UA80268C2 - Piperidine derivatives, process for the preparation thereof, pharmaceutical composition based thereon and method for treatment chemokine mediated disease - Google Patents

Abstract

The invention provides compounds of formula (I): (I) wherein: X is CH2, O, S(O)2 or NR10; Y is a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHCOR33), CH(NHSO2R34), CH2O or CH2S; Z is C(O), or when Y is a bond Z can also be S(O)2; R1 is optionally substituted aryl, optionally substituted heterocyclyl or C4-6cycloalkyl fused to a benzene ring; and R2, R3, R4, R5, R6, R7 and R8, R9, R10, R32, R33, R34 and R35 are as defined herein; are modulators of chemokine (especially CCR3) activity (for use in, for example, treating asthma). The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.

Description

Description of the invention

The present invention relates to piperidine derivatives having pharmaceutical activity, methods of obtaining such derivatives, pharmaceutical compositions containing such derivatives and the use of such derivatives as active therapeutic agents. The invention also provides a method for obtaining 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for obtaining some compounds of the invention.

Pharmaceutically active derivatives of piperidine have been disclosed (in UHO 01/62728, MO 01/62729 and MO 01/62757).

Chemokines are chemotactic cytokines released by many cells to attract macrophages, 70 T cells, eosinophils, basophils, and neutrophils to sites of inflammation, and play a role in immune system cell maturation. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14kDa proteins characterized by four conserved cysteine functional sequences. The chemokine superfamily can be divided 72 into two main groups showing characteristic structural and functional sequences, the Suv-X-Suv (C-X-C, or A) and Suz-Suv (C-C, or B) families. These were discovered based on a single amino acid insertion between

MH-proximal pair of cysteine residues and sequence similarity.

C-X-C chemokines attract several powerful chemoattractants and neutrophil activators, such as interleukin-8 (I-8) and neutrophil-activating peptide 2 (MAP-2).

C-C chemokines attract powerful chemoattractants of monocytes and lymphocytes, but not neutrophils, such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), KAMTE5 (Regulated on Activation,

Normally T-Expressed and Secreted), eotaxins and macrophage inflammatory proteins and and 18 (MIR-1A and MIR-18B).

Studies have shown that the action of chemokines is mediated by subfamilies of receptors coupled to (c-protein), among which there are receptors marked CSK1, CSK2, CSK2A, CSK2B, SSZ, SSKYA, SSK5, SS, SSK,

SSVV8, SSV9, SSV10, СШСВИ, СШСВ2, СШСВЗ and СШСВА. These receptors represent good targets for drug development (3) because agents that modulate these receptors could be useful in the treatment of the above disorders and diseases. Histamine is the basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine histidine -decarboxylase. It is found in most tissues of the body, but in high concentrations in the lungs, skin, and gastrointestinal tract. At the cellular level, inflammatory cells such as mast cells and basophils store large amounts of histamine. Degranulation of mast cells has been found to and basophils and subsequent Ge) release of histamine is a fundamental mechanism relevant for the clinical detection of an allergic process.

Histamine acts by influencing specific histamine receptors conjugated with (c-protein) of three main types, NO, H2 and

New Zealand Histamine NO antagonists comprise the largest class of drugs used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. NO antagonists are useful in controlling 3o allergic reactions, for example by blocking the action of histamine on the smooth muscle of the post-capillary veins, which leads to decreased vascular permeability, exudation, and edema. Antagonists also block the action of histamine at NO receptors on c-type nociceptive nerve fibers, resulting in reduced itching and sneezing.

Viral infections are known to cause inflammation of the lungs. It has been shown experimentally that the common cold "increases the production of mucous eotaxin in the respiratory tract." Nasal instillation of eotaxin can mimic some of the signs and symptoms of the common cold. Look, OShey |! her a). APegdu (1999) 54(11) 1204-8 Ehregitepia)! s sottop soIi ipsgease ti-soza! ociirii oi eoiahip ip iris ipaimidtsaiye (Experimental common cold

"Iz" increases mucosal eotaxin production in atopic individuals) and Kauladistpi Meii ai. p Agsp. AiPegdau Tttipoi. (2000). aiplau eriipeiia! seiyiv aypyeg migiv A iptesiop (Eotaxin expression by normal airway epithelial cells after viral A infection). со 45 The presented invention relates to the compound of formula (1): («c) schi ' On z myh voy В M--св2в3--- (СН steve ov EK со ! в й ()

F) name) 60 Where:

X represents CH", O, 5(0)" or MAO;

U represents connection, SN". MAZ5, СНоМН, СНоМНС(о), СН(ОН), СН(МНесова), сн(МНи(0)»8, СН» or сНноз; 7 represents C(O), or when U represents a bond, 7 may also be 5(O)"; 65 B" represents optionally substituted aryl, optionally substituted heterocyclyl or C 4 6 cycloalkyl fused to a benzene ring;

B" represents hydrogen, C. alkyl (as an option, substituted by C 3 -cycloalkyl) or C 3 -cycloalkyl; 22, 23, ve", 25, B and Z represent, independently, hydrogen, C 3 -alkyl or C 3 -cycloalkyl; t and n are equal, regardless, 0 or 1;

VE? represents optionally substituted aryl or optionally substituted heterocyclyl; 29, 32 and KZZ represent, independently, hydrogen, C 1 -alkyl or C 3 -cycloalkyl;

BZ and KZ represent C. alkyl or C. 6-cycloalkyl; where the above-mentioned aryl and heterocyclyl, where possible, optionally substituted by the group: halogen, cyano, nitro, hydroxy, oxo, ?, (OMA, then MeE15(0)2825, С(ОМА?9В?, с(0ОВ?8, sov, MeZSOOV, S. valkyl (itself, alternatively, monosubstituted

MMO(O)phenyl), C. haloalkyl, C. valkoxy(C. c) alkyl, C. valkoxy, C. haloalkoxy,

Si valkoxy(C. and c) alkoxy, C. valkylthio group, Sovalkenyl, Sovalkynyl, C. zocycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C.-l) alkyl, phenoxy, phenylthio group, phenyl(C.- /) alkoxy, morpholinyl, /5 Heteroaryl, heteroaryl(C..4)alkyl, heteroaryloxy or heteroaryl(C.-)alkyl; wherein any of the above phenyl and heteroaryl is optionally substituted with halogen, hydroxy, nitro,

З(О)КСі lаlalkyl), З(ОО)2МН»о, 5(0)2МН(С..аlalkyl), 5(0)2М(С.4аlalkyl)», cyano, C.ialkyl, C-alkoxy , S(O)MN",

С(ОМН(С 4.dalkyl), СОН, СО5(Су dalkyl), МНС(ОХС:. dalkyl), МНЗ(О)4(С. dalkyl), ФХОХ(С. dalkyl), SEz;

K and r are equal, independently, to 0, 1 or 2;

ВЗ, В Вб, В ВВ, ВЗ ВО, В, т, З, В, Вб, Во, ВЗ and ЗО represent, independently, hydrogen, C-alkyl (optionally substituted with halogen, hydroxy or C 3-ocycloalkyl) , СНа(С». valkenyl),

C3.vcycloalkyl, phenyl (itself, as an option, substituted with halogen, hydroxy, nitro, MH 5, MH(C). dalalkyl),

MH(C. dalkylom)", Z(0)5(C4 lalkylom), Z(O)2MH", 5(0)2MH(C 4 dalkylom), Z(0)2M(C. lalkylom)", cyano, S.. lalkil,

Si dalkoxy, C(O)MH", C(O)MH(C. dalkylom), C(O)M(C. dalkylom)", SON, SOS. dalalkyl), MNO(OX(C. dalalkyl), sch dv MNZ(O)(Sialkylom),, C(OX(C.-dalalkyl),. CEz or ОСЕ5) or heterocyclyl (itself, alternatively, substituted by halogen, hydroxy , nitro, MH", MH(C.-alkyl), M(C. dalalkyl)", З(О0)5(С44С alkyl), З(О0)2МН", and)

C(0)2MH(Si alkyl), 5(0)2M(C.4 alkyl)»o, cyano, C. alkyl, Silalkoxy, C(O)MH»o, C(OMN(C. alkyl) ),

С(ОМ(С. dalkilom)», SON, СО(С. dalkilom), MНС(ОХС. dalkilom), МНЗ(О)5(С. lalkilom), С(ОЧС. dalkilom), SEz or ОСЕ»); alternatively MAE"ZV7Ya, MeV 16, Me29v21, MAe?2v23, MA29827, can independently form a 4-7-membered heterocyclic ring selected from the group: azetidine (itself optionally substituted with hydroxy or C.4 alkyl) .

B", 5, 28 and KZ! represent, independently, C 1. alkyl (optionally substituted by halogen, hydroxy or o

C. ocycloalkyl), CNa(Co-valkenyl), phenyl (itself, alternatively, substituted with halogen, hydroxy, nitro, MH 2, (ee)

MH(C.alkyl), M(Cialkyl)" (these alkyls can combine to form a ring, as described for VK "Z and B"! above), 5(О0)5(Silalkyl), З(О)2" МН»о, 5(0)2МН(C.i.alkyl), 5(О)2M(C4alkyl)» (these oalkyls can combine to form a ring, as described for K iz and B" above), cyano, С. lalkylom, C.-.alkoxy, "

С(О)МН,., СКО)МН(C in dalalkyl), С(О)М(С. dalalkyl)o (these alkyls can combine to form a ring, as - 70 described for K 3 and K"" above) . substituted by halogen, hydroxy, nitro, MH », ;» MH(C.alkyl), M(Cialkyl)» (these alkyls can combine to form a ring as described for VK "Z and B"! above), Z(O )5(C-alkyl), З(О)2МНо, 5(О)2МН(С-alkyl), З(О)2М(С-alkyl)" (these oalkyls can combine to form a ring, as described for BK 03 and B" above), cyano, C 1 alkyl, C 4 alkoxy. with (ee) ring formation as described for B 13 and B" above), cyano, silalkyl, silalkoxy, C(O)MH", o C(O)MH (C dalalkyl), C(O)M(C. dalalkyl)o (these alkyls can be combined to form a ring, as described for К ИЗ and Б"! above), СОН, СО4(Su dalalkyl), MHC(OX( Si by dalky), MNO(O)4(Si by lalky), C(OX(Si by dalky),

SEz or OS"); (e)) 50 provided that when X represents CH" and t and n are equal to 0, then U does not represent MA; or its M-oxide; CO or a pharmaceutically acceptable salt, solvate or solvate salt thereof.

Certain compounds of the present invention may exist in distinct isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention relates to all such isomers and their mixtures in all proportions.

Suitable salts include acid addition salts such as hydrochloride, dihydrochloride, hydrobromide, phosphate, (F)sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. from the Compound of the invention can exist as solvates (as in hydrates) and the presented invention applies to all such solvates. Halogen includes fluorine, chlorine, bromine and iodine.

Alkyls are represented by a linear or branched chain such as, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Alkyls preferably contain 1-6 carbon atoms.

Alkenyl is, for example, vinyl or allyl. Alkenyls preferably contain 2-6 carbon atoms.

Alkynyl is, for example, propargyl. Alkynyls preferably contain 2-6 carbon atoms. b Cycloalkyl is monocyclic such as cyclopropyl, cyclopentyl or cyclohexyl. Cycloalkyls preferably contain 3-6 carbon atoms.

A cycloalkyl fused to a benzene ring is, for example, dicycloi|4,2,F|octa-1,3,5-trienyl. Aryl is preferably phenyl or naphthyl.

The heterocyclyl is an aromatic or non-aromatic 5- or 6-membered ring optionally fused with

One or more other rings containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; or its M-oxide, Z-oxide or 5Z-dioxide. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, 1,6-dihydropyridinyl (eg in b-oxo -1,6-dihydropyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo|rBIfuryl (also known as 7/0 benzfuryl), benzo(p|hyenyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenzi (p|hyenyl (for example in 1,1-dioxo-2,3-dihydrobenz|p|hyenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2-dihydrobenzthiazolyl (for example in 1H-benzthiazol-2-onyl) , 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl, imidazopyridinyl (like imidazo|1,2-a|pyridinyl), thieno|Z,2 -β|pyridin-b6-yl, 1,2,3-benzoxadiazolyl (also known as benzo|1,2,3|hiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3- benzoxadiazolyl), quinoxalinyl, 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), pyrazolopyridine (e.g.

C,7-dihydro-purine-2,6-dione-8-yl), quinolinyl, isoquinolinyl, 1,2-dihydroisoquinolinyl (eg in 2H-isoquinolin-1-onyl (alternatively called 1-oxo-1,2 -dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-1-one)), naphthyridinyl (for example P,b|Inaphthyridinyl or P,8Inaphthyridinyl), 1,4-dihydro|1,8)naphthyridinyl (for example in 1H-P 8|Inaphthyridin- 4-onyl), or benzothiazinyl, 4H-benzo|1,4)thiazolyl (for example, in 4H-benzo|1,4)hyazin-3-onyl)x or its M-oxide (such as pyridine M-oxide), or its 3-oxide or 5-dioxide. 1,2-dihydropyridinyl (alternative numbering in 1,6-dihydropyridinyl) may also be present in 2-oxo-1,2-dihydropyridinyl; and 2,3-dihydro-1H-indazolyl can also be present in the

C-oxo-2,3-dihydro-1H-indazolyls.

Heterocyclyl also includes cinolinyl, phthalazinyl, 3,4-dihydrophthalazinyl (eg in and) 4-oxo-3,4-dihydrophthalazinyl), benzoxazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl (eg in 3-oxo- 2,3-dihydro-4H-1,4-benzoxazinyl), 3,4-dihydro-2H-1,4-benzoxazinyl (for example, in 3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl), isoindolyl, 1,3-dihydro-2H-isoindolyl (e.g. U o z o 1,3-dioxo-1,3-dihydro-2H-isoindolyl), pyrazolotriazinyl (e.g. pyrazolo|5,1-si(1,2,griazinyl) , pyrazinyl, pyridazinyl, 9H-purinyl, pyrazolopyrimidinyl (eg pyrazolo|1,5-a|pyrimidinyl), ise) imidazobenzothiazolyl (eg imidazo|2,1-51(/1,3|benzothiazolyl), 1,2,5- oxadiazolyl, imidazopyrimidinyl c (eg imidazo|1,2-a|pyrimidinyl), quinolinyl, 1,2-dihydroquinolinyl (eg in 2-oxo-1,2-dihydroquinolinyl) or 2,1,3-benzoxadiazolyl (eg as 1 -oxide); or may additionally be its M-oxide, 5-oxide or 5-dioxide. The following examples of heterocyclyl are 1,3-benzothiazole, so 2,3-dihydro-1,3-ben Zothiazole (for example in /2-oxo-2,3-dihydro-1,3-benzothiazole), 4,5,6,7-tetrahydroindazole; 2,3-dihydro-1H-benzimidazole (eg in 2-oxo-2,3-dihydro-1H-benzimidazole) and 1,4-dihydroquinoline (eg in 4-oxo-and 4-dihydroquinoline).

The M-oxide of the compound of formula (I) or (Ia) is, for example, a 1-oxy-piperidinyl compound. "

A heteroaryl is an aromatic heterocyclyl. It is, for example, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzo|p|furyl, benz|(b)hyenyl, indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl , benzthiazolyl, 1,2,3-benzothiadiazolyl, imidazopyridinyl, ; t thieno|Z,2-b|pyridin-b-yl 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan, quinoxalinyl, pyrazolopyridine, purine, quinolinyl, isoquinolinyl, naphthyridinyl, benzothiazinyl, cinolinyl, phthalazinyl, benzoxazinyl, isoindolyl, pyrazolotriazinyl, pyrazinyl, pyridazinyl, pyrazolopyrimidinyl,

Go! imidazobenzothiazolyl, imidazopyrimidinyl, quinolinyl or 2,1,3-benzoxadiazolyl; or its M-oxide (such as pyridine M-oxide), Z-oxide or 5-dioxide. o Haloalkyl is an alkyl that carries one or more (somewhat 1-6) halogen atoms and represents, for example, CO. Alkoxyalkyl represents, for example, CH zОСНо, СНУСНоОСсСН. or SNUSnNoF(СН»)». Haloalkyloxy represents an alkoxy group bearing one or more (such as 1-6) halogen atoms and represents, for example,

Me. OS". Alkoxyalkoxy represents, for example, CH ZOSNO, СНуУСНоОСНоО or СНУСНод(СНО)»О. Phenylalkyl c represents, for example, benzyl, phenyleth-1-yl or phenyleth-2-yl. Phenylalkoxy represents, for example, benzyloxyl. Heteroarylalkyl represents, for example, pyridinylmethyl or pyrimidinylmethyl. Heteroaryloxy is, for example, pyridinyloxy or pyrimidinyloxy. Heteroarylmethoxy represents, for example, pyridinylmethoxy or pyrimidinylmethoxy.

According to one aspect of the present invention, a compound of formula (I) is proposed where: X represents iF) CH», 0, 5(0)5 or ME'9; U represents a bond, СН5, MAZ5, СНОМН, СНМНС(о), сн(ОН), СН(МНесв), име) СН(МНУ(0)283У), СНоО or СНоВ; 7 represents C(O), or when Y represents a bond, 7 can also be

Z(O0); КЕ" represents optionally substituted aryl, optionally substituted heterocyclyl or C in cycloalkyl, because it is condensed with a benzene ring; c" represents hydrogen, C in alkyl (optionally substituted

C. cycloalkyl) or Ca cycloalkyl; K?, KU, EK", Vb, VK" and KU represent, independently, hydrogen, C 1 -alkyl or C 3 -cycloalkyl; t and n are independently equal to 0 or 1; vo represents optionally substituted aryl or, substituted , optionally heterocyclyl; 79, KZ2, KZZ and EZ5 represent, independently, hydrogen or C. alkyl; B 65 represents C. alkyl where the above aryl and heterocyclyl are optionally substituted by the group: halogen, cyano, nitro, hydroxy, oxo, (0.82, оОС(ОМе Св", MA ZVT MA С(ОВ'8, MAYАС(OME ОВ,

8(0), Mv?B, in 8(0)2875, C(O)MK?YAVYA!, c(0)B8, CO, MASOVU, C. valkyl, C. haloalkyl,

C. valkoxy(C. c)alkyl, C. valkoxy, C. vhalogenalkoxy, C. valkoxy(C. c)alkoxy, C. valkylthio group,

Co valkenyl, C»ovalquinyl, Czocycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C. /)alkyl, phenoxy, phenylthio group, phenyl(C.)alkyl, heteroaryl, heteroaryl(C.)alkyl, heteroaryloxy or heteroaryl(C 4.4) Alkoxyl; where any of the above phenyl and heteroaryl is optionally substituted with the following substituent: halogen, hydroxy, nitro, 5(O)(C.i dalalkyl), 5(0)2MH»o, cyano, C.alkyl, C- daloxy, C(O)MH",

C(OMN(C 4 dalkyl), SOHN, SOX(C..dalkyl), MHC(OHS. dalkyl), MNE(O)5(C. dalkyl), C(OHS. dalkyl), SEz or OSE";

K and r are equal, independently, to 0, 1 or 2; VZ, I, 5, Bb, in, B, in, o, B, in, Z, B in, to, 70 Vo vo and VZ! represent, independently, hydrogen, C 1-alkyl (as an option, substituted by halogen, hydroxy or C3 ocycloalkyl), CNa(Co.valkenyl), phenyl (itself, as an option, substituted by halogen, hydroxy, nitro, MH 5,

MN (S.. dalkilom),. МН(С. длякілом)», З(О0)5(Si длякілом), З(О)2МН», З(О)2МН(С. длякілом),. З(О)2М(С.4.lalkilom)", cyano, S..lalkilom, Si. lalkoxy, C(O)MH»o, O(O)MM(C. dalkylom), C(O)M(C. dalkylom)", СО2Н, СО4(C. dalkylom),

МНСесохс .alkyl),,і МНО(О)5(Si.lalkyl),і С(ОХС..аlalkyl), СЕ3 or ОСЕ5) or heterocyclyl (itself optionally substituted with halogen, hydroxy, nitro, МН», МН (S..lalkilom), M(S.i lalkilom)", 5(0)5(Si lalkilom),

З(0)2МНо, 5(О2МН(Si lalkyl), 5(0)2М(С.-alkyl)о, cyano, С.-alkyl, Silalkoxy, /С(О)МН»

С(ОМН(С 4 длякілом), С(ОМ(С. длякілом)", Сон, СОС. длякілом), MNesoХs. далкілом),

МНа(0)5(С.. lalkylom), С(О)(С. dalkylom), СЕз or ОСЕз); alternatively MAV, MAV 5, MA?oV?!, MA??dV,

Me 262, can independently form a 4-7-membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter, as an option, substituted with C ylalkyl on the distal nitrogen atom; B", K?5 and 28 represent, independently, C 1 -alkyl (optionally substituted by halogen, hydroxy or C 3 -cycloalkyl), CNa(Co.valkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, MN 5,

MH(C. dalalkyl), M(C..alalkyl)o (these alkyls can combine to form a ring, as described for p. 25. KZ and B" above), 5(0)5(C..alalkyl), 5(0 )2MH", 8(02MH(C 4 alkyl), 5(0)5M(C 4 alkyl)" (these alkyls can combine to form a ring, as described for B "C and E"" above), cyano, C. dalkylom, Si.4 alkoxy, C(O)MH",

C(OMN(C in alkyl), C(O)M(C. alkyl)o (these alkyls can be combined to form a ring, as described for K IZ and B"! above), SON, CO3(Ci alkyl), MHC (O)X(Si with dalkyl), MNO(O)5(Si with lalkyl), C(OX(Si with dalkyl),

СЕз or ОСЕ)") or heterocyclyl (itself optionally substituted with halogen, hydroxy, nitro, MH 5", MH(C. dalkyl), so

M(Ci dalalkyl)o (these alkyls can combine to form a ring as described for K 3 and B" above), "0

З(0)4(С, dalalkyl), З(О)2МН», З(0)2МН(С. dalalkyl), З(О)2М(С. dalalkyl)o (these alkyls can be combined with the formation of a ring, as described for В 3 and ВК" above), cyano, Sidalkylom, C.ylalkyloxy, C(O)MH",

C(O)MH(C dalalkyl), C(O)M(C. dalalkyl)o (these alkyls can combine to form a ring, as described for KZZ and B" above), SON, CO(Cu alkyl), MHC (OX(Sui alkyl), MNU(O)5(Si alkyl), C(OX Si alkyl), 00

SEz or OSE"); provided that when X represents CH" and t and n are equal to 0, then M does not represent MAZ5; or its M-oxide; or a pharmaceutically acceptable salt, solvate or salt solvate thereof.

According to another aspect of the present invention, a compound of formula (Ia): "-c" is proposed. and ;" their university sleeps 8

Кк M-с8253-А-(СОНк Se-А- (СК 5) ш--

Y. in o

Me (in) (in) name) b 50

IR f) where: X represents CH», O, 5(O)» or MAO; in! represents optionally substituted aryl or optionally substituted heterocyclyl; BC? represents hydrogen, C 4 alkyl (as an option, substituted C with 6 cycloalkyl) or

C. cycloalkyl; VK, KZ, KU, Kb, K" and KU represent, independently, hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; t and iF) n are independently equal to 0 or 1; o represents optionally substituted aryl or optionally substituted by ime) heterocyclyl; BO represents hydrogen or C 4.4 alkyl; where the above aryl and heterocyclyl, where possible, optionally substituted by the group: halogen, cyano, nitro, hydroxy, oxo, (0) 2, OS(OMA ZV, MA Zv 5, MA" s(OV 8, 60 Me'yas(OMe?OV, 5(0)5М823, МА8(0)282?, С(О)Me?9v?", Сс(0ОВ8, sov , MeZSOOV, Valkil village,

C. haloalkyl, C. valkoxy(C. c) alkyl, C. valkoxy, C. halogenalkoxy, C. valkoxy(C. c) alkoxy,

C 1 valkylthio, Sovalkenyl, C 1 valkynyl, C 3 -cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C 1 )alkyl, phenoxy, phenylthio, phenyl(C 1 )alkyl, heteroaryl, hetero aryl(C 1 )alkyl, heteroaryloxy or heteroaryl(Ci.)alkyl; where any of the above phenyl and heteroaryl is optionally substituted with any of the above phenyl and heteroaryl is optionally substituted with the following substituent: halogen, hydroxy, nitro, 5(O)(C.i dalalkyl), 5 (0)2MH»o, cyano, C.alkyl, C-daloxy, C(O)MH»

C(OMN(C 4 dalkyl), SOHN, SOX(C..dalkyl), MHC(OHS. dalkyl), MNE(O)5(C. dalkyl), C(OHS. dalkyl), SEz or OSE";

K and r are equal, independently, to 0, 1 or 2; ВЗ, ВЯ, в, Вб, вт, ВВ, вя, 820 в, в, в в ВВ Вот в до and В represent, independently, hydrogen, C -alkyl (optionally substituted by halogen, hydroxy or

C. docycloalkyl), СНо(Со valkenyl), phenyl (itself, alternatively, substituted by halogen, hydroxy, nitro, МН 5,

MN (S. dalkilom),. MH(C. alkyl), Z(O)5(C4.alkyl), Z(O)2MH", cyano, C. alkyl, C.ialkoxy, C(O)MH",

С(ОМН(С. dalkylom), СО2Н, СО(Су dalkylom), МНО(О)(С. dalkylom), МН(О)5(С. lalkylom), and С(ОХС. dalkylom),

CEz or OSE") or heterocyclyl (itself optionally substituted with halogen, hydroxy, nitro; MH 5", MH(C. dalalkyl), 10. MS. dalalkyl) », З(0)5(C. lalalkyl), З(0)2МН», З(О)2МН(С 4. lalkylom), Z(0)2М(С 4. lalkylom) 2, cyano,

Silalkyl, Silalkoxy, C(O)MN", C(OMN(S. dalalkyl), C(O)M(S. and lalalkyl)", SON, SOS. lalalkyl),

МНСесохс а лалкілом), МНО(О)5(Су lалкілом), С(ОХ(С. лалкілом), СЕз or ОСЕ»5); alternatively ME,

MeV, MAV?! MA??? Mer?" can independently form a 4-7-membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine, or 1,4-piperazine, the latter, as a variant, substituted with C. dalkyl on the distal atom nitrogen; K?, KE? and K?8 represent, independently, C. valkyl (as an option, substituted by halogen, hydroxy or C3.ocycloalkyl), СНо(C».valkenyl), phenyl (itself, as an option, substituted by halogen, hydroxy, nitro, MH", MH(C. alkyl), M(C. alkyl)" (these alkyls can combine to form a ring, as described for B C and B" above), 5(0)5(Silalkyl), 5(0)2"MH », 5(0)2MH(C 4.alkyl), 0), M(C.,alkyl)" (these alkyls can combine to form a ring, as described for Kk 13 and VK"! above), cyano, C. alkyl, Silalkoxy, C(O)MNo, C(O)MH(C. dalalkyl), C(O)M(Si dalalkyl)" (these alkyls can combine to form a ring, as described for Kk C and B" above) , SON, SO (S. dalkilom),

МНОТ (Охс, далкилом),. МНЗ(О)2(Si dalalkyl), С(ОХ(С 1 dalalkyl), СЕз or ОСРЕз) or heterocyclyl (itself, alternatively, substituted by halogen, hydroxy, nitro, MH», МН(C.-alalkyl), M (C-i-alkyl) (these alkyls can C combine to form a ring, as described for B 13 and B"? above), 5(0)5(Ci dalalkyl), 8(0)2MH", g)

C(0).MH(C. dalalkyl), 5(0)2M(C. dalalkyl)" (these alkyls can combine to form a ring as described for K 3 and K"" above), cyano, Si dalalkyl, Si dalkoxy, C(O)MH", C(OMN(C. dalalkyl), C(O)M(C dalalkyl)" (these alkyls can combine to form a ring, as described for K "C and K"? above), SON, SOZ (Si dalkilom), co

МНесохс with a dalalkyl), МНОЗ(О)4(С. lаlkyl), С(ОХ(С. dalalkyl), СЕз or ОСЕз); or its M-oxide; or its pharmaceutically acceptable In accordance with the next aspect of the presented invention, a compound is proposed, formula (I) where: X represents O; U represents a connection, CH 5, MAU, СНоМН, СН(ОН), СН(МНО(ОВУ) су

SNeSMNU(0)283) or SNO; 7 represents C(O), or when MU represents a bond, 7 may also be 5(0) 2; IN! represents optionally substituted phenyl; K 7 represents hydrogen or S. alkyl; K?, KZ, 5, K5, VK" and KU, when o is present, all represent hydrogen; t and n are independently equal to 0 or 1; Kk 9 represents a substituted, as (ee) variant, aryl or, substituted as variant, heterocyclyl; 22 and 35 independently represent hydrogen or

C, valkil; VZ and KZ? represent C 4 alkyl; where any of the above phenyl and heteroaryl is, when possible, optionally substituted with the following substituent: halogen, cyano, hydroxy, oxo, (0) in, MA 16, « zd MA'E(OvVYA, (OMA, Kv? B (0)2A, C(O)MAYEVYA, CO», C. alkyl (itself optionally monosubstituted (with 7s MMC(O)phenyl), CEz, OSE»z, phenyl or heteroaryl; where any of the above phenyl and heteroaryl, optionally substituted with the following substituent: halogen, C 1 alkyl, C 1 alkyl, or C ed; BZ, Bb, c", 8, c, c, c, "226 c" and B" represent, independently, hydrogen, C 44 alkyl (optionally substituted hydroxy) or

C. dicycloalkyl; alternatively, M22BZ can form an azetidine ring (itself optionally substituted with hydroxy or C dalalkyl); KE" and EK? represent, independently, C. alkyl or phenyl; or a pharmaceutically acceptable salt thereof. (ab) According to a further aspect, B! represents phenyl optionally substituted with (eg, one, two, or three) halogens ( especially fluorine or chlorine), cyano, C. alkyl (especially methyl), C. i. alkoxy (especially methoxy), C(O)5(Sialkyl), 5(0)2MH", 5(0)2MH(C ..lalkyl), 5(O)2MH(C3 cycloalkyl), (o) 50 C(O)5(Ci alkyl), C(O)MH(C. . alkyl) or C(O)MH". "co According to another aspect, B! is phenyl optionally substituted (eg with one, two or three) halogens (especially fluorine or chlorine), cyano, C 1-6 alkyl (especially methyl) or C 1-6 alkoxy (especially methoxy). the VC! aspect represents phenyl substituted with one, two or three fluorines,

Chlorine, methyl or cyano. According to another aspect, BE is phenyl substituted with one, two, or three fluorines, chlorines, and methyls. Therefore, in! represents, for example, 2-methyl-4-chlorophenyl,

3-methyl-2,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl. According to a further aspect where KE" represents 3,4-dichlorophenyl.

