TREA

Bipiperidine derivatives as modulators of CCR3 activity and as H1 antagonists

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Information

  • Patent Grant
  • 6525070
  • Patent Number
    6,525,070
  • Date Filed
    Friday, April 6, 2001
    23 years ago
  • Date Issued
    Tuesday, February 25, 2003
    21 years ago
Information
Abstract
The present invention provides a compound of a formula (I): wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.
Description




FIELD AND BRIEF SUMMARY OF THE INVENTION




The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.




DESCRIPTION OF RELATED ART




Pharmaceutically active piperidine derivatives are disclosed in WO99/38514, WO99/04794 and WO00/35877.




Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys—X—Cys (C—X—C, or α) and Cys—Cys (C—C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.




The C—X—C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).




The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).




Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.




Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.




Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54(11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)




DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I):
















wherein:




q, s and t are, independently, 0 or 1;




n and r are, independently, 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2;




X is CH


2


, C(O), O, S, S(O), S(O)


2


or NR


37


; provided that when m and p are both 1 then X is not CH


2


;




Y is NHR


2


or OH;




T is C(O), C(S), S(O)


2


or CH


2


;




R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl;




R


2


and R


47


are, independently, hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl);




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, CR


3a


R


3b


R


3c


, C


2-4


alkenyl {optionally substituted by aryl or heterocyclyl}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl, aryl or oxo}, C


3-7


cycloalkenyl {optionally substituted by oxo, C


1-6


alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;




R


3a


is hydrogen, C


1-6


alkyl, C


1-6


alkoxy or C


3-7


cycloalkyl; R


3b


is aryl, heterocyclyl, S(O)


2


aryl or S(O)


2


heterocyclyl; and R


3c


is C


1-6


alkyl, C


1-4


haloalkyl, hydroxy, heterocyclyl(C


1-4


alkyl) or aryl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl {itself optionally substituted by halogen, OC(O)C


1-6


alkyl, S(O)


2


R


48


, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, S(O)


2


R


38


or C(O)NR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl), C


3-10


cycloalkyl (itself optionally substituted by C


1-4


alkyl or oxo) or NR


41


C(O)OCH


2


(fluoren-9-yl)}, NR


41


(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy {itself optionally substituted by halogen, C


1-6


alkoxy, NHCO


2


(C


1-6


alkyl), CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)}, C


1-6


alkylthio, C


1-6


haloalkylthio, C


3-10


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


d


R


15


, S(O)


2


NR


42


R


43


, NR


44


S(O)


2


R


45


, phenyl {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy, C


1-6


haloalkoxy, phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy, C


1-6


haloalkoxy, phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, SCN, CN, SO


3


H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;




d is 0, 1 or 2;




R


4


, R


5


,R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl, aryl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy);




R


15


, R


38


, R


45


and R


48


are, independently, C


1-6


alkyl (optionally substituted by halogen, hydroxy or C


3-10


cycloalkyl), C


3-6


alkenyl, aryl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy);




or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof;




provided that:




when m and p are both 1, n, q and r are all 0, T and X are both S(O)


2


, and R


1


is methoxyphenyl then R


3


is not propyl; when m, p, q and r are all 1, n is 0, Y is NH


2


, T is CO and R


1


X is (CH


3


)


2


N then R


3


is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R


1


is 3-(4-fluorobenzyl)benzimidazol-2-yl then R


3


is not 4-fluorophenyl.




Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.




Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. Another example of an addition salt is sulphate.




The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.




Halogen includes fluorine, chlorine, bromine and iodine.




Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.




Alkenyl group are, for example, vinyl or allyl.




Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl. The cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).




Cycloalkenyl is especially monocyclic and is, for example, cyclopentenyl or cyclohexenyl.




Aryl is preferably phenyl or naphthyl.




Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.




In one aspect of the invention heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or a chromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole, quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine, benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.




In a further aspect heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), quinolinyl, isoquinolinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.




An N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4′]bipiperidinyl-1′-yl compound.




In another aspect the present- invention provides a compound of formula (I′):











wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH


2


, CO, O, S, S(O), S(O)


2


or NR


37


; provided that when m and p are both 1 then X is not CH


2


; Y is NHR


2


or OH; T is CO, CS, SO


2


or CH


2


; R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl; R


2


is hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl); R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, C


3-7


cycloalkenyl {optionally substituted by C


1-6


alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, SO


2


R


38


or CONR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), NR


41


(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


COR


10


, CO


2


R


11


, CONR


12


R


13


, COR


14


, SO


d


R


15


, SO


2


NR


42


R


43


, NR


44


SO


2


R


45


, phenyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


or C


1-6


alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), phenoxy (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); R


15


, R


38


and R


45


are, independently, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both SO


2


, and R


1


is methoxyphenyl then R


3


is not propyl; when m, p, q and r are all 1, n is 0, Y is NH


2


, T is CO and R


1


X is (CH


3


)


2


N then R


3


is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R


1


is 3-(4-fluorobenzyl)benzimidazol-2-yl then R


3


is not 4-fluorophenyl.




In an further aspect the present invention provides a compound of formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH


2


, C(O), O, S, S(O), S(O)


2


or NR


37


; provided that when m and p are both 1 then X is not CH


2


; Y is NHR


2


or OH; T is C(O), C(S), S(O)


2


or CH


2


; R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl; R


2


and R


47


are, independently, hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl); R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, C


3-7


cycloalkenyl {optionally substituted by oxo, C


1-6


alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, S(O)


2


R


48


, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, S(O)


2


R


38


or C(O)NR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl), C


3-10


cycloalkyl (itself optionally substituted by C


1-4


alkyl or oxo) or NR


41


C(O)OCH


2


(fluoren-9-yl)), NR


41


C(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy (itself optionally substituted by halogen, C


1-6


alkoxy, NHCO


2


(C


1-6


alkyl), CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, C


1-6


haloalkylthio, C


3-10


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


d


R


15


, S(O)


2


NR


42


R


43


, NR


44


S(O)


2


R


45


, phenyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


or C


1-6


alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), phenoxy (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); R


15


, R


38


, R


45


and R


48


are, independently, C


1-6


alkyl (optionally substituted by halogen, hydroxy or C


3-10


cycloalkyl) or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both S(O)


2


, and R


1


is methoxyphenyl then R


3


is not propyl; when m, p, q and r are all 1, n is 0, Y is NH


2


, T is CO and R


1


X is (CH


3


)


2


N then R


3


is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R


1


is 3-(4-fluorobenzyl)benzimidazol-2-yl then R


3


is not 4-fluorophenyl.




In another aspect the variables m and p are such that m+p is 0, 1 or 2 (for example 1 or 2).




In a further aspect n is 0 or 1.




In a still farther aspect q and r are both 0.




In another aspect n, q and r are all 0.




In another aspect m, p and t are all 1.




In a further aspect s is 0.




In another aspect s is 1. In a further aspect q is 1. In a still further aspect n+r is equal to more than 1 (for example n+r is equal to 2, 3, 4 or 5).




In another aspect t+m+p is not equal to 3 (for example t+m+p is equal to 2).




In a still further aspect X is O.




In another aspect R


1


is hydrogen, C


1-6


alkyl, optionally substituted (as above) aryl or optionally substituted (as above) monocyclic heterocyclyl. In another aspect R


1


is phenyl substituted with one or more of fluorine, chlorine, C


1-4


alkyl (especially methyl) or C


1-4


alkoxy (especially methoxy).




In yet another aspect R


1


is not phenyl substituted by cycloalkyl.




In a further aspect R


1


is phenyl optionally substituted (for example with one, two or three) by halo (especially fluoro or chloro), C


1-4


alkyl (especially methyl) or C


1-4


alkoxy (especially methoxy). In a still further aspect R


1


is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.




In another aspect R


1


is one of the substituted phenyl groups exemplified in Method F below.




In a further aspect T is C(O), S(O)


2


or CH


2


. In a still further aspect T is C(O). In another aspect T is S(O)


2


or CH


2


.




In another aspect R


3


is aryl or heterocyclyl either of which is optionally substituted as described above.




In a further aspect R


3


is unsubstituted phenyl, mono-substituted phenyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.




In a still further aspect R


3


is oxo substituted heterocyclyl, said heterocyclyl optionally further substituted with one or more substituents chosen from those described above.




In another aspect R


3


is a bicyclic heterocyclyl optionally substituted as described above. Bicyclic heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo [3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl) or a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof




In yet another aspect R


3


is: C


1-6


alkyl {optionally substituted by CO


2


R


16


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by oxo}, phenyl {optionally substituted by: halogen, OH, SH, C


1-6


alkyl (itself optionally substituted by naphthyloxy (itself optionally substituted by halo or alkenyl) or NR


17


C(O)OCH


2


(fluoren-9-yl)), C


1-6


alkoxy (itself optionally substituted by CO


2


R


18


, NR


19


R


20


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, C


1-4


haloalkyl, OCF


3


, nitro, C


3-7


cycloalkyl, NR


21


R


22


, NR


23


C(O)R


24


, CO


2


R


25


, C(O)NR


26


R


27


, S(O)


2


R


28


, phenyl (itself optionally substituted by NO


2


or alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy, or adjacent substituents may join to form a dihydrophenanthrene moiety}, naphthyl {optionally substituted by NR


29


R


30


or OH}, heterocyclyl {optionally substituted by halo, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo or alkyl)), alkoxy, CF


3


, thioalkyl, C(O)R


31


, CO


2


R


32


, NR


33


C(O)R


34


, phenoxy, phenyl or nitrogen containing heterocyclyl;




R


16


, R


17


, R


18


, R


19


, R


20


, R


21


, R


22


, R


23


, R


24


, R


25


, R


26


, R


27


, R


29


, R


30


, R


31


, R


32


, R


33


and R


34


are, independently, hydrogen, C


1-6


alkyl or phenyl;




R


28


is C


1-6


alkyl; or a pharmaceutically acceptable salt thereof.




In another aspect R


3


is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C


1-4


alkyl (itself optionally substituted by S(O)


2


(C


1-4


alkyl), S(O)


2


phenyl), C


1-4


alkoxy, S(O)


k


R


46


(wherein k is 0, 1 or 2 (preferably 2); and R


46


is C


1-4


alkyl, C


1-4


hydroxyalkyl, C


3-7


cycloalkyl(C


1-4


alkyl) (such as cyclopropylmethyl) or phenyl), C


1-4


haloalkylthio, C(O)NH


2


, NHS(O)


2


(C


1-4


alkyl), S(O)


2


NH


2


, S(O)


2


NH(C


1-4


alkyl) or S(O)


2


N(C


1-4


alkyl)


2


.




In one aspect the variable R


3


can be benzo[1,2,3]thiadiazolyl, thiophenyl or phenyl; the phenyl and thiophenyl rings being optionally substituted by: halo, hydroxy, nitro, cyano, amino, C


1-4


alkyl (itself optionally substituted by S(O)


2


(C


1-4


alkyl), S(O)


2


phenyl), C


1-4


alkoxy, S(O)


k


R


46


(wherein k is 0, 1 or 2 (preferably 2); and R


46


is C


1-4


alkyl, C


1-4


hydroxyalkyl, C


3-7


cycloalkyl(C


1-4


alkyl) (such as cyclopropylmethyl) or phenyl), C


1-4


haloalkylthio, C(O)NH


2


, NHS(O)


2


(C


1-4


alkyl), S(O)


2


NH


2


, S(O)


2


NH(C


1-4


alkyl) or S(O)


2


N(C


1-4


alkyl)


2


.




In another aspect the variable R


3


can be benzo[1,2,3]thiadiazolyl or phenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino, C


1-4


alkyl (itself optionally substituted by S(O)


2


phenyl), C


1-4


alkoxy, S(O)


k


R


46


(wherein k is 0, 1 or 2; and R


46


is C


1-4


alkyl or phenyl) or C


1-4


haloalkylthio.




In a still further aspect the present invention provides a compound of formula (Ia″):











wherein:




T is C(O), C(S), S(O)


2


or CH


2


;




n is 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2 (but are especially both 1);




R


50


is hydrogen, cyano, S(O)


2


(C


1-4


alkyl), S(O)


2


(C


1-4


haloalkyl), halogen, C


1-4


alkyl, C


1-4


haloalkyl, C


1-4


alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR


12′


R


13′


, NR


9′


C(O)R


10′


, S(O)


2


R


15′


, S(O)


2


NR


42


R


43


or NR


44


S(O)


2


R


45


group);




R


51


and R


52


are, independently, hydrogen, halogen, C


1-4


alkyl or C


1-4


alkoxy;




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, aryl or heterocyclyl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo or C


1-6


alkyl), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


2


R


15


, phenyl (itself optionally substituted by NO


2


or C


1-6


alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;




R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


9′


, R


10


, R


10′


, R


11


, R


12


, R


12′


, R


13


, R


13′


, R


14


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or phenyl;




R


15


, R


15′


and R


45


are, independently, C


1-6


alkyl or phenyl;




or a pharmaceutically acceptable salt thereof.




In a further aspect R


50


, R


51


and R


52


are, independently, hydrogen, halogen, (especially fluoro or chloro), C


1-4


alkyl (especially methyl) or C


1-4


alkoxy (especially methoxy).




In a still further aspect the present invention provides a compound of formula (Ia):











wherein:




T is C(O), C(S), S(O)


2


or CH


2


;




n is 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2 (but are especially both 1);




R


35


is hydrogen, cyano, S(O)


2


(C


1-4


alkyl), S(O)


2


(C


1-4


haloalkyl), halogen, C


1-4


alkyl, C


1-4


haloalkyl, C


1-4


alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR


12′


R


13′


, NR


9′


C(O)R


10′


, S(O)


2


R


15′


, S(O)


2


NR


42


R


43


or NR


44


S(O)


2


R


45


group);




R


36


is hydrogen, halogen or C


1-4


alkyl;




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, aryl or heterocyclyl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo or C


1-6


alkyl), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


2


R


15


, phenyl (itself optionally substituted by NO


2


or C


1-6


alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;




R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


9′


, R


10


, R


10′


, R


11


, R


12


, R


12′


, R


13


, R


13′


, R


14


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or phenyl;




R


15


, R


15′


and R


45


are, independently, C


1-6


alkyl or phenyl;




or a pharmaceutically acceptable salt thereof.




In another aspect the present invention provides a compound of formula (Ia′):











wherein:




T is CO, CS, SO


2


or CH


2


;




n is 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2 (but are especially both 1);




R


35


is hydrogen, cyano, SO


2


(C


1-4


alkyl), SO


2


(C


1-4


haloalkyl), halogen, C


1-4


alkyl, C


1-4


haloalkyl, C


1-4


alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one CONR


12′


R


13′


, NR


9′


COR


10′


, SO


2


R


15′


, SO


2


NR


42


R


43


or NR


44


SO


2


R


45


group);




R


36


is hydrogen, halogen or C


1-4


alkyl;




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, aryl or heterocyclyl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo or C


1-6


alkyl), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


COR


10


, CO


2


R


11


, CONR


12


R


13


, COR


14


, SO


2


R


15


, phenyl (itself optionally substituted by NO


2


or C


1-6


alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;




R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


9′


, R


10


, R


10′


, R


11


, R


12


, R


12′


, R


13


, R


13′


, R


14


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or phenyl; R


15


, R


15′


and R


45


are, independently, C


1-6


alkyl or phenyl;




or a pharmaceutically acceptable salt thereof.




In a further aspect R


3


is heterocyclyl (such as thienyl, isoxazolyl or indolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl) optionally substituted by oxo, halogen or C


1-6


alkyl.




In yet another aspect the present invention provides a compound of formula (Ia) wherein:




T is C(O), C(S), S(O)


2


or CH


2


;




n is 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2;




R


35


is hydrogen, halogen or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR


12′


R


13′


, NR


9′


C(O)R


10′


, S(O)


2


R


15′


, S(O)


2


NR


42


R


43


or NR


44


S(O)


2


R


45


group);




R


36


is hydrogen or halogen;




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, aryl or heterocyclyl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo or C


1-6


alkyl), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


2


R


15


, phenyl (itself optionally substituted by NO


2


or C


1-6


alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;




R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


9′


, R


10


, R


10′


, R


11


, R


12


, R


12′


, R


13


, R


13′


, R


14


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or aryl;




R


15


, R


15′


and R


45


are, independently, C


1-6


alkyl or aryl;




or a pharmaceutically acceptable salt thereof.




In a further aspect R


35


and R


36


are, independently, hydrogen, halogen, (especially fluoro or chloro), C


1-4


alkyl (especially methyl) or C


1-4


alkoxy (especially methoxy). In another aspect R


35


and R


36


are both chlorine or both fluorine, especially 3,4 disposed on the phenyl ring to which they are attached.




In a further aspect the present invention provides a compound of formula (Ib):











wherein T, n and R


3


are as defined above.




In a still further aspect the present invention provides a compound of formula (Ic):











wherein T, m, p and R


3


are as defined above.




In another aspect the present invention provides a compound of formula (Id):











wherein R


3


is as defined above.




In yet another aspect the present invention provides a compound of formula (Ie):











wherein R


1


, t, s and R


3


are as defined above.




In a further aspect the present invention provides a compound of formula (If):











wherein R


1


, n, t, s and R


3


are as defined above.




In a still further aspect the present invention provides a compound of formula (Ig):











wherein R


1


, X and R


3


are as defined above.




A compound of formula (I), wherein s is 0, can be prepared by coupling a compound of formula (II):











with a compound of formula (III):











wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction by standard protecting groups known in the art and deprotected in a separate step or during the reaction work-up. For example:




when T is carbonyl, L can be OH and the coupling can be carried out in the presence of a coupling agent (such as bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, (known as PYBROP™), oxalyl chloride, thionyl chloride or N,N′-carbonyl diimidazole, or another coupling agent known to a person skilled in the art); or,




when T is sulphonyl, L can be chloro and the coupling can be carrier out in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone).




A compound of formula (I), wherein s is 1, R


47


is hydrogen and T is CO, can be prepared by reacting a compound of formula (II), wherein m and p are both 1, with an aromatic isocyanate of formula with an isocyanate O═C═N—(CH


2


)


n


—(CH


2


)


r


—R


3


.




A compound of formula (II) can be prepared by deprotecting a compound of formula (IV):











for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane).




A compound of formula (IV), wherein X is O, can be prepared by reacting a compound of formula (V):











with a compound of formula (VI):











in the presence of NaBH(OAc)


3


and acetic acid.




A compound of formula (IV), wherein X is CO or CH


2


, can be prepared by oxidising or reducing a compound of formula (VII):











A compound of formula (VII) can be prepared by reacting a compound of formula (VIII):











with a compound of formula (VI) in the presence of NaBH(OAc)


3


and acetic acid. A compound of formula (VIII) can be prepared by reduction of a compound of formula (IX):











A compound of formula (I) wherein X is NR


37


can be prepared by reacting a compound of formula (X):











with a compound of formula (XI):











in the presence of NaBH(OAc)


3


and acetic acid. A compound of formula (X) can be prepared by reacting NHR


1


R


37


with a compound of formula (XII):











in the presence of NaBH(OAc)


3


and acetic acid and then deprotecting the piperidine nitrogen {for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane)}.




Alternatively, a compound of formula (I), wherein s, n, q and r are all 0 and T is CO, can be prepared by reacting a compound of formula (XIII):











with an acid: R


3


CO


2


H. A compound of formula (XIII) can be prepared by deprotecting a compound of formula (XIV):











wherein L* is BOC or a benzyl group. A compound of formula (XIV) can be prepared by performing a fluoride displacement reaction on FR


1


in the presence of compound of formula (XV):











A compound of formula (XV) can be prepared by coupling a compound of formula (XVI) with a compound of formula (XVII):











Alternatively, a compound of formula (I) wherein s, n, q and r are all 0 and T is CO, can be prepared by performing a fluoride displacement reaction on FR


1


in the presence of compound of formula (XVIII):











provided that R


47


is not hydrogen.




A compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX):











with an appropriate mixed anhydride (such as an anhydride of formula R


3


C(O)OC(O)(C


1-6


alkyl), wherein alkyl is, for example, methyl, ethyl or iso-butyl). A compound of formula (XIX) can be prepared by deprotecting a compound of formula (XV).




Alternatively, a compound of formula (I) can be prepared by reductive ammination of a compound of formula (XX):











with an amine of formula (XXI):











under suitable conditions.




Further compounds of formula (I) can be prepared by adaptation of: the routes described above, methods described in the art or the Examples recited below.




Compounds of formula (V), (VI), (IX), (XI), (XII), (XVI) and (XVII) can be prepared by using or adapting methods described in the art.




In another aspect the present invention provides processes for the preparation of compounds of formula (I) (as defined above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) and (Ig).




The intermediates of formula (II), (IV), (XIII), (XIV) and (XVII) defined herein are novel and these, and processes for their preparation, are provided as further features of the invention.




Examples of compounds of formula (Ib) are listed in Table I below.
















TABLE I









Compound




T




n




R


3






M + H



























1




C(O)




0




C


6


H


5






433






2




C(O)




0




3,4-Cl


2


—C


6


H


3






501






3




C(O)




0




2,4-Cl


2


—C


6


H


3






501






4




C(O)




0




4-CH


3


—C


6


H


4






447






5




C(O)




0




4-CH


3


O—C


6


H


4






463






6




C(O)




0




4-CF


3


—C


6


H


4






501






7




C(O)




0




4-Cl—C


6


H


4






467






8




C(O)




0




4-NO


2


—C


6


H


4






478






9




C(O)




0




3,5-Cl


2


—C


6


H


3






501






10




C(O)




0




2-F—C


6


H


4






451






11




C(O)




0




4-cyclohexyl-C


6


H


4






515






12




C(O)




0




4-(n-butoxy)-C


6


H


4






505






13




C(O)




0




3-NMe


2


—C


6


H


4






476






14




C(O)




0




4-(NHC(O)Me)—C


6


H


4






490






15




C(O)




0




4-NEt


2


—C


6


H


4






504






16




C(O)




0




3-CO


2


Me—C


6


H


4






491






17




C(O)




0




2-C(O)NH


2


—C


6


H


4








18




C(O)




0




4-S(O)


2


Me—C


6


H


4






511






19




C(O)




0




2-I—C


6


H


4






559






20




C(O)




0




3-phenoxy-C


6


H


4






525






21




C(O)




0




2-Me—C


6


H


4






447






22




C(O)




0




3-Me—C


6


H


4






447






23




C(O)




0




3-I—C


6


H


4






559






24




C(O)




0




3-NH


2


-6-(NHC


6


H


5


)—C


6


H


3






539






25




C(O)




0




3,5-F


2


—C


6


H


3






469






26




C(O)




0




3-NO


2


-4-(tert-Bu)—C


6


H


3






534






27




C(O)




0




3-NO


2


-5-(CO


2


Me)—C


6


H


3






536






28




C(O)




0




2-Me-5-NO


2


—C


6


H


3






492






29




C(O)




0




3,5-(tert-Bu)


2


—C


6


H


3






545






30




C(O)




0




2-NO


2


-5-Me—C


6


H


3






492






31




C(O)




0




2-Br-5-MeO—C


6


H


3






541






32




C(O)




0




3-MeO-4-(CO


2


Me)—C


6


H


3








33




C(O)




0




2-(NHC(O)Me)-5-Br—C


6


H


3






568






34




C(O)




0




2-NO


2


-5-SCN—C


6


H


3






535






35




C(O)




0




3-MeO-4-Me-C


6


H


3






477






36




C(O)




0




4-CN—C


6


H


4






458






37




C(O)




0




3-CN—C


6


H


4






458






38




C(O)




0




2-phenoxy-4-Br—C


6


H


3








39




C(O)




0




2-NH


2


-5-I—C


6


H


3






574






40




C(O)




0




4-F-C


6


H


4






451






41




S(O)


2






0




2-CF


3


O—C


6


H


4






553






42




S(O)


2






0




3-NO


2


-4-Cl—C


6


H


3






548






43




S(O)


2






0




Camphor-10-yl(alternatively named 7,7-




543









dimethyl-bicyclo[2.2.1]heptan-2-on-1-yl)






44




S(O)


2






0




n-Pr




435






45




S(O)


2






0




C


6


Me


5






539






46




S(O)


2






0




4-(n-Pr)—C


6


H


4






511






47




S(O)


2






0




Naphth-2-yl




519






48




S(O)


2






0




2,6-Cl


2


—C


6


H


3






537






49




S(O)


2






0




2,6-F


2


—C


6


H


3






505






50




S(O)


2






0




4-NO


2


—C


6


H


4






514






51




S(O)


2






0




3,4-Cl


2


—C


6


H


3






537






52




S(O)


2






0




2,5-Cl


2


—C


6


H


3








53




S(O)


2






0




5-(NMe


2


)-naphth-1-yl




562






54




S(O)


2






0




2,1,3-benzthiadiazol-4-yl




527






55




S(O)


2






0




4-Et—C


6


H


4






497






56




S(O)


2






0




2,5-Cl


2


-thien-3-yl




543






57




S(O)


2






0




3,4-(MeO)


2


—C


6


H


3






529






58




S(O)


2






0




3-CF


3


-6-Cl—C


6


H


3






571






59




S(O)


2






0




5-Cl-thien-2-yl




509






60




S(O)


2






0




4-Cl—C


6


H


4






503






61




S(O)


2






0




4-(iso-Pr)—C


6


H


4






511






62




S(O)


2






0




2-Cl-4-CF


3


—C


6


H


3






571






63




S(O)


2






0




Benzofuraz-4-yl(other name 2,1,3-




511









benzoxadiazol-4-yl)






64




S(O)


2






0




3-Me-C


6


H


4






483






65




S(O)


2






0




2,4-F


2


-C


6


H


3






505






66




S(O)


2






0




2-Me-5-F—C


6


H


3






501






67




S(O)


2






0




4-CF


3


O—C


6


H


4






553






68




S(O)


2






0




iso-Pr




435






70




S(O)


2






0




4-(CO


2


H)—C


6


H


4






513






71




S(O)


2






0




chromen-2-one-6-yl




537






72




S(O)


2






0




3,5-Cl


2


—C


6


H


3






537






73




S(O)


2






0




2,3-Cl


2


—C


6


H


3






537






74




S(O)


2






1




4-NO


2


—C


6


H


4








75




S(O)


2






0




3-CF


3


—C


6


H


4






537






76




S(O)


2






0




4-(tert-Bu)—C


6


H


4






525






77




S(O)


2






0




3-CO


2


H-4-OH—C


6


H


3






529






78




S(O)


2






0




2-NO


2


—C


6


H


4






514






79




S(O)


2






0




2-F—C


6


H


4






487






80




S(O)


2






0




3-NO


2


—C


6


H


4






514






83




S(O)


2






0




Naphth-1-yl




519






84




S(O)


2






0




2-MeO-5-Cl—C


6


H


3






533






85




S(O)


2






0




3-F—C


6


H


4






487






86




S(O)


2






0




3-Cl-4-(NHC(O)Me)—C


6


H


3






560






87




S(O)


2






1




C


6


H


5






483






88




S(O)


2






0




2-NO


2


-4-MeO—C


6


H


3






544






89




S(O)


2






0




2-Me-5-NO


2


—C


6


H


3






528






90




S(O)


2






0




3-CO


2


H—C


6


H


4






513






91




S(O)


2






0




2,4,6-Me


3


—C


6


H


2






511






92




S(O)


2






0




Me






93




S(O)


2






0




3,4-Cl


2


—C


6


H


3






537






94




S(O)


2






0




4-MeO—C


6


H


4








95




S(O)


2






0




4-NHC(O)Me—C


6


H


4






526






96




S(O)


2






0




2-CF


3


—C


6


H


4






537






97




S(O)


2






0




(CH


2


)


2


CO


2


Me




479






98




S(O)


2






0




4-Me—C


6


H


4






483






99




S(O)


2






0




4-CF


3


—C


6


H


4






537






100




S(O)


2






0




4-CN—C


6


H


4






494






101




S(O)


2






0




3-NO


2


-4-Me—C


6


H


3






528






102




S(O)


2






0




1H-2-oxo-quinolin-6-yl






103




S(O)


2






0




2-(NHCOMe)-4-methylthiazol-5-yl




547






104




S(O)


2






0




Thien-2-yl




475






105




S(O)


2






0




Quinolin-8-yl






106




S(O)


2






0




2-OH-3,5-Cl


2


—C


6


H


2






553






107




S(O)


2






0




2-(CO


2


Me)—C


6


H


4






527






108




S(O)


2






0




2,5-(MeO)


2


—C


6


H


3






529






109




S(O)


2






0




phenyl




469






110




S(O)


2






0




2-Me-4-NO


2


—C


6


H


3






528






111




S(O)


2






0




5-(pyridin-2-yl)thien-2-yl




552






112




S(O)


2






0




1,3-Me


2


-5-Cl-pyrazol-4-yl




521






113




S(O)


2






0




3,5-Me


2


-isoxazol-4-yl




488






114




S(O)


2






0




2,3,6-Me


3


-4-MeO—C


6


H




541






115




S(O)


2






0




1-Me-imidazol-4-yl




473






116




S(O)


2






0




2-MeO-5-Me-C


6


H


3






513






117




S(O)


2






0




5-(isoxazol-3-yl)thien-2-yl




542






118




S(O)


2






0




2-(CO


2


Me)thien-3-yl




533






119




S(O)


2






0




4-(1,1-dimethylprop-1-yl)-C


6


H


4






539






120




S(O)


2






0




1-(N-phthalimido)-ethyl




566






121




CH


2






0




4-Me—C


6


H


4






433






122




CH


2






0




4-(CO


2


H)—C


6


H


4






463






123




CH


2






0




2-(CO


2


H)—C


6


H


4






463






124




CH


2






0




4-(NHC(O)Me)—C


6


H


4






476






125




CH


2






0




3-OH—C


6


H


4






435






126




CH


2






0




4-MeO—C


6


H


4






449






127




CH


2






0




5-Me-fur-2-yl




423






128




CH


2






0




2,5-F


2


—C


6


H


3






455






129




CH


2






0




5-NO


2


-fur-2-yl






130




CH


2






0




4-NO


2


—C


6


H


4








131




CH


2






0




4-iso-Pr-C


6


H


4






461






132




CH


2






0




phenyl




419






133




CH


2






0




2-(SO


3




−


Na


+


)—C


6


H


4






498






134




CH


2






0




4-F—C


6


H


4






437






135




CH


2






0




2,6-Cl


2


—C


6


H


3






487






136




CH


2






0




3,4-Cl


2


—C


6


H


3






487






137




CH


2






0




2,4-Cl


2


—C


6


H


3








138




CH


2






0




4-(OCH


2


CO


2


H)—C


6


H


4






493






139




CH


2






0




Pyrid-2-yl




420






140




CH


2






0




3-methylthien-2-yl




439






141




CH


2






0




3-Cl—C


6


H


4






453






142




CH


2






0




5-methylthien-2-yl




439






143




CH


2






0




3-OH-4-MeO—C


6


H


3






465






144




CH


2






0




3-NO


2


-4-OH—C


6


H


3






480






145




CH


2






0




Chromon-3-yl






146




CH


2






0




1,3-Me


2


-5-Cl-pyrazol-4-yl




471






147




CH


2






0




3,4-F


2


—C


6


H


3






455






148




CH


2






0




4-Cl-pyrazol-3-yl




443






149




C(O)




1




4-S(O)


2


Me—C


6


H


4








150




CH


2






0




2,6-Cl


2


-pyridin-4-yl






151




CH


2






0




5-(4-NO


2


—C


6


H


4


)-fur-2-yl




530






152




CH


2






0




1-(4-methylbenzyl)-pyrazol-5-yl






153




CH


2






0




Benzfur-2-yl




459






154




CH


2






0




2-phenylimidazol-4-yl




485






155




CH


2






0




5-ethylthien-2-yl




453






156




CH


2






0




2-Cl-quinolin-3-yl




504






157




CH


2






0




6-methylpyridin-2-yl




434






158




CH


2






0




1-acetylindol-3-yl




500






159




CH


2






0




6-formyl-pyridin-2-yl




448






160




CH


2






0




Quinolin-3-yl






161




CH


2






0




5-(CH


2


OC(O)CH


3


)-fur-2-yl













162




CH


2






0
















529













163




CH


2






0




Pyridin-4-yl




420






164




CH


2






0




3-OH-4-NO


2


—C


6


H


3






480






165




CH


2






0




3,5-F


2


—C


6


H


3






455






166




CH


2






0




3-CF


3


—C


6


H


3






487






167




CH


2






0




2-F-6-Cl—C


6


H


3






471






168




CH


2






0




2-(tert-butyl)S—C


6


H


4








169




CH


2






0




4-Et-C


6


H


4






447






170




CH


2






0




3-CO


2


H-4-OH—C


6


H


4






479






171




CH


2






0




3-(OCH


2


CO


2


H)—C


6


H


4






493






172




CH


2






0




2,3-methylenedioxyphenyl




463






173




CH


2






0




Thiazol-2-yl




426






174




CH


2






0




5-ethylfur-2-yl




437






175




CH


2






0




Quinolin-2-yl




470






176




CH


2






0




Quinolin-4-yl




470






177




CH


2






0




4-CH


2


CH(CH


3


)


