8, 52.0, 32.7, 23.3; Anal, calcd for C ₁₄ H ₁₇ NO ₄ : C, 63.87; H, 6.51 ; N, 5.32; Found C, 63.96; H, 6.30; N, 5.39.

Example 27

Methyl 3-(cyclohexylcarbamoyloxy)benzoate (27). This compound was synthesized and worked up as described for 1e using methyl 3- hydroxy benzoate (230 mg, 1.5 mmol, 100 mol-%) and cyclohexyl isocy- anate (330 μl_, 2.6 mmol, 175 mol-%) as starting materials. Recrystallization (EtOAc:hex) gave 27 (400 mg, quant.) as white crystals: mp 131 -132 ⁰ C; ; Rf (10% Et ₂ O in CH ₂ CI ₂ ) 0.5; ¹ H NMR (CDCI ₃ ) 7.87 (d, 1 H, J = 7.7 Hz), 7.80 (t, 1 H, J = 1.9 Hz), 7.42 (t, 1 H, J = 7.9 Hz), 7.36-7.31 (m, 1 H), 4.95 (d, 1 H, J = 7.0 Hz), 3.91 (s, 3 H), 3.64-3.51 (m, 1 H), 2.07-1.98 (m, 2 H), 1.80-1.70 (m, 2 H), 1.67-1.60 (m, 1 H), 1.45-1.32 (m, 2 H), 1.29-1.17 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 166.3, 153.3, 151.0, 131.3, 129.1 , 126.3, 126.2,

122.7, 52.1 , 50.2, 33.1 , 25.3, 24.7; Anal, calcd for C ₁₅ H ₁₉ NO ₄ : C, 64.97; H, 6.91 ; N, 5.05; Found C, 65.32; H, 6.96; N, 5.19.

Example 28 3-Cyanophenyl cyclohexylcarbamate (28). This compound was synthesized and worked up as described for 1e using 3-cyanophenol (1.05 g, 8.9 mmol, 100 mol-%) and cyclohexyl isocyanate (4.6 ml_, 36 mmol, 400 mol- %) as reagents. Purification with flash chromatography (38 % EtOAc in hex) and recrystallization (EtOAc:hex) gave compound 28 (1.47 g, 68 %) as white needles: mp 117-120 ⁰ C; Rf 0.56 (50% EtOAc in hex); ¹ H NMR (CDCI ₃ ) 7.50-7.38 (m, 4 H), 4.98 (d, 1 H, J = 7.3), 3.61 -3.51 (m, 1 H), 2.05- 1.98 (m 2 H), 1.80-1.71 (m, 2 H), 1.68-1.60 (m, 1 H), 1.44-1.33 (m, 2 H), 1.29-1.15 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 152.6, 151.2, 130.1 , 128.8, 126.5, 125.3, 118.0, 113.2, 50.3, 33.1 , 25.3, 24.7; Anal, calcd for C ₁₄ H ₁₆ N ₂ O ₂ : C, 68.83; H, 6.60; N, 11.47; Found C, 68.89; H, 6.55; N, 11.36.

Example 29

3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenol (29a). This compound was synthesized in two different methods: Method 1 : 3-cyanophenol (237 mg, 2.0 mmol, 100 mol-%), 2-amino-2- methylpropanol (450 μl_, 4.0 mmol, 200 mol-%) and bismuth trifluoro- methylsulfonate (64.5 mg, 0.1 mmol, 5 mol-%) were placed in a 10 ml_ CEM ^® microwave pressure tube irradiated for three times. The resulting mixture was diluted with EtOAc and purified with flash chromatography (40% EtOAc in hex).

Method 2: 3-cyanophenol (237 mg, 2.0 mmol, 100 mol-%), 2-amino-2- methylpropanol (450 μl, 4.0 mmol, 200 mol-%) and bismuth thfluoromethyl- sulfonate (64.5 mg, 0.1 mmol, 5 mol-%) were placed in a 5 ml_ flask and refluxed for 3 hrs. Crops from both reactions were combined and recrystal- lized (toluene) giving 29a (190 mg, 25% overall yield). Correct compound

was determined by NMR and melting point analysis: mp 159-161 ⁰ C; Rf 0.28 (65 % EtOAc in hex).

3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl cyclopentylcarbamate (29b). This compound was synthesized and worked up as described for 1e using 29a (100 mg, 0.5 mmol, 100 mol-%) cyclopentyl isocyanate (290 μl_, 2.6 mmol, 500 mol-%) as starting materials. Purification with flash chromatography (10% Et ₂ O in CH ₂ CI ₂ ) and recrystallization (EtOAc:hex) gave 29b (73 mg, 48%) as white needles: mp 139-141 ⁰ C; Rf (10 % Et ₂ O in CH ₂ CI ₂ ) 0.27; ¹ H NMR (DMSO-c/ ₆ ) 7.76 (d, 1 H, J = 7.7 Hz), 7.70 (s, 1 H), 7.38 (dd, J = 7.9 Hz), 7.23 (d, 2 H, J = 8.1 Hz), 4.98 (d, 1 H, J = 6.4 Hz), 4.10 (s, 2 H), 4.07-4.00 (m, 1 H), 2.06-1.98 (m, 2 H), 1.76-1.69 (m, 2 H), 1.66-1.60 (m, 2 H), 1.53-1.44 (m, 2 H), 1.37 (s, 6 H); ¹³ C NMR (DMSO-c/ ₆ ) 161.3, 153.7, 150.9, 129.4, 129.1 , 125.0, 124.5, 121.6, 79.1 , 67.6, 53.0, 33.1 , 28.4, 23.5; Anal, calcd for C ₁₇ H ₂₂ N ₂ O ₃ ; C, 67.53; H, 7.33; N, 9.26; Found C, 67.35; H, 7.40; N, 9.38.

Example 30

(S)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenol (30a). Zinc chloride (48 mg, 0.35 mmol, 10 mol-%) was melted in a 50 ml_ two-neck flask under high vacuum. 3-Cyanophenol (413 mg, 3.46 mmol, 100 mol-%) and chloroben- zene (10 ml_) were added and heated up to reflux under argon atmosphere. (S)-2-Aminopropanol (510 μl_, 6.5 mmol, 190 mol-%) was added and the mixture was refluxed for 22 hours. The mixture was cooled to rt and filtered through a pad of silica with EtOAc and purified with flash chromatography (33% EtOAc in hex) and recrystallized (EtOAc:Hex) giving 30a (317 mg, 52%) as white needles: mp 125-126 ⁰ C; Rf (50 % EtOAc in hex) 0.31 ; [α] _D ²⁰ 3.82 (C= 0.5, CDCI ₃ ); ¹ H NMR (CDCI ₃ ) 9.45 (bs, 1 H), 7.45 (dd, 1 H, J = 2.3, 1.6 Hz), 7.30 (td, 1 H, J = 7.7, 1.3 Hz), 7.18 (t, 1 H, J = 7.9 Hz), 6.95 (ddd, 1 H, J = 8.1 , 2.5, 1.0 Hz), 4.53 (dd, 1 H, J = 9.4, 8.0 Hz), 4.45-4.36 (m, 1 H), 3.96 (t, 1 H, J = 7.9 Hz), 1.33 (d, 3 H, J = 6.6 Hz); ¹³ C NMR (CDCI ₃ ) 164.6,

156.9, 129.6, 128.0, 119.8, 119.5, 115.1 , 74.2, 61.2, 21.1 ; Anal, calcd for C ₁₀ H ₁₁ NO ₂ : C, 67.78; H, 6.26; N, 7.90; Found C, 67.88; H, 5.85; N, 7.72. (S)-3-(4-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclopentylcarbamate (30b). This compound was synthesized and worked up as described for 1e using 30a (100 mg, 0.56 mmol, 100 mol-%) and cyclopentyl isocyanate (300 μl_, 2.7 mmol, 470 mol-%) as starting materials. Purification with flash chromatography (50 % EtOAc in hex) and recrystallization (EtOAc:hex) gave 30b (83 mg, 51 %) as white crystals: mp 139-142 ⁰ C; Rf (15% Et ₂ O in CH ₂ CI ₂ ) 0.33; [α] _D ²⁰ -53.8 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.77 (d, 1 H, J = 7.7 Hz), 7.70 (s, 1 H), 7.38 (t, 1 H, J = 8.0 Hz), 7.24 (d, 1 H, J = 8.1 Hz), 5.04 (d, 1 H, J = 6.6 Hz), 4.51 (dd, 1 H, J = 9.3, 8.1 Hz), 4.41 -4.32 (m, 1 H), 4.09-4.00 (m, 1 H), 3.94 (t, 1 H, J = 7.9 Hz), 2.06-1.97 (m, 2 H), 1.75-1.56 (m, 4 H), 1.53-1.44 (m, 2 H), 1.35 (d, 3 H, J = 6.6 Hz); ¹³ C NMR (CDCI ₃ ) 162.7, 160.1 , 153.7, 151.0, 129.1 , 125.0, 124.6, 121.6, 74.1 , 62.0, 53.0 (rotam. 52.1 ), 33.1 (rotam. 33.6), 23.5, 21.4; Anal, calcd for C ₁₆ H ₂₀ N ₂ O ₃ : C, 66.65; H, 6.99; N, 9.72; Found C, 66.68; H, 7.15; N, 9.82.

Example 31

(S)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (31). This compound was synthesized and worked up as described for 30b using 30a (85 mg, 0.48 mmol, 100 mol-%) and cyclohexyl isocyanate (120 μl_, 0.94 mmol, 200 mol-%) as starting materials. Purification with flash chromatography (50% EtOAc in hex) and recrystallization (EtOAc:hex) gave 31 (94 mg, 65%) as white crystals: mp 133-135 ⁰ C; Rf (50% EtOAc in hex) 0.40; [α] _D ²⁰ -48.9 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.77 (d, 1 H, J = 7.7 Hz), 7.70 (s, 1 H), 7.38 (t, 1 H, J = 7.9 Hz), 7.26-7.23 (m, 1 H), 4.92 (d, 1 H, J = 7.3 Hz), 4.51 (dd, 1 H, J = 9.2, 8.2 Hz), 4.42-4.32 (m, 1 H), 3.94 (t, 1 H, J = 7.9 Hz), 3.61 -3.51 (m, 1 H), 2.05-1.97 (m, 2 H), 1.78-1.70 (m, 2 H), 1.66-1.59 (m, 1 H), 1.43-1.32 (m, 2 H), 1.35 (d, 3 H, J = 6.6 Hz), 1.28-1.15 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 162.8, 153.4, 151.0, 129.1 (2C), 125.0, 124.6,

121.6, 74.1 , 62.0, 50.1 , 33.2, 25.4, 24.7, 21.4; Anal, calcd for C ₁₇ H ₂₂ N ₂ O ₃ : C, 67.53; H, 7.33; N, 9.26; Found C, 67.77; H, 7.26; N, 9.09.