According to another aspect, X represents 0. 60 According to still another aspect, Y represents a bond.

According to another aspect, 72 represents C(O).

According to the following aspect, t is equal to 0.

According to a further aspect, n is equal to 0.

According to another aspect, both t and n are equal to 0. because According to another aspect, B" represents hydrogen or C. .dylalkyl (such as methyl). According to yet another aspect, b"

represents hydrogen.

According to yet another aspect, K2, KZ, B", 25, Kk", and KZ are all hydrogen; and according to a further aspect, n is 0 and K2, 23, 2?, and 22 are all hydrogen.

According to the following aspect, K2, BZ, B", B", 25, B" and EZ all, if present, represent hydrogen.

According to the further aspect of KE? represents mono- or disubstituted phenyl, unsubstituted heterocyclyl or mono- or disubstituted heterocyclyl, the substituents being selected from those described above.

According to another aspect B is optionally substituted heterocyclyl wherein heterocyclyl is: thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl, 1,6-dihydropyridinyl (e.g. in b -oxo-1,6-dihydropyridinyl or 2-oxo-1,2-dihydropyridinyl), pyrimidinyl, indolyl, indazolyl, 2,3-dihydro-1H-indazolyl (for example, in 3-oxo-2,3-dihydro-1H- indazolyl), imidazopyridinyl (such as imidazo|1,2-a|pyridinyl), 2,1,3-benzothiadiazolyl, quinoxalinyl, quinolinyl, 1,2-dihydroquinolinyl (for example in 2-oxo-1,2-dihydroquinolinyl), 1,4-dihydroquinoline (eg in 4-oxo-1,4-dihydroquinoline), isoquinolinyl, 1,2-dihydroisoquinolinyl (eg in 2H-isoquinolin-1-onyl (alternatively named / 1-oxo-1,2- dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-1-one)), cinolinyl,

3,4-dihydrophthalazinyl (for example in 4-oxo-3,4-dihydrophthalazinyl), 2,3-dihydro-4H-1,4-benzoxazinyl (for example in /3-oxo-2,3-dihydro-4H-1, 4-benzoxazinyl), 3,4-dihydro-2H-1,4-benzoxazinyl (for example in 3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl), 1,3-dihydro-2H-isoindolyl ( for example in 1,3-dioxo-1,3-dihydro-2H-isoindolyl), pyrazolotriazinyl (for example pyrazolo|5,1-si(1,2,griazinyl), pyrazolopyrimidinyl (for example pyrazolo|1,5-a|pyrimidinyl) , imidazobenzothiazolyl (eg imidazo|2,1-51(/1,3|benzothiazolyl), imidazo-pyrimidinyl (eg imidazo|1,2-a|pyrimidinyl), or 2,1,3-benzoxadiazolyl (eg as 1- oxide), 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole (for example in 2-oxo-2,3-dihydro-1,3-benzothiazole), 4,5,6,7-tetrahydroindazole or 2,3-dihydro-IN-benzimidazole (for example in 2-oxo-2,3-dihydro-1H-benzimidazolyl). c

In yet another aspect, is aryl (like phenyl) or heterocyclyl KE? unsubstituted or substituted by one or more of: (3 oxo (where possible), halogen, C.i.alkyl, CE3, C.alkoxy, C(O)4(C.4 alkyl), C(O)2MH", 5( 0)2МН(С . dalkilu), 5(О)2М(С..ldalkilu)» or ОСЕ».

According to a further aspect, when KZ is heterocyclyl, it is optionally substituted thienyl, co-quinolinyl, 1,2-dihydroquinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl, imidazo|1, 2-α|pyridinyl, isoquinolinyl or 1,2-dihydroisoquinolinyl; or 1,2-dihydropyridone, 1,6-dihydropyridone, pyrazolyl, pyrrolyl or indolyl. (Se)

In another aspect of E? represents phenyl or heterocyclyl (as defined elsewhere above), each of which is optionally substituted with halogen, hydroxy, nitro, cyano, oxo, amino, C 1-1 alkyl (most optionally substituted with 5(0) 5(C-alkyl) or 5(O)phenyl), Si-alkoxy, (OK? where K is equal to 0, 1 or 2 (mostly about 23y; and B" represents C.alkyl, C.lhydroxyalkyl, C./cycloalkyl( Si dalalkyl) (such as cyclopropylmethyl) or (ee) phenyl), С(О)МН», МНЗ(О)5(Су.dalkyl),,и 5(0)2МН», 5(О0)2МН(С ..alkyl) or 5(0)2M(C..alkyl)" (these alkyls can combine to form a ring as described for B. "C and KE" above). According to another aspect, 22 represents hydrogen. "

According to the following aspect of VZ, 71, 75, Vb, W, vv in B vv v v rt, v v v VU! represent, independently, hydrogen, C 1-4 alkyl (optionally substituted by halogen, cishydroxy or o) with C 3.locycloalkyl), СНо(Co valkenyl), phenyl (itself optionally substituted by halogen or C 4 alkyl) or » heterocyclyl ( itself, as an option, substituted with a halogen or C 4 dalalkyl); and B", B?? and 228 represent, independently, C..4alkyl (optionally substituted by halogen, hydroxy, nitro, MH 5, MH(C..alkyl), M(C..alalkyl)",

З(0)4(С4 C alkyl), 5(0)2МН», 5(0)2МН(C. dalalkyl),. Z(0)2M(C.4 lalkylom)", cyano, Si dalkylom, S. dalkoxy,

С(О)МНо, С(О)МН(С. Далкілом), С(О)М(Сідалкілом)», СОН, СО(С. Далкілом), МНеТс(СС. Si by far), C(OHSi by far); and K?, 22? and K?8 represent, independently, C 4 alkyl (as an option, (ab) substituted with halogen, hydroxy or C 3-ocycloalkyl), СНо(C 4 valkenyl), phenyl (itself, as an option, substituted by halogen or C. . . alkyl) or heterocyclyl (itself optionally substituted by halogen or C. . . alkyl).

According to a further aspect, B, I, 15, 15, 15, 23, 23, and ZO(o) represent, independently, hydrogen, C )alkyl (optionally substituted with halogen, hydroxy or "co C3.locycloalkyl), СНо(Co valkenyl), phenyl (itself optionally substituted by halogen or C.4alkyl) or heterocyclyl (itself optionally substituted by halogen or C. dalalkyl); and B", 25, B?8 and Short circuit! represent, independently, C 1 -alkyl (as an option, substituted by halogen, hydroxy or C with ocycloalkyl), СНа(C» valkenyl), or phenyl (itself, as an option, substituted by halogen or C 4.alkyl) or heterocyclyl (itself, as an option, replaced by halogen or C. .alkyl).

GF) In another aspect 3, Gezhna Vo, in B, 8, B, to, 27, 22, 2, in, ob. 2, 29 and zo represent, independently, hydrogen or S. lalkil; and B", 225, k28 and B! independently represent C alkyl (optionally substituted by hydroxy) or phenyl. According to the following aspect of B"? represents hydrogen. 6o According to another aspect of the short circuit? represents hydrogen or C. alkyl (like methyl); (for example, KZZ represents hydrogen).

In another aspect, KZ represents S. valkyl (somewhat methyl).

According to the next aspect, KE" represents C. alkyl (such as methyl). 65 According to a further aspect, the presented invention provides a compound of formula () or (Ia) where: c represents phenyl, as an option, substituted by 2 halogens (such as chlorine ); X represents O; t is equal to 0; n is equal

O or 1; 2? 23, c", 5, b, c" and 28 all represent hydrogen; and B? represents phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl imidazo|1,2-a)pyridinyl or 1,2-dihydroisoquinolinyl optionally substituted 5(0)5( Cl.alkylom) (for example 5(0)2CHaz), halogen (for example chlorine or fluorine), MM",

Sidalcoxy (somewhat OSN"), cyano or, where possible, oxo.

According to another aspect of the present invention, a compound of formula (I) or (Ia) is proposed where: B! represents phenyl optionally substituted with 1 or 2 halogens (such as chlorine), or 1 or 2 halogens (such as chlorine) and C 1 alkyl. (like methyl); X represents O; t is equal to 0; n is equal to 0 or 1; BK 2, KZ, Kk", KR and K9, and if present, B and 28 all represent hydrogen; and ee represents phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 70. 2,3-dihydro-1,3- benzothiazolyl, imidazo|1,2-α|pyridinyl, 1,2-dihydroisoquinolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl or pyrazolyl, all of which are optionally substituted with 5(O) 25(Ci.lalkyl) ( for example. 5(0)2СН»),

З(0)2МН», З(О)2МН(C 4.alkyl), 5(0)2М(Si alkyl)» (where two alkyls can combine together to form an azetidine ring), halogen (for example, chlorine or fluorine), MN ", Si. dalkilom (like SN"), Si. lalkoxi (somehow

OSNU"), CEz, cyano or, where possible, oxo.

According to another aspect of the present invention, a compound of formula (I) or (Ia) is proposed. where: In! represents phenyl optionally substituted with 1 or 2 halogens (such as chlorine) and optionally substituted with 0 or 1

S. valkylom (something like methyl); X represents O; t is equal to 0; n is equal to 0 or 1; VK 2, KZ, Kk", KZ and VK? and, when present, B and 28, all represent hydrogen; and ee represents phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3- benzothiazolyl, imidazo|1,2-α|pyridinyl, 1,2-dihydroisoquinolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl, pyrazolyl, pyrrolyl or indolyl, all of which are optionally substituted with 8(O) 5(C /"alkyl) (for example 5(0O)2SNU3), 5(O2MH", 5(O0)2MH(C..alkyl), 5(0)2M(C..alalkyl)), halogen (for example chlorine or fluorine), MN",

S. lalkoksi (somewhat OSN"), Si. alkyl (like methyl), CEz, OSE", cyano or, where possible, oxo.

According to another aspect of the present invention, a compound of formula (I) or (Ia) is proposed where: B! represents phenyl, as an option, substituted with 1 or 2 halogens (such as chlorine) and, as an option, substituted with 0 or 1 s 29 C. lalalkyl (such as methyl); X represents O; t is equal to 0; n is equal to 0 or 1; 2, KZ, 7, 5.5 v'tav?Z all O0) represent hydrogen; and oz represents phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl, imidazo|1,2-a|pyridinyl or 1,2-dihydroisoquinolinyl, all of which are optionally substituted 5(0)5(C1.lalkyl) (for example 5(0)2CH»z), halogen (for example chlorine or fluorine), MH», Si.lalkoxy (like so

OSNU"), S. dalkylom (something like methyl), SEz, OSE", cyano or, where possible, oxo.

According to another aspect of the present invention, a compound of the formula (I) or (Ia) is proposed, where KZ is) is isoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, quinolinyl, 2-oxo-1,2-dihydroquinolinyl, сч 2чжсо-1, 2-dihydropyridinyl, 6b-oxo-1,6-dihydropyridinyl or pyrazolyl; each, as an option, substituted with a halogen (such as fluorine), C.4 alkyl (such as methyl or ethyl), CE with, C.idalkoxy (such as methoxy), (ав) 5(0)5(С1. lalkylom) (for example 5(0)2SNaz), 5(0)2MH", 5(0)2MH(C i. dalkylom), 5(0)2M(C4.dalkylom)" or ОСЕ»z. co

According to another aspect of the present invention, a compound of formula (I) or (Ia) is proposed, where KZ represents isoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, quinolinyl or 2-oxo-1,2-dihydroquinolinyl; each, as an option, substituted with a halogen (such as fluorine), C 4.4 alkyl (such as methyl or ethyl), CE with, C.daloxy (such as methoxy), 5(0)5(C..alkyl) (for example 5(0)2СН») or ОСЕ». "

According to a further aspect of B? represents 1-oxo-1,2-dihydroisoquinolinyl, as an option, substituted with C halogen (such as fluorine), C 4 alkyl (such as methyl or ethyl), C 3 , C 4 -alkyl (such as methoxy), ц З(0)5(Su dalkylom) (for example З(0)2СН») or OS». Alternatively, zx represents "» 2-oxo-1,2-dihydroquinolinyl, optionally substituted with halogen (such as fluorine), C 4-4 alkyl (such as methyl or ethyl),

CE», Si.dalkoxy (such as methoxy), 5(0)5(C..alkylom) (for example 5(0)2CH») or OSE».

According to Kk! another aspect is oxo-substituted dihydropyridinyl (such as (ee) b-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyridin-5-yl or 2-oxo-1,2 -dihydropyridin-4-yl, o oxo-substituted dihydroisoquinolinyl (such as 1-oxo-1,2-dihydroisoquinolin-4-yl), oxo-substituted dihydrophthalazinyl (such as 4-oxo-3,4-dihydrophthalazine-1 -yl), pyrazinyl (such as pyrazin-4-yl), pyrrolyl (such as co pyrrol-3-yl) or indolyl (such as indol-3-yl), each of which is further unsubstituted or substituted by halogen (such as chlorine b 50 or fluorine), S.i.alkyl (such as methyl), C3 or C3 cycloalkyl (such as cyclopropyl).

According to the following aspect, KO represents oxo-substituted dihydropyridinyl (such as i42) b-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyridin-5-yl or 2-oxo-1, 2-dihydropyridin-4-yl)) oxo-substituted dihydroisoquinolinyl (such as /1-oxo-1,2-dihydroisoquinolinyl-4-yl) or pyrazinyl (such as pyrazin-4-yl), each of which is unsubstituted further or replaced by a halogen (such as chlorine or fluorine), C 4.alkyl 2o (such as methyl) or CEz.

Gee! An example of a compound of formula (I) or (Ia) is:

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide; where M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-(methylsulfonyl)benzamide; 2-chloro-N-(2K)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-(methylsulfonyl)benzamide; 60 4-amino-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-3-methoxybenzamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-(methylsulfonyl)benzamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-5-(methylsulfonyl)thiophene-2-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)quinoline-b6-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-6b-car 65 boxamide acetate;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b6-fluoroimidazo|1,2-a|pyridine-2-carboxam

ID,

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,3-benzothiazole-b6-carboxamide;

C-cyano-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide;

M-(4-14-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-2-(methylsulfonyl)benzamide;

M-(4-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-b6-carboxam

ID, 4-amino-N-4-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-3-methoxybenzamide; 70 M-(4-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxybutyl)-2-(methylsulfonyl)benzamide;

M-42k)-3-14-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl)|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide;

M-42k)-3-I(4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-k arboxamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-Kmethylamino)sulfonyl|bSenzamide; 3,5-bid(acetylamino)-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; 3-(Acetylamino)-M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide;

M-42k)-3-14-(3)34-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-pyrazole-4-carboxamide; 2-"(Acetylamino)-5-bromo-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl)-2-OKOO-1,2-dihydropyridine-3-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-5-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-quinolinine-4-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-4-carboxamide; 2--"Acetylamino)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; ch 2-"Acetylamino)-5-chloro-N-((2K)-3-I(4-(3)4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; 2-(Acetylamino)-4-chloro-N-(2K)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; i) 5-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-Kmethylsulfonyl)amino|Senzamide; 4-chloro-N-(2K)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-Kmethylsulfonyl)amino|benzamide; 2-Amino-4-chloro-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; 5-chloro-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-6-oxo-1,6-dihydropyridine-3-carboxamide; 2-"Aminosulfonyl)-1-chloro-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl)|-2-hydroxypropyl|benzamide; ise)

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indazole-3-carboxamide; c 1-tert-butyl-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-methyl-1H-pyrazole-5-carboxamide; at

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxa so

MED;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-"-trifluoromethyl)-1H-pyrazole-4-carboxamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-methylimidazo-11,2-a|Ipyridine-33-carboxamide; with c M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-(1H-pyrazol-3-yl)benzamide; . M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-yl)|-2-hydroxypropyl)ucinoline-4-carboxamide; and?" M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-hydroxyquinoline-4-carboxamide;

IM-(3-I4-(3,4-dichlorophenoxy)piperidin-1-yl)|-2-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carbox

MED;

Go! that M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-3-carboxamide; o M-42k)-3-I(4--4-Chlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide; ko M-42k)-3-I4-(4-chlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-42k)-3-14-(4-Chloro-3-fluorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxy)xamide; with M-42k)-3-I4-(3,4-difluorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxa

MED;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-1-oxo-1,2-dihydroisoquinoline-4-k 5B arboxamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-1H-indazole-3-carboxamide;

F) M-425)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-4-oxo-13,4-dihydrophthalazine-1-kacarboxamide;

Benzoic acid in 3-Sh2-Sh2)-3-I4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxypropyl)amino)-2-oxoethyl/|amino|-, methyl ester;

propanamide,

IM-(2-(2-Ш(2К)-3-(4-(3,4-dichlorophenoxy)-1-piperidinyl/|-2-hydroxypropyl|amino|-2-oxoethyl|amino|phenyl|-;

propanamide,

IM-(2-(2-Ш(2К)-3-(4-(3,4-dichlorophenoxy)-1-piperidinyl/|-2-hydroxypropyl|amino|-2-oxoethyl|amino|phenyl|-; 65 (25)-M4-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-2-hydroxy-2-phenylethanamide; 2-I2-(4(21) -3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)amino)-2-oxoethoxy|benzamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4 -yl)|acetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-2-methoxybenzamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylamino)benzamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)nicotinamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)isonicotinamide;

M-42k)-3-14-(3,4-dichlorophenoxy)pyridin-1-yl|-2-hydroxypropyl)-3-dimethylamino)benzamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole- 2- 70 il) acetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-hydroxynicotinamide;

M-42k)-3-14-(3,4--dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(1H-indol-3-yl)acetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyldicycloyl|4,2,Fokta-1,3,5-trien-7-carboxa

MED;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4,7-dimethylpyrazolo|5,1-c|(1,2,triazine-3-carboxamide ;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)pyrazine-2-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl/-9H-purine-6-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)quinoline-b6-carboxamide;

M-(2kK)-3-(4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,7-dimethylpyrazolo|1,5-a|pyrimidine-b-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(pyrimidin-2-ylthio)dacetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-5-fluoro-1H-indole-2-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl/1,3-benzothiazole-b-carboxamide; high school

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-phenyl-1,3-oxazole-4-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl1-2-hydroxypropyl)-6-hydroxypyridine-2-carboxamide; and)

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-hydroxypyridine-2-carboxamide; sozo M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-benzimidazole-5-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-5-carboxamide; ise)

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-methyl-1H-indole-2-carboxamide; with

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-imidazole-4-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-b6-carboxamide; at

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-methyl-1H-indole-3-carboxamide; co

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-7-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-(methylamino)sulfonyl|benzamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3,4-bis(methylsulfonyl)benzamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-pyridin-3-ylacetamide; "

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-hydroxy-1H-indole-2-carboxamide; with c M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide; . M-(2k)-3-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-(methylsulfonyl)-1H-indole-2-carboxamide; and?" M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-quinoxaline-b6-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,8-naphthyridine-2-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-1H-imidazo|2,1-11,3)benzothiazole-2-carbo

Go! xamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,6-dimethylimidazo|1,2-a|pyridine-3-carboxamide; ko M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxa

MED;

Me, 20 M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl1-2-hydroxypropyl)-3-hydroxy-1H-indazole-b-carboxamide; with M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-"-trifluoromethyl)-1H-pyrazole-4-carbox

MED; 2-(1H-benzimidazol-1-yl)-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)acetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-methyl-1H-pyrazole-3-carboxamide;

F) M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide; ka b-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)imidazo|1,2-a|pyridine-2-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-2-methylimidazo|1,2-a|pyridine-3-carboxam

ID, 70 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)imidazo|1,2-a(pyrimidine-2-carboxamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(4-methylpyrimidin-2-yl)thio)acetamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-hydroxyquinoline-2-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)quinoline-8-carboxamide; 65 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-5-methylimidazo|1,2-a|pyridine-2-carboxam

ID,

M-42K)-3-I4-(3,4--dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-imidazo|1,2-a|pyridine-2-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,6-naphthyridine-2-carboxamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,1,3-benzoxadiazole-5-carboxamide 1-oxide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl1-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 4-Chloro-M-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1M-pyrazole-3-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-phenyl-1,3-oxazole-4-carboxamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide; 70 (2K)-2-Acetylamino)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-phenylethanamide;

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(2-hydroxyphenyl)acetamide; (2k)-m4-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)amino|-2-phenylet anamide; (25)-2-Acetylamino)-N-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-phenylethanamide; (25)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(Kmethylsulfonyl)amino|-2-phenylet anamide; 1-2kK-4.(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-o-tolyl-urea; 1-(k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-p-tolyl-urea; 1-4(k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide ;

M-425)-3-I(4-(3,4-dichlorophenoxy)n; peridin-1-ylI|-2-hydroxy-2-methylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-2-oxo-1,2-dihydroquinoline-4-carb oxamide; high school

M-425)-3-I(4-(3,4-dichlorophenoxy)n; peridin-1-ylI|-2-hydroxy-2-methylpropyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide; i) (25)-M4-(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-2-hydroxy-2-phenethanamide;

M-42k)-3-14-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; so zo M-(2kK)-3-14-(2-(Aminocarbonyl)-3,4-dichlorophenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisoinolin-4- carboxamide; co

3-cyano-M-(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)/benzenesulfonamide; c 5-I(4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)amino)-sulfonyl)|-2-methoxybenzamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl-1-oxo-1,2-dihydroisoquinoline-4-sulfonami o c5 and acetate; co

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,4-difluorobenzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)umethanesulfonamide;

M-4(25)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)/benzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-phenylmethanesulfonamide; "

M-425)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxyprop /l)-4-methoxybenzenesulfonamide; with c IM-(15-I4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropylamino)sulfonyl/|-2-thienyl)umethyl)benzamide; ; » 4-cyano-M-((25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzenesulfonamide;

M-15-(4(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl)|-4-methyl-1,3-thiazol- 2-yl) acetamide;

Go! M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropylthiophene-2-sulfonamide; 4-(((25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)amino)sulfonyl|benzoic acid; o M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,5-dimethoxybenzenesulfonamide; ko M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-"phenylsulfonyl)thiophene-2-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide;

Me, M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-(/1-methyl-5-trifluoromethyl)-1H-pyrazole-c -yl|Ithiophene-2-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-pyridin-2-ylthiophene-2-sulfonamide; 5-chloro-M-(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,3-dimethyl-1H-pyrazole-4-sulfone

MED; 59 M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3,5-dimethylisoxazole-4-sulfonamide;

F) M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,1,3-benzothiadiazole-4-sulfonamide; ka M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-methyl-1H-imidazole-4-sulfonamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,1,3-benzoxadiazole-4-sulfonamide; in M-425)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-isoxazole-3-ylthiophene-2-sulfonamide; methyl 3-I(4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl|hyophene-2-carboxylate; 2,6-dichloro-N-(25)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-methylbenzenesulfonamide; 65 3-chloro-M-(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)ubenzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)propane-2-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropylipropane-1-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-5-methyl-1-phenyl-1H-pyrazole-4-sulfonamide

C-chloro-M-(25)-3-I(4-13,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-methylbenzenesulfonamide; methyl 5-((25)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl|-2-methyl-3-furoate; methyl 5-(4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl|-1-methyl-1H-pyrrole-2-carboxylate; 70 M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3,4-dimethoxybenzenesulfonamide; 5-chloro-N-(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropylthiophene-2-sulfonamide;

M-425)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-morpholin-4-ylpyridin-3-sulfonamide;

M-(2-chloro-4-(((25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl|phenyl)acetamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-2,3-dihydroxyquinoxaline-b6-sulfonamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,4-dimethoxybenzenesulfonamide; 5-I4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)iamino)sulfonyl|-2-methoxybenzamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-methylbenzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,4-dimethyl-1,3-thiazole-5-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-hydroxyquinoxaline-b6-sulfonamide;

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7 - sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)pyridine-3-sulfonamide; 4-cyano-M-4(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)biphenyl-2-sulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide; ch 4-acetyl-M-(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)ubenzenesulfonamide;

M-4(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-(methylsulfonyl)benzenesulfonamide; i) 2-chloro-4-cyano-N-(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)ubenzenesulfonamide;

