Heterocyclic compounds

Abstract

The present invention relates to a compound (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid methods for use of this and other compounds.

Claims

1. A compound (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Accordingly, the present invention relates to compounds of the general formula (I)

(2) ##STR00024##
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein

(3) each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, at each occurrence independently represents H, halogen, hydroxyl, CN, NO.sub.2, CHO, COOH, CO, optionally substituted groups selected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH.sub.2 or optionally substituted NHCO-linear or branched (C.sub.1-C.sub.6)alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR, C(O)R, and SO.sub.2R wherein R at each occurrence independently represents optionally substituted groups selected from H, linear or branched (C.sub.1-C.sub.6)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetrerocyclylalkyl, heteroaryl, heteroaralkyl groups; In an alternate embodiment, R.sub.3 and R.sub.4 together may form an oxo group;

(4) A is selected from 3-7 member partially saturated, unsaturated or saturated ring which may further be having one or more than one heteroatom selected from O, S, or N;

(5) Each of E & D may independently be either nitrogen or carbon. F may be selected from C, N or O; G may be present or absent and when present represents either a bond or is selected from O, S, NR.sub.a, wherein R.sub.a represents linear or branched (C.sub.1-C.sub.6) alkyl;

(6) m=1-3; each of n, r, p and s independently represents an integer ranging from 0 to 6; q=0-4;

(7) X may be present or absent and when present is selected from CH.sub.2, O, S, and NR.sub.a, SO.sub.2NH; wherein R.sub.a is as defined earlier;

(8) T is selected from oxygen, NH, S, SO, SO.sub.2 or NR.sub.a, wherein R.sub.a is as defined earlier; each of R.sub.7 and R.sub.8 independently may be selected (C.sub.2-C.sub.4)alkyne, nitrile, or a cycloalkyl; Alternatively R.sub.7 and R.sub.8 may combine with the carbon atom to which it is attached to form a 3-7 membered cyclic ring which may optionally further have one or more than one heteroatom selected from S, N, or O;

(9) R.sub.9 & R.sub.10 may be selected from hydrogen, alkyl, alkoxy, and halogen groups.

(10) A preferred embodiment of the present invention relates to compound of the general Formula (I)

(11) ##STR00025##
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein

(12) Each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 occurrence independently represents H, halogen, hydroxyl, CN, NO.sub.2, CHO, COOH, CO, optionally substituted groups selected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH.sub.2 or optionally substituted NHCO-linear or branched (C.sub.1-C.sub.6)alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR, C(O)R, and SO.sub.2R wherein R at each occurrence independently represents optionally substituted groups selected from H, linear or branched (C.sub.1-C.sub.6)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetretocyclylalkyl, heteroaryl, heteroaralkyl groups;

(13) In an alternate embodiment, R.sub.3 and R.sub.4 together may form an oxo group;

(14) A is selected from 3-7 member partially saturated, unsaturated or saturated ring which may further be having one or more than one heteroatom selected from O, S, or N;

(15) Each of E & D may independently be either nitrogen or carbon. F may be selected from C, N or O;

(16) Each of n, r and s independently represents an integer ranging from 0 to 6; each of R.sub.5 and R.sub.6 independently may be selected (C.sub.2-C.sub.4)alkyne, nitrile, or a cycloalkyl; Alternatively R.sub.5 and R.sub.6 may combine with the carbon atom to which it is formed to form a 3-7 membered cyclic ring which may optionally further have one or more than one heteroatom selected from S, N, or O;

(17) The preferred heterocycles representing

(18) ##STR00026##
may be selected from the following bicyclic rings mentioned below

(19) ##STR00027## ##STR00028## ##STR00029##

(20) The substituent COOH may be optionally replace wherever possible with bioisosteric replacements such as:

(21) ##STR00030##
and the like;

(22) When any of the groups from R.sub.1 to R.sub.10 are substituted with one or many groups, the substituents may be independently selected from the groups comprising hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylsmino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycabonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

(23) The aryl group may be an aromatic system containing one, two or three rings wherein such rings may be attached together in a dependent manner or may be fused; in a preferred embodiment such aryl group may be selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl groups;

(24) The heteroaryl group represents 5 to 8 membered aromatic radicals, which may be single or fused containing one or more hetero atoms selected from O, N or S; in a preferred embodiment such groups may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidinyl, pyrazolopyrimidonyl, azaquinazolinyl, azaquinazolinoyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, thienopyrimidonyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, quinazolonyl, pyrimidonyl, pyridazinyl, triazinyl, benzoxazinyl, benzoxazinonyl, benzothiazmyl, benzothiazinonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl groups;

(25) The term heterocyclyl represents saturated, partially saturated or unsaturated ring-shaped radicals, the heteroatoms being selected from nitrogen, sulfur or oxygen; in a preferred embodiment such groups may be selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, and the like; examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole groups.

(26) The alkyl group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; the alkenyl group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the alkenyl group includes dienes and trienes of straight and branched chains; the alkynyl group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like. The term alkynyl includes di- and tri-ynes; the cycloalkyl or alicyclic group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; The terms bicycloalkyl means more than one cycloalkyl groups fused together; the cycloalkenyl group used either alone or in combination with other radicals, are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl 2-cyclohexenyl, 3-cyclohexenyl and the like; the alkoxy group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like; the cycloalkoxy group used either alone or in combination with other radicals, is selected from groups containing an cycloalkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from cyclopropoxy, cyclobuloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like; the aryloxy group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like; the aralkyl group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an alkyl radical, as define above, more preferably groups selected from benzyl, phenethyl, and the like; the aralkoxy group used either alone or in combination with other radicals, is selected from groups containing an aralkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from benzyloxy, phenethyloxy, and the like; the heteroaralkyl group used either alone or in combination with other radicals, is selected from groups containing an heteroaryl radical, as defined above, attached directly to an alkyl radicals, as define above, more preferably groups selected from pyridinealkyl, thiophenealkyl, quinolinealkyl, and the like; the alkenoxy group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like; the haloalkyl group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(C.sub.1-C.sub.6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; the haloalkoxy group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; the perhaloalkoxy group is selected from a suitable perhaloalkyl radical, as defined above, directly attached to an oxygen atom, more preferably groups selected from trifluoromethoxy, trifluoroethoxy, and the like; the groups heteroaryloxy, heteroaralkoxy, heterocycloxy, heterocylylalkoxy are selected from suitable heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom; the acyl group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; the acyloxy group used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like; the acylamino group used either alone or in combination with other radicals, is selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH.sub.3CONH, C.sub.2H.sub.5CONH, C.sub.3H.sub.7CONH, C.sub.4H.sub.9CONH, C.sub.6H.sub.5CONH and the like, which may be substituted; the mono-substituted amino group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (C.sub.1-C.sub.6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n-propylamine, n-butylamine, n-pentylamine and the like; the disubstituted amino group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or different, selected from (C.sub.1-C.sub.6)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; the arylamino used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamine, N-methyl anilino and the like; the oxo or carbonyl group used either alone (CO) or in combination with other radicals such as alkyl described above, for e.g. alkylcarbonyl, denotes a carbonyl radical (CO) substituted with an alkyl radical described above such as acyl or alkanoyl; the carboxylic acid group, used alone or in combination with other radicals, denotes a COOH group, and includes derivatives of carboxylic acid such as esters and amides; the ester group used alone or in combination with other radicals, denotes COO group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarboayl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benxyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; the amide group used alone or is combination with other radicals, represents an aminocarbonyl radical (H.sub.2NCO), wherein the amino group is mono- or di-substituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl amide, ethyl amide, diethyl amide, and the like; the aminocarbonyl group used either alone or in combination with other radicals, may be selected from aminocarbonyl, aminocarbonylalkyl, n-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-hydroxyaminocarbonyl, and N-alkyl-N-hydroxyaminocarbonylalkyl, each of them being optionally substituted. The terms N-alkylaminocarbonyl and N,N-dialkylaminocarbonyl denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are lower alkylaminocarbonyl having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms N-arylaminocarbonyl and N-alkyl-N-arylaminocarbonyl denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term aminocarbonylalkyl includes alkyl radicals substituted with aminocarbonyl radicals; the hydroxyalkyl group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like; the aminoalkyl group used alone or is combination with other radicals, denotes an amino (NH.sub.2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term alkylamino used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino; the alkoxyalkyl group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; the alkylthio group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted; the thioalkyl group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula SR, where R represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted. the alkoxycarbonylamino group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyol group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like; the aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino groups used alone or in combination with other radicals, is a carbonylamino (CONH.sub.2) group, attached to amino(NH.sub.2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above; the amidino group used either alone or in combination with other radicals, represents a C(NH)NH.sub.2 radical; the alkylamidino group represents an alkyl radical, as described above, attached to an amidino group; the alkoxyamino group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group; the hydroxyamino group used either alone or in combination with other radicals, represents a NHOH moiety, and may be optionally substituted with suitable groups selected from those described above; the sulfenyl group or sulfenyl derivatives used alone or in combination with other radicals, represents a bivalent group, SO or R.sub.xSO, where Rx is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above; the sulfonyl group or sulfones derivatives used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical SO.sub.2, or R.sub.xSO.sub.2, where R.sub.x is as defined above. More preferably, the groups may be selected from alkylsulfonyl wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, arylsulfonyl wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like. the sulfonyloxy group used either alone or in combination with other radicals, with other terms such as alkylsulfonyloxy, represents a divalent radical SO.sub.3, or R.sub.xSO.sub.3, where R.sub.x is as defined above. More preferably, the groups may be selected from alkylsulfonyl wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyloxy radical, such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and the like, arylsulfonyl wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as benzenesulfonyloxy and the like

