S1P receptors modulators and their use thereof

Abstract

The invention relates to novel compounds that have S1P receptor modulating activity. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, autoimmune response. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as autoimmune response.

Claims

1. A method for treating a disease or condition caused by or associated with inappropriate S1P1 receptor modulating activity or expression, wherein the disease or condition is an immunological disorder and/or immune mediated disorder, which is a member selected from the group consisting of psoriasis, multiple sclerosis, ulcerative colitis, autoimmune encephalitis, influenza virus, stroke, sepsis, pain, arthritis, atopic dermatitis and vitiligo, by the administration of an effective amount of a compound of formula (II) or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt or derivative thereof, to a subject in need thereof, ##STR00461## wherein B is a five-membered heterocyclic ring selected from one of the following: ##STR00462## the asterisks indicating the attachment within formula (II); G represents ##STR00463## R is selected from hydrogen, deuterium, alkylamino, CH.sub.2OH, alkoxy, a C.sub.1-5 alkyl chain optionally containing one or more of deuterium, O, NRR, S, and halogen, heterocycle, amide, sulphonamide, COOH, OPO.sub.3H.sub.2, and PO.sub.3H.sub.2, ##STR00464## represents an optional bridging group; A ring is phenyl or pyridinyl; R.sub.2 independently is selected from halogen, hydrogen, deuterium, CN, amino, alkylamino, alkoxy, CF.sub.3, and a C.sub.1-4 alkyl chain optionally containing one or more of deuterium, OH, NRR, S, SO, SO.sub.2, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond, a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, and sulphonamide; the groups J and D each are independently selected from hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, halogen, amino, hydroxy, cyano, aryl, heterocycle, carbocycle, and a C.sub.1-10 alkyl chain optionally containing a carbon-carbon multiple bond or a carbon-hetero multiple bond wherein one or more carbon atoms are optionally independently replaced with oxygen, sulphur, SO, SO.sub.2, NR, carbocycle or heterocycle; and R and R each are independently selected from alkyl, cycloalkyl, aryl, and heterocycle, to treat the disease or condition.

2. The method of claim 1, wherein D is selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, aryl, heterocycle and carbocycle or a C.sub.1-7 alkyl chain optionally containing a carbon-carbon multiple bond or a carbon-hetero multiple bond wherein one or more carbon atoms are optionally independently replaced with oxygen, sulphur, SO, SO.sub.2, NR, carbocycle and heterocycle; J is selected from H, deuterium, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino, halogen, amino, hydroxy, cyano or a C.sub.1-5 alkyl chain optionally containing a carbon-carbon multiple bond or a carbon-hetero multiple bond wherein one or more carbon atoms are optionally independently replaced with oxygen, sulphur, SO, SO.sub.2, NR, carbocycle and heterocycle; and R is selected from alkyl, cycloalkyl, aryl, and heterocycle.

3. The method of claim 1, wherein the compound of formula (II) is selected from the group consisting of: 1-((5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)azetidine-3-carboxylic acid, 2-amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane-1,3-diol, 2-amino-2-(5-(5-(4-propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(6-chloro-5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(1-butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 5-(3-(2-(2-amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-propoxybenzonitrile, 2-amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(2-(2-(4-fluorophenyl)-4-methyloxazol-5-yl)ethyl)benzofuran-2-yl) propane-1,3-diol, 2-amino-2-(5-(2-(2-(4-fluorophenyl)-4-methylthiazol-5-yl)ethyl)benzofuran-2-yl) propane-1,3-diol, 2-amino-2-(5-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(2-(2-(4-fluorophenyl)-5-methyloxazol-4-yl)ethyl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(3-(methyl(pyridin-2-yl)amino)propyl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(2-cyclopropylbenzofuran-5-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(4-isobutoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(6-chloro-5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 5-(3-(2-(2-amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-ethoxybenzonitrile, 2-amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)-7-methyl-benzofuran-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-7-methylbenzofuran-2-yl)propane-1,3-diol, 5-(3-(2-(2-amino-1,3-dihydroxypropan-2-yl)-7-methylbenzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-propoxybenzonitrile, N-(5-(3-(2-(2-amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-ethoxyphenyl)methanesulfonamide, 2-amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)furo[2,3-b]pyridin-2-yl)propane-1,3-diol, 2-amino-2-(5-(5-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol, 2-amino-2-((5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methylamino)propane-1,3-diol, 2-amino-2-(5-(5-(4-propoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol.

4. The method of claim 1, wherein the compound of formula (II) is administered in combination with pharmaceutical excipients.

5. The method of claim 4, wherein the pharmaceutical excipients comprise stabilizing agents, carriers and encapsulation formulations.

6. The method of claim 1, wherein the immunological disorder and/or immune mediated disorder is member selected from the group consisting of psoriasis, multiple sclerosis, ulcerative colitis, autoimmune encephalitis and influenza virus.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 illustrates post-treatment lymophocyte counts

DETAILED DESCRIPTION OF THE INVENTION

(2) The terms compound, agent, active agent, chemical agent, pharmacologically active agent, medicament, active, molecule and drug are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect. The terms also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those active agents/compounds specifically mentioned herein and compounds of the invention including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the terms compound, agent, active agent, chemical agent pharmacologically active agent, medicament, active and drug are used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable and/or, pharmacologically active salt/s, esters, amides, prodrug/s, metabolites, analogs and the like.

(3) The terms effective amount and therapeutically effective amount of an agent/s/compounds and compounds of the invention as used herein mean a sufficient amount of the compound to provide the desired therapeutic or physiological effect or outcome. A practitioner balances the potential benefits against the potential risks in determining what an appropriate effective amount is. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like.

(4) A pharmaceutically acceptable carrier, excipient or diluent may include a pharmaceutical vehicle comprised of a material that may not be biologically active or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any and/or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.

(5) The compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers or encapsulation formulations. Effective combinations are those which provide favourable synergistic effect which assist in treatment and/or prevention and/or immunotherapy better than the agents alone.

(6) As used herein, the term optionally substituted means that one or more hydrogen atoms may be replaced by a group or groups selected from: -D, F, Cl, Br, I, CF3, OH, OR7, NH2, NHR7, NR7R8, CN, NO2, SH, SR7, SOR7, SO2R7, O, S, NOH, NOR7, NHOH, NHOR7, CHO, where R7 and R8 are independently (C1-C18)alkyl, typically (C1-C12)alkyl; (C3-C18)cycloalkyl, typically (C3-C12)cycloalkyl; (C3-C18)cycloalkyl(C1-C18)alkyl, typically (C3-C12)cyclo-alkyl(C1-C6)alkyl; (C6-C24)aryl, typically (C6-C16)aryl; (C7-C25)aralkyl, typically (C7-C16)aralkyl; (C2-C18)alkenyl, typically (C2-C12)alkenyl; (C8-C26)aralkenyl, typically (C8-C16)aralkenyl; (C2-C18)alkynyl, typically (C2-C12)alkynyl; (C8-C26)-aralkynyl, typically (C8-C16)aralkynyl; or heterocyclic.

(7) As used herein, the term alkyl includes within its meaning straight and branched chain alkyl groups. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methyl pentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1- or 2-pentylheptyl, and the like.

(8) A used herein, the term cycloalkyl refers to mono- or polycyclic alkyl groups, or alkyl substituted cyclic alkyl groups. Examples of such groups include cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, ethylcyclopentyl, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cycIododecyl, decahydronaphthyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.2]decyl, bicycleo4.4.3]dodecyl, bicyclo[4.4.0]octyl and the like.

(9) As used herein, the term cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group as defined above.

(10) As used herein, the term alkenyl includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined. Examples of such alkenyl groups are vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-headienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3 cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.

(11) As used herein, the term alkynyl includes within its meaning acetylenically unsaturated alkyl groups as previously defined. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1-butynyl, n-hexynyl, methyl-pentynyl, (C7-C12)alkynyl and (C7-C12)cycloalkynyl.

(12) As used herein, the term alkylidene refers to optionally unsaturated divalent alkyl radicals. Examples of such radicals are CH2-, CH2CH2-, CHCH, CH2CH2CH2-, C(CH2)CH2-, CH2CHCH, (CH2)4-, CH2CH2CHCH, CH2CHCHCH2-, and (CH2)r- where r is 5-8. The term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system. Examples of such radicals are groups of the structures

(13) ##STR00011## ##STR00012## ##STR00013##

(14) and similar groups wherein any N or O atom is replaced by S or Se.

(15) As used herein, the term aryl refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of such groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula (I).

(16) As used herein, the term aralkyl refers to alkyl groups substituted with one or more aryl groups as previously defined. Examples of such groups are benzyl, 2-phenylethyl and 1-phenylethyl.

(17) As used herein, the terms aralkenyl and aralkynyl refer to alkenyl and alkynyl groups respectively, substituted with one or more aryl groups as previously defined. Examples of such groups are styryl, phenylacetylenyl and 2-phenyl-2-butenyl.

(18) As used herein the term saturated or unsaturated cyclic, bicyclic or fused ring system refers to a cyclic system of up to 16 carbon atoms, up to 3 of which may be replaced by O, S or N, which ring system may be substituted with one or more of R, NH2, NHR, NR2, CHO, C(O)R, CN, halo, CF3, SR, S(O)R, S(O)2R, CONH2, CONHR, CONR2, NHOH, NHOL, NO2, O, O or NHNH2; wherein each R are independently as previously defined. Examples of such ring systems are those cyclic alkylidene groups exemplified above and

(19) ##STR00014##

(20) As used herein, the term heterocyclic refers to any 3- to 16-membered monocyclic, bicyclic or polycyclic ring containing, for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur. The term heterocyclic includes any group in which a heterocyclic ring is fused to a benzene ring. Examples of heterocyclics are pyrryl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, piperidinyl, pyridinyl, furyl, thiophenyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolyl, pyrenyl, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, furfuryl, thienyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, azanorbornyl, isoquinuclidinyl and the like. Nitrogen-containing heterocyclics may be substituted at nitrogen with an oxygen atom. Sulfur-containing heterocyclics may be substituted at sulfur with one or two oxygen atoms.

(21) Configurations which result in unstable heterocyclics are not included within the scope of the definition of heterocyclic or saturated or unsaturated cyclic, bicyclic or fused ring system.

(22) As used herein, the term alkylheterocyclic refers to a heterocyclic group as defined above, which is substituted with an alkyl group as defined above.

(23) As used herein, the term heterocyclic-oxy-alkyl refers to a group of the formula heterocyclic-O-alkyl, wherein the heterocyclic and alkyl are as defined above.

(24) As used herein, the term alkoxy refers to a group of the formula alkyl-O, wherein the alkyl group is as defined above.

(25) As used herein, the term aryloxy refers to a group of the formula aryl-O, wherein the aryl group is as defined above.

(26) As used herein, the term alkanoyloxy refers to a group of the formula alkyl-C(O)O, wherein the alkyl group is as defined above.

(27) As used herein, the term group (a) refers to five member saturated or unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:

(28) ##STR00015##

(29) As used herein, the term group (b) refers to five member unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:

(30) ##STR00016##

(31) wherein each Ar and R are independently as previously defined and S and Se can be in the oxidized form S(O), S(O).sub.2 and Se(O) and Se(O).sub.2 respectively.

(32) As used herein, the term group (c) refers to five-six bicyclic member ring systems. Examples of such ring systems are:

(33) ##STR00017##

(34) wherein each R, R.sub.1 and Q.sub.1 are independently as previously defined and S and Se can be in the oxidized form such as S(O), S(O)2 and Se(O) and Se(O).sub.2 respectively.

(35) As used herein, the term group (d) refers to six-six hetero-bicyclic member ring system. Examples of such ring systems are:

(36) ##STR00018##
wherein each R, R.sub.1 and Q are independently as previously defined.

(37) The compound preparations illustrated can be carried out by generally known methods as exemplified hereinafter. The starting materials and intermediates used in the synthesis of compounds of this invention are generally commercially available or may be prepared by conventional methods of organic chemistry. Suitable methods for the synthesis of compounds of this invention and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S. Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. H. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988).

(38) Representative compounds in accordance with the invention are described in the following Tables.

(39) TABLE-US-00001 TABLE 1 Compounds of formula S. N. R X-Y G1 G2 1 CF3 CH2CH2 0 2 Me O(CH2)3 3 CH2CF3 CH2O 4 Ph CH2O 5 CH2CH2 0 6 CH2CH2 7 CH2O 8 CH2O 9 0 CH2O 10 CH2O 11 CH2O 12 CH2O 0 13 CH2O 14 CH2O 15 CH2CF3 NHSO2 16 CF3 0 17 CH2CF3 CC 18 Me 19 CC 20 0 CC 21 CC 22 CC 23 CC 0 24 CC 25 CC 26 CC 0 27 CC 28 CC 29 OMe CH2O 30 OCH2CF3 CH2O 00 31 OMe 01 02 03 32 OCH2CF3 04 05 06 33 OMe 07 08 09 34 OMe 0 35 OCH2CF3 36 CF3 OCH2CH2O 37 CN CH2O 38 N(Me)2 CH2CH2 0 39 OEt CH2O 40 OPr CH2O 41 OPr CH2O, CH2CH2 and variations thereof. G1 and G2 represent alternative groups for G

(40) TABLE-US-00002 TABLE 2 Compounds of Formula S. N. R1 R2 G 1 0 CH3 2 CH2CH2CH3 3 CH3 4 CH3 5 0 6 7 CH2CF3 Ph 8 Me Ph 9 10 0 11 12 13 0 14 15 16 17 0 18 19 20 0 21 22 23 0 24 25 26 CH2CF3 27 CH2CF3 00 28 01 CH2CF3 02 29 03 CH2CF3 04 30 05 CH2CF3 06 31 07 H, Me 08 32 09 H, Me 0 33 H, Me and variations thereof.

(41) TABLE-US-00003 TABLE 3 Compounds of formula S. N. R1 R2 X Y G 1 CH2 Ph 2 CH2 Ph 3 0 CH2 4 SO2 Ph 5 CO Ph 6 0 CH2 CH2CH2 7 CH2CF3 CH2 Ph 8 Me CH2 Ph 9 CH2 0 10 CH2 11 CH2 12 0 CO 13 CH2 CH2CH2 14 CO CH2CH2 15 0 CH2 16 CH2 CH2CH2 17 CH2 18 0 CH2 CH2CH2 19 CH2 CH2CH2 20 CH2 21 0 CH2 22 SO2 Ph 23 CH2 CH2CH2 24 0 CH2 25 CH2 CH2CH2 26 CH2CF3 CO CH2CH2 27 CH2CF3 CH2 00 01 28 02 CH2CF3 SO2 Ph 03 29 04 CH2CF3 CH2 05 06 30 07 CH2CF3 CH2 Ph 08 31 09 Me CH2 CH2 0 32 n-Hexyl Me CH2 CH2 and variations thereof.

(42) TABLE-US-00004 TABLE 4 Compounds of formula Compound No. R X R1 G 1 CH.sub.2 H 2 CH.sub.2 Cl 3 CH.sub.2 CF3 4 CH.sub.2 CF3 0 5 O iPr 6 S H 7 O 8 CH.sub.2 Me 9 0 O H 10 CH.sub.2 H 11 O CF.sub.3 12 O CH.sub.2 S H 13 O Cl 14 0 O F 15 O CF.sub.3CF.sub.2 16 O F and variations thereof.

(43) TABLE-US-00005 TABLE 5 Compounds of formula Compound No. R R1 R2 G 1 iPrO H 0 2 iPrO H 3 iPrO 3-CF3 4 MeO Cl 3-F 5 Cl Cl 2-Me 0 6 Me CF3 CF3 7 i-Pr CF3 H 8 n-Bu F 3-Cl 9 Br H 10 0 iPrO H 11 Cl Cl 2-Me 12 i-Pr CF3 2-Me 13 CF3 H 14 0 n-Pr CN 3-Me 15 nPr H 2-isoPr and variations thereof.

(44) TABLE-US-00006 TABLE 6 Compounds of formula Compound No. X R1 R2 R3 1 O OEt OEt H 2 N OEt OEt H 3 O OEt OEt OP(O)(OH).sub.2 and or salt of choice 4 O OiPr Cl H 5 0 S OEt OEt H 6 O OPr OMe H 7 O OEt CN H 8 O OPr CF3 H 9 O OPr Br H 10 O OPr Me H 11 O OBut H H 12 O O-pentyl H H 13 O -cyclohexyl H H 14 O N(Et)2 H H 15 00 O OEt 01 H 16 02 O OMe 03 H 17 04 O 05 H H 18 06 S -nPr H H and variations thereof.

(45) TABLE-US-00007 TABLE 7 Compound of formula 07 X = O, N, S Compound No. Ar X R3 1 08 O H 2 09 N H 3 0 O H 4 O H 5 S H 6 O H 7 O H 8 O H 9 O H 10 O H 11 O H 12 O H 13 0 O H 14 O H 15 O H 16 O H and variations thereof.

(46) TABLE-US-00008 TABLE 8 Compound of formula Com- pound No. T R R 1 OH 6-Cl 2 OH 7-isopropyl 3 OH 6-Cl 4 OH H 5 OH 7-Me 6 0 OH 7-Et 7 OH 8 OH 6-Cl 9 OH 6-Cl 10 OH H 11 OH H 12 OH H 13 n-Octyl OH n-Octyl And variations thereof. s represents a ring substituent.

(47) TABLE-US-00009 TABLE 9 Compound of formula X, Y and G are as defined for formula (I). Com- pound No. T R R 1 OH 6-Cl 2 0 OH 7-isopropyl 3 OH 6-Cl 4 OH H 5 OH 7-Me 6 OH 7-Et 7 OH 8 OH 6-Cl 9 OH 6-Cl 10 OH H 11 0 OH H 12 OH H 13 n-Octyl OH n-Octyl And variations thereof. s represents a ring substituent.
Methods of Synthesis:

(48) The examples (28) to (30) were prepared by the use of following procedure as in Scheme-1

(49) ##STR00452##

(50) The examples (36) to (52) were prepared by the use of following procedure as in Scheme-2 (a-b).

(51) ##STR00453##

(52) ##STR00454##
The other compounds of invention including intermediates were prepared by using various known synthesis methods like reductive amination etc. The compound preparations illustrated can be carried out by generally known methods as exemplified hereinafter. The starting materials and intermediates used in the synthesis of compounds of this invention are generally commercially available or may be prepared by conventional methods of organic chemistry. Suitable methods for the synthesis of compounds of this invention and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S. Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. H. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988). Some important Lit ref are Kim S et al, Synthesis, 2006, 5, 753-755.

EXAMPLES

(53) The following Examples describe the preparation of compounds according to the invention and are intended to illustrate the invention. The Examples are not be construed as limiting in any way the scope of the present invention. Proton NMR spectra were recorded at 300 MHz on a Bruker EM 300 spectrometer in CDCl3 unless otherwise stated. Chemical shifts for proton NMR are ppm downfield from tetramethylsilane.

(54) ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460##

Example 1

5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid

(55) Step A: Step A: 4-Hydroxy-3-iodobenzonitrile: To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH.sub.4OH (22 ml) a solution of I.sub.2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H.sub.2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H.sub.2O (3 ml). The precipitate formed was filtered off, washed with cold H.sub.2O (32 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.96 (d, 1H, 1.9 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.03 (d, 1H, J=8.5 Hz); 6.03 (s, 1H);

(56) Step B: 2-(Hydroxymethyl)benzofuran-5-carbonitrile: Propargyl alcohol (0.24 ml; 5.2 mmol) was added drop wise during 30 min to a refluxed suspension of the product of Step A (0.48 g; 1.96 mmol) and Cu.sub.2O (0.28 g; 1.96 mmol) in anhydrous pyridine (4 ml) with stirring under N.sub.2. After additional reflux for 15 min, the mixture was cooled to room temperature, diluted to 20 ml with ethyl acetate (EtOAc) and insoluble material was removed by filtration. The filtrate was evaporated to dryness under reduced pressure and the residue was diluted to 20 ml with EtOAc, washed with diluted HCl (10 ml). The insoluble material formed was filtered off and the organic phase was washed with H.sub.2O (5 ml), brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate evaporated to dryness. The residue was purified by flash column chromatography (FCC) (SiO.sub.2, CH.sub.2Cl.sub.2 and EtOAc, 9:1) to give the title compound (0.23 g; 67%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.86 (m, 1H); 7.49-7.55 (m, 2H); 6.72 (d, 1H, J=3 Hz); 4.8 (d, 2H, J=3 Hz); 2.18 (broad s, 1H);

(57) Step C: N-Hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide: A mixture of the product of Step B (0.22 g; 1.27 mmol) and HClNH.sub.2OH (0.18 g; 2.59 mmol) and N,N-diisopropylethylamine (DIPEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at 71 C. The solvents were removed in vacuo and the residue was treated with H.sub.2O (3 ml) and the product was taken up by EtOAc (315 ml). The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.2 g; 76%), as colourless solid, which was used in the next step without further purification.

(58) Step D: (5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methanol: A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (0.22 g; 1.15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at 40 C. under N.sub.2. To it 1 M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at 120 C., then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H.sub.2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO.sub.2; CH.sub.2Cl.sub.2) to give the title compound (0.13 g; 34%), as greyish solid. .sup.1H-NMR (CDCl.sub.3) 8.36 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 9 Hz); 7.79 (dd, 1H, J=3, 9 Hz); 7.68 (d, 1H, J=3 Hz); 7.55 (d, 1H, J=9 Hz); 6.98 (d, 1H, J=9 Hz); 6.73 (s, 1H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1H); 1.51 (m, 6H);

(59) Step E: 5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-carbaldehyde: A suspension of the product of Step D (0.13 g; 0.34 mmol) and MnO.sub.2 (0.15 g; 1.7 mmol) in dioxane (4 ml) was refluxed for 1 h with stirring. After cooling to room temperature, the insoluble material was removed by filtration, washed with EtOAc (20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.13 g; 100%), as greyish solid. .sup.1H-NMR (CDCl.sub.3) 9.91 (s, 1H); 8.59 (s, 1H); 8.33 (dd, 1H, J=2, 9 Hz); 7.63-7.82 (m, 4H); 6.99 (d, 1H, J=9 Hz); 4.14-4.26 (m, 4H); 1.4-1.57 (m, 6H+H.sub.2O).

(60) Step F: 5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid; To a suspension of the product of Step E (0.009 g; 0.024 mmol) and AgNO.sub.3 (0.06 g; 0.14 mmol) in EtOH (0.2 ml) H.sub.2O (0.1 ml) was added at room temperature, followed by 10% KOH (0.1 ml). The resulting black suspension was stirred for 1 h at 50 C. and cooled to room temperature and filtered. The insoluble material was washed with H.sub.2O (20.2 ml). The combined filtrates were acidified to pH=1 with HCl and the product was taken up by extraction with EtOAc (25 ml). The organic phase was washed with brine, dried over anhydrous MgSO.sub.4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO.sub.2, CH.sub.2Cl.sub.2/acetic acid (AcOH) 98/2) to give the title compound (0.00012 g; 12.8%), as a creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 8.48 (s, 1H); 8.22 (m, 1H); 7.77 (m, 1H); 7.64-7.66 (m, 2H); 7.58 (s, 1H); 6.96 (d, 1H, J=6 Hz); 4.19 (m, 4H); 1.4-1.54 (m, 6H).