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide;

M-K2)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,4-pyrazole-4-oxo-3-quinolinecarboxamide; so zo M-425)-3-(4--4-Chloro-2-methylphenoxy)piperidin-1-yl1-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide acetate; co

M-425)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; with

M-((248)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-Kmethylamino)sulfonyl|-1-oxo-1,2-dig ohydroisoquinoline-4 -carboxamide; co

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-H(2-hydroxyethyl)iamino|sulfonyl)-1-o xo-2- dihydroisoquinoline-4-carboxamide acetate; 7-Cylopropylamino)sulfonyl-N-(2)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1 2-dihydroisoquinoline-4-carboxamide; « 7-(Azetidin-1-ylsulfonyl)-M-4(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-di with c hydroisoquinoline-4-carboxamide acetate; . 7-(Aminosulfonyl)-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoly quinoline-4-carboxamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-Kdimethylamino)sulfonyl|-1-oxo-1,2-dihydroisoquinoline-4- carboxamide;

Go! M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(3-hydroxy-3-methylazetidin-1-yl)sulfonyl|-1-oxo -1,2-dihydroisoquinoline-4-carboxamide acetate; o M-K2k)-3-(4-13,4-dichloro-2-((cyclopropylamino)carbonyl|phenyxy)piperidin-1-yl)-2-hydroxypropyl|-1-oxo-1, co 2-dihydroisoquinoline- 4-carboxamide acetate;

M-42k)-3-14-(3-chloro-4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; c M-(2k)-2-Hydroxy-3-14-(4-methylsulfonyl)phenoxy|piperidin-1-yl)propyl)-1-oxo-1,2-dihydroisoquinoline-4-k arboxamide;

M-42k)-3-I4-(4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-(2kK)-3-14-(2-(Aminocarbonyl)-4-chlorophenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinol-in-4-carboxamide;

F) M-K2K)-3-(4--4-Chloro-2-K(methylamino)carbonyl|phenyxy)piperidin-1-yl)-2-hydroxypropyl|-1-oxo-1,2-dihydrocazoquinoline -4-carboxamide;

Methyl in 5-chloro-2-C1-(2K)-2-hydroxy-3-S(1-oxo-1,2-dihydroisoquinolin-4-yl)ucarbonylamino)propyl)piperidin-4-yl|)oxy benzoate acetate ;

M-(2Kk)-3-4-(2-(Aminosulfonyl-/(3,4-dichlorophenoxy)piperidin-1-yl)-2-hydroxypropyl/)|-1-oxo-1,2-dihydroisoquinoline-4 -carboxamide trifluoroacetate;

M-K2K)-3-(4-3,4-dichloro-2-(methylamino)sulfonyl|phenoxy)piperidin-1-yl)-2-hydroxypropyl|-1-oxo-1,2-dig 65 hydroisoquinoline-4 -carboxamide acetate;

M-K2K)-3-(4-3,4-dichloro-2-(cyclopropylamino)sulfonyl|Ifenoxy)piperidin-1-yl)-2-hydroxypropyl/|-1-oxo-1

2-dihydroisoquinoline-4-carboxamide acetate;

M-42k)-3-I4-(3-chloro-4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4- carboxamide;

M-4(2k)-3-4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-6-(methylsulfonyl)-IN-indole-

Z-carboxamide;

M-42k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6--"methylsulfonyl)-1H-indole-3-carboxami d;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k 70 arboxamide;

M-42k)-3-I4-(4-Chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-42k)-3-I(4--4-Chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-6--(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline- 4-carboxamide;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide ;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide acetate;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide acetate;

M-42k)-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline -4-carboxamide acetate;

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide ; high school

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k arboxamide; (8)

M-42k)-3-14-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;

M-((2K)-3-4-I3,4-dichloro-2-(methylsulfonyl)phenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisozoquinolin- 4-carboxamide acetate;

M-42k)-3-I4-(3,4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-OxO-4-"(trifluoromethyl)-1,6-dihydro ise ) operidine-3-carboxamide acetate; with

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-oxo-4-trifluoromethyl)-1,6-dihydro pyridine-3-carboxamide acetate; at

M-42k)-3-I(4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-oxo-4--trifluoromethyl)-1,6-dig so hydropyridine-3-carboxamide;

M-425)-3-(4-(3,4-dichlorophenoxy)pyridin-1-yl|-2-hydroxypropyl)-2-(2-oxoquinoxalin-1-(2H)-yl)acetamide;

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-oxo-3,4-dihydroquinoxaline-1-(2H)-carb oxamide; "

M-42k)-3-14-(4-chloro-2-methylphenoxy)piperidin-1-yl1-2-hydroxypropyl)-3-trifluoromethyl)-1H-pyrazole-4-carboxamide; . M-42k)-3-I(4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-trifluoromethyl)-1H-pyrazol-4-k arboxamide;

M-42k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydro-2-methylisoquinoline-4-k arboxamide;

Go! M-(2k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-oxo-1,2-dihydro-1-methylquinoline-4-carb oxamide; o M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k

GI arboxamide; or

M-42k)-3-14-(4-chloro-2-methylphenoxy)piperidin-1-yl|-hydroxypropyl)-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-methyl-carboxamide. c The compound of formula (I) or (Ia) can be obtained by the reaction of the compound of formula (11):

N o v M-sv283--YaisN Ssvove--(SVK8) -M t z)t p di: v 60 b5 yu de X, Kk? ZU V, ke. КВ, вк", В ВЗ, т and н are defined above, as follows: (i) when У represents a bond, СН о, ME, СНоМН, СНМНС(о), СН(ОН), СН(ЯМНСОВ), СН (МНбЗО»В, ЧНО or ЧО, then 7 represents С(О), КЗ is not hydrogen, and КЗ and 23" are defined above. with the compound of the formula (Ша): 4 а (Ша) 75 and -30-U where КО is defined above, and /! represents a leaving group (for example, a hydroxyl or chloride leaving group) in the presence of a base (for example, diisopropylethylamine), alternatively, in the presence of a coupling agent (for example, bromo-tris-pyrrolidinephosphonium hexafluorophosphate, РУВгОР or

O-(7-azabenzotriazol-1-yl)-M,M,M',M'-tetramethyluronium hexafluorophosphate); (ii) when M represents MM, and 2 represents C(O), with a compound of the formula (PIV): 9 (c) active. "the main reason is sometimes 0: M-k o where VE? defined above. зо (ии) when U represents a bond, and 7 represents 5(0)", with a compound of the formula (Ps): со (Се) (с)

P- 5 0U- s "c)

From where K is defined above, and | represents a leaving group (for example, a hydroxyl or chloride leaving group) in the presence of a base (for example, pyridine).

The compound of the formula (II) can be obtained (as described in UMO 00/58305 or MO 01/77101), or by the reaction of the compound of the formula (IM):

Kk (ee) oh where X and VE! defined above, as follows: ko (i), when t and n are equal to 0, K2, KZ, EB? and KZ represents hydrogen, and K7 and KZ2 are defined for formula (I),

With the compound of the formula (M): (22) o else I 2 X in o -А--с25 4 svv and TU 60 in which I? represents a leaving group (e.g. chlorine or nosyloxy/3-MO 5-SeNa-9(0)20-U, followed by reaction with ammonia, amine 2-MNO or with sodium azide and subsequent reduction, e.g. triphenylphosphine; 65 (i) when t and n are equal to 0, B? and EZ represent hydrogen, and B", 2, KZ and 222 are defined for the formula (I), with the compound of the formula (MI):

oh sha and / | in a combination of A and P in which P" and P" represent, alone or together, suitable protecting groups (for example, together they form phthalamide), or any of P" or p? represents 22, and then by removing the protection, using, for example, 12 whenR'ta P? form phthalamide, hydrazine; (her) when t is 0, n is 1, KE? and EZ represent hydrogen, and 27, 25, 25. B", tav is defined for the formula (I), with the compound of the formula (MI): (MI) i o

Ko SEC A--sV'KA-MR'R" sch (o) (ee) what 2 ! . ! in which P" and P? represent, singly or together, suitable protecting groups (for example, together they form phthalamide), or any of P" or P? is 22, and then deprotection using, for example, when P' tar? c form phthalamide, hydrazine; (im) when t and n are equal to 1, VK? and KZ represent hydrogen, and B", E5, VK, Kk", 8 and KZ2 are defined for - formula (I), with the compound of the formula (MIP): с - - с 2 in? Z dk -8 7 tov 1 500 A-VE- vya--svVK--MR'R" 4 so Kk o (My) ko b 50 so (F) ko in which I? defined for formula (M), and P" and P? represent, singly or together, suitable protecting groups for (e.g. together they form phthalamide), or either of P or P? represents K 2 and then deprotection using , for example, when P'tar?2 form phthalamide, hydrazine; (M) when t is 1 and n is 0, 2 and C is hydrogen, EZ and 85 are, independently, hydrogen, C 1 -alkyl or C 3 -cycloalkyl, and KE " and short circuit? determined for the formula (I), with the compound of the formula (IX): b5 and g and 2 pd and 1

M-A-- kkE- sv vA--Me'v o V . ; and in which I 2 is defined for formula (M) and P" and P? represent, alone or together, suitable protecting groups (for example, together they form phthalamide), or either of P or P? represents KV 2 and then removal 72 protection using, for example, when P'targ form phthalamide, hydrazine; (mi) when t is 1 and n is 0, B, 23, 2? and EE? represent hydrogen, and B" and EZ" are defined for the formula (I), with the compound of formula (X): 00 2 o 2 Z X 56

I-A-x 80 -so sk d

N,. 4 (8) in which I? represents a leaving group (e.g. bromine) followed by reaction with ammonia, amine EC 22-MH» co or sodium azide and subsequent reduction, e.g. triphenylphosphine; He (my) when t is equal to 1, and n is equal to 0, 22, BZ, c and 5 independently represent hydrogen, C 4 alkyl or Ca cycloalkyl, and K", 27 and KZ? are defined for formula (I), with compound of the formula (XII): cm «c) (Xi)

Z x d) lk students | | and that "

Ky S-is SA K--KR R pi shi s ;" "in which P" and P? represent, singly or together, suitable protecting groups (e.g. together they form phthalamide), or any of P" or p? represents B 32 , followed by reduction with a hydride (e.g. sodium borohydride), or addition of an acceptable organometallic agent (e.g. БЕ " MOX, where X is a halide); or, av) (mii) when t is equal to 1 and n is equal to 1, K?, BZ, BZ, 29, B" and C represent, independently, hydrogen, with C. alkyl or C3 - cycloalkyl, and B" 87 and WITH? determined for the formula (I), with the compound of the formula (XII): (e)) 20 Y (Xi) so o z pejuvenv kvA-svV'BA-MR'ya"

C o N ime) in which P" and P? represent, singly or together, suitable protecting groups (e.g. together they form phthalamide), or either P' or p? represents B, followed by reduction with a hydride (e.g. sodium borohydride), or by adding an acceptable organometallic agent (for example, in "MOMU, where MU is a halide).

When t is 0 and n is 0, 2, 83, c and 5 independently represent hydrogen, C 1 6 alkyl or

C. dicycloalkyl, compounds of formula (II) can be obtained by the reaction of compounds of formula (XII): b5

(kht . . Z i usne i to where X and KE" are defined for the formula (I), and Y Z represents hydrogen or a leaving group (for example, ethoxyl, M,O-dimethylhydroxylamine), with a compound of the formula (ХМ): (хм)

B. ""irovchnaratit. other onyvnnvlv vinnyi (7, nn VM E Co |. in which M represents a metal (for example, I and or Ma), and I 7" represents an amino group (for example, ammonium), and then rearrangement (for example, with phenyliodonium diacetate Teigapedgop I eyegz, 2001 ,42,1449.) and acceptable reduction (for example, sodium borohydride), or the addition of an acceptable organometallic agent (for example, K"Momu where M/ represents a halide).

When t is 0, n is 1, and K2, KZ, 5, K9, Kk" and KZ represent, independently, hydrogen, alkyl or C3-cycloalkyl, compounds of formula (II) can be obtained by the reaction of compounds of formula (XX): (xx) sia

Her. Y x M--sv'dZ dya x. Y Y F "so s where X, B" and B" are described in formula (I) above, and 7 represents an aldehyde, a protective group; (for example, cyanohydrin or dithiane), with a compound of the formula (XXI): o d) "(XXI) in which K?, 9, Kk" and KZ are described above, and I? represents an alkoxy or amino group (for example, ethoxy or - 70 ammonium) in the presence of a base (for example, I OA or n-butyllithium), and then hydrolytic removal of the I group. 2, with rearrangement (for example, with phenyliodonium diacetate) and acceptable reduction (for example, sodium: with" borohydride), or by adding an acceptable organometallic agent (for example, in "MoMU, where M/ represents a halide).

The compound of the formula (M) can be obtained by the reaction of the compound of the formula (XXI): bo 2 kv (kht ("c)

From Nov. to Nov. to St. in the 20th century

IR e) with a peracid (for example, meta-chloroperbenzoic acid), or using the conditions of asymmetric epoxidation (Zpagriezv, 9). At. Spent wasps 1980, 102, 5974-5976) and then by activation of an alcohol as a leaving group 22 (for example, as a nosyloxy).

Gee! The compound of the formula (MI) can be obtained: yuyu (a) when KE? and KZ represent hydrogen, the reaction of the compound of the formula (XXI): 2 4 . « in (XX) and Ak blo Kk--oN t of the customs office. b5 with a peracid (e.g. meta-chloroperbenzoic acid) or using asymmetric epoxidation conditions (ZPpagrieevzv), and then, for example, the Mitsunobu reaction, using /phthalimide, 1,1--azodicarbonyl)dipiperidine and tributylphosphine |Teggapeagop I! Hey. 1993, 34, 1639). (5) when KE? and K?9U represent, independently, hydrogen, C 4 .lalkyl or C3 vcycloalkyl, by the reaction of the compound of the formula (XXIM): and with (xx) ve. syazyae mrv: in which P" and P? represent, alone or together, suitable protecting groups (for example, together they form phthalamide), or any of P" or P? represents short-circuit, with sulfurylide | for example, trimethylsulfonium methylide,

U. At. Spent boss. 1965, 87, 1353-1364); or a phosphonium ylide (eg triphenylphosphonium methylide) and then epoxidizing the resulting alkene using a peracid (eg meta-chloroperbenzoic acid).

The compound of the formula (MII) can be obtained by the reaction of the compound of the formula (ХХМ): о (ХХ) и с 7 4 ba? t8 1 o - v'v--sVYUY-kr re in which P" and P? represent, alone or together, suitable protecting groups (for example, together they form sophthalamid.), or any of P or P? represents BC 2, with a sulfur ylide (e.g. trimethylsulfonium O methylide) or a phosphonium ylide (e.g. triphenylphosphonium methylide), followed by epoxidation of the resulting alkene using a peracid (e.g. meta-chloroperbenzoic acid).

The compound of the formula (MI) can be obtained by reacting the compound of the formula (XXM) with ethyl acetate anion (which can be obtained by the action of lithium isopropylamide on ethyl acetate), and then reducing the formed ester, or

With, for example, vinylmagnesium and subsequent hydroboration (for example, catecholborane)/oxidation (for example, with hydrogen peroxide) of an alkene.

The compound of the formula (IX) can be obtained from the compound of the formula (XXIM) in a similar way as for the compound (MIP).

The compound of the formula (X) can be obtained by the reaction of the compound of the formula (ХХМИ): "- (ХМ) Z я ва -- в но-- с- 0 Сп 2"; H, - B. (ee) o with a peracid (for example, meta-chloroperbenzoic acid), and then selective activation of the primary alcohol as a leaving group (for example, nosyloxy).

Further, compounds of formulas (I) and (Ia) can be obtained by conventional adaptation of the routes described above, methods b" described in the prior art, or examples described below. The intermediates defined above are commercially available or can be obtained using or adapting methods described in the prior art.

According to the following aspect of the invention, a method of obtaining 4-(3,4-dichlorophenoxy)piperidine is proposed, which involves the following steps: a. reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room temperature; and, (F) r. heating the thus formed mixture together with 1,2-dichloro-4-fluorobenzene at a temperature in the range of 50-902C, or at reflux of the used solvent.

According to the following aspect of the present invention, a method of obtaining 4-(3,4-dichlorophenoxy)piperidine is proposed, which involves the reaction of 4-hydroxypiperidine with a suitable base

Some C 44 alkoxide of an alkali metal (predominantly sodium or potassium) (such as C 4 tertiary alkoxide (e.g. C tertiary alkoxide)), e.g. potassium tert-butoxide or potassium 3,7-dimethyl-3-octaneoxide) in a suitable solvent (such as: ether | for example tetrahydrofuran or methyl-tert-butyl ester), an aromatic solvent (such as toluene| or a mixture of these solvents) at room temperature (10-302С); heating the mixture formed in this way together with 1,2-dichloro-4-fluorobenzene at a temperature in the range of 50-902C, or by refluxing the used solvent,

According to another aspect of the present invention, a method for obtaining 4-(3,4-dichlorophenoxy)piperidine is proposed, which involves the reaction of 4-hydroxypiperidine with a suitable base, such as a C 44 alkoxide of an alkali metal (predominantly sodium or potassium) (such a C 44 tertiary alkoxide ), for example, a C valoxide (such as a C /tertiary alkoxide, such as potassium tert-butoxide) in a suitable solvent (such as: an ether (such as tetrahydrofuran or methyl tert-butyl ester), an aromatic solvent (such as then toluene | or a mixture of these solvents) at room temperature (10-302С) and heating the mixture thus formed to a temperature within 50-902С, or under reflux of the used solvent, and adding 1,2-dichloro-4-fluorobenzene.

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

According to another aspect of the present invention, methods of obtaining compounds of formulas (I) and (Iv) are proposed.

The intermediates of formula (MI), (MII) and (MI) defined here are new and these intermediates and methods of their preparation are proposed as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, in particular, as modulators of the activity of chemokine receptors (especially CVD), and can be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically mediated diseases (including rejection of transplanted organs or tissues and the syndrome of acquired Immunodeficiency (AIDS)).

According to one aspect, examples of these conditions are: (1) (respiratory tract) obstructive airway diseases, including: chronic obstructive pulmonary disease (COPD) (somewhat irreversible COPD)); asthma, such as bronchial, allergic, exogenous, endogenous or dust asthma, especially chronic or chronic asthma (for example, late-onset asthma or airway hypersensitivity); bronchitis (such as eosinophilic bronchitis); acute, allergic, atrophic rhinitis or chronic rhinitis, including chronic rhinitis with the formation of caseous masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or Ha medicinal rhinitis; membranous rhinitis, including croupous, fibrous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis, including rhinitis nervosa (hay fever) or vasomotor rhinitis; i) sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lungs, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory airway conditions, or iatrogenically induced cough; ee) (2) (bones and joints) arthritis, including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease, Beckett's disease, Sørgen's syndrome or systemic sclerosis; Ge (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatitis, seborrheic dermatitis, pemphigoid lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, o 3z5 Urticaria, angiodermatitis, vasculitic erythema, skin eosinophils, uveitis, alopecia areata or vernal ee conjunctivitis; (4) (gastrointestinal tract) gastroenteritis, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease, or food-related allergies "that have an effect distant from the alimentary canal (eg migraine, rhinitis or eczema); (5) (Allograft rejection) acute and chronic after, for example, transplantation of kidneys, heart, liver, lungs, bone marrow, skin or cornea; or chronic graft-versus-host disease; and/or c (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), thyroiditis

Hashimoto's, myasthenia gravis, type 1 diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper ZE syndrome, leprosy (such as lepromatous leprosy), periodontal disease, Sézary syndrome, idiopathic thrombocytopenic (ee) purpura, or menstrual disorders.

The compounds of the invention are also H1 antagonists and can be used in the treatment of allergic disorders. o Compounds of the invention may also be used to control the signs and/or symptoms of what is commonly referred to as the common cold (eg, signs and/or symptoms of the common cold or influenza or other associated respiratory viral infections). b According to the following feature of the invention, a compound of formula (I) or (Ia), or its pharmaceutically acceptable salt or solvate, is proposed for use in a method of treating warm-blooded animals (like humans) with therapy (including prevention).

According to the following feature of the presented invention, a method of modulating the activity of the chemokine receptor (especially the activity of the SSKZ receptor) or antagonizing NI in warm-blooded animals, such as humans, if such treatment is necessary, is proposed, the method consists in applying to the indicated animal an effective amount of the compound of the formula ( I) or (Ia), or its pharmaceutically acceptable salt or solvate. The invention also provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament. 60 According to one aspect of the present invention, it is proposed to use a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, in the production of a medication for use in therapy (for example, modulating the activity of a chemokine receptor (especially the activity of the SSKZ receptor), or antagonizing NI , in warm-blooded animals, such as humans).

In addition, the invention provides the use of a compound of formula (I) or (Ia), or its pharmaceutically acceptable salt 65, in the production of a medicament for use in the treatment of: (1) (respiratory tract) obstructive diseases of the respiratory tract, including: chronic obstructive pulmonary disease (COPD )) (somehow irreversible SORO)); asthma, such as bronchial, allergic, exogenous, endogenous or dust asthma, especially chronic or chronic asthma (for example, late-onset asthma or airway hypersensitivity); bronchitis (such as eosinophilic bronchitis); acute, allergic, atrophic rhinitis or chronic rhinitis, including chronic rhinitis with the formation of caseous masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or medicinal rhinitis; membranous rhinitis, including croupous, fibrous or pseudo-membranous rhinitis or scrofulous rhinitis; seasonal rhinitis, including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lungs, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with/o inflammatory conditions of the respiratory tract or iatrogenic induced cough; (2) (bones and joints) arthritis, including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis, or Reiter's disease), Beckett's disease, Sørgen's syndrome, or systemic sclerosis; (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatitis, /5 seborrheic dermatitis, pemphigoid lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, angiodermatitis, vasculitic erythema, skin eosinophilia, uveitis, focal alopecia or spring conjunctivitis; (4) (gastrointestinal tract) gastroenteritis, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease, or food-related allergies such as 2o having effects distant from the alimentary canal (e.g., migraine, rhinitis, or eczema ); (Allograft rejection) acute and chronic after, for example, kidney, heart, liver, lung, bone marrow, skin or cornea transplantation; 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), erythema, thyroiditis, etc.

Hashimoto's, malignant myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper

I9ZUE, leprosy (such as lepromatous leprosy), periodontal disease, Sézary syndrome, idiopathic thrombocytopenic purpura or i) disorders of the menstrual cycle; in warm-blooded animals, like humans.

According to a further aspect, a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma (such as bronchial, allergic, exogenous, endogenous or dust asthma, especially chronic or chronic asthma (e.g. late-onset asthma or airway hypersensitivity)); or rhinitis (including ISE) chronic rhinitis with the formation of caseous masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or drug-induced rhinitis; membranous rhinitis, including croupous, fibrous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis, including rhinitis nervosa (hay fever) or vasomotor rhinitis). at

According to yet another aspect, a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.

The present invention also provides the use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, in the production of a medicament for use in the treatment of asthma or rhinitis.

In addition, the presented invention provides a method of treating a chemokine-mediated disease (especially "SSCZ-mediated disease, especially asthma) in warm-blooded animals, such as humans, the method consists in applying to the specified mammal in need of such treatment an effective amount of the compound of the formula (I ) or

And (a), or a pharmaceutically acceptable salt or solvate thereof. and?" For the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the therapeutic treatment of warm-blooded animals, such as humans, in particular the modulation of chemokine receptor activity (especially receptor activity, SSRI or NO antagonism), the indicated ingredient is usually formulated in accordance with standard pharmaceutical practice, such as pharmaceutical composition.

Therefore, according to another aspect of the present invention, a pharmaceutical composition is proposed, which contains a compound of formula (I) or (Ia), or its pharmaceutically acceptable salt or solvate (active ingredient)

GI and a pharmaceutically acceptable adjuvant, diluent or carrier. According to the following aspect of the presented 5th Invention, a method of obtaining the specified composition is proposed, the method consists in mixing the active

Me, an ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of application, the pharmaceutical composition will preferably contain from 0.05 to 9995 (mass fraction), more preferably from 0.05 to 8095, even more preferably from 0.10 to 7095 and even more preferably from 0.10 to 5095, active ingredient, all percentages show the mass fraction in the total composition. 5B The pharmaceutical compositions of the present invention can be used in a standard way for the disease to be treated, for example local (somehow to the lungs and/or respiratory tract or to the skin), oral, (F, rectal or parenteral application. For this compound of the present invention can be formed by means known in the art into the form of, for example, aerosols, dry powder compositions, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile aqueous or oily solutions or suspensions for injections.

A suitable pharmaceutical composition of the present invention is a composition suitable for oral administration in a unit dosage form, such as a tablet or capsule, which contains between 0.1mg and 1g of active ingredient 65 According to another aspect, a pharmaceutical composition of the present invention is a composition suitable for intravenous, subcutaneous or intramuscular injections.

Each patient can receive, for example, an intravenous, subcutaneous or intramuscular dose of

0.Omg/kg to 1O0Omg/kg of the compound of the present invention, preferably in the range from 0.0mg/kg to 2Omg/kg, the composition is used 1-4 times a day. Intravenous, subcutaneous or intramuscular dose can be administered by means of bolus injection. Alternatively, the intravenous dose can be administered by continuous infusion over time. Alternatively, each patient will receive a daily oral dose that is roughly equivalent to a daily parenteral dose, the composition being used 1-4 times a day.

The invention is further illustrated by the following non-limiting examples in which, unless otherwise specified: (І) H NMR data are presented in the form of delta values for the main diagnostic protons, in parts per million (ppm) relative to tetramethylsilane (TM5), as an internal standard, determined at ZOOMHz or 400 MHz, using pre-deuterated DMSO-O (20535005), methanol-Y, (СО30О0) or SOCI" as a solvent unless otherwise specified; (i) mass spectra (MS) were obtained with an electron energy of 7OeV in the chemical mode ionization (Xi) using direct exposure of samples to ionization by electron impact (EU) or bombardment with 75 fast atoms (FSA) or electrospray (ESP); where values for t/2 are given, in general, only for the original ion, and unless otherwise specified, the mass of the ion is the mass of the positive ion - (MAN);

Aduapsei Spetizighu Yuemeiortepi, Ips; (im) unless otherwise specified, reversed-phase HPLC was performed using a Zutteig MomagRak or Hiegita reversed-phase silica column; and (M) the following abbreviations are used: сч о с

Preparation 1 (2kK)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol i-o

Stage 1: 2-(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione c c c o at

(k)-2-(Oxiranylmethyl)-1H-isoindole-1,9(2H)-dione (Teigapedgop Avutteigu, 1996, 7.1641, 5 g) in a mixture of 5 ml of ethanol and 15 ml of dimethylformamide is treated 4-(3,4-dichlorophenoxy)-piperidine (bg). The mixture was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue was distilled twice from toluene. The crude material was purified by chromatography (ethyl acetate) to give the desired compound as a yellow oil.