(27) Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.

(28) Particularly useful compounds may be selected from (S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1); Lithium 3-(4-((3-(4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoic acid; 3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid; Lithium 3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid; 3-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid; 3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid; (S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((1-(tert-butoxycarbonyl)-6,7-dihydro-1H-pyrrole[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((3,4-dihydroquinolin-1(2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; (S)-3-(4-((3-((2-Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; Calcium(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; Calcium (S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; (S)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((1-Methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-(Indolin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid; (S)-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; 6-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-ium formate; 1-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-1-ium formate; (S)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(1H,4H, 6H)-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-5-(3-((4-(1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid; 3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid; (S)-3-(4-((3-((1-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; Calcium(S)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; (S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (3S)-3-(4-((3-((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (3S)-3-(4-((3-((2-phenylpyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-(Pyrrolidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid; (S)-3-(4-((3-(Piperidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid; (S)-3-(4-((3-((1-isopropylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid; (R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((6,7-Dihydro-[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; 3-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; 3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; (S)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; Calcium (S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate; (S)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid; (S)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid; (S)-3-(4-((3-((7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid; (S)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid; (S)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; and (S)-3-(4-((3-((2-((Methylamino)methyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;

(29) The following compounds can be synthesized following the similar procedure as described for example 1 with suitable modifications as are well known to a person skilled in the art and are considered to be encompassed within the scope of the present invention.

3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoic acid

(30) ##STR00031##

3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid

(31) ##STR00032##

3-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid

(32) ##STR00033##

3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid

(33) ##STR00034##

(S)-3-(4-((3-((2-methoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(34) ##STR00035##

(S)-3-(4-((3-((2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(35) ##STR00036##

(S)-3-(4-((3-((2-(methylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(36) ##STR00037##

(S)-3-(4-((3-((6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(37) ##STR00038##

(S)-3-(4-((3-((2-(2,2,2-trifluoroethyl)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(38) ##STR00039##

(S)-3-(4-((3-((2-isopropyl-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(39) ##STR00040##

(S)-3-(4-((3-((2-(dimethylamino)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(40) ##STR00041##

(S)-3-(4-((3-((2-(tert-butyl)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(41) ##STR00042##

(S)-3-(4-((3-((2-oxo-1,2,6,7-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(42) ##STR00043##

(S)-3-(4-((3-((2-cyano-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(43) ##STR00044##

(3S)-3-(4-((3-((4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(44) ##STR00045##

(3S)-3-(4-((3-((4-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(45) ##STR00046##

(46) The novel compounds of this invention may be prepared using the reactions and techniques described in the below section along with, whenever appropriate other suitable processes known to a skilled person. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention and also that certain steps may be modified, altered, obvious steps added or deleted in order to optimize as well as required for preparing the compounds of the present invention. Such, obvious changes should also be considered as being part of the present invention.

(47) ##STR00047##

(48) A compound of formula (I) can be prepared in accordance with reactions as depicted in scheme 1.

(49) The first step involves the reaction of substituted carboxylic acid (intermediate 1a) with an appropriate substituted heterocycle (intermediate 2a) under peptide bond formation conditions to give intermediate 3a. The ester of intermediate 3a can be reduced using a suitable reducing agent such as diisobutylaluminum hydride, lithium aluminum hydride or sodium borohydride etc. to give intermediate 4a. Intermediate 4a can be further reacted with compounds of formula II under Mitsunobu conditions to give intermediate 5a. Mitsunobu conditions involve reacting an alcohol intermediate 4a with a nucleophile such as a phenol (formula II), using a suitable phosphine such as tributyl phosphine, triphenyl phosphine, or triethyl phosphine and an azodicarbonyl such as ADDP or an azodicarboxylate (DEAD).

(50) Alternatively, intermediate 4a can be converted to compound having suitable leaving group such as mesylate derivative (intermediate 6a) using an appropriate set of reactants and conditions such as methanesulfonyl chloride and triethylamine.

(51) The intermediate 6a can be reacted with compound of formula II using diisopropyl ethylamine or cesium carbonate to give intermediate 5a.

(52) The intermediate 5a can be hydrolyzed to give carboxylic acid derivative of formula (I) using bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

(53) In an optional step, a pharmaceutically acceptable salt of a compound of formula (I) can be formed by reaction of appropriate compound of formula (I) with a pharmaceutically acceptable base or with and acid in a suitable solvent under standard conditions. Optionally, the formation of such salts can occur simultaneously upon hydrolysis of an ester intermediate.

(54) The formation of such salts is well known and appreciated in the art.

(55) The compounds of the present invention can be used either alone or in combination with one or more therapeutic agents selected from insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1 analogs, DPP-IV inhibitors, GPR-119 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and other anti-obesity agents or pharmaceutically acceptable salts thereof. Such use will depend on the condition of the patient being treated and is well within the scope of a skilled practitioner.

(56) Following the general process described above, including suitable modifications and additions which are within the scope of a skilled person, the following compounds of formula (I) were prepared as follows:

(57) 1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in scale. Until and otherwise mentioned the solvent used for NMR is CDCl.sub.3.

Example 1

(S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid (1)

(58) ##STR00048##

(59) ##STR00049##

Procedure

i. Methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate (intermediate 3)

(60) To 3-(methoxycarbonyl)benzoic acid intermediate 1 (10 g, 55.5 mmol) was added thionyl chloride (16.21 mL, 222 mmol) in small portions at 25 C. followed by a drop of dimethylformamide. The reaction mixture was stirred under refluxing for 3 h. Excess thionyl chloride was evaporated under reduced pressure at 100 C. The 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride intermediate 2 (12.19 g, 69.4 mmol) was dissolved in 100 mL of water, to that added solution of sodium hydroxide (4.44 g, 111 mmol) in 25 mL of water. Free base of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine was extracted in dichloromethane (75 mL), dried over anhydrous potassium carbonate. The acid chloride was dissolved in anhydrous dichloromethane (75 mL) and cooled to 0 C.

(61) To the reaction mixture added drop wise triethylamine (15.47 mL, 111 mmol) followed by solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in dichloromethane (75 mL) drop by drop at 0 C. The reaction mixture was warmed to 25 C. and stirred it for 3 h. Progress of the reaction was monitored by TLC.