2


—C


6


H


4






475






178




CH


2






0




3-MeO-4-OH-5-CO


2


H—C


6


H


2






509






179




CH


2






0




4-bromopyrazol-3-yl






180




CH


2






0




2-(OCH


2


CO


2


H)-3-MeO—C


6


H


3






523






181




CH


2






0




4-(O(CH


2


)


3


N(CH


3


)


2


)—C


6


H


4






520






182




CH


2






0




3-bromothien-2-yl




503






183




CH


2






0




3-phenoxythien-2-yl




517






184




CH


2






0




5-methylthio-thien-2-yl




471






185




CH


2






0




1-methyl-4-bromopyrazol-3-yl




501






186




CH


2






0




4-I—C


6


H


4








187




CH


2






0




6,7-Me


2


-chromon-3-yl






188




CH


2






0




2-(OCH


2


CO


2


H)-5-NO


2


—C


6


H


4






538






189




CH


2






0




2-(2,6-dichlorobenzyloxy)phenyl




593






190




CH


2






0




1-(4-chlorobenzyl)pyrazol-3-yl




533






191




CH


2






0




4-iso-propoxy-C


6


H


4






477






192




CH


2






0




1-methylbenzimidazol-2-yl




473






193




CH


2






0




3-Me-C


6


H


4






433






194




CH


2






0




Pyridin-3-yl




420






195




CH


2






0




2,4-(MeO)


2


-pyrimidin-5-yl






196




CH


2






0




3-Cl-5-CF


3


-pyridin-2-yl




522






197




CH


2






0




2,4-Me


2


-C


6


H


3






447






198




CH


2






0




1-methylindol-3-yl




472






199




CH


2






0




2-methyl-3-(CO


2


Et)-fur-5-yl






200




CH


2






0




1-Me-4-Cl-pyrazol-3-yl




457






201




C(O)




2




phenyl




461






202




C(O)




1




4-Br—C


6


H


4






525






203




C(O)




1




4-NH


2


—C


6


H


4






462






204




C(O)




1




2-Br—C


6


H


4






525






205




C(O)




1




4-F—C


6


H


4






465






206




C(O)




1




2-CF


3


—C


6


H


4








207




C(O)




1




3-Me—C


6


H


4






461






208




C(O)




1




2-Me—C


6


H


4






461






209




C(O)




1




3-Cl-4-OH—C


6


H


3






497






210




C(O)




3




9,10-dihydrophenanthren-2-yl




577






211




C(O)




1




2-NO


2


—C


6


H


4






492






212




C(O)




1




2-Cl—C


6


H


4






481






213




C(O)




1




4-Cl—C


6


H


4






481






214




C(O)




1




2-benzyloxy-C


6


H


4






553






215




C(O)




2




3,4-(OH)


2


—C


6


H


3






493






216




C(O)




1




4-NO


2


—C


6


H


4






492






217




C(O)




4




Phenyl




489






218




C(O)




1




3,4-(MeO)


2


—C


6


H


3






507






219




C(O)




1




4-EtO—C


6


H


4






491






220




C(O)




1




3-F-4-OH—C


6


H


3






481






221




C(O)




3




Phenyl




475






222




C(O)




1




3,4-methylenedioxyphenyl




491






223




C(O)




3




4-MeO—C


6


H


4






505






224




C(O)




2




4-OH—C


6


H


4






477






225




C(O)




1




4-OH—C


6


H


4






463






226




C(O)




1




4-phenyl-C


6


H


4






523






227




C(O)




1




3,4-Cl


2


—C


6


H


3






515






228




C(O)




2




3-OH—C


6


H


4






477






229




C(O)




2




4-Me—C


6


H


4






475






230




C(O)




3




4-NO


2


—C


6


H


4






520






231




C(O)




2




3,4-(MeO)


2


—C


6


H


3






521






232




C(O)




3




4-Me—C


6


H


4






489






233




C(O)




2




C


6


F


5






551






234




C(O)




3




Dibenzothien-4-yl




581






235




C(O)




1




4-Me—C


6


H


4






461






236




C(O)




2




4-SH—C


6


H


4








237




C(O)




1




4-CF


3


O—C


6


H


4






531






238




C(O)




1




4-CH


2


Br—C


6


H


4








239




C(O)




3




3,4-(MeO)


2


—C


6


H


3






535






240




C(O)




1




4-MeO—C


6


H


4






477






241




C(O)




1




4-(NMe


2


)—C


6


H


4






490






242




C(O)




2




4-MeO—C


6


H


4






491






243




C(O)




2




2-MeO—C


6


H


4






491






244




C(O)




1




3,4,5-(MeO)


3


—C


6


H


2






537






245




C(O)




2




3,4-methylenedioxyphenyl




505






246




C(O)




2




Dibenzothien-4-yl






247




C(O)




1




3-NH


2


—C


6


H


4






462






248




C(O)




1




Naphth-1-yl




497






249




C(O)




1




3-MeO-4-OH—C


6


H


3






493






250




C(O)




1




Naphth-2-yl






251




C(O)




1




3-(1-allyl-6-bromonaphth-2-yloxy)CH


2


—C


6


H


4






721






252




C(O)




1




4-NO


2


—C


6


H


4








253




C(O)




1




3-F-4-MeO—C


6


H


3






495






254




C(O)




4




3-Me—C


6


H


4






503






255




C(O)




1




3-OH—C


6


H


4






463






256




C(O)




1




4-benzyloxy-C


6


H


4






553






257




C(O)




1




4-(3-NO


2


—C


6


H


4


)—C


6


H


4






568






258




C(O)




1




2,5-(Me)


2


—C


6


H


3






475






259




C(O)




1




4-I—C


6


H


4






573






260




C(O)




1




4-(4-(1-Me-2-OH-4-(pyridin-3-yl)-butoxy)-




702









C


6


H


4


)—C


6


H


4








261




C(O)




1




3-Br—C


6


H


4






525






262




C(O)




2




3-(n-Pr)—C


6


H


4






503






263




C(O)




1




4-(4-NO


2


—C


6


H


4


CH


2


O)—C


6


H


4






598






264




C(O)




1




2,5-(OH)


2


—C


6


H


3








265




C(O)




1




2-Me-3-NO


2


—C


6


H


3






506






266




C(O)




1




4-(CH


2


NHCO


2


CH


2


(fluoren-9-yl))-C


6


H


4








267




C(O)




1




3-OH-4-MeO—C


6


H


4






493






268




C(O)




1




3-F—C


6


H


4






465






269




C(O)




1




2-F—C


6


H


4






465






270




C(O)




1




3,5-(MeO)


2


-C


6


H


3






507






271




C(O)




1




3-Cl—C


6


H


4






481






272




C(O)




1




Phenyl




447






273




C(O)




1




3,5-Me


2


—C


6


H


3






475






274




C(O)




2




3-MeO—C


6


H


4






491






275




C(O)




1




2,4-F


2


—C


6


H


3






483






276




C(O)




1




2-MeO—C


6


H


4






477






277




C(O)




1




3,4-F


2


—C


6


H


3






483






278




C(O)




1




3,5-F


2


—C


6


H


3






483






279




C(O)




5




phenyl




503






280




S(O)


2






0




5-(pyridin-2-yl)-thien-2-yl






281




C(O)




0




3-S(O)


2


Me—C


6


H


4






511






282




C(O)




0




3-MeO-4-NH


2


—C


6


H


3








283




C(O)




0




3-MeO-4-F—C


6


H


3






481






284




C(O)




0




Benzthiazol-6-yl




490






285




C(O)




0




3-MeO—C


6


H


4






477






286




C(O)




0




3-C


6


H


5


S(O)—C


6


H


4






557






287




C(O)




0




4-S(O)


2


Me—C


6


H


4






511






288




C(O)




0




2,4-Cl


2


—C


6


H


3






501






289




C(O)




0




4-NO


2


—C


6


H


4






478






290




C(O)




0




3-CN—C


6


H


4






458






291




C(O)




0




4-MeO—C


6


H


4






463






292




C(O)




0




4-CN—C


6


H


4






458






293




C(O)




0




2-S(O)


2


Me—C


6


H


4






511






294




C(O)




0




2-Cl-4-S(O)


2


Me—C


6


H


3






545






295




C(O)




0




3-(C


6


H


5


S(O)


2


CH


2


)-4-NO


2


—C


6


H


3






632






296




C(O)




0




2-(C


6


H


5


S(O)


2


CH


2


)—C


6


H


4








297




C(O)




0




Benzo[1,2,3]thiadiazol-5-yl




491






298




C(O)




0




4-EtS—C


6


H


4






493






299




C(O)




0




3-CF


3


S—C


6


H


4






533






300




C(O)




0




4-CF


3


S—C


6


H


4






533






301




C(O)




0




3-CH


3


C(O)NH—C


6


H


4






490






302




C(O)




0




3-CH


3


-4-NH


2


—C


6


H


3






462






303




C(O)




0




Indol-7-yl




472






304




C(O)




0




3-CH


3


CH


2


O-4-CH


3


O—C


6


H


3






507






305




C(O)




0




4-(2,5-dihydropyrrol-1-yl )-C


6


H


4






500






306




C(O)




1




3-Br-pyridin-5-yl




526






307




C(O)




1




1-methyl-imidazol-4-yl




451






308




C(O)




1




5-OH-indol-3-yl




502






309




C(O)




1




Thiophen-3-yl




453






310




C(O)




0




3-CH


3


CH


2


S(O)


2


—C


6


H


4






525






311




C(O)




0




3-CH


3


(CH


2


)


2


S(O)


2


—C


6


H


4






539






312




C(O)




0




3-(CH


3


)


2


CHCH


2


S(O)


2


—C


6


H


4






553






313




C(O)




0




3,4-(CH


3


S(O)


2


)


2


—C


6


H


3






589






314




C(O)




0




3-CH


3


CH


2


O-4-NH


2


—C


6


H


3






492






315




C(O)




1




Pyridin-4-yl




448






316




C(O)




0




2-CH


3


S(O)


2


CH


2


—C


6


H


4






525






317




C(O)




0




2-NH


2


—C


6


H


4






448






318




C(O)




0




1-acetyl-indol-3-yl






319




C(O)




0




Indol-3-yl






320




C(O)




0




3-NH


2


(CH


2


)


2


O—C


6


H


4








321




C(O)




0




3-CH


3


NHS(O)


2


—C


6


H


4








322




C(O)




0




3-NH


2


S(O)


2


—C


6


H


4








323




C(O)




0




3-CH


3


O(CH


2


)


2


O—C


6


H


4








324




C(O)




0




3-(CH


3


)


3


COC(O)NH(CH


2


)


2


O—C


6


H


4








325




C(O)




0




1,2,3-benzothiadiazol-6-yl






326




C(O)




0




3-HOC(O)CH


2


O—C


6


H


4








327




C(O)




0




2-CH


3


S(O)


2


-3-CN-thiophen-5-yl




542






328




C(O)




0




3-CH


3


S(O)


2


-4-NH


2


—C


6


H


3






526






329




C(O)




0




2-CH


3


S(O)


2


-3-NH


2


C(O)-thiophen-5-yl




560






330




C(O)




0




3-CF


3


O—C


6


H


4






501






331




C(O)




0




2-(CH


3


)


2


CHS(O)


2


-3-NH


2


-thiophen-4-yl




560






332




C(O)




0




2-CH


3


S(O)


2


-thiophen-5-yl




517






333




C(O)




0




3-CH


3


-5-(4-CH


3


-1,2,3-thiadiazol-5-yl)-




536









isoxazol-4-yl






334




C(O)




0




3-Cl-5-CF


3


-pyridin-2-yl




536






335




C(O)




1




4-CF


3


O—C


6


H


4






531






336




C(O)




0




1H-benzotriazol-5-yl




474






337




C(O)




0




4-CH


3


S(O)


2


CH


2


—C


6


H


4






525






338




C(O)




0




3-CH


3


S(O)


2


CH


2


—C


6


H


4






525






339




C(O)




0




2-CN—C


6


H


4






458






340




C(O)




0




Quinolin-6-yl




484






341




C(O)




0




Quinoxalin-6-yl




485






342




C(O)




0




3-NH


2


-4-CH


3


S(O)


2


-thiophen-2-yl




532













343




C(O)




0
















566













344




C(O)




0

























345




C(O)




0




3-CF


3


O—C


6


H


4






517






346




C(O)




0




2,5-(CH


3


O)


2


—C


6


H


3






493






347




C(O)




0




1-(CH


3


)


2


CH-benzotriazol-5-yl













348




C(O)




0

























349




C(O)




0




3-HO(CH


2


)


2


S(O)


2


—C


6


H


4








350




C(O)




0




2-HO(CH


2


)


2


S(O)


2


—C


6


H


4








351




C(O)




0




3-cyclopropylCH


2


S(O)


2


—C


6


H


4








352




C(O)




0




2-CH


3


S(O)


2


NH—C


6


H


4






526






353




C(O)




0




(CF


3


)(MeO)(C


6


H


5


)C




545






354




C(O)




0




(C


6


H


5


)


2


CH




523






355




C(O)




0




(4-Cl—C


6


H


4


)(CH


3


)


2


C




509






356




C(O)




0




(C


6


H


5


)(cyclohexyl)CH




529






357




C(O)




0




(4-F—C


6


H


4


)(CH


3


)CH




479






358




C(O)




1




3,4-methylenedioxy-C


6


H


4






491






359




C(O)




0




(C


6


H


5


)(cyclopentyl)CH




515






360




C(O)




0




((CH


3


)(CH


3


CH


2


)CH)(C


6


H


5


)GH




503






361




C(O)




0




1-phenyl-cyclopentyl




501






362




C(O)




0




1-(4-Cl—C


6


H


4


)cyclopentyl




535






363




C(O)




0




1-phenyl-cyclopropyl




473






364




C(O)




0




1-phenyl-cyclohexyl




515






365




C(O)




0




(C


6


H


5


)(cyclohexyl)C(OH)




545






366




C(O)




0




((CH


3


)


2


CH)(C


6


H


5


)CH




489






367




C(O)




1




pyrid-3-yl




448






368




C(O)




1




pyrid-2-yl




448






369




C(O)




1




5-Br-pyrid-3-yl




526






370




C(O)




1




2,4-(MeO)


2


—C


6


H


3






507






371




C(O)




1




4-benzyloxy-phenyl




553






372




C(O)




1




3-benzyloxy-phenyl




553













373




C(O)




1
















549













374




C(O)




0




2-EtO—C


6


H


4






491













375




C(O)




0
















549













376




C(O)




1




4-n-butoxyphenyl




519






377




C(O)




1




indol-1-yl




486






378




C(O)




1




2-NO


2


-phenyl




492






379




C(O)




1




thien-2-yl




453






380




C(O)




1




3-Cl-4-OH-phenyl




497






381




C(O)




1




2-Br-phenyl




525






382




C(O)




1




3-Br-phenyl




525






383




C(O)




1




3,5-F


2


-phenyl




483






384




C(O)




1




3-aminophenyl




462






385




C(O)




1




3,4-(OH)


2


-phenyl




479






386




C(O)




1




2,5-(MeO)


2


-phenyl




507






387




C(O)




1




4-Me-phenyl




461






388




C(O)




0




5-(4-Cl—C


6


H


4


-tetrazol-2-yl




549






389




C(O)




1




4-MeS(O)


2


-phenyl




525






390




C(O)




1




4-F-phenyl




465






391




C(O)




1




5-Cl-benzo[b]thiophen-3-yl




537






392




C(O)




1




4-CF


3


O-phenyl




531






393




C(O)




1




3-Me-5-Cl-benzo[b]thiophen-2-yl




551






394




C(O)




1




2-nitrophenyl




492






395




C(O)




1




4-Cl-5-Me-3-NO


2


-pyrazol-1-yl




530






396




C(O)




1




2-CF


3


-benzimidazol-1-yl




555






397




C(O)




1




2-EtS-benzimidazol-1-yl




547






398




C(O)




1




2-Me-4-(thien-2-yl)-thiazol-5-yl




550






399




C(O)




1




4-Br-3,5-Me


2


-pyrazol-1-yl




543






400




C(O)




1




5-Me-3,4-(NO


2


)


2


-pyrazol-1-yl




541






401




C(O)




1




4-(3-methyl-butoxy)-phenyl




533






402




C(O)




1




2-tert-butylthio-phenyl




535






403




C(O)




1




4-Cl-3,5-Me


2


-pyrazol-1-yl




499













404




C(O)




1
















535













405




C(O)




1




2,4-(NO


2


)


2


-imidazol-1-yl




527






406




C(O)




1




3,5-Me


2


-pyrazol-1-yl




465






407




C(O)




1




4-n-hexyl-phenyl




531






408




C(O)




0




2-NH


2


-pyrid-5-yl




449






409




C(O)




0




Pyrid-2-yl




434






410




C(O)




0




2-EtS-pyrid-3-yl




494






411




C(O)




0




2-OH-quinolin-4-yl




500






412




C(O)




0




2-OH-pyrid-5-yl




450






413




C(O)




0




2,6-(MeO)


2


-pyrid-3-yl




494






414




C(O)




0




2-(imidazol-1-yl)-pyrid-5-yl




500






415




C(O)




0




2-CO


2


CH


3


-pyrid-3-yl




492






416




C(O)




0




2-Me-pyrid-5-yl




448






417




C(O)




0




Quinolin-2-yl




484






418




C(O)




0




6-Me-pyrid-2-yl




448






419




C(O)




0




2-OH-6-Me-pyrid-3-yl




464






420




C(O)




0




8-OH-quinolin-2-yl




500






421




C(O)




1




3-F-phenyl




465






422




C(O)




0




Imidazo[1,2-a]pyrid-2-yl




473






423




C(O)




0




2-methyl-[1,8]naphthyridin-3-yl




499






424




C(O)




0




[1,6]naphthyridin-2-yl




485






425




C(O)




0




2-methyl-[1,6]naphthyridin-3-yl




499






426




C(O)




0




1-methyl-1H-pyrid-2-one-5-yl




464






427




C(O)




0




Quinolin-4-yl




484






428




C(O)




0




Quinolin-6-yl




484






429




C(O)




0




3-(CH


3


(CH


2


)


2


S(O)


2


)—C


6


H


4






539






430




C(O)




0




5-((pyrid-2-yl)SCH


2


)fur-2-yl




546






431




C(O)




0




2-Me-3-OH-quinolin-4-yl




514






432




C(O)




0




(pyrid-2-yl)CH═CH




460






433




C(O)




0




(2-EtS-pyrid-5-yl)CH═CH




520






434




C(O)




0




1-(5-CF


3


-pyrid-2-yl)-piperidin-4-yl




585






435




C(O)




0




2,7-Me


2


-imidazo[1,2-a]pyrid-3-yl




501






436




C(O)




0




(5-CF


3


-pyrid-2-yl)SO


2


CH(CH


3


)




594






437




C(O)




1




3-(pyrid-2-yl)pyrazol-1-yl




514






438




C(O)




0




3-NH


2


-4-CH


3


O—C


6


H


3






478






439




C(O)




0




2,5-(CH


3


O)


2


—C


6


H


3






493






440




C(O)




0




3-F-4-CH


3


—C


6


H


3






465






441




C(O)




0




3-phenyl-5-CH


3


-isoxazol-4-yl




514






442




C(O)




0




1-phenyl-5-CH


3


-pyrazol-4-yl




513






443




C(O)




0




3-CF


3


O—C


6


H


4






517






444




C(O)




0




2-CH


3


O-5-Cl—C


6


H


3






497






445




C(O)




0




2-CH


3


-3-F—C


6


H


3






465






446




C(O)




0




2-(2-phenyl-thiazol-4-yl)phenyl




592






447




C(O)




0




3,4-methylenedioxyphenyl




477






448




C(O)




0




5-phenyl-oxazol-4-yl




500






449




C(O)




0




1H-indazol-3-yl




473






450




C(O)




0




1-CH


3


-indol-3-yl




486






451




C(O)




0




1-iso-propyl-benztriazol-5-yl




516













452




C(O)




0
















473













453




C(O)




0




2-CH


3


-5-F—C


6


H


3






465






454




C(O)




0




3-CF


3


O-4-NH


2


—C


6


H


3






532






455




C(O)




0




3-CH


3


-5-CF


3


-isoxazol-4-yl




506






456




C(O)




0




(1,2,4-triazo1-1-yl)C(CH


3


)


2






466






457




C(O)




0




2-phenyl-thiazol-4-yl




516






458




C(O)




0




2-CH


3


-4-CF


3


-thiazol-5-yl




522













459




C(O)




0
















529













460




C(O)




0
















558













461




C(O)




0




3-F-4-CF


3


—C


6


H


3






519













462




C(O)




0
















501













463




C(O)




0




2-CH


3


-benzimidazol-5-yl




487













464




C(O)




1
















534













465




C(O)




0




3-iso-propoxy-4-CH


3


O—C


6


H


3






521













466




C(O)




0
















519













467




C(O)




0
















534













468




C(O)




0




2-CH


3


O-5-F—C


6


H


3






481






469




C(O)




0




3-CH


3


CH


2


O—C


6


H


4








470




C(O)




0




2-(C


6


H


5


S(O)CH


2


)—C


6


H


4








471




C(O)




0




1H-indol-3-yl




472






472




S(O)


2






1




2-NO


2


—C


6


H


4






528






473




S(O)


2






0




2-CN—C


6


H


4






494






474




C(O)




0




3-CH


3


S(O)


2


—C


6


H


4






511






475




C(O)




0




3-S(O)


2


NHCH


3


—C


6


H


4






526






476




C(O)




0




Benzo[1,2,3]thiadiazol-6-yl




491






477




C(O)




0




3-CH


3


O(CH


2


)


2


O—C


6


H


4






507






478




C(O)




0




3,4-(CH


3


S(O)


2


)


2


—C


6


H


3






589






479




C(O)




0




3-CH


3


O—C


6


H


4






463






480




C(O)




0




3-CN—C


6


H


4






458






481




C(O)




0




4-F—C


6


H


4






451






482




C(O)




0




3-CH


3


O-4-F—C


6


H


3






481






483




C(O)




0




3H-benzothiazol-2-one-6-yl




506






484




C(O)




0




2-CH


3


S(O)


2


-thien-5-yl




517






485




C(O)




0




3-CH


3


-4-NH


2


—C


6


H


3






462






486




C(O)




0




Benzothiazol-6-yl




490






487




C(O)




0




1H-5-CH


3


S(O)


2


-indol-2-yl




550






488




C(O)




0




1H-5-CH


3


O-indol-2-yl




502






489




C(O)




0




1H-indol-4-yl




472






490




C(O)




0




1H-Benzimidazol-5-yl




473






491




C(O)




0




3,4-methylenedioxyphenyl




477






492




C(O)




0




1H-5-Cl-indol-2-yl




506






493




C(O)




0




1H-5-OH-indol-2-yl




488













494




C(O)




0
















558













495




C(O)




0




3,4-difluoromethylenedioxyphenyl




513






496




C(O)




0




2-(pyrazol-1-yl)-pyridin-5-yl




500






497




C(O)




0




4-CF


3


-pyridin-3-yl




502













498




C(O)




0
















576













499




C(O)




0
















459













500




C(O)




0




3-n-propoxy-pyridin-2-yl




492






501




C(O)




1




2-(2,4-F


2


—C


6


H


3


)thiazol-4-yl




566






502




C(O)




0




1H-indol-2-yl




472






503




C(O)




1




2-phenyl-5-CH


3


-thiazol-4-yl




544






504




C(O)




0




2-S(O)


2


NH


2


-4-Cl—C


6


H


3






546






505




C(O)




0




2-CN—C


6


H


4






458






506




C(O)




0




1H-indol-7-yl




472






507




C(O)




0




1H-5-F-indol-2-yl




490






508




C(O)




0




1H-pyrazol-4-yl




423






509




C(O)




0




1-CH


3


-pyrrol-2-yl




436






511




C(O)




0




3-(pyrrol-1-yl)-4-CN-thien-2-yl




529






512




C(O)




0




3-CH


3


O-4-NH


2


—C


6


H


3






478






513




C(O)




0




lH-indol-3-yl




500







C(O)






514




C(O)




0




4-(pyrrol-1-yl)phenyl




498






515




C(O)




0




1-CH


3


-indol-2-yl




486






516




C(O)




1




1H-indol-3-yl




486






517




C(O)




1




1H-5-CH


3


O-indol-3-yl




516






518




C(O)




0




2-(pyridin-2-yl)-thien-5-yl




516






519




C(O)




0




1H-5-F-indol-2-yl




490






520




C(O)




1




3-CH


3


-benzo[b]thiophen-2-yl




517






521




C(O)




1




3,5-(CH


3


)


2


-4-NO


2


-pyrazol-1-yl




510






522




C(O)




0




2-CF


3


-[1,6]-naphthyridin-3-yl




553






523




C(O)




0




2-(1-CH


3


-5-CF


3


-pyrazol-3-yl)-thien-5-yl




587













524




C(O)




0
















638













525




C(O)




1




3-Cl—C


6


H


4






481






526




C(O)




1




5-CH


3


-3-NO


2


-pyrazol-1 -yl




496






527




C(O)




1




2-CN—C


6


H


4






472






528




C(O)




0




Quinoxalin-2-yl




485






529




C(O)




0




Pyrazin-2-yl




435













530




C(O)




0
















549













531




C(O)




0




1-tert-butyl-3-CH


3


-pyrazol-5-yl




493






532




C(O)




0




2-SH-pyridin-3-yl




466






533




C(O)




0




Quinolin-3-yl




484













534




C(O)




0
















543













535




C(O)




0




2-ethoxy-phenyl




477






536




C(O)




1




4-NO


2


-imidazol-1-yl




482






537




C(O)




0




4-CH


3


O-quinolin-2-yl




514






538




C(O)




0




2-SCH


2


CH═CH


2


-pyridin-3-yl




506






539




C(O)




0




1-iso-propyl-benztriazol-5-yl




516






540




C(O)




0




[1,8]-naphthyridin-2-yl




485






541




C(O)




1




2-CH


3


-4-phenyl-thiazol-5-yl




544






542




C(O)




0




1-CH


3


-indol-2-yl




486






543




C(O)




0




2-phenoxy-pyridin-5-yl-CH═CH




552






544




C(O)




1




3,4-Cl


2


—C


6


H


3






515






545




C(O)




0




2-S(O)


2


CH


3


-3-CN-6-CH


3


-pyridin-4-yl




551






546




C(O)




0




3H-Benzothiazol-2-one-6-yl




506






547




C(O)




0




2-CH


3


O-pyridin-3-yl




464






548




C(O)




0




Isoquinolin-1-yl




484






549




C(O)




1




4-OH—C


6


H


4






463






550




C(O)




0




Quinolin-8-yl




484






551




C(O)




0




2-CN—C


6


H


4






458






552




C(O)




0




2-CF


3


-[1,8]-naphthyridin-3-yl




553






553




C(O)




0




2-CO


2


CH


3


-pyridin-6-yl




492






554




C(O)




0




Isoquinolin-3-yl




484






555




C(O)




0




3-CH


2


S(O)


2


CH


3


—C


6


H


4






525






556




C(O)




0




2-ethoxy-pyridin-3-yl




478













557




C(O)




1
















516













558




C(O)




0




2-CH


3


O-pyridin-5-yl




464






559




C(O)




0




Indan-1-one-3-yl




487






560




C(O)




1




3-NO


2


-[1,2,4]-triazol-1-yl




483






561




C(O)




0




1-(CH


3


)


2


CH-benzotriazol-5-yl




516






562




C(O)




1




1H-2-CH


3


-indol-3-yl




500






563




C(O)




0




3,5-(CH


3


)


2


-isoxazol-4-yl




452






564




C(O)




0




1,5-(CH


3


)


2


-pyrazol-4-yl




451






565




C(O)




0




Quinoxalin-6-yl




485






566




C(O)




1




3-NO


2


-[1,2,4]triazol-1-yl




483






567




C(O)




0




1H-indol-3-yl-CH═CH




498






568




C(O)




1




4-(pyridin-2-yl)-pyrimidin-2-yl-S




558






569




C(O)




0




3-S(O)


2


NH


2


—C


6


H


4






512






570




C(O)




1




1H-5-OH-indol-3-yl




502






571




C(O)




0




4-CH


2


S(O)


2


CH


3


—C


6


H


4






525













572




C(O)




0
















500













573




C(O)




0




Isoxazol-5-yl




424






574




C(O)




1




1-CH


3


-4-NO


2


-pyrazol-5-yl




496













575




C(O)




0
















645













576




C(O)




0




3-ethoxy-4-amino-phenyl




492






577




C(O)




1




1,4-(CH


3


)


2


-3-CO


2


H-pyrrol-2-yl




508













578




C(O)




0
















473













579




C(O)




0
















491













580




C(O)




0




2-OH-quinolin-4-yl




500






582




C(O)




0




3-amino-phenyl




448






583




C(O)




0




3-NHS(O)


2


CH


3


—C


6


H


4






526






584




C(O)




0




3-C(CH


3


)


3


OC(O)NH(CH


2


)


2


O—C


6


H


4






592






585




C(O)




0




3-HO


2


CCH


2


O—C


6


H


4






507






586




C(O)




0




3-H


2


N(CH


2


)


2


O—C


6


H


4






492






587




C(O)




0




2-NHS(O)


2


CH


3


—C


6


H


4






526






588




C(O)




0




2-S(O)


2


CH


2


cyclopropyl-C


6


H


4






551






589




C(O)




0




3-S(O)


2


N(CH


3


)


2


—C


6


H


4






540






590




C(O)




0




3-NO


2


-5-S(O)


2


CH


3


—C


6


H


3






556






591




C(O)




0




3-NH


2


-5-S(O)


2


CH


3


—C


6


H


3






526






592




C(O)




0




1-S(O)


2


CH


3


-indol-3-yl






593




C(O)




0




3-CN-5-S(O)


2


CH


3


—C


6


H


3






536






594




C(O)




0




1H-5-S(O)


2


CH


3


-indol-3-yl




550






595




C(O)




0




CH(Phenyl)(CH


2


piperazin-1-yl)




545













596




C(O)




1
















518













597




C(O)




0




3-S(O)


2


NH


2


-4-Cl—C


6


H


3






546













598




C(O)




0
















474













599




C(O)




0
















487













600




C(O)




0
















507













601




C(O)




0
















487













602




C(O)




0




2-NO


2


-5-S(O)


2


CH


3


—C


6


H


3








603




C(O)




0




2-NH


2


-5-S(O)


2


CH


3


—C


6


H


3
















Examples of compounds of formula (Ic) are listed in Table II below.
















TABLE II









Compound




m




p




T




R


3













1




1




1




C(O)




3-MeO-4-NH


2


—C


6


H


3








2




0




2




C(O)




3-MeO-4-NH


2


—C


6


H


3








3




1




1




S(O)


2






5-(pyridin-2-yl)-thien-2-yl






4




0




1




C(O)




3-MeO-4-NH


2


—C


6


H


3








5




1




1




C(O)




3H-benzothiazol-2-one-6-yl













6




1




1




C(O)

























7




1




1




C(O)




[1,8]naphthyridin-2-yl













8




1




1




C(O)


























Examples of compounds of formula (Id) are listed in Table III below.













TABLE III









Compound




R


3













1




4-F—C


6


H


4








2




Phenyl






3




3,4-F


2


—C


6


H


3
















Examples of compounds of formula (If) are listed in Table IV below.













