NZ541682A - Chemical compounds - Google Patents

Abstract

A process for preparing 4-(3,4-dichlorophenoxy)piperidine that comprises the following steps: reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room temperature, and heating the mixture and 1,2-dichloro-4-fluorobenzene at a temperature in the range 50-90OC, or at reflux of the solvent used.

Description

New Zealand Paient Spedficaiion for Paient Number 541 682 *10048921291 * 54 16 8 2 Patents Form No. 5 N.Z. No.

Divided out of Parent Application No. 534296 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION CHEMICAL COMPOUNDS We, ASTRAZENECA AB, a Swedish company of S-151 85 Sodertalje, Sweden, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 1- ^tolwctual Property" Office of N.Z.

- AUG 2005 Received (Followed by 1 A) WO %8743 1A CHEMICAL COMPOUNDS The present application is a divisional of NZ 534296.

The invention of the parent application relates to piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions 5 comprising such derivatives and to the use of such derivatives as active therapeutic agents, Thepresent invention provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.

Pharmaceutically active piperidine derivatives are disclosed in WO 01/62728, WO 01/62729 and WO 01/62757.

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 r61e 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 15 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 a) and Cys-Cys (C-C, or p) families. These are distinguished on the basis of a single amino acid insertion 20 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 25 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxins and the macrophage inflammatory proteins la and 1{5 (M3P-la and MBMJ3).

Studies have demonstrated that.the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated 30 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.

PCT/S1 00258 2 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 axe of three main types, HI, H2 and H3. Histamine HI antagonists comprise the largest class of medications used in the treatment of patients with 10 allergic disorders, especially rhinitis and urticaria. Antagonists of HI are useful in controlling the allergic response by for example blocking the action of histamine on postcapillary Venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the HI receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing. 15 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 20 Arch. Allergy Immunol. (2000) 122 SI 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].) The present invention provides a compound of formula (I): OH -CR2R3- (CH&r CR5R6 (CR7R8)n—N—Z-—Y-R9 R4 R32 (0 wherein: X is CH2,0, S(0)2 or NR10; Y is abond, CH2, NR35, CH2NH, CH2NHC(0), CH(OH), CH(NHC(0)R33), CH(NHS(0)2R34), CH2O or CH2S; Z is C(O), or when Y is a bond Z can also be S(0)2; R1 is optionally substituted aryl, optionally substituted heterocyclyl or cycloalkyl 30 fused to a benzene ring; „ R4 is hydrogen, Ci^ alkyl (optionally substituted by C3.6 cycloalkyl) or C3-6 cycloalkyl; WOf >8743 '' * R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, Ci^ alkyl or C3^ cycloalkyl; m and n are, independently, 0 or 1; R9 is optionally substituted aryl or optionally substituted heterocyclyl; R10, R32 and R35 are, independently, hydrogen, Ci^ alkyl or C3^j cycloalkyl; R33 and R34 are alkyl or C3.$ cycloalkyl; wherein the foregoing aiyl and heterocyclyl moieties are, where possible, optionally substituted by. halogen, cyano, nitro, hydroxy, oxo, S(0)vR12,0C(0)NR13R14, NRI5R16, NR17C(0)R18, NR19C(O)NR20R21, S^NR^R23, NR^OHR25, C(0)NR26R27, C(0)R2S, CO2R29, NR30CO2R31, Ci^ alkyl (itself optionally mono-substituted by NHC(0)phenyI), 10 Cj-6 haloalkyl, C1-6 alkoxy(C 1 -6)alkyl, Cm alkoxy, Cm haloalkoxy, Cm alkoxy(Ci-s)a3koxy, Ci^ alkylthio, C2^ aDcenyl, C2^ alkynjd, C3.10 cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(CM)alkyl, phenoxy, phenylthio, phenyl(Ci. 4)alkoxy, morpholinyl, heteroaryl, heteroaryl(Ci4)alkyl, heteroaryloxy or heteroaryi(Ci. 4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are 15 optionally substituted with halogen, hydroxy, nitro, S(0)j(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)* cyano, CM alkyl, CM alkoxy, C(0)NH2j C(0)NH(Cm alkyl), C02H, C02(CM alkyl), NHC(0)(CM alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OGF3; k and r are, independently, 0,1 or 2; ' R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 are, independently, hydrogen, Cm alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), CH2(C2.$ alkenyl), cycloalkyl, phenyl (itself optionally substituted by . halogen, hydroxy, nitro, NH2, NH(Cm alkyl), NH(Cm alkyl)2, S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2, cyano, Cm alkyl, Cm alkoxy, 25 C(0)NH2, C(0)NH(Cm alkyl), C(0)N(CM alkyl)2, CO2H, C02(CM alkyl), NHC(0)(CM alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2, S(0)2(CM alkyl), S(0)2NH2, S(0)2NH(CM alkyl), S(0)2N(Cm alkyl)2, cyano, CM alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2, C02H, C02(CM alkyl), 30 NHC(0)(Cm alkyl), NHS(0)2(CM alkyl), C(0)(Cm alkyl), CF3 or OCF3); alternatively NR,3R54, NR15R16, NR20R21, NR^R23, NR2<SR27, may, independently, form a 4-7 membered heterocyclic ring selected from the group: azetidine (itself optionally .

PCT/SI 00258 4 substituted by hydroxy or Cm alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted by Cm alkyl on the distal nitrogen; R12, R25, R28 and R31 are, independently, Cm alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), CEfeO^w alkenyl), phenyl (itself optionally substituted by 5 halogen, hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, Cm alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for 10 R13 and R14 above), CO2H, C02(Cm alkyl), NHC(0)(CM alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Ci. 4 alkyl), S(0)2N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described 15 for R13 and R14 above), cyano, Cm alkyl, CM alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3); provided that when X is CH2 and m and n are both 0 then Y is not NR3*; or an N-oxide thereof; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

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. 25 Suitable salts include acid addition salts such as a hydrochloride, (^hydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fiunarate, maleate, tartrate, citrate, oxalate, methanesulfonate or/7-toluenesulfonate.

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-butvl. Alkyl groups preferably comprise 1-6 carbon atoms.

WO f 68743 ' 5 Alkenyi is, for example, vinyl or allyl. Alkenyl groups preferably comprise 2-6 carbon atoms.

Alkynyl is, for example, propargyl. Alkynyl groups preferably comprise 2-6 caibon atoms.

Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexyl. Cycloalkyl groups preferably comprise 3-6 carbon atoms.

Cycloalkyl fused to a benzene ring is, for example, bicyclo[4.2.0]octa-1,3,5-trienyl.

Aryl is preferably phenyl or naphthyl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused 10 to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; 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, ixnidazolyl, piperidinyl, moipholinyl, pyridinyl, 1,6-dihydropyridinyl (for example in a 6-oxo-l,6-dihydropyridinyl 15 moiety), pyrimidinyl, indolyl, 2,3-dihydroindolyi, benzo[b]furyl (also known as benzfiiryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a 1,1 -dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2-dihydrobenzthiazolyl (for example in a 1H-benzthiazol-2-one-yl moiety), 2,3-dihydrobenzthiazolyl (for example in a 2,3-20 dihydrobenzthiazol-2-one-ji moiety), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2-a]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, 3,4-dihydro-lH-2,l-benzothiazinyl (for example in a 2-dioxo-3,4-dihydro-lH-2,l-benzothiazinyl moiety), a pyrazolopyridine (for example 1H-25 pyrazolo[3,4-b]pyridinyl), a purine, 3,7-dihydro-purinyl (for example in a 3,7-dihydro-purin-2,6-dione-8-yl moiety), quinolinyl, isoquinolinyl, 1,2-dihydroisoquinolinyl (for example in a 2H-isoquinolin-l-one-yl (alternatively called 1 -oxo-1,2-dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-1-one) moiety), a naphthyridinyl (for example [l,6]naphthyridinyl or [ 1,8]naphthyridinyl), 1,4-dihydro[ 1,8]naphthyridinyl (for example 30 in a lH-[l,8]naphthyridin-4-one-yl moiety), or a benzothiazinyl, 4H-benzo[l,4]thiazinyl (for example in a 4H-benzo[ 1,4]thiazin-3-one-yl moiety); or an N-oxide thereof (such as a pyridine N-oxide), or an S-oxide or S-dioxide thereof. 1,2-Dihydropyridinyl (an alternative numbering for a 1,6-dihydropyridin)d) can also be present in a 2-oxo-l,2- PCT/SL.,/00258 6 dihydropyridinyl moiety; and 2,3-dihydro-1 H-indazolyl can also be present in a 3-oxo-2,3-dihydro-1 H-indazoIyl moiety.

Heterocyclyl also includes cinnolinyl, phthalazinyl, 3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydrophthalazinyl moiety), benzoxazinyl, 2,3-dihydro-4H-l,4-5 benzoxazinyl (for example in a 3-oxo-2,3-dihydro-4H-l ,4-benzoxazinyl moiety), 3,4-dihydro-2H-1,4-benzoxazinyl (for example in a 3-oxo-3,4-dihydro-2H-l,4-benzoxazinyi moiety), isoindolyl, l,3-dihydro-2H-isoindolyl (for example in a l,3-dioxo-l,3-dihydro-2H-isoindolyl moiety), pyrazolotriazinyl (for example pyrazolo[5,l-c][l,2,4]triazinyl), pyrazinyl, pyridazinyl, 9H-purinyl, pyrazolopyrimidinyl (for example pyrazolo[l,5-10 a]pyrimidinyl), imidazobenzothiazolyl (for example imidazo[2,1 -b] [1,3]benzothiazolyl), 1,2,5-oxadiazolyl, imidazopyrimidinyl (for example imidazo[l,2-a]pyrimidinyl), quinolinyl, 1,2-dihydroquinolinyl (for example in a 2-oxo-l,2-dihydroquinolinyl moiety) or 2,1,3-benzoxadiazolyl (for example as a 1-oxide); or it may additionally be an N-oxide thereof, or an S-oxide or S-dioxide thereof. Further examples of heterocyclyl are 1,3-15 benzothiazole, 2,3-dihydro-l ,3-benzothiazole (for example in a 2-oxo-2,3-dihydro-l ,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazole, 2,3-dihydro-1 H-benzimidazole (for example in a 2-oxo-2,3-dihydro-lH-benzimidazole moiety) and 1,4-dihydroquinoline (for example in a 4-oxo-l,4-dihydroquinoline moiety).

An N-oxide of a compound of formula (I) or (la) is, for example, a 1-oxy-20 piperidinyl compound.

Heteroaryl is an aromatic heterocyclyl. Thus it is, for example furyl, thienyl, pyrrolyi, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]fiiiyl, benz[b]thienyl, indazolyl, beiizimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl, thieno[3,2-25 b]pyridin-6-yl 1^2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan, quinoxalinyl, a pyrazolopyridine, a purine, quinolinyl, isoquinolinyl, a naphthyridinyl, a benzothiazinyl, cinnolinyl, phthalazinyi, benzoxazinyl, isoindolyl, pyrazolotriazinyl pyrazinyl, pyridazinyl, pyrazolopyrimidinyl, imidazobenzothiazolyl, imidazopyrimidinyl quinolinyl or 2,1,3-benzoxadiazolyl; or an N-oxide thereof (such as a pyridine N-oxide), or an S-oxide or S-30 dioxide thereof.

Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen atoms and is, for example, CF3. Alkoxyalkyl is, for example, CH3OCH2, CH3CH2OCH2 or CH3CH20(CH2)2. Haloalkyloxy is an alkoxy group carrying one or more (such as 1 to 6) woe W743 7 halogen atoms and is, for example, OCF3. Alkoxyalkoxy is, for example, CH3OCH2O, CH3CH2OCH2O or CH3CH20(CH2)20. Phenylalkyl is, for example, benzyl, phenyleth-1-yl or phenyleth-2-yl. Phenylalkoxy is, for example benzyloxy. Heteroarylalkyl is, for example, pyridinylmethyl or pyrimidinylmethyl. Heteroaryloxy is, for example, 5 pyridinyloxy or pyrimidinyloxy. Heteroarylalkoxy is, for example, pyridinylmethoxy or pyrimidinylmethoxy.

In one aspect the present invention provides a compound of formula (I) wherein: X is CH2, O, S(0)2 or NR10; Y is a bond, CH2, NR35, CH2NH, CH2NHC(0), CH(OH), . CH(NHC(0)R33), CH(NHS(0)2R34), CH20 or CH2S; Z is C(O), or when Y is a bond Z can 10 also be S(0)2; Rl is optionally substituted aryl, optionally substituted heterocyclyl or C4-6 cycloalkyl fused to a benzene ring; R4 is hydrogen, Cm alkyl (optionally substituted by C3-6 cycloalkyl) or C3-6 cycloalkyl; R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, Ci. 6 alkyl or C3-6 cycloalkyl; m and n are, independently, 0 or 1; R9 is optionally substituted aryl or optionally substituted heterocyclyl; R10, R32, R33 and R35 are, independently, 15 hydrogen or Cm alkyl; R34 is Cm alkyl; wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(0)kR12, 0C(0)NR13R14, NR15R16, NR17C(0)R18, NR19C(O)NR20R21, S(0)2NR22R23, NR24S(0)2R25, C(0)NR26R27, C(0)R28, C02R29, NR30CO2R31, Cm alkyl, Cm haloalkyl, Cm alkoxy(CM)alkyl, Cm alkoxy, Cm haloalkoxy, Cm alkoxy(C 1„6)alkoxy, Cm alkylthio, 20 C2-6 alkenyl, C2-6 alkynyl, C3.10 cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C M)alkyl, phenoxy, phenyltibio, phenyl(C 1 _4)alkoxy, heteroaryl, ^ heteroaryl(C 1 ^)alkyl, heteroaryloxy or heteroaryl(Ci-4)alkoxy, wherein any .of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(0)^Cm alkyl), S(0)2NH2, cyano, Cm alkyl, Cm alkoxy, 25 C(0)NH2, C(0)NH(Cm alkyl), C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OCF3; k and r are, independently, 0,1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29, R30, and R31 are, independently, hydrogen, Cm alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, 30 NH(Cm alkyl), NH(CM alkyl)2, S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(C14 alkyl), S(0)2N(Cm alkyl)2, cyano, Cm alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2, C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, PCT/SE 00258 8 hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2, S(0)2(Cm alkyl), S(0)2]S1H2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2, cyano, Cm alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(CM alkyl)2, C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OCF3); alternatively NR13R14, NR15R16, 5 NR20R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-moipholine or 1,4-piperazine, the latter optionally substituted by Cm alkyl on the distal nitrogen; R12, R25 and R28 are, independently, Cm alkyl (optionally substituted by halogen, hydroxy or C3.10 cycloalkyl), CH2(C2_6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, 10 NH(Cm alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(CM alkyl), S^NHa, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, Cm alkyl, Cm alkoxy, C(0)NH2, C(0)NH(CM alkyl), C(0)N(Cm alkyl^ (and these alkyl groups may join to form a ring as described for R and R above), C02H, 15 C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(Cm alkyl), C(0)(Cm alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm • t alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R and R14 above), S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, 20 Cm alkyl, CM alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), C02H, C02(Cm alkyl), 1 NHC(OXCm alkyl), NHS^MCm alkyl), C(0)(Cm alkyl), CF3 or OCF3); provided that when X is CH2 and m and n are both 0 then Y is not NR35; or an N-oxide thereof; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. 25 In another aspect the present invention provides a compound of formula (la): OH R1/X\7 N CR2R3 (CH2)m- — CR5R6—-(CR7R8)n—N——R > ' . R4 O ■ O3) - wherein: X is CH2, O, S(0)2 or NR10; R1 is optionally substituted aryl or optionally substituted heterocyclyl; R4 is hydrogen, Cm alkyl (optionally substituted by C3-6 cycloalkyl) or C3^ cycloalkyl; R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, Cm 30 alkyl or C3-6 cycloalkyl; m and n are, independently, 0 or 1; R9 is optionally substituted WOr *168743 < 9 >10 aryl or optionally substituted heterocyclyl; R10 is hydrogen or Ci-6 alkyl; wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(0)kR12, 0C(0)NRI3R14, NR1SR16, NR17C(0)R18, KR19C(O)NR20R21, S(0)2NR22R23, NR24S(0)2R25, C(0)NR26R27, C(0)R28, CO2R29, 5 NR30CO2R31, Cm alkyl, Cm haloalkyl, Cm alkoxy(Ci^)alkyl, Cm alkoxy, Cm haloalkoxy, Cm alkoxy(Ci^)alkoxy, Cm alkylthio, C2-6 alkenyl, C2-6 alkynyl, C3.i0 cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(CM>alkyl, phenoxy, phenylthio, phenyl(CM)alkoxy, heteroaryl, heteroaryl(Cw)alkyl, heteroaryloxy or heteroaryl(C i^)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl 10 moieties are optionally substituted with halogen, hydroxy, nitro, S(0)t(Cm alkyl), I SCO^NHz, cyano, CM alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C02H, C02(CM alkyl), NHC(OXCm alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3; k and r are, independently, 0,1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29, R30, and R31 are, independently, hydrogen, Cm alkyl (optionally substituted by 15 halogen, hydroxy or C3_io cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm alkyl), NH(Cm alkyl)2, S(0)2(Ci4 alkyl), S(0)2NH2, cyano, Cm alkjd, Cm alkoxy, G(0)NH2, C(0)NH(Cm alkyl), C02H, C02(Cm alkyl), NHC(0)(CM alkyl), NHS(0)2(Cm alkyl), C(0)(CM alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro-, NH2, NH(Cm 20 alkyl), N(Cm alkyl)2, S(0)2(CM alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2, cyano, CM alkyl, CM alkoxy, C(0)NH2, C(0)NH(CM alkyl), C(0)N(Cm alkyl)2, I C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3); alternatively NR13R14, NR15R16, NR^R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-25 morpholine or 1,4-piperazine, the latter optionally substituted by Cm alkyl on the distal nitrogen; R12, R25 and R28 are, independently, Cm alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), CH2(C2^ alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Cm alkyl), S(0)2NH2, 30 S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, Cm alkyl, Cm alkoxy, C(0)NH2, C(0)NH(Cm alkyl), C(0)N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for * < .

R13 and R14 above), C02H, C02(Cm alkyl), NHC(0)(CM alkyl), NHS(0)2(Cm alkyl), .

PCT/SI 00258 C(0)(Ci_4 alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Cm alkyl), N(Cm alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Cm alkyl), S^NH* S(0)2NH(Ci. 4 alkyl), S(0)2N(Ci-4 alkyl)2 (and these alkyl groups may join to form a ring as described 5 for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(0)NH2, C(0)NH(CM alkyl), C(0)N(Cm a]kyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), C02H, C02(Cm alkyl), NHC(0)(Cm alkyl), NHS(0)2(CM alkyl), C(0)(Cm alkyl), CF3 or OCF3); or an N-oxide thereof; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

In a further aspect the present invention provides a compound of formula (I) 0 wherein: X is O; Y is a bond, CH2, NR35, CHjNH, CH(OH), CH(NHC(0)R33), CK^NHS^^R34) or CHfeO; Z is C(0), or when Y is a bond Z can also be S(0)2; R1 is optionally substituted phenyl; R4 is hydrogen or Cm alkyl; R2, R3, R5, R6, R7 and R8 are, when present, all hydrogen; m and n are, independently, 0 or 1; R9 is optionally 15 substituted aryl or optionally substituted heterocyclyl; R32 and R35 are, independently, hydrogen or Cm alkyl; R33 and R34 are Cm alkyl; wherein the foregoing phenyl, aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, hydroxy, oxo, S(0)2R12, NR15R16, NR17C(0)R18, S(0)2NR22R23, NR^S^R25, C(0)NR26R27, CO2R29, C1-6 alkyl (itself optionally mono-substituted by NHC(O)phenyl), 20 CF3, OCF3, phenyl or heteroaryl;wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, C1-4 alkyl, Cm alkoxy or CF3; R15, R16, R17, R18, R22, R23, R24, R26, R27 and R29 are, independently, hydrogen, Cm alkyl (optionally substituted by hydroxy) or C3^ cycloalkyl; alternatively NR22RB may form an azetidine ring (itself optionally substituted by hydroxy or Cm alkyl); R12 and R25 are, 25 independently, Cm alkyl or phenyl; or a pharmaceutically acceptable salt thereof.

In a still further aspect R1 is phenyl optionally substituted (for example with one, two or three of) by halogen (especially fluoro or chloro), cyano, Cm alkyl (especially methyl), Cm alkoxy (especially methoxy), S(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2NH(C3-6 cycloalkyl), C(0)2(Cm alkyl), C(0)NH(CM alkyl) or C(0)NH2. 30 In another aspect R1 is phenyl optionally substituted (for example with one, two or three of) by halogen (especially fluoro or chloro), cyano, Cm alkyl (especially methyl) or Cm alkoxy (especially methoxy). In a further aspect R1 is phenyl substituted by one, two or three of: fluoro, chloro, methyl or cyano. In another aspect Rl is phenyl substituted by WO r "*68743 11 one, two or three of: fluoro, chloro or methyl. Thus, R1 is, for example, 2-methyl-4-chlorophenyl, 3-methyl-2,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl. In a still further aspect R1 is 3,4-dichlorophenyl.

In another aspect X is 0.

In yet another aspect Y is a bond.

In another aspect Z is C(0).

In a further aspect m is 0.

In a still further aspect n is 0.

In another aspect m and n are both 0.

In another aspect R4 is hydrogen or Ci-$ alkyl (such as methyl). In yet another i aspect R4 is hydrogen.

In yet another aspect R2, R3, R5, R6, R7 and R8 are all hydrogen; and in a further aspect n is 0, and R2, R3, R5 and R6 are all hydrogen.

In a further aspect R2, R3, R4, R5, R6, R7 and R8 are, when present, all hydrogen. 15 In a still further aspect R9 is mono- or di- substituted phenyl, unsubstituted heterocyclyl or mono- or di- substituted heterocyclyl, the substituents being chosen from those described above.

In another aspect R9 is optionally substituted heterocyclyl wherein the heterocyclyl group is: thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-20 oxadiazolyl, pyridinyl, 1,6-dihydropyridinyl (for example in a 6-oxo-l,6-dihydropyridinyl or a 2-oxo-l,2-dihydropyridinyl moiety), pyrimidinyl, indolyl, indazolyl, 2,3-dihydro-lH-; indazolyl (for example in a 3-oxo-2,3-dihydro-lH-indazolyl moiety), an imidazopyridinyl (such as imidazo[l,2-a]pyridinyl), 2,1,3-benzothiadiazolyl, quinoxalinyl, quinolinyl, 1,2-dihydroquinolinyl (for example in a 2-oxo-l,2-dihydroquinolinyl moiety), 1,4-25 dihydroquinoline (for example in a 4-oxo-1,4-dihydroquinoline moiety), isoquinolinyl, 1,2-dihydroisoquinolinyl (for example in a 2H-isoquinolin-l-one-yl (alternatively called 1-oxo-l,2-dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-l-one) moiety), cinnolinyl, 3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydrophthalazinyl moiety), 2,3-dihydxo-4H-l,4-benzoxazinyl (for example in a 3-oxo-2,3-dihydro-4H-l,4-benzOxazinyl moiety), 30 3,4-dihydro-2H-l,4-benzoxazinyl (for example in a 3-oxo-3,4-dihydro-2H-l,4- benzoxazinyl moiety), l,3-dihydro-2H-isoindolyl (for example in a l,3-dioxo-l,3-dihydro-2H-isoindolyl moiety), pyrazolotriazinyl (for example pyrazolo[5,l-c][l,2,4]triazinyl), pyrazolopyrimidinyl (for example pyrazolo[l,5-a]pyrimidinyl), imidazobenzothiazolyl (for PCT/SIL 00258 12 example imidazo[2,1 -b] [ 1,3]benzothiazolyl), imidazopyrimidinyl (for example imidazo[l,2-a]pyrimidinyl), or 2,1,3-benzoxadiazolyl (for example as a 1-oxide), 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole (for example in a 2-oxo-2,3-dihydro-l,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazole or 2,3 -dihydro-1 H-benzimidazole (for 5 example in a 2-oxo-2,3-dihydro-lH-benzimidazole moiety).

In yet another aspect the aryl (such as phenyl) or heterocyclyl group R9 is unsubstituted or substituted by one or more of: oxo (where possible), halogen, Cm alkyl, CF3, Cm alkoxy, S(OHCm alkyl), S(0)2NH2, S(0)2NH(CM alkyl), S(0)2N(Cm alkyl^ or OCF3.

In a further aspect when R9 is heterocyclyl it is an optionally substituted thienyl, quinolinyl, 1,2-dihydroquinolinyl, 1,3-benzthiazoIyl, 2,3-dihydro-l,3-benzothiazolyl, ixnidazo[l,2-a]pyridinyl, isoquinolinyl or 1,2-dihydroisoquinolinyl; or a 1,2-dihydropyridone, a 1,6-dihydropyridone, a pyrazolyl, a pyrrolyl or an indolyl.

In yet another aspect R9 is phenyl or heterocyclyl (as defined anywhere above), 15 either of which is optionally substituted by: halo, hydroxy, nitro, cyano, oxo, amino, Cm alkyl (itself optionally substituted by S(0)2(Cm alkyl) or S(0)2phenyl), Cm alkoxy, S(0)tR12 {wherein k is 0,1or 2 (preferably 2); and R12 is Cm alkyl, Cm hydroxyalkyl, C3. 7 cycloaIkyl(CM alkyl) (such as cyclopropylmethyl) or phenyl), C(0)NH2, NHS(0)2(Cm alkyl), S(0)2NH2, S(0)2NH(Cm alky!) or S(0)2N(Cm alkyl^ (and these alkyl groups may 20 join to form a ring as described for R13 and R14 above).

I In another aspect R32 is hydrogen.

In a further aspect R13, R14,R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29, R30, and R31 are, independently, hydrogen, Cm alkyl (optionally substituted by halogen, hydroxy or C3.io cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally 25 substituted by halogen or Cm alkyl) or heterocyclyl (itself optionally substituted by halogen or Cm alkyl); and R12, R25 and R28 are, independently. Cm alkyl (optionally substituted by halogen, hydroxy or C3_io cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally substituted by halogen or Cm alkyl) or heterocyclyl (itself optionally substituted by halogen or Cm alkyl).

. In a still further aspect R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24,R26, R27, R29 and R30 are, independently, hydrogen, Cm alkyl (optionally substituted by halogen, hydroxy or C3.10 cycloalkyl), CH2(C2^ alkenyl), phenyl (itself optionally substituted by halogen or Cm alkyl) or heterocyclyl (itself optionally substituted by WO r M>8743 13 halogen or Cm alkyl); and R12, R25, R28 and R31 are, independently, Cm alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), CH2(C2^ alkenyl), phenyl (itself optionally substituted by halogen or Cm alkyl) or heterocyclyl (itself optionally substituted by halogen or Cm alkyl).

In yet another aspect R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23) R24, R26, R27, R29 and R30 are, independently, hydrogen or Cm alkyl; and R12, R25, R28 and R31 are, independently, Cm alkyl (optionally substituted by hydroxy)or phenyl.

In a further aspect R10 is hydrogen.

In another aspect R35 is hydrogen or Cm alkyl (such as methyl); (for example R35 is 10 hydrogen).

In yet another aspect R33 is Ci^ alkyl (such as methyl).

In a further aspect R34 is Cm alkyl (such as methyl).

In a still further aspect the present invention provides a compound of formula (1) or (la) wherein: R1 is phenyl optionally substituted by 2 halogens (such as chlorine); X is O; 15 m is 0; n is 0 or 1; R2, R3, R4, R5, R6, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl or 1,2-dihydroisoquinolinyl optionally substituted by S(0)2(Cm alkyl) (for example S(0)2CH3), halogen (for example chlorine or fluorine), NH2, Cm alkoxy (such as OCH3), cyano or, where possible, oxo. , In another aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), or by 1 or 2 halogens (such as chlorine) and a Cm alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R2, R3, R4, R5 and R6, and, when present, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl, imidazo[l,2-25 ajpyridinyl, 1,2-dihydroisoquinolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl or pyrazolyl, all optionally substituted by S(0)2(Cm alkyl) (for example S(0)2CH3), S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl)2 (and the two alkyl groups may join together to form an azetidine ring), halogen (for example chlorine or fluorine), NH2, Cm alkyl (such as CH3), Cm alkoxy (such as OCH3), CF3, cyano or, where possible, oxo. 30 In a further aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), and optionally substituted by 0 or 1 Cm alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R2, R3, R4, R5 and R6, and, when present, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, PCT/S1 00258 14 quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyI, imidazo[l,2-a]pyridinyl, 1,2-dihydroisoquinolinyi, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl, pyrazolyl, pyrrolyl or indolyl, all of which are optionally substituted by S(0)2(Cm alkyl) (for example S(0)2CH3), S(0)2NH2, S(0)2NH(Ci_4 alkyl), S(0)2N(Cm alkyl)2, halogen (for example 5 chlorine or fluorine), NH2, CM alkoxy (such as OCH3), CM alkyl (such as methyl), CF3, OCF3, cyano or, where possible, oxo.

Id a still further aspect the present invention provides a compound of formula (I) or (la) wherein; R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), and optionally substituted by 0 or 1 alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R2, 10 R3, R4, R5, R6, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl or 1,2-dihydroisoquinolinyl, all of which are optionally substituted by S(0)2(Cm alkyl) (for example S(0)2CH3), halogen (for example chlorine or fluorine), NH2, Cm alkoxy (such as OCH3), Cm alkyl (such as methyl), CF3, OCF3, cyano or, where possible, oxo. 15 In another aspect the present invention provides a compound of formula (I) or (la) wherein R9 is isoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, quinolinyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-l,2-dihydropyridinyl, 6-oxo-l,6-dihydropyridinyl or pyrazolyl; each optionally substituted by halogen (such as fluorine), Cm alkyl (such as methyl or ethyl), CF3, Cm alkoxy (such as methoxy), S(0)2(Cm alkyl) (for example S(0)2CH3), 20 S(0)2NH2, S(0)2NH(Cm alkyl), S(0)2N(Cm alkyl^ or OCF3.

In a further aspect the present invention provides a compound of formula (I) or (la) wherein R9 is isoquinolinyl, 1 -oxo-1,2-dihydroisoquinolinyl, quinolinyl or 2-oxo-l,2-dihydroquinolinyl; each optionally substituted by halogen (such as fluorine), Cm alkyl (such as methyl or ethyl), CF3, Cm alkoxy (such as methoxy), S(0)2(Cm alkyl) (for 25 example S(0)2CH3) or OCF3.

In a still further aspect R9 is 1-oxo-l,2-dihydroisoquinolinyl optionally substituted by halogen (such as fluorine), Cm alkyl (such as methyl or ethyl), CF3, Cm alkoxy (such as methoxy), S(0)2(Cm alkyl) (for example S(0)2CH3) or OCF3. Alternatively, R9 is 2-oxo-1,2-dihydroquinolinyl optionally substituted by halogen (such as fluorine), Cm alkyl 30 (such as methyl or ethyl), CF3, Cm alkoxy (such as methoxy), S(0)2(Cm alkyl) (for example S(0)2CH3) or OCF3.

In another aspect R9 is an oxo-substituted dihydropyridinyl (such as 6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-l,2-dihydropyridin-5-yl or 2-oxo-l,2-dihydropyridin-4-yl), an WO r ''68743 oxo-substituted dihydroisoquinolinj'l (such as l-oxo-l,2-dihydroisoquinolin-4-yl), an oxo-substituted dihydrophthalazinyl (such as 4-oxo-3,4- dihydrophthalazin-1 -yl), pyrazinyl (such as pyrazin-4-yl), pyrrolyl (such as pyrrol-3-yl) or indolyl (such as indol-3-yl), each of which is not further substituted or substituted by: halogen (such as chloro or fluoro), C1.4 5 alkyl (such as methyl), CF3 or C3-5 cycloalkyl (such as cyclopropyl).