(62) The reaction mixture was poured into ice-water (125 mL), adjusted pH 4 with 10% HCl and extracted with dichloromethane (3100 mL). The combined organic fractions were washed with 5% sodium hydroxide (100 ml) followed by brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated on a rotatory evaporator under reduced pressure to afford crude amide intermediate 3.

(63) The crude product was purified by flash column chromatography using 230-400 mesh silica-gel as a stationary phase and 10-50% ethyl acetate-hexanes as a mobile phase afforded pure methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate (12 g, 39.8 mmol, 71.7% yield)

ii. (3-((6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol (intermediate 4)

(64) To a solution of methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate intermediate 3 (12 g, 39.8 mmol) in dry THF (100 mL) was added LiAlH.sub.4 (3.02 g, 80 mmol) in small portions at 25 C. The reaction mixture was stirred under refluxing for 3 h. The progress of reaction was monitored by TLC by using mobile phase 30% ethyl acetate in hexane. Suspension of aqueous sodium sulfate was added drop wise to the reaction mixture to quench excess LiAlH.sub.4. Ethyl acetate (150 mL) was added to the reaction mixture and refluxed for 30 min and decanted ethyl acetate, this process was repeated three times to ensure no product in white slug of lithium sulfate and aluminum hydroxide. The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4 and evaporated on a rotatory evaporator under reduced pressure to afford crude product as pale yellow sticky mass of intermediate 4.

(65) The crude alcohol intermediate 4 was purified by flash column chromatography using 230-400 mesh silica-gel as stationary phase and 10-50% ethyl acetate-hexane as a mobile phase afforded pure (3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol intermediate 4 (5.41 g, 20.86 mmol, 52.4% yield).

iii. (S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1)

(66) To a solution of (3-((6-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol intermediate 4 (0.16 g, 0.617 mmol) in 5 mL of anhydrous tetrahydrofuran was added triethylamine (0.258 ml, 1.851 mmol) followed by methanesulfonyl chloride (141 mg, 1.234 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-water (25 mL) and extracted with dichloromethane (325 mL). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4 and evaporated on a rotatory evaporator under reduced pressure to afford 3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl mesylate intermediate (5) as pale yellow sticky mass.

(67) To a solution of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate intermediate 6 (162 mg, 0.740 mmol) in Acetonitrile (5.00 ml) was added cesium carbonate (603 mg, 1.851 mmol) followed by solution of 3-((6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)methyl)benzyl mesylate 5 in 2 mL of acetonitrile at 25 C. Reaction mixture was stirred for 3 h at 75 C. Progress of the reaction was monitored by TLC. After completion of the reaction, volatiles were evaporated off under reduced pressure. The reaction mixture was poured into ice-water (25 mL) and product was extracted with dichloromethane (325 mL). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4 and evaporated on a rotatory evaporator under reduced pressure to afford crude product as pale yellow sticky mass. Ethereal hydrochloride solution was added to the crude product, ether was evaporated off and residue was triturated with ethyl acetate afforded 65 mg of (S)-methyl 3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate hydrochloride intermediate (7). Ester hydrochloride salt intermediate 7 (60 mg, 0.121 mmol) was hydrolyzed using mixture of THF (2 mL) and MeOH (1 mL) was added NaOH (24.19 mg, 0.605 mmol) in water (1 mL) at 25 C. Reaction mixture was stirred for 12 h at 25 C. Progress of the reaction was monitored by TLC. After completion of the reaction, volatiles were evaporated off, the residue was treated with ice-water (5 mL), adjusted pH 4 (1N HCl), exacted with dichloromethane (325 mL) and dried over anhydrous Na.sub.2SO.sub.4. Evaporation of solvents on a rotatory evaporator under reduced pressure to afford crude product. Crude acid was purified by preparative TLC to afford (S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid 1 (42 mg, 0.094 mmol, 78% yield)

(68) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.42 (s, 1H), 7.37-7.24 (m, 6H), 6.94 (d, J=8.4 Hz, 2H), 6.75 (d, J=5.2 Hz, 1H), 5.07 (s, 2H), 3.94 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78-2.72 (m, 4H), 2.57-2.55 (m, 2H), 1.77 (d, J=1.6 Hz, 3H); ESIMS: 446.2 (M+H).sup.+.

(69) The following compounds can be prepared by following the general scheme 1 and the process described in Example 1 above, including their suitable modifications well within the scope of a skilled person.

Example 2

Lithium 3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoic acid

(70) ##STR00050##

(71) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.44 (s, 1H), 7.35-7.28 (m, 7H), 6.98 (d, J=8.8 Hz, 2H), 6.09 (s, 2H), 4.27 (dd, J=6.4, 8.4 Hz, 1H), 3.86 (s, 2H), 3.57 (s, 4H), 2.53-2.41 (m, 1H), 2.33-2.32 (m, 1H)

Example 3

3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid

(72) ##STR00051##

(73) .sup.1H NMR: (CDCl.sub.3, 400 MHz): 7.47 (d, J=5.2 Hz, 1H), 7.37-7.23 (m, 6H), 7.11 (d, J=5.2 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.77-4.68 (m, 2H), 4.19 (t, J=7.6 Hz, 1H), 3.55 (t, J=6.8 Hz, 2H), 3.06-2.98 (m, 3H), 2.88-2.82 (m, 1H)

Example 4

Lithium 3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid

(74) ##STR00052##

(75) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.48 (s, 1H), 7.39-7.36 (m, 3H), 7.31 (dd, J=2, 6.8 Hz, 2H), 6.98 (dd, J=2.4, 6.8 Hz, 2H), 5.10 (s, 2H), 4.30-4.26 (m, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.89 (s, 2H), 3.83 (s, 2H), 2.97 (t, J=5.6 Hz, 2H), 2.74 (dd, J=8.8, 15.6 Hz, 1H), 2.58 (dd, J=8.8, 15.6 Hz, 1H).

Example 5

3-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid

(76) ##STR00053##

(77) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.66 (d, 1H), 7.60-7.51 (m, 3H), 7.35 (dd, J=2, 6.8 Hz, 2H), 7.03 (dd, J=2, 6.4 Hz, 2H), 5.17 (s, 2H), 4.60 (s, 2H), 4.35-4.31 (m, 1H), 4.28 (s, 4H), 3.94 (s, 4H), 2.99 (dd, J=8.4, 16.8 Hz, 1H), 2.85 (dd, J=6.4, 16.4 Hz, 1H).

Example 6

3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid

(78) ##STR00054##

(79) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.58 (s, 1H), 7.37-7.32 (m, 2H), 7.22-7.16 (m, 4H), 6.88 (dd, J=2, 6.8 Hz, 2H), 6.71 (d, J=5.2 Hz, 1H), 5.00 (s, 2H), 4.18-4.14 (m, 1H), 3.99 (s, 2H), 3.88 (s, 2H), 3.19-3.16 (m, 2H), 3.03-3.00 (m, 2H), 2.87-2.81 (m, 1H), 2.70-2.64 (m, 1H).

Example 7

(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(80) ##STR00055##

(81) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.38-7.25 (m, 6H), 6.88 (d, J=5.2 Hz, 2H), 6.33 (s, 1H), 5.04-4.98 (m, 2H), 4.05-4.00 (m, 1H), 3.80-3.71 (m, 2H), 3.64-3.55 (m, 2H), 2.92-2.61 (m, 6H), 2.39 (s, 3H), 1.82 (d, J=2.4 Hz, 3H).

Example 8

(S)-3-(4-((3-((1-(tert-butoxycarbonyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(82) ##STR00056##

(83) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.47-7.38 (m, 4H), 7.27 (d, J=8.8 Hz, 2H), 7.18 (d, J=3.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 5.94 (d, J=3.2 Hz, 2H), 5.05 (s, 2H), 4.08 (s, 2H), 4.05-4.01 (m, 1H), 3.85 (s.sub.(br), 2H), 3.30-3.15 (m, 4H), 2.78 (dd, J=8.8, 15.2 Hz, 1H), 2.65 (dd, J=8, 15.2 Hz, 1H), 1.80 (d, J=2.4 Hz, 3H), 1.59 (s, 9H).