Example 2

1-((5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)azetidine-3-carboxylic acid

(61) Step A: Methyl 1-((5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzo furan-2-yl)methyl)azetidine-3-carboxylate: A mixture the product of Example 1, Step E (0.07 g; 0.85 mmol), azetidine-3-methylcarboxylate hydrochloride (0.03 g; 0.199 mmol) and DIPEA (0.035 ml, 0.2 mmol) in 1,2-dichloroethane (1 ml) and methanol (MeOH) (3 ml) was sonicated for 30 min at room temperature, then evaporated to dryness. The yellowish residue was suspended in 1,2-dichloroethane (1 ml) and NaBH(OAc).sub.3 (0.12 g; 0.57 mmol) was added, followed by AcOH (0.01 ml). This was stirred for 1 h at room temperature and diluted to 15 ml with EtOAc, washed with 10% KOH (23 ml); brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (SiO.sub.2, EtOAc) to give the title compound (0.06 g; 68%), as creamy syrup. .sup.1H-NMR (CDCl.sub.3) 8.33 (d, 1H, J=3 Hz); 8.06 (dd, 1H, 3, 9 Hz); 7.78 (dd, 1H, J=3, 9 Hz); 6.87 (d, 1H, J=2 Hz); 6.63 (s, 1H); 4.14-4.22 (m, 4H); 3.6-3.7 (m, 5H); 3.48-3.34 (m, 2H); 1.49 (m, 6H).

(62) Step B: 1-((5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)azetidine-3-carboxylic acid: A mixture of the product of Step A (0.06 g; 0.126 mmol) and 10% KOH (0.1 ml) in dioxane (2 ml) was refluxed for 1 h and solvents were evaporated to dryness. The residue was treated with AcOH (0.5 ml) and evaporated to dryness in vacuo. The residue was purified by FCC (SiO.sub.2, CH.sub.2Cl.sub.2 saturated with concentrated NH.sub.4OH and MeOH, 85:15) to give the title compound (0.032 g; 55%), as a colourless solid. .sup.1H-NMR (CD.sub.3OD+CDCl.sub.3) 8.37 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 6 Hz); 7.77 (dd, 1H, J=3, 9 Hz); 7.68 (s, 1H); 7.6 (d, 1H, J=9 Hz); 7.02-7.07 (m, 2H); 4.38 (s, 2H); 4.05-4.21 (m, 8H); 1.44-1.49 9m, 6H).

Example 3

N-(1H-Tetrazol-5-yl)methyl-4-octylbenzylamine

(63) Step A: 4-n-Octylbenzaldehyde: A mixture of n-octylbenzene (1.2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid (TFA) was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO.sub.3 and extracted with diethyl ether (Et.sub.2O) (35 ml). The combined organic phase was washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67%). .sup.1H-NMR (CDCl.sub.3) 9.96 (s, 1H); 7.77 (d, 2H, J=8.1 Hz); 7.31 (d, 2H, J=8.1 Hz); 2.67 (t, 2H, J=7.9 Hz); 1.6 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz);

(64) Step B: 2-(4-Octylbenzylamino)acetonitrile: T a suspension of the product of Step A (0.17 g; 0.78 mmol) and aminoacetonitrile bisulphate (0.18 g; 1.17 mmol) and NaBH(OAc).sub.3 in 1,2 dichloroethane (3 ml), DIPEA (0.2 nil; 1.17 mmol) was added at room temperature followed by AcOH (0.045 ml; 0.78 mmol). The resulting mixture was stirred over a weekend at room temperature under N.sub.2 and quenched by an addition of 1 M NaOH (0.5 ml). This was diluted to 15 ml with Et.sub.2O, washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was diluted to 3 ml with anhydrous MeOH and to it NaBH.sub.4 (0.1 g; 2.6 mmol) was added portion wise at room temperature with stirring. After stirring overnight, the mixture was evaporated to dryness and the residue was diluted to 15 ml with Et.sub.2O, washed with 1N NaOH, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 6:4) to give the title compound (0.07 g; 28%) as a colourless syrup. .sup.1H-NMR (CDCl.sub.3) 7.23 (d, 2H, J=8.01 Hz); 7.14 (d, 2H, J=8.01 Hz); 3.88 (s, 2H); 3.55 (s, 2H); 2.58 (t, 2H, J=7.94 Hz); 1.6 (m, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J=6.93 Hz).

(65) Step C: N-(1H-Tetrazol-5-yl)methyl-4-n-octylbenzylamine: A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me.sub.3SiN.sub.3 (0.36 ml; 2.71 mmol) and 1M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 755 C. for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N.sub.2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et.sub.2O and dried to give a title compound (0.069 g; 84%) as colourless solid. .sup.1H-NMR (CD.sub.3OD) 7.32 (d, 2H, J=8.0 Hz); 7.21 (d, 2H, J=8.0 Hz); 4.72 (s, CD.sub.3OH); 4.34 (s, 2H); 4.16 (s, 2H); 2.59 (t, 2H, J=7.76 Hz); 1.57 (t, 2H, J=7.19 Hz); 1.25 (m, 10H); 0.84 (t, 3H, J=6.93 Hz);

Example 4

N-((1H-Tetrazol-5-yl)methyl)-4-n-octylaniline

(66) Step A: 2-(4-Octylphenylamino)acetonitrile: A mixture of 4-n-octylaniline (0.21 g; 1 mmol), BrCH.sub.2CN (0.156 mmol; 1.3 mmol) and K.sub.2CO.sub.3 (0.28 g; 2 mmol) in anhydrous CH.sub.3CN (3 ml) was stirred overnight at 60 C. under N.sub.2, then concentrated under reduced pressure. The residue was partitioned between CH.sub.2Cl.sub.2 (20 ml) and H.sub.2O (10 ml). The organic phase was dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from hexane to give the title compound (0.18 g; 74%) as creamy solid. .sup.1H-NMR (CDCl.sub.3) 7.06 (d, 2H, J=8.48 Hz); 6.63 (d, 2H, J=8.48 Hz); 4.06 (d, 2H, J=5.75 Hz); 3.83 (broad m, 1H); 2.51 (t, 2H, J=7.92 Hz); 1.55 (m, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J=6.87 Hz).

(67) Step B: N-((1H-Tetrazol-5-yl)methyl)-4-n-octylaniline: When the product of Step A was substituted for 2-(4-octylbenzylamino)acetonitrile in Example 3, Step C, the identical process afforded the title compound in 77% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3) 6.94 (d, 2H, J=8.37 Hz); 6.61 (broad s, 2H); 6.49 (d, 2H, J=8.37 Hz); 4.68 (m, 2H); 2.44 (t, 2H, J=7.94 Hz); 1.49 (t, 2H, J=7.55 Hz); 1.24 (m, 10H); 0.85 (t, 3H, J=6.95 Hz).

Example 5

2-(4-Octylphenylamino)propane-1,3-diol

(68) Step A: 2,2-Dimethyl-N-(4-octylphenyl)-1,3-dioxan-5-amine: To a mixture of 4-n-octylaniline (0.205 g; 1 mmol) and 2,2-dimethyl-1,3-dioxan-5-one (Helvetica Chimica Acta, 2003, 86, 2467; 0.13 g; 1 mmol) and NaBH(OAc).sub.3 in 1,2 dichloroethane (3.5 ml), AcOH (0.06 ml; 1 mmol) was added and the mixture was stirred for 2 h at room temperature under N.sub.2, diluted to 20 ml with Et.sub.2O and washed with 1N NaOH, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified crystallization from hexane to give the title compound (0.2 g; 63%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 6.97 (d, 2H, J=8.4 Hz); 6.54 (d, 2H, J=8.4 Hz); 4.1 (dd, broad s, 3H, J=4.2, 11.9 Hz); 3.74 (dd, 2H, J=4.2, 11.9 Hz); 3.4 (m, 1H); 2.47 (t, 2H, J=7.91 Hz); 1.55 (m, 2H+H.sub.2O); 1.46 (s, 3H); 1.43 (s, 3H); 1.25 (m, 10H); 0.86 (m, 3H).

(69) Step B: 2-(4-octylphenylamino)propane-1,3-diol: To a solution of the product of Step A (0.1 g; 0.31 mmol) in MeOH (1 ml) Me.sub.3SiCl (0.5 ml) was added at room temperature. After stirring for 1 h, the mixture was evaporated to dryness under reduced pressure to give a hydrochloride salt of the title compound (0.1 g; 100%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 10.66 (bs, 2H); 7.53 (d, 2H, J=7.98 Hz); 7.18 (d, 2H, J=7.98 Hz); 4.82 (broad s, 2H); 3.98 (broad m, 4H); 3.51 (broad m, 1H); 2.58 (t, 2H, J=7.68 Hz); 1.56 (m, 2H); 1.43 (s, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J=6.96 Hz).

Example 6

2-((4-n-Octylbenzylamino)methyl)propane-1,3-diol

(70) Step A: 4-n-Octylbenzyl alcohol: NaBH.sub.4 (0.04 g; 1.06 mmol) was added portion wise to a solution of the product of Example 3, Step A in MeOH (5 ml) at room temperature, with vigorous stirring. After 30 min of stirring, the mixture was evaporated to dryness, diluted to 10 ml with Et.sub.2O and washed with 1N NaOH, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.082 g; 100%), as colourless syrup, which was used in next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.26 (d, 2H, J=8 Hz); 7.15 (d, 2H, J=8 Hz); 4.64 (s, 2H); 2.58 (t, 2H, J=7.9 Hz); 1.56 (m, 3H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz).

(71) Step B: 4-n-octylbenzyl bromide: PBr.sub.3 (0.23 ml) was added drop wise to a stirred solution of the product of Step A (0.082 g; 0.37 mmol) in Et.sub.2O (2 ml) at 15 C. The mixture was allowed to warm up to room temperature and the stirring was continued for 4 h. This was poured onto ice (5 g) and the product was extracted with fresh Et.sub.2O (210 ml). The combined extracts were washed with 5% NaHCO.sub.3, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane) to give the title compound (0.04 g; 40%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.28 (d, 2H, J=8 Hz); 7.13 (d, 2H, J=8 Hz); 4.48 (s, 2H); 2.57 (t, 2H, J=7.9 Hz); 1.57 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

(72) Step C: 4-n-Octylbenzylamine: To a solution of the product of Step B (0.13 g; 0.459 mmol) in anhydrous hexamethylenedisilazane (HMDSA) 1M NaHMDSA in THF was added at room temperature under N.sub.2 with stirring. After stirring overnight at room temperature solvents were removed under reduced pressure and the residue was diluted to 5 ml with MeOH and 1 drop of concentrated HCl was added. This was evaporated under reduced pressure, diluted to 15 ml with Et.sub.2O and washed with 1N NaOH, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.1 g; 100%), as colourless oil, which was used in the next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.2 (d, 2H, J=8 Hz); 7.13 (d, 2H, J=8 Hz); 3.82 (s, 2H); 2.57 (t, 2H, J=7.9 Hz); 1.58 (m, 2H); 1.41 (s, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

(73) Step D: (2,2-Dimethyl-1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine: When the product of Step C was substituted for 4-n-octylaniline in Example 5, Step A, the identical process afforded the title compound in 86% yield, as a colourless syrup. .sup.1H-NMR (CDCl.sub.3) 7.23 (d, 2H, J=8 Hz); 7.11 (d, 2H, J=8 Hz); 3.96 (dd, 2H, J=5.57, 11.73 Hz); 1.73 Hz); 3.83 (s, 2H); 3.75 (dd, 2H, J=5.57, 2.69 (m, 1H); 2.56 (t, 2H, J=7.88 Hz); 1.81 (broad s, 1H+H.sub.2O); 1.4 (m, 5H); 1.25 (m, 13H); 0.86 (t, 3H, J=6.96 Hz).

(74) Step E: 2-((4-n-Octylbenzylamino)methyl)propane-1,3-diol: A solution of the product of Step D (0.6 g; 0.13 mmol) in 60% trifluoroacetic acid (TFA) in CH.sub.2Cl.sub.2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with MeOH and evaporated to dryness under reduced pressure. The residue was dissolved in iso-propanol (iPrOH) (2 ml) and one drop of concentrated HCl was added. This was evaporated under reduced pressure and treated with anhydrous Et.sub.2O. The precipitate formed was filtered off, dried in vacuo for 1 h to give a hydrochloride salt of the title compound (0.04 g; 85%), as a colourless solid. .sup.1H-NMR (D.sub.2O) 7.32 (d, 2H, J=7.56 Hz); 7.21 (d, 2H, J=7.56 Hz); 4.2 (s, 2H); 4.66 (DHO); 3.69 (s, 4H); 3.36 (s, 2H); 2.52 (t, 2H, J=7.47 Hz); 1.49 (s, 2H); 1.16 (m, 10H); 0.74 (m, 3H).

Example 7

2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-diol

(75) Step A: (2,2-dimethyl-1,3-dioxan-5-yl)-N-methyl-N-(4-octylbenzyl)methyl amine: When the product of Example 6, Step D is substituted for 4-n-octylaniline and 30% aqueous HCHO is substituted for 2,2-dimethyl-1,3-dioxan-5-one in Example 3, Step A, the identical process afforded the title compound in 100% yield, as a colourless syrup. .sup.1H-NMR (CDCl.sub.3) 7.2 (d, 2H, J=7.75 Hz); 7.11 (d, 2H, J=7.75 Hz); 3.83 (s, 2H); 3.94 (m, 4H); 3.64 (s, 2H); 2.83 (m, 1H); 2.56 (d, 2H, J=7.3 Hz); 2.29 (s, 3H); 1.58 (m, 2H+H.sub.2O); 1.25-1.42 (m, 18H); 0.86 (m, 3H).

(76) Step B: 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-diol: When the product of Step A is substituted for (2,2-dimethyl-1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine in Example 6, Step E, the identical process afforded the title compound in 79% yield, as a glassy solid. .sup.1H-NMR (D.sub.2O) 7.3 (d, 2H, J=7.8 Hz); 6.96 (d, 2H, J=7.8 Hz); 4.66 (DHO); 4.24 (s, 2H); 3.73 (m, 4H); 3.32 (m, 1H); 2.7 (s, 3H); 2.3 (t, 2H, J=7.63 Hz); 1.36 (m, 2H); 1.15 (s, 2H); 1.15 (m, 10H); 0.73 (t, 3H, J=6.73 Hz).

Example 8

4,4-Bis(hydroxymethyl)-1-(4-octylphenyl)imidazolidin-2-one

(77) Step A: tert-Butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate: To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Ooii et al, J. Org. Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc).sub.3 (0.3 g; 1.4 mmol) in 1,2-dichloroethane (3.5 ml) AcOH (0.06 ml; 1 mmol) was added at room temperature with stirring under N.sub.2. After stirring for 2 h, the mixture was diluted to 20 ml with Et.sub.2O, washed with 1.M NaOH (25 ml), brine and dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexane (5 ml) and kept in the freezer (18 C.) overnight. The crystals formed were filtered off, washed with small volume of hexane and dried to give the title compound (0.32 g; 71%), as colourless crystals. .sup.1H-NMR (CDCl.sub.3) 6.96 (d, 2H, J=8.4 Hz); 6.58 (d, 2H, J=8.4 Hz); 4.84 (broad s, 1H); 4.01 (d, 2H, J=11.9); 3.85 (broad s, 1H); 3.8 (d, 2H, J=11.9 Hz); 3.44 (s, 2H); 2.46 (t, 2H, J=7.9 Hz); 1.5 (m, 2H); 1.45 (s, 3H); 1.43 (s, 9H); 1.42 (s, 3H); 1.26 (m, 10H); 0.86 (t, 2H, J=6.95 Hz).

(78) Step B: 4,4-(2,2-Dimethyl-1,3-dioxanyl)-1-(4-octylphenyl)imidazolidin-2-one: A solution of the product of Step A (0.17 g; 0.38 mmol) and 60% NaH in mineral oil (0.043 g; 1.14 mmol) in anhydrous DMF (4 nil) was stirred overnight at 55 C. under N.sub.2. After removal of solvent in vacuo, the residue was diluted to 15 ml with Et.sub.2O, washed with 10% citric acid, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 8:2) to give the title compound (0.06 g; 42%) as a colourless solid and starting material (0.1 g; 58%). .sup.1H-NMR (CDCl.sub.3) 7.41 (d, 2H, J=8.58 Hz); 7.12 (d, 2H, J=8.58 Hz); 5.27 (broad s, 1H); 3.84 (d, 2H, J=11.3 Hz); 3.78 (d, 2H, J=11.3 Hz); 3.68 (s, 2H); 2.55 (t, 2H, J=7.83 Hz); 1.56 (m, 2H); 1.28 (m, 10H); 0.84 (t, 3H, J=6.76 Hz).

(79) Step C: 4,4-Bis(hydroxymethyl)-1-(4-octylphenyl)imidazolidin-2-one: When the product of Step B is substituted for (2,2-dimethyl-1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine in Example 6, Step E, the identical process afforded the title compound in 74% yield, as a colourless solid, after purification by FCC (SiO.sub.2, CH.sub.2Cl.sub.2 saturated with concentrated NH.sub.4OH/MeOH; 98:2). .sup.1H-NMR (CDCl.sub.3) 7.30 (d, 2H, J=8.49 Hz); 7.02 (d, 2H, J=8.49 Hz); 6.53 (s, 1H); 4.65 (broad s, 2H); 3.48-3.62 (m, 6H); 2.47 (t, 2H, J=7.94 Hz); 1.51 (m, 2H); 1.25 (m, 10H); 0.87 (t, 3H, J=6.94 Hz).

Example 9

2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid

(80) Step A: 4-n-Octyliodobenzene: To a suspension of n-octylbenzene (1 g; 5.2 mmol) and CF.sub.3SO.sub.3Ag (1.35 g; 5.2 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 ml) I.sub.2 was added at 0 C. The resulting mixture was allowed to warm up to room temperature and stirred for additional 1 h, then filtered through a pad of Celite, washed with fresh CH.sub.2Cl.sub.2 (215 ml) and combined filtrates washed with 5% Na.sub.2SO.sub.3, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title product and 2-iodo isomer (1.64 g; 100%), as creamy oil, which was used in the next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.7-7.8 (m, 0.3H); 7.56 (d, 1.7; H, J=8.3 Hz); 7.29-7.16 (m, 0.6H); 6.9 (d, 1.4H, J=8.3 Hz); 6.85-6.82 (m, 0.3H); 2.68 (t, 0.6, J=8.01 Hz); 2.52 (t, 1.4H, J=7.89 Hz); 1.56 (m, 2H); 1.25 (m, 10H); 0.86 (m, 3H).

(81) Step B: tert-Butyl 4-(benzoyloxy)piperazine-1-carboxylate: To a suspension of benzoyl peroxide+15% H.sub.2O (1.47 g; 4.55 mmol) and K.sub.2HPO.sub.4 (1.19 g; 6.8 mmol) in DMF (11.36 ml) NBOC piperazine (Sengmany et al, Tetrahedron, 2007, 63, 3672; 1 g; 5.4 mmol) was added and the mixture was stirred for 1 h at room temperature. To it, H.sub.2O (20 ml) was added and the resulting mixture was vigorously stirred until homogenous. This was extracted with EtOAc (15 ml). The organic phase was washed with H.sub.2O and combined aqueous phase was extracted with fresh EtOAc (310 ml). The combined organic phase was washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title product (0.9 g; 65%), as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 8-7.96 (m, 2H); 7.59-7.53 (m, 1H); 7.45-7.38 (m, 2H); 4.01 (m, 2H); 3.41-3.2 (m, 4H); 2.9 (m, 2H); 1.46 (s, 9H).

(82) Step C: tert-Butyl 4-(4-octylphenyl)piperazine-1-carboxylate: To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCl in THF (0.56 ml; 1.11 mmol) was added at 15 C. under N.sub.2, followed 1.27 M solution of anhydrous ZnCl.sub.2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at 0 C. The resulting mixture was stirred for 30 min on ice-bath under N.sub.2 and the solution of the product of Step B (0.16 g; 0.51 mmol) and CuCl.sub.2 (2.5 mol %) in anhydrous THF (10 ml) was added. The resulting mixture was allowed to warm up to room temperature and stirred for additional 10 min. This was diluted to 20 ml with Et.sub.2O and washed with 5% NaHCO.sub.3, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 9:1) to give the title compound (0.06 g; 31%), as a creamy syrup. .sup.1H-NMR (CDCl.sub.3) 7.07 (d, 2H, J=8.6 Hz); 6.84 (d, 2H, J=8.6 Hz); 3.55 (t, 4H, J=5 Hz); 3.06 (t, 4H, J=5 Hz); 2.51 (t, 2H, J=7.94 Hz); 1.55-1.38 (m, 11H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.93 Hz).

(83) Step D: 1-(4-n-Octylphenyl)piperazine: A solution of the product of Step C (0.06 g; 0.16 mmol) in 60% TFA in CH.sub.2Cl.sub.2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with EtOH and evaporated to dryness under reduced pressure and kept in vacuo for 1 h, to give a TFA salt of the title compound (0.07 g; 100%). .sup.1H-NMR (CDCl.sub.3) 9.5 (broad s, 2H); 7.29 (m, 4H); 3.8-3.16 (m, 8H); 2.6 (t, 2H, J=8 Hz); 1.58 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz).

(84) Step E: tert-Butyl 2-(4-(4-octylphenyl)piperazin-1-yl)acetate: To a solution of the product of Step D (0.04 g, 0.146 mmol) and tert-butyl bromoacetate (0.026 ml; 0.16 mmol) in CH.sub.2Cl.sub.2 (1 ml) DIPEA (0.052 nil; 0.32 mmol) was added at room temperature under N.sub.2. The mixture was stirred overnight at room temperature, diluted to 5 ml with Et.sub.2O and washed with 0.1 N HCl, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 7:3) to give the title compound (0.05 g; 88%), as a colourless heavy syrup. .sup.1H-NMR (CDCl.sub.3) 7.05 (d, 2H, J=8.6 Hz); 6.83 (d, 2H, J=8.6 Hz); 3.32-3.15 (m, 6H); 2.73 (m, 4H); 2.5 (t, 2H, J=7.9 Hz); 1.55 (m, 2H); 1.46 (s, 9H); 1.26 (m, 10H); 0.86 (m, 3H).

(85) Step F: 2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid: A solution of the product of Step E (0.05 g; 0.129 mmol) in 60% TFA in CH.sub.2Cl.sub.2 (5 ml) was refluxed for 2 h, cooled to room temperature then diluted to 7 ml with EtOH. The resulting mixture was evaporated to dryness under reduced pressure kept in vacuo for 1 h. The residue was treated dissolved in EtOH (2 ml) and 3 drops of concentrated NH.sub.4OH was added. The resulting mixture was partially concentrated under reduced pressure and the precipitate, formed was filtered off, washed with Et.sub.2O and dried to give the titled compound (0.02 g; 47%) as colourless solid. .sup.1H-NMR (CD.sub.3OD+CDCl.sub.3) 7.07 (d, 2H, J=8.6 Hz); 6.86 (d, 2H, J=8.6 Hz); 4.63 (s, CD.sub.3OH); 3.58 (s, 2H); 3.38 (m, 8H); 2.49 (t, 2H, J=7.8 Hz); 1.53 (m, 2H); 1.24 (m, 10H); 0.83 (m, 3H).