In a further aspect R9 is an oxo-substituted dihydropyridinyl (such as 6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-l,2-dihydropyridin-5-yl or 2-oxo-l,2-dihydropyridin-4-yl), an oxo-substituted dihydroisoquinolinyl (such as 1 -oxo-1,2-dihydroisoquinolinyl-4-yi) or pyrazinyl (such as pyrazin-4-yi), each of which is not further substituted or substituted by: 10 halogen (such as chloro or fluoro), Cm alkyl (such as methyl) or CF3.

An example of a compound of formula (I) or (la) is: //-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-15 (methylsulfonyl)benzamide; 2-chloro-JV1- {(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-(methylsulfonyl)benzamide; 4-amino-AL{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-methoxybenzamide; - iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(methylsulfonyl)benzamide; N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -5 -(methylsulfonyl)thiophene-2-cafboxamide; N- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidm-1 -yl]-2-hydroxypropyl} quinoline-6-25 carboxamide; iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-l,3-benzothiazole-6-carboxamide acetate salt; iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoroimidazo[l,2-a]pyridine-2-carboxamide; 30 iV-{ (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l,3-benzothiazole- 6-carboxamide; WO 03/068743 PCT/Sl D0258 16 3 -cyano-iV- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl }benzamide; iV-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl)-2- (methylsulfonyl)benzamide; N- { 4-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-3 -hydroxybutyl} -2-oxo-2,3-dihydro-1,3-5 benzothiazole-6-carboxamide; 4-amino-Ar- {4-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-3-hydroxybutyl} -3 -methoxybenzamide; iV- {4-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxybutyi) -2-(methylsulfonyl)benzamide; 10 iV-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide; iV-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yi]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-caiboxamide; iV-{(2<S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl)-2-15 (methylsulfonyl)benzamide; N- { (2i?)-3 -[4-(3 ,4-dicblorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -3 -[(methylamino)sulfonyi]benzami<te; 3,5-bis(acetylamino)-N-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl)-2-hydroxypropyl}benzamide; . 3-(Acetylamino)-iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzamide; //-{(2iQ-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lif>-pyrazole-4-carboxamide; 2-(Acetylamino)-5-bromo-iV-{(2if)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-25 hydroxypropyl}benzamide; N-{(2j?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-l,2-dihydropyridine-3-carboxamide; N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-5-carboxamide; 30 iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinoline-4-carboxamide; N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-l -yl) -2-hydroxypropyl) -lif-indole-4-caiboxamide; WOf A68743 17 2-(Acetylamino)-JV- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl)benzamide; 2-(Acetylamino)-5-chloro-iV- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}benzamide; 2-(Acetylamino)-4-chloro-JVr- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hycfroxypropyl}benzamide; -Chloro-iV- { (2i2)-3-[4-(3,4-dichlorophenoxy)piperidiii-1 -yl]-2-hydroxypropyl} -2-[(methylsulphonyl)amino]benzamide; 4-Chloro-A'- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl }-2-10 [(methylsulphonyl)amino]benzarnide; 2-Amino-4-chloro-7/-{(2i2)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl)benzamide; -Chloro-//- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-6-oxo-1,6-dihydropyridine- 3-carboxamide; 2-(Aminosulphonyl)-4-chloro-jV"- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl)benzamide; N- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -lH-indazole-3 -carboxamide; 1 -ter^Butyl-7V-{(2i?)-3-[4-(3,4-dichloropheiioxy)piperidin-l-yl]-2-hydroxypropyl}-3-20 methyl-iH-pyrazole-5-caiboxamide; Ar-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidia-l-yl]-2-hydroxypropyl}-4>5,6)7-tetrahydro-2iI-indazole-3-carboxamide; N- {(2R)~3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -3 -(trifluoromethyl)-iif-pyrazole-4-carboxamide; N- {(2/?)-3-[4-(3 J4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl) -2- . methylimidazo[l,2-a]pyridine-3-carboxainide; N- {(2ft)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -4-(iH-pyrazol-3-yl)benzamide; JV-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl)ciimoline-4-30 carboxamide; N- {(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidIn-1 -yl]-2-hydroxypropyl} -2-hydroxyquiiioline-4-carboxamide; PCT/SE 00258 18 • A^3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-253-dihydro-li/"-benzimidazole-1 -carboxamide; iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-4-oxo-3,4-dihydrophthalazine-1-carboxamide; N- { (2£)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} - l.£f-indole-3-carboxamide; N-{ (2i2)-3-[4-(4-ChIorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-(methylsulfonyl)benzamide; N-{ (2i?)-3-[4-(4-Chlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-1 -oxo-1,2-10 dihydroisoquinoline-4-carboxamide; I //-{(2R)-3-[4-(4-Chloro-3-fluorophenoxy)piperidin-l -yl]-2-hydroxypropyl }-l -oxo-1,2-dihydroisoquinoline-4-carboxamide; //-{ (2i?)-3-[4-(3,4-Difluorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-caiboxamide; 15 N- { (2,S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -iV-methyl-l -oxo-l,2-dihydroisoquinoline-4-carboxamide; iV-{(21S)-3-[4-(3J4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-//'-methyl-li/-indazole-3-carboxamide; N- { (2i)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -iV-methyl-4-oxo-20 3,4-dihydrqphthalazirie-l-carboxamide; Benzoic acid, 3-[[2-[[(ZR)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-^ hydroxypropyl]amino]-2-oxoeth}d]amino]-, methyl ester; Propanamide, iV-[2-[[2-[[(2i?)-3-[4-(3,4-dichlorophenoxy)-l -piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-; Propanamide, iV-[2-[[2-[[(2R)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-; (2S)-N- { (2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl)-2-hyroxy-2-phenylethanamide; 2-[2-({(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}aimno)-2-30 oxoethoxy]benzamide; N- {(2/?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-(3-oxo-2,3-dihydro-^iy-1,4-benzoxazin-4-yl]acetamide; \\0 f 168743 PCT/SE03/00258 19 N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}-2-methoxybenzamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yI]-2-hydroxypropyl}-2-(methylamino)benzamide; N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl }nicotiiiamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} isonicotinamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-3-(dimethylamino)benzamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-( 1,3-dioxo-1,3-10 dihydro-2H-isoindol-2-yl)acetamide; | N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-)4]-2-hydrcaypropyl}-6-hydroxymcotinamide; N-{(2R)-3-[4-(3,4-dichlorophe]ioxy)piperidin-l-yl]-2-hydroxypropyl}-2-(lH-indol-3-yl)acetamide; N-{(2R)-3-[4-(3,4-dichloropheiioxy)piperidin-l-yl]-2-hydroxypropyl}bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophexioxy)piperidin-l-yl]-2-hydroxypropyl}-4,7-dimethylpyrazolo[5,1 -c] [ 1,2,4]triazme-3-caiboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin.-l-yl3-2-hydroxypropyl}pyrazijae-2-20 carboxamide; N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -9H-purine-6-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinoliiie-6-carboxamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-1 -yl] -2-hydroxypropyl} -2,7-dimethylpyrazolof 1,5-a]pyrimidine-6-carboxamide; N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-(pyrimidin-2-ylthio)acetamide; N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin.-1 -yl]-2-hydroxypropyl}-5-fluoro-1 H-indole-30 2-carboxamide; N- {(2R)-3-[4-(3,4-dichlor ophenoxy)piperidin-1 -yi] -2-hydroxypropyl} -1,3-benzothiazole-6-carboxamide; WO 03/068743 PCT/SI 30258 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-5-phenyl-l,3-oxazole-4-carboxamide; N- { (2R)-3-[4-(3,4-dicMoroph.enoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-hydroxypyridine-2-carboxamide; N- { (2R)-3-[4-(3 J4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3 -oxo-3,4-dihydro-2H-l,4-benzoxazine-7-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyi} -3-hydroxypyridine-2-carboxamide; N- { (2R)-3-[4-(3,4-dichIorophepoxy)piperidiii-1 -yl] -2-hydroxypropyl} -1 H-benzimi dazole-10 5-caxboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-lH-iiidoIe-5-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-methyl-lH-indole-2-carboxamide; N-{(2R)-3-[4-(3}4-dichlorophenoxy)piperidm-I-yl]-2-hydroxypropyl}-lH-iimdazole-4-carboxamide; N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - lH-indole-6-caiboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -methyl-1H-20 indole-3-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-lH-mdole-7-caiboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-[(methylamino)sulfonyl]ben2^^ HP N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidm-1 -yl] -2-hydroxypropyl} -3,4-bis(methylsulfonyl)b«a2amide; N-{(2R)-3-[4-(3J4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyi}-2-pyridin-3-ylacetamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hyciroxypropyl}-5-hydroxy-lH-30 indole-2-caiboxamide; N-{(2R)-3-[4-(3,4-dichloropheiioxy)piperidiii-l-yl]-2-hydroxypropyl}-l,5-dimethyl-lH-' pyrazole-3-carboxamide; WO' *68743 21 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-5-(methylsiilfoiiyl)-lH-indole-2-carboxamide; N- {(2R)-3-[4-(3,4~dichlorophenoxy)piperidin- l-yl]-2-hydroxypropyl} quinoxaline-6-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)pipexidin-l-yl]-2-hydroxypropyl}-l,8-naphthyridine-2-carboxamide; N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} imidazo[2,1 -b][l,3]benzothiazole-2-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2,6-dimethylimidazo[ 1,2-a]pyridine-3-caiboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-oxo-2,3-dihydro-lH-indazole-4-carboxamide; N-{(2R)-3-[4-(3,4~dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-hydroxy-lH-indazole-6-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide; 2-(lH-benzimidazol-l-yl>N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- ' hydroxypropyl}acetamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydr6xypropyl}-l-ethyl-3-methyl-lH-pyrazole-5-catboxainide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-methyl-lH-pyrazole-3-carboxamide; N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -^-methyl-1,2,5 -oxadiazole-3-caiboxamide; 6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}iffiidazo[l,2-a]pyridme-2-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-methylimidazo[l,2-a]pyridine-3-caiboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl3-2-hydroxypropyl}imidazo[l,2-a]pyrimidine-2-carboxainide; N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} -2-[(4-methylpyrimidin-2-yl)thio]acetamide; oo o to X X §1 £ g £ 00 •o IS © s W C/5 00 VO O £ co <N c3 «o CM o m PCT/SI 00258 24 N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidiii-1 -yl] -2-hydroxypropyl} thiophene-2-sulfonamide; . 4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperi(iin-l-yl]-2-hydroxypropyl} amino)sulfonyl]benzoic acid; 5 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,5-dimethoxybenzenesulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(phenylsulfonyl)thiophene-2-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(l,3-oxazol-5-10 yl)thiophene-2-sulfonamide; ' N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidiii-1 -yl]-2-hydroxypropyl} -5-[ 1 r-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]thiophene-2-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-5-pyridin-2-ylthiophene-2-sulfonamide; 5-chloro-N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1,3-dimethyl-lH-pyrazole-4-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidih-l-yl]-2-hydroxypropyI}-3,5-dimethylisoxazole-4-sulfonamide; N- { (2S)-3-[4-(3,4-dichlorophenoxy)piperidiii-1 -yl] -2-hydroxypropyl} -2,1,3-20 benzothiadiazole-4-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-l-methyI-lH-imidazole-4-sulfonamide; N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -2,1,3- . benzoxadiazole-4-sulfonamide; N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -5-isoxazol-3-ylthiophene-2-sulfonamide; methyl 3-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)sulfonyl]tbiophene-2-carboxylate; 2,6-dichloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-30 hydroxypropyl }benzenesulfonamide; N- {(2 S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -3 -methyibenzenesulfonamide; ill WO; >68743 PCT/SE03/00258 3-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzenesulfonamide; N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl }propane-2-sulfonamide; N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl }propane-1 -sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-methyl-l-phenyl-lH-pyrazole-4-sulfonamide; 3-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-.10 methyibenzenesulfonamide; methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} amino)sulfonyl] -2-methyl-3 -furoate; methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} amino)sulfonyl] -1 -methyl-1 H-pyrrole-2-carboxylate; 15 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxyprqpyl}-3,4-dimethoxybenzenesulfonamide; -chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}thiophene-2-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}r6-moipholin-4-20 ylpyridine-3-sulfonamide; N- {2-chloro-4- [({ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} amino)sulfonyl]phenyl} acetamide; N-{(2S)-3-[4-(3,4^dichlorophenoxy)piperidin-l-yl]-2-hydtoxypropyl}-2,3-f|g| dihydroxyquinoxaline-6-sulfonamide; K-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4-dimethoxybenzenesulfonamide; -[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)sulfonyl]-2-methoxybenzamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yi]-2-hydroxypropyl}-2-30 methyibenzenesulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4-dimethyl-l,3-thiazole-5-sulfonamide; PCT/SI 00258 26 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-hydroxyquinoxaline-6-sulfonamide; N- {(2S)-3 -[4-(3 )4-dichiorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-methyI-3,4-dihydro-2H-l,4-benzoxazine-7-sulfonainide; 5 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}pyridine-3-sulfonamide; 4,-cyano-N-{(2S)-3-[4-(3)4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}biphenyl-2-sulfonamide; N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1,2-dimethyl-1H-10 imidazole-4-sulfonamide; 4-acetyl-N-{(2S)-3-[4-(3,4-dichlorqphenoxy)piperidin-l-yl]-2-hydroxypropyl}benzenesulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzenesulfonamide; 15 2-chloro-4-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)-piperidin-l-yl]-2-hydroxypropyl }benzenesulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l,3,5-triraethyl-lH-pyrazole-4-sulfonamide; iV-[(2R)-3-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]-l,4-dihydro-4-oxo-20 3-quinolinecarboxamide; //-{(2<S)-3-[4-(4-Chloro-2-methylphenoxy)piperi(iin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxainide acetate; Ar-{(25)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-caiboxanaide; N- {(25)-3 - { 4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -7-[(methylamino)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; J¥-{(2i2)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-{[(2-30 hydroxyethyl)aniino]sulfonyl}-1 -oxo-152-dihydroisoquinoline-4-carboxamide acetate salt; 7-[(Cyclopropylamino)sulfonyl] -N-{ (2i?)-3-[4-(3 J4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -1-oxo-1,2-dihydroisoquinoline-4-carboxamide; W(H >8743 27 7-(Azetidin-1 -ylsulfonyl)-iV- { (2i?)-3 -[4-(3,4-dichlorophenoxy)piperidiri-1 -yl] -2 -hydroxypropyl}-1-oxo-l ,2-dihydroisoquinoline-4-carboxamide acetate salt; 7-(Aminosulfonyl)-//- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 5 iV-{(2i?)-3-[4-(354-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(dimethylamino)sulfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide; iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-methylazetidin-1 -yl)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxainide acetate; iV-[(2R)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidin-1 -yl)-2-10 hydroxypropyl]-1 -oxo-1,2-dihydroisoqumoline-4-carboxaim<ie acetate salt; I N-{ (2JR)-3-[4-(3-Chloro-4-cyanophenoxy)piperidhi-l -yl]-2-hydroxypropyl}-l -oxo-1,2-dihydroisoquinoline-4-caiboxamide; N-((2/?)-2-Hydroxy-3 - { 4-[4-(methylsulfonyl)phenoxy]piperidin-1 -yl }propyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; N- { (2i?)-3-[4-(4-Cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; 7*/-((2i?)-3-{4-[2-(Aminocaibonyl)-4-chlorophenoxy]piperidm-l-yl}-2-hydroxypropyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxamide; iV-[(2i?)-3-(4- {4-Chloro-2-[(methylamino)carbonyl]phenoxy}piperidin-1 -yl)-2-20 hydroxypropyl]-1 -oxo-152-dihydroisoquinoline-4-caiboxamide; Methyl 5-chlon>-2-{[l-((2R)-2-hydroxy-3-{[(l-oxo-1,2-dihydroisoquinolin-4-yl)caibonyl]amino}propyl)piperidin-4-yl]oxy}benzoate acetate salt; 7/-((2R)-3-{4-[2-(Aminosulfonyl)-3,4-dichlorophenoxy]piperidin-l -yl} -2-hydroxypropyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide trifluoroacetate salt; 25 iV-[(2i?)-3-(4-{3,4-Dichloro-2-[(methylamino)sulfoiiyl]phenoxy}piperidm-l-yl)-2-hydroxypropyl]-1 -oxo-1,2-dihydroisoquinoline-4-caiboxamide acetate salt; iV-[(2i?)-3-(4-{3,4-DicWoro-2-[(cyclopropylamiiio)sulfonyl]phenoxy}piperidin-l-yl)-2-hydroxypropyi]-l-oxo-l,2-dihydroisoquinoli3ie-4-carboxamide acetate salt; Ar-{(2i?)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-30 (methylsulfonyl)- 1-oxo-1,2-dihydroisoquinoline-4-carboxamide; N- {(2i?)-3 - {4-(4-Chloro-2-methylphenoxy)piperidin-l -yl]-2-hydroxy-2-methylpropyl} -6-(methylsulphonyl)-l#-indole-3-carboxamide; GO o to u> to o s 8 0! & CT u_l ■ i to to fr. fcr4 £ & o o * X % 3 3 ►a *T3 •-< '-v-' w-' *K 1 On 1 £ O CD ? t ►—» X 8 & ? 8 t—d u N) i V Ul I I I to I CO .8 ft f cr § 8* '8 I O -4 Ui to oo >a O H c/> t* s> U\ 00 WO 168743 29 iV-{(2i?)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-oxo-354-dihydroquinoxaline-1 (2ii/)-carboxarnide; N- {(2R)-3-[4-(4-ChIoro-2-methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl} -3 -(trifluoromethyl)-liT-pyrazole-4-carboxamide; 5 iV-{(2i?)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1 #-pyrazole-4-carboxamide; iV-{(2i?)-3-{4-(3J4-Dichlorophenoxy)piperidin-l-yl}-2-hydroxypropyl}-1 -oxo-1,2-dihydro-2-methylisoquinoline-4-carboxamide; N- { (2i?)-3 - {4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-oxo-1 ,2-dihydro-10 1 -methyIquinoline-4-carboxamide; • iV-{(2R)-3-[4-(3,4-dichlorophenoxy)pipeiidin-l-yl]-2-hydroxypropyl}-8-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxamide; or, 2V- {(22?)-3-[4-(4-chloro-2-methylphenoxy)piperidin- l-yl]-2-hydroxypropyl}-8-fluoro-1 -oxo-l,2-dihydxoisoquinoline-4-carboxamide.

A compound of formula (I) or (la) can be prepared by reacting a compound of formula (D): OH ( ix £ N—CR2R3 (CH2)m- H ■ CR5R6 (CR7R8)n~N (II) R* : R32 wherein X, R1, R2, R3, R4, R5, R6, R7, R8, R32, m and n are as defined above, with: (i) when Y is a bond, CH2, NR35, CH2NH, CH2NHC(0), CH(OH), r20 CH(NHCOR33), CH(NHS02R34), CH20 or CH2S, Z is C(O), R35 is not hydrogen and, R: and R34 are as defined above, a compound of formula (Ilia): L1—CO—Y R9 (Ilia) wherein R9 is as defined above and L1 is a leavmg group (for example a hydroxy! or chloride leaving group) in the presence of a base (for example diis-opropylelthylaxnine), 25 optionally in the presence of a coupling agent (for example bromo-tris- pyrrolidinophosphonium hexafluorophosphate, PyBrOP or 0-(7-azabenzotriazol-l -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); and, (ii) when Y is NH and Z is C(O), a compound of fonnula (Hlb): 33 O N—R (1Mb) wherein R9 is as defined above.

WO 03/068743 PCT/Si. 30258 (iii) when Y is a bond and Z is S(0)2, a compound of formula (Hie): U S(0)2 R9 (lllc) wherein R9 is as defined above and L1 is a leaving group (for example a hydroxy! or chloride leaving group) in the presence of a base (for example pyridine). 5 A compound of formula (II) can be prepared as described in WO 00/58305 or WO 01/77101, or by reacting a compound of fonnula (IV): R'-^* vD™ (IV) wherein X and R1 are as defined above, with: (T) . when m and n are 0, R2, R3, R5 and R6 are hydrogen, and R4 and R32 are as 10 defined for formula (I), a compound of formula (V): . O ' \ L2 CR2R3 I \r5H6 (V) R4 in Which L2 is a leaving group (for example chloro or nosyloxy{3-N02-C6H4-S(0)20-}) followed by reaction with ammonia, an amine R32-NH2 or with sodium azide and subsequent reduction with, for example, triphenylphosphine; (ii) when m and n are 0, R2 and R3 are hydrogen and R4, R5," R6 and R32 are as defined for formula (T), with a compound of formula (VI): R2R3C— CR5R6 -NP1P2 (VI) in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for 20 example when P1 and P2 form phtalamide, hydrazine; (iii) when m is 0, n is 1, R2 and R3 are hydrogen and R4, R5, R6, R7, R8 and R32 are as defined for formula (I), with a compound of formula (VH): O K,r->1r*2 R R C" -CR R —CR R -—NP P (VII) R WO f 168743 PCT/SE03/00258 31 in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phtalamide, hydrazine; (iv) when m and n are 1, R2 and R3 are hydrogen and R4, R5, R6, R7, R8 and R32 are as defined for formula (I), with a compound of formula (VIII): oh l2 r2r3c c- H„ -cr5r6 cr7r8—np1p2 (viii) in which L2 is as defined for formula (V) and P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phthalamide, hydrazine; (v) when m is 1 and n is 0, R2 and R3 are hydrogen, R5 and R6 are, independently, hydrogen, Ci-6 alkyl or cycloalkyl, and R4 and R32 are as defined for fonnula (I), with a compound of formula (IX): oh l2 r2r3c c- h„ -cr5r6 np1p2 (ix) R in which L2 is as defined for formula (V) and P1 and P2 are, alone or together, suitable 15 protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phthalamide, hydrazine; (vi) when m is 1 and n is 0, R2, R3, R5 and R6 are hydrogen and R4 and R32 are 0k as defined for fonnula 0), with a compound of formula (X): l2 r2r3c—c cr5r6 (x) in which L2 is a leaving group (for example bromine) followed by reaction with ammonia, an amine R32-NH2 or with sodium azide and subsequent reduction with, for example, " triphenylphosphine; (viij when m is 1 and n is 0, R2, R3, R5 and R6 are, independently, hydrogen, Cus alkyl or C3.6 cycloalkyl, and R1, R4 and R32 are as defined for formula (I), with a compound 25 of formula (XT) : .

PCT/SI '00258 32 O r2r3c=c- -cr5r—np1p2 (xi) h in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by hydride reduction (for example with sodium borohydride), or by adding an appropriate organometallic species (for example R4MgX, where X is a halide); or, . (viii) when m is 1 and n is 1, R2, R3, R5 R6, R7 and R8 are, independently, hydrogen, Ci-6 alkyl or cycloalkyl, and R1, R4 and R32 are as defined for fonnula (I), with a compound of formula (XII): . O • ■ r2r3c=c- -cr5r6——cr7 r8 np1p2 (xii) H in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P! or P2 is R32, followed by hydride reduction (for example with sodium borohydride), or by adding an appropriate organometallic species (for example R4MgW, where W is a halide).

When m is 0 and n is 0, R2, R3, R5 and R6 are, independently, hydrogen, Ci^ alkyl 15 or C3-6 cycloalkyl, compounds or formula (II) can be prepared by reacting a compound of formula (XlII): /—V 0 -X—( N—CR2R3—L3 (XIII) R \ / wherein X and R1 are as defined for formula (I), and L3 is hydrogen or a leaving group (for example ethoxy, N,0-dimethylhydroxylamine), with a, compound of formula (XIV): m —cr5r—co l4 (xiv) in which M represents a metal (for example Li or Na) and L4 is an amino group (for • example ammonium) followed by rearrangement (for example with phenyhodonium diacetate, Tetrahedron Letters, 2001,42,1449.) and appropriate reduction (for example with sodium borohydride), or an appropriate organometalic addition (for example R4MgW, 25 where W is a halide).

© WO r 68743 w 33 When m is 0, n is 1 and R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, Ci.6 alkyl or C3-6 cycloalkyl, compounds of formula (IT) can be prepared by reacting a compound of formula (XX): r1^X—^ \|-cr2r- Lh (XX) wherein X, R1 and R4 are as described in formula (I) above and Z is an aldehyde protective group (for example cyanohydrin or dithiane), with a compound of formula (XXI): CR5R6 =CR7R8 C(O) L5 (XXI) in which R5, R6, R7 and R8 are as described above, and L5 is an alkoxy or amino group (for example ethoxy or ammonium) in presence of a base (for example LDA or n-butylithium), 10 followed byhydrolytic removal of the group L5, rearrangement (for example with phenyhodonium diacetate) and appropriate reduction (for example with sodium borohydride), or an appropriate organometalic addition (for example R^gW, where W is a halide).

A compound of formula (V) can be prepared by reacting a compound of formula (XXII): ho cr2r2 f=cr5r6 (xxiii) ■■ R4 with a peracid (for example meto-chloroperbenzoic acid) or using Sharpless asymmetric epoxidation conditions (J. Am. Chem. Soc. 1980,102, 5974-5976), followed by activation of the alcohol as a leaving group (for example as nosyloxy).

A compound of formula (VI) can be prepared: (a) when both R5 and R6 are hydrogen, by reacting a compound of formula (XXIQ): r2r3c -j cr5r- oh (xxiii) with a peracid (for example Tneto-chloroperbenzoic acid) or using Sharpless asymmetric 25 epoxidation conditions, followed, for example, by a Mitsunobu reaction using phthalimide, 1 ,l-(azodicarbonyl)dipiperidine and tributylphosphine (Tetrahedron Lett 1993,34,1639). (b) when R5 and R6 are, independently, hydrogen, Cw alkyl or C3-6 cycloalkyl, by reacting a compound of formula (XXIV): PCT/SL 00258 34 O r1 —cr5r6—np1p2 (xxiv) * *12 in which P and P are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, with a sulphur ylide (for example trimethylsulfoniummethylide, J. Am. Chem. Soc. 1965,87,1353-1364); or a phosphonium ylide (for example tiphenylphosphoniummethylide); followed by epoxidation of the resulting alkene using a peracid (for example meta-chloroperbenzoic acid).

A compound of formula (VII) can be prepared by reacting a compound of formula (XXV): O r- —cr5r6— cr7r—np1p2 (xxv) t n in which P and P are, alone or together, suitable protective groups (for example together they form phthalamide), or either P! or P2 is R32, with a sulfur ylide (for example trimethylsulfoniummethylide), or a phosphonium ylide (for example tiphenylphosphoniummethylide) followed by epoxidation of the resulting alkene using a peracid (for example meta-chloroperbenzoic acid), A compound of formula (VIII) can be prepared by reacting a compound of formula (XXV) with the anion of ethyl acetate (which can be prepared by the action of lithium diisopropylamide on ethyl acetate) followed by reduction of the resulting ester, or with, for example, vinyl magnesium Grignard and subsequent hydroboration (for example cathechol borane)/oxidation (for example hydrogen peroxide) of the alkene.

A compound of formula (EX) can be prepared from a compound of formula (XX3V) in a similar way as for compound (VTH).

A compound of formula (X) can be prepared by reacting a compound of formula (XXVI): ho—r2r3c c f=cr5r6 (xxvi) H2 17 - R with a peracid (for example meta-chloroperbenzoic acid), followed by selective activation of the primary alcohol as a leaving group (for example nosyloxy).

Further, compounds of formula (I) and (la) can be prepared by or by routine adaptation of: the routes described above, methods described in the art, or the Examples WO 168743 PCT/SE03/00258 recited below. The intermediates identified above are commercially available or can be prepared by using or adapting methods described in the art.

In a further aspect of the invention there is provided a process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising the steps of: a. reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room temperature; and, b. heating the mixture so produced together with l,2-dichloro-4-fluorobenzene at a temperature in the range 50-90°C, or at reflux of the solvent used.

In a further aspect the present invention provides a process for preparing 4-(3,4-10 dichlorophenoxy)piperidine comprising reacting 4-hydroxypiperidine with a suitable base {such as an alkali metal (preferably sodium or potassium) Ci-io alkoxide [such as a C4.10 tertiary alkoxide (for example a C4-5 tertiary alkoxide)], for example potassium tei-t-butoxide or potassium 3,7-dimethyl-3-octanoxide} in a suitable solvent {such as: an ether [for example tetrahydrofuran or methyl tert-butyl ester], an aromatic solvent [such as 15 toluene] or a mixture of these solvents) at room temperature (10-30°C); heating the mixture so produced together with l,2-dichloro-4-fluorobenzene at a temperature in the range 50-90°C, or at reflux of the solvent used.

In a still further aspect the present invention provides a process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising reacting 4-hydroxypiperidine with a suitable 20 base {such as an alkali metal (preferably sodium or potassium) Cmo alkoxide (such as a C4.J0 tertiary alkoxide), for example a Cj^s alkoxide (such as a tertiary alkoxide), for example potassium tert-butoxide} in a suitable solvent {such as: an ether [for example tetrahydrofuran or methyl *erf-butyl ester], an aromatic solvent [such as toluene] or a (Iff!;, mixture of these solvents} at room temperature (10-30°C), and heating the mixture so produced to a temperature in the range 50-90°C, or at reflux of the solvent used, and adding l,2-dichloro-4-fluorobenzene.

, Examples of tertiary alkoxides are potassium tert-butoxide and potassium 3,7-dimethyl-3-octanoxide.

In another aspect the present invention provides processes for the preparation of 30 compounds of formula (T) and (la).

The intermediates of fonnula (VI), (VII) and (VIII) defined herein are novel and these intermediates, and processes for their preparation, are provided as further features of the invention.

WO 03/068743 PCT/SEv >0258 36 The compounds of the invention 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 hypeiproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues 5 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), 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 |gp 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 WO )68743 PCT/SE03/00258 37 (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.

The compounds of the invention are also HI antagonists and may be used in the treatment of allergic disorders.

The compounds of the invention 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).

According to a further feature of the invention there is provided a compound of formula (I) or (la), 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), or antagonising HI, in a warm blooded animal, suchasman, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof.

The invention also provides a compound of the formula (I) or (la), 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) or (la), 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 HI, in a warm blooded animal, such as man).

The invention further provides the use of a compound of formula (1) or (la), 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 WO 03/068743 PCT/SEt . J0258 38 (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 (bay 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) or (la), 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 WO %8743 PCT/SE03/00258 39 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 5 including rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (1) or (la), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.

The present invention also provides the use of a compound of fonnula (I) or (la), or HI a pharmaceutical 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 Hp 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) or (la), or a pharmaceutically 15 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 HI, said ingredient is normally formulated in accordance with standard 20 pharmaceutical practice as a pharmaceutical composition.

^ Therefore in another aspect the present invention provides a pharmaceutical tfp • M composition which comprises a compound of the formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically : s \ 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 30 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 WO 03/068743 PCT/SEt >0258 40 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 5 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 O.lmg and lg of active ingredient In another aspect a pharmaceutical composition of the invention is one suitable for 10 intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg"1 to lOOmgkg"1 of the compound, preferably in the range of O.lmgkg"1 to 20mgkg"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by 15 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 invention will now be illustrated by the following non-limiting Examples in 20 which, unless stated otherwise: (i) when given, !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 300MHz or 400MHz using perdeuterio DMSO-D6 (CD3SOCD3), methanol-D4 (CD3OD) or CDCI3 as the solvent unless otherwise stated; 25 (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) or electrospray (ESI); 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 -30 (M+H)+; (iii) the title and sub-title compounds of the examples and methods were named using the ACD/Index name program version 4.55 from Advanced Chemistry Development, Inc; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, WO 368743 41 NovaPak or Xterra reverse phase silica column; and (v) the following abbreviations are used: APCI Atmospheric pressure CI DMF N,N-dimethylformamide HPLC High pressure liquid chromatography MTBE Methyl ferf-butyl ether DMSO dimethylsulfoxide THF tetrahydrofuran DCM dichloromethane . Preparation 1 (2R)-1 - Aroino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol Step 1: 2-{(2iS)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-li/-isoindole-1,3(2H)«dione cr xr*o OH 7" o (R)-2-(Oxiranylmethyi)-lir-isoindole-l,3(2fl)-dione (Tetrahedron Asymmetry, 1996, 7, 1641,5g) in a mixture of 50 ml of ethanol and 15 ml of DMF was treated with 4-(3,4-dichlorophenoxy)-piperidine (6g). The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum and the residue was azeotroped twice with toluene. The crude material was purified by chromatography (ethyl acetate) to give the subtitle compound as a yellow oil.