Example 32 (R)-3-(4-methyl-4,5-dihydrooxazol-2-yl)phenol (32a). This compound was synthesized and worked up as described for 30a using (R)-2-amino-1 - propanol (440 μl_, 5.6 mmol, 200 mol-%) as starting material. Purification with flash chromatography (40% EtOAc in hex) and recrystallization (EtOAc:hex) gave 32a (283 mg, 57%) as white needles: mp 126-127 ⁰ C; Rf (50% EtOAc in hex) 0.19; [α] _D ²⁰ -45.6 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 9.46 (bs, 1 H), 7.44 (dd, 1 H, J = 2.4, 1.6 Hz), 7.29 (td, 1 H, J = 7.7, 1.3 Hz), 7.18 (t, 1 H, J = 7.9 Hz), 6.95 (ddd, 1 H, J = 8.1 , 2.6, 1.0 Hz), 4.53 (dd, 1 H, J = 9.5, 8.1 Hz), 4.45-4.36 (m, 1 H), 3.96 (t, 1 H, J = 7.9 Hz), 1.33 (d, 3 H, J =

6.6 Hz); ¹³ C NMR (CDCI ₃ ) 164.5, 156.9, 129.6, 127.9, 119.8, 119.5, 115.0, 74.2, 61.1 , 21.1 ; Anal, calcd for C ₁₀ H ₁₁ NO ₂ : C, 67.78; H, 6.26; N, 7.90;

Found C, 67.89; H, 6.10; N, 7.90.

(R)-3-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (32b). This compound was synthesized and worked up as described for 31 using 32a (100 mg, 0.56 mmol, 100 mol-%) and cyclohexyl isocyanate (150 μl_, 1.2 mmol, 210 mol-%) as starting materials. Purification with flash chromatography (50% EtOAc in hex) and recrystallization (EtOAc:hex) gave 32b (46 mg, 27%) as white crystals: mp 133-134 ⁰ C; Rf (50% EtOAc in hex) 0.24; [α] _D ²⁰ 44.6 (c= 0.5, CDCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.77 (d, 1 H, J =

7.7 Hz), 7.70 (m, 1 H), 7.38 (t, 1 H, J = 7.9 Hz), 7.24 (dd, 1 H, J = 8.1 , 1.4 Hz), 4.94 (d, 1 H, J = 7.4 Hz), 4.51 (dd, 1 H, J = 9.3, 8.1 Hz), 4.42-4.32 (m,

1 H), 3.94 (t, 1 H, J = 7.9 Hz), 3.60-3.50 (m, 1 H), 2.07-1.96 (m, 2 H), 1.78- 1.70 (m, 2 H), 1.66-1.57 (m, 1 H), 1.43-1.32 (m, 2 H), 1.35 (d, 3 H, J = 6.6 Hz), 1.27-1.15 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 162.8, 153.4, 151.0, 129.1 (2C), 124.9, 124.6, 121.6, 74.1 , 62.0, 50.1 , 33.2, 25.4, 24.7, 21.4; Anal, calcd for C ₁₇ H ₂₂ N ₂ O ₃ : C, 67.53; H, 7.33, N, 9.26; Found C, 67.63; H, 7.33; N, 9.17.

Example 33

(S)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenol (33a). This compound was synthesized and worked up as described for 30a using (S)-2-amino-3- phenyl-1 -propanol (970 mg, 6.41 mmol, 190 mol-%) as starting material. Purification with flash chromatography (40 % EtOAc in hex) and recrystalli- zation (EtOAc:hex) gave 33a (446 mg, 52%) as a white waxy solid: mp 109- 111 ⁰ C; Rf (10 % Et ₂ O in CH ₂ CI ₂ ) 0.14; [α] _D ²⁰ 38.5 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.92 (s, 1 H), 7.50 (dd, 1 H ₁ J = 2.4, 1.5 Hz), 7.39 (td, 1 H, J = 7.7, 1.2 Hz), 7.30-7.18 (m, 6 H), 6.98 (ddd, 1 H, J = 8.1 , 2.6, 1.0 Hz), 4.65-4.57 (m, 1 H), 4.35 (t, 1 H, J = 9.0 Hz), 4.17 (dd, 1 H, J = 8.6, 7.2 Hz), 3.23 (dd, 1 H, J = 13.7, 4.9 Hz), 2.75 (dd, 1 H, J = 13.7, 9.0 Hz); ¹³ C NMR (CDCI ₃ ) 164.8, 156.4, 137.6, 129.7, 129.3, 128.6, 128.3, 126.6, 120.2, 119.4, 115.2, 72.0, 67.2, 41.5; Anal, calcd for C ₁₆ H ₁₅ NO ₂ : C, 75.87; H, 5.97; N, 5.53; Found C, 75.79; H, 5.74; N, 5.50. (S)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (33b). This compound was synthesized and worked up as described for 31 using 33a (143 mg, 0.57 mmol, 100 mol-%) as starting material. Purification with flash chromatography (30% EtOAc in hex) and recrystallization (EtOAc:hex) gave 33b (120 mg, 56%) as white crystals: mp 152-155 ⁰ C; Rf 0.46 (10% Et ₂ O in CH ₂ CI ₂ ); [α] _D ²⁰ 5.8 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI3) 7.78 (d, 1 H, J = 7.8), 7.70 (t, 1 H, J = 1.8 Hz), 7.39 (t, 1 H, J = 8.0 Hz), 7.33-7.21 (m, 6 H), 4.93 (d, 1 H, J = 7.6 Hz), 4.62-4.54 (m, 1 H), 4.34 (t, 1 H, J = 8.9 Hz), 4.13 (dd, 1 H, J = 8.3, 7.5 Hz), 3.61 -3.51 (m, 1 H), 3.23 (dd, 1 H, J = 13.7, 5.1 Hz), 2.72 (dd, 1 H, J = 13.7, 8.9 Hz), 2.05-1.97 (m, 2 H), 1.78-1.70 (m, 2 H), 1.66-1.61 (m, 1 H), 1.43-1.32 (m, 2 H), 1.28-1.14 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 163.3, 153.3, 151.0, 137.9, 129.2, 129.2, 129.0, 128.6, 126.5, 125.0, 124.7, 121.6, 71.9, 67.9, 50.2, 41.8, 33.2, 25.4, 24.7; Anal, calcd for C ₂₃ H ₂₆ N ₂ O ₃ : C, 72.99; H, 6.92; N, 7.40; Found C, 73.17; H, 6.70; N, 7.37.

Example 34

(/?)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenol (34a). This compound was synthesized and worked up as described for 30a using (R)-2-amino-3- phenyl-1 -propanol (768 mg, 5.08 mmol, 200 mol-%) as starting material. Purification with flash chromatography (33% EtOAc in hex) and recrystalli- zation (EtOAc:hex) gave 34a (267 mg, 41 %) as a white waxy solid: mp 108- 111 ⁰ C; Rf 0.21 (15% Et ₂ O in CH ₂ CI ₂ ); [α] _D ²⁰ -40.0 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 8.50 (bs, 1 H), 7.50 (dd, 1 H ₁ J = 2.3, 1.5 Hz), 7.36 (td, 1 H, J = 7.7, 1.1 Hz), 7.29-7.18 (m, 6 H), 6.97 (ddd, 1 H J = 8.2, 2.5, 0.9 Hz), 4.66-4.57 (m, 1 H), 4.34 (t, 1 H J = 9.0 Hz), 4.17 (dd, 1 H, J= 8.5, 7.3 Hz), 3.24 (dd, 1 H, J= 13.7, 4.8 Hz), 2.75 (dd, 1 H, J = 13.7, 9.2 Hz); ¹³ C NMR (CDCI ₃ ) 165.0, 156.6, 137.5, 129.7, 129.3, 128.6, 128.2, 126.6, 120.1 , 119.5, 115.2, 72.0, 67.0, 41.4; Anal, calcd for C ₁₆ H ₁₅ NO ₂ : C, 75.87; H, 5.97; N, 5.53; Found C, 75.96; H, 5.71 ; N, 5.25. (R)-3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (34b). This compound was synthesized and worked up as described for 31 using 34a (178 mg, 0.70 mmol, 100 mol-%) as starting material. Purification with flash chromatography (10% Et ₂ O in CH ₂ CI ₂ ) and recrystallization (EtOAc:hex) gave 34b (152 mg, 57%) as white crystals: mp 153-155 ⁰ C; Rf 0.38 (13% Et ₂ O in CH ₂ CI ₂ ); [α] _D ²⁰ -7.4 (c= 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.78 (d, 1 H, J = 7.7 Hz), 7.7 (m, 1 H), 7.39 (t, 1 H, J = 8.0 Hz), 7.33-7.20 (m, 6 H), 4.93 (d, 1 H, J = 8.0 Hz), 4.62-4.53 (m, 1 H), 4.33 (t, 1 H, J = 8.9 Hz), 4.13 (dd, 1 H, J = 8.3, 7.5 Hz), 3.62-3.50 (m, 1 H), 3.23 (dd, 1 H, J = 13.7, 5.1 Hz), 2.71 (dd, 1 H, J = 13.7, 8.9 Hz), 2.05-1.97 (m, 2 H), 1.77-1.70 (m, 2 H), 1.66-1.58 (m, 1 H), 1.43-1.32 (m, 2 H), 1.28-1.14 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 163.3, 153.3, 151.0, 137.9, 129.2, 129.2, 129.0, 128.5, 126.5, 125.0, 124.7, 121.6, 71.9, 67.9, 50.1 , 41.8, 33.2, 25.4, 24.7; Anal, calcd for C ₂₃ H ₂₆ N ₂ O ₃ : C, 72.99; H, 6.92; N, 7.40; Found C, 73.09; H, 7.09; N, 7.44.

Example 35 (S)-3-(4-((1H-lndol-3-yl)methyl)-4,5-dihydrooxazol-2-yl)phen ol (35a).

This compound was synthesized and worked up as described for 30a using

(S)-tryptophanol (326 mg, 1.71 mmol, 120 mol-%) as starting material. Re- crystallization (EtOAc:hex) gave 35a (140 mg, 35%) as a gray powder: mp 183-186 ⁰ C; Rf (50% EtOAc in hex) 0.20; [α] _D ²⁰ 58.7 (c = 0.3, MeOH); ¹ H NMR (DMSO-c/e) 10.85 (bs, 1 H), 9.68 (s, 1 H), 7.59 (d, 1 H, J = 7.9 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.31 -7.19 (m, 4 H), 7.06 (td, 1 H, J = 7.5, 1.1 Hz), 6.98 (td, 1 H, J = 7.4, 1.0 Hz), 6.93-6.89 (m, 1 H), 4.64-4.55 (m, 1 H), 4.38 (dd, 1 H, J = 9.4, 8.4 Hz), 4.07 (t, 1 H, J = 7.9 Hz), 3.13 (dd, 1 H, J = 14.8, 4.9 Hz), 2.82 (dd, 1 H, J = 14.6, 8.1 Hz); ¹³ C NMR (DMSO-c/ ₆ ) 162.1 , 157.3, 136.1 , 129.6, 128.8, 127.5, 123.4, 120.9, 118.5, 118.5, 118.4, 118.3, 114.4, 111.3, 110.4, 71.7, 66.6, 31.0; Anal, calcd for C ₁₈ H ₁₆ N ₂ O ₂ : C, 73.95; H, 5.52; N, 9.58; Found C, 73.60; H, 5.43; N, 9.39.