Example 10

2-(4-Octylphenethyl)propane-1,2,3-triol

(86) Step A: 1-Ethynyl-4-octylbenzene: A mixture of Example 3, Step A (0.1 g; 0.46 mmol), dimethyl(1-diazo-2-oxoprpyl)phosphonate (0.11 g, 0.57 mmol) and anhydrous K.sub.2CO.sub.3 (0.14 g, 1.01 mmol) in dry MeOH (5 ml) was stirred for 8 h under N.sub.2. After removing solvent under reduced pressure, the residue was diluted to 15 ml with Et.sub.2O and washed with H.sub.2O (210 ml) and dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane) to give the title compound (0.05 g; 51%) as colourless oil. .sup.1H-NMR (CDCl.sub.3) 7.38 (d, 2H, J=8.1 Hz); 7.11 (d, 2H, J=8.1 Hz); 3.0 (s, 1H); 2.58 (t, 2H, J=7.8 Hz); 1.58 (t, 3H, J=6.96 Hz); 1.27 (m, 10H); 0.86 (t, 3H, J=6.96 Hz).

(87) Step B: 2,2-Dimethyl-5-((4-octylphenyl)ethynyl)-1,3-dioxan-5-ol: To a solution of the product of Step A (0.05 g; 0.233 mmol) in anhydrous THF (2 ml) 2 M n-butyllithium in cylohexane (0.13 ml; 0.26 mmol) was added drop wise at 15 C. under N.sub.2. After stirring for 15 min at 15 C., 2,2-dimethyl-1,3-dioxan-5-one (0.034 g; 0.26 mmol) was added and the resulting mixture was allowed to warm up to room temperature, diluted to 15 ml with Et.sub.2O and washed with H.sub.2O (210 ml), brine and dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 95; 5) to give the title compound (0.03 g; 63%) as colourless oil. .sup.1H-NMR (CDCl.sub.3) 7.33 (d, 2H, J=8.09 Hz); 7.09 (d, 2H, J=8.09 Hz); 4.11 (d, 2H, J=11.76 Hz); 3.83 (d, 2H, J=11.76 Hz); 3.99 (s, 1H); 2.57 (t, 2H, J=7.88 Hz); 1.56 (t, 3H, J=6.94 Hz); 1.49 (s, 3H); 1.46 (s, 3H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.96 Hz).

(88) Step C: 2-(4-Octylphenethyl)propane-1,2,3-triol: A mixture of the product of Step B (0.03 g; 0.087 mmol) and 10% Pd/C (0.05 g) in 5% TFA in EtOH (10 ml) was stirred for 1 h under H.sub.2 (balloon) at room temperature, then filtered through a pad of Celite, washed with CH.sub.2Cl.sub.2 (210 ml). To combined filtrates were evaporated to dryness under reduced pressure and dried in vacuo for 1 h to give title compound (0.027 g; 99%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.05 (s, 4H); 3.66 (broad m, 7H); 2.61 (m, 2H); 2.51 (t, 2H, J=7.92 Hz); 1.73 (m 2H); 1.55 (t, 3H, J=6.93 Hz); 1.26 (m, 10H); 0.87 (t, 3H, J=6.93 Hz).

Example 11

3-(3-(4-n-Octylphenyl)ureido)propanoic acid

(89) Step A: Ethyl 3-(3-(4-octylphenyl)ureido)propanoate: To 4-n-octylaniline (0.1 g; 0.49 mmol) ethyl 3-isocyanatopropionate (0.08 g; 0.54 mmol) was added at room temperature. The resulting mixture was diluted to 1 ml with CH.sub.2Cl.sub.2, refluxed for 30 min and evaporated to dryness. The residue was treated with Et.sub.2O (5 ml) and the solid formed was filtered off and dried to give the title compound (0.15 g; 87%), as colourless crystals. .sup.1H-NMR (CDCl.sub.3) 7.22-7.07 (m, 4H); 6.34 (broad s, 1H); 5.34 (m, 1H); 4.15-4.07 (m, 2H); 3.54-3.46 (m, 2H); 2.73 (m, 4H); 2.57-2.51 (m, 4H); 1.58 (m, 2H); 1.27-1.19 (m, 13H); 0.86 (m, 3H).

(90) Step B: 3-(3-(4-n-Octylphenyl)ureido)propanoic acid: To a solution of the product of Step A (0.05 g; 0.143 mmol) in dioxane (1 ml) 2N KOH (0.36 ml; 0.72 mmol) was added and the mixture was refluxed for 15 min, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was diluted to 2 ml with H.sub.2O and filtered. The filtrate was acidified to pH 4 with citric acid. The solid formed was filtered off, washed with H.sub.2O (32 ml), dried in vacuo to give the title compound (0.03 g; 65%), as a colourless solid. .sup.1H-NMR (CD.sub.3OD+CDCl.sub.3) 7.16 (d, 2H, J=8.4 Hz); 7.0 (d, 2H, J=8.4 Hz); 4.21 (s, CD.sub.3OH); 3.4 (t, 2H, J=6.7 Hz); 2.73 (m, 4H); 2.5-2.44 (m, 4H); 1.5 (m, 2H); 1.2 (m, 10H); 0.81 (m, 3H).

Example 12

3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid

(91) Step A: tert-Butyl 4-n-octylphenyl(methyl)carbamate: A mixture of 4-noctylaniline (0.09 g; 0.44 mmol) and di-tert-butyl dicarbonate (0.1 g; 0.46 mmol) and a few drops of triethylamine was stirred at 50 C. for 1 h under N.sub.2, cooled to room temperature and kept in vacuo for 30 min. The residue was dissolved in anhydrous DMF (2 ml) and %60 NaH in mineral oil (0.02 g: 0.47 mmol) was added to it, followed by Mel (0.03 ml; 0.47 mmol), after stirring for 30 min under N.sub.2. The resulting mixture was stirred for 3 h at room temperature and solvent was removed in vacuo. The residue was diluted to 15 ml with Et.sub.2O and washed with 5% Na.sub.2SO.sub.3, H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.14 g; 100%), as a creamy solid. .sup.1H-NMR (CDCl.sub.3) 7.14-6.99 (m, 4H); 3.22 (s, 3H); 2.55 (m, 2H); 1.56 (m, 2H); 1.43 (s, 9H); 1.26 (m, 10H); 0.86 (m, 3H).

(92) Step B: N-Methyl-4-n-octylaniline: A solution of the product of Step A (0.14 g; 0.44 mmol) in 60% TFA in CH.sub.2Cl.sub.2 (5 ml) was stirred for 30 min at room temperature and the mixture was diluted to 5 ml with EtOH and a few drops of concentrated HCl was added. This was evaporated to dryness under reduced pressure, kept in vacuo for 1 h and the residue was partitioned between saturated NaHCO.sub.3 (5 ml) and Et.sub.2O (15 ml). The organic phase was dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 9:1) to give the title compound (0.055 g; 57%), as a creamy solid. .sup.1H-NMR (CDCl.sub.3) 7.01 (d, 2H, J=8.2 Hz); 6.55 (d, 2H, J=8.2 Hz); 3.55 (broad s, 1H); 2.81 (s, 3H); 2.49 (t, 2H, J=7.9 Hz); 1.56 (m, 2H); 1.28 (m, 10H); 0.88 (t, 3H, J=6.8 Hz).

(93) Step C: Ethyl 3-(3-methyl-3-(4-octylphenyl)ureido)propanoate: When the product of Step B is substituted for 4-n-octylaniline in Example 1, Step A, the identical process afforded the title compound in 99% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.15 (d, 2H, J=8.2 Hz); 7.05 (d, 2H, J=8.2 Hz); 4.77 (m, 1H); 4.03 (q, 2H, J=7.14 Hz); 3.54 (m, 2H); 3.37 (qr, 2H, J=6.1 Hz); 3.18 (s, 3H); 2.55 (t, 2H, J=7.5 Hz); 2.44 (t, 2H, J=6.1 Hz); 1.57 (m, 2H); 1.25 (m, 10H); 1.13 (t, 3H, J=7.14 Hz); 0.83 (t, 3H, J=6.9 Hz).

(94) Step D: 3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid: When the product of Step C is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1, Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.19 (d, 2H, J=8.3 Hz); 7.09 (d, 2H, J=8.3 Hz); 4.83 (m, 1H); 3.54 (m, 2H); 3.4 (m, 2H); 3.22 (s, 3H); 2.6-2.5 (m, 4H); 1.59 (m, 2H); 1.27 (m, 10H); 0.86 (t, 3H, J=7 Hz).

Example 13

3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1-yl)propanoic acid

(95) Step A: Ethyl 3-(3-(4-octylphenyl)-2-oxoimidazolidin-1-yl)propanoate: To a solution of the product of Example 11, Step A (0.05 g; 0.143 mmol) in anhydrous DMF (2 ml) 60% NaH in mineral oil (0.014 g; 0.344 mmol) was added at room temperature. After stirring for 1 h, to it 1,2-dibromoethane (0.172 ml; 0.2 mmol) was added. This was stirred at 50 C. for 1 h under N.sub.2, cooled to room and solvents were removed in vacuo. The residue was diluted to 15 ml with Et.sub.2O, washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc 9.5:0.5) to give the title compound (0.02 g; 37%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.4 (d, 2H, J=8.5 Hz); 7.1 (d, 2H, J=8.5 Hz); 4.13 (q, 2H, J=7.1 Hz); 3.76 (m, 2H); 3.57 (t, 2H, J=6.7 Hz); 3.5 (m, 2H); 2.6 (t, 2H, J=6.7 Hz); 2.53 (t, 2H, J=7.9 Hz); 1.55 (m, 2H); 1.24 (m, 13H); 0.85 (t, 3H, J=6.9 Hz).

(96) Step B: 3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1-yl)propanoic acid: When the product of Step A is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1, Step B, the identical process afforded the title compound in 33% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.39 (d, 2H, J=8.4 Hz); 7.11 (d, 2H, J=8.4 Hz); 3.78 (t, 2H, J=7.3 Hz); 3.6-3.4 (m, 4H); 3.22 (s, 3H); 2.66 (t, 2H, J=6.5 Hz); 2.53 (t, 2H, J=7.7 Hz); 1.55 (m, 2H); 1.25 (m, 10H); 0.85 (t, 3H, J=6.9 Hz).

Example 14

2-(3-(4-Octylbenzyl)ureido)acetic acid

(97) Step A: Ethyl 2-(3-(4-octylbenzyl)ureido)acetate: When the product of Example 6, Step C was substituted for 4-n-octylaniline and ethyl 2-isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 11, Step A, the identical process afforded the title compound in 75% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.18 (d, 2H, J=8 Hz); 7.11 (d, 2H, J=8 Hz); 4.86 (m, 1H); 4.78 (m, 1H); 4.32 (d, 2H, J=5.6 Hz); 4.16 (q, 2H, J=7.1 Hz); 3.97 (d, 2H, J=5.3 Hz); 2.56 (t, 2H, J=8 Hz); 1.56 (m, 2H); 1.25 (m, 13H); 0.86 (t, 3H, J=6.9 Hz).

(98) Step B: 2-(3-(4-Octylbenzyl)ureido)acetic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1, Step B, the identical process afforded the title compound in 87% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.15 (d, 2H, J=8 Hz); 7.07 (d, 2H, J=8 Hz); 4.63 (CD.sub.3OH); 4.26 (s, 2H); 3.86 (s, 2H); 2.52 (t, 2H, J=7.8 Hz); 1.54 (m, 2H); 1.22 (m, 10H); 0.83 (t, 3H, J=7 Hz).

Example 15

2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1-yl)acetic acid

(99) Step A: tert-Butyl 2-(2-oxoimidazolidin-1-yl)acetate: To a solution of imidazolidin-2-one (0.2 g; 2.3 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.18 g; 4.6 mmol) was added at room temperature, under N.sub.2. After stirring for 1 h, tert-butyl 2-bromoacetate (0.35 ml; 2.3 mmol) was added. The resulting mixture was stirred for additional 2 h and solvents were removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, EtOAc) to give the title compound (0.12 g; 26%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 4.61 (broad s, 1H); 3.83 (s, 2H); 3.58-3.41 (m, 4H); 1.44 (s, 9H).

(100) Step B: tert-Butyl 2-(3-(4-octylbenzyl)-2-oxoimidazolidin-1-yl)acetate: To a solution of the product of Step A (0.03 g; 0.15 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.006 g; 0.15 mmol) was added at room temperature, under N.sub.2. After stirring for 1 h, the product of Example 4, Step B (0.042 g; 0.15 mmol) was added. The resulting mixture was stirred for additional 4 h and solvents were removed in vacuo. The residue was diluted to 10 ml with EtOAc, washed with H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.01 g; 16%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.16 (d, 2H, J=8.1 Hz); 7.11 (d, 3H, J=8.1 Hz); 4.34 (s, 2H); 3.95 (s, 2H); 3.4 (m, 2H); 3.21 (m, 2H); 2.56 (t, 3H, J=7.9 Hz); 1.65 (m, 2H); 1.43 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

(101) Step C: 2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1yl)acetic acid: When the product of Step B was substituted for tert-butyl 2-(4-(4-octylphenyl)piperazin-1-yl)acetate in Example 9, Step F, the identical process afforded the title compound in 46% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.0 (m, 4H); 4.42 (s, 2H); 3.72 (s, 2H); 3.31 (m, 2H); 3.11 (m, 2H); 2.44 (t, 2H, J=7.8 Hz); 1.43 (m, 2H); 1.13 (m, 10H); 0.73 (t, 3H, J=7 Hz).

Example 16

2-(1-(4-Octylbenzyl)hydrazine-carboxamido)acetic acid

(102) Step A: tert-Butyl 2-(4-octylbenzylidene)hydrazinecarboxylate: To a mixture of Example 3, Step A (0.1 g; 0.46 mmol) and tert-butyl carbazate (0.06 g; 0.46 mmol) in anhydrous CH.sub.2Cl.sub.2 (5 ml) anhydrous MgSO.sub.4 was added and the resulting suspension was vigorously stirred for 2 h at room temperature and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.13 g; 87%) as yellowish solid, which was used in next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.8 (broad s, 1H); 7.56 (d, 2H, J=8.1 Hz); 7.15 (d, 2H, J=8.1 Hz); 2.58 (t, 2H, J=7.9 Hz); 1.59 (m, 2H); 1.52 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

(103) Step B: tert-Butyl 2-(4-octylbenzyl)hydrazinecarboxylate: To a solution of the product of Step A (0.13 g; 0.391 mmol) in anhydrous THF (1 ml) and glacial AcOH (0.6 ml) NaBH.sub.3CN (0.06 g; 0.95 mmol) was added at 0 C. (ice bath). The resulting mixture was stirred overnight at room temperature then diluted to 15 ml with Et.sub.2O. This was washed with 5% NaHCO.sub.3H.sub.2O, brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.01 g; 16%) as a colourless syrup, which was used in the next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.23 (d, 2H, J=8 Hz); 7.12 (d, 3H, J=8 Hz); 6.0 (s, 1H); 4.1 (broad s, 2H); 3.94 (s, 2H); 2.57 (t, 3H, J=7.9 Hz); 1.56 (m, 2H); 1.45 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

(104) Step C: tert-Butyl 2-(2-ethoxy-2-oxoethylcarbamoyl)-2-(4-octylbenzyl)-hydrazinecarboxylate: When the product of Step B was substituted for 4-n-octylbenzylamnie in Example 14, Step A, the identical process afforded the title compound in 84% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.14 (m, 4H); 5.95 (s, 1H); 5.87 (t, 1H, J=5 Hz); 4.5 (broad s, 1H); 4.19 (q, 2H, J=7.1 Hz); 4.03 (d, 2H, J=5 Hz); 2.57 (t, 2H, J=7.9 Hz); 1.56 (m, 2H); 1.44 (s, 9H); 1.27 (m, 13H); 0.86 (t, 3H, J=7 Hz).

(105) Step D: Ethyl 2-(1-(4-octylbenzyl)hydrazinecarboxamido)acetate: When the product of Step C was substituted for tert-butyl 4-n-octylphenyl(methyl)carbamate in Example 12, Step B, the identical process afforded the title compound in 89% yield, as a creamy solid, which was used in the next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.15 (m, 4H); 6.84 (broad m, 1H); 4.66 (s, 2H); 4.2 (q, 2H, J=7.14 Hz); 4.02 (d, 2H, J=5.8 Hz); 3.42 (bs, 2H); 2.57 (t, 2H, J=7.9 Hz); 1.57 (m, 2H); 1.27 (m, 13H); 0.86 (t, 3H, J=6.9 Hz).

(106) Step E: 2-(1-(4-Octylbenzyl)hydrazinecarboxamido)acetic acid: When the product of Step D is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 78% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.15 (m, 4H); 6.91 (t, 1H, J=5.7 Hz); 4.66 (s, 2H); 4.02 (d, 2H, J=5.7 Hz); 3.56 (bs, 3H); 2.57 (t, 2H, J=7.9 Hz); 1.58 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).

Example 17

3-(5-Octylindoline-1-carboxamido)propanoic acid

(107) Step A: 5-iodoindoline: To a solution of 5-iodoindole (0.2 g; 0.82 mmol) in AcOH (5 ml) NaBH.sub.3CN (0.2 g; 3.8 mmol) was added at 10 C. under N.sub.2. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue was diluted to 30 ml with Et.sub.2O and washed with 1 N NaOH (5 ml), H.sub.2O (25 ml), brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.2 g; 99%), which was used in next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.35 (s, 1H); 7.25 (d, 1H, J=8.15 Hz); 6.43 (d, 1H, J=8.15 Hz); 5.21 (bs, 1H); 3.54 (t, 2H, J=8.36 Hz); 2.99 (t, 2H, J=8.36 Hz).

(108) Step B: Ethyl 3-(5-iodoindoline-1-carboxamido)propanoate: When the product of Step A was substituted for 4-n-octylaniline in Example 11, Step A, the identical process afforded the title compound in 99% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.67 (d, 1H, J=8.3 Hz); 7.4 (m, 2H); 5.34 (m, 1H); 4.14 (q, 2H, J=7.1 Hz); 3.86 (t, 2H, J=8.8 Hz); 3.56 (q, 2H, J=5.9 Hz); 3.13 (t, 2H, J=8.6 Hz); 2.58 (t, 2H, J=5.7 Hz); 1.26 (t, 3H, J=7.1 Hz).

(109) Step C: Ethyl 3-(5-(oct-1-ynyl)indoline-1-carboxamido)propanoate: A mixture of the product of Step B (0.16 g; 0.41 mmol), 1-octyne (0.073 ml; 0.49 mmol), Cl.sub.2Pd(PPh.sub.3).sub.2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) was degassed under reduced pressure and saturated with dry N.sub.2. After addition of DIPEA (0.5 ml), the resulting mixture was stirred for 2 h at room temperature under N.sub.2. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc and washed with 5% citric acid, 5% NaHCO.sub.3, H.sub.2O, brine and dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO.sub.2; CH.sub.2Cl.sub.2) to give the title compound (0.1 g; 65%) as a brownish solid. .sup.1H-NMR (CDCl.sub.3) 7.75 (d, 1H, J=8.4 Hz); 7.16 (d, 1H, J=8.4 Hz); 7.1 (s, 1H); 5.34 (t, 1H, J=5.8 Hz); 4.11 (q, 2H, J=7.1 Hz); 3.82 (t, 2H, J=8.8 Hz); 3.52 (m, 2H); 3.06 (t, 2H, J=8.8 Hz); 2.56 (t, 2H, J=5.8 Hz); 2.33 (t, 2H, J=7.1 Hz); 1.53 (m, 2H); 1.52 (m, 2H); 1.26 (m, 6H); 1.23 (t, 2H, J=7.1 Hz); 0.86 (t, 3H, J=6.9 Hz).

(110) Step D: Ethyl 3-(5-octylindoline-1-carboxamido)propanoate: A mixture of the product of Step C (0.1 g; 0.27 mmol) and 10% Pd/C (0.1 g) in EtOH (15 ml) was stirred at room temperature for 1 h under H.sub.2 (balloon). The catalyst was removed by filtration through the Celite pad, washed with CH.sub.2Cl.sub.2 (210 ml) and combined filtrates were evaporated to dryness under reduced pressure to give a title compound (0.09 g; 90%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.71 (d, 1H, J=8.8 Hz); 6.94 (d, 1H, J=8.8 Hz); 6.93 (s, 1H); 5.29 (m, 1H); 4.14 (q, 2H, J=7 Hz); 3.82 (t, 2H, J=8.8 Hz); 3.57 (q, 2H, J=5.9 Hz); 3.11 (t, 2H, J=8.6 Hz); 2.59 (t, 2H, J=5.7 Hz); 2.51 (t, 2H, J=7.7 Hz); 1.57 (m, 2H); 1.26 (m, 13H); 0.86 (t, 3H, J=7 Hz).

(111) Step E: 3-(5-Octylindoline-1-carboxamido)propanoic acid: When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.68 (d, 1H, J=8.7 Hz); 6.94 (m, 2H); 5.24 (t, 1H, J=5.9 Hz); 3.86 (t, 2H, J=8.7 Hz); 3.58 (q, 2H, J=5.9 Hz); 3.11 (t, 2H, J=8.5 Hz); 2.67 (t, 2H, J=5.8 Hz); 2.5 (t, 2H, J=8 Hz); 1.54 (m, 2H); 1.25 (m, 10H); 0.86 (t, 3H, J=6.8 Hz).

Example 18

4-(4-(N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)sulfamoyl)phenyl)butyl-dihydrogen phosphate

(112) Step A: 4-Bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulfonamide: To a stirred solution of 4-bromo-benzenesulphonyl chloride (0.6 g, 2.34 mmol) in anhydrous CH.sub.2Cl.sub.2 (5 ml) and Et.sub.3N (0.65 ml, excess) at 0 C. was added (-) cis-myrtanylamine (0.36 g, 2.34 mmol) and the stirring was continued overnight at room temperature. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (15 ml) and washed with H.sub.2O (2100 ml). The organic layer was separated and dried over MgSO.sub.4 and the solvent was distilled to afford the title compound (0.87 g, 100%), as pale paste, which was solidified on standing. .sup.1H-NMR (CDCl.sub.3) 7.70 (d, 2H, J=6.78 Hz); 6.64 (d, 2H, J=6.90 Hz); 2.91 (t, 2H, J=7.59 Hz); 2.32-2.29 (m, 1H); 2.11-2.06 (m, 1H); 1.91-1.81 (m, 6H); 1.39-1.31 (m, 1H); 1.11 (s, 3H); 0.86 (s, 3H).