MS (CHIAT) 449/451 (MN) about TN NMR 5 (SOSIv) 7.92-7.81(2Н, t), 7.77-7.70 (2Н, t), 7.30 (1Н, 4 ), 6.98 (1H, 0, 6.74 (1H, ayu, 4.34420 (IN, t), 4.09-3.97 (1IN, t), 3.83 (1H, ach), 3 .73 (IN, aa), 2.93-2.79 (IN, t), 2.73-2.60 (1Н, t), 2.59-2.37 o (ЗН, t), 2, 31 (1H, 9, 2.02-1.86 (2H, t), 1.86-1.67 (2H, t). co Stage 2: (2K)-1-amino-3-I4-(3 ,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol

Fo o on c v, mini, and (5)-2-I3-I4-(3,4-dichlorophenoxy)-1-piperidinyl-2-hydroxypropyl-1H-isoindole-1,9(2H)-dione (45) 20 ml of hydrazine monohydrate are treated in ethanol (100 ml) and the mixture is heated under reflux for 3 hours. The reaction mixture is cooled and filtered. The filtrate was evaporated and the product was chromatographed (ethyl acetate) to give the desired compound as a yellow oil which cleared on standing (2.5g). 60 MS(xHIAT) 319/321 (MEN)"

So NMR 5 (SOSIi) 7.31 (IN, a), 7.00 (IN, a), 6.75 (IN, a), 4.00 (IN, zer), 3.74-3.62 ( IN, t), 2.94-2.84 (1H, t), 2.82 (1H, 4), 2.72-2.61 (1H, t), 2.65 (IN, a); 2.60-2.49 (1H, t), 2.46-2.21 (ZH, t), 2.06-1.91 (2H, t), 1.90-1.72 (2H, t ).

Preparation 2 65 4-amino-1-I4-(3,4-dichlorophenoxy)piperidin-1-yl|butan-2-ol

Stage 1: 2-4-(4-(3,4-dichlorophenoxy)piperidin-1-ylI-3-hydroxybutyl)-1H-isoindole-11,3(2H)-dione ovo; z a m m o 70 Mixture of 4-(3,4-dichlorophenoxy)piperidine MO 0058305, Me) 01771011 (4.40g) and 2-(2-oxiran-2-ylethyl)-1H-isoindol-1,3(2H )-dione (U. Mei. Spet. 1979, 22(6), 631-9. 5.00 g) in ethanol (5 Oml) is stirred at 602C for 12 hours. The mixture is cooled and left overnight. The crystals formed were collected by filtration, washed with cold ethanol and dried in vacuo to give the desired compound as a white solid (COg).

MO (HIAT) 463/465 (MAN)!

TN nMR 5 (DMSO) 7.90-7.80 (4H, t), 7.49 (1H, a), 7.25 (IN, a), 6.97 (1H, ad), 4.53- 4.33 (2H, t), 3.80-3.69 (1H, t), 3.69-3.58 (2H, t), 2.77-2.60 (2H, t), 2, 38-2.17 (4H, t), 1.94-1.84 (2H, t), 1.85-1.75 (IN, t), 1.65-1.50 (ЗН, t).

Step 2: 4-amino-1-I4-(3,4-dichlorophenoxy|piperidin-1-yl|butan-2-ol ( i! I ve s mn, in

A solution of a mixture of 2-(A4-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-1H-isoindole-1,3(2H)-dione (3.00 g) in a mixture of ethanol (/bml) and 3595 aqueous hydrazine (15ml) were heated at reflux for 4 hours. The mixture was cooled and the solvents removed in vacuo. The residue was triturated with hot dichloromethane. The white solid was removed by filtration and the filtrate was dried over sodium sodium sulfate. The mixture was filtered and the solvent was evaporated to give the desired compound as a yellow oil (2.10 g), which was used without further purification in the next step.(Se)

MO (HIAT) 333/335 (MAN)! high school

TN NMR 5 (SOSISCH) 7.29 (1H, a), 6.96 (IN, a), 6.76 (IN, ad), 4.40-4.25 (1H, t), 3.95- 3.85 (1H, t), 3.20-3.00 (2H, t), 2.96-2.79 (1H, t), 2.78-2.63 (1H, t), 2, 60-2.45 (1IN, t), 2.41-2.23 (ЗН, t), 2.10-1.88 (2Н, о t), 1.88-1.70 (ЗН, t) , 1.70-1.58 (1H, t). co

Preparation C 1-amino-4-I(I4-(3,4-dichlorophenoxy)piperidin-1-yl|butan-2-ol

Stage 1: 4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine « и а ге) - с . Mn » 8 o

A mixture of 14-(3,4-dichlorophenoxy)piperidine (MUO 0058305, UMO 01771011 (2.00g), 2-(2-bromomethyl)oxirane (9. At. Spect. bos. 1981,103, 7520-8) (1 .36g) and potassium carbonate (2.2g) in acetone (20ml) were stirred at 502°C for 12 hours. The solvent was removed in vacuo. 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, obtaining the desired compound as a yellow oil (2.50 g), which was used without further purification in the next step. o MS (CHIAT) 316/318 (MAN)

Ge) 20 "IN NMR 5 (SOCI8) 7.31 (1H, 4), 7.00 (1H, a), 6.75 (1H, aa), 4.27 (1H, aquintet), 3.02- 2.95 (1H, t), 2.78 so (IN, 9, 2.77-2.68 (2H, t), 2.57-2.49 (ZH, t), 2.39-2, 24 (2H, t), 2.03-1.94 (2H, t), 1.87-1.75 (2H, t), 1.77-1.72 (1H, t), 1.73- 1.61 (1H, t).

Step 2: 1-amino-4-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|butan-2-ol)

In a sealed metal tube, a solution of 4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine (1.00 g) in 7N ammonia in methanol (25 ml) is heated at 70:96 for 12 hours. The solvent was removed in vacuo and the residue was purified on silica gel (0-1095 7N ammonia in methanol/dichloromethane) to give the desired compound as a yellow oil (0.55 g). bo MS (HIAT) 333/335 (MEN)

TN NMR 5 (SOSI) 7.31 (1H, a), 6.99 (1H, c), 6.75 (1H, as), 4.36-4.27 (IN, t), 5 3.79 -3.70 (1H, U), 2.93-2.78 (1H, t), 2.76-2.59 (BN, t), 2.61-2.50 (1H, t), 2 .37-2.27 (1H, t), 2.03-1.90 (2H, t), 1.89-1.76 (2H, t), 1.74-1.61 (1H, t) , 1.54-1.46 (1H, t).

The preparation 4 (2K)-1-amino-3-I4-(4-chlorophenoxy)piperidin-1-yl|Ipropan-2-ol o on 5 SA

Obtained as described in the preparation of 1. "IN NMR 5 (СО500) 7.13 (2Н, а), 6.80 (2Н, 4), 4.26 (1Н, septet), 3)68-3.59 ( 1H, t), 2.77-2.65 (2H, t), 2.62 (IN, aa), 2.46 (1H, aa), 2.38-2.24 (4H, t), 1 .95-1.85 (2H, t), 1.73-1.61 (2H, t).

Drug 5 (2K)-1-amino-3-I(4-(4-chloro-3-Fluorophenoxy)piperidin-1-ylpropan-2-ol

E about under the village

Obtained as described in obtaining 1.

MS (IER) 303/305 (MAN) p 29 To NMR 5 (С050О0) 7.32 (IN, 0, 6.86 (IN, ach), 6.77 (IN, aa), 4.40 (1Н, quintet), 3.74 (1H, aao), d) 2.87-2.75 (2H, t), 2.72 (1H, da), 2.56 (1H, aa), 2.50-2 .37 (4H, t), 2.08-1.95 (2H, t), 1.85-1.72 (2H t).

Preparation 6 (2K)-1-amino-3-I(4-(3,4-difluorophenoxy)piperidin-1-ylpropan-2-ol so 30 E o on «so

E nick AnNn, sia «c)

Obtained as described in the preparation of 1. 35 MS (ER) 287 (Men so "YAN NMR 5 (C0500) 7.14 (1H, 40, 6.87 (1H, aa), 6.75-6.69 (IN , t), 4.35 (1H, septet), 3.80-3.71 (1H, t), 2.88-2.75 (2H, t), 2.75 (1H, aa), 2, 58 (1H, aa), 2.51-2.34 (4H, t), 2.07-1.94 (2H t), 1.85-1.71 (2H, t).

Preparation 7 "(2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol. with

Step 1: 4-(3,4-Dichlorophenoxy)piperidine with 4-Hydroxypiperidine (50g, 494mmol) was added portionwise to a stirred suspension of potassium tert-butoxide :c" (110.9g, 9900mmol) in tetrahydrofuran (90Oml) at room temperature and under nitrogen. The mixture is heated to reflux and 1,2-dichloro-4-fluorobenzene (98 g, 594 mmol) is added dropwise over 15 30 minutes. The mixture is stirred at reflux for another 1 hour, then it is cooled to room temperature, diluted with ethyl acetate (5000 ml) and washed with water (500 ml).

The organic phase is further diluted with ethyl acetate (500 ml) and extracted with 1M hydrochloric acid (200 ml), («c) The aqueous extract is adjusted to pH 210 by adding sodium hydroxide solution and extracted twice with tert-butyl methyl ether (75 Oml). The organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound as a dark oil, which was used essentially in the next step.

FU OO 000 Me (ER) 246/248 (MEN so TN NMR 5 (SOSIv) 7.31 (1H, 4), 7.00 (1H, s), 6.78 (IN, aa), 4.29- 4.537 (1H, t), 3.15 (2H, ayu, 2.75 (2H, 14), 1.97-2.03 (2H, t), 1.60-1.70 (2H, t).

Alternative Step 1: 4-(3,4-dichlorophenoxy)piperidine

A thin slurry of 4-hydroxypiperidine (50g, 494mmol) in tetrahydrofuran (200ml) was added to a stirred suspension of potassium tert-butoxide (110.9g, 99O0mmol) in tetrahydrofuran (b5Oml) at room temperature and

F) washed with THF (5 Oml). The resulting mixture is stirred under nitrogen for 20 minutes. of 1,2-dichloro-4-fluorobenzene (98g, 594mmol) was added and the resulting mixture was heated at reflux for 90 minutes. The reaction mixture is cooled to room temperature and 60 ml of water is added. The layers are separated and the solvent is separated from the organic fraction. The material is then partitioned between MTBE and 1095 aqueous citric acid solution. The layers are separated and the aqueous layer is further washed with MTBE (2 x 250 ml).

The aqueous phase is alkalinized to pH 10 by adding 1OH Mahon solution, and the product is extracted with isopropyl acetate (2x300O0ml). The organics were washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound as a dark oil, which was used essentially in the next step 65 (109.1 g, 9090).

Stage 2: (25)-1-azido-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol water: with Fa im, (2K)-Oxiran-2--ylmethyl Z -nitrobenzenesulfonate (21.1 g, 81.3 mmol) in dimethylformamide (30 mmol) is treated with triethylamine (22.5 mL, 163 mmol) and then with 4-(3,4-dichlorophenoxy)-piperidine (20 g, 81.3 mmol) .

The mixture is stirred overnight at 602C. Sodium azide (16g, 243.0mmol) was added to the mixture and the 7/0 reaction mixture was stirred for another 72 hours. The solution is carefully concentrated in vacuo and the residue is diluted with water (bOOml), extracted with ethyl acetate (1500ml). The organic layer is washed twice with water (500 ml), then with brine (200 ml) and concentrated in vacuo to obtain an oil.

Step 3: (2K)-1-amino-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol

The resulting oil from step 2 is dissolved in wet tetrahydrofuran (225 ml) and treated with 75 triphenylphosphine (53.3 g, 2033 mmol). The reaction mixture is heated at 602C and stirred for 4 hours.

The solvent is removed in vacuo, the residue is redissolved in 2N hydrochloric acid (1000 ml) and the aqueous layer is extracted with ethyl acetate (3 times 700 ml). The aqueous phase is alkalized with 2N sodium hydroxide solution and extracted with dichloromethane (3 times 1000 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by chromatography (895 7H ammonia in methanol/dM) to give the desired compound as a yellow oil (17Hg).

MS (HIAT) 319/321 (MN) "YAN NMR 5 (SOSIV) 7.31 (1H, a), 7.00 (IN, a), 6.75 (IN, ad), 4.0 (IN, ver), 3.74-3.62 (1H, t), 2.94-2.84 (IN, t), 2.82 (1H, a), 2.72-2.61 (IN, t) , 2.65 (1H, a), 2.60-2.49 (1H, t), 2.46-2.21 (ZH, t), 2.06-1.91 (2H, t), 1 ,90-1,72 (2H, t). p

Preparation 8 (o) (2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol

Step 1: (2-5)-1-Chloro-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol yl; (5)-(4)-Epichlorohydrin (3.5Oml, 44.7mmol) was added to a stirred solution of 4-(3,4-dichlorophenoxy)piperidine (10.0g, 40.bmmol) in ethanol (5Oml ). After 20 g, add water (5 Oml). The mixture is stirred for another 2 hours, then the solid precipitate is collected by filtration, washed with water and dried under vacuum at 502 for 2 hours, obtaining the desired compound.

MS (IER) 338/340/342/344 (MN)"

TN NMR 5 (SOSIsh) 7.31 (IN, a), 7.00 (IN, c), 6.75 (IN, a), 4.28-4.33 (IN, t), 3.89- 3.96 (1H, t), « 3.54-3.62 (ZH, t), 2.84-2.92 (1H, t), 2.65-2.72 (1H, t), 2 ,45-2.59 (ZH, t), 2.32-2.36 (1H, t), 1.90-2.01 (2H, C 70 t), 1.77-1.87 (2H, t). c Step 2: (2K)-1-amino-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol.

Mo

Go) 75 a AK AMn, av! A solution of sodium hydroxide (1.62 g, 40 mmol) in methanol. (200ml) is added to the product from the previous step and the mixture is stirred for 1 hour when the solid product has dissolved. Aqueous solution of ammonia (2895, 8 Oml) is added and stirring is continued at external temperature for 3 days. The solution is concentrated in

He») 20 vacuum to a volume of 100 ml, then dissolve in hydrochloric acid (0.5 M, 80 Oml) and extract with diethyl ether (2x200 ml). The aqueous extract is filtered to remove insoluble contamination, then basified with the addition of sodium hydroxide and extracted with dichloromethane (4 x 200 ml) with filtration of the two-phase mixture to remove insoluble contamination. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the desired compound as an oil (10.6 g).

MSx(HIAT) 319/321 (MAN)" (F. TN NMR 5 (SOSIv) 7.31 (IN, a), 7.00 (1Н, с), 6.75 (IN, aa), 4.0 (1H, sep.), 3.74-3.62 (1H, t), ko 2.94-2.84 (1H, t), 2.82 (1H, 4), 2.72-2.61 (1H, t), 2.65 (IN, a), 2.60-2.49 (1H, t), 2.46-2.21 (ZH, t), 2.06-1.91 (2H , t), 1.90-1.72 (2H, t). 60 Preparation 9 (25)-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-methylpropan- 2-ol b5

, i in IF district

Prepared as described in the preparation of 7 (Steps 2 and 3) using 70 mg of (2K)-2-methyloxiran-2-yl|methyl-3-nitrobenzenesulfonate.

MS (HIAT) 333/335 (MN)

TN nMR 5 (SOCIv) 7.30 (1H, a), 6.99 (IN, a), 6.75 (1H, ad), 4.38-4.30 (IN, t), 3.48 ( 2H, c), 2.96-2.78 (2H, t), 2.62-2.30 (4H, t), 2.00-1.90 (2H, t), 1.85-1, 72 (2H, t), 1.25 (ZH, c).

Preparation 10 75 (2K)-1-amino-3-I4-(4-chloro-2-methylphenoxy)-piperidin-1-yl|Ipropan-2-ol su si mm i-A.MH,

Prepared as described for the preparation of 7 (Steps 2 and 3) from 4-(4-chloro-2-methylphenoxy)-piperidine.

MS (ER) 299/301 (MAN). sc "YAN NMR 5 (C0500) 7.12-7.05 (2H, t), 6.87 (1H, a), 4.39 (1H, septet), 3.77-3.70 (1H, t ), 2.84-2.72 (2H, t), 2.71 (1H, aa), 2.55 (1H, aa), 2.50-2.39 (2H, t), 2.40 ( 1H, 4), 2.39 (1H, a), 2.18 (ZH, c), 2.04-1.95 (2H, o t), 1.86-1.75 (2H, t).

Preparation 11 6-C-(1--2K)-3-amino-2-hydroxypropyl|piperidin-4-yloxy)-2,3-diporbenzamide so «so

Shk o sch 1 A m, o z5 so

Stage 1: tert-butyl 4-(2-(aminocarbonyl)-3,4-dichlorophenoxy|piperidine-1-carboxylate) tert-butyl 4-I3,4-dichlorophenoxy|piperidine-1-carboxylate (7.0 g, 20.3 mmol) in 5 g of dry tetrahydrofuran (250 ml) at -702С under a nitrogen atmosphere is added dropwise t-butyllithium (1 ml, 1.3 M in b cyclohexane). The solution is stirred for another 30 minutes at this temperature and treated with granules of solid carbon dioxide (excess). The cooling bath is removed and the mixture is stirred intensively while it is heated to room temperature for 1 hour. After another 1 hour, the solution is concentrated to about of it, approximately 5 Oml, is then partitioned between aqueous sodium hydrogencarbonate solution and diethyl ether. The aqueous phase is then washed with diethyl ether (3x), then acidified to pHaA and extracted with dichloromethane (3x). The combined extracts are dried (magnesium sulfate) and concentrated. Workup of the crude carboxylic acid ( 2.5g, 6b, 4mmol) i) carbonyl-1,1-diimidazolide (1.25g, 7.7mmol) in dichloromethane (bOml) at room temperature for 72 hours gives the crude imidazolide, which is concentrated in vacuo, redissolved in ethanol (20ml) and treated with 3595 aqueous ammonia (2O0ml) in an autoclave at 10097 for 2 hours. The mixture is slowly cooled to room temperature 60 for crystallization of the desired compound. The crystalline product is filtered and washed with water.

Recrystallization from ethanol/water gave the desired compound (1.90 g).

MS (HIAT) 289/291 (M-N-VOS)" "YAN NMR 5 (SOSIv) 7.40 (1H, a), 6.83 (1H, 4), 5.91 (1H, 8), 5 .73 (t, 5), 4.52 (t, t), 3.59 (2H, t), 3.41 (2H, t), 1.86 (4H, t), 1.43 (OH, in). 65 Stage. 2: 2,3-dichloro-6-(piperidin-4-yloxy)benzamide oh, it is! with

To a stirred solution of tert-butyl 4-I-(2-(aminocarbonyl)-3,4-dichlorophenoxy|piperidine-1-carboxylate 70. (1.8g, 4.6mmol) in dichloromethane (10ml) add trifluoroacetic acid (1Oml) After 30 minutes at room temperature, the solution was concentrated in vacuo and partitioned between saturated aqueous sodium hydrogencarbonate and dichloromethane. The aqueous layer was back-extracted 3 more times with dichloromethane and 3 times ethyl acetate. The combined organic extracts were dried (anhydrous potassium carbonate) and concentrated to give the desired compound as a white solid product (1.15 g). 19 MS (HIAT) 289/291 (MN)"

TN NMR 5 (CO300) 7.49 (1H, a), 7.09 (1H, a), 4.65 (1H, M), 3.15 (2H, t), 2.84 (2H, t) , 2.02 (2H, t), 1.82 (2H, t).

Step 3: 6-(11-(2K)-3-amino-2-hydroxypropyl|piperidin-4-yl)oxy)-2,3-dichlorobenzamide

Step a: Triethylamine (1.0 bml, 7.bmmol) and (2K)- glycidyl-Z-nitrobenzenesulfonate (1.0 g, Z, vmmol) and the mixture is heated at 609C for 3 hours. Sodium azide (1.0 g, 15.2 mmol) is added and the temperature is maintained for another 48 hours. The mixture is concentrated in vacuo to almost dryness and the product is partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer is re-extracted with dichloromethane, then with ethyl acetate. The combined organic extracts were dried (anhydrous potassium carbonate) and concentrated in vacuo. in Step B: The product is redissolved in tetrahydrofuran (5Oml) and treated with water (bml) and triphenylphosphine (2.4g). The mixture is heated at 602C for 4 hours, then concentrated in a vacuum. The product Go) is partitioned between ethyl acetate and 1N aqueous hydrochloric acid. Aqueous extracts are further washed with ethyl acetate, then alkalinized with 4895 sodium hydroxide solution to pH 1.1. The aqueous layer is extracted with dichloromethane (III) and the combined organic extracts are dried (anhydrous potassium carbonate) and concentrated in vacuo to give the crude amine, which is used without any purification in the next step (See Example 132). ise)

The preparation 12 with (K)-1-(4-(3,4-dichloro-phenoxy)-piperidin-1-yl|-3-methylamino-propan-2-ol with IF.

A solution of 4-(3,4-dichlorophenoxy)-1-(2K)-oxiran-2-ylmethyl|piperidine (1g, 3, 33 mmol) and methylamine (2.5 bml « 40905 in water, 33.1 mmol) in ethanol (15 ml) is heated at 602 in a sealed vessel for 16 hours. - c The solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography, elution. 8965 of 7M ammonia in methanol in dichloromethane to give the desired compound (875mgH). "» MS (HIAT) 333/335 (MN)

TN nMR 5 (SPON) 7.31 (IN, a), 6.99 (IN, 4), 6.75 (IN, a), 4.32-4.26 (IN, t), 3.86- 3.80 (IN, t), 2.91-2.86 (1H, t), 2.71-2.65 (2H, t), 2.65 (IN, aa), 2.56-2, 51 (2H, t), 2.54 (1H, aa), 2.48-2.42 (2H, t), (ee) 2.46 (ЗН, в), 2.38-2.27 (ЗН , t).

Preparation 13 o (2K)-1-amino-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl|propan-2-ol im) b 50 o so IF. he min, p

Prepared as described in the preparation of 10 using 4-(2,4-dichloro-3-methylphenoxy)-piperidine. iF) MS (HIAT) 333/335 (MN) ko "YAN NMR 5 (С0500) 7.25 (2Н, 4), 6.94 (2Н, 4), 4.54-4.37 (1ИН, т) , 3.88-3.71 (IN, t), 3.35-3.24 (2Н, t), 2.93-2.72 (4Н, t), 2.72-2.57 (1Н, t), 2.08-1.90 (2H, t), 1.92-1.75 (2H, t). 60 Preparation 14 (25)-amino-3-(4-(3,4-dichlorophenoxy) piperidin-1-yl|propan-2-ol b5 o a loj

Obtained as described in the preparation of 7, using (25)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate.

MS(ER)Z19/321 (MAN)

TN NMR 5 (SOSIsh) 7.30 (IN, a), 6.99 (IN, a), 6.75 (IN, ad), 4.36-4.24 (1H, t), 3.75- 3.65 (1H, t), 70 2.94-2.78 (2H, t), 2.70-2.60 (2H, t), 2.59-2.51 (1H, t), 2 ,41-2.25 (ZH, t), 2.03-1.93 (2H, t), 1.87-1.77 (2H, t).

Drug 15 (2K)-1-Amino-2-methyl-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|propan-2-ol.

Step 1: 2-I(2K)-2-methyloxiranyl|methyl/|-1H-isoindole-1,3(2H)-dione. about in; inv,

Ma o

Potassium phthalimide (1.304g, 7mmol) was added to a solution of (25)-(2-methyloxiran-2-yl)umethyl Z-nitrobenzenesulfonate (1.913g, mmol) in dry dimethylformamide (15ml). The mixture was stirred at 5023 for 5 hours and then cooled to room temperature. The resulting mixture is partitioned between ethyl acetate and water.

The aqueous phase was washed with ethyl acetate (2 x 100 mL) and the combined organic extracts were washed with water (3 x 100 mL), saturated brine, dried over sodium sulfate, and concentrated in vacuo to a crude orange (3 wax. Purify by chromatography (silica, 20905 ethyl acetate in iso-hexane) to give the desired compound as a white solid (0.864g).

MS(ER)UVU(M-CO) 7 so zo TN NMR 5 (SOSIv) 7.90-7.85 (2H, t), 7.78-7.71 (2H, t), 4.02 (IN , 4), 3.71 (1Н, а), 2.82 (IN, а), 2.62 (На), 1.39 (ЗН 5). (Se)

Step 2: 2-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl|-1H-isoindole-1,3(2H)-dione. about | 70 Solution of 4-(3,4- and 8-dichlorophenoxy)piperidine (0.985 g, 4 mmol), with 2-I(2K)-2-methyloxiranil|methyl| -1H-isoindole-1,3(2H)-dione (0.869g, 4mmol) and triethylamine (0.809g, 1.12ml, 3mmol) in ethanol (20ml) were stirred at 502 for 5 hours. The resulting solution was cooled to room temperature temperature and concentrated in vacuo to a crude yellow resin. Flash chromatography (silica, 295 7N methanolic ammonia in dichloromethane as eluent) afforded the desired compound as a yellow oil (1.24 g). so MS (ARSTI) 463/465/467 (MAN)

TN NMR 5 (SOSIZ) 7.89-7.85 (2H, t), 7.76-7.72 (2H, t), 7.30 (IN, 4), 6.98 (IN, a), 6.78 (1H, ab), o 4.27-4.21 (1H, t), 3.88 (1IN, 4), 3.70 (IN, 4), 343 (IN, ra 5), 2 .96-2.81 (2H, t), 2.60-2.42 (4H, t), with 1.95-1.89 (2H, t), 1.80-1.70 (2H, t ), 1.15 (ZN, c).

Stage 3: (2) (2K)-1-amino-2-methyl-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|propan-2-ol.

Me as c) And fivch

F)

To a solution of 2-(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl|-1H-isoindole-1,3(2H)-dione (278mg,

O,bmmol) in ethanol (bml) add aqueous methylamine (4095 solution in water, bml). The mixture is stirred at 60 room temperature for 24 hours and then concentrated in vacuo to a crude yellow glass. This glass is dissolved in methanol (2ml), added to the flash cartridge of ZSC (2g), washed with methanol (25ml) and 7H ammonia in methanol (25ml). Methanolic ammonia was concentrated in vacuo to give the desired compound as a yellow glass (165 mg).

MS (IER) 333/335/337 (MN) bo TN NMR 5 (SOSIsh) 7.31 (IN, 4), 6.99 (IN, a), 6.75 (IN, ad), 4.29- 4.21 (1H, t), 2.96-2.80 (2H, t),

2.60-2.30 (4H, t), 2.00-1.90 (ZH, t), 1.85-1.75 (ZH, t), 1.13 (ZH, 5).

Preparation 16 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

And

Ua» - Ca c oo 1-oxo-7-sulfo-1,2-dihydroisoquinoline-4-carboxylic acid (5g) is added to chlorosulfonic acid (25ml). /5 The mixture is heated at 10092 for 84 hours and then slowly dropped onto ice with stirring. The mixture was filtered and the residue washed with water and ether and dried to give 7-(chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a dark yellow solid (7.5 g).

MS (ARST) 286 (M-H)

T"H NMR 5 (DMSO) 11.81 (1H, 49), 8.79 (1H, a), 8.48 (1H, 49), 8.03 (1H, 4), 7.96 (1 N, ad).

Preparation 17 7-KMethylamino)sulfonal|-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid with no

I N o pt- o "8. o so

MS (HIAT) 283 (MAN)! ise)

TN NMR 5 (DMSO) 12.93 (1H, 5), 12.13 (1IN, 4), 9.03 (IN, 4), 8.61 (IN, 4), 8.16 (IN, 4) , 8.12 (1Nao), sc 7.65 (1На), 2.43 (ЗН, а).