TABLE IV












(If)





































Com-











pound




R


1






t




s




n




R


3











 1




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 2




3-Cl-4-F—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 3




3-F-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 4




3-CH


3


O-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 5




2-CH


3


O-4-F—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 6




4-CH


3


O—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 7




4-CH


3


O—C


6


H


4






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 8




4-Cl—C


6


H


4






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 9




3,4-Cl


2


—C


6


H


3






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 10




4-CN—C


6


H


4






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 11




3,4-F


2


—C


6


H


4






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 12




4-F—C


6


H


4






0




0




0




3-CH


3


S(O)


2


—C


6


H


4








 13




4-CH


3


C(O)NH—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 14




4-CH


3


—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 15




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 16




4-Cl—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 17




4-F—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 18




2,4-Cl


2


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 19




2-Cl-4-F—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 20




2,4-F


2


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 21




2-F-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 22




2-CH


3


-4-F—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 23




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 24




3-F-4-Cl—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 25




2-CH


3


O-4-Cl—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 26




2-CH


3


O-4-F—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 27




4-CH


3


O—C


6


H


4






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 28




3-Cl-4-F—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 29




4-CH


3


—C


6


H


4






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 30




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 31




4-Cl—C


6


H


4






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 32




4-F—C


6


H


4






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 33




2,4-Cl


2


—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 34




2-Cl-4-F—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 35




2,4-F


2


—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 36




2-F-4-Cl—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 37




2-CH


3


-4-F—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 38




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 39




3-F-4-Cl—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 40




2-CH


3


O-4-Cl—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 41




2-CH


3


O-4-F—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 42




4-CH


3


O—C


6


H


4






1




0




0




1,2,3-benzthiadiazol-5-yl






 43




3-Cl-4-F—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 44




4-CH


3


—C


6


H


4






1




0




0




1,2,3-benzthiadiazol-5-yl






 45




3-Cl-4-CH


3


—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 46




4-Cl—C


6


H


4






1




0




0




1,2,3-benzthiadiazol-5-yl






 47




4-F—C


6


H


4






1




0




0




1,2,3-benzthiadiazol-5-yl






 48




2,4-Cl


2


—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 49




2-Cl-4-F—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 50




2,4-F


2


—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 51




2-F-4-Cl—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 52




2-CH


3


-4-F—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 53




3,4-Cl


2


—C


6


H


3






1




1




0




3-CN—C


6


H


4








 54




3,4-Cl


2


—C


6


H


3






1




1




0




3-CH


3


S(O)


2


—C


6


H


4








 55




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 56




3-Cl-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 57




3-F-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 58




3-CH


3


O-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 59




2-CH


3


O-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 60




4-CH


3


O—C


6


H


4






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 61




4-CH


3


C(O)NH—C


6


H


4






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 62




4-CH


3


—C


6


H


4






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 63




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 64




4-Cl—C


6


H


4






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 65




4-F—C


6


H


4






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 66




2,4-Cl


2


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 67




2-Cl-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 68




2,4-F


2


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 69




2-F-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 70




2-CH


3


-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 71




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 72




3-Cl-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 73




3-F-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 74




3-CH


3


O-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 75




2-CH


3


O-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 76




4-CH


3


O—C


6


H


4






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 77




4-CH


3


C(O)NH—C


6


H


4






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 78




4-CH


3


—C


6


H


4






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 79




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 80




4-Cl—C


6


H


4






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 81




4-F—C


6


H


4






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 82




2,4-Cl


2


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 83




2-Cl-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 84




2,4-F


2


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 85




2-F-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 86




2-CH


3


-4-F—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 87




3-Cl-4-CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








 88




3-Cl-4-CH


3


—C


6


H


3






1




0




0




3-CH


3


O-4-NH


2


—C


6


H


3








 89




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1,2,3-benzthiadiazol-5-yl






 90




3-Cl-4-CH


3


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








 91




3-Cl-4-CH


3


—C


6


H


3






1




0




0




2-CH


3


S(O)


2


-thiophen-5-yl






 92




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Quinolin-6-yl






 93




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-(CH


3


O(CH


2


)


2


O)—C


6


H


4








 94




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-(CH


3


S(O)


2


)


2


—C


6


H


3








 95




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


O—C


6


H


4








 96




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CN—C


6


H


4








 97




2-CH


3


-4-Cl—C


6


H


3






1




0




0




4-F—C


6


H


4








 98




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Indol-7-yl






 99




2-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CH


3


S(O)


2


-indol-2-yl






100




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Benzimidazol-5-yl






101




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-methylenedioxy-C


6


H


3








102




2-CH


3


-4-Cl—C


6


H


3






1




0




0




5-F-indol-2-yl






103




2-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CF


3


-thieno[3,2-b]pyridin-6-yl






104




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(pyrazol-1-yl)-pyridin-5-yl






105




3-CH


3


-4-Cl—C


6


H


3






1




0




0




Quinolin-6-yl






106




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CN—C


6


H


4








107




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-(CH


3


O(CH


2


)


2


O)—C


6


H


4








108




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-(CH


3


S(O)


2


)


2


—C


6


H


3








109




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


O—C


6


H


4








110




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CN—C


6


H


4








111




3-CH


3


-4-Cl—C


6


H


3






1




0




0




4-F—C


6


H


4








112




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CH


3


S(O)


2


-thien-2-yl






113




3-CH


3


-4-Cl—C


6


H


3






1




0




0




indol-7-yl






114




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CH


3


S(O)


2


indol-2-yl






115




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-EtO-4-NH


2


—C


6


H


3








116




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CH


3


O-indol-2-yl






117




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-methylenedioxy-C


6


H


3








118




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-F-indol-2-yl






119




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-CF


3


-thieno[3,2-b]pyridin-6-yl






120




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(pyrazol-1-yl)-pyridin-5-yl






121




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-NH


2


-4-MeO—C


6


H


3








122




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Pyrazin-2-yl






123




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-phenyl-5-Me-isoxazol-4-yl






124




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CF


3


O—C


6


H


4








125




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-MeO-5-Cl—C


6


H


3








126




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-Me-3-F—C


6


H


3








127




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-EtO—C


6


H


4








128




2-CH


3


-4-Cl—C


6


H


3






1




0




0




5-phenyl-oxazol-4-yl






129




2-CH


3


-4-Cl—C


6


H


3






1




0




0




5-F-1H-indol-2-yl






130




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2H-isoquinolin-1-one-4-yl






131




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3H-benzothiazol-2-one-6-yl






132




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Bicyclo[4.2.0]octa-1,3,5-trien-7-yl






133




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-


iso


-propylbenztriazol-5-yl






134




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-phenylcyclopropyl






135




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-NH


2


S(O)


2


-4-Cl—C


6


H


3








136




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CF


3


O-4-NH


2


—C


6


H


3








137




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-(pyrrol-1-yl)-4-CN-thien-2-yl






138




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(CH


3


O(CH


2


)


2


O)-5-NH


2


—C


6


H


3








139




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-(1-CH


3


-5-CF


3


-pyrazol-3-yl)-











thien-5-yl






140




2-CH


3


-4-Cl—C


6


H


3






1




0




0




(1,2,4-triazol-1-yl)C(CH


3


)


2








141




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-phenyl-thiazol-4-yl






142




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-4-CF


3


-thiazol-5-yl






143




2-CH


3


-4-Cl—C


6


H


3






1




0




0




[1,8]-naphthyridin-2-yl













144




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























145




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























146




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-F-4-CF


3


—C


6


H


3















147




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























148




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























149




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-benzimidazol-5-yl













150




2-CH


3


-4-Cl—C


6


H


3






1




0




1

























151




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























152




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1,5-dimethyl-pyrazol-3-yl






153




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


O-5-F—C


6


H


3








154




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-NH


2


-4-CH


3


O—C


6


H


3








155




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2,5-(CH


3


O)


2


—C


6


H


3








156




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-F-4-CH


3


—C


6


H


3








157




3-CH


3


-4-Cl—C


6


H


3






1




0




0




Pyrazin-2-yl






158




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-phenyl-5-CH


3


-isoxazol-4-yl






159




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-phenyl-5-CH


3


-pyrazol-4-yl






160




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CF


3


O—C


6


H


4








161




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


O-5-Cl—C


6


H


3








162




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-3-F—C


6


H


3








163




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


CH


2


O—C


6


H


4








164




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(2-phenyl-thiazol-4-yl)-phenyl













165




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























166




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-methylenedioxyphenyl






167




3-CH


3


-4-Cl—C


6


H


3






1




0




0




5-phenyl-oxazol-4-yl






168




3-CH


3


-4-Cl—C


6


H


3






1




0




0




Quinoxazlin-2-yl






169




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-Pyrazol-4-yl






170




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-3-yl













171




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























172




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-iso-propyl-benztriazol-5-yl






173




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-n-propoxy-pyridin-2-yl






174




3-HC


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-5-F—C


6


H


3








175




3-CH


3


-4-Cl—C


6


H


3






1




0




1




(2-S(O)


2


NHCH


3


—C


6


H


4


)S






176




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


-5-CF


3


-isoxazol-4-yl






177




3-CH


3


-4-Cl—C


6


H


3






1




0




1




2-(2,4-F


2


—C


6


H


3


)thiazol-4-yl






178




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(CH


3


O(CH


2


)


2


O)-5-NH


2


—C


6


H


3








179




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-phenyl-thiazol-4-yl













180




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























181




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























182




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-F-4-CF


3


—C


6


H


3















183




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























184




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























185




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-iso-propoxy-C


6


H


4








186




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-benzimidazol-5-yl













187




3-CH


3


-4-Cl—C


6


H


3






1




0




1

























188




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-3-yl













189




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























190




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-tert-butyl-3-CH


3


-pyrazol-5-yl













191




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























192




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


O-5-F—C


6


H


3








193




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-NH


2


-4-CH


3


O—C


6


H


3








194




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2,5-(CH


3


O)


2


—C


6


H


3








195




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CN—C


6


H


4








196




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


O-4-F—C


6


H


3








197




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-pyrrol-2-yl






198




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


CH


3


-4-NH


2


—C


6


H


3








199




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-indol-2-yl






200




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-CH


3


O-indol-3-yl






201




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-F-4-CH


3


—C


6


H


3








202




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-phenyl-5-CH


3


-pyrazol-4-yl






203




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(2-phenyl-thiazol-4-yl)-phenyl






204




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-F-indol-2-yl






205




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CF


3


O-4-NH


2


—C


6


H


3








206




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-iso-propoxy-4-CH


3


O—C


6


H


3








207




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-CH


3


O-indol-2-yl






208




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-indol-4-yl






209




2-CH


3


-4-Cl—C


6


H


3






1




0




0




4-CF


3


-pyridin-3-yl













210




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























211




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-3-yl






212




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-iso-propoxy-4-CH


3


O—C


6


H


3








213




3-CH


3


-4-Cl—C


6


H


3






1




0




1




1H-indol-3-yl













214




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























215




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-2-yl






216




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


NH


2


-4-Cl—C


6


H


3















217




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























218




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-(pyrrol-1-yl)-3-CN-thien-2-yl






219




2-CH


3


-4-Cl—C


6


H


3






1




0




0




4-(pyrrol-1-yl)phenyl






220




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-indazol-3-yl






221




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


O—NH


2


—C


6


H


3








221




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-2-yl













223




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























224




2-CH


3


-4-Cl—C


6


H


3






1




0




0




4-S(O)


2


CH


3


—C


6


H


4








225




3-CH


3


-4-Cl—C


6


H


3






1




0




0




2-(1-CH


3


-5-CF


3


-pyrazol-3-yl)-











thien-5-yl






226




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


-5-F—C


6


H


3








227




2-CH


3


-4-Cl—C


6


H


3






1




0




0




4-CH


2


S(O)


2


CH


3


—C


6


H


4








228




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Quinoxalin-2-yl






229




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-Cl-indol-2-yl






230




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


2


S(O)


2


CH


3


—C


6


H


4








231




2-CH


3


-4-Cl—C


6


H


3






1




0




1




2-(2,4-F


2


—C


6


H


3


)thiazol-4-yl






232




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


NH


2


—C


6


H


4








233




2-CH


3


-4-Cl—C


6


H


3






1




0




1




1H-indol-3-yl






234




3-CH


3


-4-Cl—C


6


H


3






1




0




0




4-S(O)


2


CH


3


—C


6


H


4








235




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-2-yl






236




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


-5-CF


3


-isoxazol-4-yl






237




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-2-yl






238




4-S(O)


2


CH


3


—C


6


H


4






1




0




0




3,4-Cl


2


—C


6


H


3








239




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-indol-3-yl






240




3-CH


3


-4-Cl—C


6


H


3






1




0




0




[1,8]-naphthyridin-2-yl






241




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


CH


3


—C


6


H


4








242




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-OH—C


6


H


4








243




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3H-Benzthiazol-2-one-6-yl






244




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-n-propoxy-pyridin-2-yl






245




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3H-Benzthiazol-2-one-6-yl






246




2-CH


3


-4-Cl—C


6


H


3






1




0




0




isoxazol-5-yl






247




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2,5-(CH


3


O)


2


—C


6


H


3








248




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-pyrazol-4-yl






249




3-CH


3


-4-Cl—C


6


H


3






1




0




0




Benzothiazol-6-yl






250




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3,5-(CH


3


)


2


-isoxazol-4-yl






251




3-CH


3


-4-Cl—C


6


H


3






1




0




0




4-CF


3


-pyridin-3-yl






252




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-indol-4-yl






253




3-CH


3


-4-Cl—C


6


H


3






1




0




0




1,5-(CH


3


)


2


-pyrazol-3-yl






254




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-indazol-3-yl






255




3-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


NH


2


—C


6


H


4








256




2-CH


3


-4-Cl—C


6


H


3






1




0




1




4-S(O)


2


CH


3


—C


6


H


4








257




2-CH


3


-4-Cl—C


6


H


3






1




0




0




Benzthiazol-6-yl






258




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-OH-indol-2-yl






259




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


2


S(O)


2


CH


3


—C


6


H


4








260




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3,4-methylenedioxyphenyl






261




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1-CH


3


-pyrrol-2-yl






262




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-CH


3


-4-NH


2


—C


6


H


3








263




3-CH


3


-4-Cl—C


6


H


3






1




0




0




Isoxazol-5-yl






264




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-OH—C


6


H


4








265




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-OH-indol-3-yl













266




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























267




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























268




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























269




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























270




3-CH


3


-4-Cl—C


6


H


3






1




0




0

























271




2-CH


3


O-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








272




2,6-(CH


3


)


2


-4-Cl—C


6


H


2






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








273




2,3-Cl


2


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








274




2,5-Cl


2


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








275




2-Cl-4-CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








276




2-Cl-5-CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








277




2-CH


3


-4-C(O)CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








278




2-(morpholin-4-yl)-C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








279




3-CH


3


CH


2


-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








280




Naphth-7-yl




1




0




0




3-HC


3


S(O)


2


—C


6


H


4








281




2-tert-butyl-C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








282




Indan-5-yl




1




0




0




3-CH


3


S(O)


2


—C


6


H


4








283




2-cyclohexyl-4-Cl—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








284




2-C(O)NH


2


-4-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








285




2-isoxazol-5-yl-4-Cl—C


6


H


4






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








286




2-CH


3


-5-Cl—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








287




phenyl




1




0




0




3-CH


3


S(O)


2


—C


6


H


4








288




2,4-Cl


2


-6-CH


2


—C


6


H


2






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








289




3-Cl-4-CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








290




2-CN-4-CH


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








291




2-CN-4-CF


3


—C


6


H


3






1




0




0




3-CH


3


S(O)


2


—C


6


H


4








292




2-CH


3


-pyridin-6-yl




1




0




0




3-CH


3


S(O)


2


—C


6


H


4








293




Pyrimidin-2-yl




1




0




0




3-CH


3


S(O)


2


—C


6


H


4








294




2-Cl-4-F—C


6


H


3






1




0




0




2-Cl-4-CH


3


S(O)


2


—C


6


H


3








295




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-CH


3


S(O)


2


—C


6


H


4








296




2-CH


3


-4-Cl—C


6


H


3






1




0




0




2-Cl-4-CH


3


S(O)


2


—C


6


H


3








297




2-CH


3


-4-Cl—C


6


H


3






1




0




0




3-S(O)


2


NH


2


-4-Cl—C


6


H


3















298




2-CH


3


-4-Cl—C


6


H


3






1




0




0

























299




2,4-Cl


2


-3-CH


3


—C


6


H


2






1




0




0




3-S(O)


2


CH


3


—C


6


H


4








300




2-ethyl-4-F—C


6


H


3






1




0




0




3-S(O)


2


CH


3


—C


6


H


4








301




2-CH


3


-4-Cl—C


6


H


3






1




0




0




1H-5-S(O)


2


CH


3


-indol-2-yl













302




2-CH


3


-4-Cl—C


6


H


3






1




0




1

























303




3-CH


3


-4-Cl—C


6


H


3






1




0




1

























304




2,4-Cl


2


-3-CH


3


—C


6


H


2






1




0




0

























305




2,4-Cl


2


-3-CH


3


—C


6


H


2






1




0




0




2-(pyrazol-1-yl)-pyridin-5-yl






306




2,4-Cl


2


-3-CH


3


—C


6


H


2






1




0




0




2-S(O)


2


CH


3


-thien-5-yl






307




2,4-Cl


2


-3-CH


3


—C


6


H


2






1




0




0




4-S(O)


2


CH


3


—C


6


H


4








308




5-CF


3


-pyridin-2-yl




1




0




0




3-S(O)


2


CH


3


—C


6


H


4








309




3,4-Cl


2


—C


6


H


3






1




1




0




phenyl






310




3,4-Cl


2


—C


6


H


3






1




1




0




4-OCH


3


—C


6


H


4








311




3,4-Cl


2


—C


6


H


3






1




1




0




4-F—C


6


H


4








312




3,4-Cl


2


—C


6


H


3






1




1




0




3-SCH


3


—C


6


H


4








313




3,4-Cl


2


—C


6


H


3






1




1




1




phenyl






314




3,4-Cl


2


—C


6


H


3






1




1




1




4-OCH


3


—C


6


H


4








315




3,4-Cl


2


—C


6


H


3






1




1




1




4-F—C


6


H


4
















Examples of compounds of formula (Ig) are listed in Table V below.
















TABLE V











R


1






X




R


3































1




3,4-Cl


2


—C


6


H


3






CH


2






3-S(O)


2


CH


3


—C


6


H


4









2




3,4-Cl


2


—C


6


H


3






NH




3-S(O)


2


CH


3


—C


6


H


4









3




3,4-Cl


2


—C


6


H


3






C(O)




3-S(O)


2


CH


3


—C


6


H


4









4




3,4-Cl


2


—C


6


H


3






S(O)


2






4-S(O)


2


CH


3


—C


6


H


4









5




3,4-Cl


2


—C


6


H


3






S(O)


2






C


6


H


5

















The compounds of formula (I):











wherein:




q, s and t are, independently, 0 or 1;




n and r are, independently, 0, 1, 2, 3, 4 or 5;




m and p are, independently, 0, 1 or 2;




X is CH


2


, C(O), O, S, S(O), S(O)


2


or NR


37


;




Y is NHR


2


or OH;




T is C(O), C(S), S(O)


2


or CH


2


;




R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl;




R


2


and R


47


are, independently, hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl);




R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, CR


3a


R


3b


R


3c


, C


2-4


alkenyl {optionally substituted by aryl or heterocyclyl}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl, aryl or oxo}, C


3-7


cycloalkenyl {optionally substituted by oxo, C


1-6


alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;




R


3a


is hydrogen, C


1-6


alkyl, C


1-6


alkoxy or C


3-7


cycloalkyl; R


3b


is aryl, heterocyclyl, S(O)


2


aryl or S(O)


2


heterocyclyl; and R


3c


is C


1-6


alkyl, C


1-4


haloalkyl, hydroxy, heterocyclyl(C


1-4


alkyl) or aryl;




wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl {itself optionally substituted by halogen, OC(O)C


1-6


alkyl, S(O)


2


R


48


, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, S(O)


2


R


38


or C(O)NR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl), C


3-10


cycloalkyl (itself optionally substituted by C


1-4


alkyl or oxo) or NR


41


C(O)OCH


2


(fluoren-9-yl)}, NR


41


C(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy {itself optionally substituted by halogen, C


1-6


alkoxy, NHCO


2


(C


1-6


alkyl), CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)}, C


1-6


alkylthio, C


1-6


haloalkylthio, C


3-10


cycloalkyl, NR


7


R


8,


NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


d


R


15


, S(O)


2


NR


42


R


43


, NR


44


S(O)


2


R


45


, phenyl {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy, C


1-6


haloalkoxy, phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy, C


1-6


haloalkoxy, phenyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy)}, SCN, CN, SO


3


H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;




d is 0, 1 or 2;




R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl, aryl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy);




R


15


, R


38


, R


45


and R


48


are, independently, C


1-6


alkyl (optionally substituted by halogen, hydroxy or C


3-10


cycloalkyl), C


3-6


alkenyl, aryl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy);




or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof; have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).




In one aspect examples of these conditions are:




(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;




(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behçet's disease, Sjogren's syndrome or systemic sclerosis;




(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;




(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);




(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or




(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.




In another aspect examples of these conditions are:




(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;




(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;




(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;




(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);




(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or




(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.




In a further aspect examples of these conditions are:




(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;




(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;




(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;




(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);




(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or




(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.




The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, are also H1 antagonists and may be used in the treatment of allergic disorders.




The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).




Thus, in a further aspect the present invention provides a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is both a modulator of chemokine receptor (especially CCR3) activity and an H1 antagonist.




According to a further feature of the invention there is provided a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).




According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a pharmaceutically acceptable salt thereof or a solvate thereof.




According to another feature of the present invention there is provided a method for antagonising H1 in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof.




The invention also provides a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.




In another aspect the invention provides the use of a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).




In a further aspect the present invention provides the use of a compound of the formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH


2


, C(O), O, S, S(O), S(O)


2


or NR


37


; Y is NHR


2


or OH; T is C(O), C(S), S(O)


2


or CH


2


; R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl; R


2


and R


47


are, independently, hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl); R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, C


3-7


cycloalkenyl {optionally substituted by oxo, C


1-6


alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, S(O)


2


R


48


, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, S(O)


2


R


38


or C(O)NR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl), C


3-10


cycloalkyl (itself optionally substituted by C


1-4


alkyl or oxo) or NR


41


C(O)OCH


2


(fluoren-9-yl)), NR


41


(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy (itself optionally substituted by halogen, C


1-6


alkoxy, NHCO


2


(C


1-6


alkyl), CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, C


1-6


haloalkylthio, C


3-10


cycloalkyl, NR


7


R


8


, NR


9


C(O)R


10


, CO


2


R


11


, C(O)NR


12


R


13


, C(O)R


14


, S(O)


d


R


15


, S(O)


2


NR


42


R


43


, NR


44


S(O)


2


R


45


, phenyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


or C


1-6


alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), phenoxy (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); R


15


, R


38


, R


45


and R


48


are, independently, C


1-6


alkyl (optionally substituted by halogen, hydroxy or C


3-10


cycloalkyl) or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).




In another aspect the present invention provides the use of a compound of the formula (I′):











wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH


2


, CO, O, S, S(O), S(O)


2


or NR


37


; Y is NHR


2


or OH; T is CO, CS, SO


2


or CH


2


; R


1


is hydrogen, C


1-6


alkyl, aryl or heterocyclyl; R


2


is hydrogen, C


1-6


alkyl, aryl(C


1-4


)alkyl or CO(C


1-6


alkyl); R


3


is C


1-6


alkyl {optionally substituted by halogen, CO


2


R


4


or phthalimide}, C


3-7


cycloalkyl {optionally substituted by C


1-4


alkyl or oxo}, C


3-7


cycloalkenyl {optionally substituted by C


1-6


alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO


2


, oxo, C


1-6


alkyl (itself optionally substituted by halogen, OC(O)C


1-6


alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C


1-6


alkyl, SO


2


R


38


or CONR


39


R


40


), naphthyloxy (itself optionally substituted by halo or C


2-6


alkenyl) or NR


4


C(O)OCH


2


(fluoren-9-yl)), NR


41


C(O)OCH


2


(fluoren-9-yl), C


1-6


alkoxy (itself optionally substituted by halogen, CO


2


R


4


, NR


5


R


6


or phenyl (itself optionally substituted by halogen or NO


2


)), C


1-6


alkylthio, nitro, C


3-7


cycloalkyl, NR


7


R


8


, NR


9


COR


10


, CO


2


R


11


, CONR


12


R


13


, COR


14


, SO


d


R


15


, SO


2


NR


42


R


43


, NR


44


SO


2


R


45


, phenyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


or C


1-6


alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), phenoxy (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy), SCN, CN, SO


3


H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R


4


, R


5


, R


6


, R


7


, R


8


, R


9


, R


10


, R


11


, R


12


, R


13


, R


14


, R


37


, R


39


, R


40


, R


41


, R


42


, R


43


and R


44


are, independently, hydrogen, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); R


15


, R


38


and R


45


are, independently, C


1-6


alkyl or aryl (itself optionally substituted by halo, C


1-6


alkyl, C


1-6


haloalkyl, CN, NO


2


, C


1-6


alkoxy or C


1-6


haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man).




The invention further provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:




(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;




(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;




(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;




(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);




(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or




(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle;




in a warm blooded animal, such as man.




In a further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}.




In a still further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.




The invention also provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection).




The present invention also provides a the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.




The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an H1 mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.




The present invention also provides a method of treating a sign and/or symptom of a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.




In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.




The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.




In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.




Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.




The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.




A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.




In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.




Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg


−1


to 100 mgkg


−1


of the compound, preferably in the range of 0.1 mgkg


−1


to 20 mgkg


−1


of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.




The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically-acceptable salt thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:















(a)














Tablet I




mg/tablet


















Compound X




100







Lactose Ph. Eur.




179







Croscarmellose sodium




12.0







Polyvinylpyrrolidone




6







Magnesium stearate




3.0


























(b)














Tablet II




mg/tablet


















Compound X




50







Lactose Ph. Eur.




229







Croscarmellose sodium




12.0







Polyvinylpyrrolidone




6







Magnesium stearate




3.0


























(c)














Tablet III




mg/tablet


















Compound X




1.0







Lactose Ph.Eur.




92







Croscarmellose sodium




4.0







Polyvinylpyrrolidone




2.0







Magnesium stearate




1.0


























(d)














Capsule




mg/capsule


















Compound X




10







Lactose Ph.Eur.




389







Croscarmellose sodium




100







Magnesium stearate




1.0


























(e)














Injection I




(50 mg/ml)











Compound X




5.0% w/v







Isotonic aqueous solution




to 100%















Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β-cyclodextrin may be used to aid formulation.




The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.




The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:




(i) when given,


1


H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6 (CD


3


SOCD


3


) or CDCl


3


as the solvent unless otherwise stated;




(ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI) or fast atom bombardment (FAB); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion −(M+H)


+


;




(iii) the title and sub-titled compounds of the examples and methods were named using the AUTONOM program from Beilstein informationssysteme GmbH;




(iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Ex-Terra reverse phase silica column; and




(v) the following abbreviations are used:





















RPHPLG




reverse phase HPLC







RT




room temperature







DEAD




diethyl-azodicarboxylate







NMP




N-methylpyrrolidone







CDI




N,N′-carbonyl diimidazole







MTBE




tert-butyl methyl ether







DMF




N,N-dimethylformamide







Boc or BOC




tert-butoxycarbonyl







HPLC




high pressure liquid chromatography







PYBROP ™




bromo-tris-pyrrolidino-phosphonium








hexafluorophosphate







THF




tetrahydrofuran







DCM




dichloromethane







TFA




trifluoroacetic acid







m. pt.




melting point







DMSO




dimethylsulfoxide







Ac




Acetate







aq




aqueous







IPA




iso-propyl alcohol







equiv.




equivalents






















EXAMPLE 1




This Example illustrates the preparation of 4-(3,4-dichlorophenoxy)piperidine.




Step a: tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate




Diethyl azodicarboxylate (41.0 ml) was added to a solution of triphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After 15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) in tetrahydrofuran (400 ml) was added dropwise over 30 min. The solution was stirred at room temperature for 16 hours and concentrated to a small volume. Purification by chromatography (ethyl acetate: iso-hexane 95:5) gave the sub-title compound as an oil (61.3 g).




MS: APCI(+ve): 246 (M-BOC+2H)




Step b: 4-(3,4-Dichlorophenoxy)piperidine




The product from Step a was dissolved in dichloromethane (600 ml) and trifluoroacetic acid (300 ml) was added. After 24 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (36.6 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the title compound as a gum (25 g).






1


H NMR: δ(CDCl


3


) 1.77 (1H, br s), 2.05-2.26 (4H, m), 3.20-3.49 (4H, m), 4.61 (1H, s), 6.69-7.52 (3H, m).




EXAMPLE 2




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate (acetate salt of Compound 281 in Table I).




Step a: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in 1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g) followed by NaBH(OAc)


3


(1.81 g) and acetic acid (0.37 g). After 18 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO


4


and concentrated. Purification by silica chromatography (dichloromethane:methanol 92:8) gave the sub-title product (1.97 g).




MS: APCI(+ve): 429 (M+H)




Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine




The product of Step a was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (15 ml) was added. After 4 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the trifluoroacetate salt of the sub-titled product as a solid (1.15 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the sub-title compound as a solid (0.68 g).






1


H NMR: δ(CDCl


3


) 1.38-1.51 (2H, m), 1.74-2.02 (6H, m), 2.38-2.50 (3H, m), 2.56-2.61 (2H, m), 2.79-2.86 (2H, m), 3.14-3.18 (2H ,m), 4.22-4.28 (1H, m), 6.73-7.32 (3H, m).




Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate




The product of Step b (0.15 g) was dissolved in THF (4 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.235 g), 3-methylsulphonylbenzoic acid (0.091 g) and N,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO


3


solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na


2


SO


4


and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH


4


OAc


aq


(0.1%) to 95% MeCN//NH


4


OAc


aq


(0.1%)) gave the title compound (0.095 g).






1


H NMR: δ( DMSO-D6) 1.44-1.94 (8H, m), 2.37-2.77 (5H, m), 3.07-3.55 (6H, m), 4.40 (1H, m), 4.50-4.53 (1H, m), 6.96-8.02 (7H, m). Melting point: 60-61° C. becomes a gum. Melting point of free base: 154° C.




EXAMPLE 3




This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone acetate (Compound 282 of Table I).




The compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.016 g).






1


H NMR: δ(DMSO-D6) 1.32-2.01 (8H, m), 2.28-2.88 (5H, m), 3.32 (4H, br s), 3.77 (3H, s), 4.13 (2H, br s), 4.39-4.44 (1H, m), 6.59-7.50 (6H, m). Melting point: 171° C. becomes a gum.




EXAMPLE 4




This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)- {3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone (Compound 4 of Table II).




Step a: tert-Butyl 4-(3,4-difluorophenoxy)-1-piperidinecarboxylate




This compound was prepared according to the method of Example 1 Step a using 3,4-difluorophenol to afford the compound as an oil (5.4 g).




MS: ESI(+ve): 213 (M-BOC+H)




Step b: 4-(3,4-Difluorophenoxy)piperidine




This compound was prepared according to the method of Example 1 Step b to afford the compound as a pale yellow oil (3 g).




MS: ESI(+ve): 214 (+H)




Step c: 3-[4-(3,4-Difluoro-phenoxy)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester




The product of Step b (0.5 g) was dissolved in 1,2-dichloroethane (7 ml). tert-Butyl 3-oxo-1-pyrrolidinecarboxylate (0.43 g) was added followed by NaBH(OAc)


3


(0.7 g) and acetic acid (0.08 g). After 24 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO


4


and concentrated. Purification by silica chromatography (100% ethyl acetate) gave the sub-title product (0.79 g).




MS: ESI(+ve): 383 (M+H)




Step d: 3,4-Difluorophenyl 1-(3-pyrrolidinyl)-4-piperidinyl ether




The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10 ml) was added and the reaction stirred for 3 hrs. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na


2


SO


4


and concentrated to give the sub-title product as an oil (0.54 g).






1


H NMR: δ(CDCl


3


) 1.60-2.39 (9H, m), 2.70-3.13 (6H, m), 4.19-4.22 (1H, m), 6.58-7.52 (3H, m).




Step e: (4-Amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone




This compound was prepared by the method of Example 2 Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.151 g).






1


H NMR: δ(CDCl


3


) 1.95-2.43 (5H, m), 2.69-2.81 (3H, m), 3.42-3.91 (10H, m), 4.19-4.23 (1H, m), 6.56-7.25 (6H, m).




Melting point: 138-139° C.




EXAMPLE 5




This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (Compound 1 in Table II).




Step a: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




This compound was prepared by the method of Example 2, Step a using 4-(3,4-difluorophenoxy)piperidine to give the sub-title compound as a solid (0.48 g).




MS: APCI(+ve): 397 (M+H)




Step b: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl




This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.36 g).




MS: APCI(+ve): 297 (M+H)




Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone




This compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.133 g).






1


H NMR: δ(CDCl


3


) 1.50-1.60 (2H, m), 1.85-1.93 (4H, m), 2.04-2.08 (2H, m), 2.58-2.62 (2H, m), 2.69-2.75 (1H, m), 2.86-2.90 (4H, m), 3.86 (3H, s), 3.86 (2H, m), 4.25-4.30 (1H, m), 6.50-6.61 (1H , m), 6.65 (1H, dd), 6.70-6.75 (1H, m), 6.85 (1H, dt), 6.94 (1H, s), 7.01-7.09 (1H, m).




EXAMPLE 6




This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone (Compound 2 in Table II).




Step a: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




This compound was prepared by the method of Example 2, Step a using 3-oxo-piperidine-1-carboxylic acid tert-butyl ester to give the sub-title compound as a solid (0.946 g).




MS: APCI(+ve): 397 (M+H)




Step b: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl




This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.706).




MS: ESI(+ve): 297 (M+H)




Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone




This compound was prepared by the same method as Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.070 g).






1


H NMR: δ(CDCl


3


) 1.41-1.67 (4H, m), 1.73-1.80 (2H, m), 1.86-2.00 (2H, m), 2.44 (3H, m), 3.00-3.13 (2H, m), 2.79-2.91 (2H, m), 3.82 (3H, s), 3.97-4.01 (1H, d), 4.14-4.17 (1H, d), 4.32 (1H, sept), 4.89 (2H, s), 6.67 (1H, d), 6.75-6.79 (1H, m), 6.80 (1H, dd), 6.87 (1H, s), 6.98-7.06 (1H, m), 7.27 (1H, q).




EXAMPLE 7




This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 280 in Table I).




The product of Example 2, Step b (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.134 g dissolved in H


2


O (1.2 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.168 g) and the reaction left to stir for 1 hr. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried with Na


2


SO


4


and concentrated. Purification reverse phase HPLC (with a gradient eluent system (25% MeCN/NH


4


OAc


aq


(0.1%) to 95% MeCN//NH


4


OAc


aq


(0.1%)) gave the title compound as a solid (0.077 g).