(113) Step B: N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl) benzene sulfonamide: A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1-ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N.sub.2 and Cl.sub.2Pd(PPh.sub.3).sub.2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl solution and diluted with H.sub.2O followed by the extraction with EtOAc (100 ml). The organic layer was separated, dried over MgSO.sub.4, filtered and the filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the product (0.11 g, 60%), as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.66 (d, 2H, J=8.43 Hz); 7.51 (d, 2H, J=8.43 Hz); 3.81 (b, 2H); 3.01-2.86 (m, 2H); 2.71-2.67 (m, 4H); 2.50-2.10 (m, 2H); 1.94-1.82 (m, 5H); 1.52-1.48 (m, 1H); 1.18 (s, 3H); 1.02 (s, 3H).

(114) Step C: N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybutyl)benzene sulfonamide: A mixture of the product of Step B (0.11 g, 0.3 mmol) and 10% Pd/C (0.06 g) in EtOH (10 ml) was stirred for 16 h under H.sub.2. The catalyst was filtered through Celite pad and the filtrate evaporated to dryness to give the title compound (0.11 g, 100%,) as creamy gum. .sup.1H-NMR (CDCl.sub.3) 7.74 (d, 2H, J=7.89 Hz); 7.29 (d, 2H, J=8.01 Hz); 4.9 (bs, 1H, NH); 3.71-3.65 (m, 2H); 2.92-2.87 (m, 2H); 2.70 (t, 2H, J=7.74 Hz); 2.45-2.30 (m, 1H); 2.25-2.10 (m, 1H); 1.86-1.58 (m, 9H); 1.3-1.1 (m, 2H); 1.08 (s, 3H); 0.83 (s, 3H).

(115) Step D: 4-(4-(N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)sulfamoyl)phenyl)butyl-dihydrogen phosphate: To a stirred solution of POCl.sub.3 (0.006 ml, 0.66 mmol) in anhydrous CH.sub.2Cl.sub.2 (3 ml) a solution of tert-butanol (0.062 ml, 0.65 mmol) and Et.sub.3N (0.09 ml, 0.65 mmol) was added drop wise at 0 C. under N.sub.2. The mixture was stirred for 0.5 h and to it a solution of the product of Step C (0.08 g, 0.22 mmol) in a mixture of anhydrous CH.sub.2Cl.sub.2 (1 ml) and Et.sub.3N (0.03 ml) was added drop wise. The mixture was stirred for 1 h at room temperature. The solvent was evaporated under reduced pressure and the residue was treated dropwise with a solution of 10% NaOH until the mixture become homogenous. This was washed with CH.sub.2Cl.sub.2 (210 ml), and the aqueous phase was acidified with 2M HCl. The product was extracted with CH.sub.2Cl.sub.2 (20 ml) and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.065 g, 65%) as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.67 (d, 2H, J=7.13 Hz); 7.23 (d, 2H); 3.94 (bs, 1H, NH); 3.86 (d, 2H, J=7.67 Hz); 2.58 (b, 2H); 2.28 (b, 1H); 2.13 (b, 1H); 1.84-1.82 (b, 5H); 1.35 (b, 4H); 1.22-1.24 (b, 2H); 0.96 (s, 3H); 0.86 (s, 3H).

Example 19

4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)propyl)phenyl)butyl-dihydrogen phosphate

(116) Step A: 2,2,2-Trifluoro-1-(1H-indol-3-yl)ethenone: To a stirred solution of indole (0.5 g, 4.3 mmol) in anhydrous Et.sub.2O (10 ml) anhydrous pyridine (0.5 ml) was added at 0 C., followed by drop wise addition of (CF.sub.3CO ).sub.2O (0.87 ml, 5.16 mmol). The mixture was stirred for 15 min and the solvent was evaporated to dryness. The residue was diluted to 20 ml with EtOAc, washed with H.sub.2O, dried over MgSO.sub.4, filtered and the filtrate was evaporated to dryness. The residue was crystallized from CH.sub.3OH to give the title compound (0.56 g; 61%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 9.04 (broad s, 1H); 8.40 (t, 1H, J=4.11 Hz); 8.06 (s, 1H); 7.48-7.45 (m, 1H); 7.40-7.35 (m, 2H).

(117) Step B: 2,2,2-Trifluoro-1-(1-(prop-2-ynyl)-1H-indol-3-yl)ethanone: A mixture of product of Step A (0.55 g, 2.58 mmol), K.sub.2CO.sub.3 (0.43 g, 3.11 mmol) and propyrgyl bromide (2 ml) in anhydrous DMF (8 ml). was stirred for 4 h. The mixture was quenched with NH.sub.4Cl solution and diluted to 50 ml with EtOAc. The organic layer separated and washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to give the title compound (0.57 g, 88%), as yellow crystalline material. .sup.1H-NMR (CDCl.sub.3) 8.41-8.38 (b, 1H); 7.99 (s, 1H); 7.48-7.31 (m, 3H); 4.96 (d, 2H, J=2.55 Hz); 2.58 (t, 1H, J=2.55 Hz).

(118) Step C: 2,2,2-Trifluoro-1-(1-(3-(4-iodophenyl)prop-2-ynyl)-1H-indol-3-yl) ethanone: A mixture of product of Step B (0.25 g, 1 mmol), 1,4 di-idobenzene (0.4 g, 1.2 mmol) Cl.sub.2Pd(PPh.sub.3).sub.2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N.sub.2. This was stirred overnight at room temperature, quenched with NaHCO.sub.3 solution and diluted to 50 ml with EtOAc. The organic layer was separated and washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.28 g, 51%), as light yellow solid. .sup.1H-NMR (CDCl.sub.3) 8.43-8.40 (b, 1H); 8.12 (b, 1H); 7.66 (t, 2H, J=8.36 Hz); 7.55-7.51 (m, 1H); 7.44-7.38 (m, 2H); 7.14 (d, 2H, J=8.30 Hz); 5.16 (s, 2H).

(119) Step D: 2,2,2-Trifluoro-1-(1-(3-(4-(4-hydroxybut-1-ynyl)phenyl)prop-2-ynyl)-1H-indol-3-yl) ethanone: When the product of Step C was substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulphonamide in Example 18, Step B, the identical process afforded the title compound in 84% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 8.43-8.40 (m, 1H); 8.14 (s, 1H); 7.56-7.53 (m, 1H); 7.44-7.37 (m, 2H); 7.37 (s, 4H); 5.19 (s, 2H); 3.8 (t, 2H, J=6.24 Hz); 2.69 (t, 2H, J=6.24 Hz); 1.76 (bs, 1H).

(120) Step E: 2,2,2-Trifluoro-1-(1-(3-(4-(4-hydroxybutyl)phenyl)propyl)-1H-indol-3-yl)ethanone: When the product of Step D was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the identical process afforded the title compound in 92% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.40 (broad s, 1H); 7.86 (s, 1H); 7.37-7.32 (m, 3H); 7.11 (d, 2H, J=8.07 Hz); 7.05 (d, 2H, J=8.07 Hz); 4.19 (t, 2H, J=7.17 Hz); 3.72-3.63 (m, 4H); 2.66-2.59 (m, 4H); 1.68-1.60 (m, 4H).

(121) Step F: 4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)propyl)phenyl)butyl-dihydrogen phosphate: When the product of Step E was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxy butyl)benzene sulphonamide in Example 18, Step D, the similar process afforded the title compound in 73% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.35 (broad s, 1H); 7.83 (s, 1H); 7.36-7.30 (m, 3H); 7.10-6.93 (m, 4H); 3.98 (m, 2H); 2.55-2.50 (m, 6H); 2.23-2.15 (m, 2H); 1.59 (b, 4H).

Example 20

4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)butyl-dihydrogen phosphate

(122) Step A: 2-(2-(4-iodophenoxy)ethyl)-6,6-dimethylbicyclo[3.1.1]heptane: To a stirred suspension of 4-iodophenol (0.5 g; 2.27 mmol) and 60% NaH (0.16 g, 2.3 mmol) in anhydrous DMF (5 ml) 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.5 g, 2.2 mmol) was added the and mixture was stirred for 3 h at room temperature. After addition of more of 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.2 g) the mixture was stirred for additional 2 h, quenched with NH.sub.4Cl solution and diluted to 20 ml with EtOAc. The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.61 g, 73%), as a colourless paste. .sup.1H-NMR (CDCl.sub.3) 7.51 (d, 2H, J=8.91 Hz); 6.64 (d, 2H, J=8.88 Hz); 3.88 (t, 2H, J=3.21 Hz); 2.34-1.84 (m, 10H); 1.17 (s, 3H); 1.01 (s, 3H).

(123) Step B: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)but-3-yn-1-ol: When the product of Step A was substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulphonamide in Example 18, Step B, the similar process afforded the title compound in 78% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.29 (d, 2H, J=8.76 Hz); 6.78 (d, 2H, J=8.82 Hz); 3.80-3.76 (m, 2H); 3.92 (t, 2H, J=1.89 Hz); 2.65 (t, 2H, J=6.21 Hz); 1.92-1.81 (m, 10H); 1.18 (s, 3H); 1.01 (s, 3H).

(124) Step C: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl) butan-1-ol: When the product of Step B was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title compound in 99% yield, as a colourless paste. .sup.1H-NMR (CDCl.sub.3) 7.05 (d, 2H, J=8.54 Hz); 6.78 (d, 2H, J=8.58 Hz); 3.91 (t, 2H, J=6.81 Hz); 3.64 (t, 2H, J=6.02 Hz); 2.57-2.53 (m, 2H); 1.90-1.57 (m, 14H); 1.18 (s, 3H); 1.01 (s, 3H).

(125) Step D: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)butyl-di-hydrogen phosphate: When the product of Step C was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybutyl)benzene sulfonamide in Example 18, Step D, the similar process afforded the title compound in 60% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.05 (d, 2H, J=8.31 Hz); 6.74 (d, 2H, J=8.16 Hz); 3.93-3.84 (m, 4H); 2.53-2.15 (m, 16H); 1.15 (s, 3H); 0.99 (s, 3H).

Example 21

2-(4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)ethanol

(126) Step A: 4-((6-Methoxybenzofuran-2-yl)ethynyl)phenyl acetate: When 4-iodophenyl acetate and 2-ethynyl-6-methoxybenzofuran were substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulphonamide and but-3-yn-1-ol respectively in Example 18, Step B, the similar process afforded the title compound in 56% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.56 (d, 2H, J=8.67 Hz); 7.41 (d, 1H, J=8.58 Hz); 7.10 (d, 2H, J=8.7 Hz); 6.97 (d, 1H, J=1.92 Hz); 6.9 (s, 1H); 6.88 (bd, 1H, J=8.61 Hz); 3.85 (s, 3H); 2.3 (s, 3H).

(127) Step B: 4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenol: When the product of Step A was substituted for N-(6,6-dimethyl bicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzenesulphonamide in Example 18, Step C, the similar process (higher pressure of H.sub.2) afforded the title compound in 96% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.25-7.19 (m, 2H); 7.02-6.97 (m, 3H); 6.38-6.35 (m, 2H); 4.81-4.72 (m, 1H); 3.75 (s, 3H); 3.24-3.16 (m, 1H); 2.83-2.73 (m, 3H); 2.27 (s, 3H); 2.13-2.07 (m, 1H); 2.06-1.92 (m, 1H).

(128) Step C: Ethyl 2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl) phenoxy) acetate: To a stirred solution of the product of Step A (0.05 g, 0.19 mmol) and K.sub.2CO.sub.3 (0.05 g, 0.36 mmol) in anhydrous DMF (5 ml) ethyl-bromo acetate (0.025 ml, 0.22 mmol) was added at room temperature. The mixture was stirred for 2 h and quenched with saturated NH.sub.4Cl solution, extracted in EtOAc (100 ml) and washed with H.sub.2O. The organic layer was separated and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.07 g; 100%), as pale oil. .sup.1H-NMR (CDCl.sub.3) 7.10 (d, 2H, J=8.39 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.80 (t, 2H, J=8.36 Hz); 6.35-6.33 (m, 2H); 4.75-4.71 (m, 1H); 4.56 (s, 2H); 4.22 (q, 2H, J=14.36, 7.17 Hz); 3.72 (s, 3H, OMe); 3.2-3.13 (m, 1H); 2.79-2.69 (m, 3H); 2.0-1.87 (m, 2H); 1.26 (t, 3H, J=7.12 Hz).

(129) Step D: 2-(4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy) ethanol: To the stirred slurry of LiAlH.sub.4 (0.01 g, 0.026 mmol) in anhydrous Et.sub.2O (5 ml) the solution of the product of Step C (0.04 g, 0.11 mmol) in anhydrous Et.sub.2O (2 ml) was added drop wise and stirring was continued for 0.5 h at room temperature. The reaction mixture was quenched with EtOAc: H.sub.2O: MeOH mixture (7 ml: 3 ml: 1 ml), diluted to 20 ml with EtOAc and filtered through Celite. The filtrate was evaporated under reduced pressure and dried in vacuo to give the title compound (0.032 g, 94%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.13 (d, 2H, J=8.54 Hz); 6.99 (d, 1H, J=8.56 Hz); 6.84 (d, 2H, J=8.58 Hz); 6.38-6.34 (m, 2H); 4.79-4.74 (m, 1H); 4.65 (t, 2H, J=4.14 Hz); 3.96-3.90 (m, 2H); 3.75 (s, 3H); 3.22-3.14 (m, 1H); 2.82-2.68 (m, 2H); 2.11-1.91 (m, 3H).

Example 22

2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl)(methyl)amino)ethanol

(130) Step A: 4-(5-(Hydroxymethyl)thiophen-2-yl)benzaldehyde: The thiphene-5-al-2-boronic acid (0.47 g, 2.97 mmol) was reduced with NaBH.sub.4 (0.15 g, 3.95 mmol) in MeOH (3 ml) and solvent was evaporated to dryness. The residue was taken in 1,4-dioxane (12 ml) and 4-bromobenzaldehyde (0.65 g, 3.5 mmol) was added. To this Pd(PPh.sub.3).sub.4 (0.05 g) was added with stirring at 80 C., followed by the addition of a solution of NaHCO.sub.3 (0.6 g) in H.sub.2O (2 ml). The mixture was stirred at reflux for 1 h and the solvents were evaporated to dryness under reduced pressure. The residue was diluted to 100 ml with EtOAc and washed with H.sub.2O. The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.61 g, 80%), as creamy paste. .sup.1H-NMR (CDCl.sub.3) 9.98 (s, 1H, CHO); 7.87 (d, 2H, J=8.3 Hz); 7.72 (d, 2H, J=8.31 Hz); 7.31 (d, 1H, J=3.74 Hz); 7.0 (d, 2H, J=3.7 Hz); 4.84 (s, 2H).

(131) Step B: 4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde: To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml) and Et.sub.3N (0.3 ml) mesyl chloride (0.4 ml) was added at 0 C. and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H.sub.2O. The organic layer was separated and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which was taken up in anhydrous toluene and 4-fluro-N-isopropylaniline (0.5 ml) was added to it. The mixture was stirred overnight at reflux and the solvent was evaporated. The residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.14 g, 20%), as light creamy paste. .sup.1H-NMR (CDCl.sub.3) 9.98 (s, 1H,); 7.82 (d, 2H, J=8.31 Hz); 7.66 (d, 2H, J=8.31 Hz); 7.28 (d, 1H, J=3.69 Hz); 6.93-6.86 (m, 3H); 6.81-6.76 (m, 2H); 4.79 (s, 2H); 4.08-3.99 (m, 1H); 1.22 (d, 6H, J=6.6 Hz).

(132) Step C: Methyl-2-((4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl)(methyl)amino)acetate: To a stirred solution of the product of Step B (0.09 g, 0.26 mmol) and sarcosine hydrochloride (0.07 g, 0.5 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.1 ml) and 10 drops of AcOH, followed by NaBH(OAc).sub.3 (0.11 g, 0.51 mmol). The mixture was stirred overnight at room temperature and diluted to 20 ml with CH.sub.2Cl.sub.2. The organic layer was washed with NaHCO.sub.3 solution, H.sub.2O and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.113 g, 100%) as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.47 (d, 2H, J=8.19 Hz); 7.28 (d, 2H, J=8.18 Hz); 7.10 (d, 1H, J=3.62 Hz); 6.88-6.85 (m, 3H); 6.85-6.77 (m, 2H); 4.44 (s, 2H); 4.07-3.98 (m, 1H); 3.69 (s, 3H); 3.24 (s, 2H); 2.37 (s, 3H); 1.21 (d, 6H, J=6.6 Hz).

(133) Step D: 2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl)(methyl)amino)ethanol: When the product of Step C was substituted for ethyl-2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)acetate in Example 21, Step D, the similar process afforded the title compound in 28% yield, as light yellow paste. .sup.1H NMR (CDCl.sub.3) 7.47 (d, 2H, J=8.05 Hz); 7.24 (d, 2H, J=8.04 Hz); 7.10 (d, 1H, J=3.60 Hz); 6.91-6.85 (m, 3H); 6.81-6.76 (m, 2H); 4.44 (s, 2H); 4.07-3.98 (m, 1H); 3.61 (t, 2H, J=5.31 Hz); 3.53 (s, 3H); 2.58 (t, 2H, J=5.31 Hz); 2.21 (s, 3H); 1.21 (d, 6H, J=6.56 Hz).

Example 23

2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzylamino) propane-1,3-diol

(134) Step A: N-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl)-2,2-dimethyl-1,3-dioxan-5-amine: When 2,2-dimethyl-1,3-dioxan-5-amine was substituted for sarcosine hydrochloride in Example 22, Step C, the similar process afforded the the title compound in 90% yield, as creamy paste. .sup.1H NMR (CDCl.sub.3) 7.47 (d, 2H, J=8.2 Hz); 7.29 (d, 2H, J=8.2 Hz); 7.0 (d, 1H, J=3.61 Hz); 6.9-6.85 (m, 3H); 6.82-6.76 (m, 2H); 4.38 (s, 2H); 4.07-4.0 (m, 1H); 3.96 (dd, 2H, J=1.7, 3.5 Hz); 3.81 (s, 2H); 3.72 (dd, 2H, J=1.8, 5.34 Hz); 2.68-2.63 (m, 1H); 1.41 (s, 3H); 1.4 (s, 3H); 1.21 (d, 6H, J=6.6 Hz).

(135) Step B: 2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzylamino) propane-1,3-diol: A solution of the product of Step A (0.025 g, 0.05 mmol) in a mixture of solvents (CH.sub.3OH, CH.sub.2Cl.sub.2, 30% HCl: 1 ml, 3 ml, 15 drops) was stirred for 3 h at room temperature. The solvents were evaporated and co-evaporated with iPrOH to give the title compound (0.012 g, 48%) as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.45 (d, 2H, J=8.12 Hz); 7.23-7.33 (m, 4H); 7.16-7.09 (m, 3H); 6.88 (d, 2H, J=3.68 Hz); 4.95 (bs, 1H); 4.21 (s, 2H); 4.07-4.02 (m, 1H); 3.92-3.68 (m, 6H); 3.29-3.26 (m, 1H); 1.03 (d, 6H, J=6.6 Hz).

Example 24

2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino)propane-1,3-diol hydrochloride

(136) Step A: N-(3-(4-(Diethoxymethyl)phenyl)prop-2-ynyl)-4-fluorobenzenamine: When 4-bromo-benzene-diethylacetal and 4-fluro-N-propyrgylaniline was substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulphonamide and but-3-yn-1-ol, respectively, in Example 18, Step B, the similar process afforded the title compound in 36% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.38 (d, 2H, J=8.7 Hz); 6.84 (d, 2H, J=8.6 Hz); 6.92 (t, 2H, J=7.8 Hz); 6.68-6.64 (m, 2H); 5.46 (s, 1H); 4.10 (s, 3H); 3.62-3.44 (m, 4H); 1.21 (t, 6H, J=7.04 Hz).

(137) Step B: N-(3-(4-(Diethoxymethyl)phenyl)propyl)-4-fluorobenzenamine:

(138) When the product of Step A was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title crude product (0.195 g; 96%) as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.35 (d, 2H, J=8.01 Hz); 7.14 (d, 2H, J=8.1 Hz); 6.85 (t, 2H, J=7.54 Hz); 6.51-6.45 (m, 2H); 5.46 (s, 1H); 3.73-3.48 (m, 4H); 3.07 (t, 2H, J=6.97 Hz); 2.71 (t, 2H, 7.45 Hz); 1.96-1.85 (m, 2H); 1.22 (t, 6H, J=7.07 Hz).

(139) Step C: 4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzaldehyde: A mixture of 4-(3-(4-flurophenylamino)propyl)benzaldehyde (0.09 g, 0.35 mmol) [prepared form the product of Step B by stirring in acidifies CHCl.sub.3] and 2-bromopropane (0.2 ml) and K.sub.2CO.sub.3 (0.1 g; 0.73 mmol) was stirred at reflux in anhydrous DMF (5 ml) for 6 h. The solvent was evaporated under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H.sub.2O. The organic layer separated and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc), to give the title compound (0.078 g, 83%) as creamy paste. .sup.1H-NMR (CDCl.sub.3) 10 (s, 1H); 7.78 (d, 2H, J=8.13 Hz); 7.32 (d, 2H, J=8.07 Hz); 6.93-6.86 (m, 2H); 6.82-6.66 (m, 2H); 3.07 (t, 2H, J=7.5 Hz); 2.71 (t, 2H, J 7.5 Hz); 2.71 (t, 2H, 7.62 Hz); 2.27-2.21 (m, 1H); 1.86-1.83 (m, 1H); 1.08 (d, 6H, J=6.6 Hz).

(140) Step D: N-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzyl)-2,2-dimethyl-1,3-dioxan-5-amine: When the product of Step C and 2,2-dimethyl-1,3-dioxan-5-amine were substituted for 4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)-thiophen-2-yl)benzaldehyde and sarcosine hydrochloride in Example 22, Step C, the similar process afforded the title compound in 48% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.24 (d, 2H, J=7.92 Hz), 7.11 (d, 2H, J=7.92 Hz), 6.87 (t, 2H, J=8.9 Hz), 6.69-6.62 (m, 2H), 3.95 (dd, 2H, J=1.7, 3.6 Hz), 3.83-3.69 (m, 4H), 3.06 (t, 2H, J=7.54 Hz), 2.66-2.58 (m, 3H), 1.83-1.76 (m, 3H), 1.41 (s, 3H), 1.4 (s, 3H), 1.08 (d, 2H, J=6.59 Hz).

(141) Step E: 2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino) propane-1,3-diol hydrochloride salt: When the product of Step D was substituted for N-(4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl)-2,2-dimethyl-1,3-dioxan-5-amine in Example 23, Step B, the identical process afforded the title compound in 67% yield, as a creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.39-7.19 (m, 6H); 7.11 (d, 2H, J=7.99 Hz); 4.21 (s, 2H); 3.94-3.67 (m, 5H); 3.4-3.7 (m, 2H); 3.3-3.26 (m, 1H); 2.56 (b, 2H); 1.68 (b, 1H); 1.22 (b, 1H); 1.04 (d, 6H, J=6.2 Hz).