Example 9

(S)-3-(4-((3-((6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(84) ##STR00057##

(85) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.51 (s, 1H), 7.42-7.33 (m, 4H), 7.25 (d, J=8.9 Hz, 2H), 6.81 (d, J=9 Hz, 2H), 6.63 (t, J=2.4 Hz, 1H), 5.89 (t, J=2.4 Hz, 1H), 5.06 (s, 2H), 4.07-3.99 (m, 3H), 3.87 (s, 2H), 3.08 (s.sub.(br), 2H), 2.80-2.74 (m, 3H), 2.61 (m, 1H), 1.80 (d, J=2.4 Hz, 3H)

Example 10

(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(86) ##STR00058##

(87) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.41-7.38 (m, 4H), 7.27 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.19-5.08 (m, 2H), 4.04-3.91 (m, 1H), 3.75 (s.sub.(br), 4H), 2.87-2.69 (m, 4H), 2.66 (s, 3H), 2.58-2.41 (m, 2H), 1.80 (d, J=2.4 Hz, 3H)

Example 11

(S)-3-(4-((3-((3-(trifluoromethyl)-6,7-dihydrothiazolo[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(88) ##STR00059##

(89) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.40-7.26 (m, 6H), 6.86 (d, J=8.8 Hz, 2H), 5.12 (dd, J=12.8, 18.4 Hz, 2H), 4.15-4.12 (m, 2H), 4.04-3.99 (m, 1H), 3.86-3.69 (m, 4H), 3.00-2.85 (m, 2H), 2.82 (dd, J=6.8, 15.2 Hz, 1H), 2.65 (dd, J=6.8, 15.2 Hz, 1H), 1.82 (J=2 Hz, 3H).

Example 12

(S)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid trifluoroacetic acid

(90) ##STR00060##

(91) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.52-7.44 (m, 2H), 7.42-7.34 (m, 4H), 7.31-7.26 (m, 4H), 6.85 (d, J=8.4 Hz, 2H), 5.09 (s, 2H), 4.70 (s, 2H), 4.34-4.29 (m, 2H), 4.04-4.00 (m, 1H), 3.32 (s, 2H), 2.85-2.78 (m, 1H), 2.70-2.63 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 13

(S)-3-(4-((3-((3,4-dihydroquinolin-1(2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(92) ##STR00061##

(93) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.32-7.22 (m, 6H), 6.99-6.90 (m, 4H), 6.60-6.57 (m, 1H), 6.50 (d, J=8.4 Hz, 2H), 5.02 (s, 2H), 4.49 (s, 2H), 4.49 (s.sub.(br), 1H), 3.36 (s.sub.(br), 2H), 3.02-2.87 (m, 4H), 2.02-2.00 (m, 2H), 1.80 (s, 3H).

Example 14

(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(94) ##STR00062##

(95) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.42-7.36 (m, 3H), 7.32-7.25 (m, 3H), 6.90 (d, J=8.4 Hz, 2H), 6.66 (s, 2H), 4.06-4.02 (m, 1H), 3.94-3.92 (m, 2H), 3.68 (s.sub.(br), 2H), 3.01 (s.sub.(br), 2H), 2.88-2.85 (m, 2H), 2.80-2.74 (m, 1H), 2.69-2.63 (m, 1H), 1.83 (d, J=2.4 Hz, 3H).

Example 15

(S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(96) ##STR00063##

(97) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.47 (s, 1H), 7.42-7.27 (m, 5H), 7.22-7.15 (m, 3H) (m, 3H), 7.05-7.02 (m, 1H), 6.93 (d, J=8.8 Hz, 2H), 5.10-5.03 (m, 2H), (m, 2H), 4.10-4.06 (m, 1H), 2.02-2.00 (m, 2H), 1.80 (s, 3H), 3.87-3.80 (m, 4H), 2.96-2.86 (m, 4H), 2.86-2.80 (m, 1H), 2.78-2.74 (m, 1H), 1.86 (d, J=2.4 Hz, 3H).

Example 16

calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(98) ##STR00064##

(99) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.40 (s, 1H), 7.35-7.23 (m, 5H), 6.88 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 5.04 (s, 2H), 4.00 (s.sub.(br), 1H), 3.64 (s, 2H), 3.32 (s, 2H), 2.68 (s, 4H), 2.40-2.37 (m, 1H), 2.33 (s, 3H), 2.27-2.21 (m, 1H), 1.74 (d, J=2 Hz, 3H).

Example 17

calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(100) ##STR00065##

(101) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.41 (s, 1H), 7.34-7.23 (m, 5H), 6.89 (d, J=8.8 Hz, 2H), 5.01 (s, 2H), 4.05-3.99 (m, 1H), 3.68 (s, 2H), 3.56 (s, 2H), 2.76-2.74 (m, 2H), 2.68 (s.sub.(br), 2H), 2.56 (s, 3H), 2.40-2.36 (m, 1H), 2.26-2.22 (m, 1H), 1.73 (d, J=2.4 Hz, 3H).

Example 18

(S)-3-(4-((3-((2-Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(102) ##STR00066##

(103) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.39-7.26 (m, 6H), 6.91-6.59 (m, 4H), 5.03 (s, 2H), 4.12-4.10 (m, 1H), 3.73 (s, 2H), 3.55 (s, 2H), 2.88-2.64 (m, 6H), 1.82 (d, J=2.4 Hz, 3H).

Example 19

Calcium(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(104) ##STR00067##

(105) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.41 (s, 1H), 7.37-7.24 (m, 5H), 6.93-6.89 (m, 3H), 5.06 (s, 2H), 3.96-3.94 (m, 1H), 3.66 (s, 2H), 3.38 (s, 2H), 2.71 (s, 4H), 2.49-2.32 (m, 2H), 1.76 (d, J=2.4 Hz, 3H).

Example 20

Calcium(S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(106) ##STR00068##

(107) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.37 (s, 1H), 7.35-7.23 (m, 5H), 7.11-7.07 (m, 3H), 6.98-6.97 (m, 1H), 6.89 (d, J=8.8 Hz, 2H), 5.05 (s, 2H), 3.99-3.97 (m, 1H), 3.64 (s, 2H), 3.52 (s, 2H), 2.79-2.77 (m, 2H), 2.65-2.64 (m, 2H), 2.42-2.36 (m, 1H), 2.28-2.22 (m, 1H), 1.74 (d, J=2.4 Hz, 3H).

Example 21

(S)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(108) ##STR00069##

(109) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.94 (s, 1H), 8.30 (s, 1H), 7.45 (s, 1H), 7.38-7.25 (m, 5H), 6.86 (d, J=2, 6.8 Hz, 2H), 5.15-5.09 (m, 2H), 4.06-4.03 (m, 1H), 3.78-3.62 (m, 4H), 2.89-2.73 (m, 6H), 1.82 (d, J=2.4 Hz, 3H).

Example 22

(S)-3-(4-((3-((1-Methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(110) ##STR00070##

(111) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.43-7.24 (m, 6H), 7.17 (s, 1H), 6.88 (td, J=5.2, 8.4 Hz, 2H), 5.03 (s, 2H), 4.07 (s, 2H), 4.02-3.97 (m, 5H), 3.75 (s, 3H), 2.78-2.72 (m, 1H), 2.66-2.60 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 23

(3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(112) ##STR00071##

(113) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.53-7.25 (m, 6H), 6.89 (d, J=8.4 Hz, 2H), 5.09 (s, 2H), 4.54-4.52 (m, 2H), 4.05-3.93 (m, 3H), 3.24-2.94 (m, 4H), 2.81-2.75 (m, 1H), 2.69-2.63 (m, 1H), 2.42 (d, J=8.8 Hz, 2H), 1.83 (d, J=2.4 Hz, 3H).