MS (APCI) 449/451 (M+H)+ * *H NMR 6 (CDC13) 7.92-7.81(2H, m), 7.77-7.70 (2H, m), 7.30 (IH, d), 6.98 (IH, t), 6.74 (IH, dt), 4.34-4.20 (IH, m), 4.09-3.97 (IH, m), 3.83 (IH, dd), 3.73 (IH, dd), 2.93-2.79 (lH,m), 2.73-2.60 (IH, m), 2.59-2.37 (3H, m), 2.31 (IH, t), 2.02-1.86 (2H, m), 1.86-1.67 (2H,m).

Step 2: (2/2)-1 -amino-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]propan-2-ol C,YY°Y^| OH (S)-2-[3-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]-li^-isoindole-1,3(2H)-dione (4g) in ethanol (100ml) was treated with 20 ml of hydrazine monohydrate and the resulting mixture was refluxed for 3h. The reaction was cooled and filtered. The A 1 6 8 2 WO 03/068743 PCT/SE< ,00258 42 filtrate was evaporated and the product was chromatographed (ethyl acetate) to give the title compound as a yellow oil which solidified on standing (2.5g).

MS (APCI) 319/321 (M+H)+ ^NMR 8 (CDC13) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.00 (IH, app. sept), 5 3.74-3.62 (IH, m), 2.94-2.84 (IH, m), 2.82 (IH, d), 2.72-2.61 (IH, m), 2.65 (IH, d); 2.60-2.49 (IH, m), 2.46-2.21(3H, m), 2.06-1.91 (2H, m), 1.90-1.72 (2H, m).

Preparation 2 4-Amino-l-[4-(3,4-dichlorophenoxy)prperidin-l-yl]butan-2-ol 10 Step 1: 2-{ 4-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -3 -hydroxybutyl} -1 if-isoindole-l,3(2H)-dione A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (4.40g) and 2-(2-oxiran-2-ylethyl)-lif-isoindole-l,3(2il0-dione (J. Med Chem. 1979, 15 22(6), 631-9. 5.OOg) in ethanol (50 ml) was stirred at 60°C for 12h. The mixture was cooled down and left overnight. The formed crystals were collected by filtration, washed with cold ethanol and dried under vacuum to afford the sub-title compound as a white solid (3.0g).

MS (APCI) 463/465 (M+H)+ *H NMR 8 (DMSO) 7.90-7.80 (4H, m), 7.49 (IH, d), 7.25 (IH, d), 6.97 (IH, dd), 4.53-4.33 (2H, m), 3.80-3.69 (IH, m), 3.69-3.58 (2H, m), 2.77-2.60 (2H, m), 2.38-2.17 (4H, m), 1.94-1.84 (2H, m), 1.85-1.75 (IH, m), 1.65-1.50 (3H, m).

Step 2: 4-amino-l-[4-(3,4-dichlorophenoxy)piperidin-l-yl]butan-2-ol :X5r°tiX~^ A solution of mixture of 2-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-lif-isoindole-l,3(2H)-dione (3.00g) in a mixture of ethanol (75 ml) and 35% aqueous hydrazine (15 ml) was heated at reflux 4h. The mixture was cooled down and the solvents removed under vacuum. The residue was triturated with warm WO )68743 PCT/SE03/00258 43 dichloromethane. The white solid was removed by filtration and the filtrate dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to afford the title compound as a yellow oil (2.10g) which was used without further purification in the next step.

MS (APCI) 333/335 (M+H)+ !H NMR S (CDCIs) 7.29 (IH, d), 6.96 (IH, d), 6.76 (IH, dd), 4.40-4.25 (IH, m), 3.95-3.85 (IH, m), 3.20-3.00 (2H, m), 2.96-2.79 (IH, m), 2.78-2.63 (IH, m), 2.60-2.45 (IH, m), 2.41-2.23 (3H, m), 2.10-1.88 (2H, m), 1.88-1.70 (3H, m), 1.70-1.58 (IH, m).

Preparation 3 1 -Amino-4-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]butan-2-ol Step 1: 4-(3,4-dichlorophenoxy)-l-(2-oxiran-2-yle1hyl)piperidine :rr0O^, . O A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) 15 (2.00g), 2-(2-bromoethyi)oxirane (J. Am. Chem. Soc. 1981,103, 7520-8) (1.36g) and potassium carbonate (2.2 g) in acetone (20 ml) was stirred at 50°C for 12h. The solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The mixture was filtered and the solvent was evaporated to afford the sub-title compound as a k20 yellow oil (2.50g) which was used without further purification in the next step.

MS (APCI) 316/318 (M+H)+ . JH NMR 8 (CDCI3) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.27 (IH, dquintet), ^ 3.02-2.95 (IH, m), 2.78 (IH, t), 2.77-2.68 (2H, m), 2.57-2.49 (3H, m), 2.39-2.24 (2H, m), 2.03-1.94 (2H, m), 1.87-1.75 (2H, m), 1.77-1.72 (IH, m), 1.73-1.61 (IH, m).

Step 2: 1 -amino-4-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]butan-2-ol citt0sO . —^Nv-^sy^v'nh2 oh In a sealed metal tube, a solution of 4-(3,4-dichlorophenoxy)-1 -(2-oxiran-2-ylethyl)piperidine (l.OOg) in 7N ammonia in methanol (25 ml) was heated at 70°C for 12h. 30 The solvent was removed under vacuum and the residue purified on silicagel (0 to 10% 7N WO 03/068743 PCT/SE*. .00258 44 ammonia in methanol/dichloromethane) to afford the title compound as a yellow oil (0.55g).

MS (APCI) 333/335 (M+H)+ ]HNMR8 (CDC13) 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.36-4.27 (IH, m), 5 3.79-3.70 (IH, m), 2.93-2.78 (IH, m), 2.76-2.59 (5H, m), 2.61-2.50 (IH, m), 2.37-2.27 (IH, m), 2.03-1.90 (2H, m), 1.89-1.76 (2H, m), 1.74-1.61 (IH, m), 1.54-1.46 (IH, m).

Preparation 4 (2R)~ 1 -Amino-3-[4-(4-chlorophenoxy)piperidin-1 -yl]propan-2-ol Prepared as described in Preparation 1. • *H NMR 8 (CD3OD) 7.13 (2H, d), 6.80 (2H, d), 4.26 (IH, septet), 3.68-3.59 (IH, m), 2.77-2.65 (2H, m), 2.62 (IH, dd), 2.46 (IH, dd), 2.38-2.24 (4H, m), 1.95-1.85 (2H, m), 1.73-1.61 (2H,m).

■ Preparation5 (2R)~ 1 -Amino-3-[4-(4-chloro-3-fluorophenoxy)piperidin-1 -yl]propan-2-ol OH cr^ Prepared as described in Preparation 1.

MS (ESI) 303/305 (M+H)+ JHNMR 8 (CD3OD) 7.32 (IH, t), 6.86 (IH, dd), 6.77 (IH, ddd), 4.40 (IH, quintet), 3.74 (IH, ddd), 2.87-2.75 (2H, m), 2.72 (IH, dd), 2.56 (IH, dd), 2.50-2.37 (4H, m), 2.08-1.95 (2H, m), 1.85-1.72 (2H, m).

Preparation 6 (22?)-l-Ammo-3-[4-(3,4-difluorophenoxy)piperidin-l-yl]propan-2-ol Prepared as described in Preparation 1.

MS (ESI) 287 (M+H)+ WO ' 068743 PCT/SE03/00258 45 *H NMR 5 (CD3OD) 7.14 (IH, dt), 6.87 (IH, ddd), 6.75-6.69 (IH, m), 4.35 (IH, septet), 3.80-3.71 (IH, m), 2.88-2.75 (2H, m), 2.75 (IH, dd), 2.58 (IH, dd), 2.51-2.34 (4H, m), 2.07-1.94 (2H,m), 1.85-1.71 (2H,m).

Preparation 7 2R)-1 -Amino-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]propan-2-ol.

Step 1: 4-(3,4-dichlorophenoxy)piperidine 4-Hydroxypiperidine (50g, 494mmol) was added portionwise to a stirred suspension of potassium terf-butoxide (110.9g, 990mmol) in THF (900ml) at room 10 temperature and under nitrogen. Hie mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98g, 594mmol) added dropwise over 30 minutes. The mixture was stirred at reflux for another 1 hour then cooled down to room temperature, diluted with ethyl acetate (500ml) and washed with water (500ml). The organic phase was diluted further with ethyl acetate (500ml) and extracted with 1M hydrochloric acid (200ml), The aqueous 15 extract was adjusted to pH>l 0 by addition of a solution of sodium hydroxide and extracted twice with terf-butylmethyl ether (750ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.

MS (ESI) 246/248 (M+H)+ 'H NMR 8 (CDCI3) 7.31 (IH, d), 7.00 (IH, d), 6.78 (IH, dd), 4.29-4.37 (IH, m), 3.15 (2H, dt), 2.75 (2H, td), 1.97-2.03 (2H, m), 1.60-1.70 (2H, m).

Alternative Step 1: 4-(3,4-dichlorophenoxy)piperidine d§| A thin slurry of 4-hydroxypiperidine (50g, 494mmol) in THF (200ml) was added to a stirred suspension of potassium fert-butoxide (110.9g, 990mmol) in THF (650ml) at room temperature and washed in with THF (50ml). The resultant mixture was stirred under nitrogen for 20 minutes. l,2-Dichloro-4-fluorobenzene (98g, 594mmol) was added and the resultant mixture heated at reflux for 90 minutes. The reaction mixture was cooled to room temperature and water (500ml) added. The layers were separated and the solvent removed 30 from the organic fraction. The material was then partitioned between MTBE and 10% aqueous citric acid solution. The layers separated and the aqueous layer washed with further MTBE (2x250ml). The aqueous phase was basified to pH>10 by addition of 10N NaOH solution and the product extracted with iso-propyl acetate (2x300ml). The organics WO 03/068743 PCT/SE )0258 46 were washed with brine (300ml), dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step (109.1 g, 90%).

Step 2: (2S)-l-a2ddo-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-oI aTT°T^ °H (2i?)-Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.lg, 81.3mmol) in DMF (300ml) was treated with triethylamine (22.6ml, 163.0mmol) followed by 4-(3,4- HP dichlorophenoxy)-piperidine (20g, 81.3mmol). The mixture was stirred overnight at 60°C. 10 Sodium azide(16g,243.9mmol) was added to the mixture and the reaction was stirred for a further 72h. The solution was carefully concentrated under vacuum and the residue was ® diluted with water (600ml), extracted with ethyl acetate (1500ml). The organic layer was washed twice with water (500ml), then brine (200ml) and concentrated under vacuum to afford an oil.

Step 3: (2R)~ 1 -Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol The resulting oil from Step 2 was dissolved in wet tetrahydrofuran (225ml) and was treated with triphenylphosphine (53.3g, 203mmol). The reaction was heated at 60°C and stirred for 4h. The solvent was removed under vacuum, the residue re-dissolved into 2N 20 hydrochloric acid (1000ml) and the aqueous layer was extracted with ethyl acetate (3 |g| times 700ml). The aqueous phase was basified with a 2N sodium hydroxide solution and extracted with dichloromethane (3 times 1000ml). The combined organic layers were washed with brine, dried over sodium sulfete, filtered and concentrated under vacuum. The (Jf^ crude material was purified by chromatography (8% 7N ammonia in methanol/DCM) to 25 give the title compound as a yellow oil (17g).

MS (APCI) 319/321 (M+H)+ *H NMR 5 (CDC13) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.0 (IH, app. sept), 3.74-3.62 (IH, m), 2.94-2.84 (IH, m), 2.82 (IH, d), 2.72-2.61 (IH, m), 2.65 (IH, d), 2.60-2.49 (IH, m), 2.46-2.21 (3H, m), 2.06-1.91 (2H, m), 1.90-1.72 (2H, m). wcr 168743 PCT/SE03/00258 47 Preparation 8 (2R)-l-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol Stepl: (2iS)-l-Chloro-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol . (S)-(+)-Epichlorohydrin (3.50ml, 44.7mmol) was added to a stirred solution of 4-(3,4-dichlorophenoxy)piperidine (lO.Og, 40.6mmol) in ethanol (50ml). After 20h, water (50ml) was added. The mixture stirred for a further 2h then the precipitated solid was collected by filtration, washed with water and dried under vacuum at 50°C for 2h to give the sub-title compound. lo MS (ESI) 338/340/342/344 (M+H)+ *H NMR 8 (CDCI3) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.28-4.33 (IH, m), 3.89-3.96 (IH, m), 3.54-3.62 (3H, m), 2.84-2.92 (IH, m), 2.65-2.72 (IH, m), 2.45-2.59 (3H, m), 2.32-2.36 (IH, m), 1.90-2.01 (2H, m), 1.77-1.87 (2H, m).

Step 2: (2Ry1 -Amino-3 -[4-(3,4-dicMorophenoxy)piperidin-l -yl]propan-2-ol aYT0NO ™ A solution of sodium hydroxide (1.62g, 40.6mmol) in methanol,(200ml) was added to the product of the previous step and the mixture stirred for lh whereupon all solid had dissolved. Aqueous ammonia solution (28%, 80ml) was added and stirring continued at ^0 ambient temperature for 3 days. The solution was concentrated in vacuo to a volume of 100ml then dissolved in hydrochloric acid (0.5M, 800ml) and extracted with diethyl ether (2 x 200ml). The aqueous extract was filtered to remove insoluble impurities then made alkaline by addition of sodium hydroxide and extracted with dichloromethane (4 x 200ml) with filtration of the two-phase mixture to remove further insoluble impurities. Organic 25 extracts were dried over anhydrous magnesium sulfete, filtered and evaporated under reduced pressure to provide the title compound as an oil (10.6g).

MS (APCI) 319/321 (M+H)+ 'H NMR 8 (CDCI3) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.0 (IH, app. sept), 3.74-3.62 (IH, m), 2.94-2.84 (IH, m), 2.82 (IH, d), 2.72-2.61 (IH, m), 2.65 (IH, d), 2.60-30 2.49 (lH,m), 2.46-2.21 (3H,m), 2.06-1.91 (2H,m), 1.90-1.72 (2H,m).

WO 03/068743 PCT/SE 30258 48 Preparation 9 (2iS)-1 -Amino-3-[4-(3>4-dichlorophenoxy)piperidin-1-yl]-2-methylpropan-2-ol OH Prepared as described in Preparation 7 (Steps 2 and 3) using [(2R)-2-methyloxiran-5 2-yl]methyl-3-nitrobenzenesulfonate.

MS (APCI) 333/335 (M+H)+ 'H NMR5 (CDC13) 7.30 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.38-4.30 (IH, m), 3.48 (2H, s), 2.96-2.78 (2H, m), 2.62-2.30 (4H, m), 2.00-1.90 (2H, m), 1.85-1.72 (2H, m), 1.25 (3H, s).

Preparation 10 (22?)-l-Amino-3-[4-(4-cMoro-2-methyiphenoxy)-piperidin-l-yl]propan-2-ol 11 i°r> ?h k^N^s^NH2 Prepared as described in Preparation 7 (Steps 2 and 3) from 4-(4-chloro-2-15 methylphenoxy)-piperidine.

MS (ESI) 299/301 (M+H)+ 'H NMR 8 (CD3OD) 7.12-7.05 (2H, m), 6.87 (IH, d), 4.39 (IH, septet), 3.77-3.70 (IH, m), 2.84-2.72 (2H, m), 2.71 (IH, dd), 2.55 (IH, dd), 2.50-2.39 (2H, m), 2.40 (IH, d), 2.39 (IH, d), 2.18 (3H, s), 2.04-1.95 (2H, m), 1.86-1.75 (2H, m).

Preparation 11 6-({l-[(2i?)-3-Amino-2-hydroxyprop>d]piperidin-4-yl}oxy)-2,3-dichlorobenzamide conhj Cl^ JL yv TY Yl oh Step 1: /erf-Butyl 4-[2-(aminocarbonyl)-3,4-dichlorophenoxy]piperidine-l-carboxylate ovnh2 c,rr°T^ T ^ o V WO' 168743 PCT/SE03/00258 49 To a stirred solution of tot-butyl 4-[3,4-dichlorophenoxy]piperidine-l-carboxylate (7.0g, 20.3mmol) in dry THF (250ml) at -70°C under a nitrogen atmosphere was added dropwise .sec-butyl lithium (18ml, 1.3M in cyclohexane). The solution was stirred a further 30min. at this temperature then treated with solid carbon dioxide pellets (excess).

The cooling bath was removed and the mixture stirred vigorously whilst warming to room temperature over lh. After a further lh the solution was concentrated to ca 50ml volume then partitioned between aqueous sodium hydrogen carbonate solution and diethyl ether. The aqueous phase was further washed with diethyl ether (3 x), then acidified to pH 4 and extracted with dichloromethane (3 x). The combined extracts were dried (magnesium 10 sulphate) and concentrated. Treatment of the crude carboxylic acid (2.5g, 6.4mmol) with carbonyl-1,1 -diimidazolide (1.25g, 7.7mmol) in dichloromethane (50ml) at room temperature for 72h gave the crude imidazolide which was concentrated in vacuo, redissolved in ethanol (20ml) and treated with 35% aqueous ammonia (20ml) in an autoclave at 100°C for 2h. The mixture was allowed to cool to room temperature slowly to 15 allow crystallization of the title compound. The crystalline product was filtered and washed with water. Recrystallization from ethanol/water gave the sub-title compound (1 90g).

MS (APCI) 289/291 (M+H-BOC)* . *H NMR 5 (CDC13) 7.40 (IH, d), 6.83 (IH, d), 5.91 (IH, s), 5.73 (IH, s), 4.52 (IH, 20 m), 3.59 (2H, m), 3.41 (2H, m), 1.86 (4H, m), 1.43 (9H, s).

^ Step 2: 2,3 -dichloro-6-(piperidin-4-yloxy)benzamide o. «m>. a o cr ~ ~NH To a stirred solution of terf-butyl 4-[-[2-(aminocarbonyl)-3}4-25 dichlorophenoxy]piperidine-l-carboxylate (1.8g, 4.6mmol) in dichloromethane (10ml) was added trifiuoroacetic acid (10ml). After 30min at room temperature the solution was concentrated in vacuo and partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous was re-extracted a further three times with dichloromethane and three times with ethy acetate. The combined organic 30 extracts were dried (anhydrous potassium carbonate) and concentrated to afford the subtitle compound as a white solid (1.15g).

WO 03/068743 PCT/SE >0258 50 MS (APCI) 289/291 (M+H)+ !H NMR 5 (CD3OD) 7.49 (IH, d), 7.09 (IH, d), 4.65 (IH, M), 3.15 (2H, m), 2.84 (2H, m), 2.02 (2H, m), 1.82 (2H, m).

Step 3: 6-({l-[(2J?)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzamide Step a: To a stirred solution of 2,3-dichloro-6-(piperidin-4-yloxy)beiizaimde (l.lg, 3.8mmol) in dimethylformamide (10ml) was added triethylamine (1.06ml. 7.6mmol) and (2R)-glycidyl-3-nitrobenzenesulfonate (1.0g, 3.8mmol) and the mixture heated at 60°C for 3h. Sodium azide (l.Og, 15.2mmol) was added and the temperature maintained for a ! 10 further 48h. The mixture was concentrated in vacuo (blast shield) to almost dryness, and the product partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous layer was reextracted with dichloromethane then with ethyl acetate. The combined organic extracts were dried (anhydrous potassium carbonate) and concentrated in vacuo.

Step b: The product was redissolved in tetrahydrofuran (50ml) and treated with water (5ml) and triphenylphosphine (2.4g). The mixture was heated at 60°C for 4h, then concentrated in vacuo. The product was partitioned between ethyl acetate and IN aqueous hydrochloric acid. The aqueous extracts were washed further with ethyl acetate then basified with 48% sodium hydroxide solution to pH 11. The aqueous layer was extracted 20 with dichloromethane (3 x), and the combined organic extracts dried (anhydrous potassium carbonate) and concentrated in vacuo to afford crude amine product which was used without any purification in the next step (See Example 132).

Preparation 12 (R)-l-[4-(3,4-Dichloro-phenoxy)-piperidin-l-yi]-3-methylamino-propan-2-ol A solutionof 4-(3,4-dichlorophenoxy)-l-[(2i?)-oxiran-2-ylmethyl]piperidine (lg, 3.3 lmmol) and methylamine (2.56ml 40% in EfeO, 33.Immol) in ethanol (15ml) was heated at 60°C in a sealed vessel for 16h. The solvent was evaporated at reduced pressure 30 and the residue purified by flash column chromatography eluting with 8% 7M ammonia methanol in dichloromethane to give the title compound (875mg).

MS (APCI) 333/335 (M+H)+ WO 068743 51 'HNMR 5 (CDC13) 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.32-4.26 (IH, m), 3.86-3.80 (IH, m), 2.91-2.86 (IH, m), 2.71-2.65 (2H, m), 2.65 (IH, dd), 2.56-2.51 (2H, m), 2.54 (IH, dd), 2.48-2.42 (2H, m), 2.46 (3H, s), 2.38-2.27 (3H, m).

Preparation 13 (2R)-1 -Amino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l -yl]propan-2-ol a Prepared as described in Preparation 10 using 4-(2,4-dichloro-3-methylphenoxy)-piperidine.

MS (APCI) 333/335 (M+H)+ *H NMR 5 (CD3OD) 7.25 (2H, d), 6.94 (2H, d), 4.54-4.37 (IH, m), 3.88-3.71 (IH, m), 3.35-3.24 (2H, m), 2.93-2.72 (4H, m), 2.72-2.57 (IH, m), 2.08-1.90 (2H, m), 1.92-1.75 (2H,m).

Prepared as described in Preparation 7 using (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate.

MS (ESI) 319/321 (M+H)+ JH NMR S (CDCI3) 7.30 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.36-4.24 (IH, m), 3.75-3.65 (IH, m), 2.94-2.78 (2H, m), 2.70-2.60 (2H, m), 2.59-2.51 (IH, m), 2.41-2.25 (3H, m), 2.03-1.93 (2H, m), 1.87-1.77 (2H, m).

Preparation 15 (2R)-1 - Amino-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol. Step 1:2-[[(2i?)-2-methyloxiranyl3methyl]-lfr-isoindole-l ,3(2jy)-dione. c.

Preparation 14 (2jS)-l-Amino-3-[4-(3,4-diclilorophenoxy)piperidin-l-yl]propan-2-ol o o WO 03/068743 PCT/SL /00258 52 To a solution of (2>S)-(2-methyloxiran-2-yl)methyl 3-nitrobenzenesulphonate (1.913g, 7mmoles) in dry dimethylformamide (15ml), was added potassium phthalimide (1.304g, 7mmoles). The mixture was stirred at 50°C for 5h and then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water. The 5 aqueous phase was washed with ethyl acetate (2x100ml) and the combined organic extracts were washed with water (3x100ml), saturated brine solution, dried over sodium sulfate and concentrated in vacuo to leave a crude orange wax. Purification by chromatography (silica, 20% ethyl acetate in iso-hexane) afforded the subtitle compound as a white solid (0.864g). MS (ESI) 189 (M-CO)+ 'HNMR 8 (CDC13) 7.90-7.85 (2H,m), 7.78-7.71 (2H,m), 4.02 (lH,d), 3.71 (IH, d), 2.82 (lH,d), 2.62 (lH,d), 1.39 (3H,s).

Step 2: 2-[(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl]-15 lif-isoindole-1,3(2H)-dione. o A solution of 4 (3,4-dichlorophenoxy)piperidine (0.985g, 4mmoles), 2-[[(2i?)-2-methyloxiranyl]methyl]-l^r-z^oindole-l,3(2ii)-dione (0.869g, 4mmoles)and triethylamine (0.809g, 1.12ml, 8mmoles) in ethanol (20ml) was stirred at 50°C for 5h. The resulting 20 solution was cooled to room temperature and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 2% of IN methanolic ammonia in dichloromethane as eluant) afforded the subtitle compound as a yellow oil (1.24g).

MS (APCI) 463/465/467 (M+H)+ teNMR 8 (CDCI3) 7.89-7.85 (2H, m), 7.76-7.72 (2H, m), 7.30 (IH, d), 6.98 (IH, 25 d), 6.78 (IH, dd), 4.27-4.21 (IH, m), 3.88 (lH,d), 3.70 (IH, d), 3.43 (IH, bd s), 2.96-2.81 (2H, m), 2.60-2.42 (4H, m), 1.95-1.89 (2H, m), 1.80-1.70 (2H, m), 1.15 (3H, s).

Step 3: (2R)-1 - Amino-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol. cu ^ ,0, , Me OH cr WO 768743 PCT/SE03/00258 53 To a solution of 2-[(2iS)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl]-l-ff-zsoindole-1,3 (2iZ)-dione (278mg, 0.6ramoles) in ethanol (5ml) was added aqueous methylamine (40% wt. solution in water, 6ml). The mixture was stirred at room temperature for 24h and then concentrated in vacuo to leave a crude yellow glass, j This glass was dissolved in methanol (2ml), added to an Isolute Flash SCX cartridge (2g), washed with methanol (25ml) and 7N ammonia in methanol (25ml). The methanolic ammonia was concentrated in vacuo to give the title compound as a yellow glass (165mg). MS (ESI) 333/335/337 (M+H)+ 'H NMR S (CDC13) 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.29-4.21 (IH, m), 10 2.96-2.80 (2H, m), 2.60-2.30 (4H, m), 2.00-1.90 (3H, m), 1.85-1.75 (3H, m), 1.13 (3H, s).

Preparation 16 7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid l-Oxo-7-sulfo-l,2-dihydroisoquinoline-4-carboxylic acid (5g) was added to chlorosulphonic acid (25ml). The mixture was heated at 100°C for 84h and then slowly dripped onto ice with stirring. The mixture was filtered and the residue was washed with water and ether and dried to yield 7-(chlorosulfonyl)-l -oxo-1,2-dihydroisoquinoline-4-| carboxylic acid as a buff solid (7.5g).

MS (APCI) 286 (M-H)' 'H NMR 6 (DMSO) 11.81 (IH, d), 8.79 (IH, d), 8.48 (IH, d), 8.03 (IH, d), 7.96 (IH, dd).

Preparation 17 7-[(Methylamino)sulfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid 7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (lg) was added to aqueous methylamine (60ml) and the mixture was stirred for 18h. Concentrated wo 03/068743 pct/se j0258 54 hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-[(methylamino)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a buff solid (0.84g).

MS (APCI) 283 (M+H)+ !H NMR 8 (DMSO) 12.93 (IH, s), 12.13 (IH, d), 9.03 (IH, d), 8.61 (IH, d), 8.16 (IH, d), 8.12 (IH, dd), 7.65 (IH, q), 2.43 (3H, d).

Preparation 18 1,2-Dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1 -oxo-4-isoquinolinecarboxylic acid 7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxyiic acid (lg) was added to ethanolamine(3ml) in tetrahydrofuran (3ml) and the mixture was stirred for 18h. Hydrochloric acid was added to acidify the mixture, which was filtered to yield 1,2-15 dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-l-oxo-4-isoquinolinecarboxylic acid as a white solid.

MS (APCI) 313 (M+H)+ 'H NMR 8 (DMSO) 12.92 (5H, s), 12.12 (5H, s), 9.01 (6H, d), 8.62 (6H, s), 8.16 (13H, d), 8.13 (13H, dd), 7.81 (6H, t), 4.67 (5H, s), 3.39-3.25 (84H, m), 2.81 (13H, q).

Preparation 19 7-[(Cyclopropylamino)sulfonyl]-1,2-dihydro-1 -oxo-4-isoquinolinecarboxylic acid 7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (lg) was 25 added to cyclopropylamine(3ml) in tetrahydrofuran (20ml) and the mixture was stirred for 18h. Hydrochloric acid was added to acidify the mixture which was filtered to yield 7-. [(cyclopropylamino)sulfonyl]-l,2-dihydro-l-oxo-4-isoquinolinecarboxylicacid as a white solid.

WO '068743 PCT/SE03/00258 55 MS (APCI) 307 (M-H)- *H NMR 8 (DMSO) 12.93 (IH, s),12.13 (IH, d), 9.03 (IH, d), 8.65 (IH, d), 8.16 (IH, d), 8.14 (IH, dd), 8.08 (IH, d), 2.13 (IH, dsextet), 0.48 (2H, td), 0.39-034 (2H, m).

Preparation 20 7 -(Azetidin-1 -ylsulfonyl)-1 -oxo-132-dihydroisoquinoline-4-carboxylic acid 7-(Chlorosirifonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxyiic acid (lg) was added to azetidine (0.7ml) and diisopropylethylamine (0.4ml) in tetrahydrofuran (5ml) and 10 acetonitrile (5ml) and the mixture was stirred for 72h then evaporated. The solid was crystallised from methanol then hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(azetidin-1 -ylsulfonyl)-1 -oxo-1 ,2-dihydroisoquinoline-4-carboxylic acid as a white solid.

MS (APCI) 309 (M+H)+ *H NMR 8 (DMSO) 12.99 (IH, s), 12.21 (IH, d), 9.12 (IH, d), 8.54 (IH, d), 8.20 (IH, d), 8.16 (IH, dd), 3.70 (4H, t), 1.99 (2H, quintet).

Preparation 21 7-(Aminosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid 7-(Chlorosulfonyl)-l-oxo-ly2-dihydroisoquinoline-4-carboxylic acid (lg) was added to 0.880 ammonia (60ml) and the mixture was stirred for 18h. Concentrated hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(aminosulfonyl)-1-oxo-l,2-dihydroisoquinoline-4-carboxylic acid as a white solid.

MS (APCI) 269 (M+H)+ !H NMR 8 (DMSO) 12.91 (IH, s), 12.08 (IH, d), 8.99 (IH, d), 8.68 (IH, d), 8.16 (IH, dd), 8.14 (IH, d), 7.53 (2H, s).

WO 03/068743 PCT/SE 30258 • 56 Preparation 22 7-[(Dimethylamiiio)sulfonyl]-l-oxo-lJ2-dihydroisoquinoline-4-carboxylic acid 7-(Chlorosulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.8g) was 5 added to dimethylamine (15ml) and the mixture was stirred for 18h. The mixture was acidified with concentrated hydrochloric acid and then filtered to yield 7-[(dimethylamino)sulfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid as a white solid. .

MS (APCI) 295 (M-H)" *HNMR 8 (DMSO) 12.96 (IH, s), 12.19 (IH, d), 9.07 (IH, d), 8.50 (IH, d), 8.18 (IH, d), 8.11 (IH, dd), 2.65 (6H, s).

Preparation 23 7-[(3 -Hydroxy-3-methylazetidin-1 -yl)sulfonyl] -1 -oxo-1,2-dihydroisoquinolme-4-15 carboxylic acid " ■ JUo ho_.X rfOH .N-J V O 7-(Chlorosulfonyl)-l-oxo-l;>2-dihydroisoquinoline-4-carboxylic acid (lg), diisopropylethylamine (3ml) and 3-methylazetidin-3-ol hydrochloride (0.8g) in tetrahydrofuran (8ml) were heated at 55°C for 3 days. The mixture was acidified with 20 hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-l-yl)sulfonyl]-1-oxo-l,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.

MS (ESI) 337 (M-H)" NMR 8 (DMSO) 12.99 (IH, s), 12.22 (IH, d), 9.11 (IH, d), 8.53 (IH, s), 8.21 (IH, d), 8.16 (IH, dd), 3.61 (2H, d), 3.46 (2H, d), 1.25 (3H, t).