Preparation 18 o 1,2-dihydro-7-((2-hydroxyethyl)amino|sulfonyl|-1-oxo-4-isoquinolinecarboxylic acid with 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid acid (1g) is added to aqueous methylamine (boOml) and the mixture is stirred for 18 hours. Concentrated hydrochloric acid is added to acidify the mixture, which is filtered through a filter. L ;" 3 Do/ton and so bo " (ab) 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1g) is added to ethanolamine (3ml) in hot tetrahydrofuran (3ml) and the mixture is stirred for 18 hours Hydrochloric acid is added to acidify the mixture which is filtered to give (o) 50 1,2-dihydro-7-((2-hydroxyethyl)amino|sulfonyl|-1-oxo-4-isoquinolinecarboxylic acid as a white solid. so MS(HIAT)ZI1Z(M kN) 7. "YAN NMR 5 (DMSO) 12.92 (5Н, c), 12.12 (5Н, c), 9.01 (6Н, 4), 8.62 ( 6H, c), 8.16 (1IZN, 4), 8.13 (1IZN, av), 7.81 (6H, 9, 4.67 (5H, c), 3.39-3.25 (84H, t), 2.81 (1ZN, a).

Preparation 19 o 7-Cykpopylamino)sulfonyl/)-1,2-dihydro-1-oxo-4-isoquinolinecarboxylic acid m J. go » jun. X; a b5 o 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1g) is added to cyclopropylamine (Zml)

in tetrahydrofuran (200 ml) and the mixture is stirred for 18 hours. Hydrochloric acid is added to acidify the mixture, which is filtered to give 7-Kcyclopropylamido)sulfonyl 1,2-dihydro-1-oxo-4-isoquinolinecarboxylic acid as a white solid. 55 MO (ARST) 307 (M-N). "YAN NMR 5 (DMSO) 12.93 (1H, c), 12.13 (IN, 4), 9.03 (IN, 4), 8.65 (1IN, 4), 8.16 (1IN, 4 ), 8.14 (1H, ab), 8.08 (1H, a), 2.13 (1H, adsextet), 0.48 (2H, 4), 0.39-0.34 (2H, t) .

Preparation 20 7-"(Azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

7-Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1g) was added to azetidine (0.7ml) and diisopropylethylamine (00.4ml) in tetrahydrofuran (5ml) and acetonitrile (5 mL) and the mixture was stirred for 72 h, then evaporated.The solid was crystallized from methanol and hydrochloric acid was added to acidify the mixture, which was filtered to give 7-(azetidin-1-ylsulfonyl)-1-oxo-1,2 -dihydroisoquinoline-4-carboxylic acid as a white solid product.

MS (HIAT) 309 (MN) s "YAN NMR 5 (DMSO) 12.99 (1H, c), 12.21 (1H, 4), 9.12 (IN, a), 8.54 (1H, 4 ), 8.20 (1H, 4), 8.16 (1H, av), ge) 3.70 (AN, 9, 1.99 (2H, quintet).

Preparation 21 7-("Aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid so

And about so

And with

BUT. o o mn, d) so 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1g) is added to 0.880 ammonia (bOml) and the mixture is stirred for 18 hours. Concentrated hydrochloric acid was added to acidify the mixture, which was filtered to give 7-(aminosulfonyl)-i-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid. ;" MS (HIAT) 269 (MEN)

TN NMR 5 (DMSO) 12.91 (1H, c), 12.08 (1H, 9), 8.99 (1H, a), 8.68 (1H, 4), 8.16 (1H, as) , 8.14 (1H 4), 7.53 (2H 5).

Drug 22

Ge | 7-KDimethylamino)sulfonyl|)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid ? And oh oh no. And her

IR e) o -- o o o 7-"Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.8g) was added to dimethylamine (15ml) and the mixture was stirred for 18 hours. The mixture was acidified with concentrated hydrochloric acid and then filtered to give 7-(dimethylamino)sulfonyl|-1-oxo-1,2-dihydroiso-dihydroisoquinoline-4-carboxylic acid as a white solid. 6o MS (HIAT) 295 (M-H)- "H NMR 5 (DMSO) 12.96 (1H, c), 12.19 (1H, 9), 9.07 (1H, 4), 8.50 ( 1H, 4), 8.18 (1H, 49), 8.11 (1H, as), 2.65 (6H, v5).

Drug 23 7-(3-Hydroxy-3-methylazetidin-1-yl)sulfonyl|)|-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid b5

M. so na i ; | 5. 7-Chlorosulfonyl)-1-oxo-1,2-dihydroiso-dihydroisoquinoline-4-carboxylic acid (1g), diisopropylethylamine (3ml) and 3-methylazetidin-3-ol hydrochloride ( 0.8g) in tetrahydrofuran (8ml) is heated at 552C for 3 days.

The mixture was acidified with hydrochloric acid and then filtered to give 7-(3-hydroxy-3-methylazetidin-1-yl)sulfonyl|-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.

MS (ER) 337 (M-H)- "NMR 5 (DMSO) 12.99 (1H, c), 12.22 (1H, 4), 9.11 (IN, 49), 8.53 (1H , 5), 8.21 (1IN, 4), 8.16 (1Н, ad), 3.61 (2Н, а), 3.46 (2Н, а), 1.25 (ЗН, 9.

The preparation 24 si o sh tsu y - or MN, sh o si o

IF / Residential complex (Te)

Ma! high school

Step 1: tert-butyl 4-(3-chloro-4-cyanophenoxy)piperidine-1-carboxylate o 4-(411-(2kK)-3-amino-2-hydroxypropyl|piperidin-4-yloxy)-2-chlorobenzonitrile (uh)

Potassium tert-butoxide (5.57g, 49.6v8mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00g, 24.84mmol) in glyme (1000ml) and the mixture was stirred for 30 minutes before the addition of 2- chloro-4-fluoro-benzonitrile (7.73 g, 49.68 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between ethyl acetate (250 mL) and water (200 mL). The organic layer is separated, dried with magnesium sulfate, and the solvent is evaporated. The residue was purified by flash chromatography, eluting with a mixture of ethyl acetate':isohexane (4:1), obtaining the desired compound as a colorless solid product (3.45 g). "» MS (IER) 337 (MN) " TN NMR 5 (SOSI) 1.47 (9Н, 8), 1.72-1.80 (2Н, t), 1.90-1.97 (2Н, t ), 3.37 (2H, aa), 3.68 (2H, aao), 4.54 (1H, aquintet), 6.86 (1H, aa), 7.01 (1H, a), 7.57 (1H, a).

Step 2: 4-(41-(2K)-3-amino-2-hydroxypropyl|piperidin-4-yl)oxy)-2-chlorobenzonitrile to a solution of tert-butyl 4-(3-chloro-4-cyanophenoxy)piperidine -1-carboxylate (2.75g, 9.09mmol) in dichloromethane (20ml) was added trifluoroacetic acid (2O0ml) and the mixture was stirred for 90 minutes. The solvents were evaporated and the residue was distilled with toluene (2x20ml) before dissolving in water (30ml) and adding sodium hydroxide to bring the solution to pH11. The free base is extracted with dichloromethane (5 x 100 ml). Organic

Gee! 250 products are combined, dried over sodium sulfate and the solvent removed under reduced pressure to give a thick oil, which is dissolved in dimethylformamide (3 mL) before addition of (2K)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.35g, 9.09mmol) and triethylamine (2.54 ml, 18.18 mmol).

The mixture is heated at 602 for 4 hours before adding sodium azide (1.36g, 27.27mmol). Heating is extended at 602C for another 72 hours. The reaction mixture was cooled and partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was separated and the solvent was removed under reduced pressure. Remainder

HF) is dissolved in tetrahydrofuran (2O0ml) and water (2ml) and triphenylphosphine (5.90g, 22.72mmol) is added. Mixture

HF is heated at 602C for 16 hours before diluting with ethyl acetate (100ml). The solution is washed with 1N NOCI (5 Oml) and the aqueous layer is separated and adjusted to pH 11 with sodium hydroxide. The product is extracted with dichloromethane in (4x10Oml). The organics are combined and dried over sodium sulfate and the solvent is removed under reduced pressure. The residue was purified by flash chromatography to give the desired compound as a pale yellow solid (1.10 g).

MS (IER) 310 (MN)

TN NMR 5 (SOCI3) 7.56 (IN, a), 7.00 (IN, sa), 6.85 (IN, ad), 4.42 (1H, septet), 3.73-3.67 ( 1H, t), 65 2.93-2.86 (1H, t), 2.86-2.78 (1IN, t), 2.71-2.62 (2H, t), 2.61-2 .55 (1IN, t), 2.45-2.30 (ЗН, t), 2.06-1.96 (2Н, t), 1.91-1.79 (2Н, t).

Preparation 25 (2K)-1-amino-3-4-I4-(methylsulfonyl)phenoxy|piperidin-1-yl-propan-2-ol o On gi Z 70 Obtained as described in the preparation of 24, starting from 1-fluoro-4 -(methylsulfonyl)benzene.

Stage 1: tert-butyl 4-I4-(methylsulfonyl)phenoxy|piperidine-1-carboxylate 58 IF: o il Z schi o

TN NMR 5 (SOSIv) 1.48 (9H, c), 1.74-1.82 (2H, t), 1.91-1.99 (2H, t), 3.04 (ZH, c), 3.38 (2H, gave), 3.69 (2H, gave), 4.57-4.62 (1H, t), 7.02 (2H, a), 7.86 (2H, a).

Step 2: (2K)-1-amino-3--4-(4--methylsulfonyl)phenoxy|piperidin-1-ylylpropan-2-ol

MS (IER) 329 (MAN)7

TN NMR 5 (SOCI) 7.85 (2H, 4), 7.01 (2H, 4), 4.47 (1H, septet), 3.73-3.67 (IN, t), 3.03 ( ZN, z), 2.95-2.88 (1IN, t), 2.86-2.78 (IN, t), 2.72-2.62 (2Н, t), 2.61-2, 55 (1H, t), 2.45-2.30 (ZH, t), 2.08-1.98 (2H,..ZhYAMM t), 1.92-1.81 (2H, t). at

Preparation 26 4-(11-(2K)-3-amino-2-hydroxypropylpiperidin-4-yloxy)benzonitrile

Ge ch M (se) - and I in,

Chu see

Prepared as described in the preparation of 24 starting from 4-fluorobenzonitrile. ("in")

Stage 1: tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate so shi s o :z» MS (IER) 303 (MAN) 7.

TN NMR 5 (SOSIv) 7.58 (2H, a), 6.95 (2H, 4), 4.55 (1H, t), 3.69 (2H, aa), 3.37 (2H, avda) , 1.97-1.90 45. H, t), 1.80-1.72 (2H, t), 1.47 (ZH, 5). o Stage 2: 4-41-(2kK)-3-Amino-2-hydroxypropylpiperidin-4-yl)oxy)benzonitrile

MS (IR) 276 (MN) o TN NMR 5 (SOSIv) 7.57 (2H, 4), 6.94 (2H, a), 4.46-4.41 (IN, t), 3.74- 3.68 (1IN, t), 2.94-2.88 (1IN, t), ka 2.83 (1Н, aa), 2.73-2.66 (1Н, t), 2.64 (1Н , aa), 2.61-2.55 (IN, t), 2.46-2.30 (ЗН, t), 2.07-1.97 (2Н, t), o 50 1.91-1 .80 (2H, t).

Drug 27

Che) tert-butyl. 4-(4-chloro-2-(methoxycarbonyl)phenoxy|piperidine-1-carboxylate os, o yu IF. de Mao a ZK 60 o

Diisopropyl azodicarboxylate (5.2 ml, 26.8 mmol) was added dropwise to the solution

of β-chloro-2-hydroxymethylbenzoate (5.0g, 26.mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (5.4g, 26.8mmol) and triphenylphosphine (7.02g, 26.8mmol) in tetrahydrofuran wounds (200 ml) at 02C. The reaction mixture 65 is heated to outside temperature overnight. The solvent was removed under reduced pressure and the residue triturated with diethyl ether (200 mL). The triphenylphosphine oxide is filtered off and the diethyl ether is removed under reduced pressure. The residue was purified by flash column chromatography, eluting with a mixture of ethyl acetate:isohexane (1:9) to give the desired compound as a brown oil (8.1 g).

MS (IER) 370 (MN)

TN NMR 5 (DMSO) 1.47 (OH, c), 1.79-1.92 (4H, hl), 3.45-3.54 (2H, t), 3.56-3.62 (2H , t), 3.89 (ZH, c), 4.5Ф4.59 (1H, t), 6.92 (1H, 49), 7.38 (1H, as), 7.77 (1H, a) .

Preparation 28 2-(1-(tert-butoxycarbonyl)piperidin-4-yl|oxy)-5-chlorobenzoic acid o' yF.

M.O z" a ZhK

Aqueous solution of 2N sodium hydroxide (20ml) was added to a solution of tert-butyl 4-(4-chloro-2-(methoxycarbonyl)phenoxy|piperidine-1-carboxylate (8.1g, 22.00mmol) in tetrahydrofuran (7Oml) at 459b. The mixture is stirred intensively for three hours, then it is adjusted to pH2 with 2N hydrochloric acid.

The product is extracted with ethyl acetate and the organic layer is washed again with water until the pH of the washings is 6.

The organic layer is dried with magnesium sulfate and evaporated. The residue was distilled with toluene to give the desired compound as a colorless solid (7.5 g).

MS (IER) 356 (MAN) s 29 IN NMR 5 (DMSO) 1.47 (9H, c), 1.79-1.88 (2H, t), 2.03-2.11 (2H, t) , 3.30 (2H, avda), 3.77-3.85 (2H, t), (U 4.72 (1H, t), 7.02 (1H, 49), 7.49 (1H, ad ), 8.12 (1H, 4), 10.91 (1H, c).

Preparation 29 4-(4-chloro-2-methylcarbamoyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester

Bromo-tris-pyrrolidinephosphonium hexafluorophosphate (1.57g, 3.37mmol) was added to a vigorously stirred mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ioxy)-5-chlorobenzoic acid (1.00g, 2, 8immol) and 40960 - s of aqueous methylamine (2ml) in DCM (1Oml), stirring is prolonged for 30 minutes, before partitioning between a 1N hydrochloric acid (1Oml) and dichloromethane (1Oml). The organic layer was separated and washed with saturated sodium bicarbonate solution (20 mL) and water (20 mL), then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:isohexane (1:11) , obtaining the desired compound as a colorless solid product (0.84 g). (ee) MS (IR) 369 (MAN) o "YAN NMR 5 (SOCIv) 8.17 (1H, a), 7.75 (1H, 8) , 7.35 (IN, aa), 6.91 (IN, 9), 4.58 (IN, Yu, 3.81-3.71 (2H, t), 3.29 (2H, aaa), 3 .00 (ZH, a), 2.08-1.98 (2H, t), 1.82-1.71 (2H, t), 1.48 (9H, c). Name) Drug 30

F 50 tert-butyl. 4-(2-(aminocarbonyl)-4-chlorophenoxy|piperidine-1-carboxylate so H.O o a m z o 60 Obtained as described in the preparation of 29, using aqueous ammonia.

MS (IER) 355 (MAN) "IN NMR 5 (SOSIv) 8.18 (1H, a), 7.67-7.61 (1H, t), 7.40 (1H, ad) 6.94 (1H , 4), 5.83-5.76 (1H, t), 4.61 (1H, t), 3.84-3.76 (2H, t), 3.26 (2H, dav), 2, 09-2.01 (2H, t), 1.82-1.73 (2H, t), 1.47 (9H, 5).

Drug 31 65 Methyl 2-(11-K2K)-3-amino-2-hydroxypropyl|piperidine-4-yloxy)-5-chlorobenzoate

And about

Glass, then Obtained as described in the preparation of 24, step 2 from tert-butyl 4-N4-chloro-2-(methoxycarbonyl)phenoxy|piperidine-1-carboxylate.

MS (IBR) 343 (MANU"

IN NMR 5 (SOSIv) 7.75 (1H, a), 7.37 (IN, aa), 6.92 (1H, 4), 4.46-4.39 (1IN, t), 3.89 ( ZN, c), 3.72-3.66 (IN, t), 2.93-2.87 (1IN, t), 2.81 (IN, ad), 2.69-2.55 (2Н, t), 2.63 (1H, ad), 2.43-2.31 (ZH, t), 2.00-1.84 (2H, t), 1.67-1.46 (2H, t) .

Preparation 32 2-(11-(2K)-3-amino-2-hydroxypropyl|piperidin-4-yloxy)-5-chloro-M-methylbenzamide by M. and I

We are MN, sia (with Fr

Obtained as described in the preparation of 24, step 2 from 4-(4-chloro-2-methylcarbamoyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester.

MS (IER) 342 (MAN) Ge)

TN NMR 5 (SOSIv) 8.18 (IN, sa), 7.88 (1Н, 8), 7.34 (1Н, ач), 6.91 (1Н, 4), 4.54748 (IN, т) , 3.73-3.67 "so (IN, t), 3.01 (ZN, a), 2.89-2.83 (1H, t), 2.83 (IN, ad), 2.68 -2.56 (2H, t), 2.63 (1H, ad), 2.44 (1H, aa), 2.39-2.33 (1H, t), 2.34 (1H, av), 2.13-2.03 (2H, t), 1.94-1.83 (2H, t). Ge

Drug 33 2-(31-(2kK)-3-amino-2-hydroxypropyl|piperidin-4-yloxy)-5-chlorobenzamide o o o m, so

We, shi cho»eoa ; c" Obtained as described in the preparation of 24, step 2 from tert-butyl 4-(2-(aminocarbonyl)-4-chlorophenoxy|piperidine-1-carboxylate. 15 MS (IER) 328 (MN) bo TN NMR 5 (SOCIv ) 8.19 (IN, a), 7.75 (1IN, 8), 7.39 (1IN, ach), 6.93 (1H, 4), 5.85 (1H, c), 4.56- 4.48 (1H, t), 3.73-3.67 (1H, t), 2.93-2.86 (1H, t), 2.83 (1H, ad), 2.73-2, 66 (1H, t), 2.63 (1H, av), 2.61-2.54 (1H, t), (in 2.44 (1H, av), 2.37-2.30 (1H , t), 2.35 (1H, aa), 2.15-2.05 (2H, t), 1.90 (2H, aa).

GF Preparation 34 tert-butyl 4-(3,4-dichloro-2-(cyclopropylamino)carbonip|phenoxy)piperidine-1-carboxylate (22)

IR e)

NM. .o s o

F) p, in pe 60 a

A solution of tert-butyl 4-133,4-dichloro-2-(1H-imidazol-1-ylcarbonyl)phenoxy|piperidine-1-carboxylate (described in the preparation of 11 step 1) (2.0 g, 4.5 mmol) in cyclopropylamine ( 12 ml) is heated at 502 for 14 hours. The solution is concentrated in vacuo, then partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic 65 products are dried over magnesium sulfate and concentrated in vacuo. Crystallization from a mixture of dichloromethane:isohexane gave the desired compound as a white solid (0.64 g).

MS (IER) 429/431 (MAN)

TN YAME 5 (DMSO) 846 (IN, a), 7.56 (1Н, а), 7.17 (IN, 4), 4.68 (IN, t), 3.42-3.27 (4Н, t), 2.74 (1H, t), 1.78 (2H, t), 1.55 (2H, t), 0.68 (2H, t), 0.44 (2H, t).

Drug 35 6-(41-(3-Amino-2-hydroxypropyl)piperidin-4-yl|oxy)-2,3-dichloro-M-cyclopropylbenzamide 70 nn. - about a

Prepared as described for the preparation of 24, step 2 from preparation 34.

MS (IER) 402 (MN)

TN NMR 5 (SOSIv) 7.35 (1H, a), 6.78 (1H, 4), 5.82 (1H, 8), 4.40-4.33 (IN, t), 3.68 ( IN, F, 2.92-2.85 (2H, t), 2.85-2.77 (2H, t), 2.81 (1H, ad), 2.62 (1H, aa), 2, 42-2.29 (ZH, t), 2.00-1.89 (2H, t), 1.88-1.79 (2H, t), 0.89 (2H, 19), 0.66- 0.62 (2H, t).

Preparation 36 tert-butyl-13,4-dichloro-2-(chlorosulfonyl)phenoxy|piperidine-1-carboxylate ni s o o

IF o i so 's

To a stirred solution of tert-butyl 4-13,4-dichlorophenoxy|piperidine-1-carboxylate (10.0g, 28.9mmol) in dry tetrahydrofuran (400ml) at -702C in a nitrogen atmosphere, t-butyllithium (26.7ml, 1.3M in cyclohexane). The solution is stirred for another 15 minutes at this temperature, and then sulfur dioxide is blown through the mixture for 10 minutes. The cooling bath is removed and the mixture is warmed to room temperature with 1 hour. M-chlorosuccinimide (4.63 g, Zbmmol) was added and the mixture was stirred at room temperature for 72 hours. The solution was concentrated in vacuo and partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic extracts are dried (magnesium sulfate) and concentrated. Chromatography on silica (ethyl acetate: isohexane/1:3) gives the desired compound as (2.40 g) « 20 MS (IER) 445 (MAN) - in s TN NMR 5 (DMSO) 7.45 (1H, 49) , 7.03 (1H, a), 4.65 (1H, t), 3.59 (2H, t), 3.33 (ЗН, 5), 1.66 (4H, t), 1.40 ( ON, 5).

Drug 37; t 2,3-dichloro-6-(piperidin-4-yloxy)benzenesulfonamide zo, so o sh )F. (He) 50 Tert-butyl-4-13,4-dichloro-2-(-chlorosulfonyl)phenoxy|piperidine-1-carboxylate (0.80 g, 1.8 mmol) is dissolved in SO TN ammonia in methanol and stirred at at room temperature for 20 minutes. The solution is concentrated in vacuo and then distilled once with toluene. The residue is again dissolved in a mixture of dichloromethane:trifluoroacetic acid 71:11 (20 ml) and stirred at room temperature for 15 minutes. The solution is concentrated in vacuo, then partitioned between ethyl acetate and a saturated aqueous solution of 99% sodium bicarbonate. The aqueous phase is re-extracted with ethyl acetate (4 times) and the combined organic products

GF) is dried with anhydrous potassium carbonate. Concentration in vacuo gave the desired compound as a white powder (0.54 g).

GF MS (IER) 325/327 (MAN)

TN NMR 5 (DMSO) 7.74 (1H, 49), 7.34 (1H, 4), 4.66 (1H, t), 2.96 (2H, t), 2.55 (2H, t) , 1.91 (2H, t), 1.63 (2H, t). Preparation 38 2,3-dichloro-M-methyl-6-(piperidin-4-yloxy)benzenesulfonamide b5

Tert-butyl 4-13,4-dichloro-2-(chlorosulfonyl)phenoxy|piperidine-1-carboxylate (0.70g, 1.8mmol) was dissolved in 4096 aqueous methylamine in water (10ml) and methanol (10ml) and stirred at at room temperature for 30 minutes. The solution is concentrated in vacuo and then distilled with toluene (4 times). The residue is again dissolved in a mixture of dichloromethane:trifluoroacetic acid (1:1) (2 Oml) and stirred at room temperature for 15-75 minutes. The solution is concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase is re-extracted with ethyl acetate (4 times) and the combined organic products are dried with anhydrous potassium carbonate. Concentration in vacuo gave the desired compound as a white powder (0.69 g).

MS (IER) 339/341 (MAN) "YAN YaMeR 5 (DMSO) 7.76 (1H, 4), 7.35 (1H, a), 4.64 (IN, t), 2.96 (2H, t), 2.54 (ZH, c), 2.54 (2H, t), 1.90 (2H, t), 1.61 (2H, t).

Preparation 39 2,3-dichloro-M-cyclopropyl-6-(piperidin-4-yloxy)benzenesulfonamide

XX century

M (o)

OpoghO o s «so si sch

Tert-butyl 4-13,4-dichloro-2-(chlorosulfonyl)phenoxy|piperidine-1-carboxylate (0.70g, 1.8mmol) was dissolved in o-cyclopropylamine (3ml) and stirred at room temperature for 30 minutes. The solution is concentrated in

Removed under vacuum and then precipitated with toluene (4 times). The residue is again dissolved in a mixture of dichloromethane/trifluoroacetic acid 1:11 (20 ml) and stirred at room temperature for 15 minutes. The solution is concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase is re-extracted with ethyl acetate (4 times) and the combined organic products are dried with anhydrous potassium carbonate. Concentration in vacuo gave the desired compound as a white powder (0.70 g).

MS (IER) 365/367 (MAN) not) with "IN YAME 5 (DMSO) 7.78 (1H, 4), 7.36 (1H, a), 4.65 (1H, t), 2.97 (2H, t), 2.55 (2H, t), 2.27 (1H, t), 1.89 "z (2H, t), 1.63 (2H, t), 0.49 (AN, t);

Preparation 40 6-(11-K2K)-3-amino-2-hydroxypropyl|piperidin-4-yl)oxy)-2,3-dichlorobenzenesulfonamide o Oo-5:0 z a o on b 50 - so c in,

Prepared as described for the preparation of 7 (Steps 2 and 3) from preparation 37.

MS (IER) 398/400 (MAN) o Preparation 41 6-(11-K2K)-3-amino-2-hydroxypropyl|piperi/adin-4-yloxy)-2,3-dichloro-M-methylbenzenesulfonamide o "nn "

Ts

60 Sha 20 b5 s

Prepared as described for the preparation of 7 (Steps 2 and 3) from preparation 38.

MS (ER) 412/414 (MAN)

Drug 42 6-(11-K2kK)-3-amino-2-hydroxypropyl|piperidin-4-yl)oxy)-2,3-dichloro-M-cyclopropylbenzenesulfonamide " ra ' 02:25:05 s. on

Prepared as described for the preparation of 7 (Steps 2 and 3) from preparation 39.

MS (IER) 438/440 (MAN)

Drug 43 7-(Methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Y o no s o 87 o vo

7-(chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (see preparation 16) (400mg) is added in portions to a solution of sodium bicarbonate (500mg) and sodium sulfite (353mg) in 4ml of water at 02. The reaction mixture was warmed to room temperature and then heated at 8092 for 2 hours. The reaction mixture is cooled to 02C and acidified to a pH of approximately 1 with concentrated hydrochloric acid. Suspension. SU is diluted with 4 ml of water and stirred for 15 minutes at 0 2С, then filtered under nitrogen. The solid product is washed twice with water and added to a degassed aqueous solution (3 ml) of potassium bicarbonate (280 mg) at 459C. Ethanol is then slowly added until the solution becomes slightly cloudy. Iodomethane (26261.1) is then added and (he) the reaction mixture is refluxed (45-50 2) for 5 hours. The reaction mixture is concentrated in vacuo, extracted with ethyl acetate, and the aqueous phase is acidified with concentrated hydrochloric acid. The reaction mixture was stirred at 09C for 30 minutes, and the solid was collected by filtration, then recrystallized from acetone to give the desired compound as a white solid (325mg). with MS (ER) 266 (M-H) with» TN NMR 5 (DMSO) 12.97 (1H, Bv), 12.19 (1H, 4), 9.07 (1H, 4), 8.70 ( 1H, 9), 8.27 (1H, a4), 8.19 (1H, a), 3.30 (ZH, 5).

Preparation 44 15 6-(Methylsulfonyl)-1H-isoindole-3-carboxylic acid ii and («c) iu MO vo

FU 50 me so iv,

Prepared as described for the preparation of 43 from preparation 16 using indole-3-carboxylic acid.