Example 25

1-((4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4-yl)methyl)azetidine-3-carboxylic acid

(142) Step A: 4-Bromo-N-(3-methoxyphenyl)benzenesulfonamide: To a stirred solution of 3-methoxyaniline (0.48 g, 3.92 mmol) in anhydrous pyridine (5 ml) 4-bromobenzene-sulphonyl chloride (0.5 g, 1.96 mmol) was added and the mixture was stirred for 0.5 h. The solvent was removed in vacuo and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.51 g, 37%) as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.65 (d, 2H, J=8.57 Hz); 7.52 (d, 2H, J=8.57 Hz); 7.10 (t, 1H, J=8.09 Hz); 6.69-6.61 (m, 2H); 4.37 (s, 2H); 3.71 (s, 3H, OMe).

(143) Step B: 4-Bromo-N-(3-methoxyphenyl)-N-methylbenzenesulfonamide: To a stirred mixture of the product of Step A (0.5 g 1.46 mmol) and K.sub.2CO.sub.3 (0.5 g) in anhydrous DMF (7 ml) was added CH.sub.3I (1 ml) and the stirring continued for 0.5 h at 50 C. The mixture was diluted to 50 ml with H.sub.2O and extracted with EtOAc (50 ml). The organic layer was washed with H.sub.2O and dried over MgSO.sub.4, passed through silica gel bead and the filtrate was evaporated to dryness to give the title compound (0.5 g, 96%) as pale solid. .sup.1H-NMR (CDCl.sub.3) 7.58 (d, 2H, J=8.64 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.18 (t, 1H, J=8.15 Hz); 6.80 (dd, 1H, J=8.34, 2.5 Hz); 6.69 (t, 1H, J=2.20 Hz); 6.58 (bd, 1H); 3.75 (s, 3H, OMe); 3.14 (s, 3H, N-Me).

(144) Step C: 4-Formyl-N-(3-methoxyphenyl)-N-methylbiphenyl-4-sulfonamide: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 73% yield, as pale solid. .sup.1H-NMR (CDCl.sub.3) 10.07 (s, 1H); 7.98 (d, 2H, J=6.56 Hz); 7.75 (d, 2H, J=8.24 Hz); 7.7 (d, 2H, J=8.82 Hz); 7.66 (d, 2H, J=8.75 Hz); 7.19 (t, 1H, J=8.13 Hz); 6.81 (dd, 1H, J=8.30, 2.45 Hz); 6.74 (t, 1H, J=2.17 Hz); 6.65 (dd, 1H, J=7.96, 1.24 Hz); 3.76 (s, 3H); 3.20 (s, 3H).

(145) Step D: Methyl-1-((4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4-yl)methyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process the title compound in 69% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.64 (d, 2H, J=8.8 Hz); 7.58 (d, 2H, J=8 Hz); 7.54 (d, 2H, J=8.15 Hz); 7.36 (d, 2H, J=8.12 Hz); 7.17 (t, 1H, J=8.14 Hz); 6.80 (dd, 1H, J=8.07, 2.21 Hz); 6.72 (t, 1H, J=2.10 Hz); 6.64 (dd, 1H, J=7.80, 1.67 Hz); 3.74 (s, 3H); 3.71 (s, 2H); 3.69 (s, 3H); 3.64-3.58 (m, 2H); 3.42-3.36 (m, 4H); 3.18 (s, 3H).

(146) Step E: 1-((4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4-yl)methyl)azetidine-3-carboxylic acid: To a stirred solution of the product of Step D (0.06 g, 0.13 mmol) in THF (3 ml) a solution of LiOH (0.006 g, 0.25 mmol) in H.sub.2O (1 ml) was added at 80 C. The mixture was stirred for 0.5 h and solvents were evaporated to dryness. The residue was purified by FCC (SiO.sub.2) to give the title compound (0.0026 g, 43%) as creamy solid. .sup.1H-NMR (CDCl.sub.3:CD.sub.3OD) 7.58 (s, 4H); 7.58 (d, 2H, J=8 Hz); 7.56 (d, 2H, J=7.23 Hz); 7.49 (d, 2H, J=8.25 Hz); 7.13 (t, 1H, J=8.14 Hz); 6.76 (dd, 1H, J=8.33, 2.05 Hz); 6.68 (t, 1H, J=2.15 Hz); 6.58 (dd, 1H, J=7.94, 1.32 Hz); 4.25 (s, 2H); 4.21-4.02 (m, 4H); 3.70 (s, 3H); 3.38-3.32 (m, 3H); 3.13 (s, 3H).

Example 26

2-(((4-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl)(methyl)amino)acetic acid

(147) Step A: 4-Fluoro-N-isopropylaniline: A mixture of 4-fluoro-aniline (1.12 g; 10 mmol), 2-bromopropane (1.13 ml) and K.sub.2CO.sub.3 (1.38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H.sub.2O and extracted with EtOAc (50 ml). The organic layer was washed with H.sub.2O (220 ml) and dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. .sup.1H-NMR (CDCl.sub.3) 6.89-6.82 (m, 2H); 6.53-6.47 (m, 2H); 3.58-3.49 (m, 1H); 1.18 (d, 6H, J=6.25 Hz).

(148) Step B: N-(4-Bromobenzyl)-4-fluoro-N-isopropylbenzenamine: When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. .sup.1H-NMR (CDCl.sub.3) 7.39 (d, 2H, J=8.18 Hz); 7.14 (d, 2H, J=8.08 Hz); 6.91-6.81 (m, 2H); 6.62-6.57 (m, 2H); 4.26 (s, 2H); 4.11-4.04 (m, 1H); 1.18 (d, 2H, J=5.34 Hz).

(149) Step C: 4-(((4-Fluorophenyl)(isopropyl)amino)methylpiphenyl-4-carbaldehyde: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 65% yield, as creamy gum. .sup.1H-NMR (CDCl.sub.3) 10.03 (s, 1H); 7.92 (d, 2H, J=7.97 Hz); 7.56 (d, 2H, J=7.95 Hz); 7.38 (d, 2H, J=8.29 Hz); 6.86 (t, 2H, J=8.46 Hz); 6.67-6.62 (m, 2H); 4.38 (s, 2H); 4.17-4.12 (m, 1H); 1.2 (d, 6H, J=6.96 Hz).

(150) Step D: Methyl-2-(((4-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl)(methyl)amino)acetate: When the product of Step C was substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde in Example 22, Step C, the similar process afforded the title compound in 96% yield, as a creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.54-7.49 (m, 4H); 7.38-7.31 (m, 4H); 6.86 (t, 2H, J=8.45 Hz); 6.83-6.64 (m, 2H); 4.37 (s, 2H); 4.19-4.09 (m, 1H); 3.70 (s, 3H); 3.69 (s, 2H); 3.28 (s, 2H); 2.4 (s, 3H); 1.17 (d, 6H, J=7.71 Hz).

(151) Step E: 2-(((4(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl)(methyl)amino)acetic acid: When the product of Step D was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 87% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.40-7.18 (m, 8H); 6.76 (t, 2H, J=8.82 Hz); 6.61-6.56 (m, 2H); 4.25 (s, 2H); 4.16 (s, 2H); 4.07-4.01 (m, 1H); 2.59 (s, 3H); 1.11 (d, 6H, J=6.48 Hz).

Example 27

1-((4-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl)azetidine-3-carboxylic acid

(152) Step A: Methyl-1-((4-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl) azetidine-3-carboxylate: When 4-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-carbaldehyde and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)-methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process afforded the title compound in 65% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.53 (d, 2H, J=8.12 Hz); 7.48 (d, 2H, J=8.2 Hz); 6.85 (t, 2H, J=9.09 Hz); 6.67-6.62 (m, 2H); 4.37 (s, 2H); 4.16-4.11 (m, 1H); 3.86 (bs, 4H); 3.69 (s, 3H); 3.58-3.51 (m, 1H); 1.19 (d, 6H, J=6.63 Hz).

(153) Step B: 1-((4-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4-yl)methyl) azetidine-3-carboxylic acid: When the product of Step A was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 60% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.66 (d, 2H, J=8.13 Hz); 7.62-7.57 (m, 4H); 7.41 (d, 2H, J=8.07 Hz); 6.95-6.85 (m, 2H); 6.85-6.75 (m, 2H); 4.44 (s, 2H); 4,39 (s, 2H); 4.39-4.2 (m, 2H); 3.5-3.45 (m, 1H); 1.26 (d, 6H, J=6.54 Hz).

Example 28

1-(4-(4-Oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzyl)azetidine-3-carboxylic acid

(154) Step A: 3-Bromo-1-(3,4,5-trimethoxyphenyl)but-2-en-1-one: 1-(3,4,5-trimethoxyphenyl) but-2-yn-1-one (0.5 g, 2.58 mmol) was dissolved in AcOH (5 ml) and 48% HBr (5 drops) was added to it. The mixture was stirred for 2 h at 50 C. This was evaporated to dryness and the residue was diluted to 50 ml with EtOAc, washed with NaHCO.sub.3 solution and H.sub.2O. The organic layer was dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and dried in vacuo to give the title compound (0.53 g, 65%), as a pale solid. .sup.1H-NMR (CDCl.sub.3) 7.30 (s, 1H); 7.03 (s, 2H); 3.91 (s, 9H); 2.79 (s, 3H).

(155) Step B: 4-(4-Oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzaldehyde: When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 5-(hydroxymethyl)thiophen-2-ylboronic acid and 4-bromobenzaldehyde, respectively, in Example 22, Step A, the similar process afforded the title compound in 81% yield, as creamy gum. .sup.1H-NMR (CDCl.sub.3) 10.05 (s, 1H); 7.92 (d, 2H, J=8.25 Hz); 7.68 (d, 2H, J=8.28 Hz); 7.23 (s, 2H); 7.10 (s, 1H); 3.91 (s, 9H); 2.55 (s, 3H).

(156) Step C: Methyl-1-(4-(4-oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step-C, the similar process afforded the title compound in 66% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.49 (d, 2H, J=8.28 Hz); 7.30 (d, 2H, J=8.29 Hz); 7.22 (s, 2H), 7.06 (s, 1H); 3.90 (s, 9H); 3.68 (s, 3H); 3.64 (s, 2H); 3.56-3.52 (m, 2H); 3.37-3.32 (m, 3H).

(157) Step D: 1-(4-(4-oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylic acid: When the product of Step C was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 53% yield, as light yellow solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.31 (d, 2H, J=8.18 Hz); 7.28 (d, 2H, J=8.28 Hz); 6.71 (s, 2H); 6.62 (s, 1H); 4.24 (s, 2H); 4.17-4.04 (m, 4H); 3.55-3.38 (s, 1H); 2.15 (s, 3H).

Example 29

1-((4-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4-yl)methyl)azetidine-3-carboxylic acid

(158) Step A: 1-(4-Bromophenyl)but-2-yn-1-one: To an ice cold solution of 4-bromobenzaldehyde (1.3 g, 7 mmol) 0.5 M solution of propynyl magnesium bromide in THF (15 ml, 7.5 mmol) was added under N.sub.2. The mixture was stirred for 10 min, quenched with saturated NH.sub.4Cl solution and diluted to 50 ml with EtOAc. The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was dissolved in 1,4-dioxane (25 ml). To it MnO.sub.2 (2 g) was added and the resulting suspension was stirred for 4 h at reflux. The mixture was filtered through Celite pad and the filtrate was evaporated to dryness and dried in vacuo to give the title compound (1.29 g, 83%) as a pale solid. .sup.1H-NMR (CDCl.sub.3) 7.97 (d, 2H, J=9 Hz); 7.61 (d, 2H, J=9 Hz); 2.14 (s, 3H).

(159) Step B: 4-But-2-ynoylbiphenyl-4-carbaldehyde: When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 58% yield, as a creamy gum. .sup.1H-NMR (CDCl.sub.3) 10.07 (s, 1H); 8.23 (d, 2H, J=8.4 Hz); 7.98 (d, 2H, J=8.4 Hz); 7.78 (d, 2H, J=8.24 Hz); 7.72 (d, 2H, J=8.54 Hz); 2.18 (s, 3H).

(160) Step C: 4-(3-Bromobut-2-enoyl)biphenyl-4-carbaldehyde: When the product of Step B was substituted for 1-(3,4,5-trimethoxyphenyl) but-2-yn-1-one in Example 28, Step A, the similar process afforded the title compound in 56% yield, as pale solid. .sup.1H-NMR (CDCl.sub.3) 10.07 (s, 1H); 8.03-7.96 (m, 4H); 7.79-7.71 (m, 4H); 7.41 (s, 1H); 2.84 (s, 3H).

(161) Step D: 4-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4-carbaldehyde: When the product of Step C and 3-trifluromethyl-boronic acid were substituted for 4-bromo benzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 73% yield, as creamy gum. .sup.1H-NMR (CDCl.sub.3) 10.07 (s, 1H); 8.1 (d, 2H, J=8.5 Hz); 7.99-7.93 (m, 3H); 7.8-7.57 (m, 5H); 7.18 (s, 1H); 2.61 (s, 3H).

(162) Step E: Methyl-1-((4-(3-(3-(trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4-yl)methyl) azetidine-3-carboxylate: When the product of Step D and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 58% yield, as a pale paste. .sup.1H-NMR (CDCl.sub.3) 8.04 (d, 2H, J=8.4 Hz); 7.78-7.51 (m, 8H); 7.4 (d, 2H, J=8.2 Hz); 7.16 (d, 1H, J=1.21 Hz); 3.76 (s, 2H); 3.7 (s, 3H); 3.73-3.62 (m, 4H); 3.47-3.41 (m, 3H); 2.58 (bs, 3H).

(163) Step F: 1-((4-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4-yl)methyl) azetidine-3-carboxylic acid: When the product of Step E was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 62% yield, as a light yellow solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.84 (d, 2H, J=8.34 Hz); 7.59-7.33 (m, 6H); 4.7 (d, 2H); 3.96-3.92 (m, 4H); 3.19-3.14 (m, 1H); 2.36 (s, 3H).

Example 30

1-(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3-carboxylic acid

(164) Step A: 5-Bromo-2-isopropoxybenzaldehyde: To a stirred solution of 2-isopropoxybenzaldehyde (0.51 g, 3.1 mmol), in DMF (10 ml) NBS (0.55 g, 3.1 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with NaHCO.sub.3 solution and extracted in EtOAc (50 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.62 g, 82%) as light yellow oil. .sup.1H-NMR (CDCl.sub.3) 10.37 (s, 1H); 7.89 (d, 1H, J=2.52 Hz); 7.55 (dd, 1H, J=8.85, 2.58 Hz); 6.87 (d, 1H, J=8.88 Hz); 4.67-4.58 (m, 1H); 1.35 (d, 6H, J=6.03 Hz).

(165) Step B: 1-(5-Bromo-2-isopropoxyphenyl)-3-phenylprop-2-yn-1-one: To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgCl in THF (1.25 ml) was added drop wise at 0 C. under N.sub.2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH.sub.4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [.sup.1H-NMR (CDCl.sub.3) 7.68 (d, 1H, J=2.49 Hz); 7.46-7.43 (m, 2H); 7.36 (dd, 1H, J=8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1H, J=6.77 Hz); 5.79 (d, 1H, J=5.23 Hz); 4.64-4.58 (m, 1H); 3.13 (d, 1H, J=5.91 Hz); 1.37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO.sub.2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. .sup.1H-NMR (CDCl.sub.3) 8.00 (d, 1H, J=2.61 Hz); 7.61-7.52 (m, 3H); 7.44-7.35 (m, 3H); 6.88 (d, 1H, J=8.91 Hz); 4.68-4.60 (m, 1H); 1.36 (d, 6H).

(166) Step C: 4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzaldehyde: A solution of the product of Step B (0.3 g, 0.88 mmol), was treated with HBr/AcOH, as described in Example 28, Step A, to give a light creamy solid (0.18 g, 68%). .sup.1H-NMR (CDCl.sub.3) 8.36 (d, 1H, J=2.43 Hz); 7.92-7.88 (m, 2H); 7.77 (dd, 1H, J=8.88, 2.46 Hz); 7.58-7.50 (m, 3H); 7.47 (d, 1H, J=8.86 Hz); 6.83 (s, 1H)], which was reacted with 4-carbaldehyde-boronic acid in Example 22, Step A, to give the title compound (0.078 g, 48%), as creamy solid. .sup.1H-NMR (CDCl.sub.3) 10.07 (s, 1H); 8.5 (d, 1H, J=2.31 Hz); 8.00-7.93 (m, 2H); 7.84 (d, 2H, J=8.22 Hz); 7.71-7.63 (m, 3H); 7.56-7.48 (m, 3H); 6.87 (s, 1H).

(167) Step D: Methyl 1-(4-(4-oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for -(5-(((4-flurophenyl))isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, as in Example 22, Step C, the similar procedure afforded the title compound in 31% yield, as light green paste. .sup.1H-NMR (CDCl.sub.3) 8.43 (d, 1H, J=2.29 Hz); 7.96-7.91 (m, 3H); 7.63 (d, 3H); 7.54-7.39 (m, 3H); 7.38 (d, 2H, J=8.18 Hz); 6.85 (s, 1H); 3.73 (s, 3H); 3.71 (s, 2H); 3.71-3.62 (broad, 2H); 3.42-3.35 (b, 3H).

(168) Step E: 1-(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3-carboxylic acid: When the product of Step D was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 36% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 8.31 (broad s, 1H); 7.86 (broad s, 3H); 7.77-7.52 (m, 7H); 6.69 (s, 1H); 4.21 (broad s, 2H); 4.18-4.02 (m, 4H); 3.3 (s, 1H).

Example 31

3-(1-Admantanyl)-4methoxybiphenyl-4-yl)methyl)azetidine-3-carboxylic acid

(169) Step A: 2-(1-Admantanyl)-4-bromophenol: To a stirred solution of 4-bromophenol (1 g; 5.8 mmol) and admant-1-ol (0.88 g; 5.8 mmol) in AcOH (5 ml) concentrated H.sub.2SO.sub.4 (1 ml) was added drop wise and stirring was continued for 50 h. The solvent was distilled to half of the volume and the mixture was poured onto ice cold H.sub.2O (100 ml) and extracted with EtOAc (150 ml). The organic layer was washed with NaHCO.sub.3 solution, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.976 g, 55%), as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.27 (d, 1H, J=2.43 Hz); 7.13 (dd, 1H, J=8.4-2.43 Hz); 6.51 (d, 1H, J=8.37 Hz); 4.76 (s, 1H, OH); 2.07 (s, 10H); 1.75 (b, 5H).

(170) Step B: 2-(1-Admantanyl)-4-bromomethoxybenzene: To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K.sub.2CO.sub.3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH.sub.3I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H.sub.2O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO.sub.4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94%), as light yellow green solid. .sup.1H-NMR (CDCl.sub.3) 7.27-7.22 (m, 2H); 6.31 (d, 1H, J=6.5 Hz); 3.78 (s, 3H); 2.04 (s, 10H); 1.74 (b, 5H).

(171) Step C: 3-(1-Admantanyl)4methoxy-4-carbaldehyde: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 42% yield, as pale solid. .sup.1H-NMR (CDCl.sub.3) 10.02 (s, 1H); 7.90 (d, 2H, J=8.22 Hz); 7.70 (d, 2H, J=8.22 Hz); 7.51 (d, 1H, J=2.31 Hz); 7.46 (dd, 1H, J=8.4-2.3 Hz); 6.95 (d, 1H, J=8.4 Hz); 3.88 (s, 3H); 2.14 (b, 6H); 2.07 (b, 3H); 1.8 (b, 6H).

(172) Step D: Methyl-1-3-(1-admantanyl)4methoxybiphenyl-4-yl)methyl)azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively in Example 22, Step C, the similar procedure afforded the title compound in 82% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 7.48 (d, 2H, J=8.16 Hz); 7.42 (d, 1H, J=2.3 Hz); 7.37 (dd, 1H, J=8.4-2.3 Hz); 7.28 (d, 2H, J=8.15 Hz); 6.91 (d, 1H, J=8.4 Hz); 3.85 (s, 3H); 3.7 (s, 3H); 3.62 (s, 2H); 3.56-3.52 (m, 2H); 3.35-3.31 (m, 3H); 2.13 (b, 5H); 2.06 (b, 3H); 1.77 (b, 5H); 1.65 (b, 2H).

(173) Step E: 3-(1-Admantanyl)-4methoxybiphenyl-4-yl)methyl)azetidine-3-carboxylic acid: When the product of Step D was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded title compound in 37% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.53 (broad s, 4H); 7.36 (d, 1H, J=2.1 Hz); 7.31 (broad d, 1H, J=8.35 Hz); 6.87 (d, 2H, J=8.47 Hz); 4.3 (s, 2H); 4.19-4.15 (m, 4H); 3.81 (s, 3H); 3.54-3.51 (m, 1H); 2.07-2.00 (m, 9H); 1.73-1.71 (m, 6H).

Example 32

1-(4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3-carboxylic acid

(174) Step A: 3-(1-Admantanyl)-4-methoxybenzaldehyde: When 4-hydroxybenzaldehyde was substituted for 4-bromophenol in Example 1, Step A, the similar procedure afforded 3-(1-admantanyl)-4-hydroxybenzaldehyde in 56% yield, as a pale white solid. .sup.1H-NMR (CDCl.sub.3) 9.84 (s, 1H); 7.78 (d, 1H, J=2.07 Hz); 7.61 (dd, 1H, J=8.13, 2.01 Hz); 6.77 (d, 1H, J=8.16 Hz); 5.88 (bs, 1H); 2.12 (s, 6H); 2.09 (s, 3H); 1.78 (s, 6H). This was methylated by similar procedure as described in Example 31, Step B, to give the title compound in 64% yield, as light yellow solid. .sup.1H-NMR (CDCl.sub.3) 9.86 (s, 1H); 7.76 (d, 1H, J=2.07 Hz); 7.7 (dd, 1H, J=8.4, 2.1 Hz); 6.95 (d, 1H, J=8.4 Hz); 3.91 (s, 3H); 2.09 (s, 9H); 1.76 (s, 6H).

(175) Step B: 4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzaldehyde: To a stirred suspension of product of Step A (0.09 g, 0.32 mmol) in MeOH (5 ml) NaBH.sub.4 (0.018 g, 0.47 mmol) was added and the mixture was stirred for 0.5 h. The solvent was evaporated to dryness and the residue was taken in NaHCO.sub.3 solution and extracted with EtOAc (25 ml). The organic layer was separated, dried over MgSO.sub.4, and filtered. The filtrate was evaporated and the residue was dried in vacuo to give a relevant benzyl alcohol (0.095 g; 100%), as a creamy gum. .sup.1H-NMR (CDCl.sub.3) 7.21 (d, 1H, J=2.17 Hz); 7.16 (dd, 1H, J=8.21, 2.17 Hz); 6.83 (d, 1H, J=8.21 Hz); 4.59 (bd, 2H, J=4.24 Hz); 3.82 (s, 3H, OMe); 2.08 (s, 6H); 2.05 (s, 3H); 1.76 (s, 6H). To a stirred solution of above product in anhydrous CH.sub.2Cl.sub.2 (5 ml) CBr.sub.4 (0.14 g, 0.42 mmol) was added, followed by PPh.sub.3 (0.11 g, 0.42 mmol). The mixture was stirred for 1 h at room temperature and the solvent was distilled off. The residue was taken in EtOAc (10 ml) and the insoluble material was filtered off. The filtrate was evaporated to give the relevant benzyl bromide (0.14 g), which was added as a solution in DMF (2 ml) to a stirred suspension of 4-hydroxybenzaldehyde (0.069 g, 0.57 mmol) and K.sub.2CO.sub.3 (0.080 g, 0.58 mmol) in anhydrous DMF (3 ml) and this was stirred for 2 h at 70 C. The mixture was quenched with saturated NH.sub.4Cl solution and extracted with EtOAc (50 ml). The organic layer was dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.05 g, 31.4%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 9.88 (s, 1H); 7.82 (d, 2H, J=8.78 Hz); 7.26-7.21 (m, 3H); 7.01 (d, 2H, J=8.7 Hz); 6.87 (d, 1H, J=8.2 Hz); 5.04 (s, 2H); 3.83 (s, 3H); 2.08 (s, 6H); 2.05 (s, 3H); 1.76 (s, 6H).