WO "*68743 57 Preparation 24 4-({ 1 -[(2i?)-3-Amino-2-hydroxypropyl]piperidin-4-yl} oxy)-2-chlorobenzonitrile c,tt°to ?h N Step 1: tot-Butyl 4-(3-chloro-4-cyanophenoxy)piperidine-l -carboxylate ci N O 1 Potassium fert-butoxide (5.57g, 49.68mmol) was added to a solution of tot-butyl 4-hydroxypiperidine-1 -carboxylate (5.00g, 24.84mmol) in glyme (100ml) and the mixture stirred for 30min. before addition of 2-chloro-4-fluoro-ben2onitrile (7.73g, 49.68mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl 10 acetate (250ml) and water (200ml). The organic layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography eluting with ethyl acetate:isohexane (4:1) to give the subtitle compound as a colourless solid (3.45g).

MS (ESI) 337 (M+H)+ ^HNMRS (CDC13) 1.47 (9H, s), 1.72-1.80 (2H, m), 1.90-1.97 (2H,m), 3.37 (2H, ddd), 3.68 (2H, ddd), 4.54 (IH, dquintet), 6.86 (IH, dd), 7.01 (IH, d), 7.57 (IH, d).

Step 2:4-({ 1 -[(2i?)-3-Amino-2-hydroxypropyi]piperidin-4-yl} oxy)-2-chlorobenzonitrile To a solution of the /erf-butyl 4-(3 -chloro-4-cyanophenoxy)piperidine-1 -20 carboxylate (2.75g, 9.09mmol) in dichloromethane (20ml) was added trifluoroacetic acid (20ml) and the mixture stirred for 90 min.. The solvents were evaporated and the residue azeotroped with toluene (2x20ml) before dissolving in water (30ml) and addition of sodium hydroxide to bring the solution to pH 11. The free base was extracted with DCM (5x 100ml). The organics were combined, dried over sodium sulfate and the solvent 25 removed under reduced pressure to give a thick oil which was dissolved in DMF (30ml) before addition of (2R)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.35g, 9.09mmol) and triethylamine (2.54ml, 18.18mmol). The mixture was heated at 60°C for 4h before addition of sodium azide (1.36g, 27.27mmol). Heating was continued at 60°C for a further 72h. The reaction mixture was cooled and partitioned between water 30 (50ml) and ethyl acetate (100ml). The organic layer was separated and the solvent removed PCT/SE J0258 58 under reduced pressure. The residue was dissolved in THF (20ml) and water (2ml) and triphenylphosphine (5.90g, 22.72mmol) added. The mixture was heated at 60°C for 16h before dilution with ethyl acetate (100ml). The solution was washed with IN HC1 (50ml) and the aqueous layer was separated and adjusted to pH 11 with sodium hydroxide. The 5 product was extracted with DCM (4x100ml). The organics were combined and dried sodium over sulfate and the solvent removed under reduced pressure. The residue was purified by flash chromatography to give the title compound as a pale yellow solid (1.10g). MS (ESI) 310 (M+H)+ *HNMR 8 (cdci3) 7.56 (IH, d), 7.00 (IH, d), 6.85 (IH, dd), 4.42 (IH, septet), ^10 3.73-3.67 (IH, m), 2.93-2.86 (IH, m), 2.86-2.78 (IH, m), 2.71-2.62 (2H, m), 2.61-2.55 (IH, m), 2.45-2.30 (3H, m), 2.06-1.96 (2H, m), 1.91-1.79 (2H, m).

Preparation 25 (2R)-l-Amino-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-l-yl}propan-2-ol. vcrxuu . 0 . . .

Prepared as described in Preparation 24 starting from l-fluoro-4-(methylsulfonyl) benzene.

Step 1: tert-Butyl 4-[4-(methylsulfonyl)phenoxy]piperidine-1 -carboxylate ^N^,o I°r ^NMRS (cdci3) 1.48 (9H, s), 1.74-1.82 (2H, m), 1.91-1.99 (2H, m), 3.04 (3H, s), 3.38 (2H, ddd), 3.69 (2H, ddd), 4.57-4.62 (IH, m), 7.02 (2H, d), 7.86 (2H, d).

Step 2: (2R)-l-Amino-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-l-yl}propan-2-ol MS (ESI) 329 (M+H)+ !H NMR 8 (cdci3) 7.85 (2H, d), 7.01 (2H, d), 4.47 (IH, septet), 3.73-3.67 (IH, m), 3.03 (3H, s), 2.95-2.88 (IH, m), 2.86-2.78 (IH, m), 2.72-2.62 (2H, m), 2.61-2.55 (IH, m), 2.45-2.30 (3H, m), 2.08-1.98 (2H, m), 1.92-1.81 (2H, m). wo '068743 pct/se03/00258 59 Preparation 26 4-({l-[(2R)-3-Amino-2-hydroxypropyl]piperidia-4-yl}oxy)benzonitrile JFXXXU Prepared as described in Preparation 24 starting from 4-fluorobenzonitrile.

Step 1: terf-Butyl 4-(4-cyanophenoxy)piperidine-l-carboxylate mO O I MS (ESI) 303 (M+H)+ .

]H NMR 8 (CDC13) 7.58 (2H, d), 6.95 (2H, d), 4.55 (IH, m), 3.69 (2H, ddd), 3.37 (2H, ddd), 1.97-1.90 (2H, m), 1.80-1.72 (2H, m), 1.47 (9H, s).

Step 2:4-({ 1 - [(2i?)-3-Amino-2-hydroxypropyl]piperidin-4-yl} oxy)benzonitrile MS (ESI) 276 (M+H)+ 'HNMR8 (cdci3) 7.57 (2H, d), 6.94 (2H, d), 4.46-4.41 (IH,m), 3.74-3.68 (IH, m), 2.94-2.88 (IH, m), 2.83 (IH, dd), 2.73-2.66 (IH, m), 2.64 (IH, dd), 2.61-2.55 (IH, m), 2.46-2.30 (3H, m), 2.07-1.97 (2H, m), 1.91-1.80 (2H, m).

Preparation 27 ferf-Butyl 4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-l-carboxylate °Y°> a o°l^ Diisopropylazodicarboxylate (5.2ml, 26.8mmol) was added dropwise to a solution of 5-cbloro-2-hydroxy methylbenzoate (5.0g, 26.8mmol), /erf-butyl 4-hydroxypiperidine-1-carboxylate (5.4g, 26.8mmol) and triphenylphosphine (7.02g, 26.8mmol) in THF (200ml) at 0°C. The reaction mixture was allowed to warm to ambient temperature overnight The solvent was removed under reduced pressure and the residue triturated with diethyl ether (200ml). The triphenylphosphineoxide was filtered off and the diethyl ether removed under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetaterisohexane (1:9) to give the title compound as a brown oil (8.1g). 54 16 82 wo 03/068743 pct/se )0258 60 MS (ESI) 370 (M+H)+ • IH NMR 5 (DMSO) 1.47 (9H, s)5 1.79-1.92 (4H, m), 3.45-3.54 (2H, m), 3.56-3.62 (2H, m), 3.89 (3H, s), 4.54-4.59 (IH, m), 6.92 (IH, d), 7.38 (IH, dd), 7.77 (IH, d).

Preparation 28 2-{ [ 1 -(fer/-Butoxycarbonyl)piperidin-4-yl]oxy } -5-chloroben2oic acid o^oh I An aqueous solution of 2N sodium hydroxide (20ml) was added to a solution of /erf-butyl 4-[4-chloro-2-(methoxycarbonyl) phenoxy]piperidine-l-carboxylate (8.1g, 10 22.0mmol) in tetrahydrofuran (70ml) at 45°C. The mixture was stirred vigorously for 3h then adjusted to pH 2 with 2N hydrochloric acid. The product was extracted with ethyl acetate and the organic layer washed repeatedly with water until the washings were pH 6. The organic layer was dried over magnesium sulfate and evaporated. The residue was azeotroped with toluene to give the title compound as a colourless solid (7.5g). 15 MS (ESI) 356 (M+H)+ 'HNMRS (DMSO) 1.47 (9H, s), 1.79-1.88 (2H, m), 2.03-2.11 (2H,m), 3.30 (2H, ddd), 3.77-3.85 (2H, m), 4.72 (IH, m), 7.02 (IH, d), 7.49 (IH, dd), 8.12 (IH, d), 10.91 (IH, s).

* Preparation 29 4-(4-Chloro-2-methylcarbamoyl-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester Bromo-tris-pyrrolidinophosphonium hexafluorophosphate(1.57g, 3.37mmol)was 25 added to a vigorously stirred mixture of 2- {[ 1 -(/ert-butoxycarbonyl)piperidin-4-yl] oxy}-5-chlorobenzoic acid (l.OOg, 2.81mmol) and 40% aq methylamine (2ml) in DCM (10ml). Stirring was continued for 30 min. before partitioning between IN hydrochloric acid (10ml) and dichloromethane (10ml). The organic layer was separated and washed with WO '>68743 61 saturated sodium bicarbonate solution (20ml) and water (20ml), then dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by fla^h column chromatography eluting with ethyl acetate:isohexane (1:1) to give the title compound as a colourless solid (0.84g).

MS (ESI) 369 (M+H)+ JH NMR8 (cdci3) 8.17 (IH, d), 7.75 (IH, s), 7.35 (IH, dd), 6.91 (IH, d), 4.58 (IH, tt), 3.81-3.71 (2H, m), 3.29 (2H, ddd), 3.00 (3H, d), 2.08-1.98 (2H, m), 1.82-1.71 (2H, m), 1.48 (9H, s). ^10 Preparation 30 fer/-Butyi 4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine-1 -carboxylate h2N^O ci oyy o ' Prepared as described in Preparation 29 using aqueous ammonia.

MS (ESI) 355 (M+H)+ !H NMR 8 (cdci3) 8.18 (IH, d), 7.67-7.61 (IH, m), 7.40 (IH, dd), 6.94 (IH, d), .83-5.76 (IH, m), 4.61 (IH, m), 3.84-3.76 (2H, m), 3.26 (2H, ddd), 2.09-2.01 (2H, m), 1.82-1.73 (2H, m), 1.47 (9H,s).

Preparation 31 Methyl 2-({ l-[(2i?)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5- chlorobenzoate I °y° Prepared as described in Preparation 24, Step 2 from tert-butyl 4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-l-carboxylate.

MS (ESI) 343 (M+H)^ !H NMR 8 (cdci3) 7.75 (IH, d), 7.37 (IH, dd), 6.92 (IH, d), 4.46-4.39 (IH, m), 3.89 (3H, s), 3.72-3.66 (IH, m), 2.93-2.87 (IH, m), 2.81 (IH, dd), 2.69-2.55 (2H, m), 2.63 (IH, dd), 2.43-2.31 (3H,m), 2.00-1.84 (2H, m), 1.67-1.46 (2H, m).

PCT/SL .00258 62 Preparation 32 2-({l-[(2i?)-3-Amino-2-hydroxyprop}4]piperidin-4-yl}oxy)-5-chloro-JV-methylbenzamide H °VNS OH .NH, •Prepared as described in Preparation 24, Step 2 from 4-(4-chloro-2-. methylcarbamoyl-phenoxy)-piperidine-1 -caiboxylic acid tert-butyl ester.

MS (ESI) 342 (M+H)+ JH NMR 8 (CDC13) 8.18 (IH, d), 7.88 (IH, s), 7.34 (IH, dd), 6.91 (IH, d), 4.54-10 4.48 (IH, m), 3.73-3^67 (IH, m), 3.01 (3H, d), 2.89-2.83 (IH, m), 2.83 (IH, dd), 2.68-2.56 (2H, m), 2.63 (IH, dd), 2.44 (IH, dd), 2.39-2.33 (1H, m), 2.34 (IH, dd), 2.13-2.03 (2H, m), 1.94-1.83 (2H, m).

Preparation 33 2-({l-[(2i?)-3-Amino-2-hydroxypropyi]piperidin-4-yl}oxy)-5-chlorobaizamide Prepared as described in Preparation 24, Step 2 from tert-butyl 4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine-1 -carboxjdate.

MS (ESI) 328 (M+H)+ JH NMR 8 (CDCI3) 8.19 (IH, d), 7.75 (IH, s), 7.39 (IH, dd), 6.93 (IH, d), 5.85 (IH, s), 4.56-4.48 (IH, m), 3.73-3.67 (IH, m), 2.93-2.86 (IH, m), 2.83 (IH, dd), 2.73-2.66 (IH, m), 2.63 (IH, dd), 2.61-2.54 (iH, m), 2.44 (IH, dd), 2.37-2.30 (IH, m), 2.35 (IH, dd), 2.15-2.05 (2H, m), 1.90 (2H, dtd). : WO )68743 63 Preparation 34 fert-Butyl 4-{3,4-dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidine-1 -carboxylate y rlN^O xxg hn CI CI yV o 1 A solution of terf-butyl 4-[3,4-dichloro-2-(lH-imidazol-l-ylcarbonyl)phenoxy] piperidine-l-carboxylate (described in Preparation 11 step 1) (2.0g, 4.5mmol) in | cyclopropyiamine (12ml) was heated at 50°C for 14h. The solution was concentrated in vacuo then partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organics were dried pver magnesium sulfete and concentrated in vacuo. Crystallization 10 from dichloromethane:isohexane gave the title compound as a white solid (0.64g).

MS (ESI) 429/431 (M+H)+ JH NMR 5 (DMSO) 8.46 (1H, d), 7.56 (1H, d), 7.17 (1H, d), 4.68 (1H, m), 3.42-3.27 (4H, m), 2.74 (1H, m), 1.78 (2H, m), 1.55 (2H, m), 0.68 (2H, m), 0.44 (2H, m).

Preparation 35 6-{[l-(3-Amino-2-hydroxypropyl)piperidin-4-yl]oxy}-2,3-dichloro-jV-cyclopropylbenzamide a ci Prepared as described in Preparation 24, Step 2 following Preparation 34. 20 MS (ESI) 402 (M+H)+ 'H NMR 5 (CDCI3) 7.35 (IH, d), 6.78 (IH, d), 5.82 (IH, s), 4.40-4.33 (IH, m), 3.68 (IH, tt), 2.92-2.85 (2H, m), 2.85-2.77 (2H, m), 2.81 (IH, dd), 2.62 (IH, dd), 2.42-2.29 (3H, m), 2.00-1.89 (2H, m), 1.88-1.79 (2H, m), 0.89 (2H, td), 0.66-0.62 (2H, m).

PCT/SE 30258 64 Preparation 36 tert-Butyl 4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-l-carboxylate so,ci aTr°r^ Y0^- o * To a stirred solution of tot-butyl 4-[3,4-dichlorophenoxy]piperidine-l-carboxylate 5 (lO.Og, 28.9mmol) in dry THF (400ml) at-70°C under a nitrogen atmosphere was added dropwise .sec-butyl lithium (26.7ml, 1.3M in cyclohexane). The solution was stirred a further 15min. at this temperature and then sulfur dioxide was bubbled through the mixture for lOmin. The cooling bath was removed and the mixture warmed to room temperature overlh. N-Chlorosuccinimide (4.63g, 35mmol) was added and the mixture stirred at room 10 temperature for 72h. The solution was concentrated in vacuo and partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organic extracts were dried (magnesium sulphate) and concentrated. Chromatography on silica (ethyl acetate: isohexane/l:3) gave the title compound (2.40g) MS (ESI) 445 (M+H)+ lR NMR 5 (DMSO) 7.45 (IH, d), 7.03 (IH, d), 4.65 (IH, m), 3.59 (2H, m), 3.33 (3H, s), 1.66 (4H, m), 1.40 (9H, s).

Preparation 37 2,3-Dichloro-6-(piperidin-4-yloxy)benzenesulfonamide CI SOjNh^ Yi . 01 ^ ^ terf-Butyl-4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1 -carboxylate (0.80g, 1.8mmol) was dissolved in 7N ammonia in methanol and stirred at room temperature for 20min. The solution was concentrated in vacuo and then azeotroped once with toluene. The residue was redissolved in dichloromethane:trifluoroacetic acid/1:1 (20ml) and stirred at room temperature for 15 minutes. The solution was concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacuo afforded the title compound as a white powder (0.54g).

WO '>68743 PCT/SE03/00258 65 MS (ESI) 325/327 (M+H)+ JH NMR 8 (DMSO) 7.74 (IH, d), 7.34 (IH, d), 4.66 (1H, m), 2.96 (2H, m), 2.55 (2H, m), 1.91 (2H, m), 1.63 (2H, m). ^ Preparation 38 2,3-Dichloro-iV-methyl-6-(piperidin-4-yloxy)benzenesulfonamide n"" o=s=o | terf-Butyl 4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy3piperidiiie-1 -carboxylate (0.70g, 1.8mmol) was dissolved in 40% aqueous methylamine in water (10ml) and 10 methanol (10ml) and stirred at room temperature for 30min. The solution was concentrated in vacuo and then azeotroped with toluene (4 times). The residue was redissolved in dichloromethane/trifluoroacetic acid (1:1) (20ml) and stirred at room temperature for 15 minutes. The solution was concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The 15 aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacuo afforded the title compound as a white powder (0.69g).

MS (ESI) 339/341 (M+H)+ | *H NMR 8 (DMSO) 7,76 (1H, d), 7.35 (1H, d), 4.64 (IH, m), 2.96 (2H, m), 2.54 (3H, s), 2.54 (2H,m), 1.90 (2H,m), 1.61 (2H,m).

Preparation 39 2,3-Dichloro-N-cyclopropyl-6-(piperidin-4-yloxy)benzenesulfonamide A ' ■ N o=s=o yy'xx tert-~Buty[ 4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-l-carboxylate (0.70g, 1.8mmol) was dissolved in cyclopropyiamine (8ml) and stirred at room temperature for 30min. The solution was concentrated in vacuo and then azeotroped with toluene (4 times). The residue was redissolved in dichloromethane: trifluoroacetic acid / PCT/SE J0258 66 1:1 (20ml) and stirred at room temperature for 15min. The solution was concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacuo afforded the title compound as a white powder (0.70g).

MS (ESI) 365/367 (M+H)+ lH NMR 8 (DMSO) 7.78 (IH, d), 7.36 (IH, d), 4.65 (IH, m), 2.97 (2H, m), 2.55 (2H, m), 2.27 (IH, m), 1.89 (2H, m), 1.63 (2H, m), 0.49 (4H, m); Preparation 40 6-({ l-[(2i?)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzenesulfonamide nh, o=s=o CI^-1 ' OH cr^ Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 37. 15 MS (ESI) 398/400 (M+H)+ Preparation 41 6-( {1 -[(2i?)-3 -Amino-2-hydroxypropyl]piperidin-4-yl} oxy)-2,3 -dichloro-JV-" methyibenzenesulfonamide hn •o=s=o OH Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 38. MS (ESI) 412/414 (M+H)+ WO 168743 67 Preparation 42 6-( {1 -[(2i?)-3-Amino-2-hydroxypropyl]piperidin-4-yl} oxy)-2,3 -dicMoro-iV-cyclopropylbenzenesulfonamide A HN o=s=o CU OH A_NH, Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 39. MS (ESI) 438/440 (M+H)+ Preparation 43 7-(Methylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid 00 To a solution of sodium bicarbonate (500mg) and sodium sulfite (353mg) in 4ml of Water at 0°C was added portionwise the 7-(chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline- 4-carboxylic acid (see Preparation 16) (400mg). The reaction was warmed to room temperature and then heated at 80°C for 2h. The reaction was cooled to 0°C and acidified to pH~l with concentrated hydrochloric acid. The suspension was diluted with 4ml of water and stirred for 15 minutes at 0°C then filtered under nitrogen. The solid was washed twice with water and was added to a degassed aqueous solution (3ml) of potassium (|p hydrogen carbonate (280mg) at 45°C. Ethanol was then slowly added until the solution became slightly cloudy. Iodomethane (262p.l) was then added and the reaction refiuxed (45-50°C) for 5h. The reaction was concentrated under vacuum, extracted with ethyl acetate and the aqueous phase acidified with concentrated hydrochloric acid. The reaction was stirred at 0°C for 30 min. and the solid collected by filtration then recrystallised from acetone to yield the title compound as a white solid (325mg).

MS (ESI) 266 (M-H)" *H NMR 5 (DMSO) 12.97 (IH, bs), 12.19 (IH, d), 9.07 (IH, d), 8.70 (IH, d), 8.27 (IH, dd), 8.19 (IH, d), 3.30 (3H, s).

PCT/SEt J0258 68 Preparation 44 6-(Methylsulphonyl)- li/-indole-3 -carboxylic acid HO- (^J—SOJAe o Prepared as described in Preparation 43 following Preparation 16 using indole-3-5 carboxylic acid.

MS (ESI) 238 (M-H)" NMR5(DMSO) 12.34(IH,bds), 12.29 (1H, v bd s), 8.31 (lH,s), 8.21 (lH,d), ^ 8.03 (lH, d), 7.69 (IH, dd), 3.20 (1H» d).

Preparation 45 6-Fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981,5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31,1277-82.

Step 1: Dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate MeoJ/>oc^OMe (Prepared according to US 5189168) To a rapidly stirred suspension of 2-bromo-4-fluorobenzoic acid (4.5g) and copper(I) bromide (175mg) in 25ml of dimethylmalonate at 0°C was added portionwise 20 sodium hydride (60% in mineral oil, 1.3g). After 10 min., the reaction wanned to room temperature and stirred for 30 minutes at room temperature then heated at 70°C for 2h. The solidified reaction was then diluted with water (80ml) and was extracted with diethyl ether (3x50ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x100). The combined organic layers were dried over 25 magnesium sulfate, filtered, concentrated under vacuum and the crude material recrystallised from diethyl ether/fro-hexane to yield the sub-title compound as a white solid (l-9g).

WO f >8743 69 'H NMR 5 (DMSO) 13.36 (IH, bs), 8.05 (IH, dd), 7.35 (IH, ddd), 7.14 (IH, dd), 5.08 (IH, s), 3.70 (6H, s).

Step 2:2-(Carboxymethyl)-4-fluorobenzoic acid F A suspension, of dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate (1.80g) in concentrated hydrochloric acid (25ml) was heated at 110°C for 48h. The reaction was ^ cooled and the sub-title compound collected as a white solid by filtration (1.50g). MS (ESI) 197 (M-H)* JH NMR 5 (DMSO) 7.97 (IH, dd), 7.24 (IH, dd), 7.20 (IH, dd), 3.96 (2H, s).

Step 3: (4Z)-6-Fluoro-4-(methoxymethylene)-lif-isochromene-l,3(4i/)-dione F ■ 2-(Carboxymethyl)-4-fluorobenzoic acid (1.40g) in a mixture of acetic acid (3ml) 15 and trimethylorthoformate (lml) was heated at 110°C for 3h. During this time the methyl y acetate generated was distilled off. When finished, the reaction was cooled to 0°C. The white solid was collected by filtration and was washed with cold water and methanol (l-32g).

MS (ESI) 207 (M-Me)" Step 4: Methyl 6-fluoro-l-oxo-l#-isochromene-4-carboxylaie To a suspension of (42)-6-fluoro-4-(methoxymethylene)-liy-isochromene-l,3(4fl)-dione (1.30g) in methanol (20ml) was slowly added sulfuric acid (1.5ml). The mixture was 25 heated at 40-50°C for 3h. As the reaction proceeded the sub-title compound crystallized PCT/SL / 00258 70 out. The reaction was cooled to room temperature and a white solid was collected by filtration and washed with cold methanol.

MS (ESI) 222 (M+H)+ 'H NMR 8 (DMSO) 8.49 (1H, s), 8.30 (1H, dd), 8.25 (IH, dd), 7.56 (IH, td), 3.87 (3H,s).

Step 5: Methyl 6-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylate ... F A mixture of methyl 6-fluoro-l-oxo-li7-isocbromene-4-carboxylate (1.53g) and 10 ammonium acetate (2.5g) in 4ml of facial acetic acid was heated at 80°C for 16h. The reaction was cooled to 40°C, diluted with 8ml of water and the solid collected by filtration (1.38g).

MS (ESI) 220 (M-H)" 'H NMR 8 (DMSO) 12.00 (1H, s), 8.46 (IH, dd), 8.32 (IH, dd), 8.10 (IH, s), 7.44 15 (1H, td), 3.83 (3H, s).

Step 6: 6-Fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxyhc acid tfO F To a solution of methyl 6-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxylate 20 (1.3g) in methanol (3ml) was added a aqueous solution (3ml) of sodium hydroxide, (lg) and the reaction mixture was heated at 80°C for 3h, The reaction was cooled to 20°C and carefully acidified with concentrated hydrochloric acid. The white precipitate was isolated by filtration, washed with water and methanol to yield the title compound (1.16g) MS (ESI) 206 (M-H)' !H NMR 8 (DMSO) 12.85 (IH, s), 11.91 (IH, d), 8.58 (IH, dd), 8.31 (IH, dd), 8.09 (lH,d), 7.41 (IH, td).

WO )68743 71 Preparation 46 7-Huoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981,5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983,31, 1277-82.

Step 1: Dimethyl [4-fluoro-2-(methoxycarbonyl)phenyl]malonate MeO^O^QMe } Prepared as described in Preparation 45, Step 1 using 2-bromo-5-fluorobenzoic acid- MS (ESI) 269/237 (M-H)" !H NMR 8 (DMSO) 7.70 (IH, dd), 7.49 (IH, td), 7.39 (IH, dd), 5.71 (IH, s), 3.68 (6H,s).

Step 2:2-(Carboxymethyl)-5-fluorobenzoic acid o^,oh HO.

~ F Prepared as described in Preparation 45, Step 2 using dimethyl [4-fluoro-2- I (methoxycarbonyl)phenyl]malonate.

MS (ESI) 197 (M-H)" JH NMR 8 (DMSO) 7.81-7.74 (1H, m), 7.62 (1H, dd), 7.41-7.35 (1H, m), 3.92 (2H,s).

Step 3: Methyl 7-fluoro-1-oxo-l.H-isochromene-4-carboxylate ,o^,o ,oN 1 0 — F Prepared as described in Preparation 45, Steps 3 and 4 using 2-(carboxymethyl)-5-25 fluorobenzoic acid.

MS. (ESI) 223 (M+H)+ PCT/Sl 00258 72 *H NMR 5 (DMSO) 8.60 (IH, dd), 8.42 (IH, s), 7.95 (IH, dd), 7.86 (IH, ddd), 3.87 (3H,s).

Step 4: Methyl 7-fIuoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxylate if v ' °"lX Prepared as described in Preparation 45, Step 5 using methyl 7-fluoro-l-oxo-liT-isochromene-4-carboxylate.

MS (ESI) 221 (M-H)- JH NMR5 (DMSO) 12.04 (IH, s), 8.82 (IH, dd), 8.03 (IH, s), 7.91 (IH, dd), 7.73 10 (IH, td), 3.83 (3H, s).

Step 5:7-Fluoro-l-oxo-l,2-dihydroisoquinoline-4-ca3boxylic acid HO Prepared as described in Preparation 45, Step 6 using methyl 7'fluoro-l-oxo-1,2-15 dihydroisoquinoline-4-carboxylate.

MS (ESI) 206 (M-H)" *H NMR 8 (DMSO) 12.81 (IH, s), 12.00 (IH, d), 8.93 (IH, dd), 8.02 (IH, d), 7.90 (IH, dd), 7.71 (IH, td).

Preparation 47 6-(Methyisulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981, J, 819-27 and Chemical & Pharmaceutical Bulletin, 1983,31,1277-82.

Step 1: 2-[2-Ethoxy-l-(ethoxycarbonyl)-2-oxoethyl]-4-(methylsulfonyl)benzoic acid WO 168743 PCT/SE03/00258 73 Prepared following literature procedure: Journal of Organic Chemistry, 1998, 63, 4116-4119.

To a very rapidly stirred suspension of 2-chloro-4-(methylsulfonyl)benzoic acid (lO.Og) and copper(T) bromide (l.Og) in 50ml of diethylmalonate at 20°C was added 5 portionwise sodium ethoxide (lO.Og). The reaction was stirred for 30 min. at room temperature then heated at 90°C for 36h. The slurry was diluted with water (200ml), aqueous ammonia was added (3ml) and the mixture extracted with diethyl ether (3x100ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x100ml). The combined organic layers were dried over 110 magnesium sulfate, filtered and concentrated under vacuum.

MS (ESI) 357/311 (M-H)" *H NMR 8 (CD3OD) 8.28 (1H, d), 8.06 (IH, dd), 7.99 (IH, d), 5.78 (IH, s), 4.20 (4H, q), 3.19 (3H,s), 1.28 (6H,t).

Step 2:2-(Carboxymethyl)-4-(methylsulfonyl)benzoic acid \v 2» ■w Prepared following literature procedure: Journal of Organic Chemistry, 1998, 63, 4116-4119.

The crude material of Step 1 was dissolved in methanol (200ml) and a solution 20 (200ml) of sodium hydroxide (13g) slowly added. The reaction was stirred at room temperature for 3h. The methanol was removed under vacuum. The aqueous layer was extracted with diethyl ether (3x100ml), acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate (3x100ml). The combined organic layers were dried over magnesium sulfate, filtered, concentrated to one third 25 volume and heated at 65°C for 3h to complete decarboxylation. A solid formed which was collected by filtration (7.1 g).

MS (ESI) 257/213 (M-H)" *H NMR 8 (DMSO) 8.10 (IH, d), 7.95 (IH, d), 7.93 (IH, dd), 4.07 (2H, s), 3.28 (3H, s). • ' PCT/St .00258 74 Step 3: (42)-4-(methoxymethylene)-6-(methylsulfonyl)-lH"-isochromene-l33(4if)-dione o=s=o I Prepared as described in Preparation 45, Step 3 using 2-(carboxymethyi)-4-(methylsu!fonyl)benzoic acid.

MS (ESI) 267 (M-Me)' JH NMR 8 (DMSO) 8.68 (IH, d), 8.32 (IH, d), 8.31 (IH, s), 7.98 (IH, dd), 4.36 (3H, s), 3.46 (3H, s).

Step 4: Methyl 6-(methylsulfonyl)-l -oxo-liJ-isochromene-4-carboxylate ,o^o o o=s=o >15 Prepared as described in Preparation 45, Step 4 using (42!)-4-(methoxymethylene)-6-(methylsulfonyl)- lff-isochromene-1,3 (4if)-dione.

JH NMR 8 (DMSO) 9.08 (IH, d), 8.56 (1H, s), 8.44 (IH, d), 8.18 (IH, dd), 3.89 (3H, s), 3.34 (3H, s).

Step 5: Methyl 6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylate jlv.o 1 o o=s=o Prepared as described in Preparation 45, Step 5 using methyl 6-(methylsulfonyl)-l-pxo-lif-isochromene-4-carboxylate.

MS (ESI) 280 (M-H)" *H NMR 8 (DMSO) 12.23 (1H, s), 9.35 (1H, d), 8.47 (IH, d), 8.17 (1H, s), 8.06 (IH, dd), 3.86 (3H, s), 3.78 (3H, s).

WO 68743 75 Step 6: 6-(Methylsulfonyl)-l -oxo-1,2-dihydroisoquinoline-4-carboxylic acid Prepared as described in Preparation 45, Step 6 using methyl 6-(methylsulfonyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ESI) 266 (M-H)' jH NMR 5 (DMSO) 12.99 (IH, s), 12.14 (IH, d), 9.45 (IH, d), 8.46 (IH, d), 8.15 | (IH, d), 8.04 (IH, dd), 3.30 (3H, s).