Example 24

(S)-3-(4-((3-(Indolin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(114) ##STR00072##

(115) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.41 (s, 1H), 7.37-7.25 (m, 5H), 7.10-7.05 (m, 2H), 6.93-6.89 (m, 2H), 6.70-6.66 (m, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.03 (s, 2H), 4.26 (s, 2H), 4.07-4.02 (m, 1H), 3.30 (t, J=8.4 Hz, 2H), 2.96 (t, J=8.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.73-2.67 (m, 1H), 1.83 (d, J=2.4 Hz, 3H).

Example 25

(S)-3-(4-((3-((5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(116) ##STR00073##

(117) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.50 (s, 1H), 7.49 (s, 1H), 7.40-7.35 (m, 3H), 7.28 (d, J=6.8 Hz, 2H), 6.93 (d, J=6.8 Hz, 2H), 5.01 (s, 2H), 4.15-4.11 (m, 2H), 4.00-3.97 (m, 1H), 3.87-3.83 (m, 4H), 2.97-2.94 (m, 2H), 2.66-2.62 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

Example 26

(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(118) ##STR00074##

(119) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.52-7.20 (m, 6H), 6.81 (d, J=8.8 Hz, 2H), 5.21-5.12 (m, 2H), 4.00-3.95 (m, 1H), 3.78-3.67 (m, 2H), 3.23-2.59 (m, 8H), 2.04-1.97 (m, 1H), 1.81 (d, J=2.4 Hz, 3H), 1.00-0.96 (m, 4H).

Example 27

(3S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid

(120) ##STR00075##

(121) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.45 (s.sub.(br), 0.78H, HCOOH), 7.52-7.15 (m, 9H), 7.16 (d, J=7.2 Hz, 1H), 6.78 (dd, J=2.8, 11.6 Hz, 2H), 5.12 (s, 2H), 4.05-4.00 (m, 1H), 3.93-3.68 (m, 4H), 3.04-3.01 (m, 2H), 2.83-2.78 (m, 3H), 2.68-2.64 (m, 1H), 2.58-2.40 (m, 6H), 1.77 (d, J=2.4 Hz, 3H).

Example 28

(S)-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(122) ##STR00076##

(123) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.43 (s, 1H), 7.39-7.24 (m, 6H), 6.86 (d, J=8.4 Hz, 2H), 6.80 (d, J=5.2 Hz, 1H), 5.06-4.99 (m, 2H), 4.17-4.00 (m, 7H), 2.77-2.71 (m, 1H), 2.65-2.59 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 29

6-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-ium formate

(124) ##STR00077##

(125) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.98 (s, 1H), 8.63 (s, 1H), 8.37 (s, 1H), 7.45 (s, 1H), 7.37-7.31 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.08 (s, 2H), 3.95-3.90 (m, 7H), 2.55-2.52 (m, 1H), 2.12 (s, 3H).

Example 30

1-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-1-ium formate

(126) ##STR00078##

(127) .sup.1H NMR (CDCl.sub.3, 400 MHz) 8.21 (s), 0.28 (formate), 7.33-7.28 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 7.19 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.55 (d, J=2.8 Hz, 1H), 6.51-6.48 (dd, J=8.8 Hz & 2.8 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 5.0 (s, 2H), 4.39 (s, 2H), 3.95-3.90 (m, 3H), 3.60 (m, 4H), 3.24 (t, 3H), 2.70 (m, 2H), 2.58 (d, 2H), 2.06 (t, 2), 1.07-1.08 (s, 3H).

Example 31

(S)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(128) ##STR00079##

(129) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.41-7.30 (m, 3H), 7.35-7.27 (m, 3H), 6.90 (d, J=8.4 Hz, 2H), 5.07 (s, 1H), 4.07-4.02 (m, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 2.98-2.95 (m, 2H), 2.86-2.68 (m, 5H), 1.83 (d, J=2.4 Hz, 3H).

Example 32

(S)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(130) ##STR00080##

(131) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.39-7.35 (m, 3H), 7.29-7.26 (m, 3H), 6.90 (d, J=8.4 Hz, 2H), 5.05 (s, 2H), 4.06-4.01 (m, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.92-2.66 (m, 6H), 1.82 (d, J=2.4 Hz, 3H).

Example 33

(S)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(1H,4H, 6H)-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(132) ##STR00081##

(133) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.32-7.53 (m, 3H), 7.19-7.29 (m, 4H), 6.82-6.84 (m, 2H), 5.16 (s, 2H), 3.90-4.06 (m, 5H), 3.57 (s, 2H), 2.80-2.85 (m, 1H), 1.81 (s, 3H);

Example 34

(S)-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(134) ##STR00082##

(135) .sup.1H NMR (DMSO, 400 MHz): 7.38 (s, 1H), 7.23-7.33 (m, 5H), 6.92 (d, J=8.8 Hz, 2H), 6.56 (s, 1H), 5.35 (s, 2H), 3.91-3.94 (m, 1H), 3.72-3.84 (m, 4H), 3.40-3.50 (m, 2H (merger), 2.86-2.94 (m, 2H), 2.73-2.76 (m, 2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);

Example 35

(S)-5-(3-((4-(1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid

(136) ##STR00083##

(137) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.42 (s, 1H), 7.34-7.31 (m, 2H), 7.27-7.26 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J=8.8 Hz, 2H), 5.09 (s, 2H), 3.95-3.91 (m, 1H), 3.65 (s, 2H), 3.29 (s, 2H), 2.74-2.71 (m, 4H), 2.63-2.52 (m, 2H), 1.76 (s, 3H).

Example 36

3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid

(138) ##STR00084##

(139) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.46 (s, 1H), 7.37-7.31 (m, 3H), 7.14 (t, J=8 Hz, 2H), 6.81-6.79 (m, 2H), 6.44 (s, 1H), 5.05 (s, 2H), 3.78 (s, 2H), 3.32 (s, 2H), 2.82-2.74 (m, 4H), 2.49-2.44 (m, 2H), 2.36-2.34 (m, 4H), 1.30-1.28 (m, 1H), 0.49-0.47 (m, 1H), 0.27-0.24 (m, 2H), 0.004-0.002 (m, 1H).

Example 37

(S)-3-(4-((3-((1-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid

(140) ##STR00085##

(141) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.53 (s, 1H), 7.47-7.32 (d, 3H), 7.24-7.12 (m, 2H), 6.85 (d, 2H), 6.51 (d, 1H), 5.58 (d, 1H), 5.0-4.95 (d, 2H), 3.9-4.1 (m, 1H), 3.87 (d, 1H), 3.80 (d, 1H), 3.48 (s, 3H), 2.9-3.1 (m, 3H), 1.08 (m, 3H).

Example 38

(S)-3-(4-((3-((2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(142) ##STR00086##

(143) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 8.23 (s, 1H), 7.40 (s, 1H), 7.35 (d, 2H), 7.32-7.24 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 6.68 (s, 2H), 5.06 (s, 2H), 3.9-4.0 (m, 1H), 3.35 (s, 3H), 2.70-2.66 (m, 2H), 2.58 (d, 2H), 2.44 (d, 3H).

Example 39

Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(144) ##STR00087##

(145) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.39 (s, 1H), 7.36-7.23 (m, 5H), 6.88 (d, J=8.8 2H), 6.78 (s, 1H), 5.04 (s, 2H), 3.99 (s.sub.(br), 1H), 3.65 (s, 2H), 3.34 (s, 2H), 2.70 (s.sub.(br), 4H), 2.37-2.31 (m, 1H), 2.25-2.19 (m, 1H), 1.73 (d, J=2.4 Hz, 3H).

Example 40

(S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(146) ##STR00088##

(147) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 12.22 (br s, 1H), 7.76 (br s, 1H), 7.42 (s, 1H), 7.37-7.25 (m, 7H), 6.94 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 3.95-3.91 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78-2.76 (m, 2H), 2.72-2.70 (m, 2H), 2.60-2.57 (m, 2H), 1.77 (s, 3H).