(176) Step C: Methyl 1-(4-(3-(1-admantanyl)-4-methoxybenzyloxy)benzyl)azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))-isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 69% yield, as a pale paste. .sup.1H-NMR (CDCl.sub.3) 7.24-7.20 (m, 2H); 7.16 (d, 2H, J=8.55 Hz); 6.91 (d, 2H, J=8.62 Hz); 6.85 (d, 1H, J=8.17 Hz); 4.92 (s, 2H); 3.82 (s, 3H); 3.69 (s, 3H); 3.52 (s, 2H); 3.49 (s, 1H); 3.47 (s, 2H); 3.31-3.24 (m, 3H); 2.08 (s, 6H); 2.04 (s, 3H); 1.75 (s, 6H).

(177) Step D: 1-(4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3-carboxylic acid: When the product of Step C was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 61% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3:CD.sub.3OD) 7.33 (d, 2H, J=8.59 Hz); 7.17-7.12 (m, 2H); 6.92 (d, 2H, J=8.64 Hz); 6.79 (d, 1H, J=8.21 Hz); 4.87 (s, 2H); 4.13 (s, 2H); 4.08-4.02 (m, 4H); 2.0 (s, 6H); 1.97 (s, 3H); 1.68 (s, 6H).

Example 33

1-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl)azetidine-3-carboxylic acid

(178) Step A: 4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzaldehyde: (6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethanol was brominated as described in Example 32, Step B and the bromination product was used in next step without further purification, where it was treated with 4-hydroxybenzaldehyde as described in Example 32, Step B to afford the title compound in 91% yield, as creamy paste.

(179) Step B: Methyl-1-(4-(2-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl) azetidine-3-carboxylate: When the product of Step A and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))-isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 76% yield, as light yellow paste. .sup.1H-NMR (CDCl.sub.3) 7.17 (d, 2H, J=8.56 Hz); 6.81 (d, 2H, J=8.61 Hz); 3.91 (t, 2H, J=1.98 Hz); 3.71-3.65 (m, 7H); 3.44-3.41 (m, 3H); 2.03-1.17 (m, 10H); 1.17 (s, 3H); 1.01 (s, 3H).

(180) Step C: 1-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl) azetidine-3-carboxylic acid: When the product of Step B was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 87% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.21 (d, 2H, J=7.98 Hz); 6.79 (d, 2H, J=7.99 Hz); 3.94-3.71 (m, 8H); 3.27-3.25 (m, 1H); 2.36-1.20 (m, 10H); 1.14 (s, 3H); 0.97 (s, 3H).

Example 34

1-(4-(12-Oxo-12H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3-carboxylic acid

(181) Step A: 6-Bromo-4-oxo-2-(phenylamino)-4H-chromene-3-carbaldehyde: To a stirred solution of 6-bromo-4-oxo-4H-chromene-3-carbaldehyde (2 g, 7.93 mmol) in anhydrous benzene (15 ml) phenyl-hydroxylamine (0.95 g, 8.71 mmol) was added. The solution was kept for 1 h at room temperature when the crystalline solid appeared. To this glacial AcOH (0.5 ml) was added and the mixture was stirred for 5 h at reflux. The solvent was distilled off and the residue was crystallized from MeOH to give the title compound (2.1 g, 78%), as yellow crystalline solid. .sup.1H-NMR (CDCl.sub.3) 12.43 (broad s, 1H); 10.28 (s, 1H); 8.34 (d, 1H, J=2.46 Hz); 7.69 (dd, 1H, J=8.76, 2.49 Hz); 7.46-7.29 (m, 6H).

(182) Step B: 2-Bromo-12H-chromeno[2,3-b]quinolin-12-one: To the product of Step A (1 g; 2.92 mmol) concentrated H.sub.2SO.sub.4 (1 ml) was gently added with stirring. The mixture was kept in sealed vial for 24 h, at room temperature, than poured onto ice water and extracted with CH.sub.2Cl.sub.2 (50 ml). The organic layer was washed with NaHCO.sub.3 solution, H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was distilled off and the residue was crystallized from CH.sub.3CN to give the title compound (0.73 g, 77%), as green yellow solid. .sup.1H-NMR (CDCl.sub.3) 9.28 (s, 1H); 8.44 (d, 1H, J=2.1 Hz); 8.1-8.06 (m, 2H); 7.94-7.84 (m, 2H); 7.63 (t, 1H, J=7.88 Hz); 7.51 (d, 1H, J=8.83 Hz).

(183) Step C: 4-(12-Oxo-12H-chromeno[2,3-b]quinolin-2-yl)benzaldehyde: When the product of Step B and 4-carbaldehyde-boronic were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 52% yield, as off white solid. .sup.1H-NMR (CDCl.sub.3) 10.08 (s, 1H); 9.33 (s, 1H); 8.6 (d, 1H, J=2.34 Hz); 8.14-8.05 (m, 3H); 8.00 (d, 2H, J=8.25 Hz); 7.96-7.89 (m, 1H); 7.85 (d, 2H, J=8.22 Hz); 7.74 (d, 1H, J=8.7 Hz); 7.64 (t, 1H, J=7.8 Hz).

(184) Step D: Methyl-1-(4-(12-oxo-12H-chromeno[2,3-b]quinolin-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 48% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 9.32 (s, 1H); 8.53 (s, 1H); 8.12-8.07 (m, 2H); 8.00 (dd, 1H, J=8.7, 2.4 Hz); 7.91 (t, 1H, J=5.55 Hz); 7.7-7.6 (m, 4H); 7.38 (d, 2H, J=8.22 Hz); 3.71 (s, 3H); 3.67 (s, 2H); 3.57-3.53 (m, 2H); 3.39-3.35 (m, 3H).

(185) Step E: 1-(4-(12-Oxo-12H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3-carboxylic acid: When the product of Step D was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 50% yield, as yellow solid. .sup.1H-NMR (CDCl+CD.sub.3OD) 9.25 (broad s, 1H); 8.44 (m, 2H); 7.76-7.54 (m, 5H); 4.31-4.07 (m, 4H); 4.27-3.95 (m, 2H).

Example 35

1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylic acid

(186) Step A: (5-Chlorobenzofuran-3-yl)methanol: To a mixture of 4-chloro-2-iodophenol (1 g, 3.92 mmol), tert-butyl(3-(tert-butyldimethylsilyl)prop-2-ynyloxy)-dimethylsilane (1.93 g, 6.8 mmol), LiCl (0.15 g; 3.5 mmol) and Na.sub.2CO.sub.3 (0.636 g; 6 mmol) in anhydrous DMF (10 ml) Pd(OAc).sub.2 (0.3 g) was added at 100 C. under N.sub.2 and heating was continued for 1.5 h. The solvent was removed in vacuo and the residue was diluted to 100 ml with EtOAc, washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the coupling product (0.64 g; 26%). This was dissolved in THF (5 ml) and 1M TBAF in THF (2 ml) was added to it and the mixture was stirred for 4 h at reflux. The solvent was distilled off and the residue was dilute to 50 ml with EtOAc, washed with 1M HCl, H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.33 g; 99%), as creamy paste. .sup.1H-NMR (CDCl.sub.3) 7.63 (d, 1H, J=2.11 Hz); 6.60 (b, 1H); 7.37 (d, 1H, J=8.72 Hz); 7.25 (dd, 1H, J=8.71, 2.13 Hz); 4.79 (s, 2H).

(187) Step B: 4-((5-Chlorobenzofuran-3-yl)methoxy)benzaldehyde: When the product of Step A was substituted for 3-(1-admantanyl)-4-methoxy benzaldehyde in Example 32, Step B, the similar procedure afforded the title compound in 9% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 9.89 (s, 1H); 7.84 (d, 2H, J=8.74 Hz); 7.72 (s, 1H); 7.60 (d, 1H, J=2.07 Hz); 7.41 (d, 1H, J=8.76 Hz); 7.28 (dd, 1H, J=8.75, 2.09 Hz); 7.09 (d, 2H, J=8.73 Hz); 5.23 (s, 2H).

(188) Step C: Methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate: When the product of Step B and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)-thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectfully, in Example 22, Step C, the similar procedure afforded the title compound in 45% yield, as off white solid. .sup.1H-NMR (CDCl.sub.3) 7.68 (s, 1H); 7.60 (bs, 1H); 7.39 (d, 2H, J=8.77 Hz); 7.28-7.18 (m, 3H); 6.93 (d, 2H, J=6.62 Hz); 5.12 (s, 2H); 3.69 (s, 3H); 3.54-3.47 (m, 5H); 3.36-3.28 (m, 4H).

(189) Step D: 1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylic acid: When the product of Step C was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 57% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) 7.78 (s, 1H); 7.57 (d, 2H, J=2.06 Hz); 7.53 (s, 1H); 7.39 (d, 1H, J=8.8 Hz); 7.36 (d, 2H, J=8.66 Hz); 7.24 (dd, 1H, J=8.75, 2.12 Hz); 7.04 (d, 2H, J=8.67 Hz); 5.18 (s, 2H); 4.20-4.06 (m, 6H); 3.36-3.27 (m, 1H).

Example 36

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(190) Step A: N-Hydroxy-3-iodo-4-isopropoxybenzimidamide: A suspension of 3-iodo-4-isopropoxybenzonitrile (0.576 g; 2 mmol), HClNH.sub.2OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50 C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H.sub.2O. The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.0 (d, 1H, J=2.22 Hz); 7.55 (dd, 1H, J=9.54, 2.28 Hz); 6.77 (d, 1H, J=8.7 Hz); 4.95 (b, 2H); 4.69-4.63 (m, 1H); 1.42 (d, 6H).

(191) Step B: 5-(3-Chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: A mixture of 3-chloro-4-propoxybenzoic acid (0.298 g, 0.93 mmol), the product of Step A (0.2 g, 0.93 mmol) and EDC (0.214 g, 1.1 mmol) in anhydrous DMF (3 ml) was stirred overnight at 45 C. 1 M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 110 C. The reaction mixture was diluted to 20 ml with H.sub.2O and extracted with EtOAc (215 ml). The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.22 g, 47.4%), as a colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.56 (d, 1H, J=2.04 Hz); 8.21 (d, 1H, J=2.37 Hz); 8.07-8.02 (m, 2H); 7.00 (d, 1H, J=8.73 Hz); 6.87 (d, 1H, J=8.67 Hz); 4.68-4.63 (m, 1H); 4.08 (t, 2H, J=6.45 Hz); 1.93-1.87 (m, 2H); 1.36 (d, 6H, J=6.06 Hz); 1.09 (t, 3H, J=7.44 Hz).

(192) Step C: 4-(5-(3-Chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: To a solution of the product of Step B (0.2 g, 0.4 mmol) in anhydrous CH.sub.2Cl.sub.2 (2 ml) 1 M BCl.sub.3 in CH.sub.2Cl.sub.2 (3 ml) was added drop wise at rt. After 1 h, more of 1M BCl.sub.3 in CH.sub.2Cl.sub.2 (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH.sub.4Cl solution and extracted with CH.sub.2Cl.sub.2 (20 ml). The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrates was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.145 g, 79%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.47 (d, 1H, J=1.95 Hz); 8.21 (d, 1H, J=2.1 Hz); 8.06-8.04 (m, 1H); 8.03-8.02 (m, 1H); 7.07 (d, 1H, J=8.49 Hz); 7.00 (d, 1H, J=8.7 Hz); 4.08 (t, 2H, J=6.45 Hz); 1.94-1.87 (m, 2H); 1.09 (t, 3H, J=7.44 Hz).

(193) Step D: tert-Butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml: 0.3 ml) was degassed with N.sub.2 and Cl.sub.2Pd(PPh.sub.3).sub.4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45 C. under N.sub.2, diluted to 20 ml with saturated NH.sub.4Cl and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.11 g, 78%), as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.34 (d, 1H, J=1.29 Hz); 8.24 (d, 1H, J=2.13 Hz); 8.08 (t, 1H, J=1.56 Hz); 8.05 (t, 1H, J=1.56 Hz); 7.53 (d, 1H, J=8.67 Hz); 7.03 (d, 1H, J=8.67 Hz); 6.75 (s, 1H); 4.26-4.19 (m, 4H); 4.06 (t, 2H, J=5.49 Hz); 1.94-1.87 (m, 2H); 1.41 (s, 9H); 1.36 (s, 6H); 1.1 (t, 3H, J=7.44 Hz).

(194) Step E: 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: To a stirred solution of product of Step D (0.1 g, 0.17 mmol) in CH.sub.2Cl.sub.2 (0.5 ml) TFA (1 ml) was added. After stirring for 1 h at room temperature, EtOH (2 ml) was added and stirring was continued for additional 1 h. The mixture was evaporated to dryness and the residue was purified by FCC (SiO.sub.2, CH.sub.2Cl.sub.2 saturated with concentrated NH.sub.4OH/MeOH; 98:2) to give the title product (0.035 g, 46%) as colourless solid. .sup.1H-NMR (DMSO-d.sub.6) 8.3 (d, 1H, J=1.11 Hz); 8.15 (d, 1H, J=2.01 Hz); 8.09 (dd, 1H, J=8.67, 2.04 Hz); 7.94 (dd, 1H, J=8.58, 1.53 Hz); 7.68 (d, 1H, J=8.61 Hz); 7.37 (d, 1H, J=8.76 Hz); 6.92 (s, 1H); 4.91 (b, 2H); 4.14 (t, 2H, J=6.36 Hz); 3.69 (d, 2H, J=10.6 Hz); 3.59 (d, 2H, J=10.6 Hz); 1.83-1.72 (m, 2H); 0.97 (t, 3H, J=7.41 Hz).

Example 37

(E)-2-Amino-2-(5-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(195) Step A: (E)-3-(3-Iodo-4-isopropoxyphenyl)-5-(4-methylstyryl)-1,2,4-oxadiazole: When (E)-3-p-tolylacrylic acid was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar process afforded the title compound in 52% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.53 (d, 1H, J=2.07 Hz); 8.01 (dd, 1H, J=8.58, 2.1 Hz); 7.82 (d, 1H, J=16.35 Hz); 7.49 (d, 1H, J=8.1 Hz); 6.97 (d, 1H, J=16.38 Hz); 6.87 (d, 1H, J=8.76 Hz); 4.69-4.6 (m, 1H); 1.4 (d, 6H, J=5.85 Hz).

(196) Step B: (E)-2-Iodo-4-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 53% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.44 (d, 1H, J=1.95 Hz); 8.0 (dd, 1H, J=8.49, 2.01 Hz); 7.84 (d, 1H, J=16.35 Hz); 7.49 (d, 1H, J=8.16 Hz); 7.07 (d, 1H, J=8.49 Hz); 16.98 (d, 1H, J=16.83 Hz); 5.61 (s, 1H).

(197) Step C: (E)-tert-Butyl 2,2-dimethyl-5-(5-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxy phenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar process afforded the title compound in 68% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.30 (d, 1H, J=1.32 Hz); 8.03 (dd, 1H, J=8.61, 1.68 Hz); 7.84 (d, 1H, J=16.38 Hz); 7.53-7.49 (m, 3H); 7.21 (d, 2H, J=5.34 Hz); 7.0 (d, 1H, J=15.15 Hz); 5.28 (s, 1H); 4.24 (b, 4H); 2.39 (s, 3H); 1.46-1.39 (m, 15H).

(198) Step D: (E)-2-Amino-2-(5-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane-1,3-diol: When the product of Step C was substituted for tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl carbamate in Example 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. .sup.1H-NMR (DMSO-d.sub.6) 8.23 (b, 1H); 7.9-7.85 (m, 2H); 7.72-7.64 (m, 3H); 7.33 (d, 1H, J=16.2 Hz); 7.25 (d, 2H, J=6.3 Hz); 6.87 (s, 1H); 4.77 (b, 2H); 3.63 (b, 2H); 3.56 (b, 2H); 2.32 (s, 3H); 1.95 (b, 2H).

Example 38

2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(199) Step A: 5-(4-Bromo-3-chlorophenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When 4-bromo-3-chlorobenzoic acid was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 72% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3) 8.55 (d, 1H, J=2.07 Hz); 8.27 (d, 1H, J=1.89 Hz); 8.04 (dd, 1H, J=8.61, 2.04 Hz); 7.91 (dd, 1H, J=8.34, 1.95 Hz); 7.79 (d, 1H, J=8.37 Hz); 6.87 (d, 1H, J=8.67 Hz); 4.7-4.6 (m, 1H); 1.4 (d, 6H, J=5.94 Hz).

(200) Step B: 4-(5-(4-Bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 86% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3) 8.47 (d, 1H, J=1.98 Hz); 8.28 (d, 1H, J=1.95 Hz); 8.03 (dd, 1H, J=8.49, 1.98 Hz); 7.92 (dd, 1H, J=8.37, 1.98 Hz); 7.84 (d, 1H, J=8.37 Hz); 7.08 (d, 1H, J=8.52 Hz); 5.65 (b, 1H).

(201) Step C: tert-Butyl 5-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 58% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.34 (d, 1H, J=1.53 Hz); 8.31 (d, 1H, J=1.95 Hz); 8.06 (dd, 1H, J=8.61, 1.68 Hz); 7.94 (dd, 1H, J=8.37, 1.98 Hz); 7.8 (d, 1H, J=8.37 Hz); 7.54 (d, 1H, J=8.61 Hz); 6.76 (s, 1H); 5.34 (bs, 1H); 4.3-4.24 (m, 4H); 1.55 (s, 9H); 1.47 (s, 6H).

(202) Step D: 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 39% yield, as creamy solid. .sup.1H-NMR (DMSO-d.sub.6) 8.31 (b, 2H); 8.05 (d, 1H, J=8.52 Hz); 8.00 (d, 1H, J=8.49 Hz); 7.94 (d, 1H, J=8.58 Hz); 7.68 (d, 1H, J=8.46 Hz); 6.91 (s, 1H); 4.88 (bs, 1H); 3.66 (bs, 2H); 3.58 (bs, 2H).

Example 39

2-Amino-2-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(203) Step A: tert-Butyl 5-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3-thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H.sub.2O (5 ml:1 ml), Pd(PPh.sub.3).sub.4 (0.03 g) was added at 80 C./, followed by the NaHCO.sub.3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc), to give the title compound (0.065 g, 71%), as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.45 (d, 1H, J=1.53 Hz); 8.25-8.22 (m, 2H); 7.94 (dd, 1H, J=8.7, 1.8 Hz); 7.55-7.42 (m, 3H); 7.38-7.37 (m, 2H); 6.78 (s, 1H); 5.43 (bs, 1H); 4.29-4.13 (m, 4H); 1.46 (s, 9H); 1.27 (b, 6H).

(204) Step B: 2-Amino-2-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step A was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. .sup.1H-NMR (DMSO-d.sub.6) 8.42 (s, 1H); 8.28 (s, 1H); 8.2 (d, 1H, J=8.41 Hz); 8.11 (d, 1H, J=8.1 Hz); 7.82 (s, 1H); 7.64-7.61 (m, 3H); 7.4 (b, 1H); 6.92 (s, 1H); 4.9 (bs, 2H); 3.66 (b, 2H); 3.59 (b, 2H).

Example 40

2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(205) Step A: 5-(3,4-Diethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When 3,4-diethoxy benzoic acid was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 60% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.57 (d, 1H, J=2.05 Hz); 8.05 (dd, 1H, J=8.58, 2.03 Hz); 8.02 (d, 1H, J=2.07 Hz); 7.76 (dd, 1H, J=8.41, 1.94 Hz); 7.66 (d, 1H, J=1.93 Hz); 6.96 (d, 1H, J=8.5 Hz); 6.87 (d, 1H, J=8.69 Hz); 4.67-4.63 (m, 1H); 4.24-4.14 (m, 4H); 1.53-1.4 (m, 6H); 1.38 (d, 6H, J=6.64 Hz).

(206) Step B: 4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 84% yield, as a creamy solid. .sup.1H-NMR (CDCl.sub.3) 8.48 (d, 1H, J=2.05 Hz); 8.04 (dd, 1H, J=8.46, 1.98 Hz); 7.76 (dd, 1H, J=8.43, 2.0 Hz); 7.65 (d, 1H, J=1.98 Hz); 7.07 (d, 1H, J=8.5 Hz); 6.96 (d, 1H, J=8.46 Hz); 5.63 (bs, 1H); 4.24-4.09 (m, 4H); 1.56-1.42 (m, 6H).

(207) Step C: tert-Butyl 5-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 66% yield, as creamy paste. .sup.1H-NMR (CDCl.sub.3) 8.35 (d, 1H, J=1.57 Hz); 8.08 (dd, 1H, J=8.62, 1.68 Hz); 7.79 (dd, 1H, J=8.44, 1.94 Hz); 7.69 (d, 1H, J=1.93 Hz); 7.52 (d, 1H, J=8.54 Hz); 6.96 (d, 1H, J=8.5 Hz); 6.75 (s, 1H); 5.32 (b, 1H); 4.36-4.15 (m, 8H); 3.95 (s, 2H); 1.54-1.47 (m, 1H).

(208) Step D: 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane-1,3-diol: When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl carbamate in Example 36, Step E, the similar procedure afforded the title compound in 61% yield, as creamy solid. .sup.1H-NMR (DMSO-d.sub.6) 8.27 (s, 1H); 7.92 (d, 1H, J=8.23 Hz); 7.75-7.61 (m, 3H); 7.17 (d, 1H, J=8.34 Hz); 6.88 (s, 1H); 4.78 (b, 2H); 4.15-4.00 (b, 4H); 3.65-3.64 (b, 2H); 3.57-3.55 (b, 2H); 1.35 (b, 6H).

Example 41

2-Amino-2-(5-(5-(4-propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(209) Step A: 5-(4-Propoxy-3-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When 4-propoxy-3-methoxybenzoic acid was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 58% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3) 8.58 (d, 1H, J=2.01 Hz); 8.06 (dd, 1H, J=8.61, 2.07 Hz); 7.77 (dd, 1H, J=8.43, 1.98 Hz); 7.66 (d, 1H, J=1.92 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.88 (d, 1H, J=8.7 Hz); 4.69-4.61 (m, 1H); 4.06 (t, 2H, J=6.81 Hz); 3.98 (s, 3H); 1.93-1.88 (m, 2H); 1.06 (t, 3H, J=7.38 Hz).