MS (ER) 238 (M-H)- "IN NMR 5 (DMSO) 12.34 (1H, Ba c), 12.29 (1H, c), 8.31 (IN, 5), 8.21 ( 1H, 4), 8.03 (IN, a), 7.69 (1H.av), 3.20 (1 H, a). o Preparation 45 o 6-Fluoro-1-oxo-1,2-dihydroisoquinoline-4 -carbonic acid

Obtained by the methods: (I ieridzv Appaiep deg Spetje, 1981,5, 819-27 and Spetisa |! 5 РНаптасецииса! VyPeip, 60 1983, 31, 1277-82.

Stage 1: Dimethyl I|5-fluoro-2-(methoxycarbonyl)phenyl|malonate b5

IS

(received according to OZ 5189168)

Sodium hydride (6095 in mineral oil, 1.3 g) is added in portions to a rapidly stirred suspension of 2-bromo-4-fluorobenzoic acid (4.5 g) and copper(I) bromide (175 mg) in 25 ml of dimethylmalonate at 09C. After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 30 minutes at room temperature at 75°C, then heated at 70°C for 2 hours. The solidified reaction mixture is then diluted with water (vOml) and extracted with diethyl ether (3x5Oml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x100). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and the crude material was recrystallized from diethyl ether/iso-hexane to give the desired compound as a white solid (1-9G).

TN NMR 5 (DMSO) 13.36 (1H, bv), 8.05 (1H, av), 7.35 (1H, avda), 7.14 (1H, av), 5.08 (1H, c) , 3.70 (EN, 5).

Stage 2: 2-"Carboxymethyl)-4-fluorobenzoic acid p v nn E 3o A suspension of dimethyl (|b-fluoro-2-(methoxycarbonyl)phenyl|malonate (1.80 g) in concentrated hydrochloric "0 acid (25 ml) is heated at 110922 for 48 hours.The reaction mixture was cooled and the desired compound was collected as a white solid by filtration (1.50OH).

MS (IBR) 197 (M-N) | "in)

TN NMR 5 (DMSO) 7.97 (1H, ad), 7.24 (1H, as), 7.20 (1H, as), 3.96 (2H, 5). with

Stage 3: (42)-6-Fluoro-(methoxymethylene)-1H-isochromene-1,3(2H)-dione with CO 15 2-("Carboxymethyl)-4-fluorobenzoic acid (1.40 g) in a mixture of acetic acid (3 ml) and trimethyl orthoformate (1 ml) is heated at 1102 for 3 hours. At this time, the formed methyl acetate is driven off. At the end ("c"), the reaction mixture is cooled to 02С. The white solid was collected by filtration and washed with cold

Ge with water and methanol (1.32 Hg).

MS (IER) 207 (M-Me):

Me, Step 4: Methyl b-fluoro-1-oxo-1H-isochromene-4-carboxylate

IR e) s! Ha! salts o o name) 60 To a suspension of (42)-6-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(2H)-dione (1.30g) in methanol (2Oml) slowly add sulfuric acid (1 .5 ml). The mixture is heated at 40-5022 for 3 hours. As the reaction proceeds, the desired compound crystallizes. The reaction mixture was cooled to room temperature and the white solid was collected by filtration and washed with cold methanol. be MS (IER) 222 (MAN)

TN NMR 5 (DMSO) 8.49 (1H, c), 8.30 (1H, av), 8.25 (1H, av), 7.56 (1H, ha), 3.81 (ZH, c) .

Step 5: Methyl b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate which

A mixture of methyl b-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g) and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid is heated at 802C for 16 hours. The reaction mixture is cooled to 402C, diluted with 8 ml of water, and the solid product is collected by filtration (1.38 g).

MS (ER) 220 (M-NU

T"H NMR 5 (DMSO) 12.00 (1H, 5), 8.46 (1H, ad), 8.32 (1H, av), 8.10 (1H, 5), 7.44 (1H, 19), 3.83 (ZN, c).

Stage 6: 6-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid and M. so s o

An aqueous solution (3ml) of sodium hydroxide is added to a solution of methyl b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (1.3g) in methanol (3ml). (1g) and the reaction mixture is heated at 802C for 3 hours. The reaction mixture is cooled to 202C and carefully acidified with concentrated hydrochloric acid. The white precipitate is isolated by filtration, washed with water and methanol, obtaining the desired compound (1.16 g) ise)

MS (IER) 206 (M-N). c "H NMR 5 (DMSO) 12.85 (1H, c), 11.91 (1H, a), 8.58 (1H, ad), 8.31 (1H, av), 8.09 (1H, a), 7.41(1 H, (9).

Drug 46 o 7-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid with

Obtained by: Iieridz Appaiep deg Spetje, 1981, 5, 819-27 and Spetisa! 5 RNagtaseciisa! BiPape, 1983, 31,1277-82. 5

Stage 1: Dimethyl I4-fluoro-2-(methoxycarbonyl)phenyl|malonate « meo. go /OMe shi -myu z

E co Prepared as described in the preparation of 45, step 1, using 2-bromo-5-fluorobenzoic acid. (av) MS (IER) 269/237 (M-H) 1H NMR 5 (DMSO) 7.70 (1H, av), 7.49 (1H, 19), 7.39 (1H, av), 5.71 (1H, c), 3.68 (6H, 5).

Stage 2: 2-"Carboxymethyl)-5-fluorobenzoic acid

F) co Prepared as described in the preparation of 45, step 2, using dimethyl

I4-fluoro-2-(methoxycarbonyl)phenyl|malonate. 60 MS (ER) 197 (M-H)-

TN NMR 5 (DMSO) 7.81-7.74 (t, t), 7.62 (t, ad), 7.41-7.35 (y, t), 3.92 (2H, c).

Stage 3: Methyl 7-fluoro-1-oxo-1H-isochromene-4-carboxylate b5

0. -20 o'clock

Prepared as described in the preparation of 45, steps C and 4, using 2-(carboxymethyl)-5-fluorobenzoic acid.

MS (IER) 223 (MEN)

T"H NMR 5 (DMSO) 8.60 (1H, aa), 8.42 (1H, 5), 7.95 (1H, av), 7.86 (1H, aaa), 3.87 (ZH, in).

Stage 4: Methyl 7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate o -o o E

Prepared as described in the preparation of 45, step 5, using methyl 7-fluoro-1-oxo-1

H-isochromene-4-carboxylate.

MS (ER) 221 (M-N) - p

TN NMR 5 (DMSO) 12.04 (1H, z), 8.82 (1H, av), 8.03 (1H, c), 7.91 (1H, as), 7.73 (1H, 9) , 3.83 (ZN, 5). 5)

Step 5: 7-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

M. so s yu" on F s o

E about

Obtained as described in the preparation of 45, step b, using methyl ee 7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ER) 206 (M-H)- "H NMR 5 (DMSO) 12.81 (1H, c), 12.00 (1H, a), 8.93 (1H, as), 8.02 (1H , 4), 7.90 (1H, ad), 7.71(1 H, (9). "

Preparation 47 6-(Methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid obtained by the following methods: | ieridz AppaIep deg Spetje, 1981, 5, 819-27 and Spetisa! 5 RIagtaseciis! ViyPeyip, ch» 1983, 31, 1277-82). " Stage 1: 2-(2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl|-4--(methylsulfonyl)benzoic acid) - b 50 a

IR e). -

Oho

Obtained by: Shoishgpa! oi Ogdapis Spetivigu, 1998, 63, 4116-4119).

Sodium ethoxide (10.0 g) is added in portions to a very rapidly stirred suspension of 2-chloro-4-methylsulfonyl)benzoic acid (10.0 g) and copper(I) ime) bromide (1.0 g) in 5 bOml of diethylmalonate at 209C. The reaction mixture was stirred for 30 minutes at room temperature, then heated at 902 for 36 hours. The slurry 60 is diluted with water (200ml), aqueous ammonia (3ml) is added and the mixture is extracted with diethyl ether (3 x 10Oml).

The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x1OOml).

The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo.

MS (IER) 3577311 (M-N)

ТН NMR 5 (СО300) 8.28 (1Н, 4), 8.06 (1Н, av), 7.99 (1Н, 9), 5.78 (1Н, c), 4.20 (АН, 4), 3.19 (ZN, 5), 1.28 (BNO. b5 and -

Step 2: 2-"Carboxymethyl)-4-(methylsulfonyl)benzoic acid

MO at 2:5:0

Obtained by: Shoishgpa! oi Ogdapis Spetivigu, 1998, 63, 4116-4119).

The crude material from step 1 is dissolved in methanol (200ml) and a solution (200ml) of sodium hydroxide (13g) is slowly added. The reaction mixture is stirred at room temperature for 3 hours. Methanol is removed /5 In vacuum. The aqueous layer is extracted with diethyl ether (3x100ml), acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate (3x100ml). The combined organic layers are dried with magnesium sulfate, filtered, concentrated to a third of the volume and heated at 659C for 3 hours until complete decarboxylation. The formed solid product was collected by filtration (7.1 g).

MS (IER) 257/213 (M-H) "H NMR 5 (DMSO) 8.10 (1H, 9), 7.95 (1H, a), 7.93 (1H, ad), 4.07 ( 2H, c), 3.28 (ZH, c).

Stage 3: (42)-4-(Methoxymethylene)-6--"methylsulfonyl)-1H-isochromene-1,3(2H)-dione c t o c 0:5:0 (Ce) . c

Obtained as described in the preparation of 45, step C, using 2-(carboxymethyl)-4-(methylsulfonyl)benzoic acid. at

MS (IR) 267 (M-Me)" co "IN NMR 5 (DMSO) 8.68 (1H, 9), 8.32 (1H, 9), 8.31 (1H, c), 7.98 ( 1H, aa), 4.36 (ZH, 5), 3.46 (ZH, 5).

Stage 4: Methyl 6-(methylsulfonyl)-1-oxo-1H-isochromene-4-carboxylate o. -0 « o I shi s shchi :» o

Oh: 5:0

Prepared as described in the preparation of 45, step 4, using co (42)-4-(methoxymethylene)-6-(methylsulfonyl)-1H-isochromene-1,3(2H)-dione. b» 50 TN NMR 5 (DMSO) 9.08 (1H, a), 8.56 (1H, c), 8.44 (1H, 9), 8.1-8 (1H, aa), 3.89 (ZN, c), 3.34 (ZN, c).

Step 5: Methyl 6-(methylsulfonyl)-1-oxo-1,2-α|-dihydrohydroisoquinoline-4-carboxylate

ИЧ f) Ч c) о «и о; With bo o25:0

Prepared as described in the preparation of 45, step 5, using methyl b-(methylsulfonyl)-i-oxo-1

H-isochromene-4-carboxylate. in5 MS (ER) 280 (M-H)- "H NMR 5 (DMSO) 12.23 (1H, 5), 9.35 (1H, 9), 8.47 (1H, 9), 8.17 ( 1H, c), 8.06 (1H, 49), 3.86 (ZH, 5), 3.78 (ZH, c).

but A o b oh3go

Step 6: bmethylsulfonyl)-1-oxo-1,2-dihydroiso-dihydroisoquinoline-4-carboxylic acid

Obtained as described in the preparation of 45, step b, using methyl 6b-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylate. 19 MS (IER) 266 (M-N)-

TN NMR 5 (DMSO) 12.99 (1H, c), 12.14 (1H, a), 9.45 (1H, 4), 8.46 (1H, a), 8.15 (1H, 4) , 8.04(1 H, as), 3.30 (ZH, 5).

Drug 48

GU ik. (8)

Stage 1: tert-butyl 4-3,4-dichloro-2-(methylsulfonyl)phenoxy|piperidine-1-carboxylate dnu so

(2K)-1-amino-3-4-IZ,4-dichloro-2-(methylsulfonyl)phenoxy|piperidine-1-ylylpropane-2- ol

To a stirred solution of tert-butyl 4-13,4-dichlorophenoxy|piperidine-1-carboxylate (10.0g, 28.9mmol) in dry tetrahydrofuran (400ml) at -702C in a nitrogen atmosphere, t-butyllithium (26.7ml) was added dropwise , 1.3M in Cyclohexane). The solution is stirred for another 15 minutes at this temperature and then treated with dimethyl disulfide (3.9 mL, 4 mmol). The solution is stirred at this temperature for 30 minutes and then a cooling bath. is removed and the mixture is stirred intensively while heating to -ZOH occurs for 30 minutes. a Saturated aqueous ammonium chloride solution (5 mL) is added and the mixture is concentrated to a volume of approximately 30 mL and partitioned between water and ethyl acetate. Organic extracts are dried with magnesium sulfate and concentrated.

Treatment of the crude residue with meta-chloroperbenzoic acid (13.3 g, 57-8695) in dichloromethane (200 ml) at room temperature

Ho) temperature for 14 hours gives crude sulfone. The solution is shaken with sodium metabisulfite solution, then the organic products are dried with magnesium sulfate and concentrated in vacuo. Chromatography on silicon dioxide - (ethyl acetate: isohexane) gives the desired compound (0.65 g) by MS (IER) 424/426 (MAN)

Ф 50 "IN YAMeR 5 (DMSO) 7.88 (TOBTO, 4), 7.42 (TOBTO, 4), 4.92 (IN, t), 3.52 (2Н, t), 3.32 (ЗН , c), 3.36-3.27 (2H, t), 1.90 (2H, t), 1.69 (2H, t), 1.40 (OH, c).

IR e) Stage 2: (2K)-1-Amino-3-14-IZ3,4-dichloro-2--methylsulfonyl)phenoxy|piperidin-1-ilyupropan-2-ol

Obtained as described in the preparation of 24, step 2 from tert-butyl 4-13,4-dichloro-2-(methylsulfonyl)phenoxy|piperidine-1-carboxylate.

MS (IER) 397/399 (MAN) o TN nNMR 5 (SOSIS) 7.60 (IN, sa), 6.94 (1H, a), 4.60-4.53 (IN, t), 3, 73-3.67 (IN, t), 3.33 (ZH, 5), 3.02-2.96 (1H, t), 2.81 (1H, az 2.79-2.73 (1H, t), 2.64-2.56 (IN, t), 15 2.63 (1Н, ad), 2.43-2.32 (ЗН, t), о 2.11-1.91 (4Н, t)

Drug 49 bo 8-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Stage 1: 2-"Carboxymethyl)-6-fluorobenzoic acid b5 sho

Prepared as described in the preparation of 45, steps 1 and 2, using 2-bromo-6-fluorobenzoic acid.

MS (IER) 197 (M-H)-

TN NMR 5 (DMSO) 7.46 (1H, 19), 7.20 (1H, aa), 7.18 (1H, a), 3.77 (2H, 5).

Stage 2: (42)-8-Fluoro-4-(methoxymethylene)-1H-isochromene-1,3(2H)-dione 0-00 20

Obtained as described in the preparation of 45, step 3, using 2-(carboxymethyl)-6-fluorobenzoic acid.

MS (IER) 207 (M-Me)"

Step 3: Methyl 8-fluoro-1-oxo-1H-isochromene-4-carboxylate

O.O

Y o shchi o E o so «so

Obtained as described in the preparation of 45, step 4, using (42)-8-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(2H)-dione. with

MS (IER) 222 (MN) o

TN NMR 5 (DMSO) 8.42 (1H, c), 8.34 (1H, a), 7.96 (1H, 19), 7.50 (1H, aa), 3.86 (2H, c) . 3 Stage 4: Methyl 8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (2,0) o. their di E 2 s and o y?

Prepared as described in the preparation of 45, step 5, using methyl 8-fluoro-1-oxo-1H-isochromene-4-carboxylate

Go! MS (ER) 220 (M-H)-

T"H NMR 5 (DMSO) 11.86 (1H, c), 8.57 (1H, 9), 8.03 (1H, c), 7.80 (1H, (9), 7.30 (1H , aa), 3.82 (ZH, 5). o Step 5: 8-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid ime) b 50 Ch o so HO , E o kept as described when obtaining ,; step ,; using methyl

F, (c) and 45 6 ko 8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ER) 206 (M-H) bo "H NMR 5 (DMSO) 12.75 (19Н, c), 11.76 (19Н, 4), 8.69 (22Н, 4), 8.02 (23Н , a), 7.78 (24H, I), 7.29 (22H, av).

Example 1

M-42k)-3-I4-(3,4-Dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide. b5 ak? h I zho i wa i i | and with -

Come on. her the same is the same her op still: whats i'm si in, shoin 'still' and pound

A mixture of 2-(methylsulfonyl)benzoic acid (0.063 g), (2K)-1-amino-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1 g) and M ,M-diisopropylethylamine (0.ml) in dry dimethylformamide (3ml) is cooled to 09s with stirring. 2-(1n-9-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.13g) is added and the mixture is stirred at 02C for 1-2 hours. A saturated solution of sodium bicarbonate (1 Oml) is added. The mixture is extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulfate.

The mixture is filtered and the solvent is evaporated. The resulting oil was purified by normal-phase chromatography using methanol/dichloromethane as eluent and reverse-phase HPLC using acetonitrile and 0.195 aqueous ammonium acetate as eluent to give the desired compound as a white solid (0.055g).

MS (HIAT) 501/503 (MN)

TN NMR 5 (DMSO) 8.57 (IN, 9, 7.96 (IN, a, 7.78 (1H, (9), 7.69 (IN, 3), 7.57 (IN, ach), 7.49 (1H, 9), 7.25 (1H, a), 6.98 (1IN, aa), 4.48-4.37 (1H, t), 3.85-3.74 (1H, t), 3.40-3.25 (1IN, t), 3.37 (ZH, c), 3.26-3.13 (IN, t), 2.83-2.69 (2H, t) , 2.44 (1H, ad), 2.37-2.26 (ZH, t), 1.95-1.84 (2H, t), 1.65-1.50 (2H, t).

Example 2

M-42k)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-methylsulfonyl)-benzamide c. at. and Ge) etc. o on Zo ma t yu" a o o . high school

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol | "c) (01g) and 4-( methylsulfonyl)benzoic acid (0.063 g). The desired compound is obtained as a white solid (g) (0.038 g).

MS (HIAT) 501/503 (MAN)

TN NMR 5 (DMSO) 8.69 (IN, 9, 8.05 (4H, ach), 7.49 (1H, 4), 7.25 (1H, a), 6.98 (IN, a), 4.76 (1H, Bgv), 4.43 (1H, t), 3.86-3.78 (1H, t), 3.43 (IN, ayu, 3.26 (ZN, 8), 3, 20 (IN, a), 2.79-2.67 (2H, t), 2.41-2.24 « 40. (AN, t), 1.95-1.85 (2H, t), 1 .66-1.54 (2H, t). ssh s Example 3 and 2-chloro-M(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)- 4--(methylsulfonyl)benzamide » a o two

S on y so kh y , Fr

Mu, oh a

Go). o С b 50

Prepared as described in Example 1 using o (2R)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1 g) and 3R-( methylsulfonyl)benzoic acid (0.074g).The desired compound is obtained as a white solid (0.033g).

MS (HIAT) 535/537 (MN)

TN NMR 5 (DMSO) 8.60 (IN, 0, 8.03 (IN, 4), 7.93 (IN, a, 7.70 (IN, 4), 7.49 (1Н, 4), 7 .25 (1H, 9), o 6.98 (IN, ach), 4.70 (1H, biv), 447-4.39 (1H, t), 3.82-3.74 (IN, t) , 3.41-3.31 (IN, t), 3.29 (ЗН, з), 3.23-3.15 (1Н, t), 2.80-2.69 (2Н, t), 2 .44-2.25 (4H, t), 1.96-1.86 (2H, t), 1.65-1.54 (2H, t). ime) Example 4 4-amino-M-(2K )-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-methoxybenzamide x Ya a i, 9 b5 . at

Obtained as described in example 1 from (2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1 g) and 4-amino- of 3-methoxybenzoic acid (0.052g).The desired compound was obtained as a white solid (0.053g).

MS (HIAT) 468/470 (MN)

TN NMR 5 (DMSO) 8.05 (IN, 9, 7.49 (1H, 9), 7.31-7.27 (2H, t), 7.25 (1H, a), 6.98 (1H , as), 6.60 (1H, 4), 5.23 (2H, 8), 4.74 (1H, bBg8), 4.47-4.38 (1IN, t), 3.80 (ЗН, 85), 3.81-3.73 (IN, t), 3.38-3.30 (1IN, t), 3.18-3.09 (1Н, t), 2.80-2.65 ( 2H, t), 2.36 (2H, ad), 2.32-2.22 (2H, t), 1.95-1.86 (2H, t), 1.66-1.54 (2H, t).

Example 5 70 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-(methylsulfonyl)benzamide vdeuvi on J o shchi p 929 th

S o o

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (01g) and 3-(methylsulfonyl)benzoic acid (0.063g).The desired compound was obtained as a white solid (0.017g).

MS (HIAT) 501/503 (MAN)

TN NMR 5 (DMSO) 8.74 (IN, 0, 8.39 (IN, 0, 8.18 (IN, ab, 8.07 (IN, ayu, 7.76 (IN, 9, 7.49 ( 1H, 9), 7.25 (1H, 4), 6.98 (IN, ad), 4.77 (1H, Bg8), 4.47-4.39 (IN, t), 3.86-3 /78 (1H, t), 3.45 (1H, ayu, 3.26 (ZH, 8), 3.24-3.14 (1H, t), 2.80-2.66 (2H, t) , 2.41-2.24 15 (4H, t), 1.95-1.86 (2H, t), 1.65-1.54 (2H, t). Ha

Example 6

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-5-(methylsulfonyl)thiophene-2-carboxamide.

IN

Obtained as described in example 1 from (2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol

Zo (0.1g) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065g). The desired compound is obtained as a white solid product (0.039 g).

MS (HIAT) 507/509 (MAN)

TN NMR 5 (DMSO) 8.85 (IN, 9, 7.84 (2H, aa), 7.49 (1H, a), 7.26 (1H, a), 6.98 (1H, as), 4.80 (1H, Bgz), « 20 4.47-4.39 (1H, t), 3.83-3.75 (1H, t), 3.45-3.38 (IN, t), 3.38 (ZN, 5), 3.18-3.09 (1H, t), 2.79-2.66 (2H, t), -v 2.37-2.22 (AN, t), 1.95-1.85 (2H, t), 1.65-1.53 (2H, t). c Example 7; c» M-42k)-3-I4-(3,4-dichlorophenoxy)piperidine- 1-yl|-2-hydroxypropyl)-quinoline-6-carboxamide shodo» with m AI re

Po) "o

Gee! 20 Obtained as described in the example from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1g) and quinoline-b-carbon acid (0.054g). The desired compound is obtained as a white solid product (0.032g). so MS (CHIAT) 474/476 (MAN)

TN NMR 5 (DMSO) 8.98 (1H, ach), 8.68 (IN, 0, 8.52 (IN, 4), 8.47 (1H, aa), 8.19 (IN, ad), 8.08 (1H, 9), 7.61 (IN, aa), 7.49 (1H, 4), 7.24 (IN, 4), 6.97 (IN, ach), 4.78 (IN , bBg5), 4.48-4.39 (IN, t), 3.90-3.82 (1H, t), 3.46 (1H, ayu, 3.31-3.23 (1H, t) , 2.82-2.70 (2H, t), 2.45-2.25 (AN, t), 1.96-1.87 (2H, t), 1.67-1.55 (2H, t).

HF) Example 8 with M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-6b- car boxamide acetate bo c o on Y b5 a

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1g) and 2-oxo-2 of ,3-dihydro-1,3-benzothiazole-b6-carboxylic acid (0.06 1g).The desired compound was obtained as the acetate, a white solid (0.10g).

MS (HIAT) 496/498 (MN)

TN NMR 5 (DMSO) 8.36 (IN, 0, 8.05 (1H, 4), 7.78 (IN, ad), 7.49 (1H, a), 7.25 (1IN, 4), 7.15 (1H, 9), 6.98 (1H, aa), 4.47-4.40 (1H, t), 3:80 (1H, quintet), 3.38 (IN, ayu, 3, 22-3.14 (IN, t), 2.80-2.67 (2Н, t), 2.41-2.25 (4Н, t), 1.95-1.86 (2Н, t), 1.91 (ZH, c), 1.66-1.54 (2H, t).

Example 9 70 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b6-fluoroimidazo|1,2-a|pyridine-2-carboxamide

IS

"s aho Z odeveya 4 a o Y

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.1g) and 6b-fluoroimidazo|1 ,2-α|pyridine-2-carboxylic acid (0.056 g). The desired compound is obtained as a white solid (0.076 g). He

MS (HIAT) 481/482 (MN) (5)

TN NMR 5 (DMSO) 8.80-8.78 (IN, t), 8.63 (IN, 0, 8.33 (IN, 8), 7.68 (IN, aa), 7.50 (1Н , a), 7.52-7.44 (IN, t), 7.28 (1IN, a), 7.00 (1H, ad), 4.89 (1H, 5), 4.52-4, 44 (1H, t), 3.83-3.74 (1H, t), 3.44-3.28 (2H, t), 2.83-2.66 (2H, t), 2.44- 2.23 (AN, t), 2.02-1.90 (2Н, t), 1.82-1.72 (2Н, t).

Example 10 d)

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide so

S Y o sh zn F s u so o

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol « 20 (0.1g) and 1-oxo -1,2-dihydroisoquinoline-4-carboxylic acid (0.059g). The desired compound is obtained as a white solid product (0.047g). MS (HIAT) 490/492 (MH) and TN NMR 5 (DMSO) 11 .59 (IN, a), 8.33 (IN, 9, 8.22 (2Н, а, 7.73 (IN, 0, 7.54-7.48 (ЗН, т), 7.26 (1Н , a), 6.98 (1H, aa), 4.79 (1H, 5), 448-440 (1H, t), 3.85-3.76 (IN, t), 3.43-3, 31 (1IN, t), 3.14 (1H, quintet), 2.83-2.69 (2H, t), 2.45-2.25 (AN, t), 1.96-1.87 ( 2H, t), 1.67-1.55 (2H, t).

Ge | Example 11 about M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-1,3-benzothiazole-b6-carboxamide.

With the name of M

F IF. he i I so s Mu o

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol and F) (0.1 g) and 1.3 -benzothiazole-b6-carboxylic acid (0.056g). The desired compound was obtained as a white solid (0.066 g).

MS (HIAT) 480/482 (MAN) bo TN NMR 5 (DMSO) 9.54 (IN, c), 8.67 (IN, 4), 8.60 (IN, 0, 8.15 (IN, a ), 8.02 (1H, ad), 7.49 (1H, 9), 7.25 (1H, 4), 6.98 (IN, ad), 4.78 (1H, bBge), 4.47 -4.39 (IN, t), 3.87-3.79 (1H, t), 3.44 (1H, ayu, 3.23 (1H, quintet), 2.82-2.68 (2H, t), 2.40 (1H, aa), 2.37-2.23 (ZH, t), 1.96-1.86 (2H, t), 1.66-1.54 (2H, t) .

Example 12

3-cyano-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide b5 -BO0-

tk: "so that

Obtained as described in example 1 from (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.2g) and 3-cyanobenzoic acid ( 0.092g).The desired compound is obtained as a white solid product (0.050g).