((S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(148) ##STR00089##

(149) .sup.1H NMR (DMSO, 400 MHz): 12.25 (m, 2H), 7.48-7.51 (m, 2H), 7.39 (s, 3H), 7.27 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.09 (s, 2H), 4.40-4.47 (m, 1H), 4.10-4.20 (m, 2H), 3.70-3.90 (m, 4H), 2.66-2.66 (m, 2H), 1.77 (s, 3H), 1.36-138 (m, 6H).

Example 42

(S)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(150) ##STR00090##

(151) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 12.22 (br s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.37-7.24 (m, 5H), 6.92 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 3.95-3.91 (m, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.46 (s, 2H), 2.84-2.81 (m, 2H), 2.74-2.70 (m, 2H), 2.58-2.53 (m, 2H), 1.90 (s, 3H).

Example 43

(S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(152) ##STR00091##

(153) .sup.1H NMR (DMSO, 400 MHz): 8.83 (s, 1H), 7.24-7.41 (m, 6H), 6.92-6.94 (m, 2H), 5.09 (s, 2H), 3.91-3.94 (m, 1H), 3.73 (s, 2H), 3.45 (s, 2H), 2.86-2.94 (m, 2H), 2.73-2.76 (m, 2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);

Example 44

(S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(154) ##STR00092##

(155) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.79 (s, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.36-7.31 (m, 3H), 7.26-7.24 (d, J=8 Hz, 2H), 6.94-6.92 (d, J=8 Hz, 2H), 5.07 (s, 2H), 3.93 (br s, 1H), 3.70 (s, 2H), 3.50 (s, 2H), 2.89 (s, 2H), 2.74 (s, 2H), 1.76 (s, 3H), 1.23 (s, 2H).

(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(156) ##STR00093##

(157) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.41 (s, 1H), 7.35 (d, J=6.4 Hz, 2H), 7.30 (m, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.73 (s, 1H), 5.07 (s, 2H), 3.96-3.92 (m, 3H), 3.68 (s, 2H), 3.52 (s, 2H), 2.84 (t, 2H), 2.66 (t, 2H), 2.08 (s, 3H), 1.77 (s, 3H)

Example 46

(S)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(158) ##STR00094##

(159) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.42 (s, 1H), 7.35-7.24 (m, 6H), 7.1-6.93-6.91 (m, 2H), 5.07 (s, 2H), 3.9 (m, 1H), 3.68 (s, 2H), 3.41 (s, 2H), 2.71-2.70 (m, 2H), 2.67-2.66 (m, 6H), 1.76 (s, 3H).

Example 47

(S)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(160) ##STR00095##

(161) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.53 (s, 1H), 7.40-7.22 (m, 4H), 7.1-6.68 (m, 3H), 5.08 (s, 2H), 4.12-4.03 (m, 1H), 3.78-3.71 (m, 2H), 3.50 (s, 2H), 3.17 (s, 6H), 2.95-2.88 (m, 2H), 2.83-2.63 (m, 2H), 1.83 (s, 3H).

Example 48

(3S)-3-(4-((3-((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(162) ##STR00096##

(163) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.93-7.90 (m, 2H), 7.82-7.76 (m, 2H), 7.53-7.16 (m, 7H), 6.92-6.86 (m, 3H), 5.11-5.01 (m, 3H), 4.45-4.30 (m, 1H), 4.07-3.98 (m, 3H), 3.30-3.20 (m, 1H), 3.097-3.090 (m, 3H), 3.03 (s, 1H), 2.87-2.68 (m, 4H), 2.33-1.98 (m, 8H), 1.84-1.82 (m, 5H), 1.62-1.60 (m, 4H)

Example 49

(S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydrothieno[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(164) ##STR00097##

(165) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.48 (s, 1H), 7.43-7.27 (m, 6H), 6.91 (dd, J=8.8, 2 Hz, 2H), 5.07 (s, 2H), 4.07-4.03 (m, 1H), 3.80 (s, 2H), 3.72 (s, 2H), 3.32 (s, 3H), 3.15-3.09 (m, 2H), 2.92-2.89 (m, 2H), 2.84-2.78 (m, 1H), 2.74-2.68 (m, 1H) 1.83 (d, J=2.4 Hz, 3H)

Example 50

(S)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(166) ##STR00098##

(167) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.09 (s, 1H), 7.53-7.26 (m, 6H), 6.87 (dd, J=6.8, 2 Hz, 2H), 5.17-5.08 (m, 2H), 4.07-4.02 (m, 1H), 3.98 (s, 3H), 3.75 (s.sub.(br), 2H), 3.58 (s.sub.(br), 2H), 2.88-2.63 (m, 6H), 1.82 (d, J=2.4 Hz, 3H)

Example 51

(3S)-3-(4-((3-((2-phenylpyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(168) ##STR00099##

(169) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.43-7.45 (m, 2H), 7.21-7.35 (m, 9H), 6.89-6.91 (d, J=8 Hz, 2H), 5.0 (s, 2H), 4.03 (m, 1H), 3.81-3.85 (m, 1H), 3.37-3.41 (m, 1H), 3.11-3.17 (m, 3H), 2.74-2.80 (m, 1H), 2.64-2.69 (m, 1H), 3.37-2.14-2.51 (m, 2H), 1.85-1.92 (m, 1H), 1.81 (s, 3H), 1.71-1.75 (m, 2H);

Example 52

(S)-3-(4-((3-(Pyrrolidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid

(170) ##STR00100##

(171) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.51 (s, 1H, HCOOH), 7.60 (s, 1H), 7.55-7.45 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.14 (s, 2H), 4.34 (s, 2H), 4.02-3.98 (m, 1H), 3.27-3.24 (m, 4H), 2.62-2.50 (m, 2H), 2.08-2.04 (m, 4H), 1.80 (d, J=2.4 Hz, 3H)

Example 53

(S)-3-(4-((3-(Piperidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid

(172) ##STR00101##

(173) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.50 (s, 1H, HCOOH), 7.58-7.43 (m, 4H), 7.29 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 4.23 (s, 2H), 4.09-4.03 (m, 1H), 3.12-3.08 (m, 4H) 2.63-2.49 (m, 2H), 1.83-1.79 (m, 7H), 1.64-1.61 (m, 2H)

Example 54

(S)-3-(4-((3-((1-isopropylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid

(174) ##STR00102##

(175) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.41 (s, 1H, HCOOH), 7.54 (s, 1H), 7.43-7.40 (m, 3H), 7.29 (dd, J=7.2, 2 Hz, 2H), 7.21 (s, 1H), 6.93 (dd, J=6.8, 2 Hz, 2H), 5.11 (s, 2H), 4.45-4.41 (m, 1H), 4.14 (s, 2H), 4.07 (s, 2H), 4.02-3.95 (m, 1H), 3.88 (s, 2H), 2.63-2.59 (m, 2H), 1.80 (d, J=2.4 Hz, 3H), 1.42 (d, J=6.8 Hz, 6H).

Example 55

(R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(176) ##STR00103##

(177) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.31 (s, 0.36H, Residual HCOOH), 7.47-7.25 (m, 6H), 6.86 (td, J=9.6, 2.8 Hz, 2H), 6.34 (s, 1H), 5.04 (s, 2H), 4.07-4.01 (m, 3H), 3.8 (s.sub.(br), 2H), 3.20-3.12 (m, 2H), 2.97-2.95 (m, 2H), 2.78-2.73 (m, 1H), 2.66-2.61 (m, 1H), 2.41 (s, 3H), 1.80 (d, J=2.4 Hz, 3H).