1


H NMR: δ(DMSO-D6) 1.45-1.58 (4H, m), 1.79-1.90 (4H, m), 2.28-2.46 (5H, m), 2.66-2.73 (2H, m), 3.67-3.71 (2H, m), 4.35-4.43 (1H, m), 6.93-8.60 (9H, m). Melting point: 139-140° C.




EXAMPLE 8




This Example illustrates the preparation of 4-(3,4-difluoro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 3 in Table II).




This compound was prepared by the method of Example 7 using product of Example 5, step b to give the title compound as a solid (0.095 g).






1


H NMR: δ(CDCl


3


) 1.67-1.80 (4H, m), 1.87-2.01 (1H, t), 2.30 (1H, t), 2.39-2.50 (2H, m), 2.74-2.78 (2H, m), 3.89 (2H, d), 4.16-4.20 (1H, m), 6.56-6.60 (1H, m), 6.67-6.63 (1H, m), 7.03 (1H, q), 7.26 (1H, t), 7.52 (1H, d), 7.53 (1H, d), 7.70 (1H, d), 7.76 (1H, dt), 8.60 (1H, d). Melting point: 128-129° C.




EXAMPLE 9




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone (Compound 293 Table I).




Step 1: Preparation of 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) in tetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g, 0.77 mol). The resultant slurry was stirred for 30 minutes before cooling the reaction mixture with ice/water, acetic acid (47 ml) is then added (exotherm) which caused precipitation. The slurry was allowed to warm to room temperature before the addition of sodium triacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF (500 ml). The resultant slurry was stirred overnight at room temperature. To the reaction mixture was added water (2000 ml) to give a solution. The solution was then extracted with diethyl ether (3×1800 ml). The aqueous phase was basified with 10% aq NaOH (950 ml) and extracted with dichloromethane (DCM) (3×1500 ml). The combined DCM layers are dried (MgSO


4


), filtered and the solvent removed to give the sub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H) 285).




Step 2: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




To a solution of potassium tert-butoxide (139.0 g, 1.24 mol) in THF (500 ml) was added a solution of the product of Step 1 (176.2 g, 0.62 mol) in THF (1000 ml). The reaction mixture was stirred 10 minutes before the additon of 3,4 dichlorofluorobenzene (122.8 g, 0.74 mol), this caused a green colouration that subsequently faded. The reaction mixture was then heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature before the addition of saturated NaHCO


3


(1600 ml). The layers were separated and the organic layer stripped to leave an orange semi-solid. The solid was dissolved in DCM (1500 ml) and dried (MgSO


4


), filtered and the solvent removed. To the resultant solid was added methyl tert-butyl ether (MTBE) (54 ml) and iso-hexane (1000 ml) to give a slurry which was stirred overnight. The slurry was then filtered and washed with isohexane (200 ml) and the solid dried in vacuo at 50° C. to give the sub-titled compound as a pale powder, (211.6 g, 80%; MS: (M+H) 429).




Step 3: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidine




The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (100 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO


4


), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).




Step 4: Preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone




Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (275 ml) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase was dried (MgSO


4


), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).




Melting point 141° C.


1


H NMR: (400 MHz, CDCl


3


) δ1.39-1.63 (1H, m), 1.72-2.04 (6H, m), 2.42-2.68 (2H, m), 2.73-2.92 (3H, m), 3.00-3.08 (1H, m), 3.23 (1H, s), 3.28 (2H, s), 3.34-3.40 (1H, m), 3.46-3.52 (1H, m), 4.21-4.30 (1H, m), 4.62-4.68 (1H, m), 4.80-4.86 (1H, m), 6.72-6.76 (1H, m), 6.97-7.00 (1H, m), 7.28-7.32 (1H, m), 7.32-7.37 (1H, m), 7.56-7.61 (1H, m), 7.64-7.70 (1H, m), 8.05-8.10 (1H, m).




EXAMPLE 10




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 281 Table I).




Oxalyl chloride (30 mls, 0.35 mol) was added dropwise over 10 minutes to a stirred suspension of 3-methanesulfonyl-benzoic acid (6 g, 0.03) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 4 hours at room temperature. The solution was then evaporated under high vacuum to give a solid which was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (100 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (9.3 g, 0.028 mol) and triethylamine (8.4 ml, 0.06 mol) in dichloromethane (100 ml). The resultant solution was stirred at room temperature for 3 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (2×100 ml). The organic phase was dried (MgSO


4


), filterered and the solvent removed to give a pale yellow foam. The foam was dissolved in methanol (100 ml) and allowed to crystallise. The crystals were filtered, washed with methanol and then dried to give the title compound (12.2 g, 84%).




Melting point 157° C.


1


H NMR: (400 MHz, CDCl


3


) δ 1.40-1.65 (2H, m), 1.75-1.85 (3H, m), 1.93-2.03 (3H, m), 2.42-2.51 (2H, m), 2.58 (1H, tt), 2.74-2.91 (3H, m), 3.00-3.14 (1H, m), 3.07 (3H, s), 3.62-3.76 (1H, m), 4.27 (1H, septet), 4.69-4.80 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.31 (1H, d), 7.64 (1H, t), 7.69 (1H, dt), 7.97-7.98 (1H, m), 8.00 (1H, dt).




The hydrochloride salt (melting point 159° C.) was prepared by evaporation to dryness of a clear solution of Compound 281 of Table I and HCl in ethanol.




EXAMPLE 11




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-thiophen-5-yl)-methanone (Compound 332 of Table I).




Oxalyl chloride (32 ml, 0.37 mol) was added dropwise over 10 minutes to a stirred suspension of 5-(methylsulfonyl)-2-thiophenecarboxylic acid (6.64 g, 0.032) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 2 hours at room temperature. The solution was then removed to give a solid which was redissolved in dichloromethane and the solvent again removed to give a yellow solid. The solid acid chloride was dissolved in DCM (150 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (10 g, 0.03 mol) and triethylamine (9 ml, 0.065 mol) in dichloromethane (300 ml). The resultant solution was stirred at room temperature for 2 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (300 ml). The organic phase was dried (MgSO


4


), filterered and the solvent removed to give an orange foam. The solid was dissolved in dichloromethane (200 ml) and purified by chromatography using ethyl acetate and then acetone as the eluant. The purified material was precipitated from acetone by the addition of iso-hexane. The crystals were filtered, washed with isohexane and then dried to give the title compound (11.5 g, 74%).




Melting point: 153-154° C.


1


H NMR (399.98 MHz, DMSO-D6) δ 1.42-1.48 (2H, m), 1.56-1.62 (2H, m), 1.77-1.84 (2H, m), 1.90-1.96 (2H, m), 2.37-2.43 (2H, m), 2.56-2.63 (2H, m), 2.75-2.80 (2H, m), 2.89-3.14 (2H, m), 3.29-3.32 (1H, m), 3.41 (3H, s), 4.41-4.45 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.49 (2H, q), 7.77 (1H, d).




EXAMPLE 12




This Example illustrates the preparation of [4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 1 of Table IV)




A solution of 4-(2-methyl-4-chloro-phenoxy)-piperidine (0.87 mmol) and 1-(3-methanesulfonyl-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at room temperature for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Silica). The product was eluted with DCM/MeOH mixtures and further purified by Reverse Phase preparative chromatography, MeOH/aqueous TFA gradient on a Symmetry column. The free base was isolated by dissolving in EtOAc and washing with sodium bicarbonate solution, drying the organic layer with MgSO


4


and evaporation left the product as a white solid (0.047 g; M.pt. 83-84° C.).






1


H NMR (300 MHz, DMSO-D6) δ 1.2-2.8 (bm, 14H), 2.15 (s, 3H), 3.1 (bm, 1H), 3.25 (s, 3H), 3.5 (bm, 1H), 4.4 (bm, 1H), 4.5(bm, 1H), 7.0 (d, 1H), 7.12 (m, 1H), 7.2 (d, 1H), 7.7 (m, 2H), 7.9 (s, 1H), 8.0 (dd, 1H).




EXAMPLE 13




This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone ditrifluoroacetate (Compound 23 of Table IV).




A solution of the 4-(4-chloro-2-methyl-phenoxy)-piperidine (0.87 mmol) and 1-(4-nitro-3-methoxy-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at RT for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Si). The product was eluted with DCM/MeOH mixtures and further purified by SCX, eluting the product with 10% aq NH


3


in MeOH. The nitro compound was dissolved in THF (10 ml) and hydrogenated over 10% Pd on C at 3 atmospheres in Peteric apparatus. The mixture was filtered and the filtrate evaporated, the residue was then purified by RPHPLC, using a Symmetry column and eluting with MeOH/aqueous TFA mixtures. The product was isolated as the trifluoroacetate by evaporation of the appropriate HPLC fractions (0.046 g; m.pt. 84-85° C.).






1


H NMR (400 MHz, DMSO-D6) δ 1.4-2.4 (m, 13H), 2.9 (m, 2H), 3.15 (m, 2H), 3.4 (m, 1H), 3.55 (m, 2H), 3.8 (s, 3H), 4.2 (bs, 2H), 4.55 and 4.8 (2 bm, 1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.85 (s, 1H), 7.0-7.22 (m, 2H), 7.25 (s, 1H), 9.5 (bm, 1H).




EXAMPLE 14




This Example illustrates the preparation of 2-[1′-(3-methanesulfonyl-benzoyl)-[1,4′]bipiperidinyl-4-yloxy]-5-trifluoromethyl-benzonitrile trifluoroacetate (Compound 291 of Table IV).




The product of Method E (183 mg, 0.5 mmol) was dissolved in DMSO (2 ml) and treated with sodium hydride (22 mg 1 equiv. of 60%) under an inert atmosphere. After stirring the mixture at RT for 1 hour, 2-fluoro-5-trifluoromethyl-benzonitrile (1 equiv.) was added. After stirring at RT for 24 hours, the reaction mixture was acidified (glacial acetic acid) and filtered. The filtrate was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.06 g; m.pt. 110-111° C.).






1


H NMR (400 MHz, DMSO-D6) δ 1.0-3.8 (m, 20 H), 4.5-5.3 (m, 2H), 7.5 (d, 1H), 7.75 (m, 3H), 8.02 (m, 2H).




EXAMPLE 15




This Example illustrates the preparation of (3-methanesulfonyl-phenyl)-[4-(6-methyl-pyridin-2-yloxy)-[1,4′]bipiperidinyl-1′-yl]-methanone trifluoroacetate (Compound 292 of Table IV).




The product of Method E (1 mmol) and potassium tert-butoxide (2 mmol) were stirred together in dry THF (20 ml) at RT. After 10 mins 2-fluoro-6-methyl-pyridine (1 mmol) was added and the reaction mixture stirred at reflux overnight. The reaction mixture was cooled, diluted with water and extracted into ethyl acetate (3×50 ml). The combined extracts were dried (MgSO


4


) and evaporated. The residue was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.03 g; m.pt. 61-62° C.).






1


H NMR (400 MHz, DMSO-D6) δ 1.6-3.8 (m, 15H), 2.4 (s, 3H), 3.3 (s, 3H), 4.5-5.4 (m, 3H), 6.6 (m, 1H), 6.02 (dd, 1H), 7.6 (q, 1H), 7.82 (m, 2H), 7.95 (s, 1H), 8.02 (m, 1H), 9.7 (bs, 1H)




EXAMPLE 16




This Example illustrates the preparation of N-{3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 583 of Table I).




To (3-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.133 g) in pyridine (2 mL) was added methanesulfonyl chloride (0.024 ml) and the reaction left to stir for 5 minutes. The solvent was evaporated, water (0.5 mL) added and the solvent re-evaporated. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH


4


OAc aq (0.1%)) gave the title compound (0.050 g; m.pt. 94-95° C.).






1


H NMR (399.978 MHz, CDCl


3


) δ 1.59-2.09 (8H, m), 2.22 (2H, br s), 2.54-2.60 (1H, m), 2.81 (2H, br s), 3.02 (5H, br s), 3.51-3.75 (1H, br m), 4.25-4.28(1H, m), 4.29 (1H, br s), 6.70-7.52 (8H, m).




EXAMPLE 17




This Example illustrates the preparation of N-{2-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 587 of Table I).




To a solution of (2-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.2 g) in pyridine (2 ml) at 0° C. was added methane sulphonyl chloride (0.039 ml). The mixture was allowed to warm to room temperature and the pyridine removed by evaporation. The residue was azeotroped with water and the product purified by RPHPLC (Symmetry column, eluting 25% to 95% MeCN/0.1% NH


4


OAc aq at 20 ml/min over 6 minutes) to give the product as a colourless solid (0.09 g).






1


H NMR: (399.978 MHz, CDCl


3


) δ 1.49-1.69 (5H, m), 1.77-1.84 (2H, m), 1.87-1.94 (1H, m), 1.95-2.02 (2H, m), 2.43-2.50 (2H, m), 2.59 (1H, tt), 2.78-2.84 (2H, m), 2.87-3.03 (1H, m), 3.08 (3H, s), 3.17 (1H, sextet), 4.27 (1H, septet), 6.75 (1H, dd), 6.99 (1H, d), 7.15 (1H, td), 7.24 (1H, d), 7.31 (1H, d), 7.43 (1H, td), 7.62 (1H, d).




EXAMPLE 18




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(1-methanesulfonyl-1H-indol-3-yl)-methanone hydrochloride (Compound 592 of Table I).




To a solution of Compound 471 of Table I (0.17 g) in dimethylformamide (3 ml) at 0° C. under an atmosphere of nitrogen, was added sodium hydride (0.014 g of a 60% suspension in oil). The mixture was stirred for 5 minutes then methanesulphonyl chloride (0.027 ml in 1 ml of dimethylformamide) was added and then mixture allowed to warm to room temperature over 12 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO


4


) and the solvent removed by evaporation. The residue was purified by RPHPLC (Symmetry, 25% to 95% MeCN/0.1% NH


4


OAc aq over 6 minutes, 20 ml/min, 220 nm) to give a colourless solid (0.062 g; m.pt. 173-175° C.).






1


H NMR: (299.944 MHz DMSO-D6) δ 1.72-1.87 (2H, m), 2.01-2.34 (5H, m), 2.48-2.55 (1H, m), 2.98-3.13 (2H, m), 3.13-3.27 (2H, m), 3.39-3.47 (2H, m), 3.53-3.62 (2H, m), 3.64 (3H, s), 4.35-4.58 (1H, m), 4.65-4.76 (1H, m), 7.12 (1H, dd), 7.39-7.48 (2H, m), 7.52 (1H, t), 7.61 (1H, t), 7.79 (1H, d), 7.88 (1H, s), 7.95 (1H, d).




EXAMPLE 19




This Example illustrates the preparation of 1-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-2-phenyl-3-piperazin-1-yl-propan-1-one (Compound 595 of Table I).




Compound 575 of Table I (0.178 g) was treated with 6N hydrochloric acid (5 ml) and stirred at room temperature for 24 hours. 2N Sodium hydroxide solution was added and the reaction mixture extracted with ethyl acetate. The organic extracts were combined, washed with water, dried (MgSO


4


) and evaporated to give a white solid. Purification was by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)). (Any excess NH


4


OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO


3


followed by drying of the organics with MgSO


4


and evaporation of solvent.) The title compound was a white solid (0.087 g).






1


H NMR (399.98 MHz, DMSO-D6) δ 1.20-1.95 (9H, m), 2.10-2.53 (9H, m), 2.59-2.65 (2H, m), 2.70-2.77 (1H, m), 2.89-3.12 (4H, m), 4.02-4.47 (4H, m), 6.89-7.00 (1H, m), 7.16-7.32 (6H, m), 7.44-7.52 (1H, m).




EXAMPLE 20




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-1-oxy-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone.




The product Example 10 (0.100 g) in dichloromethane (5 ml) was treated with m-chloroperbenzoic acid (0.043 g) and the reaction stirred at room temperature for 0.5 hours. Saturated aqueous sodium hydrogencarbonate was added and the reaction mixture extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO


4


) and evaporated to give a brown foam. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH


4


OAc aq (0.1%)) gave the title compound as a white solid (0.021 g).






1


H NMR (299.946 MHz, DMSO-D6) δ 1.70-2.91 (15H, m), 3.24-3.44 (3H, m), 3.55-3.68 (1H, m), 4.55-4.76 (2H, m), 6.99-7.06 (1H, m), 7.29-7.33 (1H, m), 7.53 (1H, dd), 7.71-7.79 (2H, m), 7.93 (1H, s), 7.99-8.05 (1H, m).




EXAMPLE 21




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 1 of Table I).




To a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.1 g, see step b of Example 2) in dichloromethane (5 ml) and triethylamine (0.2 ml) was added benzoyl chloride (0.045 ml) and the reaction mixture was stirred for 2 hours. The mixture was washed with water, dried (MgSO


4


), filtered and the solvents evaporated to leave a gum. Purification by RPHPLC [with an eluent system (50% MeCN/0.1% NH


4


OAc aq), any excess NH


4


OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO


3


followed by drying of the organics with MgSO


4


and evaporation of solvent] and trituration of the resulting product with diethyl ether gave a solid which was filtered and dried to give the title compound (0.120 g; m.pt. 122° C.).






1


H NMR (299.944 MHz CDCl


3


) δ 1.42-1.62 (2H, m), 1.78-1.82 (3H, m), 1.95-2.01 (3H, m), 2.39-2.69 (3H, m), 2.69-3.09 (4H, m), 3.63-3.95 (1H, m), 4.24-4.29 (1H, m), 4.62-4.89 (1H, m), 6.73-6.77 (1H, m), 6.99 (1H, d), 7.26-7.29 (1H, m), 7.39 (5H, s).




EXAMPLE 22




This Example illustrates the preparation of [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone (Compound 4 of Table V).




Step 1: 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester




4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO


4


) and evaporated to give the sub-title compound (14.58 g).






1


H NMR (299.944 MHz, CDCl


3


) δ 1.45 (9H, s), 1.49-1.62 (2H, m), 1.87-1.96 (2H, m), 2.89-2.98 (2H, m), 3.16-3.26 (1H, m), 3.91-4.01 (2H, m), 7.21-7.57 (3H, m).




Step 2: 4-(3,4-dichloro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester




The product from Step 1(1 g) and m-chloroperbenzoic acid (1.19 g) were stirred at ambient temperature in dichloromethane (10 ml) for 18 hours. Sodium metabisulphite (1.19 g) in water (5 ml) was added and stirring was continued for 0.5 hours after which the reaction mixture was extracted with dichloromethane. The combined organics were washed with saturated sodium bicarbonate solution, dried (MgSO


4


) and evaporated to give the sub-title compound (0.34 g).






1


H NMR (399.978 MHz, CDCl


3


) δ 1.45 (9H, s), 1.56-1.65 (2H, m), 1.94-2.00 (2H, m), 2.62-2.70 (2H, m), 3.01-3.09 (1H, m), 4.21-4.30 (2H, m), 7.66-7.70 (2H, m), 7.93-7.98 (1H, m).




Step 3: 4-(3,4-dichloro-benzenesulfonyl)-piperidine




The product of step 2 was deprotected following the procedure of Example 1 step b.


1


H NMR (299.944 MHz, CDCl


3


) δ 1.64-1.71 (2H, m), 1.96-2.05 (2H, m), 2.55-2.64 (2H, m), 2.99-3.10 (1H, m), 3.19-3.27 (2H, m), 7.66-7.71 (2H, m), 7.92-7.98 (1H, m).




Step 4: 4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1- carboxylic acid tert-butyl ester following the procedure of Example 2 step a.




Step 5: 4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl




The product of step 4 was deprotected following the procedure of Example 2 step b.


1


H NMR (299.946 MHz, DMSO-D6) δ 1.22-1.61 (7H, m), 1.77-1.83 (2H, m), 2.09-2.16 (1H, m), 2.25-2.45 (3H, m), 2.87-2.98 (4H, m), 3.35-3.43 (1H, m), 7.81 (1H, dd), 7.96 (1H, d), 8.05 (1H, d)




Step 6: [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone




The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.




1H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.62 (5H, m), 1.70-1.85 (4H, m), 2.13 (3H, t), 2.72-3.04 (4H, m), 3.27 (3H, s), 3.37-3.48 (1H, m), 4.44-4.52 (1H, m), 7.63 (2H, d), 7.81 (1H, dd), 7.95-8.00 (3H, m), 8.06 (1H, d).




[4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 5 of Table V). The product of step 5 was coupled to benzoic acid following the procedure of Example 2 step c.


1


H NMR (299.946 MHz, DMSO-D6) δ 1.31-1.69 (5H, m), 1.82 (3H, d), 2.15 (2H, d), 2.69-2.75 (1H, m), 2.90-2.97 (4H, m), 3.33-3.43 (1H, m), 3.48-3.63 (1H, m), 4.42-4.53 (1H, m), 7.39 (5H, dt), 7.81 (1H, dd), 7.96 (1H, d), 8.06 (1H, d).




EXAMPLE 23




This Example illustrates the preparation of 3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-1-ethyl-7-methyl-1H-[1,8]naphthyridin-4-one (Compound 534 of Table I).




4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.155 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO


3


solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO


4


and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH


4


OAc aq (0.1%)) %)) (any excess NH


4


OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO


3


followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.184 g; m.pt. 189-190° C.)




MS: APCI


+


(M+H) 543


1


H NMR (299.946 MHz, DMSO-D6) δ 1.37 (3H, t), 1.47-1.69 (5H, m), 1.78-1.84 (1H, m), 1.89-1.97 (2H, m), 2.36-2.41 (2H, m), 2.49-2.56 (1H, m), 2.66 (3H, s), 2.70-2.79 (3H, m), 2.95-3.04 (1H, m), 3.52-3.59 (1H, m), 4.38-4.57 (4H, m), 6.95-6.99 (1H, m), 7.22-7.24 (1H, m), 7.35-7.40 (1H, m), 7.46-7.51 (1H, m), 8.37 (1H, s), 8.43-8.45 (1H, m).




EXAMPLE 24




This Example illustrates the preparation of 4-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-2H-isoquinolin-1-one (Compound 572 of Table I).




4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO


3


solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO


4


and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH


4


OAc aq (0.1%))) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO


3


followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.153 g).




MS: APCI


+


(M+H) 500


1


H NMR (299.944 MHz CDCl


3


) δ 1.37-1.66 (2H, m), 1.73-1.88 (3H, m), 1.93-2.05 (3H, m), 2.41-2.51 (2H, m), 2.52-2.63 (1H, m), 2.75-2.86 (2H, m), 2.86-3.09 (2H, m), 3.71-3.90 (1H, m), 4.23-4.32 (1H, m), 4.77-4.93 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.27-7.32 (3H, m), 7.54-7.67 (1H, m), 7.57 (1H, t), 7.74 (1H, t), 8.46 (1H, d).




EXAMPLE 25




This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone (Compound 579 of Table I).




Step a: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester




To a solution of 2-amino-5-fluoropyridine (1.12 g) in diethyl ether (25 ml) was added ethyl bromopyruvate (1.25 ml). the mixture was stirred for 1 hour. The resultant solid was filtered off, suspended in ethanol and heated at reflux for 4 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate solution (100 ml). The organic layer was separated, dried, (magnesium sulfate) and the solvent removed by evaporation. The residue was purified by flash chromatography (silica) eluting with ethyl acetate: hexane (3:1) to give the sub-title compound as a colourless solid (1.12 g).




MS: ES


+


(M+H) 209


1


H NMR (399.98 MHz, CDCl


3


) δ 1.44 (3H, t), 4.46 (2H, q), 7.19 (1H, ddd), 7.68 (1H, dd), 8.07-8.09 (1H, m), 8.19 (1H, s).




Step b: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid




A solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1 g) in 4N HCl was refluxed for 4 hours. The solvent was evaporated to give the sub-title compound as a white solid (0.86 g).




MS: ES


+


(M+H) 181


1


H NMR (399.98 MHz, DMSO-D6) δ 7.81-7.89 (2H, m), 8.71 (1H, s), 9.03 (1H, s).




Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone




4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO


3


solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO


4


and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH


4


OAc aq (0.1%) to 95% MeCN//NH


4


OAc aq (0.1%)) (any excess NH


4


OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO


3


followed by drying of the organics with magnesium sulfate and evaporation of solvent) gave the title compound (0.104 g).




MS: APCI


+


(M+H) 491


1


H NMR (399.978 MHz, CDCl


3


) δ 1.61 (1H, qd), 1.75-2.02 (7H, m), 2.42-2.51 (2H, m), 2.59-2.67 (1H, m), 2.75-2.86 (3H, m), 3.12-3.21 (1H, m), 4.23-4.29 (1H, m), 4.76-4.85 (1H, m), 5.23-5.32 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.16 (1H, ddd), 7.30 (1H, d), 7.58 (1H, dd), 8.07 (2H, s).




EXAMPLE 26




This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid phenylamide (Compound 309 of Table IV).




Phenylisocyanate(0.078 ml) was added to a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see Example 2 step b) in dichloromethane (5 ml). The mixture was stirred at 23° C. for 16 hours. The resulting precipitate was filtered, washed with dichloromethane (2×5 ml) then crystallised from acetonitrile to afford the title compound as a solid (0.2 g; melting point 215-216° C.).






1


H NMR (DMSO-D6) δ 1.35 (2H, qd), 1.53-1.62 (2H, m), 1.72-1.78 (2H, m), 1.89-1.96 (2H, m), 2.36-2.42 (2H, m), 2.44-2.52 (1H, m), 2.72-2.78 (4H, m), 4.15 (2H, d), 4.39-4.45 (1H, m), 6.91 (1H, tt), 6.98 (1H, dd), 7.19-7.23 (2H, m), 7.25 (1H, d), 7.43-7.46 (2H, m), 7.49 (1H, d), 8.46 (1H, s).




4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbothioic acid phenylamide was prepared using the methodology of Example 26 and employing phenylisothiocyanate, (melting point 162-163° C.).


1


H NMR: (DMSO-d6) δ 1.39-1.49 (2H, m), 1.53-1.62 (2H, m), 1.79 (2H, d), 1.89-1.96 (2H, m), 2.39 (2H, t), 2.54-2.63 (1H, m), 2.73-2.80 (2H, m), 3.04 (2H, t), 4.39-4.46 (1H, m), 4.72 (2H, d), 6.98 (1H, dd), 7.06-7.10 (1H, m), 7.23-7.30 (5H, m), 7.49 (1H, d), 9.24 (1H, s).




EXAMPLE 27




This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid (3-methanesulfonyl-phenyl)-amide (Compound 54 of Table IV).




Hydrogen peroxide (100 μl, 30%) was added to a cooled (0° C.) solution of Compound 312 of Table IV (0.13 g) in trifluoroacetic acid (1 ml). The mixture was allowed to reach ambient temperature and stirred for a further 1 hour. The solution was quenched with water(5 ml), basified to pH11 with 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solution was separated, washed with water(2×5 ml), dried (MgSO


4


), filtered and the filtrate evaporated to leave a gum. The gum was dissolved in acetonitrile and purified by RPHPLC (Nova Pak column) eluting with acetonitrile/0.1% ammonium acetate aq (1:1). The required fractions were evaporated and then lyophilised to give the title compund as a colourless powder (0.03 g).






1


H NMR (DMSO-D6) δ 1.31-1.42 (2H, m), 1.53-1.62 (2H, m), 1.77 (2H, d), 1.89-1.96 (2H, m), 2.36-2.43 (3H, m), 2.74-2.82 (4H, m), 3.16 (3H, s), 4.18 (2H, d), 4.42 (1H, septet), 6.98 (1H, dd), 7.25 (1H, d), 7.44-7.52 (3H, m), 7.80-7.83 (1H, m), 8.09 (1H, t), 8.90 (1H, s).




Selected proton NMR data and/or melting point data are provided for certain further compounds in Tables VI and VII below.













TABLE VI









Com-







pound






(Table






no.)




NMR data











 3 (I)




δ(D


2


O) 1.97-1.69(2H, m), 2.21-2.08(2H, m), 2.51-2.23(4H,







m), 3.07-2.96(1H, m), 3.31 -3.17(2H, m), 3.45 -3.32(2H, m),







3.56-3.45(1H, m), 3.75-3.56(2H, m), 4.88-4.70(3H, m),







7.07-7.02(1H, m), 7.36-7.30(1H, m), 7.46-7.37(1H, m),







7.55(2H, d), 7.74-7.72(1H, m)






 8 (I)




δ(CDCl


3


) 1.67-1.41(2H, m), 1.86-1.76(3H, m), 2.04-1.93(3H,







m), 2.51-2.42(3H, m), 2.62-2.56(1H, m), 2.88-2.76(3H, m),







3.06(1H, t), 3.66(1H, d), 4.28(1H, septet), 4.76(1H, d), 6.75(1H,







dd), 6.99(1H, d), 7.31(1H, d), 7.56(2H, d), 8.28(2H, d)






 18 (I)




δ(CD


3


OD) 1.59-1.41(2H, m), 1.83-1.68(2H, m), 2.08-1.93(4H,







m), 2.56-2.48(4H, m), 2.68-2.61(1H, m), 2.91-2.80(3H, m),







3.15-3.02 (1H, m), 3.71-3.57(1H, m), 4.23-4.14(1H, m),







4.40(1H, septet), 4.50 (3H, s), 4.75-4.57(1H, m), 6.91(1H, dd),







7.12(1H, d), 7.40(1H, d), 7.66(2H, d), 8.04(2H, d)






 36 (I)




δ(CD


3


OD) 1.62-1.42(2H, m), 1.94-1.72(3H, m), 2.11-1.98(3H,







m), 2.61-2.52(2H, m), 2.95-2.82(3H, m), 3.15(1H, t),







3.68-3.63(1H, m), 4.42(1H, septet), 4.71-4.67(2H, m),







6.91(1H, dd), 7.11(1H, d), 7.40(1H, d), 7.60(2H, d), 7.86(2H, d)






 37 (I)




δ(CD


3


OD) 2.06-1.76(3H, m), 2.45-2.12(5H, m), 3.05-2.88(1H,







m), 3.42-3.25(3H, m), 3.71-3.50(2H, m), 3.93-3.74(1H,







m), 4.63(1H, septet), 4.94-4.82(2H, m), 7.03-6.95(1H, m),







7.24(1H, dd), 7.47-7.42(1H, m), 7.71-7.66(1H, m), 7.78(1H,







td), 7.90-7.86(2H, m)






149 (I)




δ(CDCl


3


) 1.50-1.27(2H, m), 1.90-1.75(5H, m), 2.02-1.92(2H,







m), 2.56-2.39(4H, m), 2.63(1H, t), 2.81-2.72(2H, m),







3.09-3.01(3H, m), 3.82(2H, s), 3.91(1H, d), 4.25(1H, septet),







4.67(1H, d), 6.75(1H, dd), 6.99(1H, d), 7.31(1H, dd), 7.45(2H,







d), 7.90(2H, d)






203 (I)




δ(DMSO-D6) 1.61-1.44(2H, m), 2.24-2.01(4H, m),







2.61-2.53(2H, m), 3.16-2.99(2H, m), 3.60-3.30(5H, m),







3.67(2H, s), 3.77(3H, s), 4.13(1H, d), 4.53(1H, d),







4.69-4.60(1H, m), 7.05(1H, ddd), 7.14(1H, d), 7.42-7.25(3H,







m), 7.55(2H, dd), 10.98-10.78(3H, m)






205 (I)




δ((CD


3


)


2


CO) 1.26(2H, quintet), 1.76-1.58(4H, m),







1.98-1.90(2H, m), 2.42-2.35(2H, m), 2.58-2.45(2H, m),







2.81-2.71(2H, m), 3.00(1H, t), 3.70(2H, s), 4.00(1H, d),







4.39(2H, septet), 4.51(1H, d), 6.92(1H, dd), 7.07-7.01(2H, m),







7.13(1H, d), 7.30-7.25(2H, m), 7.40(1H, d)






220 (I)




δ(DMSO-D6) 1.58-1.44(2H, m), 2.28-1.97(5H, m),







2.59-2.53(2H, m), 3.18-2.93(3H, m), 3.34-3.25(1H, m),







3.51-3.36(2H, m), 3.66-3.56(2H, m), 4.11(1H, d),







4.53(1H, d), 4.64(1H, septet), 6.92-6.82(2H, m), 6.99(1H, d),







7.10-7.03(1H, m), 7.36(1H, dd), 7.55(1H, ddd),







10.99-10.87(1H, m)






225 (I)




δ((CD


3


)


2


CO) 1.71-1.51(2H, m), 2.13-2.08(2H, m),







2.40-2.21(3H, m), 2.61-2.54(1H, m), 3.05(1H, t),







3.55-3.15(6H, m), 3.69-3.61(2H, m), 4.16(1H, d),







4.76-4.63(2H, m), 4.91-4.86(1H, m), 6.78-6.76(2H, m),







7.12-7.02(3H, m), 7.32(1H, dd), 7.51(1H, dd)






244 (I)




δ(DMSO-D6) 1.55-1.42(2H, m), 2.25-1.96(6H, m),







2.66-2.54(2H, m), 3.14-2.96(2H, m), 3.32-3.26(1H, m),







3.51-3.35(2H, m), 3.62(3H, s), 3.71-3.64(2H, m), 3.74(6H,







s), 4.14(1H, d), 4.54(1H, d), 4.66 4.58(1H, m), 6.53(2H, s),







7.04(1H, dd), 7.35(1H, d), 7.54(1H, tt)