(S)-3-(4-((1H-lndol-3-yl)methyl)-4,5-dihydrooxazol-2-yl)phen yl cyclo- hexylcarbamate (35b). This compound was synthesized and worked up as described for 31 using 35a (crude, 70 mg, 0.24 mmol, 100 mol-%) as start- ing material. Flash chromatography (10% Et ₂ O in CH ₂ CI ₂ ) and recrystalliza- tion (EtOAc: hex) gave 35b (35 mg, 35%) as white crystals: mp 149-151 ⁰ C; Rf 0.23 (10% Et ₂ O in CH ₂ CI ₂ ); [α] _D ²⁰ 21.9 (c = 0.5, CDCI ₃ ); ¹ H NMR (CDCI ₃ ) 8.11 (bs, 1 H), 7.79 (d, 1 H, J = 7.8 Hz), 7.72 (s, 1 H), 7.66 (d, 1 H, J = 7.8 Hz), 7.41 -7.33 (m, 2 H), 7.20 (td, 1 H, J = 7.5, 1.1 Hz), 7.13 (td, 1 H, J = 7.4, 1.0 Hz), 7.28-7.24 (m, 1 H), 7.04 (d, 1 H, J = 2.2 Hz), 4.94 (d, 1 H, J = 7.8 Hz), 4.75-4.67 (m, 1 H), 4.33 (t, 1 H, J = 8.9 Hz), 4.15 (t, 1 H, J = 7.9 Hz), 3.62-3.51 (m, 1 H), 3.36 (dd, 1 H, J = 14.5, 4.6 Hz), 2.88 (dd, 1 H, J = 14.6, 8.9 Hz), 2.05-1.97 (m, 2 H), 1.78-1.70 (m, 2 H), 1.67-1.58 (m, 1 H), 1.43-1.32 (m, 2 H), 1.28-1.14 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 163.2, 153.4, 151.0, 136.2, 129.2 (2C), 127.7, 125.0, 124.6, 122.4, 122.1 , 121.6, 119.5, 118.8, 112.0, 111.1 , 72.3, 67.0, 50.2, 33.2, 31.3, 25.4, 24.7; Anal, calcd for C ₂₅ H ₂₇ N ₃ O ₃ : C, 71.92; H, 6.52; N, 10.06; Found C, 71.58; H, 6.32; N, 10.05.

Example 36 (£)-ethyl 2-(1-(3-hydroxyphenyl)ethylidene)hydrazinecarboxylate (36a).

A mixture of 3 ^' -hydroxyacetophenone (4.09 g, 30 mmol, 1 equiv.), ethyl

carbazate (3.28 g, 31.5 mmol, 1.05 equiv.) and p-TsOH (280 mg, 1.5 mmol, 0.05 equiv.) in dry toluene (100 ml_) was refluxed overnight under Dean- Stark conditions. Evaporation of solvent under reduced pressure gave crude product, which was washed with diethyl ether to remove excess reac- tants giving 4.63 g (69 %) of the title compound as pale brown solid. ¹ H NMR (DMSO-de, 500.1 MHz) 10.08 (bs, 1 H), 7.26-7.14 (m, 3H), 6.80 (ddd, J = 7.9, 2.4, 0.9 Hz), 4.20 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm; ¹³ C NMR (DMSO-d ₆ , 125.1 MHz) 158.1 , 155.1 , 140.6, 130.1 , 126.4, 118.0, 116.9, 113.5, 61.4, 15.5, 14.8 ppm; MS (ES ⁺ ) calcd. for C ₁₁ H ₁₄ N ₂ O ₃ 222.25, found: [M + H] ⁺ 223.25.

3-(1,2,3-Thiadiazol-4-yl)phenol (36b). Hydrazone 36a (3.5 g, 15.7 mmol, 1 equiv.) was stirred overnight with an excess amount of thionyl chloride (35 ml_, 30 equiv.) at room temperature. The remaining thionyl chloride was evaporated under reduced pressure. The reaction crude was filtered trough a plug of silica (PE/EtOAc 1 :1 ) and then recrystallized from CHCI ₃ giving 2.0 g (71 %) of product as pale yellow solid. ¹ H NMR (DMSO-d ₆ , 500.1 MHz) 9.76 (bs, 1 H), 9.59 (s, 1 H), 7.60-7.57 (m, 2H), 7.38 (dd, J = 7.9, 7.9 Hz, 1 H) ppm; ¹³ C NMR (DMSO-d ₆ , 125.1 MHz): 162.9, 158.9, 134.0, 132.8, 131.3, 118.9, 117.3, 114.8 ppm; Anal, calcd for C ₈ H ₆ N ₂ O ₁ S: C, 53.92; H, 3.39; N, 15.72; found: C, 53.45; H, 3.42; N, 15.41 ; MS (ES ⁺ ) calcd. for C ₈ H ₆ N ₂ OS 178.21 , found: [M + H] ⁺ 179.28.

3-(1,2,3-Thiadiazol-4-yl)phenyl cyclohexylcarbamate (36c). To a mixture of 3-(1 ,2,3-thiadiazol-4-yl)phenol (36b, 178.21 mg, 1 mmol) in dry toluene (3 ml_) was added cyclohexyl isocyanate (140 μl_, 1.1 mmol, 1.1 equiv.). The reaction mixture was gently refluxed over night and monitored by TLC. After refluxing the reactants 5 h, a further amount of isocyanate (0.5 equiv.) was added. The reaction mixture was cooled and solvent evaporated. Purification by recrystallization (EtOAc/Hex 1 :2) gave the product as pale crystals (200 mg, 66 %). Mp. 137.6-138.8 ⁰ C; 1 H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.83 (s, 1 H), 7.49 (pt, J = 8.1 Hz, 7.9 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 4.97 (d, J = 7.3, 1 H), 3.62-3.55 (m, 1 H),

2.05-2.02 (m, 2H), 1.75 (dt, J = 13.5, 3.9 Hz, 2H), 1.66-1.17 (m, 6H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.0, 153.4, 151.7, 132.0, 130.5, 130.0, 124.1 , 122.6, 120.7, 50.2, 33.2, 25.4, 24.7 ppm; Anal, calcd for C ₁₅ H ₁₇ N ₃ O ₂ S: C, 59.39; H, 5.65; N, 13.85; found: C, 59.18; H, 5.73; N, 13.53; MS (ES ⁺ ) calcd. for C ₁₅ H ₁₇ N ₃ O ₂ S 303.39, found: [M + H] ⁺ 304.18.

Example 37

3-(1,2,3-Thiadiazol-4-yl)phenyl cyclopentylcarbamate (37). This compound was prepared according to the method described above for 36c. Pu- rification by recrystallization (EtOAC/Hex 1 :2) gave the product as white crystals (210 mg, 73 %). Mp. 141.2-142.2 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.83 (s, 1 H), 7.49 (pt, J = 8.1 , 7.9 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 5.04 (d, J = 6.2 Hz, 1 H), 4.08 (m, 1 H), 2..07- 2.01 (m, 2H), 1.76-1.72 (m, 2H), 1.68-1.63 (m, 2H), 1.55-1.48 (m, 2H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.0, 153.7, 151.7, 131.9, 130.5, 130.0, 124.1 , 122.7, 120.7, 53.0, 33.1 , 23.5 ppm; Anal, calcd for C ₁₄ H ₁₅ N ₃ O ₂ S: C, 58.11 ; H, 5.23; N, 14.52; found: C, 57.76; H, 5.27; N, 14.24; MS (ES ⁺ ) calcd. for C ₁₄ H ₁₅ N ₃ O ₂ S 289.36, found: [M + H] ⁺ 290.42.

Example 38

3-(1,2,3-Thiadiazol-4-yl)phenyl butylcarbamate (38). This compound was prepared according to the method described above for 36c. Purification by recrystallization (EtOAc/Hex 1 :2) gave the product as pale brown crystals (244 mg, 81 %). Mp. 101.6-102.9 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.83 (s, 1 H), 7.49 (pt, J = 8.1 , 7.9 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 5.07 (s, 1 H), 3.32-3.28 (m, 2H), 1.61 -1.55 (m, 2H), 1.45-1.38 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.0, 154.3, 151.6, 131.9, 130.6, 130.0, 124.1 , 122.6, 120.6, 41.0, 31.8, 19.8, 13.7 ppm; Anal, calcd for C ₁₃ H ₁₅ N ₃ O ₂ S: C, 56.30; H, 5.45; N, 15.15; found: C, 55.95; H, 5.46; N, 15.14.

Example 39

3-(1,2,3-Thiadiazol-4-yl)phenyl benzylcarbamate (39). This compound was prepared according to the method described above for 36c. Purification by flash chromatography (EtOAc/PE 1 :4) gave the product as white solid (263 mg, 84 %). Mp. 109.0-109.6 ⁰ C; ¹ H NMR (CDCI ₃ , 500. 1 MHz) 8.66 (s, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 7.86 (s, 1 H), 7.51 (pt, J = 8.0 Hz, 1 H), 7.40-7.32 (m, 6H), 5.40 (s, 1 H), 4.49 (d, J = 6.0 Hz, 2H) ppm; ¹³ C NMR (CDCI ₃ , 125. 1 MHz) 161.9, 154.4, 151.6, 137.8, 132.0, 130.6, 130.0, 128.7, 127.69, 127.65, 124.2, 122.6, 120.6, 45.3 ppm; Anal, calcd for C ₁₆ H ₁₃ N ₃ O ₂ S: C, 61.72; H, 4.21 ; N, 13.50; found: C, 61.58; H, 4.32; N, 12.95; MS (ES ⁺ ) calcd for C ₁₆ H ₁₃ N ₃ O ₂ S 311.36, found: [M + H] ⁺ 312.33.

Example 40

3-(1,2,3-Thiadiazol-4-yl)phenyl phenylcarbamate (40). This compound was prepared according to the method described above for 36c. Purification by flash chromatography (EtOAc/PE 1 :4) and recrystallization (EtOAc/Hex 1 :3) gave the product as white crystals (130 mg, 44 %). Mp. 155.4-156.0 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.66 (s, 1 H), 7.94-7.90 (m, 2H), 7.53 (pt, J = 8.0 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 (pt, J = , 2H), 7.30-7.28 (m, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.07 (s, 1 H) ppm; ¹³ C NMR (CDCI ₃ , 125 MHz); Anal, calcd for C ₁₅ H ₁₁ N ₃ O ₂ S: C, 60.59; H, 3.73; N, 14.13. Found: C, 61.65; H, 3.95; N, 13.76.

Example 41 3-(1,2,3-Thiadiazol-4-yl)phenyl isopropylcarbamate (41). To a mixture of 3-(1 ,2,3-thiadiazol-4-yl)phenol (36b, 89.1 mg, 0.5 mmol) and triethyl amine (0.42 μl_, 0.06 equiv.) in toluene (2 ml_) was added isopropyl isocyanate (54 μl_, 1.1 mmol, 1.1 equiv.). The reaction mixture was stirred at 80 ⁰ C until phenol could not be detected on TLC. The reaction mixture was cooled and solvent evaporated. Purification by flash chromatography (EtOAc/PE 1 :1 ) and recrystallization (EtOAc/Hex 1 :2) gave the product as white crys-

tals (87.6 mg, 67 %). Mp. 130.4-131.4 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.48 (pt, J = 8.1 , 7.9 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 4.96 (d, J = 5.7 Hz, 1 H), 3.90 (m, 1 H), 1.25 (d, J = 6.6 Hz, 6H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.1 , 153.4, 151.7, 132.0, 130.5, 130.0, 124.1 , 122.7, 120.7, 43.5, 22.9 ppm; Anal, calcd for C ₁₂ H ₁₃ N ₃ O ₂ S: C, 54.56; H, 4.96; N, 15.91 ; found: C, 54.12; H, 4.96; N, 15.82; MS (ES ⁺ ) calcd for C ₁₂ H ₁₃ N ₃ O ₂ S 263.32, found: [M + H] ⁺ 264.26.