Example 56

(R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(178) ##STR00104##

(179) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 8.15 (s, 0.3H, Residual HCOOH), 7.41-7.27 (m, 6H), 6.88 (d, J=8.4 Hz, 2H), 5.15-5.07 (m, 2H), 4.06-4.02 (m, 1H), 3.90-3.82 (m, 4H), 2.96-2.92 (m, 2H), 2.88-2.64 (m, 7H), 1.82 (d, J=2.4 Hz, 3H)

Example 57

(S)-3-(4-((3-((6,7-Dihydro-[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(180) ##STR00105##

(181) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.59-7.58 (m, 2H), 7.58-7.43 (m, 3H), 7.29 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.14 (s, 2H), 4.58-4.55 (m, 2H), 4.19 (s, 2H), 4.15 (s, 2H), 4.01-3.97 (m, 1H), 3.44-3.41 (m, 2H), 2.70-2.58 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

Example 58

3-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid

(182) ##STR00106##

(183) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.42-4.27 (m, 5H), 6.87 (dd, J=11.2, 3 Hz, 2H), 6.34 (s, 1H), 5.05 (s, 2H), 4.06-4.02 (m, 2H), 3.98 (s, 2H), 3.74 (s, 2H), 3.10-3.04 (m, 2H), 2.92-2.89 (m, 2H), 2.79-2.73 (m, 1H), 2.67-2.61 (m, 1H), 2.41 (s, 3H), 1.81 (d, J=2.4 Hz, 3H).

Example 59

3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(184) ##STR00107##

(185) .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.42-7.35 (m, 4H), 7.29-7.27 (m, 2H), 6.88 (d, J=8.8 Hz, 2H), 5.14-5.07 (m, 2H), 4.06-4.03 (m, 1H), 3.93-3.85 (m, 4H), 2.99-2.97 (m, 2H), 2.86-2.64 (m, 7H), 1.82 (d, J=2.4 Hz, 3H

Example 60

Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(186) ##STR00108##

(187) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.39 (s, 1H), 7.36-7.23 (M, 5H), 6.88 (d, J=8.8 Hz, 2H), 5.03 (s, 2H), 4.02-3.09 (m, 1H), 3.69 (s, 2H), 3.39 (s, 2H), 2.80-2.77 (m, 2H), 2.72-2.69 (m, 2H), 2.41-2.36 (m, 1H), 2.27-221 (m, 1H), 1.73 (d, J=2.4 Hz, 3H).

Example 61

(S)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(188) ##STR00109##

(189) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 8.34 (br s, 1H), 7.41 (s, 1H), 7.36-7.29 (m, 3H), 7.27-7.24 (m, 3H), 6.67 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 3.95-3.91 (m, 1H), 3.67 (s, 2H), 3.42 (s, 2H), 2.77-2.66 (m, 5H), 2.57-2.51 (m, 2H), 1.76 (s, 3H), 0.67-0.62 (m, 2H), 0.53-0.49 (m, 2H

Example 62

(S)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(190) ##STR00110##

(191) .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 7.42 (s, 1H), 7.37-7.26 (m, 3H), 7.25-7.13 (m, 3H), 6.93 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 3.94-3.87 (m, 1H), 3.68 (br s, 4H), 3.43 (br s, 4H), 2.80-2.73 (m, 4H), 2.59-2.50 (m, 2H), 2.91-1.81 (m, 4H), 1.76 (s, 3H)

Example 63

(S)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(192) ##STR00111##

(193) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.56 (s, 2H), 7.50-7.41 (m, 3H), 7.28 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.35 (s, 1H), 5.12 (s, 2H), 4.15 (s, 2H), 4.01-3.97 (m, 1H), 3.84 (s, 2H), 3.25-3.22 (m, 2H), 2.96-2.93 (m, 2H), 2.66-2.52 (m, 2H), 2.10 (s, 3H), 1.79 (d, J=2.4 Hz, 3H).

Example 64

Calcium (S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

(194) ##STR00112##

(195) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.38 (s, 1H), 7.34-7.24 (m, 5H), 6.88 (d, J=8 Hz, 2H), 5.02 (s, 2H), 4.02-4.01 (m, 1H), 3.66 (s, 2H), 3.26 (s, 2H), 2.73-2.71 (m, 2H), 2.58 (s, 2H), 2.41-2.37 (m, 1H), 2.27-2.24 (m, 1H), 2.03-2.00 (m, 1H), 1.72 (s, 3H), 0.98-0.093 (m, 2H), 0.86-0.82 (m, 2H).

Example 65

(S)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid

(196) ##STR00113##

(197) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.80 (s, 1H), 7.69 (s, 1H), 7.61-7.52 (m, 3H), 7.30 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 5.17 (s, 2H), 4.54 (s, 2H), 4.30 (s, 2H), 4.01-3.99 (m, 1H), 3.66 (s.sub.(br), 2H), 3.31-3.27 (m, 2H), 2.69-2.58 (m, 2H), 1.80 (d, J=2.4 Hz, 3H)

Example 66

(S)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid

(198) ##STR00114##

(199) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.00 (s, 1H), 7.54 (s, 1H), 7.45-7.42 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.13 (s, 2H), 4.01-3.99 (m, 3H), 3.74 (s, 2H), 3.14 (s, 6H), 3.10-3.07 (m, 2H), 2.90-2.87 (m, 2H), 2.64-2.60 (m, 2H), 1.80 (d, J=2.4 Hz, 3H).

Example 67

(S)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid

(200) ##STR00115##

(201) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.10 (s, 1H), 7.67 (s, 1H), 7.62-7.54 (m, 3H), 7.30 (dd, J=6.8, 1.6 Hz, 2H), 6.96 (d, J=6.8, 1.6 Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H), 4.25 (s, 2H), 4.01-3.99 (m, 1H), 3.63 (s, 2H), 3.09-3.05 (m, 2H), 2.70-2.58 (m, 2H), 1.80 (d, J=2.4 Hz, 3H)

Example 68

(S)-3-(4-((3-((7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(202) ##STR00116##

(203) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 8.59 (d, J=4 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.62-7.51 (m, 4H), 7.30 (dd, J=8.8, 2 Hz, 2H), 6.96 (d, J=8.8, 2 Hz, 2H), 5.17 (s, 2H), 4.57 (s, 2H), 4.49 (s, 2H), 4.01-3.97 (m, 1H), 3.75-3.72 (m, 2H), 3.41-3.38 (m, 2H), 2.69-2.58 (m, 2H), 1.80 (d, J=2.4 Hz, 3H).

Example 69

(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid

(204) ##STR00117##

(205) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.66 (s, 1H), 7.60-7.52 (m, 2H), 7.30 (dd, J=6.8, 2 Hz, 2H), 6.90 (dd, J=6.8, 2 Hz, 2H), 6.50 (s, 1H), 5.17 (s, 2H), 4.51 (s, 2H), 4.18 (s, 2H), 4.01-3.97 (m, 1H), 3.12-3.09 (m, 2H), 2.67-2.60 (m, 2H), 1.80 (d, J=2.4 Hz, 3H), 1.00-0.97 (m, 2H), 0.66-0.64 (m, 2H)

Example 70

(S)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid

(206) ##STR00118##

(207) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.68 (s, 1H), 7.62-7.54 (m, 3H), 7.30 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.17 (s, 2H), 4.56 (s, 2H), 4.40 (s, 2H), 4.01-3.97 (m, 1H), 3.67 (s.sub.(br), 2H), 3.07-3.04 (m, 2H), 2.69-2.58 (m, 2H), 2.20 (s, 3H), 1.80 (d, J=2.4 Hz, 3H).

Example 71

(S)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid

(208) ##STR00119##

(209) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.66 (s, 1H), 7.62-7.53 (m, 3H), 7.30 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.53 (s, 1H), 5.17 (s, 2H), 4.51 (s, 2H), 4.51 (s, 2H), 4.20 (s, 2H), 4.01-3.97 (m, 1H), 3.57 (s.sub.(br), 2H), 2.81-2.78 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.57 (m, 2H), 1.80 (d, J=2.4 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).