Preparation 48 (2R)-1 -Amino-3 - {4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidin-1 - yl}propan-2-ol I o=s=o ayvr^ ?h Step 1: ter/-butyl 4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidine-l-carboxylate o=s=o a o 1 To a stirred solution of ferf-butyl 4-[3,4-dichlorophenoxy]piperidine-l -carboxylate (lO.Og, 28.9mmol) in dry THF (400ml) at —70°C under a nitrogen atmosphere was added dropwise sec-butyl lithium (26.7ml, 1.3M in cyclohexane). The solution was stirred a further 15min. at this temperature and then was treated with dimethyldisulfide (3.9ml, 43mmol). The solution was stirred at this temperature for 30 min. and then the cooling 20 bath removed and the inixture stirred vigorously whilst warming to-30°C over 30 min. Saturated aqueous ammonium chloride solution (5ml) was added and the mixture concentrated to ca 30ml volume and partitioned between water and ethyl acetate. The organic extracts were dried over magnesium sulphate and concentrated. Treatment of the crude residue with meta-chloroperbenzoic acid (13.3g, 57-86%) in dichloromethane 25 (200ml) at room temperature for 14h gave the crude sulfone. The solution was shaken with pct/si. ,00258 76 sodium metabisulfite solution, then the organics dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica (ethyl acetate: isohexane) gave the subtitle compound (0.65g) MS (ESI) 424/426 (M+H)+ *H NMR 8 (DMSO) 7.88 (IH, d), 7.42 (IH, d), 4.92 (IH, m), 3.52 (2H, m), 3.32 (3H, s), 3.36-3.27 (2H, m), 1.90 (2H, m), 1.69 (2H, m), 1.40 (9H, s).

Step 2: (2i?)-1 -Amino-3-{4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidin-1 -yl}propan-2-ol Prepared as described in Preparation 24, Step 2 from fert-butyl 4-[3,4-dichloro-2 (methylsulfonyl)phenoxy]piperidine-l-carboxylate.

MS (ESI) 397/399 (M+H)+ *H NMR 8 (CDC13) 7.60 (IH, d), 6.94 (IH, d), 4.60-4.53 (IH, m), 3.73-3.67 (IH, m), 3.33 (3H, s), 3.02-2.96 (IH, m), 2.81 (IH, dd), 2.79-2.73 (IH, m), 2.64-2.56 (IH, m), 15 2.63 (lH,dd), 2.43-2.32 (3H,m), 2.11-1.91 (4H,m) Preparation 49 8-Fluoro-1-oxo-1 ^-dihydroisoquinoline-4-carboxylic acid Stepl: 2-(Carboxymethyl)-6-fluorobenzoic acid o OH ho f Prepared as described in Preparation 45, Step 1 and 2 using 2-bromo-6 fluorobenzoic acid.

MS (ESI) 197 (M-H)- *H NMR 8 (DMSO) 7.46 (IH, td), 7.20 (IH, dd), 7.18 (IH, d), 3.77 (2H, s) Step 2: (4Z)-8-Fluoro-4-(methoxymethylene)-li/-isochromene-l,3(4/f)-dione r\ a o f Prepared as described in Preparation 45, Step 3 using 2-(carboxymethyl)-6-fluorobenzoic acid WO *68743 77 MS (ESI) 207 (M-Me)* Step 3: Methyl 8-fluoro-1 -oxo- lff-isochromene-4-carboxylate Prepared as described in Preparation 45, Step 4 using (4Z)-8-fluoro-4-(methoxymethylene)-li?-isochromene-l,3(4i?)-dione.

MS (ESI) 222 (M+H)+ 5H NMR 8 (DMSO) 8.42 (lH, s), 8,34 (IH, d), 7.96 (III, td), 7.50 (IH, dd), 3.86 (2H,s).

Step 4: Methyl 8-fluoro-l-oxo-l,2-dihydroisoquinoIine-4-carboxylate i . j ,o f o Prepared as described in Preparation 45, Step 5 using methyl 8-fluoro-l -oxo-IH-15 isochromene-4-carboxylate MS (ESI) 220 (M-H)' lB NMR 8 (DMSO) 11.86 (IH, s), 8.57 (IH, d), 8.03 (lH, s), 7.80 (IH, td), 7.30 0' (IH, dd), 3.82 (3H, s). ^ 20 Step 5: 8-Fuoro-1-oxo-l,2-dihydroisoquinoline-4-carboxylic acid % HO Prepared as described in Preparation 45, Step 6 using methyl 8-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ESI) 206 (M-H)- !HNMR8 (DMSO) 12.75 (19H, s), 11.76 (19H, d), 8.69 (22H, d), 8.02 (23H, d), 7.78 (24H, td), 7.29 (22H, dd).

PCT/SE J0258 78 Example 1 i\T-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl3-2-hydroxypropyl}-2-(methylsulfonyl)benzamide. 2o*ojtv? oo=s=o A mixture of 2-(methylsulphonyl)benzoic acid (0.063g), (2R)-l-amino-3-[4-(3,4- dichloi;ophenoxy)piperidin-1 -yl]propan-2-ol (0.1 g) and 7^-diisopropylethylamine (0.1ml) in dry dimethylformamide (3ml) was cooled to 0°C with, stirring. 2-(lH-9-Azabenzotriazole-1 -yl)-1,1,3,3-tetramethyluroxiium hexafluorophosphate (0.13g) was added and the mixture was stirred at 0°C for l-2h. Saturated sodium bicarbonate solution 10 (10ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulphate. The mixture was filtered and the solvent was evaporated. The resulting oil was purified by normal phase chromatography using methanol/dichloromethane as eluent, and by reverse phase HPLC using acetonitrile and 0.1% aqueous ammonium acetate as eluent, to give the title 15 compound as a white solid (0.055g).

MS (APCI) 501/503 (M+H)+ *H NMR 8 (DMSO) 8.57 (IH, t), 7.96 (IH, dd), 7.78 (IH, td), 7^9 (IH, td), 7.57 (IH, dd), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.48-4.37 (IH, m), 3.85-3.74 (IH, m), 3.40-3.25 (IH, m), 3.37 (3H, s), 3.26-3.13 (IH, m), 2.83-2.69 (2H, m), 2.44 (IH, dd), 2.37-2.26 (3H, m), 1.95-1.84 (2H, m), 1.65-1.50 (2H, m).

Example 2 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-(methylsulfonyl)benzamide Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlor ophenoxy)piperidin-1 -yl]propan-2-ol (O.lg) and 4-(methylsulphonyl)benzoic acid (0.063g). Title compoimd obtained as white solid (0.038g).

MS (APCI) 501/503 (M+H)+ WO < '68743 79 JH NMR 5 (DMSO) 8.69 (1H, t), 8.05 (4H, dd), 7.49 (IH, d), 7.25 (1H, d), 6.98 (IH, dd), 4.76 (IH, brs), 4.43 (IH, mult), 3.86-3.78 (IH, m), 3.43 (IH, dt), 3.26 (3H, s), 3.20 (1H, dd), 2.79-2.67 (2H, m), 2.41-2.24 (4H, m), 1.95-1.85 (2H, m), 1.66-1.54 (2H, m).

Example 3 2-ChIoro-iV- { (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-(methyisulfonyl)benzamide o. / s. o o ci Prepared as described in Example 1 using (2R)-l-amino-3-[4-(3,4- dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 3-(methylsulfonyl)benzoic acid (0.074g). Title compound obtained as white solid (0.033g).

MS (APCI) 535/537 (M+H)+ *H NMR 8 (DMSO) 8.60 (IH, t), 8.03 (IH, d), 7.93 (IH, dd), 7.70 (IH, d), 7.49 15 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.70 (IH,brs), 4.47-4.39 (IH, m), 3.82-3.74 (IH, m), 3.41-3.31 (IH, m), 3.29 (3H, s), 3.23-3,15 (1H, m), 2.80-2.69 (2H,m), 2.44-2.25 (4H, m), 1.96-1.86 (2H, m), 1.65-1.54 (2H, m).

Example 4 4-Amino-Ar-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-methoxybenzamide ,^NH* r 0 Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 4-amino-3-methoxybenzoic acid 25 (0.052g). Title compound obtained as white solid (0.053g).

MS (APCI) 468/470 (M+H)+ *H NMR 8 (DMSO) 8.05 (IH, t), 7.49 (IH, d), 7.31-7.27 (2H, m), 7.25 (IH, d), 6.98 (IH, dd), 6.60 (IH, d), 5.23 (2H, s), 4.74 (IH, brs), 4.47-438 (IH, m), 3.80 (3H, s), \ J PCT/SL. ,,00258 80 3.81-3.73 (1H, m), 3.38-3.30 (1H, m), 3.18-3.09 (IH, m), 2.80-2.65 (2H, m), 2.36 (2H, dd), 2.32-2.22 (2H, m), 1.95-1.86 (2H, m), 1.66-1.54 (2H, m).

Example 5 N- {(2R}-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3 -(methylsulfbnyl)benzamide o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 3-(methylsulfonyl)benzoic acid 10 (0.063g). Title compound obtained as white solid (0.017g).

MS (APCI) 501/503 (M+H)+ 'H NMR 8 (DMSO) 8.74 (IH, t), 8.39 (IH, t), 8.18 (IH, dt), 8.07 (IH, ddt), 7.76 (IH, t), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.77 (1H, brs), 4.47-4.39 (IH, m), 3.86-3.18 (IH, m), 3.45 (1H, dt), 3.26 (3H, s), 3.24-3.14 (IH, m), 2.80-2.66 (2H, m), 2.41-2.24 15 (4H, m), 1.95-1.86 (2H, m), 1.65-1.54 (2H, m).

Example 6 JV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(methylsulfonyl)thiophene-2-carboxamide.

O "yyy shh- o § a.K?> *-s 5 o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol (0.1 g) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065g). Title compound obtained as white solid (0.039g).

MS (APCI) 507/509 (M+H)+ !HNMR8 (DMSO) 8.85 (IH, t), 7.84 (2H, dd), 7'.49 (IH, d), 7.26 (IH, d), 6.98 (IH, dd), 4.80 (lH,brs), 4.47-4.39 (IH, m), 3.83-3.75 (IH, m), 3.45-3.38 (IH, m), 3.38 (3H, s), 3.18-3.09 (IH, m), 2.79-2.66 (2H, m), 2.37-2.22 (4H, m), 1.95-1.85 (2H, m), 1.65-1.53 (2H,m).

WO )68743 81 .

Example 7 N- { (2i?)-3-[4-(334-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} quinoline-6-caiboxamide "O °h h o Prepared as described in Example from (2R)-1-amino-3-[4-(3,4- dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and quinoline-6-caiboxylic acid (0.054g). Title compound obtained as white solid (0.032g).

MS (APCI) 474/476 (M+H)+ *H NMR 8 (DMSO) 8.98 (1H, dd), 8.68 (IH, t), 8.52 (IH, d), 8.47 (IH, dd), 8.19 10 (IH, dd), 8.08 (IH, d), 7.61 (IH, dd), 7.49 (IH, d), 7.24 (IH, d), 6.97 (IH, dd), 4.78 (IH, brs), 4.48-4.39 (1H, m), 3.90-3.82 (IH, m), 3.46 (IH, dt), 3.31-3.23 (IH, m), 2.82-2.70 (2H, m), 2.45-2.25 (4H, m), 1.96-1.87 (2H, m), 1.67-1.55 (2H, m).

Example 8 7/-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-2,3- dihydro-l,3-benzothiazole-6-carboxamide acetate salt o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 2-oxo-2,3-dihydro-l,3-20 benzothiazole-6-carboxylic acid (0.061 g). Title compound obtained as acetate salt, a white solid (0.1 Og).

MS (APCI) 496/498 (M+H)+ JH NMR 8 (DMSO) 8.36 (IH, t), 8.05 (IH, d), 7.78 (IH, dd), 7.49 (IH, d), 7.25 (IH, d), 7.15 (IH, d), 6.98 (IH, dd), 4.47-4.40 (IH, m), 3;80 (IH, quintet), 3.38 (IH, dt), 25 3.22-3.14 (IH, m), 2'80-2.67 (2H, m), 2.41-2.25 (4H, m), 1.95-1.86 (2H, m), 1.91 (3H, s), 1.66-1.54 (2H, m).

PCT/SE. ,00258 • 82 Example 9 N-{(2i?)-3-[4-(3}4-DicUorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoroimidazo[l,2-a]pyridine-2-carboxamide a a xytxtn/p. o . Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4- dichlorophenoxy)piperidin-I-yl]propan-2-ol (0.1 g) and 6-fhioroimidazo[l,2-a]pyridine-2-carboxylic acid (0.056g). Title compound obtained as white solid (0.076g).

MS (APCI) 481/482 (M+H)+ JHNMR8 (DMSO)8.80-8.78 (IH,m), 8.63 (IH, t), 8.33 (IH,s),7.68 (lH,dd), 10 7.50 (1H, d), 7.52-7.44 (1H, m), 7.28 (1H, d), 7.00 (IH, dd), 4.89 (IH, s), 4.52-4.44 (IH, m), 3.83-3.74 (IH, m), 3.44-3.28 (2H, m), 2.83-2.66 (2H, m), 2.44-2.23 (4H, m), 2.02-1.90 (2H, m), 1.82-1.72 (2H, m).

Example 10 N- { (2jR)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2- dihydroisoquinoline-4-carboxamide Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol (O.lg) and l-oxo-l,2-dihydroisoquinoline-4-20 carboxylic acid (0.059g) Title compound obtained as white solid (0.047g).

MS (APCI) 490/492 (M+H)+ JH NMR 8 (DMSO) 11.59 (IH, d), 8.33 (IH, t), 8.22 (2H, dd), 7.73 (IH, t), 7.54-7.48 (3H, m), 7.26 (IH, d), 6.98 (IH, dd), 4.79 (IH, s), 4.48-4.40 (IH, m), 3.85-3.76 (IH, m), 3.43-3.31 (IH, m), 3.14 (IH, quintet), 2.83-2.69 (2H, m), 2.45-2.25 (4H, m), 1.96-1.87 25 (2H, m), 1.67-1.55 (2H, m).

© WCK %8743 PCT/SE03/00258 83 Example 11 jV-{(2i?)-3-[4-(3>4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l,3-benzothiazole-6-carboxamide o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol (O.lg) and l,3-benzothiazole-6-carboxylic acid (0.056g). Title compound obtained as white solid (0.066g).

. MS (APCI) 480/482 (M+H)+ 'H NMR 8 (DMSO) 9.54 (IH, s), 8.67 (IH, d), 8.60 (1H, t), 8.15 (IH, d), 8.02 (IH, dd), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.78 (IH, brs), 4.47-4.39 (IH, m), 3.87-3.79 . (IH, m), 3.44 (IH, dt), 3.23 (IH, quintet), 2.82-2.68 (2H, m), 2.40 (IH, dd), 2.37-2.23 (3H, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m).

Example 12 3-Cyano-iV- { (2jR)-3-[4-(3 ,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxyprqpjdjbenzamide :»°~o xva., 0 Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.2g) and 3-cyanobenzoic acid (0.092g).

Title compound obtained as white solid (0.050g).

MS (APCI) 448/450 (M+H)+ 1HNMR8 (cdci3) 8.10 (IH, s), 7.79 (IH, d), 7.58 (IH, t), 7.31 (IH, d), 7.00 (IH, d), 6.80 (IH, t), 6.75 (IH, dd), 4.38-4.25 (IH, m), 4.00-3.87 (IH, m), 3.81-3.68 (IH, m), 3.36 (IH, dt), 2.98-2.85 (IH, m), 2.75-2.63 (IH, m), 2.63-2.53 (IH, m), 2.48 (IH, dd), 2.37 (IH, d), 2.32 (2H, t), 2.07-1.90 (2H, m), 1.90-1.73 (2H, m).

PCT/SE 00258 84 Example 13 N- {4- [4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -3-hydroxybutyl}-2-(methylsulfonyl)benzamide Prepared as described in Example 1 from 4-amino-l-[4-(3,4- dichlorophenoxy)piperidin-l-y!3butan-2-ol (0.26g) and 2-(methylsulphonyl)benzoic acid (0.156g). The title confound was obtained as a white solid (0.170g).

MS (APCI) 515/517 (M+H)+ JH NMR 8 (cdci3) 8.09 (1H, dd), 7.65 (IH, dd), 7.59 (IH, td), 7.53 (IH, dd), 7.31 10 (IH, d), 6.99 (IH, d), 6.74 (IH, dd), 6.74 (1H, dd), 4.32-4.23 (IH, m), 3.92-3.83 (IH, m), 3.83-3.74 (IH, m), 3.57-3.46 (IH, m), 3.37 (3H, s), 2.94-2.85 (IH, m), 2.70-2.60 (IH, m), 2.60-2.50 (IH, m), 2.40 (IH, dd), 2.35 (IH, dd), 2.32-2.23 (IH, m), 2.01-1.89 (2H, m), 1.88-1.69(2H,m), 1.67-1.55 (2H,m).

Example 14 N- { 4-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-3-hydroxybutyl}-2-oxo-2,3-dihydro-1,3 -benzothiazole-6-carboxamide aYY°sTsi ?H ? aXJ \ Prepared as described in Example 1 from 4-amino-l-[4-(3,4-20 dichlorophenoxy)piperidin-l-yl]butan-2-ol(0.26g) and2-oxo-2,3-dihydro-l,3- benzothiazole-6-carboxylic acid (0.152g). Title compound obtained as a white solid (0.105g).

MS (APCI) 510/512 (M+H)+ JH NMR 8 (cdci3) 7.88 "(IH, d), 7.71 (IH, dd), 7.48-7.39 (IH, m), 7.31 (IH, d), 25 7.13 (IH, d), 7.00 (IH, d), 6.76 (IH, dd), 4.36-4.27 (IH, m), 3.93-3.83 (2H, m), 3.49-3.38 (IH, m), 2.97-2.87 (IH, m), 2.73-2.53 (2H, m), 2.46-2.32 (2H, m), 2.36-2.27 (IH, m), 2.06-1.91 (2H, m), 1.90-1.75 (3H, m), 1.66-1.53 (IH, m).

WOr ^68743 PCT/SE03/00258 > 85 Example 15 4-Amino-iV-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-3-methoxybenzamide cu Xr°o cr ^ "n' ^ -°> oh o nh2 Prepared as described in Example 1 from 4-amino-l-[4-(3,4- dichlorophenoxy)piperidin-l -yl]butan-2-ol (0.26g) and 4-amino-3-methoxybenzoic acid (0.130g). Title compound obtained as white solid (0.080g).

MS (APCI) 482/484 (M+H)+ I *H NMR 5 (CDC13) 7.39 (1H, d), 7.31 (1H, d), 7.15 (1H, dd), 7.04 (IH, bs), 7.00 (IH, d), 6.75 (IH, dd), 6.65 (IH, d), 4.29 (IH, septet), 4.08 (2H, bs), 3.90 (3H, s), 3.89-3.75 (2H, m), 3.49-3.36 (IH, m), 2.96-2.85 (IH, m), 2.73-2.61 (1H, m), 2.61-2.50 (IH, m), 2.44-2.34 (2H, m), 2.35-2.23 (IH, m), 2.07-1.90 (2H, m), 1.90-1.71 (2H, m), 1.70-1.48 (2H,m).

Example 16 N-{4-[4-(3,4-Dichlorophenoxy)piperidin-l-yi]-2-hydroxybutyl}-2- (methylsulfonyl)benzamide - -—- o°s- cr ^ oh h Prepared as described in Example 1 from l-amino-4-[4-(3,4-20 dichlorophenoxy)piperidin-1 -yl]butan-2~ol (0.2g) and 2-(methylsulphonyl)benzoic acid (0.12g). Title compound obtained as white solid (0.090g), MS (APCI) 515/517 (M+H)+ *H NMR 8 (CDCI3) 8.10 (IH, d), 7.67 (IH, td), 7.61 (IH^ td), 7.55 (IH, dd), 7.30 (lH,.d), 6.98 (IH, d), 6.73 (IH, dd), 6.61 (IH, t), 4.33-4.23 (IH, m), 4.06 (IH, octet), 3.70 25 (IH,' ddd), 3.36-3.29 (IH, m), 3.37 (3H, s), 2.97-2.82 (IH, m), 2.78-2.68 (IH, m), 2.64 (IH, dt), 2.60-2.47 (2H, m), 2.38-2.22 (IH, m), 2.02-1.41 (6H, m).

The compounds of Examples 17 and 18 were prepared in a similar way to Example 1 following Preparation 13 starting from 4-(2,4-dichloro-3-methylphenoxy)piperidine PCT/SI 00258 86 (WO 00/58305, WO 01/77101).

Example 17 iV-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-5 oxo-1,2-dihydroisoquinoline-4-carboxamide a Prepared as described in Example 1 following Preparation 13.

MS (APCI) 504/506 (M+H)+ *H NMR 5 (DMSO) 11.58 (1H, s), 8.31 (IH, t), 8.22 (2H, d), 7.72 (IH, t), 7.56-10 7.48 (2H, m), 7.35 (IH, d), 7.10 (IH, d), 4.80-4.70 (lH,m), 4.53-4.44 (IH, m), 3.85-3.75 (IH, m), 3.39 (IH, dt), 3.15 (IH, quintet), 2.78-2.64 (2H, m), 2.40 (3H, s), 2.39-2.27 (4H, m), 1.96-1.83 (2H, m), 1.74-1.61 (2H, m).

Example 18 ?/-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-2- (methylsulfonyl)benzamide ci r» ^ ?H H axr°"g- Prepared as described in Example 1 following Preparation 13.

MS (APCI) 515/517 (M+H)+ JH NMR 5 (CDC13) 8.10 (IH, dd), 7.67 (IH, t), 7.62 (IH, t), 7.54 (IH, dd), 7.19 (IH, d), 6.74 (IH, d), 6.55 (IH, t), 4.41- 4.27 (IH, m), 4.03-3.89 (IH, m), 3.68 (IH, ddd), 3.44 <1H, dt), 3.36 (3H, s), 3.00-2.87 (IH, m), 2.80-2.66 (IH, m), 2.63-2.51 (2H, m), 2.51-2.42 (IH, m), 2.47 (3H, s), 2.42-2.29 (IH, m), 2.03-1.76 (4H, m).

WO' 168743 87 Example 19 iV-{(2i$)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide Prepared as described in Example 1 following Preparation 14.

MS (APCI) 501/503 (M+H)+ 'HNMRS (CDCI3) 8.10 (IH, dd), 7.68 (IH, td), 7.62 (IH, td), 7.54 (IH, dd), 7.31 . (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 6.53 (IH, t), 4.35-4.22 (IH, m), 4.04-3.91 (IH, m), 3.68 (IH, ddd), 3.45 (IH, dt), 3.36 (3H, s), 2.98-2.85 (1H, m), 2.80-2.66 (IH, m), 2.65-10 2.52 (2H, m), 2.46 (IH, dd), 2.41-2.28 (IH, m), 2.04-1.88 (2H, m), 1.87-1.67 (2H, m).

Example 20 iV-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-h.ydroxypropyl}-3-[(methylamino)sulfonyl]benzamide O °"V Prepared as described in Example 1 following Preparation 7.

MS (APCI) 516/518 (M+H)+ lB. NMR S (CDCI3) 8.25 (IH, s), 7.99 (IH, d), 7.95 (IH, d), 7.55 (IH, t), 7.41 (IH, t), 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.95 (IH, s), 4.36-4.25 (IH, m), 4.16-4.05 # 20 (IH, m), 3.75 (IH, ddd), 3.31 (IH, ddd), 3.02-2.90 (IH, m), 2.74-2.56 (2H, m), 2.68 (3H, s), 2.51 (lH,dd), 2.37-2.26 (lH,m), 2.37 (lH,dd), 2.07-1.91 (2H,m), 1.91-1.72 (2H,m).

Example 21 3,5-Bis(acetylamino)-jV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-25 hydroxyprop)d}benzamide NHAc yyxx oh H cr ^ nhag o Prepared as described in Example 1 following Preparation 7.

PCT/SE W258 88 MS (APCI) 537/539 (M+H)+ 'H NMR 8 (CDCI3) 9.00 (2H, s), 7.86 (IH, s), 7.66 (2H, s), 7.50 (IH, s), 7.31 (1H, d), 6.99 (IH, d), 6.74 (IH, dd), 4.42-4.27 (IH, m), 4.19-4.03 (IH, m), 3.63-3.46 (IH, m), 3.42-3.26 (IH, m), 3.05-2.91 (IH, m), 2.91-2.74 (IH, m), 2.75-2.54 (4H, m), 2.17-1.96 5 (2H,m), 2.11 (6H,s), 1.97-1.79 (2H,m).

Example 22 - 3-(Acetylamiiio)-iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzamide NHAc "rry^ h O Prepared as described in Example 1 following Preparation 7.

MS (APCI) 480/482 (M+H)+ !H NMR 8 (CDCI3) 7.88 (IH, s), 7.78 (IH, d), 7.55-7.45 (2H, m), 7.39 (IH, t), 7.31 (IH, d), 6.99 (IH, d), 6.82 (IH, t), 6.75 (IH, dd), 4.37-4.22 (IH, m), 3.99-3.85 (IH, m), 15 3.77-3.63 (IH, m), 3.38 (IH, quintet), 2.96-2.83 (IH, m), 2.75-2.63 (IH, m), 2.63-2.51 (IH, m), 2.52-2.24 (3H, m), 2.20 (3H, s), 2.08-1.90 (2H, m), 1.90-1.69 (2H, m).

Example 23 | iV-{(2R)-3-[4-(3,4-Dichlorop]ienoxy)piperidin-l-yl]-2-hydroxypropyl}-li/- pyrazole-4-caiboxamide YY Y^l §n H f N ^NH o Prepared as described in Example 1 following Preparation 7.

MS (APCI) 413/415 (M+H)+ *H NMR 8 (CDCI3) 8.02 (2H, s), 7.33 (IH, d), 7.00 (1H, s), 6.95 (IH, t), 6.76 (IH, 25 d), 4.44-4.33 (IH, m), 4.07-3.98 (IH, m), 3.74-3.61 (1H, m), 3.40 (IH, td), 2.98 (IH, td), 2.89-2.77 (2H, m), 2.62 (2H, d), 2.68-2.56 (IH, m), 2.18-1.99 (2H, m), 1.98-1.82 (2H, m).

WO' >68743 PCT/SE03/00258 89 Example 24 2-(Acetylamino)-5-bromo-iV-{(2i?)-3-[4-(3,4-diclilorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzamide Prepared as described in Example 1 following Preparation 7.

MS (APCI) 558/460/562 (M+H)+ !H NMR 8 (CDC13) 10.98 (IH, s), 8.52 (IH, d), 7.66 (1H, s), 7.55 (1H, d), 7.32 * (1H, d), 7.26 (1H, s), 7.16-7.05 (2H, m), 7.00 (IH, s), 6.76 (IH, d), 4.42-4.30 (IH, m), 4.06-3.94 (IH, m), 3.72-3.59 (2H, m), 3.43-3.29 (IH, m), 2.95 (IH, t), 2.75 (2H, t), 2.59-10 2.43 (3H, m), 2.19 (3H, s), 2.13-1.96 (5H, m), 1.96-1.78 (3H, m).

Example 25 JV-{(2R)-3-[4-(3,4-Dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-l,2- dihydropyridine-3-carboxamide \\ cr ■ ■ ° ° Prepared as described in Example 1 following Preparation 7.

MS (APCI) 440/442 (M+H)+.

JH NMR 8 (cdci3) 9.86 (IH, t), 8.61 (IH, dd), 7.53 (IH, dd), 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 6.52 (IH, t), 4.33-4.24 (IH, m), 3.97-3.89 (IH, m), 3.70 (IH, ddd), 20 3.44 (IH, td), 2.94-2.85 (IH, m), 2.73-2.63 (IH, m), 2.59-2.50 (IH, m), 2.49-2.37 (2H, m), 2.30 (IH, t), 2.04-1.90 (2H, m), 1.87-1.72 (2H, m).

PCT/Sl 00258 90 Example 26 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-5 -carboxamide ^XXXXa o Prepared as described in Example 1 following Preparation 7.

' MS (APCI) 490/492 (M+H)+ !H NMR 5 (DMSO) 11.34 (IH, d), 8.46 (1H, t), 8.28 (1H, d), 7.78 (IH, dd), 7.50 (IH, t), 7.49 (IH, d), 7.25 (IH, d), 7.23-7.16 (IH, m), 6.98 (IH, dd), 6.81 (IH, d), 4.72 (IH, d), 4.49-4.37 (IH, m), 3.87-3.76 (IH, m), 3.46-3.35(IH, m), 3.30-3.16 (IH, m), 2.83-10 2.67 (2H, m), 2.47-2.23 (4H, m), 1.97-1.84 (2H, m), 1.68-1.50 (2H, m).

Example 27 iVL{(2i2)-3-[4-(3,4-DicMorophenoxy)piperidui-l-yl]-2-hydroxypropyl}quinoline-4-carboxamide cu xnq j: >y l ki a Prepared as described in Example 1 following Preparation 7.

MS (APCI) 474/476 (M+H)+ *H NMR S (CD3OD) 1.69-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.53-2.65 (m, 4H), 2.84-2.94 (m, 2H), 3.39 (dd, IH), 3.54 (dd, IH), 3.99-4.05 (m, IH), 4.33-4.40 (m, IH), 20 6.81 (dd, IH), 7.03 (d, IH), 7.29 (d, IH), 7.52 (d, IH), 7.59 (t, IH), 7.73 (t, IH), 8.00 (d, IH), 8.15 (d, IH), 8.83 (d, IH).

Example 28 N- { (2J2)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - lif-indole-25 4-carboxamide 'TY°T^ ?h h o ^ Prepared as described in Example 1 following Preparation 7.

WO f "68743 91 MS (APCI) 462/464 (M+H)+ ^NMRS (CD3OD) 1.82-1.91 (m, 2H), 2.00-2.13 (m,2H), 2.63-2.76 (m, 4H), 2.96-3.05 (m, 2H), 3.44 (dd, IH), 3.54 (dd, IH), 4.04-4.11 (m, IH), 4.43-4.50 (m, IH), 5.50 (s, IH), 6.56 (d, IH), 6.90 (dd, IH), 7.12 (d, 1H), 7.32 (d, IH), 7.38 (d, IH), 7.43 (d, 5 1H), 7.63 (dd,lH), 8.14 (s,lH).

Example 29 •2-(Acetylamino)-iV-{ (2iJ)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}benzamide a ?H H O HNs_,Me T O Prepared as described in Example 1 following Preparation 7.

MS (APCI) 480/482 (M+H)+ JH NMR 8 (CDCI3) 11.05 (IH, bd s), 8.60 (IH, d), 7.52-7.46 (2H, m), 7.31 (IH, d), 7.08 (IH, t), 6.99 (IH, d), 6.81 (IH, bd s), 6.76 (IH, dd), 4.36-4.28 (IH, m), 3.96-3.90 (IH, 15 m), 3.72-3.64 (IH, m), 3.40-3.32 (IH, m), 2.94-2.86 (2H, m), 2.72-2.58 (2H, m), 2.49-2.31 (3H, m), 2.20 (3H, s), 2.03-1.93 (2H, m), 1.89-1.79 (2H, m).

Example 30 ^ 2-(Acetylamino)-5-chloro-iV"-{ (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2- hydfoxypropyl}benzamide XFQJUl cu a' O HN^Me T 0 Prepared as described in Example 1 following Preparation 7.

MS (APCI) 514/516/518 (M+H)+ *H NMR 8 (CDCI3) 10.94 (IH, bd s), 8.59 (IH, d), 7.47 (IH, d), 7.43 (IH, dd), 7.32 25 (IH, d), 7.00 (IH, d), 6.87 (IH, bd s), 6.76 (IH, dd), 4.36-4J28 (IH, m), 3.97-3.90 (IH, m), 3.68-3.61 (IH, m), 3.38-3.32 (IH, m), 2.94-2.88 (IH, m), 2.72-2.58 (2H, m), 2.50-2.33 (3H, m), 2.19 (3H, s), 2.05-1.95 (2H, m), 1.90-1.80 (2H, m).

PCT/SEc ,00258 92 Example 31 2-(Acetylamino)-4-chloro-iV-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}benzamide aS^°V\ m O HN_.Me T O Prepared as described in Example 1 following Preparation 7.