MS (HIAT), 448/450 (MN)

TN NMR 5 (SOCI3) 810 (1H, 5), 7.79 (1IN, sa), 7.58 (IN, 0, 7.31 (IN, a), 7.00 (1H, a), 6, 80 (1H, 9, 6.75 (IN, ach), 4.38425 (1H, t), 4.00-3.87 (1IN, t), 3.81-3.68 (1IN, t), (IN, ayu, 2.98-2.85 (1H, t), 2.75-2.63 (IN, t), 2.63-2.53 (1H, t), 2.48 (1H, aa), (1H, 49), 2.32 (2H, 9, 2.07-1.90 (2H, t), 1.90-1.73 (2H, t).

Example 13

M-(4-14-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-2-(methylsulfonyl)benzamide. and oh oh or "in the va

Obtained as described in example 1 from 4-amino-1-(4-(3,4-dichlorophenoxy)piperidin-1-yl|butan-2-ol (0.26g) and c 2-(methylsulfonyl)benzoic acid ( 0.156 g). The required compound is obtained as a white solid product (0.170 g). o

MS (HIAT) 515/517 (MAN)

TN NMR 5 (SOCI) 8.09 (1H, as), 7.65 (1H, aa), 7.59 (1H, 1), 7.53 (IN, as), 7.31 (1H, sa) , 6.99 (1H, o), 6.74 (1H, aa), 6.74 (IN, ad), 4.32-4.23 (1H, t), 3.92-3.83 (IN , t), 3.83-3.74 (1H, t), 3.57-3.46 (1IN, t), 3.37 (ZH, 8), 2.94-2.85 (1H, t ), 2.70-2.60 (1H, t), 2.60-2.50 (IN, t), 2.40 (IN, ad), 2.35 (IN, aa), so 2.32 -2.23 (1H, t), 2.01-1.89 (2H, t), 1.88-1.69 (2H, t), 1.67-1.55 (2H, t). (That)

Example 14

M-(4-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-b-carboxamide c Obtained as described in example 1 from 4-amino-1-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|bsutan-2-ol (0.26 g) and c 2-oxo-2, of 3-dihydro-1,3-benzothiazole-b6-carboxylic acid (0.152 g). The desired compound is obtained as a white solid "» product (0.105 g).

MS (HIAT) 510/512 (MAN) "YAN NMR 5 (SOSIv) 7.88 (1H, a), 7.71 (1H, as), 7.48-7.39 (IN, t), 7, 31 (IN, a), 7.13 (1H, a), 7.00 (IN, (ee) a), 6.76 (1H, ad), 4.36-4.27 (1H, t), 3.93-3.83 (2H, t), 3.49-3.38 (1H, t), 2.97-2.87 (1H, t), 2.73-2.53 (2H, o t), 2.46-2.32 (2H, t), 2.36-2.27 (1H, t), 2.06-1.91 (2H, t), 1.90-1.75 ( ЗН, t), 1.66-1.53 (1Н, t).

Example 15 ime) 4-amino-M-4-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-3-hydroxybutyl)-3-methoxybenzamide so IF on pp

Si Y o.

F) 2 g Obtained as described in example 1 from 4-amino-1-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|bsutan-2-ol (0.26 g) and 4-amino- of 3-methoxybenzoic acid (0.130g). The desired compound is obtained as a white solid product (0.080g). in MS (HIAT) 482/484 (MH) "YAN nNMR 5 (SOCIv) 7.39 (1H, 4), 7, 31 (IN, 4), 7.15 (IN, ad), 7.04 (IN, B5), 7.00 (IN, 4), 6.75 (1H, av), 6.65 (1H, 4 ), 4.29 (IN, septet), 4.08 (2H, re"), 3.90 (ZH, 58), 3.89-3.75 (2H, t), 3.49-3.36 (1H, t), 2.96-2.85 (IN, t), 2.73-2.61 (IN, t), 2.61-2.50 (1IN, t), 2.44-2 .34 (2H, t), 2.35-2.23 (1H, t), 2.07-1.90 (2H, t), 1.90-1.71 (2H, t), 1.70 -1.48(2H, t). 65 Example 16

M-(4-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxybutyl)-2-(methylsulfonyl)benzamide si o s. o. s , it on 70 Obtained as described in example 1 from 1-amino-4-14-(3,4-dichlorophenoxy)piperidin-1-yl|Ibutan-2-ol (0.2 g) and 2-(methylsulfonyl)benzoic acid (0.12 g). The required compound obtained as a white solid product (0.090 g).

MS (HIAT) 515/517 (M-H)" "YAN nNMR 5 (SOSIv) 8.10 (1H, 4), 7.67 (1H, i), 7.61 (IN, 1), 7.55 (IN, a, 7.30 (IN, a), 6.98 (1H, o), 6.73 (IN, aa) 6.61 (IN, 0, 4.33-4.23 (IN, t ), 4.06 (1H, octet), 3.70 (1H, aada), 3.36-3.29 (IN, t), 3.37 75 (ZN, 8), 2.97-2.82 (1H, t), 2.78-2.68 (1H, t), 2.64 (1H, 40, 2.60-2.47 (2H, t), 2.38-2.22 (1H, t), 2.02-1.41 (6Н, t).

The compounds of examples 17 and 18 are obtained as in example 1 from preparation 13, starting from 4-(2,4-dichloro-3-methylphenoxy)piperidine.

Example 17

M-42k)-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-5 oxo-1,2-dihydroisoquinoline-4-carboxamide o n

M.O on Y sm shchi an | Mini about

I c zo Obtained as described in example 1 from preparation 13.

MS (HIAT) 504/506 (MN) ee, "YAN NMR 5 (DMSO) 11.58 (IN, c), 8.31 (IN, 0, 8.22 (2Н, а), 7.72 (1Н , 9, 7.56-7.48 (2H, t), 7.35 (1H, c a), 7.10 (IN, a), 4.80-4.70 (1H, t), 4, 53-4.44 (1IN, t), 3.85-3.75 (1H, t), 3.39 (IN, ayu, 3.15 (1H, quintet), 2.718-2.64 (2H, t ), 2.40 (ZH, c), 2.39-2.27 (4H, t), 1.96-1.83 (2H, t), 1.74-1.61 (2H, t). at

Example 18 ee

M-42k)-3-I4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide o. ""about NM with . from 0 to 2879

Y , oo Obtained as described in example 1 from preparation 13.

MS (HIAT) 515/517 (MEN) and TN NMR 5 (SOSIv) 8.10 (1H, a), 7.67 (IN, 0, 7.62 (IN, 0, 7.54 (1H, aa) , 7.19 (1H, a), 6.74 (1H, o), ka 6.55 (IN, 09, 4.41-4.27 (1H, t), 4.03-3.89 (1IN , t), 3.68 (IN, cottage), 3.44 (1H, ayu, 3.36 (ZN, c), 3.00-2.87

AN, t), 2.80-2.66 (1Н, t), 2.63-2.51 (2Н, t), 2.51-2.42 (1Н, t), 2.47 (ЗН, c), 2.42-2.29 (1H, t), 2.03-1.76 (4H, t).

Me Example 19 with M-4(25)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl1|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide. and in IF: ХВ

F! c 5) dovo 60 Obtained as described in example 1 from preparation 14.

MS (HIAT) 501/503 (MAN)

TN NMR 5 (SOSIL) 8.10 (IN, a), 7.68 (IN, 4), 7.62 (1H, 1), 7.54 (1H, ach), 7.31. (IN, 4), 6.99 (IN, a), 6.75 (1H, ach), 6.53 (IN, 9, 4.357.22 (1H, t), 4.04-3.91 (IN . 66 (1H, t), 2.65-2.52 (2H, t), 2.46 (1H, ad), 2.41-2.28 (IN, t), 2.04-1.88 ( 2H, t), 1.87-1.67 (2H, t).

Example 20

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-K(Kmethylamino)sulfonyl|benzamide'ones

Obtained as described in example 1 from preparation 7.

MS (HIAT) 516/518 (MEN)

TN NMR 5 (SOSISCH) 8.25 (IN, B), 7.99 (IN, a), 7.95 (IN, a), 7.55 (IN, 0, 7.41 (IN, 9, 7 .31 (IN, o), 7.00 (IN, 9), 6.75 (IN, ad), 4.95 (IN, c), 4.36-4.25 (1H, t), 4, 16-4.05 (IN, t), 3.75 (1IN, aad), 3.31 (IN, ada), 3.02-2.90 (1Н, t), 2.74-2.56 ( 2H, t), 2.68 (ZH, 85), 2.51 (1H, aa), 2.37-2.26 (1H, t), 2.37 (1H, aa), 2.07-1 .91 (2H, t), 1.91-1.72 (2H, t).

Example 21 3,5-bid(acetylamino)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl)benzamide - . with se; he h a MNAg sch a o

MS (HIAT) 537/539 (MN)

TN NMR 5 (SOSIi) 9.00 (2H, 8), 7.86 (IN, 5), 7.66 (2H, 8), 7.50 (1H, 8), 7.31 (IN, 4) , 6.99 (1H, o), 6.74 (1H, aa), 4.42-4.27 (1H, t), 4.19-4.03 (1H, t), 3.63-3 .46 (IN, t), 3.42-3.26 (1H, t), 3.05-2.91 (IN, t), c 2.91-2.74 (1H, t), 2, 75-2.54 (4H, t), 2.17-1.96 (2H, t), 2.11 (6H, c).

It was obtained as described in example 1 from preparation 7. ish 1.97-1.79 (2H, t). with

Example 22 3-(Acetylamino)-M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)/benzamide o on z - s :» Obtained as described in example 1 from preparation 7.

MS (HIAT) 480/482 (MAN)

IN NMR 5 (SOSIv) 7.88 (IN, 5), 7.78 (IN, a), 7.55-7.45 (2H, t), 7.39 (IN, 9, 7.31 (IN , a), 6.99 (1H, (ee) a), 6.82 (1H, 9, 6.75 (IN, ad), 4.37-4.22 (1H, t), 3.99- 3.85 (1H, t), 3.77-3.63 (IN, t), 3.38 (1H, quintet), o 2.96-2.83 (1H, t), 2.75-2 .63 (1H, t), 2.63-2.51 (1H, t), 2.52-2.24 (ЗН, t), 2.20 (ЗН, в), 2.08-1.90 (2H, t), 1.90-1.69 (2H, t). ime) Example 23 bo 50 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2- hydroxypropyl)-1H-pyrazole-4-caoboxamide so v o on B, vk o o yuyu Obtained as described in example 1 from preparation 7.

MS (HIAT) 413/415 (MEN) in TN NMR 5 (SOSIi) 8.02 (2H, 8), 7.33 (IN, a), 7.00 (IN, c), 6.95 (IN, 0, 6.76 (IN, a), 4.44-4.33 (1H, t), 4.07-3.98 (1H, t), 3.74-3.61 (IN, t), 3.40 (1H, (4), 2.98 (IN, 4), 2.89-2.77 (2H, t), 2.62 (2H, a), 2.68-2.56 (1H , t), 2.18-1.99 (2H, t), 1.98-1.82 (2H, t).

Example 24 2-"(Acetylamino)-5-bromo-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide b5 as a

Obtained as described in example 1 from preparation 7.

MS (HIAT) 558/460/562 (MN)"

TN NMR 5 (SOSI) 10.98 (IN, 8), 8.52 (1IN, a), 7.66 (1H, c), 7.55 (IN, 4), 7.32 (IN, 4) , 7.26 (1H, c), 75 7.16-7.05 (2H, t), 7.00 (1H, 5), 6.76 (1H, 4), 4.42-4.30 ( 1H, t), 4.06-3.94 (1H, t), 3.72-3.59 (2H, t), 3.43-3.29 (1H, t), 2.95 (1H, 9, 2.75 (2H, 9, 2.59-2.43 (ZH, t), 2.19 (ZH, c), 2.13-1.96 (5H, t), 1.96-1 ,78 (ZN, t).

Example 25

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxamide c o OH - -

SI; sch and ze; at

Obtained as described in example 1 from preparation 7.

MS (HIAT) 440/442 (MAN). Gee)

TN NMR 5 (SOSIv) 9.86 (IN, 9, 8.61 (IN, aa), 7.53 (1H, aa), 7.31 (IN, 9), 6.99 (IN, a), 6.75 (1H, ab), so 6.52 (1H, 9, 4.33-4.24 (1H, t) with 3.97-3.89 (IN, t), 3.70 (1H, yes), 3.44 (1H, 94), 2.94-2.85 (1H, t), 2.73-2.63 (IN, t), 2.59-2.50 (1H, t) , 2.49-2.37 (2H, t), 2.30 (1H, 9, 2.04-1.90 (2H, t), 1.87-1.72 (2H, t). s

Example 26 Fr

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-5-carboxamide g) a o « on 7 mo shA . what with and with" | at

Obtained as described in example 1 from preparation 7. so 45 MS (HIAT) 490/492 (MN)!

TN NMR 5 (DMSO) 11.34 (1H, 4), 8.46 (IN, 9, 8.28 (1H, a), 7.78 (1H, as), 7.50 (IN, 9, 7 .49 (1H, 9), (av) 7.25 (TOBTO, 4), 7.23-7.16 (IN, t), 6.98 (1H, ad), 6.81 (1IN, 4) , 4.72 (1H, 4), 4.49-4.37 (1H, t), 3.87-3.76 (IN, t), 3.46-3.35 (IN, t), 3 ,30-3.16 (IN, t), 2.83-2.67 (2Н, t), 2.47-2.23 (4Н, t), 1.97-1.84 (2Н, t) , ime) 1.68-1.50 (2H, t).

Ge) 50 Example 27 so M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)quinoline-4-carboxamide

G i-i v o a ti syh ime)

Obtained as described in example 1 from preparation 7. 60 MS (CHIAT) 474/476 (MEN) "YAN NMR 5 (СО500) 1.69-1.79 (t, 2H), 1.90-2.00 ( t, 2H), 2.53-2.65 (t, 4H), 2.84-2.94 (t, 2H), 3.39 (ad, 1H), 3.54 (da, yin), 3 .99-4.05 (t, 1H), 4.33-4.40 (t, 1H), 6.81 (da, tn), 7.03 (a, 1), 7.29 (a, tn ), 7.52 (a, 1H), 7.59 (i, 1H), 7.73 (i, 1H), 8.00 (a, IV), 8.15 (a, 1Hn), 8.83 (a, 1H).

Example 28 bo M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-4-carboxamide -B4-

and M with pi m y

Obtained as described in example 1 from preparation 7. 70 MS (CHIAT) 462/464 (MAN) "YAN NMR 5 (С0О50О0) 1.82-1.91 (t, 2Н), 2.00-2.13 ( t, 2H), 2.63-2.76 (t, 4H), 2.96-3.05 (t, 2H), 3.44 (ad,

TOBTO), 3.54 (ad, 1H), 4.04-4.11 (t, 1H), 4.43-4.50 (t, 1H). 5.50 (c, 1H), 6.56 (a, yin), 6.90 (aa, tn), 7.12 (d, TOBTO), 7.32 (y, 1H), 7.38 (a , 1H), 7.43 (d, 1H), 7.63 (aa, 1H), 8.14 (8, 1H).

Example 29 75 2-"-"Acetylamino)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzamide; about us Me in Obtained as described in example 1 from preparation 7. p

MS (HIAT) 480/482 (MN) o

TN NMR 5 (SOSIi) 11.05 (IN, ra 5), 8.60 (IN, a), 7.52-7.46 (2H, t), 7.31 (IN, a), 7.08 (IN, 0, 6.99 (IN, a), 6.81 (IN, ra c), 6.76 (1H, aa), 4.36-4.28 (IN, t), 3.96- 3.90 (1H, t), 3.72-3.64 (1IN, t), 3.40-3.32 (IN, t), 2.94-2.86 (2H, t), 2, 72-2.58 (2H, t), 2.49-2.31 (ЗН, t), 2.20 (ЗН, в), 2.03-1.93 (2Н, t), 1.89- 1.79 (2H, t). soso Example 30 2-(Acetylamino)-5-chloro-M-((2K)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|- 2-hydroxypropyl)benzamide, is), p

Y d) 0 - - s Obtained as described in example 1 from preparation 7. ;" MS (HIAT) 514/516/518 (MAN)"

TN NMR 6(SOSi) 10.94 (IN, ra c), 8.59 (IN, a), 7.47 (1Н, 4), 7.43 (1Н, aa), 7.32 (1Н, 4 ), 7.00 (1H, 4), 6.87 (IN, ra zv), 6.76 (IN, aa), 4.36-4.28 (IN, t), 3.97-3.90 (IN, t), 3.68-3.61 (1Н, t), 3.38-3.32 (1Н,

Go! t), 2.94-2.88 (1H, t), 2.72-2.58 (2H, t), 2.50-2.33 (ЗН, t), 2.19 (ЗН, в) , 2.05-1.95 (2H, t), 1.90-1.80 (2H, t).

Example 31 - 2-"""Acetylamino)-4-chloro-N-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl)|-2-hydroxypropyl)/benzamide Zone with b 50 and J

F)

GF Prepared as described in Example 1 from preparation 7.

MS (HIAT) 514/516/518 (MAN)" in TN NMR 5 (SOSIz) 11.19 (1H, Ba 5), 8.73 (1H, a), 7.42 (1H, a), 7, 32 (1H, a), 7.05 (1H, 4), 7.00 (1H, 9), 6.78-6.74 (2H, t), 4.36-4.28 (1H, t) , 3.96-3.88 (1IN, t), 3.70-3.62 (1Н, t), 3.38-3.30 (1Н, t), 2.94-2.88 (1Н, t), 2.70-2.58 (2H, t), 2.49-2.30 (ZH, t), 2.20 (ZH, c), 2.04-1.96 (2H, t) , 1.90-1.78 (2H, t).

Example 32 5-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)amino|Sbenzamide b5 m y: m on y mA 70 Obtained as described in example 1 from preparation 7.

MS (HIAT) 550/552/554 (MN)

TN NMR 5 (SOSIv) 7.69 (1H, a), 7.52 (1H, 5), 7.45 (IN, 4), 7.31 (IN, 4), 7.00 (IN, 4) , 6.75 (1H, av), 4.36-4.28 (1H, t), 3.96-3.90 (1H, t), 3.72-3.64 (1H, t), 3 .36-3.30 (1H, t), 3.04 (ZH, 5), 2.95-2.89 (1H, t), 2.714-2.56 (2H, t), 2.50-2 .30 (ZH, t), 2.05-1.95 (2H, t), 1.90-1.88 (2H, t).

Example 33 "70 inzome 4-Chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-Kmethylsulfonyl)amino|Sbenzamide

Obtained as described in example 1 from preparation 7. p

MS (HIAT) 550/552/554 (MN) "NMR 5 (SOSIv) 7.75 (1H, 4), 7.48 (1H, 4), 7.31 (IN, 4), 7.09 ( IN, a), 7.00 (IN, a), 6.75 (1H, av), o 4.38-4.28 (1H, t), 3.97-3.87 (1H, t), 3.72-3.66 (1H, t), 3.34-3.28 (1H, t), 3.08 (ЗН, в), 2.98-2.90 (1H, t), 2.716- 2.58 (2H, t), 2.50-2.30 (ZH, t), 2.10-1.94 5 (2H, t), 1.90-1.74 (2H, t).

Example 34 ee 2-amino-4-chloro-M-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl|benzamide c

Y k av) a a - 0 . d). Mn;

Prepared as described in Example 1 from preparation 7.

MS (HIAT) 472/474/476 (MN)! "

IN NMR 5 (SOCI8) 7.31 (1H, a), 7.27 (1H, 9), 6.99 (1H, 4), 6.75 (IN, ad), 6.67 (IN, a) . 1IN, t), 3.68-3.62 (1H, t), 3.36-3.29 (1H, t), and 2.94-2.86 (1H, t), 2.70-2 .54 (2H, t), 2.47-2.29 (2H, t), 2.26-2.16 (1H, t), 2.04-1.94 (2H, t), 1.88 -1.78 (2H, t). i" Example 35 5-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-6-oxo-1,6 -dihydropyridine-3-carboxamide y (o) ZE Ba. te y: "that How and I so - SCHE and: Still (av) still and ih y - he y; Z Her ta and and pt,

NK and dec, I... shk with NN DSHNNNYH and Y more! below Add to a solution of /(2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (150 mg, 047 mmol) and triethylamine (48 mg, 66 IA, 0.47mmol) in dichloromethane (20ml) was added a solution of 5-chloro-6b-hydroxynicotinyl chloride (9mg, 0.47mmol) in dichloromethane (100ml). The mixture was stirred at room temperature for 3 hours and then the solution was concentrated in vacuo to a crude oil. Purification by reversed-phase HPLC (0.195 ammonium

HF) acetate/acetonitrile) to give the desired compound as a colorless glass (150 mg, 6790). t MS (HIAT) 474/476/478 (MN)! "YAN NMR 5 (SOSIv) 8.07 (IN, 4), 8.04 (IN, 4), 7.31 (IN, 4), 7.09 (IN, Ba zv), 6.99 (1Н, a), 6.75 (1H, av), in 4.36426 (1H, t), 4.00-3.90 (IN, t), 3.68-3.58 (1H, t), 3, 32-3.22 (1H, t), 2.96-2.86 (1H, t), 2.76-2.58 (2H, t), 2.51-2.35 (ЗН, t), 2.04-1.94 (2H, t), 1.88-1.76 (2H, t).

Example 36 2-"-"Aminosulfonyl)-4-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl)|-2-hydroxypropyl)/benzamide b5 -58v-

and he and in with I 5o,n, o

Obtained as described in example 1 from preparation 7. 70 MS (HIAT) 536/538/540 (MN) "YAN NMR 5 (SOSIv) 8.39 (IN, 4), 7.90 (IN, ra c), 7.78 (1H, ach), 7.45 (1H, 4), 7.32 (1IN, 49), 7.00 (1H, 9), 6.76 (IN, ach), 4.38422 (2H , t), 3.76-3.62 (1H, t), 3.30-3.20 (1H, t), 3.10-3.00 (1IN, t), 2.80-2.68 (2H, t), 2.60-2.40 (ZH, t), 2.10-2.00 (2H, t), 1.96-1.86 (2H, t).

Example 37 75 M-42k)-3-I4-(3,4-Dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indazole-3-carboxamide; WITH, -

And about

Obtained as described in example 1 from preparation 7.

MS (HIAT) 463/465 (MN) s "IN YMRe 5 (SOSIv) 8.43-8.33 (2H, t), 7.54 (1H, 4)5 7.43 (1H, 9, 7, 32 (IN, a), 6.99 (1H, 4), 6.75 (1H, ad), he) 4.38-4.28 (1H, t), 4.15-4.05 (1H, t), 3.75-3.65 (1H, t), 3.60-3.48 15 (1H, t), 3.02-2.92 (1H, t), 2.80-2.50 (4H, t) with 2.45-2.37 (1H, t), 2.10-1.95 (2H, t), 1.90-1.75 (2H, t).

Example 38 1-tert-butyl-N-(2K)-3-I(4-73,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-methyl-1H-pyrazole-5-carboxy Samid Ge)

Si in Me cm «v) h m (ge) 1

Oh you

Obtained as described in example 1 from preparation 7.

MS (HIAT) 483/485 (MN)

TN NMR 5 (SOSI) 7.31 (IN, 4), 6.99 (IN, 4), 6.75 (1H, ad), 643 (IN, ra 5), 6.21 (1H, c), 4.35-4.25 in s (IN, t), 3.92-3.82 (IN, t), 3.70-3.58 (IN, t), 3.38-3.28 (1Н , t), 2.95-2.85 (2H, t), 2.70-2.50 (2H, t), "» 2.45-2.30 (ЗН, t), 2.24 (ЗН , 5), 2.05-1.90 (2H, t), 1.90-1.78(2H, t), 1.67(9H, c). " Example 39

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxa

M mid (ee) ta o ikh) on z ts ma a n

IR e) 0

Obtained as described in example 1 from preparation 7. 59 MS (HIAT) 467/469 (MEN)

HF) "YAN NMR 5 (DMSO) 12.69 (1H, c), 7.83 (1H, Ba c), 7.49 (1H, a), 7.25 (1IN, 4), 6.98 ( 1H, as), 4.80 (1H, o),

HF 4.43 (1H, quintet), 3.73 (1H, a), 3.39-3.16 (2H, t), 2.80-2.52 (6H, t), 2.38-2 .23 (4H, t), 1.96-1.86 (2H t), 1.78-1.58 (6H, t). in Example 40

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-"-trifluoromethyl)-1H-pyrazole-4-caobox copper b5

Also MN and drink in

Obtained as described in example 1 from preparation 7. 70 MS (HIAT) 481/483 (MAN)

TN NMR 5 (SOSIi) 8.11 (IN, 8), 7.32 (IN, 4), 7.00 (IN, 4), 6.75 (1H, ach), 6.70 (IN, ra in ), 4.38-4.28 (IN, t), 4.00-3.90 (IN, t), 3.70-3.60 (IN, t), 3.42-3.32 (1Н , t), 2.98-2.88 (1H, t), 2.75-2.58 (2H, t), 2.50-2.36 (ZH, t), 2.10-1.96 (2H, t), 1.92-1.76 (2H, t).

Example 41 75 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-methylimidazo|1,2AIpyridine-3-carboxamide» c) SIH

Obtained as described in example 1 from preparation 7. c 25 MS (HIAT) 477/479 (MAN)

TN NMR 5 (SOSII) 940 (1H, a), 7.58 (IN, a), 7.36-7.30 (2H, t), 7.00 (IN, 4), 6.92 (IN, 0, 6.76 (1H, o ad), 6.35 (IN, Bra in), 4.38-4.28 (1H, t), 4.01-3.93 (IN, t), 3, 82-3.72 (1Н, t), 3.48-3.40 (1IN, t), 2.98-2.90 (IN, t), 2.75 (ЗН, в), 2.70- 2.58 (1H, t), 2.54-2.30 (4H, c), 2.06-1.96 (2H, t), 1.94-1.76 (2H, t).

Example 42 ee 30 M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-(1H-pyrazol-3-yl)benzamide c - c

Me y: y on y 35 M g) o "

Obtained as described in example 1 from preparation 7. with MS (HIAT) 489/491 (MN). TN YAME 5 (SOSIv) 7.84 (2H, a), 7.76 (2H, a), 7.64 (1H, 49), 7.34-7.29 (2Na t), 7.00 (1H , 4), 6.75 (1H, av), 6.66 "» (IN, a), 4.45435 (1H, t), 4.18-4.08 (1H, t), 3.78- 3.66 (IN, t), 3.52-3.42 (1H, t), 3.06-2.96 (1H, t), 2.90-2.80 (2H, t), 2, 75-2.63 (ZH, t), 2.18-2.03 (2H, t), 2.00-1.80 (2H, t).

Example 43

Ge | M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)cinoline-4-carboxamido o - t Со он

Obtained as described in example 1 from preparation 7. o MS (ARSI) 475/477 (MEN)7 "YAN NMR 5 (SOSIZ) 9.41 (1Н, 5), 8.61 (1Н, а), 8, 38 (IN, a), 7.94-7.82 (2H, t), 7.33 (1H, 49), 7.20 (1H, Ba ko 8), 7.01 (IN, a), 6 .76 (IN, aa), 4.46-4.36 (IN, t), 4.18408 (IN, t), 3.88-3.78 (1IN, t), 3.56-3.46 (1H, t), 3.06-2.96 (1H, t), 2.94-2.78 (2H, t), 10 2.70-2.60 (ЗН, t), 2.03- 1.89 (4H, t). 6o0 Example 44

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide b5 o o OH and c; IF: hm ee 70 Obtained as described in example 1 from preparation 7.