253 (I)




δ(CDCl


3


) 1.47-1.19(2H, m), 2.00-1.76(6H, m), 2.62-2.37(4H,







m), 2.80-2.70(2H, m), 2.98(1H, t), 3.65(2H, s), 3.88(3H, s),







3.92-3.89(1H, m), 4.25(1H, septet), 4.68(1H, d),







6.77-6.72(1H, m), 6.89(1H, d), 6.94-6.92(2H, m),







7.01-6.96(2H, m), 7.30(1H, dd)






258 (I)




δ(DMSO-D6) 1.40-1.26(3H, m), 1.78-1.59(5H, m),







1.98-1.92(1H, m), 2.17(3H, s), 2.21(3H, s), 2.45-2.37(2H, m),







2.60-2.48(3H, m), 3.01(1H, t), 3.70-3.57(2H, m), 3.89(1H, d),







4.39(1H, septet), 4.55(1H, d), 7.00(1H, d), 7.13(1H, d),







7.41(1H, d), 7.95-7.89(3H, m)






267 (I)




δ(CDCl


3


) 1.74-1.61(2H, m), 2.21-2.09(3H, m), 2.32-2.25(1H,







m), 2.48(1H, t), 2.67-2.53(2H, m), 2.89(1H, t),







3.31-3.05(5H, m), 3.71(4H, s), 3.82(2H, s), 4.08(1H, d),







4.59-4.53(1H, m), 4.94(1H, d), 6.89 (1H, dd), 6.93(1H, dd),







6.97(1H, d), 7.34(1H, d), 7.40(1H, d), 7.58-7.54(1H, m),






268 (I)




δ(CDCl


3


) 1.24(1H, dq), 1.41(1H, dq), 1.88-1.72(4H, m),







2.00-1.91(2H, m), 2.53-2.37(3H, m), 2.59(1H, dt),







2.78-2.70(2H, m), 2.98(1H, t), 3.73(2H, s), 3.89(1H, d),







4.24(1H, septet), 4.68(1H, d), 6.74(1H, dd), 7.03-6.91(4H, m),







7.29-7.25(1H, m), 7.30(1H, d)






272 (I)




δ(CDCl


3


) 1.18(1H, dq), 1.40(1H, dq), 1.86-1.68(4H, m),







2.00-1.91(2H, m), 2.43-2.35(2H, m), 2.48(1H, td),







2.57(1H, dt), 2.77-2.68(2H, m), 2.95(1H, dt), 3.74(2H, s),







3.91(1H, d), 4.23(1H, septet), 4.69(1H, d), 6.74(1H, dd),







6.98(1H, d), 7.35-7.23(6H, m)






274 (I)




δ(DMSO-D6) 1.74-1.59(5H, m), 1.77(3H, dq), 2.65-2.36(4H,







m), 2.86-2.74(6H, m), 2.95(1H, t), 3.74(3H, s), 3.93(1H, d),







4.40(1H, septet), 4.53(1H, d), 6.73-6.70(1H, m),







6.80-6.78(2H, m), 6.93(1H, dd), 7.18-7.13(2H, m),







7.41(1H, d)






276 (I)




δ((CD


3


)


2


CO) 1.63-1.51(2H, m), 2.02-1.98(2H, m),







2.21-2.15(2H, m), 2.58-2.31(4H, m), 2.96(1H, t),







3.40-3.03(4H, m), 3.60-3.49(2H, m), 3.72(3H, s),







4.02(1H, d), 4.63-4.55(1H, m), 4.77-4.72(1H, m),







6.76(1H, t), 6.84(1H, d), 6.96-6.93(1H, m), 7.03(1H, d),







7.11-7.07(1H, m), 7.16-7.15(1H, m), 7.37-7.31(1H, m)






286 (I)




δ(CD


3


OD) 1.90-1.63(2H, m), 2.49-2.05(6H, m),







3.28-2.87(7H, m), 3.84-3.44(5H, m), 4.69-4.56(1H, m),







4.85-4.78(2H, m), 7.04-6.94(1H, m), 7.28-7.21(1H, m),







7.45(1H, t), 7.60-7.55(3H, m), 7.64-7.61(1H, m),







7.66(1H, t), 7.77-7.73(2H, m), 7.85-7.81(2H, m)






291 (I)




δ(CD


3


OD) 1.98-1.71(3H, m), 2.46-2.11(5H, m),







3.18-2.98(1H, m), 3.45-3.26(2H, m), 3.70-3.46(4H, m),







3.86(3H, s), 4.66-4.56(1H, m), 4.84-4.80(2H, m),







7.04-6.94(3H, m), 7.27-7.20(1H, m), 7.47-7.42(3H, m)






293 (I)




δ(CD


3


OD) 1.88-1.73(2H, m), 2.22-1.92(5H, m), 2.31(1H,







d), 2.87-2.79(1H, m), 3.06-2.97(1H, m), 3.17(3H, s),







3.57-3.31(5H, m), 4.55-4.44(1H, m), 4.73-4.65(2H, m),







6.92-6.82(1H, m), 7.12(1H, td), 7.40-7.31(2H, m), 7.63(1H,







dt), 7.75-7.68(1H, m), 7.99(1H, dt)






294 (I)




δ(CD


3


OD) 1.98-1.70(2H, m), 2.45-2.08(6H, m), 2.97(1H,







t), 3.21(3H, s), 3.41-3.21(3H, m), 3.72-3.49(3H, m),







4.67-4.56(1H, m), 4.95-4.81(2H, m), 7.03-6.94(1H, m),







7.27-7.20(1H, m), 7.47-7.42(1H, m), 7.74-7.62(1H, m),







8.02(1H, ddd), 8.13(1H, dd)






295 (I)




δ(CD


3


OD) 2.04-1.74(3H, m), 2.36-2.12(4H, m),







2.48-2.40(1H, m), 3.03-2.87(1H, m), 3.43-3.15(3H, m),







3.80-3.47(3H, m), 4.68-4.58(1H, m), 4.85-4.80(2H, m),







5.13(2H, s), 7.03-6.96(1H, m), 7.27-7.21(1H, m),







7.46-7.42(1H, m), 7.63-7.56(3H, m), 7.79-7.69(4H, m),







8.12(1H, d)






296 (I)




δ(CD


3


OD) 2.46-1.75(8H, m), 2.96(1H, t), 3.32(2H, s),







3.72-3.19(4H, m), 3.97-3.92(1H, m), 4.69-4.56(1H, m),







4.98-4.79(2H, m), 7.03-6.94(1H, m), 7.24(1H, d),







7.69-7.35(10H, m)






297 (I)




δ(CD


3


OD) 1.66-1.51(2H, m), 1.89-1.69(3H, m),







2.08-1.96(3H, m), 2.71-2.50(3H, m), 3.01-2.81(3H, m),







3.24-3.10(1H, m), 3.84-3.71(1H, m), 4.46-4.38(1H, m),







4.79-4.67(1H, m), 6.92(1H, dd), 7.14(1H, d), 7.41(1H, d),







7.81(1H, dd), 8.39(1H, d), 8.71(1H, s)






298 (I)




δ(CD


3


OD) 1.33(3H, t), 1.62-1.41(2H, m), 1.95-1.74(3H, m),







2.11-1.98(3H, m), 2.73-2.52(3H, m), 2.95-2.79(3H, m),







3.03(2H, q), 3.26-3.09(1H, m), 3.93-3.78(1H, m),







4.48-4.39(1H, m), 4.78-4.56(1H, m), 6.91(1H, dd),







7.11(1H, d), 7.42-7.34(5H, m)






299 (I)




δ(CD


3


OD) 1.99-1.72(3H, m), 2.36-2.11(4H, m), 2.44(1H, d),







3.06-2.87(1H, m), 3.42-3.23(2H, m), 3.71-3.46(4H, m),







3.95-3.77(1H, m), 4.67-4.55(1H, m), 4.84-4.80(1H, m),







7.03-6.94(1H, m), 7.27-7.20(1H, m), 7.47-7.43(1H, m),







7.66-7.61(2H, m), 7.87-7.81(2H, m)






300 (I)




δ(CD


3


OD) 1.96-1.72(3H, m), 2.33-2.09(4H, m),







2.46-2.41(1H, m), 3.02-2.87(1H, m), 3.43-3.22(3H, m),







3.72-3.47(3H, m), 3.93-3.78(1H, m), 4.66-4.56(1H, m),







4.84-4.80(1H, m), 7.03-6.94(1H, m), 7.28-7.21(1H, m),







7.47-7.43(1H, m), 7.59(2H, d), 7.83(2H, d)






301 (I)




(500.076MHz, DMSO-D6) δ 1.33-1.44(m, 2H), 1.55-1.60(m,







2H), 1.66-1.73(m, 1H), 1.78-1.86(m, 1H), 1.91(s, 3H),







1.91-1.96(m, 2H), 2.05(s, 3H), 2.39(t, 2H), 2.55(t, 1H),







2.74-2.79(m, 3H), 2.94-3.04(m, 1H), 3.56-3.66(m, 1H),







4.42(septet, 1H), 4.45-4.52(m, 1H), 6.98(dd, 2H), 7.02(d, 2H),







7.25(d, 1H), 7.35(t, 1H), 7.49(d, 1H), 7.58(d, 1H), 7.66(s, 1H)






302 (I)




(500.076MHz, DMSO-D6) δ 1.36(dq, 2H), 1.54-1.60(m, 2H),







1.72-1.75(m, 2H), 1.91(s, 3H), 1.91-1.95(m, 2H), 2.05(s, 3H),







2.39(t, 2H), 2.74-2.78(m, 2H), 2.80-2.87(m, 1H),







4.05-4.19(m, 2H), 4.42(septet, 1H), 5.22(s, 2H), 6.58(d, 1H),







6.97-6.99(m, 2H), 7.00(s,1H), 7.25(d, 1H), 7.49(d, 1H)






303 (I)




(500.076MHz, DMSO-D6) δ 1.54-1.63(m, 4H), 1.69-1.82(m,







4H), 1.91-1.96(m, 2H), 1.91(s, 3H), 2.35-2.44(m, 2H),







2.73-3.04(m, 7H), 4.39-4.46(m, 2H), 6.48-6.49(m, 1H),







6.98(d, 1H), 7.02-7.07(m, 3H), 7.26(s, 1H), 7.34(t, 1H),







7.49(d, 1H), 7.62(d, 1H)






304 (I)




(500.076MHz, DMSO-D6) δ 1.33(t, 3H), 1.36-1.43(m, 2H),







1.54-1.60(m, 2H), 1.70-1.80(m, 2H), 1.91-1.96(m, 2H),







1.91(s, 3H), 2.39(t, 2H), 2.51-2.55(m, 1H), 2.74-2.79(m,







2H), 3.79(s, 3H), 4.01-4.05(m, 1H), 4.02(q, 2H), 4.42(septet,







1H), 4.47-4.53(m, 1H), 6.94(s, 2H), 6.97-6.99(m, 2H), 7.25(d,







1H), 7.49(d, 1H)






305 (I)




(500.076MHz, DMSO-D6) δ 1.37-1.46(m, 2H), 1.54-1.61(m,







2H), 1.67-1.83(m, 2H), 1.91-1.96(m, 2H), 1.91(s, 3H),







2.40(t, 2H), 2.53-2.58(m, 1H), 2.74-2.80(m, 2H),







2.99-3.10(m, 1H), 3.63-3.74(m, 1H), 4.42(septet, 1H),







4.46-4.54(m, 1H), 6.29-6.30(m, 1H), 6.98(dd, 1H), 7.25(d,







1H), 7.43-7.44(m, 1H), 7.48(t, 3H), 7.64(d, 2H)






306 (I)




(500.076MHz, DMSO-D6) δ 1.22-1.40(m, 2H), 1.54-1.61(m,







2H), 1.75(t, 2H), 1.91-1.96(m, 2H), 2.38(t, 2H),







2.53-2.60(m, 1H), 2.71-2.77(m, 2H), 3.03(t, 1H), 3.79(s,







2H), 3.98-4.03(m, 1H), 4.36-4.40(m, 1H), 4.40-4.45(m,







1H), 6.98(dd, 1H), 7.25(d, 1H), 7.50(d, 1H), 8.34(s, 1H),







8.40(s, 1H), 8.57(d, 1H)






307 (I)




(500.076MHz, DMSO-D6) δ 1.17-1.31(m, 2H), 1.53-1.59(m,







2H), 1.69(t, 2H), 1.88-1.94(m, 2H), 2.35(t, 2H),







2.45-2.52(m, 1H), 2.68-2.74(m, 2H), 2.95(t,1H), 3.50(s,







2H), 3.59(s, 3H), 4.06-4.10(m, 1H), 4.36-4.43(m, 2H),







6.88(s, 1H), 6.97(dd, 1H), 7.25(d, 1H), 7.45(s, 1H), 7.49(d, 1H)






308 (I)




(500.076 MHz, DMSO-D6) δ 1.03(dq, 1H), 1.18(dq, 1H),







1.49-1.58(m, 3H), 1.68(d, 1H), 1.83-1.90(m, 2H), 1.91(s, 3H),







2.23-2.30(m, 2H), 2.41-2.49(m, 3H), 2.57-2.67(m, 2H),







2.90(t, 1H), 3.66(q, 2H), 4.01(d, 1H), 4.38(septet, 1H), 4.43(d,







1H), 6.58(dd, 1H), 6.88(d, 1H), 6.96(dd, 1H), 7.07(d, 1H),







7.12(d, 1H), 7.23(d, 1H), 7.49(d, 1H), 8.58(s, 1H)






309 (I)




(500.076MHz, DMSO-D6) δ 1.46-1.56(m, 2H), 1.89-1.98(m,







2H), 2.03-2.18(m, 4H), 2.23(d, 1H), 2.55-2.61(m, 1H),







3.02-3.17(m, 4H), 3.42-3.51(m, 2H), 3.98(s, 2H), 4.16(d,







1H), 4.54(d, 1H), 4.60-4.66(m, 1H), 6.93-6.97(m, 1H),







7.01-7.09(m, 1H), 7.15(s, 1H), 7.25(s, 1H), 7.34-7.38(m, 1H),







7.54-7.58(m, 1H)






310 (I)




(500.076MHz, DMSO-D6) δ 1.11(t, 3H), 1.39-1.48(m, 2H),







1.55-1.60(m, 2H), 1.65-1.72(m, 1H), 1.81-1.87(m, 1H),







1.90-1.95(m, 2H), 1.90(s, 3H), 2.39(t, 2H), 2.53-2.59(m,







1H), 2.74-2.83(m, 2H), 3.03-3.10(m, 1H), 3.36(q, 2H),







3.47-3.55(m, 1H), 4.42(septet, 1H), 4.46-4.54(m, 1H),







6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H), 7.72-7.78(m, 2H),







7.86(s, 1H), 7.96(d, 1H)






311 (I)




(500.076MHz, DMSO-D6) δ 0.92(t, 3H), 1.40-1.49(m, 2H),







1.55-1.64(m, 2H), 1.57(sextet, 2H), 1.65-1.73(m, 1H),







1.81-1.88(m, 1H), 1.91(s, 3H), 1.91-1.96(m, 2H),







2.36-2.44(m, 2H), 2.54-2.61(m, 1H), 2.73-2.84(m, 2H),







3.02-3.11(m, 1H), 3.45-3.53(m, 1H), 4.40-4.46(m, 1H),







4.50-4.54(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H),







7.72-7.78(m, 2H), 7.86(s, 1H), 7.96(d, 1H)






312 (I)




(500.076MHz, DMSO-D6) δ 0.98(d, 6H), 1.39-1.49(m, 2H),







1.54-1.61(m, 2H), 1.64-1.71(in. 1H), 1.81-1.87(m, 1H),







1.90-1.95(m, 2H), 1.91(s, 3H), 2.02(septet, 1H), 2.39(t, 2H),







2.53-2.59(m, 1H), 2.74-2.79(m, 2H), 3.03-3.11(m, 1H),







3.45-3.52(m, 1H), 4.42(septet, 1H), 4.47-4.53(m, 1H), 6.98(dd,







1H), 7.25(d, 1H), 7.49(d, 1H), 7.71-7.77(m, 2H), 7.88(s, 1H),







7.98(d, 1H)






313 (I)




(500.076MHz, DMSO-D6) δ 1.41-1.53(m, 2H), 1.54-1.62(m,







2H), 1.66-1.74(m, 1H), 1.84-1.89(m, 1H), 1.91-1.96(m,







2H), 1.91(s, 3H), 2.36-2.44(m, 2H), 2.54-2.62(m, 1H),







2.73-2.87(m, 4H), 3.10(t, 1H), 3.50(s, 3H), 3.52(s, 3H),







3.52-3.58(m, 1H), 4.40-4.46(m, 1H), 4.48-4.54(m, 1H),







6.97-7.00(m, 1H), 7.23-7.29(m, 1H), 7.50(d, 1H), 8.06(d,







1H), 8.16(s, 1H), 8.29(d, 1H)






314 (I)




(500.076MHz, DMSO-D6) δ 1.34(t, 3H), 1.35-1.41(m, 2H),







1.54-1.60(m, 2H), 1.74(d, 2H), 1.90-1.96(m, 2H), 1.90(s,







3H), 2.39(t, 2H), 2.50-2.55(m, 1H), 2.73-2.79(m, 2H),







2.80-2.89(m, 1H), 4.01(q, 2H), 4.08-4.19(m, 2H),







4.42(septet, 2H), 5.06(s, 2H), 6.62(d, 1H), 6.77(d, 1H),







6.81(s, 2H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H)






315 (I)




(DMSO-D6) δ 1.53-1.82(m, 2H), 2.02-2.36(m, 5H),







2.60-2.67(m, 1H), 3.07-3.15(m, 2H), 3.31-3.38(m, 1H),







3.43-3.53(m, 2H), 4.12-4.19(m, 4H), 4.51(d, 1H),







4.68(septet, 1H), 4.85(s, 1H), 7.06(ddd, 1H), 7.37(dd, 1H),







7.56(t, 1H), 7.94(d, 2H), 8.86(d, 2H), 11.47(s, 1H)






316 (I)




(DMSO-D6) δ 1.58-2.28(m, 4H), 2.67-2.84(m, 1H),







2.91-3.04(m, 2H), 2.97(s, 2H), 3.06-3.26(m, 2H),







3.24-3.42(m, 1H), 3.44-3.67(m, 3H), 3.57(s, 3H),







4.55-4.77(m, 2H), 4.83(s, 1H), 7.00-7.09(m, 2H),







7.35-7.58(m, 5H)






317 (I)




(DMSO-D6) δ 1.52(dq, 2H), 1.74-1.92(m, 2H),







1.93-2.04(m, 4H), 2.42-2.50(m, 2H), 2.55(m, 1H),







2.77-2.85(m, 2H), 2.87-2.96(m, 2H), 4.22-4.30(m,







3H), 6.69-6.74(m, 2H), 6.76(d, 1H), 6.99(d, 1H),







7.07(dd, 1H), 7.16(dt, 1H), 7.29(s, 2H), 7.32(s, 1H)






318 (I)




(DMSO-D6) δ 1.7 1(m, 2H), 2.18(m, 3H), 2.70(s, 3H),







3.02(m, 1H), 3.15(m, 2H), 3.32(m, 3H), 3.50(m, 2H), 4.63(m,







1H), 7.05(ddd, 1H), 7.36(m, 4H), 7.56(t, 1H), 7.66(d, 1H),







8.11(s, 1H), 8.37(d, 1H)






319 (I)




(DMSO-D6) δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H),







1.90(m, 2H), 2.40(m, 2H), 2.58(m, 1H), 2.79(m, 2H), 2.87(m,







2H), 4.30(d, 2H), 4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H),







7.25(d, 1H), 7.43(d, 1H), 7.49(d, 1H), 7.65(m, 2H)






321 (I)




(DMSO-D6) δ 1.67-1.78(m, 2H), 1.95-2.09(m, 3H),







2.18-2.27(m, 2H), 2.44(d, 3H), 2.77-2.88(m, 1H),







3.08-3.19(m, 3H), 3.33-3.52(m, 5H), 3.59-3.67(m,







1H), 4.60-4.68(m, 1H), 4.84(s, 1H), 7.05(ddd, 1H),







7.14-7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H), 7.61(q, 1H),







7.70-7.71(m, 2H), 7.78-7.80(m, 1H), 7.86-7.89(m, 1H)






322 (I)




(DMSO-D6) δ 1.65-1.80(m, 2H), 1.99-2.09(m, 2H),







2.19-2.30(m, 3H), 2.77-2.90(m, 1H), 3.07-3.21(m, 3H),







3.30-3.37(m, 3H), 3.47-3.57(m, 2H), 3.59-3.71(m, 1H),







4.59-4.69(m, 1H), 4.82-4.86(m, 1H), 7.05(ddd, 1H), 7.37(dd,







1H), 7.49(s, 2H), 7.55(t, 1H), 7.64-7.69 (m, 2H), 7.84-7.86(m,







1H), 7.92(td, 1H)






323 (I)




(DMSO-D6) δ 1.64-1.78(m, 2H), 1.99-2.09(m, 2H),







2.17-2.29(m, 3H), 2.70-2.85(m, 1H), 3.04-3.19(m, 3H),







3.28-3.38(m, 3H), 3.31(s, 3H), 3.46-3.55(m, 2H), 3.66(t,







2H), 4.12(t, 2H), 4.56-4.68(m, 1H), 4.81-4.86(m, 1H),







6.94-6.97(m, 2H), 7.04(dd, 1H), 7.05(ddd, 1H), 7.34-7.39(m,







2H), 7.55(t, 1H)






324 (I)




(CDCl


3


) δ 1.45(s, 9H), 1.48-1.67(m, 4H), 1.75-1.85(m, 2H),







1.90-2.03(m, 3H), 2.42-2.51(m, 2H), 2.56(m, 1H),







2.71-2.84(m, 3H), 2.91-3.06(m, 1H), 3.54(q, 2H),







3.75-3.88(m, 1H), 4.03(t, 2H), 4.27(septet, 1H),







4.68-4.82(m, 1H), 4.93-5.01(m, 1H), 6.75(dd, 1H),







6.90-7.00(m, 3H), 7.25-7.32(m, 3H)






325 (I)




(DMSO-D6) δ 1.70-1.84(m, 2H), 2.00-2.09(m, 2H),







2.20-2.29(m, 3H), 2.81-2.91(m, 1H), 3.09-3.21(m, 3H),







3.28-3.38(m, 3H), 3.48-3.57(m, 2H), 3.61-3.70(m, 1H),







4.61-4.72(m, 1H), 4.82-4.86(m, 1H), 7.05(ddd, 1H),







7.14-7.27(m, 1H), 7.37(dd, 1H), 7.56(t, 1H), 7.76-7.79(m,







1H), 8.51(s, 1H), 8.80(d, 1H)






326 (I)




(DMSO-D6) δ 1.70-1.78(m, 2H), 2.00-2.09(m, 2H),







2.18-2.26(m, 2H), 3.05-3.17(m, 2H), 3.24-3.40(m, 2H),







3.97-4.06(m, 2H), 4.44-4.52(m, 2H), 4.59-4.70(m, 2H),







4.73(s, 2H), 4.81-4.86(m, 1H), 4.91-4.93 (m, 2H),







6.90-6.93(m, 1H), 6.96-7.04(m, 1H), 7.07-7.11(m, 1H),







7.17-7.20(m, 1H), 7.34-7.43(m, 2H), 7.52-7.55(m, 1H)






327 (I)




(CDCl


3


) δ 1.52-1.63(m, 4H), 1.77-1.86(m, 2H),







1.92-2.03(m, 4H), 2.44-2.50(m, 2H), 2.58-2.67(m, 1H),







2.77-2.83(m, 2H), 3.05(bs, 1H), 3.36(s, 3H), 4.26-4.31(m,







2H), 6.74-6.77(m, 1H), 6.99-7.01(m, 1H), 7.30-7.33(m,







1H), 7.47(s, 1H)






328 (I)




(CDCl


3


) δ 1.43-1.67(m, 4H), 1.73-1.91(m, 4H),







1.95-2.02(m, 2H), 2.42-2.50(m, 2H), 2.52-2.62(m, 1H),







2.77-2.85(m, 2H), 2.92(bs, 2H), 3.06(s, 3H), 4.23-4.30(m,







1H), 5.26(s, 2H), 6.73-6.79(m, 2H), 6.99-7.00(m, 1H),







7.29-7.32(m, 1H), 7.47-7.50(m, 1H), 7.82-7.82(m, 1H)






329 (I)




(CDCl


3


) δ 1.50-1.69(m, 4H), 1.77-1.86(m, 2H),







1.92-2.02(m, 4H), 2.45-2.49(m, 2H), 2.59-2.65(m, 1H),







2.79-2.83(m, 2H), 3.02(bs, 1H), 3.39(s, 3H), 4.26-4.30(m,







2H), 5.88(bs, 1H), 6.74-6.77(m, 1H), 6.99-7.00(m, 1H),







7.30-7.32(m, 1H), 7.46(bs, 1H), 7.65(s, 1H)






330 (I)




(DMSO-D6) δ 1.73-3.63(m, 17H), 4.57-4.70(m, 1H),







7.01-7.88(m, 7H)






331 (I)




(DMSO-D6) δ 1.21(d, 6H), 1.37-2.03(m, 8H), 2.33-3.42(m,







7H), 4.15-4.19(m, 1H), 4.37-4.45(m, 1H), 5.89(s, 2H),







6.96-8.34(m, 4H)






332 (I)




(DMSO-D6) δ 1.41-1.94(m, 8H), 2.37-2.78(m, 8H), 3.32(s,







3H), 4.38-4.46(m, 1H), 6.96-7.78(m, 5H)






333 (I)




(CDCl


3


) δ 1.80-1.96(m, 5H), 2.38(s, 4H), 2.41-3.00(m, 12H),







3.57-3.60(m, 1H), 4.26(s, 1H), 4.73-4.76(m, 1H), 6.73-7.32(m,







3H)






334 (I)




(DMSO-D6) δ 1.33-1.93(m, 8H), 2.33-3.27(m, 7H),







4.39-4.45(m, 1H), 4.49-4.53(m, 1H), 6.96-8.98(m, 5H)






335 (I)




(CDCl


3


) δ 1.16-1.30(m, 1H), 1.33-1.48(m, 1H),







1.76-2.75(m, 12H), 2.96-3.05(m, 1H), 3.72(s, 2H),







3.89-3.93(m, 1H), 4.21-4.30(m, 1H), 4.66-4.71(m, 1H),







6.72-7.32(m, 7H)






336 (I)




(DMSO-D6) δ 1.37-2.83(m, 17H), 4.38-4.47(m, 1H),







5.76(s, 1H), 6.96-7.96(m, 6H)






337 (I)




(DMSO-D6) δ 1.33-1.99(m, 8H), 2.36-2.60(m, 4H),







2.73-2.82(m, 2H), 2.94(s, 3H), 2.98-3.09(m, 1H), 3.55-3.66(m,







1H), 4.38-4.46(m, 1H), 4.56(s, 2H), 6.96-7.00(m, 1H),







7.23-7.27(m, 1H), 7.41-7.52(m, 5H)






338 (I)




(DMSO-D6) δ 1.35-1.99(m, 8H), 2.37-2.46(m, 2H),







2.55-2.63(m, 2H), 2.73-2.85(m, 2H), 2.92(s, 3H),







2.97-3.06(m, 1H), 3.55-3.65(m, 1H), 4.41-4.49(m,







1H), 4.56(s, 2H), 6.96-7.01(m, 1H), 7.25-7.27(m, 1H),







7.39-7.52(m, 5H)






 1(III)




δ(DMSO-D6) 1.57-1.36(2H, m), 2.25-1.87(5H, m),







2.45-2.33(2H, m), 3.16-2.97(2H, m), 3.37-3.17(4H,







m), 3.45-3.40(1H, m), 4.12(0H, t), 4.53(1H, d), 4.67-4.58(1H,







m), 4.84-4.77(1H, m), 5.45(1H, d), 7.03(1H, ddd), 7.19(2H,







t), 7.42-7.33(3H, m), 7.55(1H, m), 10.59-10.38(1H, m)






 2(III)




δ(DMSO-D6) 1.60-1.36(2H, m), 2.27-1.93(5H, m),







2.61-2.57(1H, m), 2.90-2.73(1H, m), 3.13-2.94(2H,







m), 3.41-3.23(3H, m), 4.17-3.85(2H, m), 4.68-4.47(2H,







m), 4.84-4.77(1H, m), 5.43(1H, d), 7.09-6.99(1H, m),







7.40-7.27(6H, m), 7.55(1H, t), 11.13-10.92(1H, m)






 3(III)




δ(DMSO-D6) 1.27-1.07(1H, m), 1.57-1.36(1H, m),







2.24-1.89(5H, m), 2.66-2.56(1H, m), 2.93-2.79(1H,







m), 3.16-3.00(2H, m), 3.51-3.39(2H, m), 4.18(1H, t),







4.67-4.46(2H, m), 4.84-4.78(1H, m), 5.51-5.43(1H,







m), 6.05(1H, s), 7.04(1H, dd), 7.24-7.17(1H, m), 7.48-7.33(3H,







m), 7.55(1H, dd), 10.41-10.23(1H, m)


























TABLE VII









Com-







Can be






pound





MP





prepared






(Table)




MS




(° C.)






1


HNMR




using:











 3




495




181-182




(DMSO-D6) δ 1.2-2.8(bm,




Example






(IV)




(M +





14H), 3.1(bm, 1H), 3.35(s, 3H),




12







H)





3.5(bm, 1H), 4.4(m, 1H),









4.5(bm, 1H), 6.82(dd, 1H),









7.1(dd, 1H), 7.4(t, 1H),









7.7(m, 2H), 7.9(s, 1H),









8.0(dd, 1H)






 2




495




111-112




(DMSO-D6) δ 1.6-2.3(bm,




Example






(IV)




(M +





(8H), 3.0-3.6(bm, 8H), 3.3(s,




12 and







H)





3H), 4.5-4.8(m, 2H), 6.9-7.1(m,




final









1H), 7.2-7.4(m, 2H), 7.8(m,




product









2H), 7.94(d, 1H), 8.03(d, 1H),




isolated as









10.9(bm, 1H)




Hydro-










chloride










by treat-










ment with










a solution










of HCl in










dioxan










and eva-










poration






 7




459




149-150




(DMSO-D6) δ 1.2-3.7(bm,




As for 2






(IV)




(M +





16H), 3.75(s, 3H), 3.85(bm,




(IV)







H)





1H), 4.6(bm, 1H), 5.05(bm,




above









1H), 6.9(m, 4H), 7.78(m, 2H),









7.92(d, 1H), 8.05(m, 1H), 11.0









and 11.8(bm, 1H)






 8




463




126-127




(DMSO-D6) δ 1.2-3.6(bm,




As for 2






(IV)




(M +





16H), 3.9(bm, 1H), 4.6 bm, 1H),




(IV)







H)





5.14(bm, 1H), 7.0(d, 2H),




above









7.38(d, 2H), 7.75(m, 2H),









7.9(m, 1H), 8.05(m, 1H), 11.3









and 11.95(bm, 1H)






 9




497




78-80




(DMSO-D6) δ 1.2-4.0(bm,




As for 2






(IV)




(M +





17H), 4.6(bm, 1H), 5.2(bm,




(IV)







H)





1H), 7.0(dd, 1H), 7.3(m, 1H),




above









7.58(d, 1H), 7.78(d, 2H),









7.95(d, 1H), 8.05(m, 1H)









11.0 and 11.65(bm, 1H)






 10




454




78-80




(DMSO-D6) δ 1.2-3.6(m,




Example






(IV)




(M +





17H), 4.25(bm, 1H), 4.98(m,




12







H)





1H), 7.03(d, 2H), 7.72(m, 4H),









7.9(s, 1H), 8.0(m, 1H)






 11




465




82-83




(DMSO-D6) δ 1.2-3.4(m,




Example






(IV)




(M +





16H), 3.5(bm, 1H), 4.3(bm,




12







H)





1H), 4.85(m, 1H), 6.7(m, 1H),









7.0(m, 1H), 7.3(q, 1H),









7.7(m, 2H), 7.9(s, 1H),









8.0(m, 1H)






 12




447




64-65




(DMSO-D6) δ 1.2-3.3(m,




Example






(IV)




(M +





16H), 3.45(bm, 1H), 4.25(m,




12







H)





1H), 4.8(m, 1H), 6.9(m, 2H)









7.1(t, 2H), 7.75(m, 2H),









7.9 (s, 1H), 8.0(dd, 1H)






 13




500




110-111




(DMSO-D6) δ 1.2-4.8(bm,




As for 2






(IV)




(M +





24H), 6.95(dd, 2H), 7.5(m,




(IV)







H)





2H), 7.8(m, 2H), 7.95(s, 1H)




above









8.02(d. 1H), 9.85(d, 1H),









10.7(bm, 1H)






 14




457




140-142




(DMSO-D6) δ 1.2-4.8(m,




Example






(IV)




(M +





24H), 6.86(bm, 2H), 7.02(m,




12







H)





2H), 7.75(bm, 2H), 7.90(s, 1H),









8.03(bm, 1H)






 15




491




94-95




(DMSO-D6) δ 1.2-4.8(bm,




Example






(IV)




(M +





24H). 6.8(bd, 1H), 7.0(bs, 1H),




12







H)





7.3(d, 1H), 7.75(m, 2H), 7.9(s,









1H), 8.0(m, 1H)






 16




477




150-152




(DMSO-D6) δ 1.2-4.6(bm,




Example






(IV)




(M +





21H), 7.0(bm, 2H), 7.3(bm,




12.