Example 72

(S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

(210) ##STR00120##

(211) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.56-7.55 (m, 2H), 7.49-7.42 (m, 3H), 7.28 (dd, J=6.8, 2 Hz, 2H), 6.93 (dd, J=6.8, 2 Hz, 2H), 5.12 (s, 2H), 4.09 (s, 2H), 4.01-3.97 (m, 1H), 3.88 (s, 2H), 3.18-3.14 (m, 2H), 3.07-3.04 (m, 2H), 2.66-2.56 (m, 2H), 2.50 (s, 3H), 1.79 (d, J=2.4 Hz, 3H)

Example 73

(S)-3-(4-((3-((2-((Methylamino)methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid

(212) ##STR00121##

(213) .sup.1H NMR (CD.sub.3OD, 400 MHz) : 7.67 (s, 1H), 7.62-7.60 (m, 1H), 7.55-7.53 (m, 2H), 7.30 (dd, J=6.8, 2 Hz, 2H), 7.03 (s, 1H), 6.96 (dd, J=6.8, 2 Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H), 4.36 (s, 2H), 4.27 (s, 2H), 4.01-3.98 (m, 1H), 3.62 (s.sub.(br), 2H), 3.24-3.21 (m, 2H), 2.71 (s, 3H), 2.69-2.62 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

(214) The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

(215) The compounds of formula (I or pharmaceutical compositions containing them are useful as ligands of the GPR 40 receptor suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.

(216) The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.

Biological Activity

(217) The biological activity of the compounds of the present invention was tested in the following in vitro and in vivo models mentioned here.

Summary of the In Vitro Screening Protocol

(218) To determine the EC.sub.50 of the compounds on intracellular Ca.sup.2+ flux using a fluorescent assay (FLIPR)

(219) GPR40 expressing stable cells were seeded at 25,000 numbers/well. 50 L/well of assay buffer (20 mM HEPES+ 1HBSS) was added to the cells and the cells were cultured for 20 mm at 37 C. Cells were loaded with 50 L/well of Calcium 5 dye and cultured for 45 min at 37 C.

(220) The cells were challenged with compounds at a top concentration of 1000 nM (1:3 step down dilution10 points). Intracellular Calcium flux was assessed by use of Screen Works 3.1 tool and statistical analysis was carried using Graph Pad Prism 4

(221) Many of the compounds of the present invention demonstrated nanomolar potency and significant % stimulation on intracellular Ca.sup.2+ flux when measured using fluorescent (FLIPR) assay

(222) The compounds exhibited potency in nanomolar range. (Table 1)

(223) TABLE-US-00001 TABLE 1 In vitro EC50 values of the GPR 40 agonists of the present invention in FLIPR assay Compound EC.sub.50(nM) 1 117 7 1.8 16 2.72 17 10.2 19 2.32 22 36.3

(224) Promoter-Luciferase Assay to Measure GPR40 Activation

(225) GPR40 activation was measured in HEK293 cells stably transfected with GPR40 cDNA (ChemiBrite cell lines from Millipore, US). These cells were transiently transfected with a pGL2 (Promega Inc.) plasmid having a 5SRE sequence, cloned 5 of a luciferase gene along with a -galactosidase plasmid as normalizing control. Briefly, 35000 cells/well were seeded in a 96 well plates. After overnight incubation at 37 C. the cells were washed with PBS and transfected with the 5-SRE-Luciferase plasmid and the -galactosidase plasmid. 6 h post transfection, media was removed and replaced with fresh media with different concentration of drugs and incubated for 16 more hours. The cells were then lysed in 50 L of Glo-Lysis buffer (Promega) for 30 min at room temperature. The cells were then centrifuged and lysates were collected. Luciferase activity was measured by adding 100 L of luciferase substrate (Promega) in 20 L of lysate and measuring the luminescence in luminometer. The -galactosidase activity was also measured by adding 20 L of lysates with 20 L of -galactosidase buffer (Promega) and monitoring the absorbance at 415 nm. Luciferase values were divided by -galactosidase values to normalize transection efficiency (Table 2)

(226) TABLE-US-00002 TABLE 2 In vitro EC50 values of the GPR 40 agonists of the present invention in Luciferase assay. Compound # EC.sub.50 (nM) 1 7.5 7 1.49 8 11.8 10 16.9 12 5.6 13 0.8 14 0.8 15 4.6 16 4.6 17 4.7 18 8.8 19 0.2 20 2.7 21 2.8 22 31.46 23 5.3 24 0.7 26 4.1 30 4.5 31 9.7 32 4.8 35 204 38 17.8 39 1.7 40 8 43 7.3 44 4.8 46 6 47 9 50 20.8 51 3.0 55 56.5 58 3.7 60 5.6 61 12.6 62 3.0 63 4.4 64 1.2 65 1.6 68 11.9 69 0.8 71 0.4 72 2.3

(227) Most of the compounds of the present invention were evaluated against CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 and there was no significant CYP inhibitory effect. The compounds did not show significant hERG binding at 10 M.

(228) In Vivo Efficacy Studies:

(229) Primary Screening Protocol for GRP40 agonist test compounds in n-STZ rat model

(230) Wistar rat pups of 1-2 day old injected with Streptozotocin (STZ) at 120 mg/kg dose by intraperitoneal route. All pups allowed grow normally and at the age of 12-14 week they were screen for glucose intolerance by performing the oral glucose tolerance test by tail clip method using glucometer. Animals showing glucose intolerance were selected for evaluation of test compound. Three to seven days of rest period animals were kept on overnight fasting. Next day morning blood glucose levels measured using glucometer and animals were grouped such that their pretreatment glucose levels were not significantly different between groups. Animals were administered with test compound and then then 15-60 min after the compound administration O min blood glucose levels were measured and immediately glucose load at 2 g/kg was administered orally. Blood glucose levels were measured at 30, 60 and 120 min after glucose load using by tail clip method using glucometer. Blood was also collected at 10 min after glucose load for measurement of insulin levels. Glucose area under the curve (AUC) was calculated using Graph Pad Prism software and % reduction in AUC-glucose vs vehicle treated control was calculated (Table 3).

(231) TABLE-US-00003 TABLE 3 Efficacy of the GPR 40 agonist of the present invention in n-STZ rat model Dose % improvement in AUC Compound (per oral) glucose vs. control 7 0.1 mg/Kg 30.4 1 mg/Kg 46.0 10 mg/Kg 57.0 10 0.1 mg/Kg 21.1 1 mg/Kg 35.7 10 mg/Kg 45.0 16 1 mg/Kg 44.6 10 mg/Kg 59.6 17 1 mg/Kg 37.1 10 mg/Kg 44.7 60 1 mg/Kg 44 10 mg/Kg 47 64 1 mg/Kg 46 10 mg/Kg 47

(232) In the n-STZ rat OGTT model the ED.sub.50 of compounds 16, 60 & 64 has been found 0.05 mg/Kg, 0.04 mg/Kg & 0.09 mg/Kg respectively.

(233) Few compounds have exhibited significant pharmacokinetics parameters in rats (Table 4)

(234) TABLE-US-00004 TABLE 4 Pharmacokinetics parameters of compounds 16, 60, & 64 Parameters 16 60 64 Dose (po) mg/Kg 3 3 3 T.sub.max (h) 0.25 1 2 C.sub.max (g/mL) 5.92 2.10 7.77 1.94 8.06 2.19 AUC (0-t) 7.63 1.27 52.52 12.62 82.42 27.63 T.sub.1/2, po (h) 1.77 0.42 5.45 0.79 4.51 0.61 Mean residence time (h) 2.19 0.31 5.74 0.10 6.59 0.93 iv dose (mg/Kg) 1 1 1 C.sub.0(g/mL) 5.02 0.37 3.39 0.33 10.16 1.54 AUC (0-t) 3.18 0.40 18.61 2.17 56.14 4.35 (g .Math. h/mL) Vss (L/Kg) 0.34 0.03 0.33 0.01 0.16 0.01 CL (mL/min./Kg) 5.26 0.65 0.89 0.10 0.27 0.03 T.sub.1/2, iv (h) 1.45 0.12 5.57 1.46 7.77 1.07 Mean residence time (h) 1.09 0.07 6.28 0.77 10.07 1.36 % F 83 93 45

(235) The compounds of formula (I) or pharmaceutical compositions containing them are suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc.

(236) The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.

(237) The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.