" MS (APCI) 514/516/518 (M+H)+ 'H NMR 5 (CDC13) 11.19 (1H, bd s), 8.73 (1H, d), 7.42 (IH, d), 7.32 (IH, d), 7.05 I (1H, d), 7.00 (1H, d), 6.78-6.74 (2H, m), 4.36-4.28 (1H, m), 3.96-3.88 (IH, m), 3.70-3.62 (IH, m), 3.38-3.30 (1H, m), 2.94-2.88 (1H, m), 2.70 - 2.58 (2H, m), 2.49-2.30 (3H, m), 10 2.20 (3H, s), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m).

Example 32 -Chloro-iV-{(2i2)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-[(meth)dsulphonji)amino]benzamide :xro. o NHSOjMe Prepared as described in Example 1 following Preparation 7.

MS (APCI) 550/552/554 (M+H)+ !H NMR 8 (CDCI3) 7.69 (IH, d), 7.52 (1H, s), 7.45 (1H, d), 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.36-4.28 (IH, m), 3.96-3.90 (IH, m), 3.72-3.64 (IH, m), 3.36-3.30 (IH, 20 m), 3.04 (3H, s), 2.95-2.89 (IH, m), 2.74-2.56 (2H, m), 2.50-2.30 (3H, m), 2.05-1.95 (2H, m), 1.90-1.88 (2H,m).

Example 33 4-CUoro-N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-25 [(methyisidphonyl)amino]beiizamide 0H H xrxixs a' O NHSOjMe.

Prepared as described in Example 1 following Preparation 7.

WO 168743 93 MS (APCI) 550/552/554 (M+H)+ 'H NMR 5 (CDCls) 7.75 (1H, d), 7.48 (IH, d), 7.31 (IH, d), 7.09 (1H, dd), 7.00 (IH, d), 6.75 (IH, dd), 4.38-4.28 (IH, m), 3.97-3.87 (IH, m), 3.72-3.66 (IH, m), 3.34-3.28 (IH, m), 3.08 (3H, s), 2.98-2.90 (IH, m), 2.76-2.58 (2H, m), 2.50-2.30 (3H, m), 2.10-1.94 5 (2H,m), 1.90-1.74 (2H,m).

Example 34 ' 2-Amino-4-chloro-i\T-{ (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}benzamide o nh2 Prepared as described iii Example 1 following Preparation 7.

MS (APCI) 472/474/476 (M+H)+ *H NMR 5 (cdci3) 7.31 (IH, d), 7.27 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 6.67 (IH, d), 6.61 (IH, dd), 6.55 (IH, t), 5.64 (2H, bd s), 4.34-4.24 (IH, m), 3.92-3.82 (IH, m), 15 3.68-3.62(lH,m), 3.36-3.29 (lH,m), 2.94-2.86 (lH,m), 2.70-2.54 (2H,m), 2.47-2.29 (2H,m),2.26-2.16 (IH,m),2.04-1.94(2H,m), 1.88-1.78 (2H,m).

F,x amp! p. 3 5 -Chloro-iV"-{(2i?)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-6-oxo-l,6-i0 dihydropyridine-3-carboxamide ixrxucvic o To a solution of (2JR)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (150 mg, 0.47 mmol) and triethylamine (48 mg, 66 fA, 0.47 mmol) in dichloromethane (20 ml) was added a solution of 5-chloro-6-hydroxymcotinyl chloride (90 mg, 0.47 mmol) 25 in dichloromethane (10 ml). The mixture was stirred at room temperature for 3h and then the solution was concentrated in vacuo to leave a crude oil. Purification by reverse phase HPLC (Symmetry, 0.1% ammonium acetate / acetonitrile) afforded the title compound as a colourless glass (150 mg, 67%).

MS (APCI) 474/476/478 (M+H)+ PCT/St, 00258 94 !H NMR 8 (CDC13) 8.07 (1H, d), 8.04 (IH, d), 7.31 (1H, d), 7.09 (IH, bd s), 6.99 (1H, d), 6.75 (1H, dd), 4.36-4.26 (IH, m), 4.00-3.90 (IH, m), 3.68-3.58 (1H, m), 3.32-3.22 (1H, m), 2.96-2.86 (IH, m), 2.76-2.58 (2H, m), 2.51-2.35 (3H, m), 2.04-1.94 (2H, m), 1.88-1.76 (2H, m).

Example 36 2-(Aminosulphonyl)-4-cMoro-iVr-{(2^)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzamide C,TY°T^ ?H« fra SOjNHJ O Prepared as described in Example 1 following Preparation 7.

MS (APCI) 536/538/540 (M+H)+ !H NMR 8 (CDCI3) 8.39 (IH, d), 7.90 (IH, bd s), 7.78 (1H, dd), 7.45 (IH, d), 7.32 (IH, d), 7.00 (IH, d), 6.76 (1H, dd), 4.38-4.22 (2H, m), 3.76-3.62 (IH, m), 3.30-3.20 (IH, m), 3.10-3.00 (IH, m), 2.80-2.68 (2H, m), 2.60-2.40 (3H, m), 2.10-2.00 (2H, m), 1.96-1.86 15 (2H,m).

Example 37 - iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yI]-2-hydroxypropyl}-ii/"-indazole-3-carboxamide CI o Prepared as described in Example 1 following Preparation 7.

MS (APCI) 463/465 (M+H)+ lH NMR 8 (CDCI3) 8.43-8.33 (2H, m), 7.54 (IH, d), 7.43 (IH, t), 7.32 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.38-4.28 (IH, m), 4.15-4.05 (IH, m), 3.75-3.65 (1H, m), 3.60-3.48 25 (IH, m), 3.02-2.92 (IH, m), 2.80-2.50 (4H, m), 2.45-2.37 (IH, m), 2.10-1.95 (2H, m), 1.90-1.75 (2H, m).

WO f 68743 95 Example 38 1 -iert-Butyl-iV-{ (2i?)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl} -3-methyl-ii?-pyrazole-5-carboxamide CU — n ^ Me o IBu Prepared as described in Example 1 following Preparation 7.

MS (APCI) 483/485 (M+H)+ JH NMR 5 (CDCI3) 7.31 (1H, d), 6.99 (1H, d), 6.75 (IH, dd),'6.43 (1H, bd s), 6.21 (1H, s), 435-4.25 (IH, m), 3.92-3.82 (IH, m), 3.70-3.58 (IH, m), 3.38-3.28 (IH, m), 2.95-> 2.85 (2H, m), 2.70-2.50 (2H, m), 2.45-2.30 (3H, m), 2.24 (3H, s), 2.05-1.90 (2H, m), 1.90-10 1.78 (2H, m), 1.67 (9H, s).

Example 39 AL{(2/?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4,5,6,7-tetrahydro-2jy-indazole-3-carboxamide «H h r "nh CI ^ H XXXI o Prepared as described in Example 1 following Preparation 7.

MS (APCI) 467/469 (M+H)+ ®H NMR 8 (DMSO) 12.69 (IH, s), 7.83 (IH, bd s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (1H, dd), 4.80 (IH, d), 4.43 (IH, quintet), 3.73 (IH, q), 3.39-3.16 (2H, m), 2.80-2,52 (6H, 20 m), 2.38-2.23 (4H, m), 1.96-1.86 (2H, m), 1.78-1.58 (6H, m).

Example 40 N- { (2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl}-3 -(trifluoromethyl)-ii?-pyrazole-4-carboxamide o Prepared as described in Example 1 following Preparation 7. t MS (APCI) 481/483 (M+H)+ c,VV°Nr^si °H FaCv aXJ 54 16 8 2 WO 03/068743 PCT/St 00258 96 *H NMR 8 (CDC13) 8.11 (IH, s), 7.32 (IH, d), 7.00 (IH, d), 6.75 (1H, dd), 6.70 (IH, bd s), 4.38-4.28 (IH, m), 4.00-3.90 (IH, m), 3.70-3.60 (IH, m), 3.42-3.32 (1H, m), 2.98-2.88 (IH, m), 2.75-2.58 (2H, m), 2.50-2.36 (3H, m), 2.10-1.96 (2H, m), 1.92-1.76 (2H, m).

Example 41 N- { (2R)-3 -£4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -2-methylimidazo[l ,2-a;]pyridine-3-carboxamide O Me '• Prepared as described in Example 1 following Preparation 7.

MS (APCI) 477/479 (M+H)+ !H NMR 8 (CDCI3) 9.40 (IH, d), 7.58 (IH, d), 7.36-7.30 (2H, m), 7.00 (IH, d), 6.92 (IH, t), 6.76 (IH, dd), 6.35 (IH, bd s), 4.38-4.28 (IH, m), 4.01-3.93 (IH, m), 3.82-3.72 (IH, m), 3.48-3.40 (IH, m), 2.98-2.90 (IH, m), 2.75 (3H, s), 2.70-2.58 (IH, m), 2.54-15 2.30 (4H, s), 2.06-1.96 (2H, m), 1.94-1.76 (2H, m).

Example 42 N-{ (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-4-(7.££-| pyrazol-3-yl)benzamide 0 Prepared as described in Example 1 following Preparation 7.

MS (APCI) 489/491 (M+H)+ • JH NMR 8 (cdci3) 7.84 (2H, d), 7.76 (2H, d), 7.64 (IH, d), 7.34-7.29 (2H, m), 7.00 (IH, d), 6.75 (IH, dd), 6.66 (IH, d), 4.45-4.35 (IH, m), 4.18-4.08 (IH, m), 3.78-3.66 (lH,m), 3.52-3.42 (lH,m), 3.06-2.96 (lH,m), 2.90-2.80 (2H,m), 2.75-2.63 (3H,m), 2.18-2.03 (2H, m), 2.00-1.80 (2H, m).

WO [ >68743. 91 Example 43 N- { (2R)-3-[4-(3,4-DicMorophenoxy)piperidin-1 -yl]-2-hydroxypropyi} cinnoline-4-carboxamide ixrtijca j o > Prepared as described in Example 1 following Preparation 7.

•MS (APCI) 475/477 (M+H)+ !H NMR 8 (cdci3) 9.41 (1H, s), 8.61 (IH, d), 8.38 (1H, d), 7.94-7.82 (2H, m), 7.33 (IH, d), 7.20 (IH, bd s), 7.01 (1H, d), 6.76 (IH, dd), 4.46-4.36 (IH, m), 4.18-4.08 (IH, m), 3.88-3.78 (IH, m), 3.56-3.46 (IH, m), 3.06-2.96 (IH, m), 2.94-2.78 (2H, m), 10 2.70-2.60 (3H,m), 2.03-1.89 (4H,m).

Example 44 7/-{(2i?)-3-[4-(3,4-Dichlorophenoxy)pipeiidin-l-yl]-2-hydroxypropyl}-2-oxo-l,2-dihydroquinoline-4-carboxamide :»ooxi' 0 Prepared as described in Example 1 following Preparation 7.

MS (APCI) 490/492 (M+H)+ JH NMR 8 (DMSO) 8.69 (IH, t), 7.74 (IH, d), 7.53 (IH, t), 7.49 (IH, d), 7.34 (IH, d), 7.25 (IH, d), 7.18 (IH, t), 6.98 (IH, dd), 6.54 (IH, s), 4.50-4.40 (IH, m), 3.87-3.77 20 (IH, m), 3.48-3.40 (IH, m), 3.28-3.18 (IH, m), 2.82-2.70 (2H, m), 2.44-2.24 (4H, m), 1.97-1.87 (2H, m), 1.68-1.56 (2H, m).

Example 45 N-{3-[4-(3,4-Diclilorophenoxy)piperidin-l-yl]-2-h.ydroxypropyl}-2-oxo-2,3-25 dihydro- lif-benamidazole-1 -carboxamide 01yvy^1 °h h Oo PCT/SL 00258 98 Prepared as described in. Example 35, using 2-oxo-2,3-dihydro-l#-ben2imidazole-1-carbonyl chloride.

MS (APCI) 479/481 (M+H)+ 'H NMR 8 (CDC13) 9.02 (IH, t), 8.17-8.14 (IH, d), 7.32 (IH, d), 7.18-7.12 (2H, 5 m), 7.08-7.05 (IH, m), 7.00 (IH, d), 6.75 (IH, dd), 4.42-4.32 (1H, m), 4.16-4.06 (IH, m), 3.71-3.61 (IH, m), 3.49-3.39 (IH, m), 3.04-2.94 (IH, m), 2.85-2.75 (2H, m), 2.71-2.57 (3H, m), 2.16-1.98 (2H, m), 1.96-1.80 (2H, m).

Example 46 iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}-4-oxo-3,4- dihydrophthalazine-1-carboxamide Y^°v[/Ssl 9H H o ;■ Prepared as described in Example 1 following Preparation 7.

MS (APCI) 491/493/495 (M+H)+ . lHNMR5 (CDC13) 9.13 (IH, d), 8.43 (IH, d), 7.91-75 (3H, m), 7.32 (IH, d), 7.00 (lH, d), 6.76 (IH, dd), 4.40-4.32 (IH, m), 4.08-3.98 (IH, m), 3.76-3.66 (IH, m), 3.46-3.38 (IH, m), 3.00-2.92 (IH, m), 2.80-2.66 (2H, m), 2.58-2.44 (3H, m), 2.14-1.98 (2H, m), 1.96-1.80 (2H, m). > ■ Example 47 iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-li/'-indole-3-carboxamide Prepared as described in Example 1 following Preparation 7. 25 MS (APCI) 462/464/466 (M+H)+ !H NMR 8 (cdci3) 9.03 (IH, bd s), 8.07-8.04 (IH, d), 7.84 (IH, s), 7.45-7.41 (IH, m), 7.32 (IH, d), 7.28-7.22 (2H, m), 6.99 (IH, d), 6.82 (IH, t), 6.74 (IH, dd), 4.44-4.34 WO' >68743 99 (1H, in), 4.16-4.06 (IH, m), 3.78-3.68 (IH, m), 3.56-3.44 (IH, m), 3.04-2.94 (IH, m), 2.92-2.82 (2H, m), 2.77-2.65 (3H, m), 2.18-1.98 (2H, m), 1.98-1.78 (2H, m).

Example 48 N- { (2R)- 3 -[4-(4-Chlorophenoxy)piperidin-1 -yl] -2 -hydroxypropyl} -2- (methylsulfonyl)benzamide oo=s=o I Prepared as described in Example 1 following Preparation 4.

MS (APCI) 467/469 (M+H)+ !H NMR 5 (cd3od) 8.08 (IH, d), 7.79 (IH, t), 7.71 (IH, t), 7.61 (IH, d), 7.26 (2H, d), 6.95 (2H, d), 4.56-4.45 (IH, m), 4.21-4.08 (IH, m), 3.47 (2H, d), 3.35 (3H, s), 3.22-3.08 (2H, m), 3.01-2.77 (4H, m), 2.18-2.00 (2H, m), 1.99-1.83 (2H, m).

Example 49 N- { (2i?)-3-[4-(4-Qiloropheiioxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2- dihydroisoquinoline-4-carboxamide Prepared as described in Example 1 following Preparation 4.

MS (APCI) 466/468 (M+H)+ 'HNMR8 (DMSO) 11.57(lH,d), 8.30(lH,t), 8.22 (2H,d),7.73 (lH,t), 7.58- 7.45 (2H, m), 7.30 (2H, d), 6.97 (2H, d), 4.75 (IH, s), 4.41-4.29 (IH, m), 3.87-3.74 (IH, m), 3.46-3.26 (IH, m), 3.22-3.07 (IH, m), 2.85-2.67 (2H, m), 2.41-2.21 (4H, m), 2.00-1.84 (2H,m), 1.70-1.5l(2H,m).

PCT/SJL 00258 100 Example 50 iV^{(2i?)-3-[4-(4-Chloro-3-fluorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo l,2-dihydroisoqmnoline-4-carboxamide Prepared as described in Example 1 following Preparation 5.

. MS (APCI) 474/476 (M+Hf JH NMR 8 (CD3OD) 8.25 (1H, d), 8.08 (IH, d), 7.67 (IH, ddd), 7.48 (2H, t), 7.21 (IH, t), 6.75 (IH, d), 6.66 (IH, ddd), 4.30 (IH, dq), 3.95-3.87 (IH, m), 3.45 (IH, dd), 3.29 ' 3.24 (IH, m), 2.80-2.69 (2H, m), 2.45-2.31 (4H, m), 1.95-1.86 (2H, m), 1.73-1.62 (2H, m) Example 51 N- { (2i?)-3 - [4-(3,4-Difluorophenoxy)piperidin-1 -yi]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-caiboxamide 'a~'° Prepared as described in Example 1 following Preparation 6.

MS (APCI) 458 (M+H)+ ' 'H NMR 8 (CD3OD) 8.25 (IH, dd), 8.08 (IH, d), 7.67 (IH, ddd), 7.50-7.46 (2H, m), 7.03 (IH, dt), 6.76 (IH, ddd), 6.63-6.59 (IH, m), 4.24 (IH, dquintet),-3;94-3.87 (IH, m), 3.45 (IH, dd), 3.26 (IH, dd), 2.74 (2H, d), 2.45-2.30 (4H, m), 1.90 (2H, dt), 1.72-1.61 20 (2H,m).

Example 52 iV-{ (2iS)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} -//-methyl-1 ■ oxo-1,2-dih.ydroisoquinoline-4-carboxamide i&xi OH | A Prepared as described in Example 1 following Preparation 12. MS (APCI) 504/506 (M+H)+ WO ( 68743 101 JHNMR8 (DMSO) 1.25-1.42 (m, 1H), 1.57-1.73 (m, 2H), 1.89-2.15 (m, 3H), 2.26-2.42 (m, 2H), 2.69-2.85 (m, IE), 2.90-3.15 (m, 4H), 3.63-3.77 (m, IH), 3.97-4.09 (m, 1H), 4.26-4.49 (m, IH), 4.79-4.95 (m, 1H), 6.91-7.01 (m, IE), 7.18-7.31 (m, 2H), 7.45-7.57 (m, 3H), 7.73 (t, 1H), 8.23 (d, 1H), 11.51 (s, IH).

Example 53 N-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidm-l-ylJ-2-hydroxypropyl}-7vr-methyl-lif-indazole-3 -carboxamide xr*o cu "T T 1 y" I )= .NH I ■ O Prepared as described in Example 1 following Preparation 12.

MS (APCI) 477/479 (M+H)+ JH NMR 5 (DMSO) 1.36-1.51 (m, 1H), 1.58-1.67 (m, IH), 1.72-1.81 (m, IH), 1.86-1.96 (m, IH), 2.04-2.21 (m, 2H), 2.26-2.39 (m, 2H), 2.71-2.81 (m, IH), 3.13 (s, 3H), 3.49-3.57 (m, IH), 3.78-3.93 (m, IH), 3.98-4.06 (m, 1H), 4.31-4.48 (m, IH), 4.71-4.83 (m, 15 1H), 6.93-7.00 (in, IH), 7.16-7.25 (m, 2H), 7.34-7.43 (m, IH), 7.49 (d, IH), 7.58 (t, IH), 7.95 (dd, IH), 13.34-13.49 (m, IH).

Example 54 7/-{(26)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-//-methyl-4-0 oxo-3,4-dihydrophtfialazine-l-carboxamide Jj u Prepared as described in Example 1 following Preparation 12.

MS (APCI) 505/507 (M+H)+ 'H NMR 8 (cd3od) 1.44-1.55 (m, IH), 1.69-1.80 (m, 2H), 1.93-2.02 (m, IH), 25 2.15-2.24 (m, IH), 2.19 (d, IH), 2.46-2.60 (m, 2H), 2.84-2.93 (m, IH), 3.20 (s, 3H), 3.42-3.51 (m, IH), 3.75 (dd, 1H), 3.84 (qt, IH), 4.16-4.25 (m, IH), 4.35-4.41 (m, IH), 6.79 (ddd, IH), 7.00 (dd, IH), 7.28 (dd, IH), 7.72-7.89 (m, 3H), 8.31 (t, IH).

PCT/S1 .00258 102 Example 55 Benzoic acid, 3-[[2-[[(2.R)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]-, methyl ester o H o Prepared as described in Example 1 following Preparation 7.

MS (APCI) 510/512 (M+H)+ " *H NMR 8 (CDC13) 8.17 (IH, t), 7.95 (IH, dd), 7.38 (IH, t), 7.31 (IH, d), 6.98 (1H, d), 6.91 (IH, t), 6.78-6.68 (2H, m), 6.57 (IH, d), 4.32-4.20 (IH, m), 3.92 (2H, d), 3.89 (3H, s), 3.80-3,69 (IH, m), 3.52-3.40 (IH, m), 3.26 (IH, dt), 2.87-2.74 (IH, m), 2.62-2.39 (2H, 10 m), 2.32 (IH, dd), 2.28-2.14 (2H, m), 2.00-1.84 (2H, m), 1.83-1.66 (2H, m).

Example 56 Propanamide, iVr-[2-[[2-[[(2iJ)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]- a' RiT- o Prepared as described in Example 1 following Preparation 7.

MS (APCI) 523/525 (M+H)+ !H NMR 8 (CDCI3) 7.48 (IH, t), 7.31 (IH, d), 7.23-7.11 (2H, m), 7.05 (IH, d), 6.98 (2H, d), 6.83-6.71 (2H, m), 6.67 (IH, d), 4.54 (IH, t), 4.31-4.17 (IH, m), 3.92 (IH, d), 20 3.79-3.66 (IH, m), 3.45 (IH, td), 3.22 (IH, td), 2.78-2.66 (IH, m), 2.61-2.43 (IH, m), 2.49 (2H, q), 2.37 (IH, t), 2.26-2.06 (3H, m), 1.98-1.82 (2H, m), 1.82-1.64 (2H, m), 1.29 (3H, ; : t). , _ :■■■ Example 57 Propanamide, iV-[2-[[2-[[(2i?)-3-[4-(3,4-dichloropbenoxy)-l-piperidinyl]-2- hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]- a OH u O G a)d' WO' 168743 103 Prepared as described in Example 1 following Preparation 7.

MS (APCI) 494/496 (M+H)+ "H NMR 8 (CDC13) 7.73 (2H, dd), 7.32 (1H, dd), 7.29-7.21 (2H, m),7.02-6.97 (IH, m), 6.97-6.88 (1H, m), 6.80-6.71 (1H, m), 6.60-6.49 (IH, m), 4.36-4.23 (IH, m), 4.14 (2H, 5 t), 3.89-3.75 (1H,m), 3.62-3.48 (IH, m), 3.31-3.17 (IH, m), 2.94-2.81 (IH, m), 2.72-2.59 (IH, m), 2.60-2.47 (1H, m), 2.43-2.22 (3H, m), 2.40 (3H, s), 2.05-1.89 (2H, m), 1.88-1.72 (2H,m).

Example 58 . (2S)-N- { (2K)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2- 1 hyroxy-2-phenylethanamide Prepared as described in Example 1 following Preparation 7.

MS (APCI) 453/455/457 (M+H)+ *H NMR 8 (CDCI3) 7.44-7.26 (6H, m), 6.98 (1H, d), 6.74 (IH, dd), 6.54 (IH, bd s), .06 (IH, s), 4.34-4.24 (IH, m), 3.83-3.73 (IH, m), 3.56-3.43 (IH, m), 3.32-3.20 (IH, m), 2.88-2.80 (IH, m), 2.62-2.52 (2H, m), 2.33-2.10 (3H, m), 2.02-1.90 (2H, m), 1.86-1.70 (2H,m). ^0 Example 59 2-[2-({ (2R)-3 -[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} amino)-2-oxoethoxy]benzamide 0^,0, O NHj Prepared as described in Example 1 following Preparation 7. 25 MS (APCI) 496/498 (M+H)+ 'H NMR 8 (CDCI3) 7.97 (IH, d), 7.48 (IH, t), 7.36-7.28 (2H, m), 7.17-7.07 (IH, m), 7.13 (2H, t), 6.99 (IH, s), 6.93 (IH, d), 6.75 (IH, d), 5.99 (IH, s), 4.68 (2H, s), 4.35-4.22 (IH, m), 3.89-3.77 (IH, m), 3.67-3.54 (IH, m), 3.22 (IH, quintet), 2.91-2.79 (IH, m), •2.68-2.46 (2H, m), 2.43-2.20 (3H, m), 2.04-1.88 (2H,m), 1.88-1.71 (2H,m).

PCT/SI 00258 104 Example 60 N- {(2R)-3-[4-(334-Dichlorophenoxy)piperidin-l -yl] -2-hydroxypropyl}-2-(3 -oxo- 233-dihydro-4£T-l ,4-benzoxazin-4-yl)acetamide 0 ' Prepared as described in Example 1 following Preparation 7.

MS (APCI) 508/510 (M+H)+ JH NMR 8 (cdci3) 7.31 (IH, d), 7.08-7.01 (4H, m), 6.99 (IH, d), 6.74 (IH, dd), 6.53 (IH, bd s), 4.69 (2H, s), 4.56 (2H, q), 4.34-4.24 (IH, m), 3.80-3.72 (IH, m), 3.52-3.42 (IH, m), 3.28-3.18 (IH, m), 2.88-2.80 (IH, m), 2.63-2.45 (4H, m), 2.36-2.21 (3H, m), . 2.00-1.90 (2H, m), 1.86-1.70 (2H, m).

Further Examples of compounds of tie invention which have been prepared as described in Example 1 following Preparation 7 are presented in the Table below.

Example Name (M+H)+ 61 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 452 2-methoxybenzamide 62 N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - 451 2-(methylamino)benzamide 63 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 423 hydroxypropyl}nicotinamide 64 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 423 hydroxypropyl}isonicotinamide 65 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 465 3-(dimethylainino)ben2amide 66 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 505 2-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)acetamide 67 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 439 6-hydroxynicotinamide • WO, >68743 105 68 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 475 2-(lH-indol-3-yl)acetamide 69 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin.-l-yl]-2- 448 hydrqxypropyl}bicyclo[4.2.0]octa-l,3,5-trieae-7-carboxamide 70 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 492 4,7-dimethylpyrazolo[5,1-c] [1,2,4]triazine-3-carboxamide 71 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 424 hydroxypropyl}pyrazine-2-carboxamide 72 N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - 464 9H-purme-6-carboxamide 73 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 473 hydroxypropyl} quinoHne-6-carboxamide 74 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 491 2 J-dimethylpyrazolo[ 1,5-a]pyriinidine-6-carboxamide 75 N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidm-l-yl]-2-hydroxypropyl}- 470 2-(pyrimidin-2-ylthio)acetamide 76 N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -ylj-2-hydroxypropyl}- 479 5-fluoro-1 H-indole-2-carboxamide 77 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl} - 479 1,3-benzodiiazole-6-carboxamide 78 N-{(2R)-3-[4-(3J4-dichloroplienoxy)piperidin-l-yl]-2-liydroxypropyl}- 489 -phenyl-l,3-oxazole-4-carboxamide 79 N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} - 439 6-hydroxypyridine-2-carboxamide 80 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl3-2-hydroxypropyl}- 493 3-oxo-3,4-diliydro-2H-1,4-benzoxazine-7-C5arboxamide 81 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 439 3-hydroxypyridiiie-2-carboxainide 82 N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - 462 lH-benzimidazole-5-carboxamide 83 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}- 461 lH-indole-5-carboxamide 84 N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-1 -yl]-2-hydroxypropyl} - 475 PCT/SL ,00258 106 1-methyl-lH-indole-2-carboxamide 85 N- {(2R)^3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} - 412 lH-imidazole-4-caiboxamide 86 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}- 461 lH-indole-6-carboxamide 87 N-{(2R)-3-[4-(3,4-dichloroph.enoxy)piperidin-l-yl]-2-hydroxypropyl}- 475 1 -methyl-1 H-indole-3-carboxamide 88 N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - 461 1 H-indole-7-carboxamide 89 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-h.ydroxypropyl}- 515 3-[(methylainino)siilfoiiyI]ben2axmde 90 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 578 3.4-bis(methylsulfonyl)benzamide 91 N-{(2R)-3-[4^3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 437 2-pyridin-3-ylacetamide 92 N-{(2R)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}- 477 5-hydroxy-lH-indole-2-carboxamide 93 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yi]-2-hydroxypropyl}- 440 1.5-dimethyl-lH-pyrazole-3-carboxamide 94 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidiii-l-yl3-2-hydroxypropyl}- 539 5 -(methylsulfonyl)-1 H-indole-2-carboxamide 95 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2- 474 hydroxypropyl} quinoxaline-6-carboxamide 96 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-)d]-2-hydroxypropyl}- 474 1,8-naphttiyridine-2-caibox2umde 97 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 518 hydroxypropyl}imidazo[2,l-b][l,3]benzothiazole-2-carboxamide 98 N- { (2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 ->d] -2-hydroxypropyl} - 490 2.6-dimethylimidazo[l,2-a]pyridine-3-carboxamide 99 N-{(2R)-3-[4-(3,4-dichlorophenoxy)pipeiidiii-l-yl]-2-hydroxypropyl}- 478 3-oxo-2}3-dihydro-lH-indazole-4-carboxamide 100 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yi]-2-hydroxypropyl}- 478 3-oxo-2,3 -dihydro-1 H-indazole-6-carboxamide wo M>8743 107 101 N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 480 3-(trifluoromethyl)- lH-pyrazole-4-carboxamide 102 2-(l H-benzimidazol-1 -yl)-N-{ (2R)-3 -[4-(3,4- 476 dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}acetamide 103 N-{(2R)-3-[4-(3,4-dichlorophenoxy)pipeiidin-l-yl]-2-hydroxypropyl}- 454 1 -ethy 1-3 -methyl-1 H-pyr azole-5-carb oxamide 104 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 426 5-methyl-lH-pyrazole-3-carboxamide 105 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yi]-2-hydroxypropyl}- 428 4-methyl-l,2,5-oxadiazole-3-carboxamide . 106 6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2- 496 hydroxypropyl }imidazo[ 1,2-a]pyridine-2-carboxamide 107 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}- 476 2-jnethylimidazo[l,2-a]pyridiiie-3-carboxamide 108 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidiii-1 -yl]-2- 463 hydroxypropyl}imidazo[l,2-a]pyrimidine-2-carboxaiiiide 109 N-{(2R)-3-[4-(3)4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}- 484 2-[(4-methylpyrimidiii-2-yl)thio]acetamide 110 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 489 4-oxo-1,4-dihy droquinoline-2-carboxamide 111 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 473 hydroxypropyl}quinoline-8-carboxamide 112 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}- 476 ^ 5-methylimidazo[l)2-a]pyridme-2-carboxamide 113 N-{(2R)-3-[4-(3,4-dichloropheiioxy)piperidin-l-yl]-2- 462 hydroxypropyl} imidazo[ 1,2-a]pyridine-2-carboxamide 114 N-{(2R)-3-[4-(3J4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyi}- 474 1,6-naphthyridine-2-carboxamide 115 N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidiii-1 -yl]-2-hydroxypropyl} - 480 2,l,3-benzoxadiazole-5-carboxamide 1-oxide m PCT/SE\. ,00258 108 Example 116 iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl3-2-hydroxypropyl}-6-oxo-l,6-dihydropyridine-3-carboxamide ^oxvcr0 o Prepared as described in Example 1 following Preparation 7.

• MS (APCI) 440/442 (M+H)+ NMR 8 (CD3OD) 8.07 (1H, d), 7.99 (IH, dd), 7.39 (IH, d), 7.15 (IH, d), 6.92 (IH, dd), 6.53 (IH, d), 4.52 (IH, septet), 4.09-4.01 (IH, m), 3.49 (IH, dd), 3.34 (IH, d), 3.11-3.02(2H,m),2.86-2.67(4H,m),2.14-2.03 (2H,m), 1.95 (3H,s), 1.97-1.84(2H,m).