Example 42 3-(1,2,3-Thiadiazol-4-yl)phenyl dodecylcarbamate (42). This compound was prepared according to the method described above for 41 , but in 0.28 mmol scale. Purification by flash chromatography (EtOAc/PE 1 :3) and re- crystallization (EtOAc/Hex 1 :2) gave the product as white crystals (98.8 mg, 90 %). Mp. 106.4-107.4 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.83 (s, 1 H), 7.50 (pt, J = 8.1 , 7.8 Hz , 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 5.06 (s, 1 H), 3.29 (dt, J = 6.7, 6.7 Hz , 2H), 1.62-1.59 (m, 2H), 1.37-1.27 (m, 20H), 0.88 (t, J = 6.7 Hz , 3H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.1 , 154.3, 151.7, 132.0, 130.4, 130.1 , 124.2, 122.7, 120.7, 41.4, 31.9, 29.8, 29.62, 29.58, 29.5, 29.3, 29.3, 26.8, 22.7, 14.1 ppm; Anal, calcd for C ₂₁ H ₃₁ N ₃ O ₂ S: C, 64.75; H, 8.02; N, 10.79; found: C, 64.67; H, 8.26; N, 10.75; MS (ES ⁺ ) calcd for C ₂₁ H ₃₁ N ₃ O ₂ S 389.56, found: [M + H] ⁺ 390.28.

Example 43

3-(1,2,3-Thiadiazol-4-yl)phenyl hexylcarbamate (43). This compound was prepared according to the method described above for 41 , but in 1.0 mmol scale. Purification by flash chromatography (EtOAc/PE 1 :2) gave the product as white solid (284 mg, 93 %). Mp. 100.8-101.3 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.65 (s, 1 H), 7.89 (d, J = 7.7 Hz, 1 H), 7.83 (s, 1 H), 7.49 (pt, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 5.07 (s, 1 H), 3.31 -3.27 (m, 2H), 1.62-1.30 (m, 8H), 0.91 (t, J = 6.7 Hz, 3H) ppm. ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.1 , 154.3, 151.7, 132.0, 130.4, 130.1 , 124.2, 122.7, 120.7,

41.4, 31.4, 29.8, 26.4, 22.5, 14.0 ppm. Anal, calcd for C ₁₅ H ₁₉ N ₃ O ₂ S: C, ; H, 8.02; N, 10.79. Found: C, 64.67; H, 8.26; N, 10.75

Example 44 3-(1,2,3-Thiadiazol-4-yl)phenyl (4-phenyl-butyl)carbamate (44). This compound was prepared according to the method described above for 41 , but in 1.0 mmol scale. Purification by flash chromatography (EtOAc/PE 1 :1 ) gave the product as white solid (294 mg, 83 %). Mp. 112.2-113.2 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 8.64 (s, 1 H), 7.89 (d, J = 7.7 Hz, 1 H), 7.82 (s, 1 H), 7.49 (pt, J = 8.0 Hz, 1 H), 7.31 -7.28 (m, 2H), 7.23-7.19 (m, 4H), 5.1 (s, 1 H), 3.32 (dt, J = 6.6, 6.6 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 1.76-1.61 (m, 4H) ppm. ¹³ C NMR (CDCI ₃ , 125.1 MHz) 162.0, 154.3, 151.7, 142.0, 132.0, 130.4, 128.38, 128.37, 125.9, 124.2, 122.6, 120.7, 41.1 , 35.4, 29.4, 28.5 ppm. Anal, calcd for C ₁₉ H ₁₉ N ₃ O ₂ S: C, 58.99; H, 6.27; N, 13.76; found: C, 58.84; H, 6.27; N, 13.87.

Example 45

3-(2-Methoxyethoxymethoxy)-benzonitrile (45a). To an ice cold mixture of 3-cyanophenol (1.79 g, 15 mmol, 1 equiv.) and triethyl amine (2.7 ml_, 19.5 mmol, 1.3 equiv.) in dry THF (60 ml_) was added dropwise meth- oxyethoxymethyl chloride (2.7 ml_, 24.0 mmol, 1.6 equiv.) under argon atmosphere. The mixture was allowed to cool to room temperature and then refluxed overnight. The mixture was poured to ethyl acetate, washed with water and brine and dried (Na ₂ SO ₄ ). Evaporation of solvent under reduced pressure gave 2.74 g (88%) of the product as white solid. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.39-7.34 (m, 2H), 7.30-7.27 (m, 2H), 5.28 (s, 2H), 3.83-3.81 (m, 2H), 3.56-3.54 (m, 2H), 3.37 (s, 3H) ppm.

N-Hydroxy-3-(2-methoxy-ethoxymethoxy)-benzamidine (45b). A mixture of MEM-protected 3-cyanophenol 45a (2.74 g, 13.0 mmol, 1 equiv.), hydro- xylamine hydrochloride (1.36 g, 19.5 mmol, 1.5 equiv.) and triethyl amine (2.7 ml_, 19.5 mmol, 1.5 equiv.) in EtOH was stirred overnight at room tern-

perature. The solvent was evaporated under reduced pressure and the reaction crude was dissolved in EtOAc/CH ₂ CI ₂ mixture. The organic phase was washed with brine and dried over anhydrous Na ₂ SO ₄ . Evaporation of solvent gave the crude product, which was purified by flash chromatogra- phy (PE/EtOAc 1 :1 ) giving 2.4 g (77%) of the pure product as viscous liquid. ¹ H NMR (DMSO-de, 500.1 MHz) 9.67 (s, 1 H), 7.37-7.30 (m, 3H), 7.06 (d, J = 7.5 Hz, 2H), 5.81 (s, 2H), 5.30 (s, 2H), 3.77-3.75 (m, 2H), 3.52-3.49 (m, 2H), 3.00 (s, 3H) ppm. N-Acetoxy-3-(2-methoxy-ethoxymethoxy)-benzamidine (45c). To an ice cold solution of 45b (673 mg, 2.8 mmol, 1 equiv.) and triethyl amine (0.5 ml_, 3.6 mmol, 1.3 equiv.) in CHCI ₃ was added dropwise acetyl chloride (0.2 ml_, 2.8 mmol, 1 equiv.). The solution was stirred at room temperature for 1 h and then washed with brine, dried (Na ₂ SO ₄ ) and solvent evaporated. Purification by flash chromatography (PE/EtOAc 1 :2) gave 0.42 g (54%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.37-7.31 (m, 3H), 7.18-7.15 (m, 1 H), 5.28 (s, 2H), 5.24 (bs, 2H), 3.83-3.81 (m, 2H), 3.56-3.54 (m, 2H) 3.36 (s, 3H), 2.25 (s, 3H) ppm.

3-[3-(2-Methoxyethoxymethoxy)-phenyl]-5-methyl-1,2,4-oxadiaz ole (45d). Acetylated amidoxime 45c (420 mg, 1.5 mmol, 1 equiv.) was dis- solved in dry THF (5 ml_) and solution of TBAF (47.3 mg, 0.15 mmol, 0.1 equiv.) in THF was added dropwise under argon atmosphere. The reaction was stirred at rt for 3 hours and then poured into ethyl acetate and washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ) and evaporated giving 396 mg (100%) of the title compound as yellowish liquid. The prod- uct was used as such for the preparation of 45e. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.73 (s, 1 H), 7.70 (d, J = 7.7 Hz, 1 H), 7.39 (pt, J = 7.9 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 5.33 (s, 2H), 3.86-3.84 (m, 2H), 3.58-3.56 (m, 2H), 3.37 (s, 3H), 2.65 (s, 3H) ppm. 3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenol (45e). The compound 45d (396 mg, 1.5 mmol, 1 equiv.) in CH ₂ CI ₂ (6 ml_) was treated with anhydrous ZnBr ₂ (1.69 g, 7.5 mmol, 5 equiv.), and the mixture was stirred overnight at room

temperature. The solvent was decanted and the solid washed with 1 :1 mixture EtOAc/CH ₂ CI ₂ . The combined organic phases were washed with sat. NaHCO ₃ , brine and water, and dried with anhydrous Na ₂ SO ₄ . Evaporation of solvent gave the crude product, which was purified by recrystallization giving 130.2 mg (49%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.63 (d, J = 7.7 Hz, 1 H), 7.55 (s, 1 H), 7.35 (pt, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 2.66 (s, 3H) ppm.

3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl cyclohexylcarbamate (45f). To a mixture of 3-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenol (45e, 44.0 mg, 0.25 mmol, 1 equiv.) and thethyl amine (catalytic amount, 1 small drop) in dry toluene (2 ml_) was added cyclohexyl isocyanate (60 μl_, 0.5 mmol, 2 equiv.). The reaction mixture was gently refluxed for 2.5 hours. The reaction mixture was cooled and solvent evaporated. Purification by flash chromatography (EtOAc/Pe 1 :2) gave the product as pale crystals (67.0 mg, 89 %). Mp. 169.2-170.0 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.89 (d, J = 7.6 Hz, 1 H), 7.83 (s, 1 H), 7.45 (pt, J = 7.8 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 4.99 (s, 1 H), 3.57 (m, 1 H), 2.64 (s, 3H), 2.02-2.00 (m, 2H), 1.75-1.73 (m, 2H), 1.63- 1.61 (m, 1 H), 1.42-1.16 (m, 5H); ¹³ C NMR (CDCI ₃ , 125.1 MHz) 176.6, 167.8, 153.3, 151.4, 129.7, 128.0, 124.5, 124.0, 120.7, 50.2, 33.2, 25.4, 24.7, 12.3 ppm; Anal, calcd for Ci ₆ H ₁₉ N ₃ O ₃ : C, 63.77; H, 4.36; N, 13.94; found: C, 63.21 ; H, 6.49; N, 13.53.