(210) Step B: 4-(5-(4-Propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 80% yield, as creamy solid. .sup.1H-NMR (CDCl.sub.3) 8.48 (d, 1H, J=1.98 Hz); 8.04 (dd, 1H, J=8.46, 1.98 Hz); 7.7 (dd, 1H, J=8.43, 2.01 Hz); 7.65 (d, 1H, J=1.95 Hz); 7.07 (d, 1H, J=8.49 Hz); 6.97 (d, 1H), J=8.46 Hz); 5.63 (s, 1H); 4.06 (t, 2H, J=6.8 Hz); 4.02 (s, 3H); 1.94-1.87 (m, 2H); 1.06 (t, 3H, J=7.41 Hz).

(211) Step C: tert-Butyl 5-(5-(5-(4-propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 68% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.35 (d, 1H, J=1.23 Hz); 8.08 (dd, 1H, J=8.61, 1.68 Hz); 7.8 (dd, 1H, J=8.41, 1.98 Hz); 7.68 (d, 1H, J=1.92 Hz); 7.52 (d, 1H, J=8.64 Hz); 6.98 (d, 1H, J=8.49 Hz); 6.75 (s, 1H); 5.32 (bs, 1H); 4.26 (b, 4H); 4.06 (t, 2H, J=6.81 Hz); 3.98 (s, 3H); 1.93-1.88 (m, 2H); 1.49 (s, 9H); 1.44 (s, 6H); 1.06 (t, 3H, J=7.38 Hz).

(212) Step D: 2-Amino-2-(5-(5-(4-Propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 57% yield, as colourless solid. .sup.1H-NMR (DMSO-d.sub.6) 8.28 (s, 1H); 7.92 (d, 1H, J=2.82 Hz); 7.61 (m, 3H); 7.16 (d, 1H, J=8.53 Hz); 6.88 (s, 1H); 4.78 (b, 2H); 4.01 (t, 2H, J=6.03 Hz); 3.99 (s, 3H); 3.77-3.57 (m, 4H); 1.78-1.71 (m, 2H); 0.96 (t, 3H, J=7.29 Hz).

Example 42

5-(3,4-Diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1,2,4-oxadiazole

(213) Step A: 2-Methylbenzofuran-5-carbonitrile: 2-Iodo-4-cynophenol (0.25 g, 1 mmol) and saccharin (0.1 g) in HMDSA (2 ml) was refluxed for 2 h under N.sub.2, until the solution became clear. The solvent was distilled off under reduced pressure and the residue was dissolved in anhydrous THF (2 ml). This was added to a solution made by mixing anhydrous ZnCl.sub.2 (0.3 g; 2.2 mmol) with 0.5 M 1-propynyl magnesium bromide in THF (7.8 ml) in anhydrous THF (5 ml) at room temperature under N.sub.2. To it, Pd (PPh.sub.3).sub.4 (0.15 g) was added at room temperature under N.sub.2 followed by catalytic amount of CuI. The mixture was stirred at room temperature for 3 h and quenched with saturated NH.sub.4Cl solution. The mixture was diluted to 50 ml with EtOAc and washed with H.sub.2O. The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was evaporated and the residue was dissolved in 1,4-dioxane (4 ml) and 1 M TBAF in THF (0.3 ml) was added and this was stirred for 4 h at reflux. The solvent was distilled off and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give the title compound (0.145 g, 91%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 7.78 (s, 1H); 7.46-7.44 (m, 2H); 6.41 (bs, 1H); 2.47 (s, 3H).

(214) Step B: 5-(3,4-Diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1,2,4-oxadiazole: The product Step A was converted to N-hydroxy-2-methylbenzofuran-5-carboximidamide by method described for Example 36, Step A. When N-hydroxy-2-methylbenzofuran-5-carboximidamide and 3,4-diethoxybenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid, respectively, in Example 36, Step B, the similar procedure afforded the title compound in 6% yield, as colourless solid. 1H-NMR (CDCl.sub.3) 8.28 (bs, 1H); 8.00 (dd, 1H, J=8.55, 1.68 Hz); 7.8 (dd, 1H, J=8.4, 1.98 Hz); 7.68 (d, 1H, J=1.92 Hz); 7.47 (d, 1H, J=8.58 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.45 (s, 1H); 4.23-4.16 (m, 4H); 2.48 (3H); 1.52-1.47 (m, 6H).

Example 43

2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(215) Step A: Ethyl 2-(2-formyl-5-methoxyphenoxy)acetate: A mixture of 2-hydroxy-4-methoxybenzaldehyde (1 g; 6.58 mmol), BrCH.sub.2CO.sub.2Et (0.806 ml; 7.24 mmol) and K.sub.2CO.sub.3 (1 g, 7.24 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and H.sub.2O (100 ml). The organic layer was separated and dried over MgSO.sub.4, and filtrate evaporated, to give the product (1.29 g; 97%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 1.28 (tr, 3H, J=7.11 Hz); 3.84 (s, 3H); 4.25 (q, 2H, J=7.14, 14.28 Hz); 4.69 (s, 2H); 6.30 (d, 1H, J=2.16 Hz); 6.58 (dd, 1H, J=1.77, 8.73 Hz); 7.83 (d, 1H, J=8.7 Hz); 10.36 (s, 1H).

(216) Step B: Ethyl 6-methoxybenzofuran-2-carboxylate: A mixture of the product of Step A (1.28 g, 5.37 mmol) and DBU (0.3 ml) was heated for 3 h at 160 with stirring, cooled to room temperature and dissolved in EtOAc: MeOH mixture (99:1). The mixture was filtered through the silica bead and the filtrate was evaporated to give the title compound (1.11 g; 77%), as colourless solid. .sup.1H-NMR (CDCl.sub.3) 1.40 (tr, 3H, J=7.13 Hz); 3.85 (s, 3H); 4.40 (q, 2H, J=7.13, 14.25 Hz); 4.45 (s, 1H); 6.91 (dd, 1H, J=2.25, 8.68 Hz); 7.04 (d, 1H, J=1.87 Hz); 7.51 (d, 1H, J=5.17 Hz),

(217) Step C: 6-Methoxybenzofuran-2-carboxylic acid: To a stirred solution of Product of Step B (0.25 g, 1.21 mmol) in a mixture of THF, MeOH and H.sub.2O (5 ml: 2 ml: 1 ml), LiOH (0.145 g, 6 mmol) in H.sub.2O (0.5 ml) was added and the mixture was stirred for 3 h at room temp. The solvents were distilled off and the residue was portioned between EtOAc (20 ml) and 1M HCl (2 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.21 g, 91%), as a colourless solid. .sup.1H-NMR (DMSO-d.sub.6) 7.61 (d, 1H, J=8.67 Hz); 7.54 (s, 1H); 7.24 (d, 1H, J=1.59 Hz); 6.93 (dd, 1H, J=8.67, 2.4 Hz); 3.8 (s, 3H).

(218) Step D: 3-(3-Iodo-4-isopropoxyphenyl)-5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazole: When the product of Step C was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 67% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.6 (d, 1H, J=2.04 Hz); 8.08 (dd, 1H, J=8.58, 2.1 Hz); 7.63 (b, 1H); 7.57 (d, 1H, J=8.7 Hz); 7.13 (d, 1H, J=1.8 Hz); 6.97 (dd, 1H, J=8.7, 2.19 Hz); 6.87 (d, 1H, J=8.73 Hz); 4.69-4.59 (m, 1H); 3.88 (s, 3H); 1.4 (d, 6H, J=6.33 Hz).

(219) Step E: 2-Iodo-4-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step D was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 65% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.53 (d, 1H, J=2.01 Hz); 8.06 (dd, 1H, J=8.49, 2.01 Hz); 7.64 (b, 1H); 7.6 (d, 1H, J=8.7 Hz); 7.13 (b, 1H); 7.08 (d, 1H, J=8.46 Hz); 6.98 (dd, 1H, J=8.7, 2.22 Hz); 3.89 (s, 3H).

(220) Step F: tert-Butyl 5-(5-(5-(6-methoxybenzoluran-2-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step E was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 64% yield, as pale paste.

(221) Step G: 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step F was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 26% yield, as creamy green solid. .sup.1H-NMR (CD.sub.3OD) 8.39 (d, 1H, J=1.74 Hz); 8.08 (dd, 1H, J=8.73, 1.89 Hz); 7.68 (b, 1H); 7.63 (d, 1H, J=8.73 Hz); 7.58 (d, 1H, J=8.7 Hz); 7.14 (d, 1H, J=1.8 Hz); 7.03 (s, 1H); 6.92 (dd, 1H, J=8.7, 2.22 Hz); 3.98 (d, 2H, J=1.00 Hz); 3.88 (d, 2H, J=11.01 Hz); 3.85 (s, 3H).

Example 44

2-Amino-2-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(222) Step A: 3-(3-Iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)-1,2,4-oxadiazole: When 4-propylbenzoic acid was substituted for 3-chloro-4-propoxy benzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 82% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.58 (d, 1H, J=2.04 Hz); 8.11-8.05 (m, 3H); 7.34 (d, 2H, J=8.25 Hz); 6.88 (d, 1H, J=8.73 Hz); 4.7-4.59 (m, 1H); 2.67 (t, 2H, J=7.83 Hz); 1.72-1.41 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).

(223) Step B: 2-Iodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 82% yield, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.48 (d, 1H, J=1.98 Hz); 8.08 (d, 2H, J=8.25 Hz); 8.03 (dd, 1H, J=8.49, 2.01 Hz); 7.33 (d, 2H, J=8.25 Hz); 7.07 (d, 1H, J=8.49 Hz); 2.66 (t, 2H, J=7.5 Hz); 1.71-1.61 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).

(224) Step C: tert-Butyl 2,2-dimethyl-5-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzo-furan-2-yl)-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 35% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.35 (s, 1H); 8.13-8.06 (m, 3H); 7.52 (d, 1H, J=8.64 Hz); 7.34 (d, 2H, J=8.22 Hz); 6.75 (s, 1H); 5.35 (s, 1H); 4.26 (b, 4H); 2.67 (t, 2H, J=7.41 Hz); 1.74-1.67 (m, 2H); 1.64 (s, 6H); 1.5 (s, 9H); 0.96 (t, 2H, J=7.29 Hz).

(225) Step D: 2-Amino-2-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 28% yield, as creamy solid. .sup.1H-NMR (DMSO-d.sub.6) 8.30 (s, 1H); 8.08 (d, 2H, J=6.6 Hz); 7.94 (d, 1H, J=7.5 Hz); 7.68 (d, 1H, J=7.5 Hz); 7.46 (d, 2H, J=7.5 Hz); 6.92 (s, 1H); 3.67 (b, 2H); 3.59 (b, 2H); 2.65 (b, 2H); 1.63-1.6 (m, 2H); 0.88 (t, 2H, J=6.3 Hz).

Example 45

2-Amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(226) Step A: 5-(4-Ethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When 4-ethoxybenzoic acid was substituted for 3-chloro-4-propoxy benzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 53% yield, as white solid. .sup.1H-NMR (CDCl.sub.3) 8.57 (d, 1H, J=2.04 Hz); 8.11 (d, 2H, J=8.88 Hz); 8.05 (dd, 1H, J=8.58, 2.04 Hz); 6.99 (d, 2H, J=8.88 Hz); 6.87 (d, 1H, J=8.67 Hz); 4.69-4.61 (m, 1H); 4.11 (q, 2H, J=6.99, 13.98 Hz); 1.45 (t, 3H, J=6.99 Hz).

(227) Step B: 4-(5-(4-Ethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 87% yield, as white solid. .sup.1H-NMR (CDCl.sub.3) 8.47 (d, 1H, J=1.95 Hz); 8.11 (d, 2H, J=8.94 Hz); 8.03 (dd, 1H, J=8.46, 2.01 Hz); 7.07 (d, 2H, J=8.49 Hz); 4.11 (q, 2H, J=6.96, 13.98 Hz); 1.45 (t, 3H, J=6.96 Hz).

(228) Step C: tert-Butyl 5-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 60% yield, as pale paste. .sup.1H-NMR (CDCl.sub.3) 8.34 (s, 1H); 8.14 (d, 2H, J=8.88 Hz); 8.07 (dd, 1H, J=8.61, 1.68 Hz); 7.51 (d, 1H, J=8.52 Hz); 7.00 (d, 2H, J=8.94 Hz); 6.75 (s, 1H); 5.34 (s, 1H); 4.3-4.14 (b, 4H); 4.1 (t, 2H, J=7.02 Hz); 1.44-1.39 (b, 18H).

(229) Step D: 2-Amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 32% yield, as light yellow solid. .sup.1H-NMR (DMSO-d6) 8.09 (s, 1H); 7.96 (d, 2H, J=8.4 Hz); 7.7 (d, 1H, J=8.4 Hz); 7.15 (d, 2H, J=9 Hz); 6.98 (s, 1H); 5.1 (b, 2H); 4.13 (q, 2H, J=6.9, 13.8 Hz); 3.73 (d, 2H, J=8.1 Hz); 3.64 (d, 2H, J=8.1 Hz); 1.34 (t, 3H, J=6.9 Hz).

Example 46

2-Amino-2-(6-chloro-5-(5-(4-propyl phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(230) Step A: 2-Chloro-N-hydroxy-5-iodo-4-isopropoxybenzimidamide: To a stirred solution of 2-chloro-4-isopropoxybenzonitrile (0.8 g, 4.1 mmol) and CF.sub.3CO.sub.2Ag (1.3 g, 5.1 mmol) in CH.sub.2Cl.sub.2 (50 ml) I.sub.2 (1 g, 4 mmol) was added and the mixture was stirred for 6 h at reflux. This was filtered through the Celite bead and the washed with CH.sub.2Cl.sub.2. The combined filtrates were evaporated to dryness and the residue was purified by FCC (SiO.sub.2, hexane/EtOAc) to give 2-chloro-5-iodo-4-isopropoxybenzonitrile (0.335 g, 26%), as white solid. 1H NMR (CDCl.sub.3) 7.99 (s, 1H); 6.82 (s, 1H); 4.66-4.58 (m, 1H); 1.41 (d, 6H, J=6.03 Hz. This (0.32 g, 1 mmol) was converted to the title compound (0.335 g; 95%) according to the procedure of Example 36 Step A. .sup.1H NMR (CDCl.sub.3) 7.89 (s, 1H); 6.79 (s, 1H); 4.86-4.49 (m, 1H); 1.4 (d, 6H)

(231) Step B: 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)-1,2,4-oxadiazole: When the product of Step A and 4-propylbenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 20% yield, as white solid. .sup.1H NMR (CDCl.sub.3) 8.46 (s, 1H); 8.10 (d, 2H, J=8.25 Hz); 7.34 (d, 2H, J=8.28 Hz); 6.92 (s, 1H); 7.67-7.59 (m, 1H); 2.67 (t, 2H, J=7.35 Hz); 1.72-1.65 (m, 2H); 1.43 (d, 6H, J=6.06 Hz); 0.96 (t, 3H, J=7.32 Hz).

(232) Step C: 5-Chloro-2-iodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3yl)phenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 55% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.37 (s, 1H); 8.10 (d, 2H, J=8.25 Hz); 7.33 (d, 2H, J=8.25 Hz); 7.16 (s, 1H); 5.78 (b, 1H); 2.67 (t, 2H, J=7.38 Hz); 1.74-1.56 (m, 2H); 0.96 (t, 3H, J=7.32 Hz).

(233) Step D: 2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was replaced with the tert-butyl 5-(6-chloro-5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) the similar procedure as in Example 36, Step E gave the title compound (0.006 g, 40%) as white solid. .sup.1H NMR (CD.sub.3OD) 8.12 (d, 2H, J=8.28 Hz); 8.12 (s, 1H); 7.75 (s, 1H); 7.43 (d, 2H, J=8.31 Hz); 6.9 (s, 1H); 3.88 (d, 2H, J=10.9 Hz); 3.78 (d, 1H, J=10.9 Hz); 2.7 (t, 2H, J=7.41 Hz); 1.76-1.64 (m, 2H); 0.97 (t, 3H, J=7.32 Hz).

Example 47

2-Amino-2-(5-(5-(1-butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(234) Step A: 1-Butyl-1H-pyrazole-4-carboxylic acid: To a stirred suspension of 4-iodopyrazole (0.3 g, 1.55 mmol) and 60% NaH (0.08 g, 2 mmol) in anhydrous THF (1 ml) butyl bromide (0.5 ml) was added and the mixture was stirred overnight at 70 C. The mixture was quenched with saturated NH.sub.4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was distilled off and the residue was dried in vacuo to give 1-butyl-4-iodo-1H-pyrazole (0.39 g, 100%), as colourless oil. .sup.1H NMR (CDCl.sub.3) 7.47 (s, 1H); 7.39 (s, 1H); 4.09 (t, 2H, J=7.14 Hz); 1.85-1.75 (m, 2H); 1.35-1.23 (m, 2H); 0.91 (t, 3H, J=7.32 Hz). To a stirred solution of the above product (0.36 g, 1.44 mmol) in anhydrous THF (0.5 ml) 2M iPrMgCl in THF (2 ml) was added at 0 C. and after warming up to room temperature anhydrous DMF (1 ml) was added to it. This was stirred for 1 h at room temperature, than quenched with saturated NH.sub.4Cl and extracted with EtOAc (30 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give 1-butyl-1H-pyrazole-4-carbaldehyde (0.27 g; 100%), as pale oil. .sup.1H NMR (CDCl.sub.3) 9.82 (s, 1H); 7.93 (s, 1H); 7.89 (s, 1H); 4.13 (t, 2H, J=7.11 Hz); 1.9-1.8 (m, 2H); 1.4-1.22 (m, 2H); 0.92 (t, 3H, J=7.29 Hz). To a stirred solution of above aldehyde (0.22 g, 1.44 mmol) in the mixture of dioxane and H.sub.2O (15 ml: 3 ml) KMnO.sub.4 (0.25 g; 1.58 mmol) was added over a period of 30 min. The mixture was evaporated to dryness and the residue was treated in the mixture of EtOAc and MeOH (20 ml: 5 ml) and filtered through Celite pad. The filtrate was evaporated to dryness to give the title compound (0.24 g; 100%), as creamy crystalline solid. .sup.1H NMR (CDCl.sub.3) 7.8 (s, 1H); 7.56 (b, 1H); 4.05 (b, 2H); 1.7 (b, 2H); 1.18 (b, 2H); 0.83 (b, 3H).

(235) Step B: 5-(1-Butyl-1H-pyrazol-4-yl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B the similar procedure afforded the title compound in 17% yield, as creamy gum. .sup.1H NMR (CDCl.sub.3) 8.53 (d, 1H, J=2.07 Hz); 8.1 (s, 1H); 8.08 (s, 1H); 8.00 (dd, 1H, J=8.61, 2.16 Hz); 8.87 (d, 1H, J=8.73 Hz); 4.68-4.6 (m, 2H); 4.2 (t, 2H, J=7.11 Hz); 2.02-1.85 (m, 2H); 1.42-1.32 (m, 2H); 0.95 (t, 3H, J=7.32 Hz).

(236) Step C: 4-(5-(1-Butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4-isopropoxy phenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 72% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.45 (d, 1H, J=1.98 Hz); 8.12 (s, 1H); 8.09 (s, 1H); 7.99 (dd, 1H, J=8.49, 2.01 Hz); 7.06 (d, 1H, J=8.49 Hz); 4.2 (t, 2H, J=7.08 Hz); 2.02-1.85 (m, 2H); 1.42-1.26 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).

(237) Step D: tert-Butyl 5-(5-(5-(1-butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 68% yield, as pale paste. .sup.1H NMR (CDCl.sub.3) 8.3 (s, 1H); 8.13 (s, 1H); 8.01 (s, 1H); 7.51 (d, 1H, J=8.7 Hz); 6.74 (s, 1H); 5.32 (s, 1H); 4.29-4.18 (m, 6H); 2.02-1.91 (m, 2H); 1.54-1.34 (b, 17H); 0.96 (t, 3H, J=7.35 Hz).

(238) Step E: 2-Amino-2-(5-(5-(1-butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 46% yield, as light creamy solid. .sup.1H NMR (CD.sub.3OD) 8.46 (broad s, 1H); 8.32 (broad s, 1H); 8.13 (broad s, 1H); 8.02 (d, 1H, J=7.98 Hz); 7.62 (d, 1H, J=8.31 Hz); 6.97 (s, 1H); 4.25 (t, 2H, J=6.21 Hz); 3.93 (b, 4H); 1.91-1.86 (m, 2H); 1.36-1.31 (m, 2H); 0.95 (t, 3H, J=7.02 Hz).

Example 48

2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(239) Step A: 3-Nitro-4-propoxybenzoic acid: To a stirred solution of 3-nitro-4-propoxymethylbenzoate (0.35 g, 1.46 mmol) in a mixture of THF and EtOH (3 ml: 1 ml) the solution of LiOH (0.345 g; 15 mmol) in H.sub.2O (1 ml) was added and the mixture was stirred for 4 h at room temperature. The solvent was distilled off and the residue was treated with 1 M HCl and extracted with EtOAc (50 ml). The organic layer was washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.32 g, 97%), as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.53 (d, 1H, J=1.65 Hz); 8.21 (dd, 1H, J=8.79, 1.62 Hz); 7.12 (d, 1H, J=8.82 Hz); 4.14 (t, 2H, J=6.39 Hz); 1.94-1.82 (m, 2H); 1.07 (t, 3H, J=7.35 Hz).

(240) Step B: 3-(3-Iodo-4-isopropoxyphenyl)-5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazole: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 66% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.64 (d, 1H, J=2.13 Hz); 8.55 (d, 1H, J=2.1 Hz); 8.3 (dd, 1H, J=8.82, 2.16 Hz); 8.2 (dd, 1H, J=8.58, 2.01 Hz); 7.2 (d, 1H, J=8.88 Hz); 6.96 (d, 1H, J=8.85 Hz); 4.7-4.62 (m, 1H); 4.16 (t, 2H, J=6.39 Hz); 1.94-1.84 (m, 2H); 1.42 (d, 6H, J=6.03 Hz); 1.08 (t, 3H, J=7.35 Hz).

(241) Step C: 2-Iodo-4-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 77% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.65 (d, 1H, J=2.16 Hz); 8.47 (d, 1H, J=1.95 Hz); 8.3 (dd, 1H, J=8.82, 2.19 Hz); 8.03 (dd, 1H, J=8.49, 2.01 Hz); 7.21 (d, 1H, J=8.88 Hz); 7.08 (d, 1H, J=8.49 Hz); 4.17 (t, 2H, J=6.39 Hz); 1.96-1.84 (m, 2H); 1.09 (t, 3H, J=7.38 Hz).