Example 117 4-Chloro-N-{ (2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -lif-pyrazole-3-carboxamide O C! Prq>ared as described in Example 1 following Preparation 7. ' MS (APCI) 447/449 (M+H)+ JH NMR 8 (CD3OD) 7.77 (IH, s), 7.37 (1H, d), 7.09 (IH, d), 6.88 (IH, dd), 4.39 (IH, t), 3.95 (IH, quintet), 3.49 (IH, dd), 3.40 (IH, dd), 2.86-2.77 (2H, m), 2.52-2.39 (2H, m), 2.49 (2H, d), 2.06-1.96 (2H, m), 1.85-1.74 (2H, m).

Example 118 N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl}-5 -phenyl-1,3-oxazole-4-carboxamide cw ' c" ty ?HH M 1 K, , K, , ') o Prepared as described in Example 35 following Preparation 7 from 5-phenyl-1,3- oxazole-4-carbonyl chloride.

WO J68743 109 MS (APCI) 490/492 (M+H)+ 'H NMR 8 (cd3od) 8.12 (IH, s), 8.10-8.08 (2H, m), 7.40-7.35 (3H, m), 7.29 (IH, d), 7.04 (IH, d), 6.81 (1H, dd), 4.39 (IH, septet), 3.95 (IH, quintet), 3.44-3.33 (2H, m), 2.96-2.87 (2H, m), 2.67-2.55 (4H, m), 2.03-1.93 (2H, m), 1.85 (3H, s), 1.85-1.75 (2H, m).

Example 119 iy"-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3,5-dimethyl-lif-pyrazole-4-carboxamide ^°onxk^» 1 0 Prepared as described in Example 1 following Preparation 7.

MS (APCI) 441/443 (M+H)+ NMR 8 (cd3od) 7.28 (IH, d), 7.00 (IH, d), 6.79 (IH, dd), 4.34-4.26 (IH, m), 3.86 (IH, quintet), 3.41 (IH, dd), 3.21 (IH, del), 2.78-2.67 (2H, m), 2.41-2.30 (4H, m), 2.29 (6H, s), 1.95-1.86 (2H, m), 1.73-1.63 (2H, m).

Example 120 (2i?)-2-(Acetylamino)-JV-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyi}-2-phenylethanamide O CIYV°n OH H HN^ ::"a 20 Prepared as described in Example l following Preparation 7.

MS (APCI) 494/496 (M+H)+ !H NMR 8 (cd3od) 7.34 (2H, d), 7.29-7.18 (4H, m), 6.99 (IH, t), 6.78 (IH, dd), 5.29 (IH, s), 4.27 (IH, septet), 3.76-3.65 (IH, m), 3.26-3.08 (2H, m), 2.65-2.49 (2H, m), 2.30-2.15 (4H, m), 1.91 (3H, s), 1.90-1.81 (2H, m), 1.69-1.58 (2H, m).

PCT/SL ,00258 110 Example 121 iV-{ (2i?)-3-[4-(3,4-Dichloroplienoxy)piperidiii-1 -yl]-2-hydroxypropyl} -2-(2-hydroxyphenyl)acetamide TY p ?H H OH Prepared as described in Example 1 following Preparation 7.

MS (APCI) 453/455 (M+H)+ 'HNMRS (CD3OD) 7.28 (1H, d), 7.05-6.97 (3H, m), 6.78 (IH,dd), 6.72-6.67 (2H, m), 4.27 (IH, dq), 3.72 (IH, quintet), 3.43 (2H, dd), 3.21-3.08 (2H, m), 2.68-2.57 (2H, m), 2.32-2.20 (4H, m), 1.90-1.81 (2H, m), 1.69-1.58 (2H, m).

Example 122 (2R)-N- { (2i2)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-[(methylsulfonyl)amino]-2-phenylethanamide Wp OHhW^ Prepared as described in Example 1 following Preparation 7.

MS (APCI) 530/532 (M+H)+ 'HNMR8 (CD3OD) 7.37 (2H, d), 7.31-7.21 (4H, m), 6.99 (IH, d), 6.78 (IH, dd), 4.96 (IH, s), 4.27 (IH, septet), 3.70 (IH, quintet), 3.24 (IH, dd), 3.13 (IH, dd), 2.72 (3H, s), 2.66-2.56 (2H, m), 2.32-2.18 (4H, m), 1.91-1.82 (2H, m), 1.70-1.59 (2H, m).

Example 123 (2iS)-2-(Acetylamino)-jV-{(2i?)-3-[4-(3,4-dicUorophenoxy)piperidin-l-yl]-2-hydroxypropyl} -2-phenylethanamide • ■ O CIY5T°T^SI OH H Prepared as described in Example 1 following Preparation 7.

V MS (APCI) 494/496 (M+H)+ WO' 68743 111 ]H NMR 8 (CD3OD) 7.34 (2H, d), 7.30-7.18 (4H, m), 6.99 (1H, dd), 6.78 (IH, ddd), 5.29 (IH, s), 4.30-4.23 (IH, m), 3.76-3.65 (IH, m), 3.17-3.07 (2H, m), 2.65-2.48 (2H, m), 2.30-2.14 (4H, m), 1.92-1.80 (2H, m), 1.91 (3H, s), 1.68-1.57 (2H, in).

Example 124 (2<S)-Ar-{(2j?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-phenyIethanamide CVt°-0 9h h aXs> Prepared as described in Example 1 following Preparation 7.

MS (APCI) 530/5322 (M+H)+ !H NMR 8 (CD3OD) 7.47 (2H, d), 7.40-7.30 (4H, m), 7.08 (IH, d), 6.87 (IH, dd), 5.06 (IH, s), 4.39-4.32 (IH, m), 3.83 (IH, quintet), 3.27 (2H, d), 2.80 (3H, s), 2.73-2.59 (2H, m), 2.38-2.24 (2H, m), 2.28 (2H, d), 1.99-1.89 (2H, m), 1.78-1.67 (2H, m).

Example 125 l-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-o-tolyl-urea A solution of o-tolylisocyanate (64ml, 0.51mmol) in dichloromethane (1ml) was added to a suspension of (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0,15g, 0.47mmol) in dichloromethane (3ml) over a five minute period. After lh methanol (1ml) was added and the solvents removed under vacuum. The residue was purified by reverse phase chromatography (C8 Symmetry column) to give the title compound (87mg).

MS (APCI) 452/454 (M+H)+ .

'HNMR8 (DMSO) 7.81 (IH, d), 7.78 (IH, s), 7.50 (IH, dd), 7.26 (IH, dd), 7.10 (IH, t), 7,05 (IH, s), 6.99 (IH, ddd), 6.86 (IH, t), 6.63 (IH, t), 4.74 (IH, d), 4.49-4.40 (IH, m), 3.72-3.63 (IH, m), 3.32-3.30 (IH, m), 2.99-2.90 (IH, m), 2.79-2.67 (2H, m), 2.35-2.24 (4H, m), 2.18 (3H, s), 1.97-1.88 (2H, m), 1.69-1.56 (2H, m).

PCT/SL .00258 112 Example 126 l-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin.-l-yl]-2-liydroxypropyl}-3-p-tolyl-urea ■ yfxxz H H a- — — -nYN na Prepared as described in Example 125 following Preparation 1.

MS (APCI) 452/454 (M+H)+ !H NMR 8 (DMSO) 8.52 (1H, s), 7.55 (1H, d), 7.31 (2H, d), 7.31 (IH, s), 7.07 (2H, d), 7.03 (1H, d), 6.15 (IH, t), 4.82-4.76 (1H, m), 4.55-4.45 (IH, m), 3.76-3.67 (IH, m), 3.36-3.32 (IH, m), 3.03-2.95 (IH, m), 2.83-2.72 (2H, m), 2.40-2.31 (4H, m), 2.27 (3H, s), 2.03-1.92 (2H, m), 1.75-1.61 (2H, m).

Example 127 . 7/-{(2iS)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-metliylpropyl}-l-oxo-1,2-dihydroisoquinoline-4-carboxamide Prepared as described in Example 1 following Preparation 9.

MS (APCI) 504/506/508 (M+H)+ *HNMR8 (CD3OD) 8.37 (1H, d), 8.18 (IH, d), 7.78 (1H, t), 7.59 (1H, s), 7.58 (IH, t), 7.37 (IH, d), 7.07 (lH, d), 6.86 (IH, dd), 4.33-4.28 (IH, m), 3.60-3.45 (2H, m), 3.04-2.92 (2H, m), 2.60-2.45 (4H, m), 1.98-1.86 (2H, m), 1.72-1.60 (2H, m), 1.25 (3H, s).

Example 128 iV-{(2iS)-3-[4-(3,4-Dichloroplienoxy)piperidin-l-yl]-2-liydroxy-2-methylpropyl}-2-oxo-1,2-dihydroquinoline-4-caiboxamide Prepared as described in Example 1 following Preparation 9.

MS VAPCI) 504/506/508 (M+H)+ vj WO )68743 113 JH NMR 8 (CDC13) 7.93 (1H, d), 7.53 (1H, t), 7.34-7.20 (4H, m), 6.98 (1H, d), 6.75-6.69 (2H, m), 4.32-4.22 (IH, m), 3.68-3.40 (2H, m), 3.00-2.80 (2H, m), 2.70-2.48 (4H, m), 2.00-1.86 (2H, m), 1.84-1.72 (2H, m), 1.26 (3H, s).

Example 129 N- {(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxy-2-methylpropyl} -4-oxo-3,4-dihydrophtlialazine-1 -carboxamide o ' Prepared as described in Example 1 following Preparation 9.

MS (APCI) 505/507/509 (M+H)+ !H NMR 8 (cdci3) 10.18 (IH, bs), 9.15 (IH, d), 8.44 (IH, d), 8.06 (IH, bd s), 7.89 (IH, t), 7.81 (IH, t), 7.31 (IH, d), 7.01 (IH, d), 6.78 (IH, dd), 4.35-4.25 (IH, m), 3.58-3.37 (2H, m), 3.04-2.82 (2H, m), 2.66-2.46 (4H, m), 2.06-1.96 (2H, m), 1.94-1.80 (2H, m), 1.23 (3H, s).

Example 130 »* (2iS)-A''-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl} -2-hydroxy-2-phenethanamide Prepared as described in Example 1 following Preparation 9.

MS (APCI) 467/469/471 (M+H)+ !H NMR 8 (cdci3) 7.46-7.29 (6H, m), 6.98 (IH, d), 6.78 (IH, bd s), 6.75 (IH, dd), 5.08 (IH, s), 4.28-4.20 (IH, m), 3.71 (IH, bd s), 3.35-3.20 (2H, m), 2.86-2.69 (2H, m), 2.53-2.39 (2H, m), 2.31 (2H, s), 1.97-1.85 (2H, m), 1.82-1.70 (2H, m), 1.04 (3H, s).

PCT/SL ,00258 114 Example 131 N- { (2iJ)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl}-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide Prepared as described in Example 1 following Preparation 10.

" MS (APCI) 470/472 (M+H)+ !H NMR 5 (CD3OD) 8.25 (1H, d), 8.08 (IH, d), 7.67 (IH, t), 7.48 (2H, t), 7.05-6.96 (2H, m), 6.77 (1H, d), 4.36-4.25 (IH, m), 3.98-3.87 (IH, m), 3.45 (IH, dd), 3.28 (IH, dd), 2.80-2.67 (2H, m), 2.49-2.34 (4H,m), 2.08 (3H, s), 1.98-1.84 (2H, m), 1.78-1.64 (2H, m).

Example 132 N-((2R)-3 - { 4-[2-(Aminocarbonyl)-3,4-dichlorophenoxy]piperidin-1 -yl} -2-hydroxypropyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide o^nh2 e« H irV° aJJ u^aylx o - The crude amine product obtained from Preparation 11 was redissolved in . dichloromethane and treated with diisopropylethylamine (0.85ml) and l-oxo-1,2- dihydroisoquinoline-4-carbonyl chloride (0.40g) at room temperature. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution and the mixture concentrated in vacuo, azeotoping with toluene. Extraction of the solid residue into 20 dichloromethane/methanol, filtering solids and chromatography on silica (dichloromethane:7N ammonia in methanol/15:2) gave the target compound as a white solid (0.3 lg).

MS (APCI) 533/535 (M+H)+ .

!H NMR 8 (CD3OD) 8.25 (lH, d), 8.12 (IH, d), 7.69 (lH, m), 7.55 (IH, s), 7.49 25 (IH, m), 7.44 (IH, d), 7.05 (IH, d), 4.20 (IH, m), 3.55-2.96 (10H, m), 2.25-1.98 (4H, m). wot >68743 115 Example 133 3-Cyano-iV-{(2iS)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzenesulfonamide '/ ** ° 0 To a solution of (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2- ol (0.200g, 0.63mmol) in 4ml of pyridine at 0°C was added 3-cyanobenzenesulfonyl chloride (0.127g, 0.63mmol). After 30 min, the reaction was allowed to warm to room temperature and was stirred for 2h. The reaction was concentrated under vacuum, and the | residue partitioned between 10% aqueous sodium hydrogen carbonate and ethyl acetate. 10 The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude material was purified on silica gel (0 to 5% 7N ammonia in methanol/dichloromethane) to afford the title compound as a white foam (0.120g).

MS (ESI) 484/486 (M+H)+ JH NMR 8 (DMSO) 8.22 (IH, d), 8.16-8.07 (2H, d), 7.82 (2H, t), 7.50 (IH, d), 7.25 15 (IH, d), 6.97 (IH, dd), 4.71 (d, IH), 4.47-4.34 (IH, m), 3.63-3.51 (IH, m), 2.93 (IH, dd), 2.71 (IH, dd), 2.69-2.55 (2H, m), 2.32-2.12 (4H, m), 1.95-1.79 (2H, m), 1.65-1.45 (2H, m), 1.65-1.45 (2H,m).

Example 134 JO 5-[({ (2iS)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} amino)- sulfonyl]-2-methoxybenzamide o" o 5 Prepared as described in Example 133 following Preparation 7 using 3-(aminocaibonyl)-4-methoxybenzenesulfonyl chloride.

MS (APCI) 531/533 (M+H)+ JHNMR8 (DMSO) 8.20 (IH, d), 7.87 (IH, dd), 7.73 (2H, s), 7.55 (IH, s), 7.49 (IH, d), 7.32 (IH, d), 7.25 (IH, d), 6.97 (IH, dd), 4.67 (IH, d), 4.41 (IH, septet), 3.96 (3H, s), 3.58 (IH, q), 2.82 (IH, d), 2.68-2.57 (3H, m), 2.30-2.16 (4H, m), 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).

PCT/SE*,.,00258 116 Example 135 iV-{ (2iS)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-1 -oxo-1,2-dihydroisoquinoline-4-sulfonamide acetate salt ' (2R)-1 -Amino-3-[4-{3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol (0.15g) in pyridine (2ml) was treated with l-oxo-l,2-dihydroisoquinoline-4-sulfonyl chloride (0.1 lg) and the mixture was stirred at ambient temperature for 18h. After further additions of the sulfonyl chloride (0.05g) and stirring for 24h the solvent was evaporated. Purification by 10 column chromatography and reverse phase HPLC (symmetry C8 column and acetonitrile/0.1% aqueous ammonium acetate) yielded the title compound as a white solid (0.06g).

MS (APCI) 526/528 (M+H)+ JH NMR S (DMSO) 8.39 (IH, d), 8.32 (IH, d), 7.95 (IH, s), 7.86 (IH, ddd), 7.64 15 (IH, t), 7.39 (IH, d), 7.11 (IH, d), 6.89 (IH, dd), 4.45-4.39 (IH, m), 3.82-3.75 (IH, m), 3.34 (IH, s), 2.97 (IH, dd), 2.92 (IH, dd), 2.81-2.72 (2H, m), 2.55-2.42 (2H, m), 2.02-1.92 (2H, m), 1.95 (3H, s, OAc), 1.82-1.72 (2H, m).

| Example 136 Ar-{(21S)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4- difluorobenzenesulfonamide 0,^0^ ^ ^ °"0 F Prepared as described in Example 133 following Preparation 7 using 2,4-difluorobenzenesulfonyl chloride.

MS (APCI) 493/495 (M+H)+ *H NMR 8 (DMSO) 7.94 (IH, s), 7.86 (IH, td), 7.55 (IH, ddd), 7.49 (IH, d), 7.28 (IH, ddd), 7.25 (IH, d), 6.97 (IH, dd), 4.69 (IH, d), 4.42 (IH, septet), 3.60 (IH, sextet), 2.96 (lH, dd),2.81 (IH, dd), 2.68-2.58 (2H,m), 2.34-2.16(4H,m), 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).

WO t >68743 117 Further Examples of compounds of the invention which have been prepared according to Example 133 following Preparation 7 are now listed in the following table.

Example Name (M+H)+ 137 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-| 396 hydroxypropyl}methanesulfonamide 138 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 458 hydroxypropyl }benzenesulfonamide 139 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yI]-2- 472 hydroxypropyl}-l-phenylmethanesulfonamide 140 N-{(2S)-3-[4-(3,4-dicblorophenoxy)piperidin-l-yi]-2- 488 hydroxypropyl}-4-methoxybenzenesulfonamide 141 N-({5-[({(2S)-3-[4-(3,4-dichlorophenoxy)pipeiidin-l-yl]-2- 597 hydroxypropyl}amino)sulfonyl]-2-thienyI}methyl)benzamide 142 4-cyano-N- { (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2- 483 hydroxypropyl}benzenesulfonamide 143 N-{ 5-[({ (2S)-3-[4-(3,4-dicblorophenoxy)piperidin-1 -yl]-2- 536 hydroxypropyl}amino)sulfonyl]-4-methyl-l,3-thiazol-2-yl}acetamide 144 N- {(2S)-3-[4-(3,4-diclilorophenoxy)piperidin-1 -yl]-2- 464 hydroxypropjd}thiophene-2-sulfonamide 145 4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 502-hydroxypropyl} amino)sulfonyl]benzoic acid 146 N-{(2S)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2- 518 hydroxypropyl} -2,5-dimethoxybenzenesulfonamide 147 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 604 hydroxypropyl} -4-(phenylsulfonyl)thiophene-2-sulfonamide 148 N-{ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2- 531 hydroxypropyl}-5-(l,3-oxazol-5-yl)thiophene-2-sulfonamide 149 N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2- 612 hydroxypropyl}-5-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]thiophene-2-sulfonamide 00 >n <N © gs W CO H <-> oo Tt* in in t--Tf VO i—( <n cs $ o o <o CO in (N <s in VO cs in cs r» rf (N o\ Tf oo CO «n vo o in o <s in hi M 0 J3 en T r- fO o O £ o in in <M in co in »n in m vo in <n oo in 0\ in 8.

VO (N VO m vo s in vo WO J68743 119 166 methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2- 519 hydroxypropyl} amino)sulfonyl]-1 -methyl-lH-pyrrole-2-caiboxylate 167 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 518 hydroxypropyl} -334-dimethoxybeazenesulfonamide 168 5-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 498 hydroxypropyl}thiophene-2-sulfonamide 169 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 544 hydroxypropyl} -6-(morpholin-4-yl)pyridine-3-sulfonamide 170 N-{2-chloro-4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l- 549 yl]-2-hydroxypropyl}amino)sulfonyl]phenyl}acetamide 171 N-{(2S)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2- 542 hydroxypropyl}-2}3-dihydroxyquinoxaline-6-sulfonamide 172 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 518 hydroxypropyi}-2,4-dimethoxybeirzenesiilfonamide 173 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidiii-l -yl]-2- 531 hydroxypropyl} amino)sulfonyl]-2-methoxybenzamide 174 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 472 hydroxypropyl} -2-methylbenzenesulfonamide 175 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 493 hydroxypropyl}-2,4-dimethyl-l ,3-thiazole-5-sulfoiiainide 176 N-{(2S)-3-[4-(3 >4-dichlorophenoxy)piperidin-1 -yl] -2- 526 hydroxypropyl} -2-hydroxyquinoxaline-6-sulfonamide 177 N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2- 529 hydroxypropyl} -4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide 178 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl3-2- 459 hydroxypropyl}pyridine-3-sulfonamide 179 4'-cyano-N-{(2S)-3-[4-(3,4-dichlorophexioxy)piperidin-l-yl]-2- 559 hydroxypropyl}biphenyl-2-sulfonamide 180 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-}d]-2- 476 .. hydroxypropyl} -1,2-dimethyl-1 H-imidazole-4-sulfonamide PCT/SE^/00258 120 181 4-acetyl-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 500 hydroxypropyl}benzenesulfonamide 182 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 536 hydroxypropyl}-4~(methylsulfonyl)benzenesulfonamide 183 2-chloro-4-cyano-N-{(2S)-3-[4-(3,4-dichloroph.enoxy)-piperidin- 517 l-yl]-2-hydroxypropyl}benzenesulfonamide 184 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 490 hydroxypropyl} -1,3,5-trimethyl-1 H-pyrazole-4-sulfonamide ' Example 185 N-[(2i?)-3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]-2-hydroxypropyl]-l ,4-dihydro-5 4-oxo-3-quinolinecaiboxamide o o Prepared as described in Example 1 following Preparation 7 using 4-oxo-l ,4-dihydroquinoIine-3-carboxylic acid.

MS (APCI) 490/492 (M+H)+ . .

'H NMR 5 (DMSO) 10.21 (5H, t), 8.74 (6H, s), 8.26 (6H, dd), 7.74 (10H, ddd), 7.68 (8H, d), 7.49 (1 IH, d), 7.48-7.44 (1 IH, m), 7.25 (6H, d), 6.98 (6H, dd), 4.80 (4H, s), ^ 4.44 (6H, septet), 3.75 (6H, s), 3.55 (7H, ddd), 3.26-3.19 (20H, m), 2.78-2.68 (12H, m), 2.34 (20H,d), 2.33-2.25 (24H,m), 1.96-1.88 (12H, m), 1.69-1.58 (12H,m). .

Example 186 //-{(2iS)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-l -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt Prepared as described in Example 35 following Preparation 10 using (2S)-oxiran-2-20 ylmethyl-3-mtrobenzenesulfonate and 1 -oxo-1,2-diliydroisoquinoline-4-carbonyl chloride. MS (APCI) 470/472 (M+H)+ WO k >68743 121 JH NMR 8 (DMSO) 8.32 (1H, t), 8.22 (2H, d), 7.73 (IH, td), 7.52 (IH, td), 7.52 (IH, s), 7.20 (IH, d), 7.14 (1H, dd), 6.98 (IH, d), 4.38 (IH, septet), 3.81 (IH, quintet), 3.43-3.36 (IH, m), 3.18-3.11 (IH, m), 2.75-2.63 (2H, m), 2.42-2.28 (4H, m), 2.14 (3H, s), 1.94-1.84 (2H, m), 1.88 (3H, s, OAc), 1.70-1.58* (2H, m).

Example 187 A^(2S)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide Prepared as described in Example 35 following Preparation 14 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyi chloride.

MS (APCI) 490/492/494 (M+H)+ 'H NMR 8 (CD3OD) 8.40 (IH, d), 8.21 (IH, d), 7.74 (IH, t), 7.54 (IH, t), 7.50 (IH, s), 7.32 (IH, d), 7.00 (1H, d), 6.76 (IH, dd), 4.36-4.24 (IH, m), 3.99-3.93 (IH, d), 3.73-15 3.68 (IH, d), 3.33-3.28 (IH, m), 2.96-2.84 (IH, m), 2.75-2.30 (5H, m), 2.04-1.94 (2H, m), " 1.88-1.76 (2H, s).

Example 188 jV-{(2iS)-3-{4-(3s4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-iO dihydroisoquinoline-4-caxboxamide Prepared as described in Example 35 following Preparation 15 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 504/506/508 (M+H)+ ' . '. • lH NMR 8 (CD3OD) 8.38 (lH,d), 8.19 (IH, d)7.80 (IH, t)^ 7.61 (IH, t), 7.60 (IH, t), 7.38 (IH, d), 7.09 (IH, d), 6.87 (IH, dd), 4.37-4.30 (IH, m), 3.64 (IH, d), 3.42 (IH, d), 3.03-2.83 (2H, m), 2.60-2.46 (4H, m), 1.96-1.86 (2H, m), 1.72-1.60(2H, m), 1.26 (3H, s).

PCT/SEw/00258 122 Example 189 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -7-[(methylamino)sulfonyl] -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide 7-[(Methylamino)sulfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (O.lg) in dimethyl formamide (7ml) was treated with N,N-caibonyldiimidazole (0.06g) and the mixture was heated at 55°C for 45 min. (2R)-l-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.1 lg) in dimethyl formamide (1ml) was added and the mixture was stirred at ambient temperature for 18h. 1 Drop of water was added and the solvent was evaporated. Purification using reverse phase HPLC (Symmetry C8 column) and acetonitrile/aqueous ammonium acetate as eluent yielded the title compound as a white solid (0.03g).

MS (APCI) 583/585 (M+H)+ JH NMR 5 (DMSO) 8.59 (1H, s), 8.44 (1H, d), 8.42 (IH, t), 8.04 (IH, dd), 7.73 (IH, s), 7.62 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.79 (IH, s), 4.44 (IH, septet), 3.80 (IH, quintet), 3.45-3.37 (IH, m), 3.18-3.11 (IH, m), 2.81-2.69 (2H, m), 2.42 (3H, s), 2.39-2.25 (4H, m), 1.96-1.87 (2H, m), 1.66-1.55 (2H, m).

I Example 190 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl }-7-{[(2- hydroxyethyl)amino]sulfohyl}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt ::^oo Prepared as described in Example 189 following Preparation 7 using l,2-dihydro-7-[[(2-hydroxyethyl)amino] sulfonyl]-1 -oxo-4-isoquinolinecarboxylic acid.

MS (APCI) 613/615 (M+H)+ JH NMR 8 (DMSO) 8.61 (IH, s), 8.42 (IH, d), 8.42 (IH, t), 8.07 (IH, dd), 7.71 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.44 (IH, septet), 3.81 (IH, quintet), WO' ^68743 PCT/SE03/00258 123 3.46-3.37 (1H, m), 3.35 (2H, t), 3.18-3.10 (1H, m), 2.80-2.68 (2H, m), 2.80 (2H, t), 2.42-2.25 (4H, m), 1.96-1.87 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).

Example 191 7-[(Cyclopropylamino)sulfonyl]-jV4(22?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyi}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide "D'O ~ " a' o o'o Prepared as described in Example 189 following Preparation 7 using 7-[(cyclopropylammo)sulfonyl]-l,2-dihydro-l-oxo-4-isoquinolinecarboxylic acid. 10 MS (APCI) 609/611 (M+H)+ lH NMR 8 (DMSO) 8.64 (IH, s), 8.44 (1H, d), 8.41 (IH, t), 8.07 (IH, dd), 7.72 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.78 (IH, s), 4.44 (IH, septet), 3,81 (IH, quintet), 3.45-3.38 (IH, m), 3.18-3.10 (IH, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 2.15-2,09 (IH, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m), 0.50-0.44 (2H, m), 0.38-0.32 15 (2H, m).

Example 192 7-(Azetidin-l-ylsulfonyl)-iV-{(2i?)-3-[4-(3,4-diclilorophenoxy)piperidin-l-yl]-2-^ hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt Prepared as described in Example 189 following Preparation 7 using 7-(azetidin-l-ylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 609/611 (M+H)+ 'H NMR 8 (DMSO) 8.53 (IH, t), 8.52 (IH, d), 8.44 (IH, t), 8.09 (IH, dd), 7.77 25 (IH, s), 7.50 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.43 (IH, septet), 3.81 (IH, quintet), 3.69 (4H, t), 3.47-3.37 (IH, m), 3.21-3.10 (IH, m), 2.83-2.68 (2H, m), 2.40-2.24 (4H, m), 2.05-1.86 (2H, m), 1.97 (2H, quintet), 1.88 (3H, s, OAc), 1.68-1.53 (2H,m). - PCT/SEv, .00258 124 Example 193 7 -(Aminosulfonyl)-iV- { (2R)-3-[4-(3,4-dicMorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide :xrouxs Prepared as described in Example 189 following Preparation 7 using 7- (aminosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 569/571 (M+H)+ | NMR 8 (DMSO) 8.65 (1H, s), 8.40 (IH, d), 8.39 (1H, t), 8.09 (1H, dd), 7.69 (IH, s), 7.49 (IH, d), 7.50 (2H, s), 7.25 (IH, d), 6.98 (IH, dd), 4.77 (IH, s), 4.44 (IH, 10 septet), 3.85-3.77 (IH, m), 3.41 (IH, dt), 3.14 (IH, dt), 2.81-2.69 (2H, m), 2.41-2.25 (4H, m), 1.96-1.86 (2H, m), 1.67-1.54 (2H, m).

Example 194 iV-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-15 [(dimethylamino)sulfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide Ck pcnoutj Prepared as described in Example 189 following Preparation 7 using 7-[(dimethylamino)sulfonyl]-l-oxo-1,2-dihydroisoquinoline-4-caxboxylic acid.

MS (APCI) 597/599 (M+H)+ *H NMR 8 (DMSO) 8.49 (IH, s), 8.48 (IH, d), 8.43 (IH, t), 8.04 (IH, dd), 7.75 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.44 (IH, septet), 3.81 (IH, quintet), 3.46-3.37 (IH, m), 3.18-3.11 (IH, m), 2.82-2.69 (2H, m), 2.64 (6H, s), 2.42-2.26 (4H, m), 1.95-1.86 (2H, m), 1.89 (3H, s, OAc), 1.60 (2H, dt).

WO >68743 pHs-l 125 Example 195 iV-{(2i?)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-methylazetidin-1 -yI)sulfonyl]-l -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt ci ci »°ia Prepared as described in Example 189 following Preparation 7 using 7-[(3-hydroxy-3-methylazetidin- l-yl)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid. MS (APCI) 639/641 (M+H)+ 'H NMR 5 (DMSO) 8.53 (1H, d), 8.51 (IH, d), 8.45 (1H, t), 8.08 (1H, dd), 7.77 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (1H, dd), 4.44 (JH, septet), 3.82 (IH, quintet), 3.60 (2H, d), 3.45 (2H, d), 3.45-3.40 (IH, m), 3.19-3.10 (IH, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 1.96-1.84 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).

Example 196 N-[(2R)-3 -(4- { 3,4-Dichloro-2-[(cyclopropylamino)carbonyl]phenoxy }piperidin-1 - yl)-2-hydroxypropyl]-l-oxo-l,2-diliydroisoquinoline-4-caiboxamide acetate salt Y hnY° ii^I c,yvor^ h 0 O . • ' Prepared as described in Example 35 following Preparation 35 using 1 -oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 573/575 (M+H)+ JH NMR S (CD3OD) 8.25 (IH, d), 8.09 (IH, d), 7.68 (IH, t), 7.49 (IH, s), 7.48 (IH, t), 7.38 (IH, d), 6.97 (IH, d), 4.54-4.48 (IH, m), 4.03-3.97 (IH, m), 3.44 (IH, dd), 3.30 (IH, dd), 2.90-2.79 (2H, m), 2.76-2.58 (5H, m), 1.98-1.89 (2H, m), 1.87-1.79 (2H^ m), 1.85 (3H, s, OAc), 0.70-0.65 (2H, m), 0.52-0.48 (2H, m).

PCT/SE^,00258 126 Example 197 N-{ (2R)-3-[4-(3 -Chloro-4-cyanophenoxy)piperidia-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide ' co-o Prepared as described in Example 35 following Preparation 24 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyi chloride.

MS (APCI) 481 (M+H)+ > fH NMR 8 (CD3OD) 8.36 (1H, dd), 8.19 (lH,d), 7.86 (2H, d), 7.77-7.75 (2H,m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (IH, m), 4.07-4.01 (IH, m), 3.57 (IH, dd), 3.38 (IH, 10 dd), 3.08 (3H, s), 2.98-2.88 (2H, m), 2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).

Example 198 iy-((22Q-2-Hydroxy-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-l-yI}propyl)-l-15 oxo-l^-dihydroisoquinoline-4-cafboxamide Prepared as described in Example 35 following Preparation 25 using 1-oxo-1,2-dihydroisoquinoline-4-caibon>i chloride.