Example 46 N-Cyclopentylpropionyloxy-3-(2-methoxy-ethoxymethoxy)- benzamidine (46a). To an ice cold solution of 45b (563 mg, 2.3 mmol, 1 equiv.) and triethyl amine (0.4 ml_, 3.0 mmol, 1.3 equiv.) in CHCI ₃ (20 ml_) was added dropwise cyclopentylpropionyl chloride (0.4 ml_, 2.3 mmol, 1 equiv.). The solution was stirred at room temperature for 1 h and then washed with brine, dried (Na ₂ SO ₄ ) and solvent evaporated. Purification by flash chromatography (PE/EtOAc 1 :2) gave 247 mg (30%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.37-7.31 (m, 3H), 7.18-7.15 (m, 1 H),

5.30 (s, 2H), 5.13 (bs, 2H), 3.83-3.81 (m, 2H), 3.57-3.55 (m, 2H) 3.37 (s, 3H), 2.52 (t, J = 7.7 Hz, 2H), 1.88-1.50 (m, 9H), 1.17-1.10 (m, 2H) ppm. 3-[3-(2-Methoxyethoxymethoxy)-phenyl]-5-(2-cyclopentyl-ethyl )-1,2,4- oxadiazole (46b). Acetylated amidoxime 46a (247 mg, 0.7 mmol, 1 equiv.) was dissolved in dry THF (2 ml_) and solution of TBAF (22 mg, 0.7 mmol, 1 equiv.) in THF was added dropwise under argon atmosphere. The reaction was stirred overnight at room temperature and then poured into ethyl acetate and washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ) and evaporated giving 191 mg (86%) of the title compound as viscous liquid. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.74-7.70 (m, 2H), 7.38 (pt, J = 8.1 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1 H), 5.33 (s, 2H), 3.85-3.83 (m, 2H), 3.58- 3.56 (m, 2H), 3.37 (s, 3H), 2.95 (t, J = 7.6 Hz, 2H), 1.86-1.15 (m, 11 H) ppm. S-^-^-cyclopentyl-ethylJ-i^^-oxadiazol-S-yOphenol (46c). The compound 46b (191 mg, 0.6 mmol, 1 equiv.) in CH ₂ CI ₂ (2 ml_) was treated with anhydrous ZnBr ₂ (631 mg, 2.8 mmol, 5 equiv.), and the mixture was stirred overnight at room temperature. The solvent was decanted and the solid washed with 1 :1 mixture EtOAc/CH ₂ CI ₂ . The combined organic phases were washed with sat. NaHCO ₃ , brine and water, and dried with anhydrous Na ₂ SO ₄ . Evaporation of solvent gave 72.2 mg (47%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.66 (d, J = 7.7 Hz, 1 H), 7.54 (s, 1 H), 7.35 (pt, J = 8.0 Hz, 1 H), 7.0 (d, J = 8.2 Hz, 1 H), 2.96 (t, J = 7.7 Hz, 2H), 1.90-1.15 (m, 11 H) ppm. ¹³ C NMR (CDCI ₃ , 125.1 MHz) 180.3, 168.0, 156.0, 130.3, 128.3, 120.0, 118.2, 114.1 , 39.6, 32.9, 32.3, 26.0, 25.1 ppm. 3-(5-(2-cyclopentyl-ethyl)-1,2,4-oxadiazol-3-yl)phenyl cyclohexylcar- bamate (46d). This compound was prepared according to the method described above for 45f. Purification by flash chromatography (EtOAc/PE 1 :1 ) and recrystallization (EtOAc/Hex 1 :3) gave the product as white crystals (44.2 mg, 46 %). Mp. 125.2-125.9 ⁰ C; ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.90 (d, J = 7.7 Hz, 1 H), 7.84 (s, 1 H), 7.45 (pt, J = 8.0 Hz, 1 H), 7.28 (d, J = 9.3 Hz, 1 H), 4.94 (d, J = 7.4 Hz, 1 H), 3.60-3.54 (m, 1 H), 2.95 (t, J = 7.4 Hz, 2H), 1.84-1.15 (m, 21 H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 180.2, 167.7, 153.3,

151.4, 129.7, 128.2, 124.4, 124.1 , 120.8, 50.2, 39.6, 33.2, 32.9, 32.3, 26.0, 25.4, 25.1 , 24.7 ppm; Anal, calcd for C ₂₂ H ₂₉ N ₃ O ₃ : C, 68.72; H, 7.62; N, 10.96; found: C, 68.78; H, 7.74; N, 10.77.

Example 47

N-trimethylacetoxy-3-(2-methoxy-ethoxymethoxy)-benzamidin e (47a).

To an ice cold solution of 45b (721 mg, 3.0 mmol, 1 equiv.) and thethyl amine (0.5 ml_, 3.9 mmol, 1.3 equiv.) in CHCI ₃ (30 ml_) was added dropwise trimethylacetyl chloride (0.4 ml_, 3.0 mmol, 1 equiv.). The solution was stirred at room temperature for 2.5 h and then washed with brine, dried (Na ₂ SO ₄ ) and solvent evaporated. Purification by flash chromatography (PE/EtOAc 1 :2) gave 666 mg (68%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.37-7.36 (m, 2H), 7.32 (pt, J = 8.1 Hz, 1 H), 7.17-7.15 (m, 1 H), 5.28 (s, 2H), 5.05 (bs, 2H), 3.82-3.80 (m, 2H), 3.56-3.54 (m, 2H), 3.13 (s, 3H), 1.33 (s, 9H) ppm.

3-[3-(2-Methoxyethoxymethoxy)-phenyl]-5-tert-butyl-1,2,4-oxa diazole (47b). Acetylated amidoxime 47a (666 mg, 2.1 mmol, 1 equiv.) was dissolved in dry THF (6 ml_) and solution of TBAF (66 mg, 0.21 mmol, 0.1 equiv.) in THF was added dropwise under argon atmosphere. The reaction was stirred at room temperature for 3 hours and then poured into ethyl acetate and washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ) and evaporated giving 525 mg (81 %) of the title compound as viscous liquid. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.75-7.72 (m, 2H), 7.38 (pt, J = 8.0 Hz, 1 H), 7.18 (d, J = 8.3 Hz, 1 H), 5.33 (s, 2H), 3.85-3.84 (m, 2H), 3.58- 3.56 (m, 2H), 3.38 (s, 3H), 1.49 (s, 9H) ppm.

3-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)phenol (47c). The compound 47b (525 mg, 1.7 mmol, 1 equiv.) in CH ₂ CI ₂ (1.5 ml_) was treated with anhydrous ZnBr ₂ (1.91 g, 8.5 mmol, 5 equiv.), and the mixture was stirred overnight at room temperature. The solvent was decanted and the solid washed with 1 :1 mixture EtOAc/CH ₂ CI ₂ . The combined organic phases were washed with sat. NaHCO ₃ , brine and water, and dried with anhydrous

Na ₂ SO ₄ . Evaporation of solvent gave and the purification by flash chromatography (Hex/EtOAc 1 :1 ) gave 86.0 mg (24%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.74 (d, J = 7.7 Hz, 1 H), 7.64 (s, 1 H), 7.42 (pt, J = 8.0 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 1.57 (s, 9H) ppm. 3-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)phenyl cyclohexylcarbamate (47d). This compound was prepared according to the method described above for 45f. Purification by flash chromatography (EtOAc/Hex 1 :2) and recrystalli- zation (EtOAc/Hex 1 :2) gave the product as white crystals (28.0 mg, 20 %). ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.92 (d, J = 7.7 Hz, 1 H), 7.85 (s, 1 H), 7.45 (pt, J = 7.9 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 1 H), 4.92 (s, 1 H), 3.61 -3.54 (m, 1 H), 2.04-2.02 (m, 2H), 1.76-1.61 (m, 3H), 1.49 (s, 9H), 1.40-1.35 (m, 2H), 1.27- 1.19 (m, 3H) ppm. ¹³ C NMR (CDCI ₃ , 125.1 MHz) 186.3, 167.6, 153.3, 151.4, 129.6, 128.4, 124.3, 124.1 , 120.8, 50.2, 33.6, 33.2, 28.4, 25.4, 24.7 ppm.

Example 48

3-[3-(2-Methoxyethoxymethoxy)-phenyl]-1,2,4-oxadiazole-5-car boxylic acid ethyl ester (48a). To an ice cold solution of 45b (721 mg, 3.0 mmol, 1 equiv.) and triethyl amine (0.5 ml_, 3.9 mmol, 1.3 equiv.) in CHCI ₃ (30 ml_) was added dropwise ethyl chlorooxoacetate (0.3 ml_, 3.0 mmol, 1 equiv.). The solution was stirred overnight at room temperature and then washed with brine, dried (Na ₂ SO ₄ ) and solvent evaporated. Purification by flash chromatography (PE/EtOAc 1 :2) gave 193 mg (20%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.81 -7.79 (m, 2H), 7.42 (pt, J = 8.0 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 5.33 (s, 2H), 4.57 (q, J =7.2 Hz, 2H), 3.86-3.84 (m, 2H), 3.58-3.56 (m, 2H), 3.38 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H) ppm. 3-(3-Hydroxy-phenyl)-1,2,4-oxadiazole-5-carboxylic acid ethyl ester (48b). The above prepared compound 48a (193 mg, 0.6 mmol, 1 equiv.) in CH ₂ CI ₂ (3 ml_) was treated with anhydrous ZnBr ₂ (673 mg, 3.0 mmol, 5 equiv.), and the mixture was stirred overnight at room temperature. The solvent was decanted and the solid washed with 1 :1 mixture EtOAc/CH ₂ CI ₂ .

The combined organic phases were washed with sat. NaHCO ₃ , brine and water, and dried with anhydrous Na ₂ SO ₄ . Evaporation of solvent and the purification by flash chromatography (Hex/EtOAc 1 :1 ) gave 95.0 mg (68%) of the title compound. ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.74 (d, J = 7.7 Hz, 1 H), 7.62 (s, 1 H), 7.38 (pt, J = 8.0 Hz, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 5.03 (bs, 1 H), 4.57 (q, J = 7.2 Hz, 2H), 1.49 (t, J =7.2 Hz, 3H) ppm.

3-(3-Cyclohexylcarbamoyloxy-phenyl)-1,2,4-oxadiazole-5-carbo xylic ethyl ester (48c). This compound was prepared according to the method described above for 45f. Purification by flash chromatography (EtOAc/Hex 1 :2) gave the product as white solid (61.0 mg, 68 %). ¹ H NMR (CDCI ₃ , 500.1 MHz) 7.99 (d, J = 7.7 Hz, 1 H), 7.93 (s, 1 H), 7.49 (pt, J = 8.0 Hz, 1 H), 7.33 (d, J =8.1 Hz, 1 H), 4.94 (d, J = 7.4 Hz, 1 H), 4.57 (q, J = 7.1 Hz, 2H), 3.60-3.55 (m, 1 H), 2.04-2.02 (m, 2H), 1.77-1.74 (m, 2H), 1.65-1.64 (m, 1 H), 1 .49 (t, J = 7.1 Hz, 3H),1 .43-1 .18 (m, 5H) ppm; ¹³ C NMR (CDCI ₃ , 125.1 MHz) 168.9, 166.6, 154.1 , 153.2, 151 .5, 129.9, 126.8, 125.3, 124.3, 121.1 , 64.0, 50.2, 33.2, 25.4, 24.7, 14.2, 14.0 ppm.

Example 49

3-Hydroxybenzamide (49a). 3-Cyanophenol (295 mg, 2.48 mmol, 100 mol-%) and NaBO ₃ - 4 H ₂ O (1146 mg, 7.45 mmol, 300 mol-%) in H ₂ O (8 ml_) were heated to 50 ⁰ C and MeOH (14 ml_) was added until mixture was clear. The mixture was stirred at 50 ⁰ C for 70 hours and excess MeOH was evaporated and the pH of remaining mixture was adjusted to 5 with cone. HCI (aq). Mixture was extracted with CH ₂ CI ₂ (12 ml_) and with EtOAc (5x15 ml_). Organic phases were combined, washed with brine (25 ml_) and dried over Na ₂ SO ₄ . Filtering and evaporation of solvents gave 49a as spectro- scopically pure white solid (183 mg, 54%): mp 165-168 ⁰ C; Rf (50% EtOAc in hex) 0.10.