H)





2H), 7.75(m, 2H), 7.9(s, 1H),









8.0(m, 1H)






 17




461




219-220




(DMSO-D6) δ 1.2-4.8(bm,




As for 2






(IV)




(M +





21H), 6.9-7.3(m, 4H), 7.75(m,




(IV)







H)





2H), 7.92(s, 1h), 8.02(m. 1H).




above






 18




511




104-105




(DMSO-D6) δ 1.2-5.0(bm,




Example






(IV)




(M +





21H), 7.3(d, 1H)7.4(dd, 1H),




12 and







H)





7.6(dd, 1H), 7.75(m, 2H),




final









7.95(s, 1H), 8.0(d, 1H), 9.5 and




product









9.7(bs, 1H)




isolated










as trifluor-










oacetate










by evap-










oration of










Reverse










Phase










HPLC










fractions.






 19




495




76-77




(DMSO-D6) δ 1.2-5.0(bm,




As for 18






(IV)




(M +





21H), 7.2(m, 1H), 7.3(m, 1H),




(IV)







H)





7.45(m, 1H), 7.75(m, 2H),




above









7.95(s, 1H), 8.05(m, 1H),









9.5(bm, 1H)






 20




479




230-232




(DMSO-D6) δ 1.2-3.7(bm,




As for 2






(IV)




(M +





19H), 4.4-4.7(bm, 2H), 7.02(t,




(IV)







H)





1H), 7.3(m, 2H), 7.75(m, 2H),




above









7.95(s, 1H), 8.02(d, 1H)






 21




495




69-70




(DMSO-D6) 1.2-4.0(m, 19H),




As for 18






(IV)




(M +





4.4-4.8(m, 2H), 7.3(m, 2H),




(IV)







H)





7.5(m, 1H), 7.75(m, 2H), 7.98(s,




above









1H), 8.0(m, 1H), 9.5(bm, 1H)






 22




475




130-132




(CDCl


3


) δ 1.0-3.6(m, 19H),




As for 2






(IV)




(M +





3.7(s, 3H), 4.6(m, 2H),




(IV)







H)





6.6-6.9(m, 3H), 7.7(m, 2H),




above









8.0(m, 2H)






 24




462




72-73




(DMSO-D6) 1.6(m, 2H), 1.8(m,




Example






(IV)




(M +





1H), 2.01(m, 4H), 2.3(m, 1H),




13







H)





2.5(m, 2H), 2.9(m, 2H), 3.2(m,









2H), 3.4(m, 1H), 3.58(m, 2H),









3.8(s, 3H), 4.3(bs, 2H), 4.6 and









4.8(m, 1H), 6.7(d, 1H),









6.8-7.0(m,









3H), (m, 1H), 7.5(m, 1H),









9.5(bs, 1H)






 26




458




111-112




(DMSO-D6) δ 1.4-3.6(m,




Example






(IV)




(M +





17H), 3.8(2s, 6H), 4.2-4.5(m,




13







H)





3H), 6.7(m, 2H), 6.82(m, 2H),









6.9-7.2(m, 2H)






 27




440




73-75




(DMSO-D6) δ 1.6-1.9(m,




Example






(IV)




(M +





3H), 2.0-2.3(m, 5H),




13







H)





2.4-2.6(m, 2H), 2.9(m, 2H),









3.18(m, 2H), 3.4(m, 1H), 3.5(m,









2H), 3.7(s, 3H), 3.8(s, 3H),









4.2(bs, 2H), 4.4 and 4.6(2m,









1H), 6.7(d, 1H), 6.9(m, 5H),









7.0(d, 1H), 9.7(bm, 1H)






 28




462




81-83




(DMSO-D6) δ 1.6(m, 2H),




Example






(IV)




(M +





1.8(m, 1H), 2.05(m, 4H), 2.3(m,




13







H)





1H), 2.5(m, 1H), 2.9(m, 2H),









3.2(m, 2H), 3.3(m, 2H), 3.4(m,









1H), 3.55(m, 2H), 3.8(s, 3H),









4.3(bs, 2H), 4.6 and 4.8(m, 1H),









6.62(d, 1H), 6.81(d, 1H), 6.9(s,









1H), 7.05(m, 1H), 7.35(m, 2H),









9.76(bm, 1H)






 29




424




97-99




(DMSO-D6) δ 1.4-2.6(m,




Example






(IV)




(M +





14H), 2.9(m, 2H), 3.2(m, 2H),




13







H)





3.4(m, 1H), 3.55(m, 2H), 3.8(s,









3H), 4.3(bs, 2H), 4.5 and 4.7(m,









1H), 6.65(d, 1H), 6.9(m, 4H),









7.1(m, 1H), 9.5(bs, 1H)






 30




458




78-79




(DMSO-D6) δ 1.5-2.6(m,




Example






(IV)




(M +





13H), 2.3(s, 3H), 2.9(m, 2H),




13







H)





3.2(m, 2H), 3.4(m, 1H), 3.55(m,









2H), 4.3(bs, 2H), 4.55 and









4.75(m, 1H), 6.62(d, 1H),









6.85(m, 3H), 7.0(dd, 1H),









7.32(t, 1H), 9.5(bs, 1H)






 31




444




100-101




(DMSO-D6) δ 1.6(m, 2H),




Example






(IV)




(M +





1.8(m, 1H), 2.0(m, 4H), 2.3(m,




13







H)





1H), 2.5(m, 2H), 2.9(m, 2H),









3.18(m, 2H), 3.4(m, 1H), 3.5(m,









2H), 3.8(s, 3H), 4.2(bs, 2H),









4.6 and 4.8(m, 1H), 6.62(d, 1H),









6.8(m, 2H), 7.0(m, 2H), 7.36(m,









2H), 9.7(bs, 1H)






 32




428




74-75




(DMSO-D6) 1.6(m, 2H), 1.8(m,




Example






(IV)




(M +





1H), 2.0(m, 4H), 2.3(m, 1H),




13







H)





2.5(m, 2H), 2.9(m, 2H), 3.2(m,









2H), 3.4(m, 1H), 3.5(m, 2H),









3.8(s, 3H), 4.2(bs, 2H), 4.5









and 4.7(m, 1H), 6.7(d, 1H),









6.85(d, 1H), 6.9(s, 1H), 7.02(m,









1H), 7.04(m, 1H), 7.18(m, 2H),









9.6(m, 1H)






 33




478




117-119




(DMSO-D6) δ 1.6-3.6(m,




Example






(IV)




(M +





17H), 3.8(s, 3H), 4.25(bs, 2H),




13







H)





4.6 and 4.9(m, 1H), 6.6(d,









1H), 6.8(m, 2H), 7.3(m, 1H),









7.4(m, 1H), 7.6(m, 1H),









9.5(bs, 1H)






 34




462




109-110




(DMSO-D6) δ 1.6-3.6(m,




Example






(IV)




(M +





17H), 3.8(s, 3H), 4.25(bs, 2H),




13







H)





4.55 and 4.85(m, 1H), 6.6(d,









1H), 6.8(m, 2H), 7.2(m, 1H),









7.3(m, 1H), 7.45(m, 1H),









9.5(bs, 1H)






 37




442




89-90




(DMSO-D6) δ 1.6-3.6(m,




Example






(IV)




(M +





20H), 3.8(s, 3H), 4.25(bs, 2H),




13







H)





4.45 and 4.75(m, 1H), 6.6(d,









1H), 6.8(m, 2H), 7.0(m, 3H),









9.6(bs, 1H)






 38




471




143-145




(DMSO-D6) δ 1.6-3.6(m,




As for 18






(IV)




(M +





19H), 4.2-4.8(m, 2H),




(IV)







H)





7.0(m, 1H), 7.2(d, 1H), 7.22(s,




above









1H), 7.8(d, 1H), 8.5(d, 1H),









8.8(s, 1H)






 39




475




141-142




(DMSO-D6) δ 1.6-3.6(m,




As for 18






(IV)




(M +





16H), 4.2-4.8(m, 2H), 6.9(m,




(IV)







H)





1H), 7.2(m, 1H), 7.5(m, 1H),




above









7.8(d, 1H), 8.5(d, 1H), 8.8(d,









1H)






 41




471




160-162




(DMSO-D6) δ 1.6-3.6(m,




As for 18






(IV)




(M +





16H), 3.8(s, 3H), 4.2-4.8(m,




(IV)







H)





2H), 6.7(m, 1H), 6.9-7.2(m,




above









2H), 7.8(d, 1H), 8.5(d, 1H),









8.8(d, 1H)






 42




453




116-118




(DMSO-D6) δ 1.6-3.6(m,




As for 18






(IV)




(M +





16H), 3.7(s, 3H), 4.2-4.8(m,




(IV)







H)





2H), 6.8-7.1(m, 3H), 7.82(d,




above









1H), 8.52(d, 1H), 8.8(d, 1H),









9.6(bs, 1H)






 43




475




109-110




(DMSO-D6) δ 1.6-3.6(m,




As for 18






(IV)




(M +





16H), 4.2-4.8(m, 2H), 7.07(m,




(IV)







H)





1H), 7.35(m, 2H), 7.82(d, 1H),




above









8.52(d, 1H), 8.8(d, 1H), 9.6(bs,









1H)






 44




437




136-137




(DMSO-D6) δ 1.6-3.2(m,




Example






(IV)




(M +





15H), 3.3(s, 3H), 3.6(m, 1H),




12







H)





4.22(m, 1H), 4.5(m, 1H), 6.8(d,









2H), 7.10(d, 2H), 7.82(d, 1H),









8.52(d, 1H), 8.8(d, 1H)






 89




471




100-102




(DMSO-D6) δ 1.0-4.2(m,




As for 18






(IV)




(M +





21H), 6.0(m, 1H), 6.18(m, 1H),




(IV)







H)





6.42(m, 1H), 7.02(d, 1H), 7.6(d,




above









1H), 7.85(d, 1H)






 47




441




133-136




(DMSO-D6) δ 1.6-4.8(m,




As for 18






(IV)




(M +





18H), 6.9-7.2(m, 4H), 7.82(d,




(IV)







H)





1H), 8.52(d, 1H), 8.8(d, 1H)




above






 48




491




105-106




(DMSO-D6) δ 1.6-4.8(m,




As for 18






(IV)




(M +





18H), 6.3(d, 1H), 6.4(d, 1H),




(IV)







H)





6.58(s, 1H), 6.9(d, 1H), 7.52(d,




above









1H), 7.8(d, 1H)






 49




475




123-125




(DMSO-D6) δ 1.6-4.8(m,




As for 18






(IV)




(M +





18H), 7.2(m, 1H), 7.3(m, 1H),




(IV)







H)





7.45(m, 1H), 7.82(d, 1H),




above









8.52(d, 1H), 8.8(d, 1H)






 50




459




93-94




(DMSO-D6) δ 1.6-4.8(m,




As for 18






(IV)




(M +





18H), 7.05(m, 1H), 7.3(m, 2H),




(IV)







H)





7.82(d, 1H), 8.52(d, 1H), 8.8(d,




above









1H), 9.7(bm, 1H)






271




507




102-103




(DMSO-D6) δ 1.6-3.8(m, Example






(IV)




(M +





16H), 3.3(s, 3H), 3.8(d, 3H),




12







H)





4.4-4.7(m, 2H), 6.95(m, 1H),









7.1(m, 2H), 7.78(m, 2H), 7.95(s,









1H), 8.03(d, 1H)






272




505




97-98




(DMSO-D6) δ 1.6-4.8(m,




As for 18






(IV)




(M +





27H), 7.1(s, 2H), 7.6(m, 2H),




(IV)







H)





7.95(s, 1H), 8.03(d, 1H)




above






273




511




110-112




(DMSO-D6) δ 1.4-3.8(m,




As for 18






(IV)




(M +





16H), 3.3(s, 3H), 4.4-5.0(m,




(IV)







H)





2H), 7.22(m, 2H), 7.3(m, 1H),




above









7.75(m, 2H), 7.95(s, 1H),









8.02(d, 1H)






274




511




114-115




(DMSO-D6)6 1.4-3.8(m, 16H),




Example






(IV)




(M +





3.3(s, 3H), 4.4-5.0(m, 2H),




12







H)





7.02(m, 1H), 7.4(m, 2H), 7.75(m,









2H), 7.95(s, 1H), 8.02(d, 1H)






275




491




88-89




(DMSO-D6) δ 1.4-3.8(m,




Example






(IV)




(M +





16H), 2.25(s, 3H), 3.3(s, 3H),




12







H)





4.2-4.8(m, 2H), 7.02(m, 2H),









7.22(m, 1H), 7.75(m, 2H), 7.95(s,









1H), 8.02(d, 1H)






276




491




182-183




(DMSO-D6) δ 1.4-3.8(m,




Example






(IV)




(M +





16H), 2.25(s, 3H), 3.3(s, 3H),




12







H)





4.4-4.6(m, 2H), 6.74(d, 1H),









7.02(s, 1H), 7.22(d, 1H), 7.75(m,









2H), 7.90(s, 1H), 8.0(d, 1H)






277




499




162-164




(DMSO-D6) δ 1.6-3.8(m,




As for 2






(IV)




(M +





19H), 2.25(s, 3H), 3.3(s, 3H),




(IV)







H)





4.5-5.0(m, 2H), 7.14(t, 1H),




above









7.8(m, 4H), 7.95(m, 1H), 8.02(d,









1H), 10.9(bm, 1H)






278




528




120-122




(DMSO-D6) δ 1.5-5.0(m,




As for 2






(IV)




(M +





29H), 6.9-7.2(m, 4H), 7.75(m,




(IV)







H)





2H), 7.9(s, 1H), 8.02(d, 1H),




above









10.2(bs, 1H), 11.0-11.3(bm,









1H)






279




505




97-99




(DMSO-D6) δ 1.18(t, 3H),




Example






(IV)




(M +





1.6-3.7(m, 17H), 2.62(q, 2H),




12







H)





3.3(s, 3H), 4.4-4.8(m, 1H),









6.8-7.1(m, 2H), 7.3(m, 1H),









7.75(m, 2H), 7.95(s, 1H), 8.02(m,









1H), 9.4(bs, 1H)






280




494




138-140




(DMSO-D6) δ 1.8(m, 2H),




As for 2






(IV)




(M +





2.1-4.4(m, 14H), 3.3(s, 3H),




(IV)







H)





4.62(bm, 1H), 4.9 and 5.1(m,




above









1H), 7.65(m, 1H), 7.8(m, 2H),









7.85(m, 2H), (d, 1H), 8.01(d,









1H), 8.3(t, 1H), 9.0(t, 1H),









9.15(t, 1H), 10.35(bs, 1H),









11.5(bs, 1H)






281




499




98-99




(DMSO-D6) δ 1.2(s, 9H),




Example






(IV)




(M +





1.3-3.6(m, 20H), 4.5(m, 1H),




12







H)





6.8(t, 1H), 6.9(d, 1H), 7.1(t,









1H), 7.2(d, 1H), 7.7(m, 2H),









7.9(s, 1H), 8.0(d, 1H)






282




483




79-80




(DMSO-D6) δ 1.2-3.6(m,




Example






(IV)




(M +





22H), 3.3(s, 3H), 4.22 and 4.5(m,




12







H)





2H), 6.67(d, 1H), 6.8(s, 1H),









7.08(d, 1H), 7.75(m, 2H), 7.9(s,









1H), 8.0(d, 1H)






283




559




113-115




(DMSO-D6) δ 1-1.48(m,




Example






(IV)




(M +





29H), 3.3(s, 3H), 7.0(m, 1H),




12







H)





7.18(m, 2H), 7.75(m, 2H), 7.9(s,









1H), 8.0(m, 1H)






284




520




111-112




(DMSO-D6) δ 1.6-4.0(m,




As for 18






(IV)




(M +





19H), 4.6 and 4.9(m, 2H), 7.2(m,




(IV)







H)





1H), 7.4-7.8(m, 6H), 7.95(s,




above









1H), 8.02(d, 1H), 9.5(bm, 1H)






285




544




111-112




(DMSO-D6) 5 1.6-3.2(m, 15H),




Example






(IV)




(M +





3.3(s, 3H), 3.5(m, 1H), 4.5 and




12







H)





4.6(m, 2H), 6.9(d, 1H), 7.35(d,









1H), 7.5(dd, 1H), 7.75(m, 2H),









7.81(d, 1H), 7.9(s, 1H), 8.0(dd,









1H), 8.68(d, 1H)






286




491




115-117




(DMSO-D6) δ 1.6-3.2(m,




Example






(IV)




(M +





16H), 3.3(s, 3H), 3.35-3.6(m,




12







H)





3H), 4.9(m, 2H), 6.9(m, 1H),









7.0-7.2(m, 2H), 7.75(m, 2H),









7.92(s, 1H), 8.02(m, 1H)






287




443




142-144




(DMSO-D6) δ 1.6-3.4(m,




Example






(IV)




(M +





14H), 3.3(s, 3H), 3.4-3.7(m,




12







H)





2H), 4.6-4.8(m, 2H), 7.0(m,









3H), 7.3(m, 2H), 7.75(m, 2H),









7.92(s, 1H), 8.04(dd, 1H)






288




525




84-86




(DMSO-D6) δ 1.6-3.4(m,




As for 18






(IV)




(M +





22H), 4.2-4.7(m, 2H), 7.38(d,




(IV)







H)





1H), 7.5( d, 1H), 7.75(m, 2H),




above









7.95(s, 1H), 8.02(m, 1H)






289




491




149-151




(DMSO-D6) δ 1.3-2.0(m,




Example






(IV)




(M +





8H), 2.22(s, 3H), 2.3-2.6(m,




12







H)





4H), 2.8(m, 2H), 3.1(m, 1H),









3.3(s, 3H), 3.5(m, 1H),









4.3-4.6(m, 2H), 6.84(dd, 1H),









7.0(d, 1H), 7.2(m, 1H), 7.75(m,









2H), 7.9(s, 1H), 8.0(dd, 1H)






290




502




93-95




(DMSO-D6) δ 1.6-4.0(m,




As for 18






(IV)




(M +





16H), 3.3(s, 3H), 4.4-5.1(m,




(IV)







H)





2H), 7.4(t, 1H), 7.8(m, 3H),




above









7.9-8.1(m, 3H), 9.5-10.0(bm,









1H)






293




445




66-68




(DMSO-D6) δ 1.6-3.0(m,




Example






(IV)




(M +





7H), 2.8(m, 1H), 3.2(m, 3H),




15







H)





3.3(s, 3H), 3.4-3.7(m, 4H),









4.62(m, 1H), 5.1-5.4(m, 2H),









7.2(m, 11-1), 7.8(m, 2H),









7.95(m, 1H), 8.02(d, 1H), 8.6(m,









2H), 9.5(bs, 1H)






339




(M +




foam




(DMSO-D6) δ 1.42-1.70(m,




Example






(I)




H)





5H), 1.84-1.94(m, 3H),




2 step c







458





2.35-2.42(m, 2H),









2.54-2.62(m, 1H),









2.73-2.87(m, 3H),









3.02-3.10(m, 1H),









3.30-3.36(m, 1H),









4.39-4.44(m, 1H),









4.53-4.57(m, 1H),









6.95-6.99(m, 1H),









7.24-7.25(m, 1H),









7.47-7.50(m, 1H),









7.56-7.67(m, 2H),









7.77-7.82(m, 1H),









7.94-7.96(m, 1H)






(340)




(M +




156-157




(DMSO-D6) δ 1.40-1.99(m,




Example






(I)




H)





8H), 2.35-2.46(m, 2H),




2 step c







484





2.54-2.62(m, 1H),









2.73-2.85(m, 3H),









3.02-3.13(m, 1H),









3.60-3.72(m, 1H),









4.39-4.47(m, 1H),









4.51-4.64(m, 1H),









6.96-7.00(m, 1H),









7.25-7.26(m, 1H),









7.50(d, 1H), 7.59-7.63(m,









1H), 7.74-7.78(m, 1H),









8.06-8.09(m, 2H),









8.45-8.48(m, 1H),









8.96-8.98(m, 1H)






341




(M +




127-129




(DMSO-D6) δ 1.44-1.99(m,




Example






(I)




H)





8H), 2.40-2.48(m, 2H),




2 step c







485





2.58-2.67(m, 1H),




using









2.75-2.90(m, 3H),




Quinoxa-









3.04-3.16(m, 1H),




line-6-









3.56-3.69(m, 1H),




carboxylic









4.40-4.49(m, 1H),




acid









4.53-4.63(m, 1H),




(obtained









6.96-7.00(m, 1H),




from









7.26-7.27(m, 1H),




hydrolysis









7.48-7.51(m, 1H),




of the









7.85-7.88(m, 1H),




commer-









8.09-8.11(m, 1H),




cially









8.16-8.19(m, 1H),




available









9.01(s, 2H)




Quinoxa-










line-6-










carboxylic










acid










methyl










ester)






342




(M +




foam




(DMSO-D6) δ 1.36-1.44(2H,




Example






(I)




H)





m), 1.55-1.61(2H, m),




2 step c







532





1.76-1.82(2H, m),




using









1.89-1.96(2H, m),




3-Amino-









2.34-2.41(3H, m),




4-meth-









2.72-2.80(2H, m),




anesulfon-









2.95(2H, t), 3.21(3H, s),




nyl-thio-









4.15-4.22(2H, m),




phene-2-









4.38-4.46(1H, m),




carboxylic









5.87(2H, s), 6.96-6.99(2H,




acid









m), 7.24-7.26(2H, m),




(obtained









7.49(1H, d), 8.34(1H, s)




from










hydrolysis










of the










commer-










cially










available










3-Amino-










4-meth-










anesulfon-










yl-thio-










phene-2-










carboxylic










acid










methyl










ester)






 63




491




127-129




(DMSO-D6) δ 1.42-1.96(8H,




Example






(IV)




(M +





m), 2.26(3H, s), 2.32-2.41(2H,




2 step c







H)





m), 2.53-2.59(2H, m),









2.67-3.11(4H, m), 3.24(3H,









s), 4.28-4.35(2H, m),









6.77-6.81(1H, m), 6.95(1H,









d), 7.26(1H, dd), 7.50(1H,









ddd), 7.70(1H, d),









7.76-7.82(1H, m), 7.98(1H,









ddd)






 79




497




168-169




(DMSO-D6) δ 1.41-1.49(2H,




Example






(IV)




(M +





m), 1.53-1.60(2H, m), 1.80(2H,




2 step c







H)





d), 1.92(2H, dz), 2.27(3H, s),









2.38(2H, t), 2.54-2.62(2H, m),









2.77(2H, t), 2.93-3.12(2H, m),









3.40(3H, s), 4.33(2H, dt),









6.80(1H, dd), 6.95(1H, d),









7.26(1H, d), 7.49(1H, d),









7.77(1H, d)






423




(M +




181-183




(DMSO-D


6


) δ 1.44-1.63(6H,




Example






(I)




(H





m), 1.91-1.98(3H, m),




2 step c







499





2.36-2.39(2H, m),









2.53-2.62(4H, m),









2.76-2.90(2H, m),









3.03-3.11(1H, m),









3.34-3.42(1H, m),









4.40-4.45(1H, m),









4.56-4.64(1H, m),









6.96-6.99(1H, m),









7.24(1H, s), 7.48-7.51(1H,









m), 7.61-7.65(1H, m),









8.39-8.47(2H, m),









9.06-9.08(1H, m)






578




(M +




145-147




(DMSO-D


6


) δ 1.33-1.45(2H,




Example






(I)




H)





m), 1.53-1.64(2H, m),




2 step c







473





1.76-1.94(4H, m),









2.36-2.44(2H, m),









2.55-2.64(1H, m),









2.70-2.80(3H, m),









3.03-3.15(1H, m),









4.35-4.44(1H, m),









4.51-4.61(1H, m),









5.08-5.20(1H, m),









6.93-7.00(2H, m),









7.25-7.34(2H, m),









7.45-7.50(1H, m),









7.57-7.63(1H, m),









8.33(1H, s), 8.50-8.62(1H, m)






580




(M +




>200




(DMSO-D


6


) δ 1.43-1.65(4H,




Example






(I)




H),





m), 1.85-1.96(3H, m),




2 step c







500





2.32-2.41(2H, m),









2.54-2.62(2H, m),









2.73-3.14(4H, m),









3.40-3.47(1H, m),









4.37-4.45(1H, m),









4.53-4.62(1H, m),









6.45(1H, d), 6.93-7.00(1H,









m), 7.17-7.26(2H, m),









7.33-7.59(4H, m),









11.99(1H, s)






419




(M +




>200




(DMSO-D


6


) δ 1.25-1.68(5H,




Example






(I)




H)





m), 1.72-1.81(2H, m),




2 step c







464





1.88-1.95(2H, m), 2.22(3H, s),









2.31-2.40(2H, m),









2.60-2.78(3H, m),









2.92-3.00(1H, m),









3.44-3.52(1H, m),









4.36-4.49(2H, m),









5.92-6.11(1H, m),









6.91-7.06(1H, m),









7.25(1H, s), 7.30-7.41(1H,









m), 7.44-7.54(1H, m)









11.86(1H, s)






550




(M +




80-85




(DMSO-D


6


) δ 1.40-1.65(5H,




Example






(I)




H)





m), 1.83-1.96(3H, m),




2 step c







484





2.31-2.43(2H, m),









2.50-2.56(1H, m),









2.69-2.92(4H, m),









3.08-3.17(1H, m),









4.36-4.42(1H, m),









4.65-4.73(1H, m),









6.94-7.00(1H, m),









7.19-7.25(1H, m),









7.45-7.50(1H, m),









7.58-7.71(3H, m),









8.00-8.05(1H, m),









8.39-8.46(1H, m),









8.91-8.96(1H, m)






426




(M +




158-159




(DMSO-D6) δ 1.36-1.45(2H,




Example






(I)




H)





m), 1.53-1.61(2H, m),




2 step c







464





1.72-1.79(2H, m),









1.88-1.96(2H, m),









2.35-2.43(2H, m),









2.52-2.57(1H, m),









2.72-2.79(2H, m),









2.85-2.94(2H, m),









3.32-3.38(1H, m),









3.49(3H, s), 3.99-4.12(1H,









m), 4.34-4.51(1H, m),









6.36(1H, d), 6.90-7.06(1H,









m), 7.21-7.29(1H, m),









7.42-7.54(2H, m),









7.91-8.03(1H, m)






416




(M+




133-135




(DMSO-D6) δ 1.38-1.45(2H,




Example






(I)




H)





m), 1.53-1.60(2H, m),




2 step c







448





1.66-1.84(2H, m),









1.88-1.95(2H, m),









2.34-2.41(2H, m),









2.51-2.58(1H, m),









2.73-2.78(3H, m),









3.01-3.10(1H, m),









3.29-3.36(3H, m),









3.53-3.63(1H, m),









4.38-4.53(2H, m),









6.94-7.01(1H, m),









7.21-7.28(1H, m),









7.29-7.35(1H, m),









7.47-7.52(1H, m),









7.68-7.75(1H, m),









8.42-8.50(1H, m)






575




(M +




140-142





Example






(I)




H)






2 step c







645






534




(M +




189-190





Example






(I)




H)






2 step c







543






294




(M +




foam




(CDCl


3


) δ 1.32-1.45(1H,




Example






(IV)




H)





m), 1.56-1.71(2H, m),




2 step c







529





1.79-2.01(5H, m),









2.46-2.61(3H, m),









2.79-2.87(3H, m),









2.92-3.16(4H, m),









3.36-3.42(1H, m),









4.28-4.33(1H, m),









4.79(1H, t), 6.90(2H, dd),









7.12(1H, dt), 7.49(1H, dd),









7.89(1H, ddd), 8.01(1H, dd)






 67




(M +




132-133




(CDCl


3


) δ 1.38-1.65(2H,




Example






(IV)




H)





m), 1.73-2.04(6H, m),




2 step c







495





2.40-2.67(3H, m),









2.72-2.89(3H, m),









2.99-3.08(1H, m),









3.23-3.28(3H, m),









3.33-3.53(1H, m),









4.21-4.33(1H, m),









4.61-4.86(1H, m),









6.87-6.92(2H, m),









7.10-7.14(1H, m),









7.31-7.37(1H, m),









7.55-7.70(2H, m),









8.07(1H, td)






 83




(M +




foam




(CDCl


3


) δ 1.50-1.63(2H,




Example






(IV)




H)





m), 1.85-2.00(6H, m),




2 step c







501





2.44-2.51(2H, m),









2.56-2.66(1H, m),









2.80-2.88(2H, m),









3.01(2H, s), 3.20(3H, s),









4.27-4.51(3H, m),









6.91(2H, dd), 7.13(1H, dt),









7.23(1H, d), 7.63(1H, d)






295




(M +





(CDCl


3


) δ 1.75-2.03(10H,




Example






(IV)




H)





m), 2.18-2.19(3H, m),




2 step c







491





2.44-2.54(2H, m),









2.77-2.89(3H, m),









3.00-3.09(1H, m),









3.23-3.28(3H, m),









3.36-3.52(1H, m),









4.63-4.85(1H, m),









6.70-6.75(1H, m),









7.05-7.11(2H, m),









7.31-7.37(1H, m),









7.56-7.68(2H, m),









8.05-8.10(1H, m)






568




(M +





(DMSO-D6) δ 1.21-1.95(8H,




Example






(I)




H)





m), 2.35-2.42(2H, m),




2 step c







558





2.57-2.66(1H, m),









2.72-2.77(2H, m),









3.08-3.17(1H, m),









4.08-4.13(1H, m),









4.29(2H, d), 4.40-4.46(3H,









m), 6.96-7.00(1H, m),









7.25-7.26(1H, m),









7.48-7.51(1H, m),









7.58-7.62(1H, m),









8.01-8.07(2H, m),









8.40-8.43(1H, m),









8.75-8.78(2H, m)






296




(M +





(CDCl


3


) δ 1.58-1.68(4H,




Example






(IV)




H)





m), 1.85(2H, s), 2.00(2H, s),




2 step c







525





2.19(3H, 2.51-2.59(3H, m),









2.80-2.92(3H, m),









2.98-3.16(4H, m),









3.37-3.43(1H, m),









4.33(1H, s), 4.76-4.85(1H,









m), 6.72-6.74(1H, m),









7.06-7.12(2H, m),









7.45-7.53(1H, m),









7.88-7.91(1H, m),









8.00-8.02(1H, m)






471




472





δ 1.40(m, 2H), 1.57(m, 2H),




Example






(I)




(M +





1.79(m, 2H), 1.90(m, 2H), 2.40




2 step c







H)





(m, 2H), 2.58(m, 1H), 2.79(m,









2H), 2.87(m, 2H), 4.30(d, 2H),









4.43(m, 1H), 6.97(dd, 1H), 7.13









(m, 2H), 7.25(d, 1H), 7.43(d, 1H),









7.49(d, 1H), 7.65(m, 2H)






475




526





(DMSO-D6) δ 1.67-1.78(m,




Example






(I)




(M +





2H), 1.95-2.09(m, 3H),




2 step c







H)





2.18-2.27(m, 2H), 2.44(d 3H),









2.77-2.88(m, 1H),









3.08-3.19(m, 3H),









3.33-3.52(m, 5H),









3.59-3.67(m, 1H),









4.60-4.68(m, 1H), 4.84(s, 1H),









7.05(ddd, 1H), 7.14-7.27(m,









1H), 7.37(dd, 1H), 7.55(t, 1H),









7.61(q, 1H), 7.70-7.71(m,









2H), 7.78-7.80(m, 1H),









7.86-7.89(m, 1H),






569




512





(DMSO-D6) δ 1.65-1.80(m,




Example






(I)




(M +





2H), 1.99-2.09(m, 2H),




2 step c







H)





2.19-2.30(m, 3H),









2.77-2.90(m, 1H),









3.07-3.21(m, 3H),









3.30-3.37(m, 3H),









3.47-3.57(m, 2H),









3.59-3.71(m, 1H),









4.59-4.69(m, 1H),









4.82-4.86(m, 1H),









7.05(ddd, 1H), 7.37(dd, 1H),









7.49(s, 2H), 7.55(t, 1H),









7.64-7.69(m, 2H),









7.84-7.86(m, 1H), 7.92(td, 1H)






477




507





(DMSO-D6) δ 1.64-1.78(m,




Example






(I)




(M +





2H), 1.99-2.09(m, 2H),




2 step c







H)





2.17-2.29(m, 3H),









2.70-2.85(m, 1H),









3.04-3.19(m, 3H),









3.28-3.38(m, 3H),









3.31(s, 3H), 3.46-355(m,









2H), 3.66(t, 2H), 4.12(t, 2H),









4.56-4.68(m, 1H),









4.81-4.86(m, 1H),









6.94-6.97(m, 2H),









7.04(dd, 1H), 7.05(ddd, 1H),









7.34-7.39(m, 2H), 7.55(t, 1H),






584




592





(CDCl


3


) δ 1.45(s, 9H),




Example






(I)




(M +





1.48-1.67(m, 4H),




2 step c







H)





1.75-1.85(m, 2H),









2.03(m, 3H), 2.42-2.51(m, 2H),









2.56(m, 1H), 2.71-2.84(m, 3H),









2.91-3.06(m, 1H), 3.54(q, 2H),









3.75-3.88(m, 1H), 4.03(t, 2H),









4.27(septet, 1H),









4.68-4.82(m, 1H),









4.93-5.01(m, 1H), 6.75(dd,









1H), 6.90-7.00(m, 3H),









7.25-7.32(m, 3H)






325




491





(DMSO-D6) δ 1.69-1.83(2H,




Example






(I)




(M +





m), 1.98-2.11(3H, m),




2 step c







H)





2.17-2.28 (3H, m),




using









2.81-2.92(1H, m),




acid









3.08-3.21(3H, m),




prepared









3.47-3.59(2H, m),




according









3.61-3.71(1H, m),




to









4.61-4.73(2H, m),




Journal









4.82-4.86(1H, m),




of Heter-









7.05(1H, ddd), 7.37(1H, dd),




ocyclic









7.56(1H, t), 7.77(1H, ddd),




chemistry,









8.51(1H, s), 8.80(1H, d)




1972,










p1149






585




507





(DMSO-D6) δ 1.70-1.78(m,




Example






(I)




(M +





2H), 2.00-2.09(m, 2H),




2 step c,







H)





2.18-2.26(m, 2H),




using 3-









3.05-3.17(m, 2H),




tert-but-









3.24-3.40(m, 2H),




oxycar-









3.97-4.06(m, 2H),




bonyl-









4.44-4.52(m, 2H),




methoxy-









4.59-4.70(m, 2H),




benzoic









4.73(s, 2H), 4.81-4.86(m,




acid,









1H), 4.91-4.93(m, 2H),




followed









6.90-6.93(m, 1H),




by the









6.96-7.04(m, 1H),




addition









7.07-7.11(m, 1H),




of (1M)









7.17-7.20(m, 1H),




HCl in









7.34-7.43(m, 2H),




ether to









7.55(m, 1H),




form final










compound










as hydro-










chloride










salt. (HCl










cleaved










tert-butyl










ester to










leave










acid.)