(242) Step D: tert-Butyl 2,2-dimethyl-5-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 54% yield, as pale solid. .sup.1H NMR (CDCl.sub.3) 8.68 (d, 1H, J=2.16 Hz); 8.35-8.31 (m, 2H); 8.06 (dd, 1H, J=8.64, 1.71 Hz); 7.54 (d, 1H, J=8.64 Hz); 7.21 (d, 1H, J=8.97 Hz); 6.76 (s, 1H); 5.33 (s, 1H); 4.3-3.95 (m, 6H); 2.41-1.87 (m, 2H); 1.58-1.21 (m, 15H); 1.09 (t, 3H, J=7.44 Hz).

(243) Step E: 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxy phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 49% yield, as creamy solid. .sup.1H NMR (DMSO-d.sub.6) 8.6 (s, 1H); 8.37 (d, 1H, J=8.37 Hz); 8.31 (s, 1H); 7.94 (d, 1H, J=8.52 Hz); 7.68 (d, 1H, J=8.52 Hz); 7.59 (d, 1H, J=8.82 Hz); 6.91 (s, 1H); 4.87 (b, 2H); 4.23 (t, 2H, J=5.82 Hz); 3.67 (d, 2H, J=10.05 Hz); 3.58 (d, 2H, J=9.96 Hz); 1.78-1.71 (m, 2H); 0.97 (t, 3H, J=7.26 Hz).

Example 49

5-(3-(2-(2-Amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-propoxybenzonitrile

(244) Step A: 3-Cyano-4-propoxybenzoic acid: To a stirred solution of 3-bromo-4-propoxybenzaldehyde (0.6 g, 2.47 mmol) in anhydrous DMF (5 ml) CuCN (0.67 g; 7.4 mmol) was added and the mixture was stirred for 4 h at reflux. After cooling to room temperature, the mixture was treated with EtOAc (50 ml) and 1M HCl (10 ml) and stirred for 15 min. The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give 5-formyl-2-propoxybenzonitrile (0.41 g; 88%), as yellow oil .sup.1H NMR (CDCl.sub.3) 9.87 (s, 1H); 8.07 (d, 1H, J=1.95 Hz); 8.03 (dd, 1H, J=8.67, 2.1 Hz); 7.06 (d, 1H, J=8.7 Hz); 4.13 (t, 2H, J=6.45 Hz); 1.97-1.85 (m, 2H); 1.1 (t, 3H, J=7.35 Hz). The above benzaldehyde was oxidised via a similar procedure as described in Example 47 Step A, to give the title compound (0.29 g; 68%), as white solid. .sup.1H NMR (CDCl.sub.3) 8.3 (d, 1H, J=1.71 Hz); 8.23 (dd, 1H, J=8.88, 2.1 Hz); 7.00 (d, 1H, J=7.62 Hz); 4.12 (t, 2H, J=6.48 Hz); 1.97-1.85 (m, 2H); 1.09 (t, 3H, J=7.38 Hz).

(245) Step B: 5-(3-(3-Iodo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 57% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.55 (d, 1H, J 2.1 Hz); 8.4 (d, 1H, J=2.1 Hz); 8.31 (dd, 1H, J=8.85, 2.16 Hz); 8.04 (dd, 1H, J=8.61, 2.1 Hz); 7.09 (d, 1H, J=8.94 Hz); 6.88 (d, 1H, J=8.7 Hz); 4.7-4.6 (m, 1H); 4.14 (t, 2H, J=6.48 Hz); 1.98-1.87 (m, 2H); 1.42 (d, 6H, J=6.06 Hz); 1.18 (t, 3H, J=7.38 Hz).

(246) Step C: 5-(3-(4-Hydroxy-3-iodophenyl)-1,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile: When the product of Step B was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 74% yield, as creamy solid. .sup.1H NMR (CDCl.sub.3) 8.46 (d, 1H, J=1.95 Hz); 8.4 (d, 1H, J=2.13 Hz); 8.31 (dd, 1H, J=8.88, 2.19 Hz); 8.02 (dd, 1H, J=8.49, 1.68 Hz); 7.1 (d, 1H, J=8.94 Hz); 7.09 (d, 1H, J=8.49 Hz); 5.64 (bs, 1H); 4.12 (t, 2H, J=6.48 Hz); 2.02-1.86 (m, 2H); 1.1 (t, 3H, J=7.38 Hz).

(247) Step D: tert-Butyl 5-(5-(5-(3-cyano-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 44% yield, as pale paste. .sup.1H NMR (CDCl.sub.3) 8.42 (d, 1H, J=2.16 Hz); 8.34 (dd, 1H, J=6.63, 2.19 Hz); 8.06 (dd, 1H, J=8.61, 1.71 Hz); 7.99 (b, 1H); 7.52 (d, 1H, J=8.58 Hz); 7.1 (d, 1H, J=8.94 Hz); 6.76 (s, 1H); 5.33 (s, 1H); 4.26 (t, 4H, J=1.4 Hz); 4.15 (t, 2H, J=1.4 Hz); 4.15 (t, 2H, J 6.48 Hz); 2.02-1.87 (m, 2H); 1.56-1.38 (m, 15H); 1.1 (t, 3H, J=7.38 Hz).

(248) Step E: 5-(3-(2-(2-Amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile: When product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) in Example 36, Step E, the similar procedure afforded the title compound in 29% yield, as off white solid. .sup.1H NMR (DMSO-d.sub.6) 8.49 (d, 1H, J=2.22 Hz); 8.39 (dd, 1H, J=8.91, 2.22 Hz); 8.28 (d, 1H, J=1.41 Hz); 7.93 (dd, 1H, J=8.55, 1.71 Hz); 7.68 (d, 1H, J=8.58 Hz); 7.48 (d, 1H, J=9.06 Hz); 6.89 (s, 1H); 4.78 (b, 2H); 4.22 (t, 2H, J=6.42 Hz); 3.68-3.52 (m, 4H); 1.84-1.73 (m, 2H); 1.0 (t, 3H, J=7.41 Hz).

Example 50

2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol

(249) Step A: 3-Bromo-4-propoxybenzoic acid: 3-Bromo-4-propoxybenzaldehyde was oxidized by KMnO.sub.4, according to the procedure as described in Example 47, Step A, to give the title compound in 96%, as white solid. .sup.1H-NMR (DMSO-d.sub.6) 0.98 (t, 3H, J=7.32 Hz); 1.68-1.79 (m, 2H); 4.06 (t, 2H, J=6.39 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.87 (dd, 1H, J=2.07, 8.61 Hz); 8.01 (d, 1H, J=2.04 Hz); 11.2 (broad s, 1H).

(250) Step B: 4-(5-(3-Bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 70% yield, as white solid. .sup.1H NMR (CDCl.sub.3) 8.47 (s, 1H); 8.38 (s, 1H); 8.08 (d, 1H, J=9.09 Hz); 8.03 (d, 1H, J=8.79 Hz); 7.7 (d, 1H, J=8.55 Hz); 6.98 (d, 1H, J=8.67 Hz); 4.08 (t, 2H, J=6.39 Hz); 1.96-1.84 (m, 2H); 1.1 (t, 3H, J=7.35 Hz).

(251) Step C: tert-Butyl 5-(5-(5-(3-bromo-4-propoxy-phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When with the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 98% yield, as pale paste.

(252) Step D: 2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1,3-diol: When the product of Step C is substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 10% yield, as light yellow solid. .sup.1H NMR (CD.sub.3OD) 8.32 (b, 2H); 8.1 (d, 1H, J=8.46 Hz); 8.00 (d, 1H, J=8.52 Hz); 7.59 (d, 1H, J=8.61 Hz); 7.18 (d, 1H, J=8.58 Hz); 6.91 (s, 1H); 4.1 (t, 2H, J=6.06 Hz); 3.91 (d, 2H, J=10.98 Hz); 3.03 (d, 2H, J=10.95 Hz); 3.32 (b, 2H); 1.9-1.8 (m, 2H); 1.1 (t, 3H, J=7.35 Hz).

Example 51

2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1,3-diol

(253) Step A: 2-Iodo-4-octylaniline: To a stirred mixture of 4-octyl aniline (0.33 g, 1.6 mmol) and H.sub.2O.sub.2 (30%, 0.5 ml) in CH.sub.3OH (1.5 ml) was added I.sub.2 (0.2 g, 0.8 mmol) and the mixture was stirred overnight at room temperature. The solvent was distilled off and the residue was diluted to 10 ml with CH.sub.2Cl.sub.2, washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.46 g, 86%) as yellow paste. .sup.1H NMR (CDCl.sub.3) 7.44 (d, 1H, J=1.83 Hz); 6.93 (dd, 1H, J=8.07, 1.86 Hz); 6.65 (d, 1H, J=8.1 Hz); 4.1 (b, 2H); 2.43 (t, 2H, J=7.5 Hz); 1.54-1.49 (m, 2H); 1.26 (b, 10H); 0.87 (t, 3H, J=6.39 Hz).

(254) Step B: 2-Iodo-4-octylbenzenethiol: To a stirred mixture of the product of Step A (0.4 g; 1.21 mmol) in 35% HCl (0.2 ml) an ice cold solution of NaNO.sub.2 (0.1 g, 1.3 mmol) in H.sub.2O (1 ml) was added at 0 C., followed by a solution of K-ethylxhanthate, freshly prepared by rapid stirring of a mixture of KOH (0.085 g, 1.5 mmol) and CS.sub.2 (0.173 g, 1.5 mmol) in a mixture of EtOH and H.sub.2O (1 ml: 1.5 ml) for 2.5 h at room temperature. The resulting mixture was stirred for 5 h at 55 C., than cooled to room temperature and extracted with EtOAc (50 ml). The organic layer was separated, washed with H.sub.2O, dried over MgSO.sub.4 and filtered. The filtrate was evaporated and the residue was diluted to 20 ml with EtOH and KOH (0.5 g, 3.62 mmol) was added. This was stirred for 5 h at reflux and the mixture was evaporated to dryness and the residue was treated with 1M HCl and extracted with EtOAc (20 ml). The organic layer was separated, dried over MgSO.sub.4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO.sub.2; hexane/EtOAc) to give the title compound (0.1 g, 24%), as a yellow paste, which was used as such in next step. .sup.1H NMR (CDCl.sub.3) 7.75 (b, 1H); 7.28 (d, 1H, J=7.95 Hz); 7.00 (dd, 1H, J=7.95, 2.0 Hz); 7.02 (s, 1H); 2.51-2.45 (m, 2H); 1.53 (b, 2H); 1.25 (b, 10H); 0.86 (t, 3H, J=6.42 Hz).

(255) Step C: tert-Butyl 2,2-dimethyl-5-(5-octylbenzo[b]thiophen-2-yl)-1,3-dioxan-5-ylcarbamate When with the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 24% yield, as white solid. .sup.1H NMR (CDCl.sub.3) 7.65 (d, 1H, J=8.16 Hz); 7.47 (s, 1H); 7.1 (d, 1H, J=6.18 Hz); 7.1 (s, 1H); 5.44 (b, 1H); 4.16 (b, 4H); 2.66 (t, 2H, J=7.5 Hz); 1.6-1.1 (m, 27H); 0.86 (t, 3H, J=6.18 Hz).

(256) Step D: 2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1,3-diol: When tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was replaced with the product of Step C the similar procedure as described in Example 36, Step E gave the title compound (0.008 g, 38%) as light yellow solid. .sup.1H NMR (CD.sub.3OD) 7.74 (d, 1H, J=8.28 Hz); 7.6 (s, 1H); 7.4 (s, 1H); 7.2 (dd, 2H, J=8.34, 1.59 Hz); 4.0 (d, 2H, J=11.46 Hz); 3.94 (d, 2H, J=11.46 Hz); 2.7 (t, 2H, J=7.53 Hz); 1.64 (b, 2H); 1.34-1.26 (b, 10H); 0.85 (t, 3H, J=4.8 Hz).

Example 52

2-Amino-2-(5-octylbenzofuran-2-yl)propane-1,3-diol

(257) Step A: 2-Iodo-4-octylphenol: A mixture of 4-octyl phenol (0.15 g, 0.73 mmol), CF.sub.3CO.sub.2Ag (0.25 g, 1 mmol) and I.sub.2 (0.185 g, 0.73 mmol) in CH.sub.2Cl.sub.2 (10 ml) was stirred for 0.5 h at 0 C., then for 0.5 h at room temperature. The solution was filtered through Celite bead and washed with CH.sub.2Cl.sub.2 (30 ml). The filtrates were evaporated to dryness to give the title compound (0.21 g, 87%) as fawn oil. .sup.1H NMR (CDCl.sub.3) 7.32 (d, 1H, J=8.34 Hz); 7.28 (d, 1H, J=1.26 Hz); 6.98 (dd, 1H, 8.37, 1.71 Hz); 6.62 (s, 1H); 4.69 (t, 2H, J=5.88 Hz); 3.62-3.38 (m, 4H); 2.59 (t, 2H, J=7.29 Hz); 1.56-1.51 (m, 2H); 1.34-1.2 (m, 10H); 0.81 (t, 3H, J=6.48 Hz).

(258) Step B: tert-Butyl 2,2-dimethyl-5-(5-octylbenzofuran-2-yl)-1,3-dioxan-5-ylcarbamate: When with the product of Step A was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 53% yield, as a light yellow paste. .sup.1H NMR (CDCl.sub.3) 7.33 (d, 1H, J=6.27 Hz); 7.32 (s, 1H); 7.01 (dd, 1H, J=8.4, 1.71 Hz); 6.59 (s, 1H); 5.3 (s, 1H); 4.17 (s, 4H); 2.64 (t, 2H, J=7.77 Hz); 1.62-1.24 (m, 27H); 0.86 (t, 3H, J=6.42 Hz).

(259) Step C: 2-Amino-2-(5-octylbenzofuran-2-yl)propane-1,3-diol: When the product of Step B was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxy phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 51% yield, as off white solid. .sup.1H NMR (DMSO-d.sub.6) 7.44 (d, 1H, J=1.98 Hz); 7.0 (dd, 1H, J=8.28, 1.98 Hz); 6.87 (d, 1H, J=8.22 Hz); 5.11 (s, 1H); 2.47 (t, 2H, J=7.5 Hz); 1.56-1.51 (m, 2H); 1.27-1.26 (m, 10H); 0.87 (t, 3H, J=6.45 Hz).

Example 53

2-(4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxathazol-3-yl)indoline-1-carboxamido)acetic acid

(260) Step A: N-Hydroxy-1H-indole-4-carboximidamide: A mixture of 4-cyanoindole (0.64 g; 4.5 mmol), HClH.sub.2NOH (1.1 g; 15.8 mmol), and Na.sub.2CO.sub.3 (0.79 g; 7.43 mmol) in H.sub.2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6 h under N.sub.2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (310 ml). The organic phase was separated, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. .sup.1H-NMR (DMSO-d.sub.6+CDCl.sub.3+CD.sub.3OD) 7.4-7.3 (m, 1H); 7.2-7.12 (m, 2H); 7.01 (t, 1H, J=7.8 Hz); 6.74 (d, 1H, J=3.1 Hz); 3.68 (HDO); 1.71 (broad s, H.sub.2O).

(261) Step B: 5-(3,4-Diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole To a solution of 3,4-diethoxybenzoic acid (0.11 g; 0.52 mmol), and the product of Step A (0.09 g; 0.51 mmol) in anhydrous THF (2 ml), PyBroP (0.25 g; 0.54 mmol) was added followed by DIPEA (0.21 ml; 1.22 mmol), with stirring, at room temperature under N.sub.2. After 2 h of stirring, the mixture was diluted to 15 ml with EtOAc, washed with saturated NH.sub.4Cl (25 ml), brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was suspended in anhydrous toluene (10 ml). To it 1M TBAF in THF (0.5 ml) was added and the reaction mixture was refluxed for 3 h under N.sub.2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H.sub.2O (5 ml) and the solid was purified by FCC (SiO.sub.2; CH.sub.2Cl.sub.2) to give the title compound (0.06 g; 34%) as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.42 (s, 1H); 8.06 (dd, 1H, J=2, 8.4 Hz); 7.83 (d, 1H, J=8.4 Hz); 7.74 (d, 1H, J=2 Hz); 7.54 (d, 1H, J=8.1 Hz); 7.37-7.31 (m, 3H); 6.98 (d, 1H, J=8.5 Hz); 4.26-4.16 (m, 4H); 1.5 (m, 6H).

(262) Step C: 5-(3,4-Diethoxyphenyl)-3-(indolin-4-yl)-1,2,4-oxadiazole: To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH.sub.3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at 0 C. with stirring. After the addition was completed (5 min), the reaction was quenched with H.sub.2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (22 ml), brine and dried over anhydrous MgSO.sub.4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. .sup.1H-NMR (CDCl.sub.3) 7.78 (dd, 1H, J=1.9, 7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=7.2 Hz); 7.17 (t, 1H, J=7.7); 6.97 (d, 1H, J=8.5 Hz); 6.75 (d, 1H, J=7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J=8.9 Hz); 3.45 (tr, 2H, J=8.9 Hz); 1.7 (broad s, 1H+H.sub.2O); 1.49 (m, 6H).

(263) Step D: Ethyl 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-Andoline-1-carboxamido)acetate: When the product of Step E was substituted for n-octylaniline and ethyl isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 1, Step A the similar process afforded the title compound in 61%, as colourless solid. .sup.1H-NMR (CDCl.sub.3) 8.11 (d, 1H, J=7.4 Hz); 7.78 (dd, 2H, J=2, 7.1 Hz); 7.67 (d, 1H, J=2 Hz); 7.31 (t, 1H, J=8 Hz); 6.97 (d, 1H, J=8.5 Hz); 5.13 (t, 1H, J=5.1 Hz); 4.28-4.04 (m, 10H); 3.61 (t, 1H, J8.6 Hz); 1.52-1.47 (m, 6H); 1.32 (t, 3H, J=7.1 Hz);

(264) Step E: 2-(4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indoline-1-carboxamido)acetic acid: When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1, Step B the identical process afforded the title compound in 75% yield. .sup.1H-NMR (DMSO-d.sub.6) 8.03 (d, 1H, J=9 Hz); 7.73 (dd, 1H, J=2, 8 Hz); 7.61-7.59 (m, 2H); 7.29 (t, 1H, J=7.9 Hz); 7.17 (d, 1H, J=8.6 Hz); 7.09 (broad m, 1H); 4.17-4.0 (m, 4H); 3.98 (t, 2H, J=5.8 Hz); 3.74 (d, 2H, J=5.2 Hz); 3.47 (t, 2H, J=9 Hz); 1.38-1.32 (m, 6H).

Example 54

3-(4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indoline-1-carboxamido)propanoic acid

(265) Step A: Ethyl 3-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indoline-1-carboxamido)propanoate: When the product of Example 16 Step C was substituted for n-octylaniline in Example 11, Step A the identical process afforded the title compound in 52% yield. .sup.1H-NMR (CDCl.sub.3) 8.1 (d, 1H, J=9 Hz); 7.79-7.75 (m, 2H); 7.67 (d, 1H, J=2 Hz); 7.31 (t, 1H, J=8 Hz); 6.97 (d, 1H, J=8.5 Hz); 5.38 (tr, 1H, J=5.7 Hz); 4.24-4.12 (m, 6H); 3.98 (t, 2H, J=8.6 Hz); 3.63-3.55 (m, 4H); 2.61 (t, 2H, J=5.9 Hz); 1.27 (t, 3H, J=9 Hz);

(266) Step B: 3-(4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indoline-1-carboxamido)propanoic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1, Step B the identical process afforded the title compound in 61% yield. .sup.1H-NMR (CDCl.sub.3) 8.03 (d, 1H, J=9 Hz); 7.72 (dd, 1H, J=1.9, 8.4 Hz): 7.59-7.56 (m, 2H); 7.27 (t, 1H, J=7.9 Hz); 7.16 (d, 1H, J=8.6 Hz); 6.76 (t, 1H, J=5.3 Hz); 4.04-4.16 (m, 4H); 3.92 (t, 2H, J=8.6 Hz); 3.43 (tr, 2H, J=8.4 Hz); 3.36-3.28 (m, 2H+H.sub.2O); 2.48-2.42 (m, 2H); 1.37-1.32 (m, 6H).

Example 55

S1P Receptors Activity Evaluation

(267) Selected Compounds of the Examples were evaluated at Millipore Corporation, USA, using S1P1 receptor; [.sup.35S]-GTPgamaS binding assay. A [35S]-GTPgamaS binding assay at Millipore was conducted by GPCR Profiler Custom Service Laboratory, Temecula, Calif., Millipore, Inc. to monitor dose-dependent agonist selectivity for selected Examples against the S1P1 receptors. The assay was completed with sample compounds subjected to an eight-point, four-fold dose response curve with starting concentration of 10 M. Selectivity was determined upon initial addition of compounds followed by a 30 minute incubation at 30 C. Following compound incubation, bounded [35S]-GTPgamaS was determined by filtration and scintillation counting. Percentage activation and inhibition values were determined relative to the reference agonist at S1P1 and are shown in Table 10.

(268) Independently, selected compounds were evaluated for S1P1 and S1P3 agonistic activity. The S1P1 assay system was GTPgama-S35 binding in membranes from CHO K1 cells, expressing S1P1 human receptor. The S1P3 assay system was calcium mobilization in CHO K1 cells expressing S1P3 human receptor. There was no significant background response to S1P in the CHO K1 cells with either assay. Compounds were tested initially at a concentration of 10 M. Those compounds with significant efficacy (Emax>0.15 relative to S1P) at either receptor type were used to generate concentration-effect (dose response) curves at that receptor. These analyses provided efficacy (Emax) and potency (EC.sub.50) of the compounds relative to S1P, shown in Table 10.

(269) TABLE-US-00010 TABLE 10 S1P1 and S1P3 agonistic activity of selected compounds of Formula (I): Efficacy Entry EC.sub.50(M) EC.sub.50S.sub.1P.sub.1/ (% of EC.sub.50(M) Number Example S1P1 EC.sub.50S.sub.1P maximum) S.sub.1P.sub.3 1 3 0.29 135.5 102.5 ND 2 9 1.63 761.7 88 ND 3 11 0.46 215 96 ND 4 13 3.21 1500 58 ND 5 17 1.76 542 97 ND 6 19 5.99 2799 130 ND 7 27 0.6 280.4 127 ND 8 29 0.2 93.46 102 ND 9 32 0.06 28 107 ND 10 33 0.14 65.42 97 ND 11 36 0.047 4.18 101 NA 12 37 1.82 160.8 40 NA 13 38 0.26 28.17 74 NA 14 39 3.46 305 16 NA 15 40 0.057 4.75 106 0.38 NA = no activity; ND = not determined.

Example 56

Lymphopenia Assay

(270) The study was performed at vivoPharm Pty Ltd, Adelaide, Australia, to determine the ability of the compounds of invention to induce lymphopenia in female BALB/c mice. On day 0, 27 female BALB/c mice were randomised based on body weight into nine groups of three mice each. Animals received a single i.p. administration of Test compounds and blood was collected by cardiac puncture either 6 or 24 h after administration. Treatment with 3 mg/kg of Example 40 was shown to decrease lymphocyte counts at both 6 and 24 h, compared to untreated animals (FIG. 1). Changes to other haematological parameters were not observed.