3-Carbamoylphenyl cyclohexylcarbamate (49b). This compound was synthesized and worked up as described for 1e using compound 49a (140 mg, 1.0 mmol, 100 mol-%) and cyclohexyl isocyanate (0.28 ml_, 2.2 mmol, 220 mol-%) as starting materials and DMF (4 ml_) as solvent. Purification by flash chromatography (10% MeOH in CH ₂ CI ₂ ) and recrystallization (EtOAc) gave 49b (40mg, 15 %) as white crystals; mp 169-179 ⁰ C; Rf (15% MeOH in CH ₂ CI ₂ ) 0.36; ¹ H NMR (DMSO-c/ ₆ ) 8.01 (s, 1 H), 7.78 (d, 1 H, J = 7.9 Hz), 7.71 (d, 1 H, J = 7.8 Hz), 7.58 (s, 1 H), 7.44 (m, 2H), 7.26-7.24 (m,

1 H), 3.36-3.28 (m, 1 H), 1.86-1.80 (m, 2H), 1.74-1.68 (m, 2H), 1.59-1.53 (m, 1 H), 1.30-1.20 (m, 4 H), 1.17-1.08 (m, 1 H); ¹³ C NMR (DMSO-c/ ₆ ) 167.8,

154.2, 151.9, 136.3, 130.0, 125.6, 124.8, 121.7, 50.7, 33.4, 26.0, 25.4; Anal, calcd for C ₁₄ H ₁₈ N ₂ O ₃ C, 64.10; H, 6.92; N, 10.68; Found C, 64.32; H, 6.97; N, 10.47

Example 50

4-(3-Methoxy-phenyl)-oxazole (50a). 2-Bromo-1 -(3-methoxyphenyl)- ethanone (230 mg, 1.0 mmol, 100 mol-%) and formamide (0.4 ml_, 10 mmol, 1000 mol-%) were placed in a 10 mL microwave tube and irradiated (300W) until the temperature reached 100 ⁰ C (took 30 sec) and kept at that temperature for 30 sec. The irradiation was repeated and the mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic phase was dried over Na2SO ₄ , filtered and evaporated. Purification by flash chromatography (10% EtOAc in hex) and recrystallization (Hex/CH ₂ CI ₂ ) gave 50a (90 mg, 51 %) as light yellow crystals; mp. 81 -82 ⁰ C; Rf (EtOAc) 0.6; ¹ H NMR (CDCI ₃ ) 7.93-7.92 (m, 2 H), 7.34-7.32 (m, 1 H), 7.32-7.30 (m,

2 H), 6.90-6.85 (m, 1 H), 3.85 (s, 3 H); ¹³ C NMR (CDCI ₃ ) 160.0, 151.2,

140.3, 133.9, 132.0, 129.8, 117.9, 114.1 , 110.8, 55.2; Anal, calcd for C ₁₀ H ₉ NO ₂ : C, 68.56; H, 5.18; N, 8.00; Found C, 68.04; H, 5.10; N, 7.74; HRMS (ESI) [M+Na+] calcd for C ₁₀ H ₉ NO ₂ 198.0531 ; Found 198.0524. 4-(3-Hydroxyphenyl)oxazole (50b). Compound 50a (200 mg, 1.1 mmol, 100 mol-%) and butylpyridinimum bromide (490 mg, 2.2 mmol, 200 mol-%)

were placed in a 10 mL microwave tube and irradiated (300W) until the temperature reached 100 ⁰ C (took 30 sec.) and kept at that temperature for 30 sec. Another portion of ionic liquid (430 mg, 2.0 mmol, 180 mol-%) was added and irradiation was repeated for five times. The mixture was diluted with CH ₂ CI ₂ (10 ml) and purified with flash chromatography (CH ₂ CI ₂ ). Re- crystallization (Hex/CH ₂ CI ₂ /MeOH) gave light yellow crystals (100 mg, 56%); mp. 123-124 ⁰ C; Rf (10% MeOH in CH ₂ CI ₂ ) 0.5; ¹ H NMR (DMSO-c/ ₆ ) 9.53 (s, 1 H), 8.56 (d, 1 H, J = 0.9 Hz), 8.43 (d, 1 H, J = 0.9 Hz), 7.23-7.20 (m, 3H), 6.76-6.70 (m, 1 H); ¹³ C NMR (DMSO-c/ ₆ ) 157.7, 152.5, 139.3, 135.0, 131.9, 129.8, 116.1 , 115.0, 112.0; Anal, calcd for C ₉ H ₇ NO ₂ : C, 67.07; H, 4.38; N, 8.69; Found C, 66.89; H, 4.30; N, 8.32. 3-(Oxazol-4-yl)phenyl cyclohexylcarbamate (50c). This compound was synthesized and worked up as described for 1e using compound 50b (100 mg, 0.62 mmol, 100 mol-%) and cyclohexyl isocyanate (115 mg, 0.93 mmol, 150 mol-%) as starting materials. Purification by flash chromatography (1 % MeOH in CH ₂ CI ₂ ) and recrystallization (EtOAc/hex) gave 50c (160 mg, 90%) as white crystals; mp 139.5-140.5 ⁰ C; Rf (10% MeOH in CH ₂ CI ₂ ) 0.4; ¹ H NMR (CDCI ₃ ) 7.93 (d, 2H, J = 6.9 Hz), 7.58 (d, 1 H, J = 7.8 Hz), 7.53 (s, 1 H), 7.39 (t, 1 H, J = 7.9 Hz), 7.10 (dd, 1 H, J = 8.1 , 1.6 Hz), 4.95 (br d, 1 H, J = 6.8 Hz), 3.64-3.52 (m, 1 H), 2.08-1.97 (m, 1 H), 1.80-1.70 (m, 2H), 1.67-1.58 (m, 1 H), 1.44-1.32 (m, 2H), 1.30-1.14 (m, 3H); ¹³ C NMR (CDCI ₃ ) 153.5, 151.5, 151.2, 139.8, 134.0, 132.0, 129.6, 122.3, 121.4, 118.9, 50.1 , 33.2, 25.4, 24.7; Anal, calcd for C ₉ H ₇ NO ₂ : C, 67.12; H, 6.34; N, 9.78; Found C, 67.05; H, 6.61 ; N, 9.71.

Example 51

2-(3-Methoxy-phenyl)-thiazole (51a). To a mixture of 3-methoxy ben- zothioamide (420 mg, 2.5 mmol, 100 mol-%) in THF (2.5 mL) was added 2- bromoacetaldehyde diethyl acetal (0.5 mL, 3.3 mmol, 132 mol-%) and the mixture placed in an CEM 10 mL glass tube. The mixture was irradiated with CEM microwave apparatus for 30 min (power 300 W, T _max = 115 ⁰ C).

The mixture was purified by flash chromatography (1 % EtOAc in toluene) giving 51a (200 mg, 42%) as an oil: Rf (10% EtOAc in toluene) 0.5; ¹ H NMR (CDCI ₃ ) 7.85 (d, 1 H ₁ J = 3.3 Hz), 7.55 (dd, 1 H ₁ J = 2.4, 1.7 Hz) 7.51 (ddd, 1 H ₁ J = 7.7, 1.5, 1.0 Hz) 7.33 (t, 1 H, J = 8.1 Hz), 7.30 (d, 1 H ₁ J = 3.3 Hz), 6.96 (ddd, 1 H, J = 8.2, 2.6, 0.9 Hz), 3.86 (s, 3H); ¹³ C NMR (CDCI ₃ ) 168.2, 159.9, 143.5, 134.7, 129.9, 119.1 , 118.8, 116.2, 111.0, 55.3. 2-(3-Hydroxy-phenyl)-thiazole (51b). Compound 51a (170 mg, 0.9 mmol, 100 mol-%) and 1 -butyl-3-methylimidazolium bromide (700 mg, 3.2 mmol, 350 mol-%) were irradiated with CEM microwave apparatus in an open vessel for 2x30 sec (power 300 W, air cooling, T _max 100 ⁰ C). The reaction mixture was partitioned between EtOAc (30 ml_) and water (30 ml_). The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. Resulting crude product was purified by flash chromatography (25% EtOAc in hex) and recrystallized (EtOAc/hex) giving 51b (70 mg, 44%) as a white solid: mp 141 -143 ⁰ C, Rf (35% EtOAc in hex) 0.5; ¹ H NMR (CDCI ₃ ) 7.87 (d, 1 H, J = 3.2 Hz), 7.52 (ddd, 1 H, J = 2.5, 1.6, 0.4 Hz), 7.49 (ddd, 1 H. J = 7.7, 1.6, 1.0 Hz), 7.34 (d, 1 H, J = 3.3 Hz), 7.31 (ddd, 1 H, J = 8.1 , 7.7, 0.4 Hz), 6.92 (ddd, 1 H, J = 8.1 , 1.6, 1.0 Hz), 5.68 (br s). 3-(Thiazol-2-yl)phenyl cyclohexylcarbamate (51c). This compound was synthesized and worked up as described for 1e using compound 51b (30 mg, 0.23 mmol, 100 mol-%) and cyclohexyl isocyanate (43 mg, 0.35 mmol, 150 mol-%) as starting materials. Purification by flash chromatography (1 - 2% MeOH in CH ₂ CI ₂ ) and recrystallization (EtOAc/hex) gave 51c (35 mg, 50%) as white crystals; mp 147 ⁰ C; Rf (EtOAc) 0.8; ¹ H NMR (CDCI ₃ ) 7.86 (d, 1 H, J = 3.2 Hz), 7.81 -7.74 (m, 2H), 7.42 (t, 1 H, J = 7.9 Hz) 7.34 (d, 1 H, J = 3.2 Hz), 7.21 (dd, 1 H, J = 8.1 , 1 ,6 Hz) 4.98, (br d, 1 H, J = 7.3 Hz), 3.67- 3.52 (m, 1 H), 2.10-1.98 (m, 2H), 1.80-1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.45-1.32 (m 2H), 1.30-1.14 (M, 3H); ¹³ C NMR (CDCI ₃ ) 167.4, 153.3, 151.6, 143.7, 134.8, 129.8, 123.3, 123.2, 119.8, 119.1 , 50.2, 33.2, 25.4, 24.7, Anal, calcd for Ci ₆ H ₁₈ N ₂ O ₂ S: C, 63.55; H, 6.00; N, 9.26; Found C, 63.38; H, 5.78; 9.14.

Example 52

4-(3-Methoxyphenyl)-1H-imidazole (52a). 2-Bromo-1 -(3-methoxyphenyl)- ethanone (530 mg, 2.3 mmol, 100 mol-%) and formamide (2 ml_, 50 mmol, 2200 mol-%) were placed in a 10 ml_ flask and heated up until the temperature (T _0l ι) reached 165 ⁰ C (took 90 min.) The mixture was cooled to rt and partitioned between EtOAc (30 ml_) and water (50 ml_). The aqueous layer was collected and made basic (pH 12) with NaOH (35%) and extracted with EtOAc (2x50 ml_). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. Recrystallization (MeOH/H ₂ O, 40:1 ) of crude product gave 52a (340 mg, 85%) as light yellow crystals: mp. 121 -122 ⁰ C; Rf (EtOAc) 0.1 ; ¹ H NMR (CDCI ₃ ) 11.16 (br s, 1 H), 7.68 (d, 1 H, J = 1.0 Hz), 7.34 (d, 1 H, J = 1.0 Hz), 7.31 -7.23 (m, 3 H), 6.80-6.76 (m, 1 H), 3.74 (s, 3 H); ¹³ C NMR (CDCI ₃ ) 159.9, 138.4, 135.7, 134.3, 129.8, 117.4, 115.9, 112.7, 110.2, 55.1 ; Anal, calcd for C ₁₀ H ₁₀ N ₂ O: C, 68.95; H, 5.79; N, 16.08; Found C, 68.83; H, 5.43; 16.32.