586




492





(DMSO-D6) δ 1.56-1.87(3H,




Prepared






(I)




(M +





m), 1.94-2.17(5H, m),




by de-







H)





3.06-3.27(7H, m),




protection









3.50-3.78(3H, m), 4.19(2H,




of 584 (I)









t), 4.57-4.69(1H, m),




using









4.80-4.85(1H, m),




trifluor-









6.98-7.10(4H, m),




oacetic









7.34-7.44(2H, m),




acid in









7.57(1H, dd)




dichloro-










methane






588




551




  145




(CDCl


3


) δ 0.09(2H,




Example






(I)




(M +





dd), 0.44(2H, dd),




2 step c







H)





0.83-0.89(1H, m), 1.78(2H,









m), 1.96-2.09(3H, m),









2.18-2.28(4H, m),









2.78-2.89(1H,









m), 3.08-3.20(4H, m),









3.34(2H, s), 3.47-3.65(3H,









m), 4.59-4.68(1H, m),









4.84(1H, s), 7.05(1H, ddd),









7.36(1H, dd), 7.55(1H,t),









7.73-7.81(2H, m), 7.90(1H,









t), 8.00(1H, d)






 71




497





(CDCl


3


) δ 1.56(2H,




Example






(IV)




(M +





qd), 1.79-1.99(8H, m), 2.19(3H,




2 step c







H)





s), 2.45-2.52(2H, m), 2.60(1H,









tt), 2.76-2.83(2H, m),









2.91-3.11(2H, m), (3H, s),









4.28-4.35(1H, m), 6.74(1H,









d), 7.05-7.12(2H, m), (1H,









d), 7.63(1H, d)






245




486




120-126




(CDCl


3


) δ 1.45-1.61(2H,




Example






(IV)




(M +





m), 1.80-2.03(6H, m), 2.19(3H,




2 step c







H)





s), 2.45-2.53(2H, m),




using 2-









2.54-2.62(1H, m),




Oxo-2,3-









2.79-3.09(4H, m),




dihydro-









3.80-3.99(1H, m),




benzothia-









4.28-4.34(1H, m),




zole-6-









4.62-4.81(1H, m), 6.73(1H,




carboxylic









d), 7.05-7.12(3H, m),




acid









7.30(1H, dd), 7.47(1H, d)




prepared










according










to Chem.










Pharm.










Bull.










1988, 36










p2253






297




526




115-117




(CDCl


3


) δ 1.42-1.64(2H,




Example






(IV)




(M +





m), 1.78-1.87(3H, m),




2 step c







H)





1.93-2.01(3H, m), 2.19(3H,









s), 2.44-2.51(2H, m),









2.57(1H, tt), 2.75-2.88(3H,









m), 3.01-3.14(1H, m),









3.64-3.73(1H, m),









4.27-4.33(1H, m),









4.65-4.74(1H, m), 6.73(1H,









d), 7.07(1H, dd), 7.11(1H, d),









7.52(1H, dd), 7.58(1H, d),









8.11(1H, d)






298




480




120-126




(CDCl


3


) δ 1.31-1.66(2H,




Example






(IV)




(M +





m), 1.70-2.05(6H, m), 2.19(3H,




2 step c







H)





s), 2.38-2.60(3H, m),









2.73-2.83(2H, m),









2.85-3.11(2H, m),









3.71-3.86(1H, m),









4.26-4.35(1H, m),









4.76-4.92(1H, m), 6.73(1H,









d), 7.07(1H, dd), 7.11(1H, s),









7.19-7.34(1H, m), 7.57(1H,









t), 7.59-7.68(1H, m),









7.73(1H, t), 8.46(1H, d)






214




514




   96




(CDCl


3


) δ 1.42-1.62(2H,




Example






(IV)




(M +





m), 1.74-2.02(6H, m), 2.19(3H,




2 step c







H)





s), 2.44-2.61(3H, m),









2.75-2.85(3H, m),









2.95-3.11(1H, m),









3.42(21H, s), 3.45(3H, s),









3.78-3.93(1H, m),









4.26-4.36(1H, m),









4.64-4.81(1H, m), 6.74(1H,









d), 7.02-7.15(3H, m),









7.27(1H, s), 7.38(1H, d)






589




540





(CDCl


3


) δ 1.52-1.62(2H,




Example






(I)




(M +





m), 1.68(1H, d), 1.84(1H, d),




2 step c







H)





1.92(2H, d), 2.35-2.42(2H,









m), 2.52-2.55(1H, m),









2.63(6H, s), 2.72-2.83(3H,









m), 2.99-3.13(2H, m),









3.46-3.56(2H, m),









4.38-4.45(1H, m), 4.49(1H,









d), 6.98(1H, dd), 7.25(1H, d),









7.49(1H, d), 7.73-7.75(2H, m),









7.81-7.83(1H, m), 8.31(1H, s)






590




556





(DMSO-D6) δ 1.43-1.62(4H,




Example






(I)




(M +





m), 1.66(1H, d), 1.85(1H, d),




2 step c







H)





1.89-1.97(2H, m),









2.35-2.44(3H, m),









2.73-2.87(3H, m), 3.11(1H,









t), 3.42(3H, s), 3.52(1H, d),









4.39-4.46(1H, m), 4.50(1H,









d), 6.98(1H, dd), 7.25(1H, d),









7.49(1H, d), 8.36(1H, t),









8.54(1H, t), 8.67(1H, t)






591




526





(DMSO-D6) δ 1.29-1.39(2H,




Example






(I)




(M +





m), 1.90(2H, d), 2.11-2.18(1H,




2 step c







H)





m), 2.39(2H, t), 3.13(2H, t),









3.44-3.52(2H, m),









3.65-3.73(2H, m),









3.82-3.91(4H, m),









3.94-4.01(2H, m),









4.47-4.57(1H, m), 6.15 (1H,









d), 6.88-6.93(1H, m),









6.95(1H, dd), 7.03(1H, d),









7.31(1H, t), 7.62-7.65(1H, m),









8.32-8.51(2H, m), 8.95(1H, t)






593




536





(DMSO-D6) δ 1.42-1.63(4H,




Example






(I)




(M +





m), 1.66(1H, d), 1.84(1H, d),




2 step c







H)





1.89-1.97(2H, m),









2.32-2.45(1H, m),









2.50-2.61(2H, m),









2.72-2.87(3H, m), 3.08(1H,









t), 3.37(3H, s), 3.48(1H, d),









4.37-4.46(1H, m),









4.46-4.55(1H, m), 6.98(1H,









dd), 7.25(1H, d), 7.49(1H, d),









8.21(1H, t), 8.30(1H, t),









8.48(1H, t)






594




550





(DMSO-D6) δ 1.38-1.52(2H,




Example






(I)




(M +





m), 1.53-1.64(2H, m), 1.84(2H,




2 step c







H)





d), 1.88-1.98(2H, m),









2.37-2.45(4H, m),









2.58-2.68(1H, m),









2.74-2.82(3H, m), 3.17(3H,









s), 4.37-4.50(2H, m),









6.99(1H, dd), 7.00-7.02(1H,









m), 7.26(1H, d), 7.49(1H, d),









7.61(1H, d), 7.70(1H, dd),









8.23(1H, d)






299




525





(DMSO-D6) δ 1.38-1.5(2H,




Example






(IV)




(M +





m), 1.60-1.70(2H, m),




12







H)





1.81-2.00(2H, m), 2.40(3H,









s), 2.41-3.31(9H, m),









3.35(3H, s), 3.41-3.58(1H,









m), 4.4-4.55(2H, m), 7.09(1H,









d), 7.34(1H, d), 7.71(2H, m),









7.90(1H, s), 8.0(1H, m)






300




489





(DMSO-D6) δ 1.10(3H, t),




Example






(IV)




(M +





1.35-1.50(2H, m),




12







H)





1.58-1.70(2H, m),









1.81-1.97(2H, m),









2.25-3.20(1 1H, m),









3.32(3H, s), 3.4-3.6(1H,









m), 4.25-4.6(2H, m),









6.85-7.00(3H, m),









7.63-7.78(2H, m), 7.90(1H,









s), 7.98-8.02(1H, m)






143




465





(CDCl


3


) δ 1.63-1.74(2H,




Example






(IV)




(M +





m), 1.78-1.88(3H, m),




2 step c







H)





1.92-2.04(3H, m), 2.19(3H, s),









2.43-2.55(2H, m), 2.64(1H,









tt), 2.76-2.94(3H, m),









3.13-3.27(1H, m),









4.25-4.35(2H, m),









4.82-4.90(1H, m), 6.74(1H,









d), 7.07(1H, dd), 7.11(1H, d),









7.56(1H, dd), 7.85(1H, d),









8.25(1H, dd), 8.32(1H, d),









9.19(1H, dd)






301




530





(CDCl


3


) δ 1.57-1.71(2H,




Example






(IV)




(M +





m), 1.80-1.91(3H, m),




2 step c







H)





1.95-2.06(3H, m), 2.20(3H, s),









2.47-2.55(2H, m),









2.61-2.72(1H, m),









2.79-2.86(2H, m),









2.91-3.35(2H, m), 3.08(3H, s),









4.28-4.37(1H, m),









4.69-4.80(2H, m), 6.74(1H, d),









6.90(1H, d), 7.07(1H, dd),









7.12(1H, d), 7.57(1H, d),









7.79(1H, dd), 8.32(1H, d)






572




500





(CDCl


3


) δ 1.37-1.66(2H,




Example






(I)




(M +





m), 1.73-1.88(3H, m),




2 step c







H)





1.93-2.05(3H, m),









2.41-2.51(2H, m),









2.52-2.63(1H, m),









2.75-2.86(2H, m),









2.86-3.09(2H, m),









3.71-3.90(1H, m),









4.23-4.32(1H, m),









4.77-4.93(1H, m), 6.75(1H,









dd), 6.99(1H, d), 7.27-7.32(3H,









m), 7.54-7.67(1H, m), 7.57(1H,









t), 7.74(1H, t), 8.46(1H, d)






120




480





(CDCl


3


) 8 1.46-1.66(2H,




Example






(IV)




(M +





m), 1.79-2.01(6H, m), 2.19(3H,




2 step c







H)





s), 2.45-2.52(2H, m), 2.59(1H,




using









tt), 2.75-2.84(2H, m),




acid









2.92-3.20(2H, m)




available









3.74-4.00(1H, m),




from









4.27-4.35(1H, m),




Bionet









4.55-4.90(1H, m), 6.49(1H,




Research









dd), 6.74(1H, d), 7.07(1H, dd),




Ltd.,









7.11(1H, d), 7.76(1H, d),




Highfield









7.8(1H, dd), 8.03(1H, d),




Industrial









8.48(1H, d), 8.57(1H, d)




Estate,










Camelford,










Cornwall,










PL32 9QZ,










United










Kingdom






145




538





(CDCl


3


) δ 1.35-1.73(2H,




Example






(IV)




(M +





m), 1.77-1.89(3H, m),




2 step c







H)





1.92-2.06(3H, m), 2.19(3H,




using









s), 2.43-2.64(3H, m),




acid









2.74-2.83(2H, m),




available









2.83-2.94(1H, m),




from









3.00-3.12(1H, m),




Peakdale









3.38-3.54(1H, m),




Inc. 109









4.26-4.35(1H, m),




East









4.76-4.92(1H, m), 6.73(1H,




Scotland









d), 7.07(1H, dd), 7.11(1H, d),




Drive









7.70(1H, d), 7.98(1H, dd),




Bear,









8.19(1H, d)




DE,










19701-1756










USA






240




465





(CDCl


3


) δ 1.62-1.74(2H,




Example






(IV)




M +





m), 1.77-1.86(3H, m),




2 step c







H)





1.93-2.03(3H, m), 2.33(3H, s),









2.41-2.54(2H, m), 2.65(1H,









tt), 2.78-2.86(1H, m),









2.89(2H, td), 3.21(1H, td),









4.21-4.35(2H, m),









4.81-4.90(1H, m), 6.67(1H,









dd), 6.78(1H, d), 7.20(1H, d),









7.57(1H, dd), 7.85(1H, d),









8.25(1H, dd), 8.32(1H, d),









9.19(1H, dd)






267




453





(CDCl


3


) δ 1.62(2H,




Example






(IV)




(M +





qd), 1.79-2.01(6H, m),




2 step c







H)





2.19(3H, s), 2.4(2H, m),









2.64(1H, tt), 2.74-2.85(2H,









m), 3.12-3.22(1H, m),









4.26-4.32(1H, m),









4.77-4.86(1H, m),









5.24-5.33(1H, m), 6.74(1H, d),









6.84(1H, td), 7.07(1H, dd),









7.11(1H, d), 7.21(1H, dd),









7.23(1H, dd), 7.60(1H, dd),









8.06(1H, d), 8.13(1H, dt)






199




470





(CDCl


3


) δ 1.57-1.67(2H,




Example






(IV)




(M +





m), 1.81-1.88(2H, m),




2 step c







H)





1.93-2.01(4H, m), 2.20(3H,









s), 2.50(2H, td), 2.65(1H, tt),









2.82(2H, td), 2.96-3.20(2H,









m), 4.28-4.35(1H, m),









4.74(2H, d), 6.73-6.75(2H,









m), 7.12(3H, m), 7.28(1H, d),









7.35(1H, dd), 9.35(1H, s)






181




538





(CDCl


3


) δ 1.50-1.65(2H,




Example






(IV)




(M +





m), 1.70-1.83(3H, m),




2 step c







H)





1.93-2.04(3H, m), 2.32(3H,









s), 2.40-2.50(2H, m),









2.52-2.62(1H, m),









2.76-2.92(3H, m),









3.01-3.10(1H, m),









3.38-3.52(1H, m),









4.22-4.30(1H, m),









4.77-4.90(1H, m), 6.67(1H,









dd), 6.77(1H, d), 7.20(1H, d),









7.70(1H, d), 7.98(1H, dd),









8.19(1H, d)






216




526





(CDCl


3


) δ 1.47-1.66(2H,




Example






(IV)




(M +





m), 1.79-1.88(3H, m),




2 step c







H)





1.95-2.04(3H, m), 2.32(3H,









s), 2.53-2.61(2H, m),









2.70(1H, tt), 2.76-2.89(3H,









m), 2.99-3.13(1H, m),









3.63-3.74(1H, m),









4.27-4.33(1H, m),









4.63-4.77(114, m), 6.67(1H,









dd), 6.77(1H, d), 7.20(1H, d),









7.50(1H, dd), 7.56(1H, d),









8.09(1H, d)






266




480





(CDCl


3


) δ 1.37-1.67(2H,




Example






(IV)




(M +





m), 1.76-1.85(3H, m),




2 step c







H)





1.93-2.01(3H, m), 2.32(3H,









s), 2.41-2.48(2H, m),









2.50-2.60(1H, m),









2.77-2.85(2H, m),









2.86-3.10(2H, m),









3.73-3.85(1H, m),









4.23-4.29(1H, m),









4.77-4.92(1H, m), 6.67(1H,









dd), 6.77(1H, d), 7.20(1H, d),









7.21-7.31(1H, m),









7.54-7.68(1H, m), 7.56(2H,









t), 7.73(1H, t), 8.46(1H, d)






540




485





(CDCl


3


) δ 1.69-1.84(4H,




Example






(I)




(M +





m), 1.95-2.02(4H, m),




2 step c







H)





2.43-2.53(2H, m), 2.65(1H,









tt), 2.79-2.93(3H, m),









3.18-3.25(1H, m),









4.23-4.35(2H, m),









4.82-4.90(1H, m), 6.75(1H,









dd), 7.00(1H, d), 7.31(1H, d),









7.57(1H, dd), 7.86(1H, d),









8.25(1H, dd), 8.32(1H, d),









9.19(1H, dd)






204




470





(CDCl


3


) δ 1.57-1.67(2H,




Example






(IV)




(M +





m), 1.77-1.85(2H, m),




2 step c







H)





1.94-2.02(4H, m), 2.33(3H,









s), 2.45-2.52(2H, m),









2.61-2.69(1H, m),









2.81-2.86(2H, m),









2.97-3.18(2H, m),









4.24-4.30(1H, m), 4.74(2H,









d), 6.68(1H, dd), 6.73(1H, d),









6.78(1H, d), 7.04(1H, td),









7.20(1H, d), 7.28(1H, d),









7.35(1H, dd), 9.34(1H, s).






104




480





(CDCl


3


) δ 1.49-1.63(2H,




Example






(IV)




(M +





m), 1.76-2.00(6H, m), 2.33(3H,




2 step c







H)





s), 2.43-2.49(2H, m), 2.59(1H,









tt), 2.79-2.85(3H, m),









3.00-3.18(1H, m),









3.81-3.96(1H, m),









4.24-4.29(1H, m),









4.67-4.83(1H, m), 6.49(1H,









dd), 6.67(1H, dd), 6.78(1H,









d), 7.20(1H, d), 7.76(1H, d),









7.88(1H, dd), 8.03(1H, d)









8.48(1H, d), 8.57(1H, d)






243




486





(DMSO-D6/CDCl


3


) δ




Example






(IV)




(M +





1.43-1.59(2H, m),




2 step c







H)





1.73-1.98(6H, m), 2.32(3H,









s), 2.43-2.48(2H, m),









2.79-2.87(2H, m),









2.91-3.40(5H, m),









4.23-4.30(1H, m), 6.68(1H,









dd), 6.78(1H, d), 7.14(1H, d),









7.19(1H, d), 7.26(1H, dd),









7.43(1H, d), 7.51(1H, s).






191




514





(CDCl


3


) δ 1.46-1.59(2H,




Example






(IV)




(M +





m), 1.76-2.00(6H, m),




2 step c







H)





2.32(3H, s), 2.44-2.48(2H,









m), 2.54-2.59(1H, m),









2.78-2.85(3H, m), 3.42(3H,









s), 3.45(3H, s), 3.79-3.92(1H,









m), 4.23-4.30(1H, m),









4.67-4.79(1H, m), 6.67(1H,









dd), 6.77(1H, d), 7.02(1H, d),









7.15(1H, s), 7.20(1H, d,









7.37(1H, d)






519




490





(CDCl


3


) δ 1.61(2H,




Example






(I)




(M +





qd), 1.77-1.85(2H, m),




2 step c







H)





1.94-2.02(4H, m),









2.38-2.51(2H, m), 2.65(1H,









tt), 2.80-2.85(2H, m),









2.95-3.14(2H, m),









4.25-4.30(1H, m),









4.73-4.77(2H, m), 6.73(1H,









d), 6.75(1H, dd), 7.00(1H,









d), 7.03(1H, td), 7.27(1H,









dd), 7.31(1H, d), 7.35(1H, d









9.49(1H, s)






494




558





(CDCl


3


) δ 1.48-1.71(2H,




Example






(I)




(M +





m), 1.74-1.83(3H, m),




2 step c







H)





1.93-2.03(3H, m),









2.42-2.50(2H, m),









2.55-2.62(1H, m),









2.76-2.93(3H, m),









3.01-3.10(1H, m),









3.40-3.50(1H, m),









4.22-4.31(1H, m),









4.77-4.90(1H, m), 6.75(1H,









dd), 6.98(1H, d), 7.30(1H,









d), 7.67(1H, d), 7.98(1H,









dd), 8.19(1H, d)






238




511




172-173




(CDCl


3


) δ 1.53-1.63(2H,




Example






(IV)




(M +





m), 1.82-1.89(3H, m),




21







H)





2.00-2.05(3H, m),









2.05-2.61(3H, m),









2.80-2.84(3H, m),









2.98-3.09(1H, m), 3.03(3H,









s), 3.77(1H, br s),









4.41-4.45(1H, m), 4.70(1H,









hr s), 6.99(2H, d),









7.21-7.26(1H, m),









7.44-7.54(2H, m), 7.86(2H, d)






496




500





(DMSO-D6) δ 1.46(2H, qd),




Example






(I)




(M +





1.54-1.61(2H, m),




2 step c







H)





1.65-1.88(3H, m),









1.89-1.97(2H, m),









2.37-2.42(2H, m),









2.54-2.61(1H, m),









2.73-2.83(2H, m),









3.04-3.17(1H, m),









3.61-3.72(1H, m),









4.39-4.56(2H, m), 6.62(1H,









dd), 6.98(1H, dd), 7.25(1H,









d), 7.49(1H, d), 7.87(1H,









dd), 7.97(1H, dd), 8.04(1H,









dd), 8.52(1H, dd), 8.65(1H, dd)






483




506





(DMSO-D6) δ 1.41(2H, qd),




Example






(I)




(M +





1.53-1.62(2H, m),




2 step c







H)





1.68-1.82(2H, m),









1.89-1.96(2H, m),









2.36-2.43(3H, m),









2.53-2.59(3H, m),









2.74-2.80(3H, m),









4.39-4.45(1H, m), 6.97(1H,









dd), 7.13(1H, d), 7.25(1H,









d), 7.30(1H, dd), 7.49(1H,









d), 7.66(1H, d)






302




498





(CDCl


3


) δ 1.40-1.74(2H,




Example






(IV)




(M +





m), 1.79-2.02(6H, m), 2.20(3H,




2 step c







H)





s), 2.42-2.61(3H, m), 2.67(1H,









td), 2.74-2.84(2H, m), 3.16(1H,









t), 3.91-4.00(1H, m),









4.26-4.36(1H, m),









4.58-4.78(5H, m), 6.74(1H,









d), 6.76-6.79(1H, m),









6.98-7.02(3H, m), 7.07(1H,









dd), 7.12(1H, d)






303




498





(CDCl


3


) δ 1.42-1.61(2H,




Example






(IV)




(M +





m), 1.77-1.90(3H, m),




2 step c







H)





1.93-2.03(3H, m), 2.33(3H,









s), 2.41-2.49(2H, m),









2.57(1H, tt), 2.67(1H, t),









2.77-2.84(2H, m), 3.16(1H,









t), 3.95(1H, d), 4.24-4.29(1H,









m), 4.59-4.77(5H, m), 6.68(1H,









dd), 6.75-6.79(2H, m),









6.97-7.00(3H, m), 7.21(1H, d)






596




518





(CDCl


3


) δ 1.43-1.64(2H,




Example






(I)




(M +





m), 1.77-1.89(3H, m),




2 step c







H)





1.94-2.01(3H, m),









2.41-2.50(2H, m), 2.57(1H,









tt), 2.68(1H, t), 2.76-2.83(2H,









m), 3.16(1H, t), 3.94-3.97(1H,









m), 4.24-4.30(1H, m),









4.58-4.63(1H, m), 4.68(2H,









s), 4.76(2H, d), 6.76-6.78(2H,









m), 6.98-7.00(3H, m), 7.26(1H,









s), 7.31(1H, d)






467




534





(DMSO-D6) δ 1.35-1.50(2H,




Example






(I)




(M +





m), 1.52-1.65(3H, m),




2 step c







H)





1.68-1.84(2H, m),









1.88-1.98(2H, m),









2.35-2.44(2H, m),









2.54-2.61(1H, m),









2.73-2.82(3H, m), 3.37(3H,









s), 3.57(2H, s), 3.60-3.71(1H,









m), 4.38-4.56(2H, m), 6.98(1H,









dd), 7.07(1H, dd), 7.24(1H, d),









7.26(1H, d), 7.47(1H, d),









7.50(1H, d)






269




453





(CDCl


3


) δ 1.55-1.68(4H,




Example






(IV)




(M +





m), 1.75-2.01(4H, m), 2.33(3H,




2 step c







H)





s), 2.41-2.51(2H, m), 2.64(1H,









tt), 2.78-2.87(3H, m),









3.12-3.24(1H, m),









4.21-4.29(1H, m),









4.76-4.88(1H, m),









5.23-5.34(1H, m), 6.67(1H,









dd), 6.78(1H, d), 6.84(1H, t),









7.19-7.26(2H, m), 7.60(1H, d),









8.06(1H, s), 8.13(1H, dd)






597




546





(CDCl


3


) δ 1.39-1.66(2H,




Example






(I)




(M +





m), 1.73-1.86(4H, m),




2 step c







H)





1.92-2.03(2H, m),









2.41-2.50(2H, m),









2.53-2.63(1H, m),









2.76-2.88(2H, m),









2.98-3.12(1H, m),









3.62-3.77(1H, m),









4.24-4.29(1H, m),









4.62-4.78(1H, m), 6.75(1H,









dd), 6.99(1H, d), 7.31(2H, d),









7.53(1H, dd), 7.57(1H,




t),









8.12(1H, d)






598




474





(CDCl


3


) δ 1.58-1.75(2H,




Example






(I)




(M +





m), 1.80-1.88(2H, m),




2 step c







H)





1.91-2.05(4H, m),









2.53-2.61(2H, m),









2.71-2.90(4H, m),









3.18-3.22(1H, m),









4.27-4.33(1H, m), 4.84(1H,









d), 5.55(1H, d), 6.75(1H,









dd), 6.95(1H, dd), 7.00(1H,









d), 7.31(1H, d), 8.09(1H, s),









8.46(1H, dd), 8.62(1H, dd)






579




491





(CDCl


3


) δ 1.61(1H, qd),




Example






(I)




(M +





1.75-2.02(7H, m),




2 step c







H)





2.42-2.51(2H, m),









2.59-2.67(1H, m),









2.75-2.86(3H, m),









3.12-3.21(1H, m),









4.23-4.29(1H, m),









4.76-4.85(1H, m),









5.23-5.32(1H, m), 6.75(1H,









dd), 6.99(1H, d), 7.16(1H,









ddd), 7.30(1H, d), 7.58(1H,









dd), 8.07(2H, s)






599




487





(CDCl


3


) δ 1.58-1.67(1H,




Example






(I)




(M +





m), 1.75-2.02(7H, m),




2 step c







H)





2.43-2.51(3H, m),









2.59-2.68(1H, m), 2.61(3H,









s), 2.76-2.85(3H, m),









3.12-3.23(1H, m),









4.23-4.28(1H, m),









4.78-4.87(1H, m),









5.30-5.38(1H, m),









6.67(1H, d), 6.75(1H, dd),









7.20(1H, dd), 7.30(1H, d),









7.51(1H, d), 8.01(1H, s)






600




507





(CDCl


3


) δ 1.61(1H,




Example






(I)




(M +





qd), 1.70-2.04(7H, m),




2 step c







H)





2.41-2.53(2H, m), 2.63(1H,









t), 2.73-2.88(3H, m),









3.09-3.23(1H, m),









4.21-4.31(1H, m),









4.74-4.86(1H, m),









5.20-5.30(1H, m), 6.75(1H,









dd), 6.99(1H, d), 7.19(1H, d),









7.30(1H, d), 7.55(1H, d),









8.04(1H, s), 8.19(1H, s)






304




505





(CDCl


3


) δ 1.57-1.68(2H,




Example






(IV)




(M +





m), 1.82-2.01(6H, m),




2 step c







H)





2.46-2.54(2H, m), 2.46(3H,









s), 2.59-2.69(1H, m),









2.73-2.90(3H, m),









3.10-3.23(1H, m),









4.32-4.39(1H, m),









4.76-4.85(1H, m),









5.22-5.32(1H, m),









6.75(1H, d), 7.14-7.27(2H,









m), 7.58(1H, dd), 8.07(2H, s)






601




487





(CDCl


3


) δ 1.55-1.65(1H,




Example






(I)




(M +





m), 1.75-2.01(7H, m), 2.40(3H,




2 step c







H)





s), 2.44-2.50(2H, m), 2.63(1H,









qt), 2.73-2.86(3H, m),









3.10-3.22(1H, m),









4.22-4.28(1H, m),









4.75-4.86(1H, m),









5.22-5.34(1H, m), 6.66(1H,









dd), 6.75(1H, dd), 6.99(1H, d),









7.30(1H, d), 7.34(1H, s), 7.97(1H,









s), 7.99(1H, d)






343




566





(CDCl


3


) δ 1.39-1.65(1H,




Example






(I)




(M +





m), 1.77-1.89(4H, m),




2 step c







H)





1.94-2.03(3H, m),









2.43-2.50(2H, m),









2.54-2.62(1H, m),









2.77-2.90(3H, m),









3.03-3.13(1H, m), 3.53(3H,









s), 3.65-3.74(1H, m),









4.26-4.31(1H, m), 4.26(2H,









s), 4.69-4.79(1H, m),









6.75(1H, dd), 6.99(1H, d),









7.26-7.35(3H, m), 8.00(1H, d)






603




526





(CDCl


3


) δ 1.49-1.58(2H,




Example






(I)




(M +





m), 1.76-1.84(3H, m),




2 step c







H)





1.90-2.01(4H, m),









2.44-2.48(2H, m),









2.53-2.59(1H, m),









2.78-2.82(2H, m),









2.78-3.00(5H, m),









3.15-3.19(1H, m),









4.24-4.29(1H, m), 4.96(2H,









s), 6.74-6.80(2H, m),









6.99(1H, d), 7.31(1H, d),









7.66-7.70(2H, m)






534




543





(CDCl


3


) δ 1.49(3H, t),




Example






(I)




M +





1.57-2.00(6H, m),




2 step c







H)





2.43-2.52(2H, m),









2.56-2.62(3H, m), 2.67(3H,









s), 2.78-2.84(3H, m),









3.10-3.19(1H, m),3.74(1H,









d), 4.25(1H, dquintet),









4.42-4.49(2H, m), 4.76(1H,









d), 6.75(1H, dd), 6.99(1H,









d), 7.23(1H, d), 7.30(1H, d),









8.09(1H, s), 8.60(1H, d)






 5




474






Example






(II)




(M +






2 step c







H)






 6




468





(DMSO-D6) δ 1.39-1.45(1H,




Example






(II)




(M +





m), 1.54-1.93(6H, m),




2 step c







H)





2.32-2.39(2H, m),









2.49-2.53(2H, m),









2.72-3.02(4H, m),









3.29-3.32(2H, m),









4.31-4.34(1H, m),









6.75-6.79(1H, m), 7.08(1H,









ddd), 7.30(2H, dt),









7.49-7.56(2H, m), 7.76(1H,









t), 8.24(1H, dd)






 7




453





(DMSO-D6) δ 1.45-1.69(5H,




Example






(II)




(M +





m), 1.84-1.99(3H, m), 2.40(2H,




2 step c







H)





t), 2.59-2.66(1H, m),









2.73-2.92(3H, m),









3.03-3.14(1H, m),









3.69-3.76(1H, m),









4.31-4.37(1H, m),









4.55-4.61(1H, m), 6.78(1H,









dd), 7.09(1H, ddd), 7.31(1H,









dt), 7.69-7.78(2H, m),









8.49-8.65(2H, m), 9.15(1H, dd)






 8




441





(DMSO-D6) δ 1.34-1.45(2H,




Example






(II)




(M +





m), 1.52-1.61(2H, m),




2 step c







H)