MS (APCI) 500 (M+H)+ 'H NMR 8 (CD3OD) 8.36 (IH, dd), 8.19 (IH, d), 7.86 (2H, d), 7.77-7.75 (2H, m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (IH, m), 4.07-4.01 (IH, m), 3.57 (IH, dd), 3.38 (IH, dd), 3.08 (3H, s), 2.98-2.88 (2H, m), 2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).

WO >68743 127 Example 199 N- { (222)-3-[4-(4-Cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide Prepared as described in Example 35 following Preparation 26 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 447 (M+H)+ !H NMR 8 (DMSO) 8.31 (1H, t), 8.22 (2H, d), 7.75-7.71 (3H, m), 7.54-7.50 (2H, m), 7.12 (2H, d), 4.80-4.73 (1H, m), 4.56-4.49 (1H, m), 3.83-3.77 (IH, m), 3.42-3.35 (2H, 10 m), 3.18-3.1 l(lH,m), 2.81-2.71 (2H,m), 2.41-2.27 (4H,m)i 1.98-1.91 (2H, m), 1.68-1.59 (2H,m).

Example 200 7/-((2i?)-3-{4-[2-(Aminocarbonyl)-4-chlorophenoxy]piperidin-l -yl}-2-15 hydroxypropyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide '^1 ?" H a o o NH Prepared as described in Example 35 following Preparation 33 using l-oxo-1,2-dihydroisoqumolme-4-carbonyl chloride.

MS (APCI) 499 (M+H)+ *HNMR 8 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.78 (IH, d), 7.67 (IH, td), 7.48 (IH, t), 7.47 (IH, s), 7.35 (IH, dd), 7.08 (IH, d), 4.56-4.50 (IH, m), 3.94-3.89 (IH, m), 3.46 (IH, dd), 3.27 (IH, dd), 2.79-2.70 (2H, m), 2.46-2.36 (4H, m), 2.03-1.95 (2H, m), 1.82-1.73 (2H, m).

PCT/St.,, 00258 128 Example 201 iV-[(2R)-3 -(4- { 4-Chloro-2-[(methylamino)carbonyl]phenoxy }piperidin-1 -yl)-2-hydroxypropylj-l -oxo-1,2-diliydroisoquinoline-4-carboxamide O^NH .jo ,NH O 0"O ?H H • Prepared as described in Example 35 following Preparation 32 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 513 (M+H)+ !H NMR 8 (cd3od) 8.25 (1H, d), 8.09 (1H, d), 7.67 (IH, td), 7.63 (IH, d), 7.48 (IH, s), 7.48 (IH, td), 7.33 (IH, dd), 7.07 (IH, d), 4.59-4:51 (IH, m), 4.01-3.94 (IH, m), 10 3.46 (IH, dd), 3.28 (IH, dd), 2.91-2.80 (2H, m), 2.83 (3H, s), 2.66-2.54 (4H, m), 2.05-1.94 (2H,m), 1.90-1.79 (2H,m).

Example 202 Methyl 5-chloro-2-{[l-((2i?)-2-hydroxy-3-{[(l-oxo-l,2-dihydroisoqiiinolin-4-15 yl)carbonyl]amino}propyl)piperidin-4-yl]oxy}benzoate acetate salt Prepared as described in Example 35 following Preparation 31 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 513 (M+H)+ 'H NMR 8 (cd3od) 8.25 (IH, dd), 8.09 (IH, d), 7.67 (IH, td), 7.60 (IH, d), 7.49 (IH, s), 7.48 (IH, td), 7.38 (IH, dd), 7.06 (IH, d), 4.59-4.54 (IH, m), 4.05-3.99 (IH, m), 3.76 (3H, s), 3.45 (IH, dd), 3.30 (IH, dd), 3.03-2.92 (2H, m), 2.79-2.61 (4H, m), 2.00-1.86 (4H, m), 1.84 (3H, s, OAc).

WO J68743 129 Example 203 iV^X2i?)-3-{4-[2-(Aminosulfonyl)-3,4-dichlorophenoxy]piperidin-l-yl}-2-hydroxypropyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide trifluoroacetiate salt Prepared as described in Example 35 following Preparation 40 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 569/571 (M+H)+ | JH NMR 6 (cd3od) 8.26 (IH, d), 8.09 (IH, d), 7.71 (IH, t), 7.62 (IH, d), 7.52 (IH, s), 7.48 (IH, t), 7.18 (IH, d), 5.02 (IH, s), 4.23-4.15 (IH, m), 3.55 (IH, t), 3.46-3.33 10 (5H, m), 3.16-3.08 (2H, m), 2.26 (2H, t), 2.15-2.00 (2H, m).

Example 204 iV-[(2i?)-3-(4-{ 3,4-Dichloro-2-[(methylamino)sulfonyl]phenoxy}piperidin-1 -yl)-2-hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt HN'' o=s=o °wn vv • i5 , . ° | Prepared as described in Example 35 following Preparation 41 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 583/585 (M+H)+ JH NMR 5 (cd3od) 8.25 (IH, d), 8.08 (IH, d), 7.69 (IH, td), 7.60 (IH, d), 7.49 20 (IH, s), 7.48 (IH, td), 7.16 (IH, d), 4.73-4.68 (IH, m), 4.05-3.99 (IH, m), 3.44 (IH, dd), 3.30 (IH, dd), 3.15-3.04 (2H, m), 2.78-2.63 (4H, m), 2.52 (3H, s), 2.07-1.93 (4H, m), 1.85 (3H, s, OAc).

PCT/SEw,00258 130 Example 205 iV-[(2i?)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)sulfonyl]phenoxy}piperidin-l-yl)-2-hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt .A Prepared as described in Example 35 following Preparation 42 using 1-oxo-1,2- dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 609/611 (M+H)+ 'HNMR S (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.68 (IH, t), 7.61 (IH, d), 7.49 (IH, s), 7.47 (IH, t), 7.17 (IH, d), 4.72-4.65 (IH, m), 4.03-3.96 (IH, m), 3.44 (IH, dd), 10 3.30 (IH, dd), 3.11-2.99 (2H, m), 2.73-2.58 (4H, m), 2.19-2.13 (IH, m), 2.04-1.90 (4H, m), 1.83 (3H, s, OAc), 0.50-0.43 (4H, m).

Example 206 N-{ (2/2)-3-[4-(3 -Chloro-4-cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -7-15 (methylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide o=s=o Prepared as described in Example 189 following Preparation 24 using 7-(methylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 559 (M+H)+ NMR 8 (CD3OD) 8.78 (IH, d), 8.35 (IH, d), 8.14 (IH, dd), 7.68 (IH, s), 7.60 (IH, d), 7.12 (IH, d), 6.95 (IH, dd), 4.56-4.51 (IH, m), 4.01-3.95 (IH, m), 3.47 (IH, dd), 3.28 (IH, dd), 3.10 (3H, s), 2.94-2.85 (2H, m), 2.64-2.52 (4H, m), 2.04-1.95 (2H, m), 1.86 (3H,s), 1.83-1.74 (2H,m).

WO ;68743 131 Example 207 N- {(2R)-3 - {4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxy-2-methylpropyl} -6-(methylsulphonyl)- lH-indole-3-carboxamide V6 H o Prepared as described in Example 189 following Preparation 10 using 6- (methylsulphonyl)-lif-indole-3-carboxyiic acid MS (APCI) 520/522/524 (M+H)+ ^ *H NMR 8 (CD3OD) 8.35 (IH, d), 8.19 (IH, s), 8.07 (IH, d), 7.69 (1H, dd), 7.11 (IH, d), 7.08 (IH, dd), 6.88 (IH, d), 4.56-4.48 (IH, m), 4.20-4.12 (IH, m), 3.57 (IH, dd), 10 3.43 (IH, dd), 3.19-3.12 (5H, s), 3.03-2.98 (2H, m), 2.94 (IH, dd), 2.85 (IH, m), 2.18 (3h, s), 2.16-2.08 (2H, m), 2.03-1.94 (2H, m).

Example 208 N- { (2R)-3 - { 4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-15 (methylsulphonyl)-liy-indole-3-carboxamide o ^ Prepared as described in Example 189 following Preparation 8 using 6- (methylsulphonyl)-liWndole-3-carboxylic acid.

MS (APCI) 540/542/544 (M+H)+ .

XU NMR 5 (CD3OD) 8.35 (IH, d), 8.34 (IH, s), 8.06 (IH, d), 7.69 (IH, dd), 7.38 (IH, d), 7.09 (IH, d), 6.87 (IH, dd), 4.50-4.43 (IH, m), 4.12-4.06 (IH, m), 3.57 (IH, dd), 3.41 (IH, dd), 3.13 (3H, s), 3.07-2.99 (2H, m), 2.81-2.68 (4H, m), 2.12-2.04 (2H, m), 1.94-1.82 (2H,m).

PCT/SIw00258 132 Example 209 N-{ (2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -7-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-caiboxamide Prepared as described in Example 189 following Preparation 7 using 7-fluoro-l - oxo-1 ;2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 508/510 (M+H)+ lR NMR 8 (DMSO) 11.73 (IH, s), 8.39-8.26 (2H, m), 7.88 (IH, dd), 7.64 (IH, td), 7.54 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.79-4.71 (IH, m), 4.48-4.38 (IH, 10 m), 3.85-3.75 (IH, m), 3.46-3.34 (IH, m), 3.19-3.09 (IH, m), 2.82-2.65 (2H, m), 2.43-2.23 (4H, m), 1.97-1.84 (2H, m), 1.67-1.53 (2H, m).

Example 210 iV-{(ZR)-3-[4-(4-Chloro-2-methyiphenoxy)piperidin-l-yl]-2-hydroxyprop)d}-7-15 fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide ' Prepared as described in Example 189 following Preparation 10 using 7-fluoro-1- oxo-1,2-dih.ydroisoquinoline-4-carboxylic acid.

MS (APCI) 488 (M+H)+ W JH NMR 8 (DMSO) 8.42-8.28 (2H, m), 7.88 (IH, dd), 7.64 (IH, td), 7.55 (IH, s), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.43-4.33 (IH, m), 3.85-3.75 (IH, m), 3.45-3.34 (IH, m), 3.20-3.08 (IH, m), 2.75-2.60 (2H, m), 2.42-2.25 (4H, m), 2.14 (3H, s), 1.94-1.81 (2H,m), 1.70-1.56 (2H,m).

WO. J68743 133 Example 211 N- { (2R)-3 -[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl }-6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide Prepared as described in Example 189 following Preparation 10 using 6- (methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid. | MS (APCI) 548 (M+H)+ jH NMR 8 (DMSO) 11.98 (IH, s), 8.89 (1H, d), 8.44 (IH, d), 8.42 (1H, t), 8.01 (IH, dd), 7.76-7.72 (IH, m), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.77 (IH, d), 4.43-10 4.34 (IH, m), 3.86-3.77 (IH, m), 3.42 (IH, td), 3.28 (3H, s), 3.17 (IH, quintet), 2.77-2.63 (2H, m), 2.42-2.29 (4H, m), 2.14 (3H, s), 1.95-1.84 (2H, m), 1.71-1.58 (2H, m).

Example 212 N- { (2i?)- 3 -[4-(2,4-Dichloro-3 -methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl} -6-15 (methylsulfonyl)-l -oxo-1,2-dihydroisoquinoline-4-carboxamide . ' aa°ox Prepared as described in Example 189 following Preparation 13 using 6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 581/583 (M+H)+ 'H NMR 8 (DMSO) 11.97 (IH, d), 8.89 (IH, d), 8.44 (IH, d), 8.42 (IH, t), 8.01 (IH, dd), 7.76-7.72 (IH, m), 7.35 (IH, d), 7.10 (IH, d), 4.80-4.73 (IH, m), 4.53-4.44 (IH, m), 3.86-3.76 (IH, m), 3.42 (IH, td), 3.28 (3H, s), 3.21-3.12 (IH, m), 2.79-2.65 (2H, m), 2.40 (3H, s), 2.42-2.30 (4H, m), 1.95-1.85 (2H, m), 1.74-1.61 (2H, m).

PCT/SE. 00258 134 Example 213 iV-{ (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-7-(methylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt CK CI Prepared as described in Example 189 following Preparation 7 using 7- (methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid MS (APCI) 568/566 (M+H)+ lH NMR 5 (DMSO) 8.70 (1H, s), 8.46 (1H, d), 8.16 (1H, dd), 8.10 (IH, t), 7.70 (IH, s), 7.45 (IH, d), 7.18 (IH, d), 6.94 (IH, dd), 4.39 (IH, septet), 3.82 (1H, quintet), 3.42 10 (IH, dt), 3.30-3.09 (IH, m), 3.22 (3H, s), 2.82-2.67 (2H, m), 2.45-2.27 (4H, m), 1.99-1.80 (2H,m), 1.89 (3H, s, OAc), 1.72-1.53 (2H,m).

Example 214 iV-{(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-15 (methylsiilfonyl)-l-oxo-l,2-diliydroisoquinoline-4-carboxamidfi acetate salt • ■ O O Prepared as described in Example 189 following Preparation 10 using 7-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 548/550 (M+H)+ JH NMR 5 (DMSO) 8.68 (IH, d), 8.48 (IH, d), 8.43 (IH, t), 8.20 (IH, dd), 7.76 (IH, s), 7.21 (IH, d), 7.15 (IH, dd), 6.98 (IH, d), 4.84-4.72 (IH, m), 4.46-4.31 (IH, m), 3.88-3.74 (IH, m), 3.49-3.34 (IH, m), 3.28 (3H, s), 3.22-3.08 (IH, m), 2.78-2.60 (2H, m), 2.44-2.24 (4^ m), 2.14 (3H, s), 1.98-1.79 (2H, m), 1.74-1.54 (2H, m).

WO J68743 135 Example 215 N-{(2i?)-3-[4-(2,4-DicMoro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt .Prepared as described in Example 189 following Preparation 13 using 7- (methylsulfonyl)-l -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 582/584 (M+H)+ * 'H NMR 6 (DMSO) 8.68 (1H, d), 8.47 (IH, d), 8.44 (IH, t), 8.20 (IH, dd), 7.76 (IH, s), 7.35 (IH, d), 7.10 (IH, d), 4.53-4.44 (IH, m), 3.81 (IH, quintet), 3.42 (IH, dt), 10 3.20-3.09 (IH, m), 2.77-2.65 (2H, m), 2.40 (3H, s), 2.39-2.28 (4H, m), 1.95-1.85 (2H, m), 1.87 (3H, s, OAc), 1.73-1.61 (2H, m).

Example 216 N- { (2R)-3 -[4-(3,4-Dichloroplxenoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-15 (methylsulfonyl)-1 -oxo-1 ^-dihydroisoquinoline-4-carboxamide W Prepared as described in Example 189 following Preparation 7 using 6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (ESI) 568/570 (M+H)+ Example 217 N- {(2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide PCT/SEo^/00258 136 Prepared as described in Example 189 following Preparation 7 using 6-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylicacid.

MS (APCI) 508/510 (M+H)+ JH NMR 5 (DMSO) 11.70 (1H, d), 8.34 (1H, t), 8.28 (IH, dd), 8.03 (1H, dd), 7.64 5 (IH, d), 7.49 (IH, d), 7.38 (1H, td), 7.25 (IH, d), 6.98 (IH, dd), 4.80-4.70 (IH, m), 4.44 (IH, septet), 3.87-3.73 (IH, m), 3.45-3.36 (IH, m), 3.14 (IH, quintet), 2.84-2.66 (2H, m), 2.43-2.21 (4H,m), 1.99-1.84 (2H,m),1.69-1.51 (2H,m).

Example 218 ^10 7\T-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6- fluoro-l-oxo-l,2-dibydroisoquinoline-4-carboxamide Prepared as described in Example 189 following Preparation 10 using 6-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.

MS (ESI) 488/490 (M+Hf Example 219 N- { (2i?)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5 -carboxamide YS ?»» jfr° o cf3 Prepared as described in Example 35 following Preparation 10 using 2-oxo-4-(trifluoromethyl)-l52-dihydropyrimidine-5-carbonyl chloride.

MS (ESI) 489/491 (M+H)+ WO ;68743 137 Example 220 //-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4-(trifluoromethyl)-l,2-dihydropyrinMdine-5-carboxamide ° H oh u ( cr o cf3 Prepared as described in Example 35 following Preparation 13 using 2-oxo-4-(trifluoromethyl)-1 ,2-dihydropyrimidine-5-carbonyl chloride.

MS (ESI) 523/525 (M+H)+ Example 221 N-((2R)-3 - { 4-[3,4-Dichloro-2-(methylsulfonyl)phenoxy]piperidin-1 -yl} -2- hydroxypropyl)-l-oxo-l,2-dihydroisoquinoline-4-caiboxamide acetate Prepared as described in Example 35 following Preparation 48 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride. - MS (APCI) 568/570 (M+H)+ NMR 8 (CD3OD) 8.35 (IH, d), 8.18 (IH, d), 7.78 (IH, t), 7.76 (IH, d), 7.58 (IH, s), 7.57 (IH, t), 7.28 (IH, d), 4.87-4.80 (IH, m), 4.13-4.07 (IH, m), 3.54 (IH, dd), 3.40 (IH, dd), 3.35 (3H, s), 3.16-3.06 (2H, m), 2.85-2.69 (4H, m), 2.16-2.00 (4H, m), 1.94 (3H, s).

Example 222 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide acetate salt o ' cf3 Prepared as described in Example 35 following Preparation 7 using 6-oxo-4- (trifluoromethyl)-l,6-dihydropyridine-3-carbonyl chloride, which was prepared by PCT/SEw.00258 138 hydrolysis with sodium hydroxide followed by treatment with thionyl chloride of the commercially available 6-chloro-4-trifluoromethyI methyl nicotinoate).

. MS (APCI) 508/510 (M+H)+ *HNMR8 (DMSO) 8.35 (IH, t), 7.77 (1H, s), 7.49 (IH, d), 125 (IH, d), 6.98 (1H, 5 dd), 6.72 (IH, s), 4.43 (1H, septet), 3.71 (1H, quintet), 3.29 (1H, dt), 3.06 (1H, dt), 2.78 -2.66 (2H, m), 2.36-2.24 (4H, m), 1.95-1.86 (2H, m), 1.90 (3H, s), 1.65-1.54 (2H, m).

Example 223 N- { (2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl}-6-10 oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxaimde acetate salt °y~s| oh h o cfs Prepared as described in Example 35 following Preparation 10 using 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-caibonyl chloride.

MS (APCI) 488/490 (M+H)+ JH NMR 8 (DMSO) 8.35 (IH, t), 7.77 (1H, s), 7.20 (1H, s), 7.15 (1H, dd), 6.98 (IH, d), 6.73 (IH, s), 4.42 - 4.34 (IH, m), 3.72 (IH, quintet), 3.33 - 3.27 (IH, m), 3.06 (IH, dt), 2.71 - 2.61 (2H, m), 2.37 - 2.25 (4H, m), 2.14 (3H, s), 1.93-1.84 (2H, m), 1.91 . (3H, s), 1.69 - 1.58 (2H, m).

Example 224 N- { (2R)-3-[4-(2,4-Dichloro-3 -methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide a H N i,0 r^i ?H H if Y CI' o cf, Prepared as described in Example 35 following Preparation 13 using 6-oxo-4-25 (trifluoromethyl)-l,6-dihydropyridine-3-caibonyl chloride.

MS (APCI) 522/524 (M+H)+ ' WO 368743 PCT7SE03/00258 139 JH NMR 8 (DMSO) 8.32 (IH, t), 7.79 (IH, s), 7.35 (IH, d), 7.10 (IH, d), 6.69 (IH, s), 4.49 (IH, septet), 3.72 (IH, quintet), 3.30 (IH, dt), 3.07 (IH, dt), 2.74 - 2.64 (2H, m), 2.40 (3H, s), 2.37 - 2.25 (4H, m), 1.94 - 1.84 (2H, m), 1.89 (3H, s), 1.71 - 1.61 (2H, m).

Example 225 N- {(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-2-(2-oxoquinoxalin-1 (2H)-yl)acetamide °0^N Prepared as described in Example 1 following Preparation 7 using (2-10 oxoquinoxalin-1 -(2#)-yl)acetic acid.

MS (APCI) 505/507 (M+H)+ JH NMR 8 (CPC13) 8.37 (IH, s), 7.92 (IH, d), 7.61 (IH, t), 7.49 (IH, d), 7.40 (IH, t), 7.32 (IH, d), 6.99 (IH, d), 6.74 (IH, dd), 6.72 (IH, bd s), 4.91 (2H, m), 4.36-4.26 (1H, m), 3.86-3.76 (IH, m), 3.52-3.42 (IH, m), 3.26-3.18 (IH, m), 2.88-2.80 (IH, m), 2.63-15 2.53 (2H,m), 2.40-2.26 (3H, m), 2.06-1.92 (2H,m), 1.87-1.73 (2H,m).

Example 226 //-{(2i?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-3d]-2-hydroxypropyl}-3-oxo-3,4-| dihydroquinoxaline-1 (2fl)-caiboxamide o oH h p Hh C.^ o Prepared as described in Example 35 following Preparation 7 using 3-oxo-3,4-dihydroquinoxaline-l(2H)-carbon3d chloride.

. MS (APCI) 505/507 (M+H)+ !H NMR 8 (CDCI3) 8.26 (IH, s), 7.43 (IH, d), 7.31 (IH, d), 7.19-7.09 (IH, m), 25 6.99 (IH, d), 6.94 (IH, d), 6.75 (IH, dd), 5.72 (IH, t), 4.44 (2H, s), 4.30-4.22 (IH, m), 3.88-3.81 (IH, m), 3.58-3.52 (IH, m), 3.17-3.11 (IH, m), 2.93-2.85 (IH, m), 2.67-2.61 (IH, m), 2.57-2.53 (IH, m), 2.44-2.40 (IH, m), 2.36-2.29 (2H, m), 2.00-1.90 (2H, m), 1.80-1.70 (2H, m).

PCT/SEo-, 00258 140 Example 227 N- { (2R)-3 - [4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3 -(trifluoromethyl)- li/-pyrazole-4-carboxamide cr — ° cf3 Prepared as described in Example 1 following Preparation 10 using 3- (trifluoromethyl)-li7-pyrazole-4-carboxylic acid MS (APCI) 460/462 (M+H)+ ' 'HNMRS (DMSO) 8.41 (IH, s), 8.15 (1H, t), 7.20 (1H, d), 7.14 (IH, dd), 6.98 (IH, d), 4.42-4.36 (IH, m), 3.77-3.71 (IH, m), 3.39-3.33 (IH, m), 3.10-3.04 (IH, m), 2.73-10 2.63 (2H, m), 2.36-2.26 (4H, m), 2.14 (3H, s), 1.92-1.82 (2H, m), 1.70-1.60 (2H, m).

Example 228 iV-{(2i?)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)- lif-pyrazole-4-carboxamide a- - XXXtly^" ° CFs Prepared as described in Example 1 following Preparation 13 using using 3-(trifluoromethyl)- l/T-pyrazole-4-carboxylic acid.

MS (APCI) 495/497 (M+H)+ !H NMR 8 (DMSO) 8.41 (IH, s), 8.15 (IH, t), 7.34 (IH, d), 7.09 (IH, dd), 4.50-20 4.42 (IH, m), 3.77-3.71 (IH, m), 3.37-3.33 (IH, m), 3.10-3.04 (IH, m), 2.74-2.64 (2H, m), 2.39 (3H, s), 2.36-2.26 (4H, m), 1.96-1.86 (2H, m), 1.69-1.62 (2H, m).

Example 229 N-{ (2R)-3-{ 4-(3,4-Dichlorophenoxy)piperidin-1 -yl }-2-hydroxypropyl}-1 -oxo-1,2-25 dihydro-2-methylisoquinoline-4-carboxamide WO v J68743 141 Prepared as described in Example 1 following Preparation 7 using 2-methyl-l-oxo-l,2-dihydroisoquinoIine-4-carboxylic acid.

MS (APCI) 504/506/508 (M+H)+ 'H NMR 8 (CDC13) 8.47 (1H, d), 8.14 (IH, d), 7.70 (1H, t), 7.61 (1H, s), 7.53 (1H, 5 t), 7.33 (IH, d), 7.00 (IH, d), 6.76 (1H, dd), 6.58 (1H, bd t), 4.42-4.32 (1H, m), 4.06-3.96 (IH, m), 3.80-3.70 (1H, m), 3.63 (3H, s), 3.44-3.34 (IH, m), 3.02-2.92 (1H, m), 2.78-2.68 (2H, m), 2.59- 2.45 (3H, m), 2.16-2.00 (2H, m), 1.96-1.80 (2H, m).

Example 230 110 N-{ (2R)-3-{ 4-(3,4-Dichloroplienoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-oxo-1,2- dihydro-l-methjdquinoline-4-carboxamide Prepared as described in Example 1 following Preparation 7 using 1 -methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid.

MS (APCI) m/z 504/506/508 (M+H)+ ^NMR 8 (CDCI3) 7.97 (IH, d), 7.62 (1H, t), 7.40 (IH, d), 7.32 (1H, d), 7.28 (IH, t), 7.00 (IH, d), 6.83 (1H, s), 6.76 (IH, dd), 6.72 (IH, t), 4.39-4.31 (IH, m), 4.04-3.94 (IH, m), 3.78-3.70 (IH, m), 3.72 (3H, s), 3.47-3.37 (IH, m), 3.00-2.90 (IH, m), 2.75-2.67 (2H, V m), 2.56-2.42 (3H, m), 2.10-1.94 (2H,m), 1.94-1.78 (2H, m).

Example 231 N- { (2J?)-3-[4-(3,4-dichloroplienoxy)piperidin-1 -yl]-2-hydroxypropyl}-8-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide 9H H cr- Prepared as described in Example 35 foEowing Preparation 7 using 8-fluoro-l-oxo- l,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 508/510 (M+H)+ PCT/SEo^/00258 142 Example 232 N- { (2i?)-3-[4-(4-chloro-2-methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl }-8-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxamide v Prepared as described in Example 35 following Preparation 10 using 8-fluoro-l - oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 488/490 (M+H)+ Example 233 iV-{(2/2)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4- (trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide °XfXlx« cr ^ o cf, Prepared as described in Example 35 following Preparation 7 using 2-oxo-4-(trifluoromethyl)-l,2-dihydropyrimidine-5-carbonyl chloride.

. MS (EPCI) 509/511 (M+H)+ Example 234 N- { (2i?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-methyl-2-oxo-l,2-dihydropyrimidine-5-carboxamide toXxxxj&f Prepared as described in Example 35 following Preparation 7 using 4-methyl-2-oxo-1 ^-dihydropyrimidine-5-carbonyl chloride.

MS (EPCI) 455/457 (M+H)+ WO >68743 w 143 Example 235 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 (5xl06 ml"1) and loaded with 5|iM FLUO-3/AM + Pluronic F127 2J2jxl/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118mM, MgS04 0.8mM; glucose 5.5mM, Na2C03 8.5mM, KC15mM, HEPES 20mM, CaCl2 1.8mM, BSA 0.1%, pH 7.4) for one hour at room temperature. Alter loading, cells were centrifuged at | 0 200g for 5min and resuspended in LKS at 2.5x106 ml*1. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5pM fibronectin for twoh) at 25jil/well. The plate was centrifuged at 200g for 5min and the cells were washed twice with LKS (200yl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to a final 15 concentration of 0.1 %(v/v) DMSO. Assays were initiated by the addition of an A50 concentration of eotaxin and the transient increase in fluo-3 fluorescence (Iex = 490nm and lan = 520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.). .

Compounds of the Examples were found to be antagonists if the increase in 20 fluorescence induced by eotaxin (a selective CCR3 agonist) was inhibited in a concentration dependent manner. The concentration of antagonist required to inhibit the fluorescence by 50% can be used to determine the ic50 for the antagonist at the CCR3 receptor.

Example 236 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 10x106 ml"1 in RPMI containing 200 KJ/ml penicillin, 200 jxg/ml 30 streptomycin sulfate and supplemented with 10% HEFCS, at room temperature.

Eosinophils (700 jil) were pre-incubated for 15 mins at 37° C with 7 p.1 of either vehicle or compound (lOOx required final concentration in 10% DMSO). The chemotaxis PCT/SEw/00258 • 144 plate (ChemoTx, 3p.ni pore, Neuroprobe) was loaded by adding 28jil of a concentration of eotaxin 0.1 to 1 OOnM (a selective CCR3 agonist over this concentration range) 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 |il of eosinophil 5 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% CO2 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 . ^10 through the filter were pelleted by centrifugation (300xg 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 jj.1 of PBS containing 0.5% Triton xl 00 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 15 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 eotaxin mediated human eosinophil chemotaxis if the concentration response to eotaxin was shifted to the right of the control curve. Measuring the concentration of eotaxin required to give 50% 20 . chemotaxis in the presence or absence of. compounds enables the apparent affinity of the compounds at CCR3 to be calculated, or the assay can be used to determine activity of compounds at a set concentration of compound against a predifined concentration of eotaxin.

Example % inhibition at 3nM eotaxin (luM compound) 106 "17 103 45 102 46 105 47 104 52 95 WOt J68743 145 53 105 58 104 132 101 186 104 192 103 197 103 206 99 212 103 215 103 227 103 Example 237 Guinea-pig isolated trachea (See for example, Harrison, R.W.S., Carswell, H. & Young, J.M. (1984) European 5 J. Pharmacol., 106,405-409.) Male albino Dunkin-Hartley guinea-pigs (250g) 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 20ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 10 117.6, NaH2P04 0.9, NaHC03 25.0, MgS04 1.2, KQ 5.4, CaCl2 2.6 and glucose 11.1. The I buffer was maintained at 37°C and gassed with 5% CO2 in oxygen. Indomethacin (2.8p.M) 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 15 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 20 achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 logio unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added PCT/SEo..,00258 146 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[Aso] values) of histamine in the absence and presence of the test compound. Affinity (pA2) values of test compounds were subsequently calculated using the following equation: log(r-l) = logflB] + pA2 where r = [A]so in presence of test compound/[A]so in absence of antagonist and [B] is the concentration of test compound. Compounds of Ihe Examples were found to be HI antagonists.

Example 238 .

Histamine HI receptor binding activity of compounds of the invention was assessed by competition displacement of InM [3H]-pyrilamine (Amersham, Bucks, Product code TRK 608, specific activity 30Ci/mmol) to 2|xg membranes prepared from recombinant CHO-Kl cells expressing the human HI receptor (Euroscreen SA, Brussels, Belgium, product code ES-390-M) in assay buffer (50mM Tris pH 7.4- containing 2mM 20 MgCl2,250mM sucrose and lOOmM NaCl) for 1 hour at room temperature.

Example HI pKi /[1328_S] 8.4 17 8.1 45 7.7 46 8.2 47 8.1 52 8.4 53 8.1 58 7.2 132 6.6 186 7.9 WO v J68743 147 192 8.7 197 6.8 206 6.6 212 7.8 215 7.3 227 7.6 148

Claims (7)

WHAT WE CLAIM IS:

1. A process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising the steps of: a) reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room temperature; and, b) heating the mixture so produced and 1,2-dichloro-4-fluorobenzene at a temperature in the range 50-90°C, or at reflux of the solvent used.

2. A process as claimed in claim 1 wherein the suitable base is an alkali metal Cmo alkoxide

3. A process as claimed in claim 2 wherein the alkali metal is sodium or potassium.

4. A process as claimed in claim 2 or 3 wherein the suitable base is an alkali metal C4-10 tertiary alkoxide.

; 5. A process as claimed in any one of claims 1,2, 3 or 4 wherein the suitable base is potassium terf-butoxide or potassium 3,7-dimethyl-3-octanoxide.

6. A process as claimed in any preceding claim wherein the solvent is an ether, an aromatic solvent or a mixture of these solvents.

7. A process according to claim 1, substantially as herein described or exemplified. Intellectual Property Office of N.Z. 13 dec 2005 RECEIVED ASTRAZENECA AB By Their Attorneys HES