4-(3-Hydroxyphenyl)-1H-imidazole (52b). Compound 52a (650 mg, 3.73 mmol, 100 mol-%) was dissolved to dry CH ₂ CI ₂ (37 ml) and cooled to -78 ⁰ C. BBr ₃ (1 M in CH ₂ CI ₂ , 6.5 ml_, 175 mol-%) was added dropwise during 15 min. The mixture was stirred at -78 ⁰ C for 25 min and another protion of BBr3 (1 M in CH ₂ CI ₂ , 4.7 ml_, 125 mol-%) was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was diluted with water (150 ml_) and the organic phase was separated. The aqueous phase was neutralized with 35% NaOH (pH adjusted to 6) and extracted with EOAc (80+70+2x50 ml_). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated resulting in 52b (350 mg, 59%) as solid: Rf (20% MeOH in CH ₂ CI ₂ ) 0.1 ; ¹ H NMR (CDCI ₃ ) 9.35 (br s, 1 H), 7.81 (br s, 1 H), 7.53 (br s, 1 H), 7.19-7.11 (m, 3H), 6.62 (dt, 1 H, J = 7.1 , 2.1 Hz). S^I^CyclohexylcarbamoylJ-IH-imidazol^-ylJphenyl cyclohexylcar- bamate (52c). This compound was synthesized and worked up as described for 1e using compound 52b (140 mg, 0.87 mmol, 100 mol-%) and

cyclohexyl isocyanate (120 mg, 0.87 mmol, 100 mol-%) as starting materials. Purification by flash chromatography (25-70% EtOAc in hex) and re- crystallization (EtOAc/hex) gave 52c (154 mg, 43%) as a white solid; mp 158-165 ⁰ C; Rf (EtOAc) 0.55; ¹ H NMR (CDCI ₃ ) 8.06 (d, 1 H, J = 1.2 Hz), 7.54-7.44 (m, 3H), 7.28 (t, 1 H, J = 7.8 Hz), 6.97 (dd, 1 H, J = 8.0, 1.6 Hz), 6.22 (d, 1 H, J = 7.6 Hz), 5.12 (d, 1 H, J = 8.1 Hz), 3.82-3.71 (m, 1 H), 3.63- 3.51 (m, 1 H), 2.10-1.95 (m, 4H), 1.82-1.71 (m, 4H), 1.71 -1.59 (m, 2H), 1.45-1.31 (m, 4H), 1.31 -1.14 (m, 6H); ¹³ C NMR (CDCI ₃ ) 154.0, 151.2, 148.0, 141.9, 136.2, 134.5, 129.4, 122.0, 120.6, 118.4, 111.4, 50.4, 50.3, 33.2, 32.9, 25.4, 25.3, 24.9, 24.7; Anal, calcd for C ₂₃ H ₃₀ N ₄ O ₃ : C, 67.29; H, 7.37; N, 13.65; Found C, 67.30; H, 7.37; 13.63.

Example 53

Methyl 3-hydroxybenzimidate hydrochloride (53a). To a mixture of 3- cyanophenol (1840 mg, 15.5 mmol, 100 mol-%) in dry CH ₂ CI ₂ (36 ml_) was added dry MeOH (3.2 ml_, 79 mmol, 510 mol-%) and the mixture was bubbled with HCI gas in an ice bath. The mixture was stirred at 2 ⁰ C for 3 days and solvents were evaporated. Filtering and washing with dry Et ₂ O gave 53a as a white powder (2.67 g, 92 %): ¹ H NMR (DMSO-c/ ₆ ) 11.68 (bs, 1 H), 10.34 (s, 1 H), 7.57-7.53 (m, 1 H), 7.46-7.41 (m, 2H), 7.24-7.21 (m, 1 H), 4.27 (s, 3H).

(S)-Methyl 2-(3-hydroxyphenyl)-4,5-dihydrooxazole-4-carboxylate

(53b). (S)-Serine methylester hydrochloride (127 mg, 0.82 mmol, 100 mol- %) was suspended in dry CH ₂ CI ₂ and Et ₃ N was added (180 μl_, 1.28 mmol, 160 mol-%) followed by 53a (153 mg, 0.82, 100 mol-%) and the mixture was refluxed overnight. Solvent was evaporated and remaining solid partitioned between H ₂ O (10 ml_) and EtOAc (15 ml_). Organic phase was washed with H ₂ O (10 ml_). Aqueous phases were combined and back- washed with EtOAc (2x15 ml_). Organic phases were combined, washed with brine (20 ml_), dried over Na ₂ SO ₄ , filtered and evaporated. Purification by flash chromatography (twice, 70% EtOAc:hex, then 5% MeOH:CH ₂ CI ₂ )

gave compound 53b as an oil (122 mg, 68%); Rf (60% EtOAc:hex) 0.28; [α] _D ²⁰ 64.5 (c = 1.8, CDCI ₃ ); ¹ H NMR (CDCI ₃ ) 8.16 (s, 1 H), 7.43-7.42 (m, 1 H), 7.40 (d, 1 H, J = 7.8 Hz), 7.20 (t, 1 H, J = 7.9 Hz), 6.97 (ddd, 1 H, J = 8.2, 2.5, 0.9 Hz), 4.96 (dd, 1 H, J = 10.7, 7.9 Hz), 4.69 (dd, 1 H, J = 8.7, 7.9), 4.59 (dd, 1 H, J = 10.7, 8.8 Hz), 3.71 (s, 3H); ¹³ C NMR (CDCI ₃ ) 171.4, 170.0, 156.5, 129.6, 127.3, 120.4, 119.8, 115.4, 69.6, 67.8, 52.7; HRMS (ESI): calcd for [M+H ⁺ ] C ₁₁ H ₁₁ NO ₄ : 222.0766, found 222.0759. (S)-Methyl 2-(3-(cyclohexylcarbamoyloxy)phenyl)-4,5-dihydrooxazole- 4-carboxylate (53c). This compound was synthesized and worked up as described for 1e using 53b (120 mg, 0.54 mmol, 100 mol-%) and cyclohexyl isocyanate (200 μl_, 1.57 mmol, 290 mol-%) as starting materials. Purification with flash chromatography (70% EtOAc:hex) and recrystallization (EtOAc:hex) gave compound 53c as white crystals (141 mg, 75%); mp; Rf (17% Et ₂ O:CH ₂ CI ₂ ) 0.33; [α] _D ²⁰ 72.5 (c = 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.81 (d, 1 H, J = 7.8 Hz), 7.75 (s, 1 H), 7.39 (t, 1 H, J = 7.9 Hz), 7.29-7.26 (m, 1 H), 4.94 (dd, 2H, J = 10.5, 8.0), 4.69 (t, 1 H, J = 7.8), 4.59 (dd, 1 H, J = 10.6, 8.8), 3.82 (s, 3H), 3.59-3.52 (m, 1 H), 2.04-1.97 (m, 2H), 1.78-1.70 (m, 2H), 1.67-1.59 (m, 1 H), 1.43-1.32 (m, 2H), 1.27-1.16 (m, 3H); ¹³ C NMR (CDCI ₃ ) ¹³ C NMR (CDCI ₃ ); 171.4, 165.6, 153.3, 151.0, 129.2, 128.1 , 125.3, 125.2, 121.9, 69.6, 68.6, 52.7, 50.1 , 33.2, 25.4, 24.7; Anal, calcd for C ₁₈ H ₂₂ N ₂ O ₅ : C, 62.42; H, 6.40; N, 8.09; Found C, 62.45; H, 6.12; N, 8.02.

Example 54

(R)-Methyl 2-(3-hydroxyphenyl)-4,5-dihydrooxazole-4-carboxylate (54a). This compound was synthesized and worked up as described for 53b using (R)-serine methylester hydrochloride (125 mg, 0.80 mmol, 100 mol-%) and 53a (150 mg, 0.80 mmol, 100 mol-%) as starting materials. Purification by flash chromatography gave compound 54a as an oil (121 mg, 68%); Rf (70% EtOAc:hex) 0.33; [α] _D ²⁰ -57.4 (c = 1 , CDCI ₃ ); ¹ H NMR (CDCI ₃ ) 8.57 (s, 1 H), 7.42 (dd, 1 H, J = 2.4, 1.6 Hz), 7.38 (app. ddd, 1 H), 7.18 (t, 1 H, J = 7.9), 6.96 (ddd, 1 H, J = 8.2, 2.5, 0.9), 4.96 (dd, 1 H, J =

10.7, 7.8), 4.69 (dd, 1 H, J = 8.7, 7.9 Hz), 4.58 (dd, 1 H ₁ J = 10.7, 8.8), 3.69 (s, 3H); ¹³ C NMR (CDCI ₃ ) 171.3, 167.1 , 156.6, 129.6, 127.2, 120.3, 119.8, 115.4, 69.6, 67.7, 52.7; HRMS (ESI): calcd for [M+H ⁺ ] C ₁₁ H ₁₁ NO ₄ : 222.0766, found 222.0766 (R)-Methyl 2-(3-(cyclohexylcarbamoyloxy)phenyl)-4,5-dihydrooxazole- 4-carboxylate (54b). This compound was synthesized and worked up as described for 1e using 54a (120 mg, 0.54 mmol, 100 mol-%) and cyclohexyl isocyanate (200 μl_, 1.57 mmol, 290 mol-%) as starting materials. Purification by flash chromatography (70% EtOAc:hex) and recrystallization (EtOAc:hex) gave compound 54b as white crystals (136 mg, 73%); mp; Rf (17% Et ₂ O:CH ₂ CI ₂ ) 0.33; [α] _D ²⁰ -68.3 (c = 0.5, CHCI ₃ ); ¹ H NMR (CDCI ₃ ) 7.81 (d, 1 H, J = 7.8 Hz), 7.75 (s, 1 H), 7.39 (t, 1 H, J = 8.0 Hz), 7.29-7.26 (m, 1 H), 4.95 (dd, 2H, J = 10.5, 8.0 Hz), 4.69 (t, 1 H, J = 8.3 Hz), 4.59 (dd, 1 H, J = 10.5, 8.8 Hz), 3.82 (s, 3H), 3.60-3.51 (m, 1 H), 2.04-1.97 (m, 2H), 1.78-1.70 (m, 2H), 1.67-1.59 (m, 1 H), 1.43-1.32 (m, 2H), 1.27-1.16 (m, 3H); ¹³ C NMR (CDCI ₃ ) ¹³ C-NMR (CDCI ₃ ); 171.4, 165.6, 153.3, 151.0, 129.2, 128.1 , 125.3, 125.2, 121.9, 69.6, 68.6, 52.7, 50.1 , 33.2, 25.4, 24.7; Anal, calcd for C ₁₈ H ₂₂ N ₂ O ₅ : C, 62.42; H, 6.40; N, 8.09; Found C, 62.47; H, 6.15; N, 8.03.