1.76-1.86(2H, m),









1.87-1.96(2H, m),









2.33-2.44(2H, m),









2.56-2.63(1H, m),









2.72-2.81(3H, m),









3.05-3.14(1H, m),









4.29-4.38(1H, m),









4.51-4.61(1H, m),









5.09-5.19(1H, m),









6.73-6.79(1H, m),









6.94-6.99(1H, m),









7.04-7.12(1H, m),









7.28-7.34(2H, m), 7.61(1H,









dd), 8.30(1H, s), 8.56(1H, dt)






305




514





(DMSO-D6) δ0 1.42-1.51(2H,




Example






(IV)




(M +





m), 1.60-1.93(6H, m),




2 step c







H)





2.41-2.47(2H, m), 2.41(3H,









s), 2.54-2.60(1H, m),









2.72-2.80(2H, m),









3.05-3.15(1H, m),









3.29-3.35(1H, m),









3.60-3.71(1H, m),









4.44-4.54(2H, m),









6.59-6.64(1H, m),









7.07-7.13(1H, m),









7.31-7.38(1H, m),









7.89(1H, m), 7.95-7.99(1H,









m), 8.01-8.07(1H, m),









8.50-8.54(III, m),









8.63-8.67(1H, m)






306




531





(DMSO-D6) δ 1.39-1.95(8H,




Example






(IV)




(M +





m), 2.40(3H, s), 2.42-2.47(2H,




2 step c







H)





2.55-2.63(2H, m),









2.72-2.81(2H, m),









2.94-3.09(2H, m), 3.42(3H,









s), 4.14-4.32(1H, m),









4.46-4.54(1H, m), 7.10(1H,









d), 7.36(1H, d), 7.49(1H, d),









7.78(1H, d)






307




525





(DMSO-D6) δ 1.39-1.95(9H,




Example






(IV)




(M +





m), 2.42(3H, s), 2.44-2.48(1H,




2 step c







H)





m), 2.55-2.61(1H, m),









2.70-2.83(2H, m),









2.99-3.10(1H, m), 3.29(3H, s),









3.41-3.52(2H, m),









4.46-4.58(2H, m), 7.11(1H, d),









7.36(1H, d), 7.66(2H, dd),









7.99(2H, dd)






308




512





(DMSO-D6) δ 1.60-4.25(18H,




Prepared






(IV)




(M +





m), 4.55-4.80(1H, m),




in a







H)





5.22-5.45(1H, m), 7.05(1H, t),




similar









7.75-7.82(2H, m), 7.85(1H, s),




manner to









8.00-8.18(2H, m), 8.60(1H, s),




Example









9.63(1H, br s)




15 and










isolated










as the










trifluor-










oacetate










salt






 1




509




87-88




(DMSO-D6) δ 1.11-1.18(2H,




Example






(V)




(M +





m), 1.36-1.53(4H, m),




2 step c







H)





1.63-1.78(2H, m), 2.07(2H, t),









2.48-2.52(2H, m),









2.81-2.84(4H, m),









3.01-3.04(2H, m),









3.27-3.27(3H, m),









3.49-3.50(1H, m),









4.44-4.53(1H, m),









7.15-7.18(1H, m),









7.44-7.45(1H, m),









7.50-7.53(1H, m),









7.69-7.76(2H, m),









7.90(1H, t), 7.98-8.02(1H, m)






 2




510





(CDCl


3


) δ 1.38-1.48(3H,




Example






(V)




(M +





m), 1.59(1H, brs),




12







H)





1.81-2.07(4H, m),









2.34(2H, t), 2.55-2.60(1H,









m), 2.84-2.92(3H, m),









3.07(4H, s), 3.21(1H, hr s),









3.60(1H, d), 3.68(1H, br s),









4.74(1H, br s), 6.41(1H, dd),









6.64(1H, d), 7.16(1H, d),









7.62-7.70(2H, m),









7.97-8.02(2H, m)






 3




523





(DMSO-D6) δ 1.42-1.56(4H,




Prepared






(V)




(M +





m), 1.64-1.86(4H, m), 2.33(2H,




in a







H)





t), 2.54-2.61(1H, m),




similar









2.76-2.85(1H, m),




maner to









2.87-2.93(2H, m),




Example









3.04-3.12(1H, m), 3.28(3H,




12 using









s), 3.36-3.44(1H, m),




(3,4-Di-









3.48-3.57(1H, m),




chloro-









4.47-4.55(1H, m),




phenyl)-









7.70-7.77(2H, m), 7.80(1H,




piperidin-









d), 7.91-7.95(2H, m),




4-yl-meth-









8.00(1H, dt), 8.14-8.16(1H, m)




anone










hydro-










chloride










free base










was made










insitu










using










triethyl-










amine






310




478




169-170




(DMSO-D6) δ 1.29-1.40(2H,




Example






(IV)




(M +





m), 1.53-1.62(2H, m),




26 using







H)





1.71-1.77(2H, m),




4-Meth-









1.89-1.96(2H, m),




oxyphenyl-









2.35-2.42(2H, m),




isocyanate









2.45-2.49(1H, m),









2.68-2.79(4H, m), 3.70(3H,









s), 4.10-4.17(2H, m),









4.38-4.45(1H, m),









6.78-6.82(2H, m), 6.98(1H,









dd), 7.25(1H, d), 7.30-7.34(2H,









m), 7.49(1H, d), 8.30(1H, s)






311




466




  217




(DMSO-D6) δ 1.29-1.40(2H,




Example






(IV)




(M +





m), 1.53-1.62(2H, m),




26 using









1.72-1.78(2H, m),




4-Fluoro-









1.89-1.96(2H, m),




phenyl-









2.36-2.42(2H, m),




isocyanate









2.44-2.49(1H, m),









2.71-2.79(4H, m),









4.11-4.17(2H, m),









4.38-4.45(1H, m), 6.98(1H,









dd), 7.05(2H, t), 7.25(1H,









d), 7.45(2H, tt), 7.49(1H,









d), 8.50(1H, s)






312




494




170-172




(DMSO-D6) δ 1.29-1.40(2H,




Example






(IV)




(M +





m), 1.52-1.62(2H, m),




26 using







H)





1.72-1.78(2H, m),




3-(Meth-









1.89-1.96(2H, m),




ylthio)-









2.36-2.42(2H, m), 2.43(3H,




phenyl-









s), 2.44-2.48(1H, m),




isocyanate









2.71-2.79(4H, m), 4.15(2H,









d), 4.38-4.45(1H, m), 6.81(1H,









d), 6.98(1H, dd), 7.15(1H, t),









7.24-7.27(2H, m), 7.43(1H,









t), 7.49(1H, d), 8.48(1H, s)






313




462




178-179




(DMSO-D6) δ 1.22-1.34(2H,




Example






(IV)




(M +





m), 1.52-1.61(2H, m),




26 using







H)





1.65-1.72(2H, m),




Benzyl-









1.88-1.95(2H, m),




isocyanate









2.33-2.46(3H, m),









2.61-2.76(4H, m),









3.99-4.05(2H, m), 4.22(2H,









d), 4.37-4.44(1H, m),









6.97(1H, dd), 7.04(1H, t),









7.18-7:31(6H, m), 7.49(1H, d)






314




492




166-167




(DMSO-D6) δ 1.21-1.32(2H,




Example






(IV)




(M +





m), 1.51-1.61(2H, m),




26 using







H)





1.64-1.71(2H, m),




4-Methox-









1.88-1.95(2H, m),




ybenzyl-









2.32-2.46(3H, m),




isocyanate









2.59-2.67(2H, m),









2.69-2.76(2H, m), 3.71(3H,









s), 4.01(2H, d), 4.14(2H, d),









4.37-4.44(1H, m),









6.83-6.87(2H, m),









6.94-6.99(2H, m),









7.14-7.18(2H, m),









7.25(1H, d), 7.49(1H, d)






315




480




209-210




(DMSO-D6) δ 1.21-1.32(2H,




Example






(IV)




(M +





m), 1.52-1.61(2H, m),




26 using







H)





1.65-1.71(2H, m),




4-Fluor-









1.88-1.95(2H, m),




obenzyl-









2.32-2.46(3H, m),




isocyanate









2.60-2.68(2H, m),









2.70-2.76(2H, m), 4.01(2H,









d), 4.19(2H, d),









4.38-4.44(1H, m), 6.97(1H,









dd), 7.05(1H, t), 7.11(2H, t),









7.24-7.29(3H, m), 7.49(1H, d)











MS = Mass Spectrum has been obtained using either APCI+ or ES+ or ES−













The preparations of certain intermediates are now presented.




Method A




1-(3-Methoxy-4-nitro-benzoyl)-piperidin-4-one




CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g) stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride (6.9 g) and triethylamine (7.8 ml) were added and the mixture stirred overnight. The mixture was diluted with ethyl acetate, washed with 2N HCl (100 ml) then saturated NaHCO


3


solution (200 ml) then saturated brine (200 ml). The organic layer was dried (MgSO


4


) and evaporated to leave a residue which was purified by column chromatography (silica, mixtures of MeOH in dichloromethane) to give the product as a yellow solid (8.5 g; MS: APCI


+


(M+H) 279).




Method B




1-(3-Methanesulfonyl-benzoyl)-piperidin-4-one




PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO


3


solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate: dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI


+


(M+H) 282).




Method C




1-(Benzo [1,2,3]thiadiazole-5-carbonyl)-piperidin-4-one




CDI (4.5 g) added to a solution of the benzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml) at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine (4.3 ml) were added and the mixture stirred overnight. The resulting mixture was diluted with ethyl acetate, washed with 2M HCl (100 ml), saturated NaHCO


3


solution (200 ml) and then with saturated brine (200 ml). The organic layer was dried (MgSO


4


) and evaporated to leave a residue which was purified by column chromatography (silica, eluting with mixtures of ethyl acetate in dichloromethane) to give the product as a yellow oil (2.1 g; MS: APCI


+


(M+H)262).




Method D




[1,4′]Bipiperidinyl-4-ol




4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and 4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200 ml) with acetic acid (4 ml) at RT for 30 minutes. Sodium triacetoxyborohydride (23 g) was then added and the mixture stirred at RT overnight. The mixture was evaporated to dryness and the residue taken into water, extracted with diethyl ether (3×200 ml), the aqueous was basified to pH 9-10 and extracted with dichloromethane (3×200 ml). The dichloromethane extracts were combined, dried (MgSO


4


) and evaporated to leave an oil (19 g; same compound as Example 9 step 1). The oil was dissolved in methanol (300 ml) and treated with concentrated hydrochloric acid (5 ml). The mixture was stirred overnight and then evaporated to dryness to leave the title compound as the hydrochloride salt (15 g).






1


H NMR (400 MHz, DMSO-D6) δ 1.6-2.4 (m, 9H), 2.8-3.5 (m, 8H), 3.62 (m, 1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).




Method E




(4-Hydroxy-[1,4′]bipiperidinyl-1′-yl)-(3-methanesulfonyl-phenyl)-methanone




PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonyl benzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, see Method D) and Hunig's base (34 ml) in dichloromethane (500 ml). The resulting mixture was stirred at RT overnight, then washed with saturated NaHCO


3


solution (300 ml) followed by saturated brine (300 ml). The organic layer was dried (MgSO


4


) and evaporated to leave an oily residue. Column chromatography (silica, 20% methanol in DCM) gave the product as a white solid (16 g; MS: APCI


+


(M+H) 367).




Method F




4-(3-Chloro-4-fluoro-phenoxy)-piperidine




DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (10 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH


3


in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).






1


H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.46 (2H, m), 1.83-1.91 (2H, m), 2.53-2.59 (2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H, septet), 6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).




The following intermediates were prepared in similar manner to Method F:


















MS: (M + H)

























4-(4-chloro-2-methyl-phenoxy)-piperidine




226






4-(4-chloro-3-fluoro-phenoxy)-piperidine




230






4-(4-chloro-2-methoxy-phenoxy)-piperidine




242






4-(4-fluoro-2-methoxy-phenoxy)-piperidine




226






4-(4-methoxy-phenoxy)-piperidine




208






4-p-tolyloxy-piperidine




192






4-(4-chloro-3-methyl-phenoxy)-piperidine




226






4-(4-chloro-phenoxy)-piperidine




212






4-(4-fluoro-phenoxy)-piperidine




196






4-(2,4-dichloro-phenoxy)-piperidine




246






4-(2-chloro-4-fluoro-phenoxy)-piperidine




230






4-(2,4-difluoro-phenoxy)-piperidine




214






4-(4-chloro-2-fluoro-phenoxy)-piperidine




230






4-(4-fluoro-2-methyl-phenoxy)-piperidine




210






4-(4-chloro-2,6-dimethyl-phenoxy)-piperidine




240






4-(2,3-dichloro-phenoxy)-piperidine




246






4-(2,5-dichloro-phenoxy)-piperidine




246






4-(2-chloro-4-methyl-phenoxy)-piperidine




226






4-(2-chloro-5-methyl-phenoxy)-piperidine




226






1-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone




234






4-(2-chloro-6-methyl-phenoxy)-piperidine




226






4-[2-(piperidin-4-yloxy)-phenyl]-morpholine




263






4-(4-chloro-2-ethyl-phenoxy)-piperidine




240






7-(piperidin-4-yloxy)-quinoline




229






4-(2-tert-butyl-phenoxy)-piperidine




234






4-(indan-5-yloxy)-piperidine




218






4-(4-chloro-2-cyclohexyl-phenoxy)-piperidine




294






5-chloro-2-(piperidin-4-yloxy)-benzamide




255






4-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine




279






4-(5-chloro-2-methyl-phenoxy)-piperidine




226






4-phenoxy-piperidine




178






4-(2,4-dichloro-6-methyl-phenoxy)-piperidine




260






4-(3-chloro-4-methyl-phenoxy)-piperidine




226






5-chloro-2-(piperidin-4-yloxy)-benzonitrile




237






4-(2,4-dichloro-3-methyl-phenoxy)-piperidine




260






4-(2-ethyl-4-fluoro-phenoxy)-piperidine




224






4-(4-methanesulfonyl-phenoxy)-piperidine




297














Method G




4-Amino-3-ethoxy-benzoic acid




Potassium hydroxide (0.278 g) was added to a solution of 3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reaction treated with microwaves (300W, 100° C.) for 5 minutes. The reaction mixture was acidified using 2N HCl and extracted with ethyl acetate. The extracts were combined, washed with water, dried (MgSO


4


) and evaporated to give 3-ethoxy-4-nitro-benzoic acid (0.325 g).




3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium on charcoal under an atmosphere of hydrogen (1 bar) for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to leave the product as a beige solid (0.245 g; MS: ES


−


(M-H) 180).




Method H




3,4-bis-Methanesulfonyl-benzoic acid




To 3-fluoro-4-nitro-benzoic acid tert-butyl ester (0.5 g) in DMSO was added NaSO


2


Me. The reaction mixture was heated to 100° C. for 24 hours. A mixture of water, diethyl ether and ethyl acetate (1:1:1) was added and the resulting mixture was extracted with diethyl ether/ethyl acetate (1:1). The organic extracts were combined, dried with MgSO


4


and concentrated to leave a residue which was purified by chromatography (using 80% ethyl acetate/20% hexane) to give 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (366 mg).


1


H NMR (399.98 MHz, DMSO-D6) 1.59 (9H, s), 3.50 (3H, s) 3.52 (3H, s), 8.37-8.65 (3H, m).




To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) in dichloromethane was added trifluoroacetic acid and the reaction mixture was stirred for 3 hours. The mixture was evaporated and trituration of the residue with diethyl ether gave the title compound (0.29 g; MS: APCI


+


(M+H) 279).




Method I




4-Carbamoyl-5-methanesulfonyl-thiophene-2-carboxylic acid




To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester (0.5 g) in THF/H


2


O (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloric acid (2M) was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined and the solvent evaporated to leave a mixture of 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid and the title compound. This mixture was used without further purification.


1


H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).




Method J




3-(2-Methyl-propane-1-sulfonyl)-benzoic acid




To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate (1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65 ml). The mixture was heated by microwaves (600W) at 150° C. for 15 minutes. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous layer was separated, acidified to pH 1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extract was evaporated to leave a residue which was purified by flash chromatography (Biotage 12S eluting with ethyl acetate:hexane:acetic acid, 29:70:1) to give the title product as a white solid (0.34 g).






1


H NMR: (399.98 MHz, DMSO-D6) δ 0.98 (6H, d), 2.03 (1H, septet), 3.29 (2H, d), 7.81 (1H, t), 8.16 (1H, ddd), 8.27 (1H, dt), 8.38 (1H, t).




3-Cyclopropylmethanesulfonyl-benzoic acid was prepared in a similar manner to that described in Method J. MS: (M-H) 239;


1


H NMR: (DMSO-d6) δ 0.06-0.10 (2H, m), 0.40-0.45 (2H, m), 0.82-0.89 (1H, m), 3.34 (2H, d), 7.80 (1H, t), 8.14 (1H, d), 8.28 (1H, d), 8.39 (1H, s).




Method K




3-(2-Methoxy-ethoxy)-benzoic acid methyl ester




To a solution of methyl 3-hydroxybenzoate (5.7 g) and 2-bromoethylmethyl ether (5.2 g) in dimethylformamide (100 ml) was added caesium carbonate (24.3 g). The reaction mixture was stirred for 12 hours. The mixture was then patitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was separated, dried (MgSO


4


) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (Biotage 12M, eluting iso-hexane then MeOH:dichloromethane 2:98) to give the product as a colourless oil (5.3 g).






1


H NMR: (CDCl


3


) δ 3.44 (3H, s), 3.75 (2H, t), 3.89 (3H, s), 4.15 (2H, t), 7.13 (1H, ddd), 7.32 (1H, t), 7.57 (1H, dd), 7.62 (1H, dt).




3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester can be prepared in a similar manner to that described in Method K:


1


H NMR: (299.944 MHz CDCl


3


) 1.49 (9H, s), 3.91 (3H, s), 4.56 (2H, s), 7.13-7.68 (4H, m).




Method L




3-(2-Methoxy-ethoxy)-benzoic acid




To a suspention of 3-(2-methoxy-ethoxy)-benzoic acid methyl ester (5.3 g) in tetrahydrofuran (200 ml) was added lithium hydroxide monohydrate (5.3 g) followed by water until an homogeneous solution was obtained. The reaction mixture was stirred for 12 hours, acidified and partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was separated, dried (MgSO


4


) and the solvent removed under reduced pressure to yield a colourless solid (3.6 g).






1


H NMR: (DMSO-D6) δ 3.31 (3H, s), 3.67 (2H, t), 4.14 (2H, t), 7.20 (1H, ddd), 7.41 (1H, t), 7.44 (1H, dd), 7.53 (1H, dt)




3-(2-tert-Butoxycarbonylamino-ethoxy)-benzoic acid can be prepared in a similar manner to that described in Method L.




3-tert-Butoxycarbonylmethoxy-benzoic acid can be prepared in a similar manner to that described in Method L:


1


H NMR (299.944 MHz, DMSO-D6) δ 2.51 (9H, s), 4.74 (2H, s), 7.18 (1H, dq), 7.38 (1H, m), 7.41 (1H, m), 7.55 (1H, dt), 13.03 (1H, s).




Method M




4-(2-Carboxy-2-phenyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester




Piperazine-1-carboxylic acid tert-butyl ester (17.43 g) and 2-phenylacrylic acid (18 g) in iso-propanol (500 ml) was heated at reflux for four days. The resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give the title compound as a white solid (17 g; MS: APCI


+


(M+H) 335).




Method N




5-Methanesulfonyl-1H-indole-2-carboxylic acid




To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH (0.098 g). The reaction mixture was left to stir for 2 hours. Acetic acid was added and the product extracted with dichloromethane. The organic extracts were combined, dried with magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a solid (0.110 g).






1


H NMR (299.946 MHz, DMSO-D6) δ 3.18 (3H, s), 7.32-7.33 (1H, m), 7.61-7.64 (1H, m), 7.73-7.77 (1H, m), 8.30-8.31 (1H, m).




Method O




5-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid was prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (see Example 25) using the commercially available 5-methyl-1,8a-dihydro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. 6-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid and 6-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester were prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid and its ester above.




Method P




Preparation of 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l


6


-benzo[1,4]thiazine-6-carboxylic acid




Step 1: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l


6


-benzo[1,4]thiazine-6-carboxylic acid methyl ester











To a solution of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g) in dichloromethane (25 ml) was added 32% peracetic acid dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 48 hours and then diluted with dichloromethane. The organic phase was washed once with water, twice with aqueous sodium sulfite solution, and once with saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated to give the sub-title compound as a solid (1.012 g).






1


H NMR (399.978 MHz, CDCl


3


) δ 3.58 (3H, s), 4.00 (3H, s), 4.27 (2H, s), 7.96-7.99 (2H, m), 8.04-8.06 (1H, m).




Step 2: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l


6


-benzo[1,4]thiazine-6-carboxylic acid




To a solution of 4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g, from step 1) in MeOH (7 ml) was added dropwise a solution of sodium hydroxide (0.6 g) in water (5 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with water, cooled in an ice/water bath. Slow acidification with HCl (1N) to pH 2 yielded a precipitate which was isolated by filtration to give the title compound (0.595 g) as a solid.






1


H NMR (399.978 MHz, DMSO-D6) δ 3.49 (3H,s), 4.91 (2H,s), 7.90-8.03 (3H,m).




Method Q




Preparation of 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl




Step a: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester




To a solution of 4-(4-methanesulfonyl-phenoxy)-piperidine (0.7 g) dissolved in THF (5 ml) and 1,2-dichloroethane (10 ml) with 1-Boc-4-piperidone (0.71 g) was added NaBH(OAc)


3


(0.926 g) and acetic acid (0.18 g). After 16 hours at RT aqueous NaOH (1M) solution and dichloromethane were added and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, dried with magnesium sulfate and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol 90:10) to give the sub-title product (1.1 g; MS: APCI


+


(M+H) 439).




Step b: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl




The product of step a was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (5 ml) was added. After 16 hours at room temperature the solution was evaporated to leave the title compound as a TFA salt. The free base (0.7 g; oil; MS: APCI


+


(M+H) 339) was liberated by addition of aqueous NaOH (1M) and extraction with dichloromethane followed by evaporation of the solvent.




3-Methanesulfonyl-5-nitro-benzoic acid and 3-cyano-5-methanesulfonyl-benzoic acid can be prepared according to a method described in EP-A1-556674.




2-amino-5-MeSO


2


-benzoic acid can be prepared according to a method described in J. Org. Chem. (1953) 18 1380.




3-Ethanesulfonyl-benzoic acid can be prepared according to a method described in J. Chem. Soc. 1946, 763.




3-Methylsulfamoyl-benzoic acid and 3-dimethylsulfamoyl-benzoic acid can be prepared according to a method described in DE2133038. 3-Methylsulfamoyl-benzoic acid


1


H NMR: (399.98 MHz, DMSO-D6) δ 7.42 (3H, d), 7.63 (1H, q), 7.76 (1H, t), 8.01 (1H, m), 8.18 (1H, dt), 8.31 (1H, t), 13.48 (1H, s).




Other intermediates can be prepared by literature methods, by adaptation of literature methods or are available commercially. For example:




(2-methyl-4-nitro-2H-pyrazol-3-yl)methanecarboxylic acid, 2-{1-[sulfonyl chloride]-ethyl}-isoindole-1,3-dione and (1,3-dimethyl-3,7-dihydro-purine-2,6-dion-8-yl)methanecarboxylic acid are available from Salor (Aldrich Chemical Company Inc 1001 West Saint Paul Avenue Milwaukee, Wis. 53233 USA);




[4-amino-5-(iso-propyl-sulfonyl)-thiophen-3-yl]carboxylic acid, [3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-isoxazol-4-yl]carboxylic acid, 3-cyano-4-(pyrrol-1-yl)-thiophen-5-yl)carboxylic acid, 4-isopropylsulfanyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 1-cyclopropyl-5-methoxy-2-methyl-2,3-dihydro-1H-indole-3-carboxylic acid, (5-(isoxazol-3-yl)-thiophen-2-yl)sulfonyl chloride, 4-bromo-1-methyl-1H-pyrazol-3-ylmethanal, 4-chloro-1H-pyrazol-3-ylmethanal and 1-(4-chloro-benzyl)-1H-pyrazol-3-ylmethanal are available from Maybridge Chemical Company Ltd.; Trevillett, Tintagel, Cornwall PL34 0HW, UK;




(5-methanesulfonyl-1H-indol-2-yl)carboxylic acid is available by hydrolysis of an ester available from Maybridge Chemical Company Ltd., details above;




(4-chloro-5-methyl-3-nitro-pyrazol-1-yl)methanecarboxylic acid, (5-methyl-3,4-dinitro-pyrazol-1-yl)methanecarboxylic acid and (2,4-dinitro-imidazol-1-yl)methanecarboxylic acid are available from ASINEX Ltd., 6 Schukinskaya ulitsa, Moscow 123182, Russia;




(6-(imidazol-1-yl)-pyridin-3-yl)carboxylic acid and 2-methyl-2-([1,2,4]triazol-1-yl)-propanoic acid are available from Bionet Research Ltd, 3 Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, UK; and,




(2-methyl-[1,8]naphthyridin-3-yl)carboxylic acid, (2-methyl-[1,6]naphthyridin-3-yl)carboxylic acid and (5-trifluoromethyl-thieno[3,2-b]pyridin-6-yl)-methanecarboxylic acid are available from Peakdale Fine Chemicals Ltd., 7 Brookfield Industrial Estate, Glossop, Derbyshire, SK13 6LQ, UK.




EXAMPLE 28




Pharmacological Analysis: Calcium Flux [Ca


2+


]


i


Assay




Human Eosinophils




Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al.,


J. Immunol. Methods,


1991, 145, 105-110). The cells were resuspended (5×10


6


ml


−1


) and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118 mM, MgSO


4


0.8 mM, glucose 5.5 mM, Na


2


CO


3


8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl


2


1.8 mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×10


6


ml


−1


. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μM fibronectin for two hours) at 25 μl/well. The plate was centrifuged at 200 g for 5 min and the cells were washed twice with LKS (200 μl; room temperature).




A compound of the Examples was pre-dissolved in DMSO and added to a final concentration of 0.1% (v/v) DMSO. Assays were initiated by the addition of an A


50


concentration of eotaxin and the transient increase in fluo-3 fluorescence (1


Ex


=490 nm and 1


Em


=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).




Human Eosinophil Chemotaxis




Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al.,


J. Immunol. Methods,


1991, 145, 105-110). The cells were resuspended at 10×10


6


ml


−1


in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.




Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μl of either vehicle or compound (100× required final concentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 μl of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO


2


atmosphere to allow chemotaxis.




The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300×g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 μl of PBS containing 0.5% Triton×100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al.,


J. Immunol. Methods,


1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.




Compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis.




EXAMPLE 29




Guinea-Pig Isolated Trachea




(See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984) European J. Pharmacol., 106, 405-409.)




Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in 20 ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 117.6, NaH


2


PO


4


0.9, NaHCO


3


25.0, MgSO


4


1.2, KCl 5.4, CaCl


2


2.6 and glucose 11.1. The buffer was maintained at 37° C. and gassed with 5% CO


2


in oxygen. Indomethacin (2.8 μM) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.




Experimental Protocols




At the beginning of each experiment a force of 1 g was applied to the tissues and this was reinstated over a 60 minute equilibration period until a steady resting tone was achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 log


10


unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added. Following an incubation period of 60 minutes a second E/[A] curve was performed to histamine.




Contraction responses were recorded as a percentage of the first curve maximum.




Data Analysis




Experimental E/[A] curve data were analysed for the purposes of estimating the potencies (p[A


50


] values) of histamine in the absence and presence of the test compound. Affinity (pA


2


) values of test compounds were subsequently calculated using the following equation:








log


(


r


−1)=


log[B]+pA




2








where r=[A]


50


in presence of test compound/[A]


50


in absence of antagonist and [B] is the concentration of test compound. Compounds of the Examples were found to be H1 antagonists.



Claims
  • 1. A compound of formula (I): wherein:q=0 or 1;s=0; t=1; n and r are, independently, 0, 1, 2, 3, 4 or 5; p=1; m=1; X is O; Y is NHR2 or OH; T is C(O), C(S), S(O)2 or CH2; R1 is phenyl or naphthyl optionally substituted as presecribed below for aryl moieties; R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is aryl, optionally substituted as presecribed below; wherein, unless stated otherwise, the foregoing aryl moieties are optionally substituted by: (a) halogen, (b) OH, (c) SH, (d) NO2, (e) oxo, (f) C1-6 alkyl, the alkyl being optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl, the phenyl being optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40) naphthyloxy, the naphthyloxy being optionally substituted by halo or C2-6 alkenyl, C3-10 cycloalkyl, the cycloalkyl being optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl); (g) NR41C(O)OCH2(fluoren-9-yl), (h) C1-6 alkoxy, the C1-6 alkox being optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl, the phenyl being optionally substituted by halogen or NO2; (i) C1-6 alkylthio, (j) C1-6 haloalkylthio, (k) C3-10 cycloalkyl, (l) NR7R8, (m) NR9C(O)R10, (n) CO2R11 (o) C(O)NR12R13, (p) C(O)R14, (q) S(O)dR15, (r) S(O)2NR42R43, (s) NR44S(O)2R45, (t) phenyl, the phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, the alkoxy being optionally substituted by halogen, or OH, phenyl, the phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy, (u) phenoxy, the phenoxy being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, the phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy, (v) SCN, (w) CN, (x) SO3H (or an alkali metal salt thereof), (y) methylenedioxy or (z) difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihycfrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl, aryl, the aryl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy; R15, R38, R45 and R48 are, independently, C1-6 alkyl, the alkyl being optionally substituted by halogen, hydroxy or C3-10 cycloalkyl, C3-6 alkenyl, aryl, the aryl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy; or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof.
  • 2. A compound as claimed in claim 1 wherein n is 0 or 1.
  • 3. A compound as claimed in claim 1 wherein q and r are both 0.
  • 4. A compound as claimed in claim 1 wherein R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl or C1-4 alkoxy.
  • 5. A compound of formula (Ia″): wherein:T is C(O), C(S), S(O)2 or CH2; n is l; n and p are 1; R50 is hydrogen, cyano, S(O)2(C1-4 alkyl), S(O)2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl, said phenyl being optionally substituted by one or two halogen atoms or by one C(O)NR12′R13′, NR9′C(O)R10′, S(O)2R15′, S(O)2NR42 R43 or NR44S(O)2R45 group; R51 and R52 are, independently, hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy; R3 is aryl; wherein, unless stated otherwise, the foregoing aryl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl, said alkyl being optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl, said phenyl being optionally substituted by halo or C1-6 alkyl, naphthyloxy, said naphthyloxy being optionally substituted by halo or C2-6 alkenyl, or NR4C(O)OCH2fluoren-9-yl)), C1-6 alkoxy, said C1-6 alkoxy being optionally substituted by halogen, CO2R4,NR5R6 or phenyl, said phenyl being optionally substituted by halogen or NO2, C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl, said phenyl being optionally substituted by NO2 or C1-6 alkoxy, said C1-6 alkoxy being optionally substituted by OH, phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety; R4, R5, R6, R7, R8, R9, R9′, R10,R10′, R11, R12, R12′, R13, R13′, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or phenyl; R15, R15′ and R45 are, independently, C1-6 alkyl or phenyl; or a pharmaceutically acceptable salt thereof.
  • 6. A compound as claimed in claim 1 wherein T is C(O), S(O)2 or CH2.
  • 7. A compound of formula (If): wherein R1, n, t, s and R3 are as defined in claim 1.
  • 8. A compound as claimed in claim 1 wherein R3 is phenyl optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2(C1-4 alkyl), S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2; and R46 is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl(C1-4 alkyl) or phenyl), C1-4 haloalkylthio, C(O)NH2, NHS(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH (C1-4 alkyl) or S(O)2N(C1-4 alkyl)2.
  • 9. A compound as claimed in claim 5 wherein n is 0 or 1.
  • 10. A compound as claimed in claim 7 wherein R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl or C1-4 alkoxy.
  • 11. A process for preparing a compound of formula (I) as claimed in claim 1, which comprises:a) when R47 is not hydrogen, coupling a compound of formula (II): with a compound of formula (III): wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction;b) when s is 1, R47 is hydrogen and T is CO, reacting a compound of formula (II): with an isocyanate O═C═N—(CH2)n—(CH2)r—R3;c) reductively aminating of a compound of formula (XX): with an amine of formula (XXI): d) performing a fluoride displacement reaction on F-R1 in the presence of compound of formula (XVIII): provided that R47 is not hydrogen.
  • 12. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 13. A method of treating asthma or rhinitis, said method comprising administering to a warm blooded animal a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof in an amount effective to treat asthma or rhinitis.
Priority Claims (3)
Number Date Country Kind
0008626 Apr 2000 GB
0019111 Aug 2000 GB
0003664 Oct 2000 SE
US Referenced Citations (3)
Number Name Date Kind
4695575 Janssens et al. Sep 1987 A
5977138 Wang et al. Nov 1999 A
6066636 Kozlowski et al. May 2000 A
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Number Date Country
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0 151 826 Aug 1985 EP
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WO 0066559 Nov 2000 WO
0066559 Nov 2000 WO