Example 55

Dimethyl 4-(cyclohexylcarbamoyloxy)phthalate (55).This compound was synthesized and worked up as described for 1e using dimethyl 4- hydroxyphtalate (120 mg, 0.54 mmol, 100 mol-%) and cyclohexyl isocyanate (200 μl_, 1.57 mmol, 290 mol-%) as starting materials. Purification by recrystallization (EtOAc:hex) gave compound 55 as white crystals (190 mg, 80%); mp 112-112.5 ⁰ C; Rf (EtOAc) 0.5; ¹ H NMR (CDCI ₃ ) 7.75 (d, 1 H, J = 8.5 Hz), 7.46 (d, 1 H, J = 2.1 Hz) 7.32 (dd, 1 H, J = 8.5, 2.1 Hz), 5.05 (d, 1 H ₁ J = 7.4 Hz) 3.90 (s, 3 H), 3.89 (s, 3 H), 3.62-3.49 (m, 1 H), 2.06-1.95 (m, 2 H), 1.80-1.70 (m, 2 H), 1.67-1.59 (m, 1 H), 1.44-1.30 (m, 2 H), 1.28-1.16 (m, 3 H); ¹³ C NMR (CDCI ₃ ) 167.5, 167.1 , 153.2, 152.4, 133.9, 130.5, 127.8,

123.7, 121.8, 52.7, 52.6, 50.3, 33.1 , 25.3, 24.7; Anal, calcd for C ₁₇ H ₂ iNO ₆ : C, 60.89; H, 6.31 ; N, 4.18; Found C, 60.98; H, 6.38; N, 4.27.

Example 56 3-(/V-hydroxycarbamimidoyl)phenyl cyclohexylcarbamate (56). 3-

Cyanophenyl cyclohexylcarbamate (28, 0.95 g, 3.9 mmol, 1 equiv.), hydro- xylamine hydrochloride (0.41 g, 5.9 mmol, 1.5 equiv.) and triethyl amine (0.8 ml_, 5.9 mmol, 1.5 equiv.) in EtOH ( 20 ml_) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the reaction crude was dissolved in EtOAc/CH ₂ CI ₂ mixture. The organic phase was washed with brine and dried over anhydrous Na ₂ SO ₄ . Evaporation of solvent gave the crude product, which was purified by recrystalliza- tion (EtOAc/Hex 1 :1 ) giving 314 mg (29%) of the title compund as white crystals. Mp. 154.5-154.8 ⁰ C; ¹ H NMR (DMSO-d ₆ , 500.1 MHz) 9.71 (s, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 1 H), 7.41 -7.38 (m, 2H), 7.13 (d, J = 7.9 Hz, 1 H), 5.86 (s, 1 H), 1.88-1.86 (m, 2H), 1.76-1.74 (m, 2H), 1.61 -1.59 (m, 1 H), 1.35-1.14 (m, 5H) ppm; Anal, calcd for C ₁₄ H ₁₉ N ₃ O ₃ : C, 60.63; H, 6.91 ; N, 15.15; found: C, 60.68; H, 6.95; N, 15.14.

Example 57

2-Hydroxyisonicotinic acid methyl ester (57a). A mixture of 2- hydroxyisonicotinic acid (0.28 g, 2.0 mmol, 1 equiv.) and a catalytic amount of concentrated H ₂ SO ₄ (1 drop) in methanol (8 ml_) was refluxed overnight. Evaporation of solvent gave crude product, which was purified by flash chromatography (EtOAc/MeOH 1 :1 ) giving 0.25 g (82 %) of the product as white solid. ¹ H NMR (CHCI ₃ , 500.1 MHz) 13.00 (bs, 1 H), 7.44 (d, J = 6.7 Hz, 1 H), 7.21 (s, 1 H), 6.79 (d, J = 6.7 Hz, 1 H), 3.93 (s, 3H) ppm. 2-Cyclohexylcarbamoyloxy-isonicotinic acid methyl ester (57b). To a mixture of 2-hydroxyisonicotinic acid methyl ester (57a, 76.6 mg, 0.5 mmol) and triethyl amine (0.42 μl_, 0.06 equiv.) in toluene (2 ml_) was added cyclohexyl isocyanate (0.13 ml_, 1.0 mmol, 2 equiv.). The reaction mixture

was stirred overnight at 80 ⁰ C. The reaction mixture was cooled and solvent evaporated. Acid free ethyl acetate was added to the crude product and the solvent decanted. Evaporation of solvent gave 56.0 mg (20 %) of the product as white solid. ¹ H NMR (CDCI ₃ , 500.1 MHz) 10.43 (d, J = 6.3 Hz, 1 H), 8.50 (d, J = 7.7 Hz, 1 H), 7.22 (d, J = 1.4 Hz, 1 H), 6.79 (dd, J = 7.7, 1.4 Hz, 1 H), 3.88-3.81 (m, 1 H), 2.00-1.25 (m, 10H) ppm.

Animals and preparation of rat brain homogenate for FAAH assay.

Eight-week-old male Wistar rats were used in these studies. All animal ex- periments were approved by the local ethics committee. The animals lived in a 12-h light/12-h dark cycle (lights on at 0700 h) with water and food available ad libitum.

The rats were decapitated, whole brains minus cerebellum were dissected and homogenized in one volume (v/w) of ice-cold 0.1 M potassium phos- phate buffer (pH 7.4) with a Potter-Elvehjem homogenizer (Heidolph). The homogenate was centrifuged at 10,000 g for 20 min at 4 ⁰ C and the resulting supernatant was used as a source of FAAH activity. The protein concentration of the supernatant (7.2 mg/ml) was determined by the method of Bradford with BSA as a standard. ³⁴ Aliquots of the supernatant were stored at -80 ⁰ C until use.

Animals and preparation of rat cerebellar membranes for MGL assay.

Four-week-old male Wistar rats were used in these studies. All animal experiments were approved by the local ethics committee. The animals lived in a 12-h light/12-h dark cycle (lights on at 0700 h), with water and food available ad libitum. The rats were decapitated, eight hours after lights on (1500 h), whole brains were removed, dipped in isopentane on dry ice and stored at -80 ⁰ C. Membranes were prepared as previously described. ^35"37 Briefly, cerebella (minus brain stem) from eight animals were weighed and homogenized in nine volumes of ice-cold 0.32 M sucrose with a glass Teflon homogenizer. The crude homogenate was centrifuged at low speed

(1000 x g for 10 min at 4°C) and the pellet was discharged. The supernatant was centrifuged at high speed (100,000 x g for 10 min at 4°C). The pellet was resuspended in ice-cold deionized water and washed twice, repeating the high-speed centrifugation. Finally, membranes were resus- pended in 50 mM Tris-HCI, pH 7.4 with 1 mM EDTA and aliquoted for storage at -80 ⁰ C. The protein concentration of the final preparation, measured by the Bradford method, ³⁴ was 11 mg ml ^"1 .

In vitro assay for FAAH activity. The endpoint enzymatic assay was de- veloped to quantify FAAH activity with tritium labelled arachidonoyletha- nolamide [ethanolamine 1 - ³ H]. The assay buffer was 0.1 M potassium phosphate (pH 7.4) used and test compounds were dissolved in DMSO (the final DMSO concentration was max 5% v/v). The incubations were performed in the presence of 0.5% (w/v) BSA (essentially fatty acid free). Test compounds were preincubated with rat brain homogenate protein (18 μg) for 10 min at 37 °C (60 μl). At the 10 min time point, arachidonoylethanola- mide was added so that its final concentration was 2 μM (containing 50 x 10 ^"3 μCi of 60 Ci/mmol [ ³ H]AEA) and the final incubation volume was 100 μl. The incubations proceeded for 10 min at 37 °C. Ethyl acetate (400 μl) was added at the 20 min time point to stop the enzymatic reaction. Additionally, 100 μl of unlabelled ethanolamine (1 mM) was added as a ^' carrier ^' for radioactive ethanolamine. Samples were centrifuged at 16,000 g for 4 min at RT, and aliquots (100 μl) from aqueous phase containing [ethanolamine 1 - ³ H] were measured for radioactivity by liquid scintillation counting (Wallac 1450 MicroBeta; Wallac Oy, Finland).

In vitro assay for MGL activity. The assay for MGL has been described previously. ³⁸ Briefly, experiments were carried out with preincubations (80 μl, 30 min at 25°C) containing 10 μg membrane protein, 44 mM Tris-HCI (pH 7.4), 0.9 mM EDTA, 0.5% (wt/vol) BSA and 1.25% (vol/vol) DMSO as a solvent for inhibitors. The preincubated membranes were kept at 0°C just

prior to the experiments. The incubations (90 min at 25°C) were initiated by adding 40 μl of preincubated membrane cocktail, in a final volume of 400 μl. The final volume contained 5 μg membrane protein, 54 mM Tris-HCI (pH 7.4), 1.1 mM EDTA, 100 mM NaCI, 5 mM MgCI ₂ , 0.5% (wt/vol) BSA and 50 μM of 1. At time-points of 0 and 90 min, 100 μl-samples were removed from the incubation, acetonitrile (200 μl) was added to stop the enzymatic reaction and the pH of the samples was simultaneously decreased to 3.0 with phosphoric acid (added to acetonitrile) to stabilize compound 1 against acyl migration to 1 (3)-AG. Samples were centhfuged at 23,700 g for 4 min at RT prior to HPLC analysis of the supernatant.

HPLC method. The analytical HPLC was performed as previously described. ¹¹ Briefly, the analytical HPLC system consisted of a Merck Hitachi (Hitachi Ltd., Tokyo, Japan) L-7100 pump, D-7000 interface module, L- 7455 diode-array UV detector (190 - 800 nm, set at 211 nm) and L-7250 programmable autosampler. The separations were accomplished on a Zor- bax SB-C18 endcapped reversed-phase precolumn (4.6 x 12.5 mm, 5 μm) and column (4.6 x 150 mm, 5 μm) (Agilent, U.S.A). The injection volume was 50 μl. A mobile phase mixture of 28% phosphate buffer (30 mM, pH 3.0) in acetonitrile was used at a flow rate of 2.0 ml min ^"1 . Retention times were 5.8 min for 1 , 6.3 min for 1 (3)-AG and 10.2 min for arachidonic acid. The relative concentrations of 1 , 1 (3)-AG and arachidonic acid were determined by the corresponding peak areas. This was justified by the equivalence of response factors for the studied compounds, and was supported by the observation that the sum of the peak areas was constant throughout the experiments.

Data analyses. The results from the enzyme inhibition experiments are presented as mean ± 95% confidence intervals of at least three independ- ent experiments performed in duplicate. Data analyses for the dose-

response curves were calculated as non-linear regressions using Graph- Pad Prism 4.0 for Windows.

The structures of compounds and their inhibition potencies for FAAH and MGL-like enzyme activity are presented in the Table 1.

Table 1. IC ₅₀ values for the inhibition of FAAH and MGL-like enzymes activity by compounds tested.

Values represent the mean of three independent experiments (n=3) performed in duplicate (95% confidence intervals (95% Cl) are given in parentheses). b Remaining enzyme activity (%) at 100 μM compound concentration (n=2).

⁰ Not stable in used assay conditions. d Remaining enzyme activity at 1 mM was -22%. e Remaining enzyme activity (%) at 10 μM compound concentration (n=2). f Remaining enzyme activity (%) at 1 μM compound concentration (n=2). 9 Values represent the mean of two independent experiments (n=2) performed in duplicate (95% confidence intervals (95% Cl) are given in parentheses). h Remaining enzyme activity (%) at 100 nM compound concentration (n=1 ). ' Remaining enzyme activity (%) at 1 μM compound concentration (n=1 ).

¹ Represents the value of one experiment (n=1 ) performed in duplicate (95% confidence intervals (95% Cl) are given in parentheses).

Table 2. IC ₅₀ values for the inhibition of FAAH and MGL-like enzymes activity by pyridinylcarbamates tested.