MS (HIAT) 490/492 (MAN) "YAN NMR 5 (DMSO) 8.69 (IN, 9, 7.74 (1H, 4), 7.53 (IN, 0, 7.49 (IN, 4) , 7.34 (1H, 4), 7.25 (1H, 9), 7.18 (IN, 9, 6.98 (1H, aa), 6.54 (1H, 5), 4.50-4 .40 (1H, t), 3.87-3.77 (1H, t), 3.48-3.40 (1H, t), 3.28-3.18 (1H, t), 2.82 -2.70 (2H, t), 2.44-2.24 (4H, t), 1.97-1.87 (2H, t), 1.68-1.56 (2H, t).

Example 45

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI-2-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide in o o o o . o U ch 29 Obtained as described in example 35, using 2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride. Gee)

MS (HIAT) 479/481 (MN)

TN nMR 5 (SOCI3) 9.02 (1H, 0, 8.17-8.14 (IN, a), 7.32 (IN, a), 7.18-7.12 (2H, t), 7 .08-7.05 (1H, t), 7.00 (1H, 4), 6.75 (IN, aa), 4.42-4.32 (1H, t), 4.16-4.06 (1IN, t), 3.71-3.61 (1IN, t), 3.49-3.39 (1Н, t), so z 3.04-2.94 (1Н, t), 2.85 -2.75 (2H, t), 2.71-2.57 (ZH, t), 2.16-1.98 (2H, t), 1.96-1.80 (2H, t).

Example 46 (se)

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide c «c) i J a No. -MN b « | t c Obtained as described in example 1 from preparation 7. . MS (HIAT) 491/493/495 (MAN)" and? "YAN NMR 5 (SOSIv) 9.13 (IN, 4), 8.43 (1Н, а), 7.91-75 (ЗН, т) , 7.32 (1H, 4), 7.00 (IN, 4), 6.76 (1H, av), 4.40-4.32 (1H, t), 4.08-3.98 (1H , t), 3.76-3.66 (1H, t), 3.46-3.38 (IN, t), 3.00-2.92 (1H, t), 2.80-2.66 (2H, t), 2.58-2.44 (ZH, t), 2.14-1.98 (2H, t), 1.96-1.80 (2H, t).

Ge | Example 47 o M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-3-carboxamide o a oso 0 o...on so : no A ch o ' (F) Obtained as described in example 1 from preparation 7. ko MS (HIAT) 462/464/466 (MN)!

TN NMR 5 (SOSIi) 9.03 (1H, ra c), 8.07-8.04 (1H, s), 7.84 (IN, 5), 7.45-7.41 (1H, t) , 7.32 (1H, 9), in 7.28-71.22 (2H, t), 6.99 (1H, a), 6.82 (IN, 0, 6.74 (IN, ach), 4, 44-4.34 (1H, t), 4.16-4.06 (1IN, t), Z.78-3.68 (IN, t), 3.56-3.44 (IN, t), 3.04-2.94 (1H, t), 2.92-2.82 (2H, t), 2.77-2.65 (ZH, t), 2.18-1.98 (2H, t ), 1.98-1.78 (2H, t).

Example 48

M-42k)-3-I4-(4-chlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)benzamide b5 c i povo

Obtained as described in example 1 from preparation 4.

MS (HIAT) 467/469 (MAN)"

TN nMR 5 (COO500) 8.08 (IN, a), 7.79 (IN, 9, 7.71 (IN, 0, 7.61 (IN, a), 7.26 (2H, 4), 6 .95 (2H, d), 4.56-4.45 (1H, t), 4.21-4.08 (IN, t), 3.47 (2H, 4), 3.35 (ЗН, 8 ), 3.22-3.08 (2H, t), 3.01-2.77 (4H, t), 2.18-2.00 (2H, t), 1.99-1.83 (2H , t).

Example 49 t M-42k)-3-I4-(4-chlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide? Fno no Ki s yours

Obtained as described in example 1 from preparation 4. Ge

MS (HIAT) 466/468 (MN) (5) "YAN NMR 5 (DMSO) 11.57 (1Н, а), 8.30 (IN, 0, 8.22 (2Н, а), 7.73 ( IN, 0, 7.58-7.45 (2H, t), 7.30 (2H, a), 6.97 (2H, a), 4.75 (1H, c), 4.41-4, 29 (1H, t), 3.87-3.74 (1H, t)z3 3.46-3.26 (1H, t), 3.22-3.07 (1H, t), 2.85- 2.67 (2H, t), 2.41-2.21 (4H, t), 2.00-1.84 (2H, t), 1.70-1.51 (2H, t).

Example 50 g)

M-42k)-3-I4-(4-chloro-3-fluorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide c

E o z o F schi in: | at

Sak o « 20 Obtained as described in example 1 from preparation 5. with MS (HIAT) 474/476 (MEN) . "YAN NMR 5 (20500) 8.25 (1H, 4), 8.08 (1H, 4), 7.67 (1H, aa), 7.48 (2H, 0, 7.21 (IN, 9, 6.75 (1H, 9), "» 6.66 (1H, aa), 4.30 (IN, ach), 3.95-3.87 (1IN, t), 3.45 (1H, aa) , 3.29-3.24 (1H, t), 2.80-2.69 (2H, t), 2.45-2.31 (4H, t), 1.95-1.86 (2H, t), 1.73-1.62 (2H, t).

Example 51 (ee) (22) so o

M-42k)-3-I4-(3,4-difluorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxa copper 29 Obtained as described in example 1 from preparation 6.

GF) MS (HIAT) 458 (MAN)! t IN NMR 5 (CO500) 8.25 (1H, ad), 8.08 (1H, a), 7.67 (1H, aa), 7.50-7.46 (2H, t), 7.03 (1H, ayu, 6.76 (IN, aa), 6.63-6.59 (IN, t), 4.24 (1H, hiquintet), -3:94-3.87 (1H, t), 3.45 (IN, aa), 3.26 (1H, ach), 2.74 (2H, 49), 2.45-2.30 (4H, t), 1.90 (2H, ayu, 1, 72-1.61 (2H, t). 60

Example 52

M-(25)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide b5 vo and he is I

Mines with 0 70 Obtained as described in example 1 from preparation 12.

MS (HIAT) 504/506 (MAN) "YAN NMR 5 (DMSO) 1.25-1.42 (t, 1H), 1.57-1.73 (t, 2H), 1.89-2.15 (t, ZN), 2.26-2.42 (t, 2H), 2.69-2.85 (t, 1), 2.90-3.15 (t, 4H), 3.63-3 .77 (t, 1H), 3.97-4.09 (t, 1H), 4.26449 (t, 1H), 4.79495 (t, 1H), 6.91-7.01 (t, 1H ), 7.18-7.31 (t, 2H), 7.45-7.57 (t, ZH), 7.73 (i, 1H), 8.23 (a, 1H), 11.51 ( 8.1H).

Example 53

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-1H-indazole-3-carboxamidoone - I in Sa m o

Obtained as described in example 1 from preparation 12. p

MS (CHIAT) 477/479 (MEN) o "YAN NMR 5 (DMSO) 1.36-1.51 (t, 1H), 1.58-1.67 (t, 1H), 1.72-1, 81 (t, 1H), 1.86-1.96 (t, 1H), 2.04-2.21 (t, 2H), 2.26-2.39 (t, 2H), 2.71- 2.81 (t, 1H), 3.13 (v, ЗН), 3.49-3.57 (t, 1H), 3.78-3.93 (t, 1H), 3.98-4, 06 (t, 1H), 4.31448 (t, 1H), 4.71-4.83 (t, 1H), 6.93-7.00 (t, 1H), 7.16-7.25 ( t, 2H), 7.34-7.43 (t, 1H), 7.49 so zo (d, 1H), 7.58 (I, 1H), 7.95 (da, 1H), 13.34 -13.49 (t, 1H).

Example 54 (Se)

M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-M-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxamide "c) si o X o (ee)

Obtained as described in example 1 from preparation 12. ), 1.69-1.80 (t, 2H), 1.93-2.02 (t, 1H), 2.15-2.24 (t, 1H), 2.19 (49, 1H), 2.46-2.60 (t, 2H), 2.84-2.93 (t, 71H), 3.20 (in, ЗН), 3.42-3.51 (t, 71), 3, 75 (aa, 1), 3.84 (di, tn), 416425 (t, 1H), 4.35-4.41 (t, 1H), 6.79 (d4da, 1n), 7.00 (da , 1H), 7.28 (ad, 1H), 7.72-7.89 (t, ЗН), 8.31 (i, 1H).

So Example 55 av | Benzoic acid with 3-C2-(Х(2К)-3-І4-(3,4-dichlorophenoxy)-1-piperidinyl)|-2-hydroxypropylamino|-2-oxoethyl|amino|-, methyl ester

SS

- her and Al tu o. 5 o o o Obtained as described in example 1 from preparation 7.

MS (HIAT) 510/512 (MEN) where TN NMR 5 (SOSIi) 8.17 (IN, 0, 7.95 (IN, a, 7.38 (IN, 0, 7.31 (IN, 4), 6.98 (IN, 4), 6.91 (1H, 9, 6.78-6.68 (2H, t), 6.57 (1IN, a), 4.32420 (1H, t), 3, 92 (2H, a), 3.89 (ZH, c), 3.80-3.69 (1H, t), 3.52-3.40 60 (1H, t), 3.26 (1H, ab , 2.87-2.74 (1H, t), 2.62-2.39 (2H, t), 2.32 (1H, ad, 2.28-2.14 (2H, t), 2, 00-1.84 (2H, t), 1.83-1.66 (2H, t).

Example 56

propanamide,

IM-(2-(2-(Ш(2К)-3-І4-(3,4-diporphenoxy)-1-piperidinyl|-2-hydroxypropyl|amino|-2-oxoethyl|amino|phenyl|/|- b5 VodF on i m» Me o 70 Obtained as described in example 1 from preparation 7.

MS (HIAT) 523/525 (MANU

TN NMR 5 (SOSIi) 7.48 (IN, 0, 7.31 (IN, a), 7.23-7.11 (2Н, т), 7.05 (IN, а), 6.98 (2Н , 4), 6.83-6.71 (2H, t), 6.67 (1IN, a), 4.54 (IN, 9, 4.31417 (1IN, t), 3.92 (IN, a ), 3.79-3.66 (1IN, t), 3.45 (1Н, 3), 3.22 (IN, 19), 2.78-2.66 (1Н, t), 2.61- 2.43 (1H, t), 2.49 (2H, a), 2.37 (1IN, 9, 2.26-2.06 (ZH, t), 1.98-1.82 (2H, 75 . t), 1.82-1.64 (2H, t), 1.29 (ZH, 9.

Example 57

propanamide,

IM-(2-(2-(Ш(2К)-3-І4-(3,4-dichlorophenoxy)-1-piperidinyl|-2-hydroxypropyl|amino)|-2-oxoethyl|amino|)phenyl|- da o he a AL u "oi o sch

Prepared as described in Example 1 from preparation 7. (8)

MS (CHIAT) 494/496 (MN) "YAN NMR 5 (SOSIv) 7.73 (2Н, ach), 7.32 (1Н, ach), 7.29-7.21 (2Н, t), 7, 02-6.97 (IN, t), 6.97-6.88 (1H, t), 6.80-6.71 (1H, t), 6.60-6.49 (1H, t), 4.36-4.23 (IN, t), 4.14 (2Н, 09, 3.89-3.75 (IN, t), 3.62-348 (IN, t, oso 3.31-3 .17 (1H, t), 2.94-2.81 (1IN, t), 2.72-2.59 (1H, t), 2.60-2.47 (1H, t), 2.43 -2.22 (ZH, t), 2.40 (ZH, 5), 2.05-1.89 (2H, t), 1.88-1.72 (2H, t).

Example 58 (25)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-hydroxy-2-phenylethanamide o' g)

СО ниа он их ос - с ц Obtained as described in example 1 from preparation 7. is" MS (CHIAT) 453/455/457 (MAN)"

TN NMR 5 (SOCI3) 7.44-7.26 (6H, t), 6.98 (IN, a), 6.74 (1H, aa), 6.54 (IN, ra 5), 5.06 (1H, 5), 4.34-4.24 (1H, t), 3.83-3.73 (1H, t), 3.56-3.43 (1IN, t), 3.32-3 .20 (1H, t), 2.88-2.80 (1H, t), 2.62-2.52 (2H, (ee) t), 2.33-2.10 (ЗН, t), 2.02-1.90 (2H, t), 1.86-1.70 (2H, t). o Example 59 2-I2-(4(21)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)amino)-2-oxoethoxy|benzamide ime) bu 20 shi "s on t so now wk; c) -5 o nn,

Obtained as described in example 1 from preparation 7. o MS (HIAT) 496/498 (MN) co TN NMR 5 (SOSIi) 7.97 (IN, 4), 7.48 (IN, 9, 7.36- 7.28 (2H, t), 7.17-7.07 (IN, t), 7.13 (2H, 0, 6.99 (IN, 8), 6.93 (IN, a), 6, 75 (IN, a), 5.99 (IN, 5), 4.68 (2H, 5), 4.35-422 (1H, t), 3.89-3.77 (1H, t), because 3.67-3.54 (1H, t), 3.22 (1H, quintet), 2.91-2.79 (1H, t), 2.68-2.46 (2H, t), 2, 43-2.20 (ZH, t), 2.04-1.88 (2H, t), 1.88-1.71 (2H, t).

Example 60

IM-(2X)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazine- 4-yl)acetamide b5 i and

Obtained as described in example 1 from preparation 7.

MS (HIAT) 508/510 (MAN)"

IN NMR 5 (SOSIv) 7.31 (1H, 9), 7.08-7.01 (4H, t), 6.99 (IN, a), 6.74 (1H, as), 6.53 ( 1H, Ba c), 4.69 (2H, 8), 4.56 (2H, a), 4.34-4.24 (1H, t), 3.80-3.72 (1H, t), 3.52-3.42 (1H, t), 3.28-3.18 (IN, t), 2.88-2.80 75. MH, t), 2.63-2.45 (4H, t), 2.36-2.21 (ZH, t), 2.00-1.90 (2H, t), 1.86-1.70 (2H, t).

The following examples of compounds of the invention, which were obtained as described in example 1 from preparation 7, are presented in the table below. menus

Gov2 Msh(2vuZ4-(3,4-dichlorophenoxy)piperidin-1-yl)2-tihydroxypropyl)-2-(methylamino)benzamide ro63 |M-(28uZ-4-(3,4-dichlorophenoxy)piperidin-1-yl )-2-hydroxypropyl)-nicotinamide

H64.Msh(2vuZ-4-(3,4-dichlorophenoxy)piperidin-1-yl|2-tihydroxypropyl)-isonicotinamide (65. M-(otu ZA (3,-dichlorophenoxy)piperidin-1-yl|-2- hydroxypropyl)-3-(dimethylamino)benzamide Gα vv m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(1,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)lacetamide

GB? Mn(ovu3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-hydroxynicotinamide and) in m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidine- 1-yl|-2-hydroxypropyl)-2-(1H-indol-3-yl)acetamide in m-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2 -hydroxypropyl)-dicycloyl4,2,F|octa-1,3,5-triene-7-carboxamide

Г70 M-(oVu ZA (3 A dichlorophenoxy)piperidin-1-yl-2-hydroxypropyl-4,7-dimethylpyrazolo 5, 1-с|/ /2,А| griazine-3Z-carboxamide (ee) 71 m-( 2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-pyrazine-2-carboxamide 424

Go7200Msh(2vuZa-(3,4-dichlorophenoxy)piperidin-1-yl)2-tihydroxypropyl)-purine-6-carboxamide i-th

Goth78.0M-(evuz4-(3,4-dichlorophenoxy)piperidin-1-yl).2-hydroxypropylquinoline-6-carboxamide se m-(2K)-3-(4-(3,4-dichlorophenoxy)piperidine-1 -yl|-2-hydroxypropyl)-2,7-dimethylpyrazolo|1,5-a|pyrimidine-b6-carboxamide o

Goth75.0m-(evuz4-(3,4-dichlorophenoxy)piperidin-1-yl).2-hydroxypropyl)-2-(pyrimidine-2-ylthioacetamide

Ho7600Msh(2vuZ44-(3,4-dichlorophenoxy)piperidin-1-yl)2-tihydroxypropyl)-B-fluoro-1H-indole-2-carboxamide (he) m-(2k)-3-I4-(3, 4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,3-benzothiaziole-6-carboxamide m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2 -hydroxypropyl)-5-phenyl-1,3-oxazole-4-carboxamide

Got7900 Mn(2vuZ4-(3,4-dichlorophenoxy)piperidin-1-yl)2-tihydroxypropyl)-6-hydroxypyridine-2-carboxamide « ovo m-(2k)-3-(4-(3,4-dichlorophenoxy) piperidin-1-yl|-2-hydroxypropyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide

Bovine Mn(2-narrow-(3,4-dichlorophenoxy)piperidin-1-yl)2-tihydroxypropyl)-3-hydroxypyridine-2-carboxamide with m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidine- 1-yl|-2-hydroxypropyl)-1H-benzimidazole-5-carboxamide h 83 m-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)- 1 H-indole-5-carboxamide 461 t " m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-methyl-1H-indole-2 -carboxamide m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-imidazole-4-carboxamide vv m-(2k)-3-(4 -(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-6-carboxamide som-(2k)-3-I4-(3,4-dichlorophenoxy)piperidine-1- yl|-2-hydroxypropyl)-1-methyl-1H-indole-3-carboxamide

And av | m-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-indole-7-carboxamide

ШЕ m-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-(methylamino)sulfonyl|benzamido rorovo|M-(28uZ-4-( 3,4-dichlorophenoxy)piperidin-1-yl|.2-hydroxypropyl)-3,4-bis(methylsulfonyl)benzamide (e) 20 re Mn(2vzch4-(3,4-dichlorophenoxy)piperidin-1-yl)- 2-thihydroxypropyl)-2-pyridin-3-ylacetamide 92 - -3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-5-hydroxy-1 H-Indole-2- carboxamide A so M-42)-3-I4-(3,4 and 1-yl|-2-hy, yl)-5-hy 1n- 2b and m-(2k)-3-(4-(3 ,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide m-(2k)-3-(4-(3,4-dichlorophenoxy)piperidine -1-yl|-2-hydroxypropyl)-5-(methylsulfonyl)-1H-indole-2-carboxamide rev |M-(28uZ-4-(3,4-dichlorophenoxy)piperidin-1-yl).2-hydroxypropylquinoxaline -6-carboxamide ab m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,8-naphthyridine-2-carboxamide

HF) m-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-imidazo(24-51(1,3|benzothiazole-2-carboxamide ko rev M -(oto ZA (3,4-dichlorophenoxy)piperidin-1-yl|-2-tihydroxypropyl)-2,6-dimethylimidazo| 1,2-a|pyridine-3-carboxamide in m-(2k)-3-( 4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide in Holo. |M-(28uZ-4- (3,4-dichlorophenoxy)piperidin-1-yl)-2-hydroxypropyl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide m-(2k)-3-I4-(3, 4-Dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide rolo2. |M-(28uZ-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-acetamide m-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1- yl|-2-hydroxypropyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide m-(2k)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2 -hydroxypropyl)-5-methyl-1H-pyrazole-3-carboxamide 65 m-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-methyl -1,2,5-oxadiazole-3-carboxamide 106 Mm-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-imidazo|1,2-a| pyridine-2-carboxamide 496

Head m-(28u3-4-(3,4-dichlorophenoxy)piperidin-1-yl|2-tihydroxypropyl)-imidazo|1,2-a|pyrimidine-2-carboxamide

Head |M-(28uZ-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-((4-methylpyrimidin-2-ylthioacetamide m-(2k)-3-(4- (3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide royala m-(evu for (3,4-dichlorophenoxy)piperidin-1-yl )-2-hydroxypropyl)-quinoline-8-carboxamide m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-imidazo|1,2-a|) pyridine-2-carboxamide m-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1,6-naphthyridine-2-carboxamide and,

Example 116

M-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide wash: a bo; and 2 o

Obtained as described in example 1 from preparation 7.

MS (HIAT) 440/442 (MEN) "YAN YAME 5 (СО300) 8.07 (IN, а), 7.99 (1Н, аа), 7.39 (IN, а), 7.15 (1Н, 4), 6.92 (IN, aa), 6.53 (IN, 4) ch 25 4.52 (1H, septet), 4.09401 (IN, t), 3.49 (1H, ach), 3 ,34 (1H, a), 3.11-3.02 (2H, t), 2.86-2.67 (4H, t), o 2.14-2.03 (2H, t), 1, 95 (ZH, 5), 1.97-1.84 (2H, t),

Example 117 4-chloro-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1H-pyrazole-3-carboxamide at 35 o'clock p.m

Obtained as described in example 1 from preparation 7.

MO (HIAT) 447/449 (MAN)! "Ж NMR 5 (С0О50О0) 7.77 (1H, 8), 7.37 (IN, 4), 7.09 (IN, 4), 6.88 (IN, a, 4.39 (IN, О, 3.95 (1H, « quintet), 3.49 (1H, ach), 3.40 (1H, aa), 2.86-2.77 (2H, t), 2.52-2.39 (2H, t ), 2.49 (2H, a), 2.06-1.96 (2H, with c t), 1.85-1.74 (2H, t).

Example 118 and . . . . . . a M-(2k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-5-phenyl-1,3-oxazole-4-carboxamide o a Mini - (22) so o

Obtained as described in example 35 from preparation 7 of 5-phenyl-1,3-oxazole-4-carbonyl chloride.

MS (CHIAT) 490/492 (MAN) "YAN NMR 5 (С0500) 8.12 (1Н, 5), 8.10-8.08 (2Н, t), 7.40-7.35 (ЗН, t ), 7.29 (1IN, a), 7.04 (1Н, 4), 6.81 o (IN, aa), 4.39 (1Н, septet), 3.95 (1Н, quintet), 3, 44-3.33 (2H, t), 2.96-2.87 (2H, t), 2.67-2.55 (4H, t), 2.03-1.93 (2H, t), 1.85 (ZH, 5), 1.85-1.75 (2H, t. eat) Example 119

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide: ma) b5 be

Obtained as described in example 1 from preparation 7.

MS (HIAT) 441/443 (MEN) "YAN NMR 5 (С0500) 7.28 (1H, 4), 7.00 (1H, 4), 6.79 (IN, ad), 4.34-4, 26 (1H, t), 3.86 (1H, quintet), 3.41 (1H, ad), 3.21 (1H, ad), 2.78-2.67 (2H, t), 2.41 -2.30 (4H, t), 2.29 (6H, 5), 1.95-1.86 (2H t), 1.73-1.63 (2H, t).

Example 120 (2K)-2-Acetylamino)-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-phenylethanamide

Obtained as described in example 1 from preparation 7.

MS (HIAT) 494/496 (MN) "YAN NMR 5 (С0500) 7.34 (2Н, а), 7.29-7.18 (4Н, т), 6.99 (IN, 0, 6.78 (1H, aa), 5.29 (1H, 5), 4.27 (1H, 2o septet), 3.76-3.65 (1IN, t), 3.26-3.08 (2H, t) , 2.65-2.49 (2H, t), 2.30-2.15 (4H, t), 1.91 (ZH, c), 1.90-1.81 (2H, t), 1 .69-1.58 (2H, t).

Example 121

M-((2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-2-(2-hydroxyphenyl)acetamide t» C c; sia on H n o o so y

Obtained as described in example 1 from preparation 7.is),

MS (HIAT) 453/455 (MAN) sch "YAN NMR 5 (С0О500) 7.28 (IN, 4), 7.05-6.97 (ZN, t), 6.78 (IN, ad), 6 ,72-6.67 (2H, t), 4.27 (1H, ad), 3.72 (IN, quintet), 3.43 (2H, aa), 3.21-3.08 (2H, t ), 2.68-2.57 (2H, t), 2.32-2.20 (4H, t), 1.90-1.81 (2H, t), about 1.69-1.58 ( 2H, t). He)

Example 122 (2k)-m4-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(methylsulfonyl)amino|-2-phenylet anamide " " c o. Km 7 s t purely

I si MAK, so o 8 ("c") Obtained as described in example 1 from preparation 7.

GI MS (CHIAT) 530/532 (MAN) "YAN NMR 5 (С0500) 7.37 (2Н, 4), 7.31-7.21 (4Н, т), 6.99 (1Н, а), 6 .78 (1H, ach), 4.96 (1H, c), 4.27 (1H,

Pho septet), 3.70 (1H, quintet), 3.24 (1H, aa), 3.13 (IN, aa), 2.72 (ZH, c), 2.66-2.56 (2H, t), 2.32-2.18 (4H, so t), 1.91-1.82 (2H, t), 1.70-1.59 (2H, t).

Example 123 (25)-2-Acetylamino)-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-phenylethanamide o o a o nm ho) vk! M » s you SO

Obtained as described in example 1 from preparation 7. 65 MS (HIAT) 494/496 (MN) "YAN NMR 5 (С050О0) 7.34 (2Н, а), 7.30-7.18 (4Н, т) , 6.99 (1H, as), 6.78 (1H, aa), 5.29 (1H, c), 4.30-4.23

(IN, t), 3.76-3.65 (1H, t), 3.17-3.07 (2H, t), 2.65-2.48 (2H, t), 2.30-2 .14 (4H, t), 1.92-1.80 (2H, t), 1.91 (ZH, 5), 1.68-1.57 (2H, t).

Example 124 (25)-M-(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(Kmethylsulfonyl)amino|-2-phenylet anamide bich on and AJ IF

Obtained as described in example 1 from preparation 7.

MS (ARSTI) 530/5322 (MN)

TN NMR 5 (C0500) 7.47 (2H, a), 7.40-7.30 (4H, t), 7.08 (IN, 4), 6.87 (1H, aa), 5:06 ( 1H, c), 4.39-4.32 (IN, t), 3.83 (IN, quintet), 3.27 (2H, a), 2.80 (ЗН, 5), 2.73-2 .59 (2H, t), 2.38-2.24 (2H, t), 2.28 (2H, a), 1.99-1.89 (2H, t), 1.78-1.67 (2H, t).

Example 125 1-(k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-o-tolyl-urea 8, IF. g. D. V s i si r o

A solution of o-tolyl isocyanate (b4 mL, 0.51 mmol) in dichloromethane (1 mL) was added to a suspension of oduzo (2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|propane- 2-ol (0.15g, 0.47/mmol) in dichloromethane (3mL) for 5 minutes. After 1 hour, methanol (mL) was added and the solvents were removed in vacuo. The residue was purified by reversed-phase chromatography (Symmetrical column C8), obtaining the desired compound (87 mgH).

MS (ARO) 452/454 (MAN)"

TN NMR 5 (DMSO) 7.81 (1H, a), 7.78 (IN, 8), 7.50 (1H, ach), 7.26 (1H, aa), 7.10 (IN, 0, 7.05 (1H, 5), o 3z5 6.99 (1H, cottage), 686 (IN, 0, 6.63 (IN, 0, 4.74 (1H, a), 4.49-4.40 (IN, t), 3.72-3.63 (1Н, t), 3.32-3.р30 00 (IN, t), 2.99-2.90 (1Н, t), 2.79- 2.67 (2H, t), 2.35-2.24 (4H, t), 2.18 (ZH, c), 1.97-1.88 (2H, t), 1.69-1, 56 (2H, t).

Example 126 1-(k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-p-tolyl-urea « mn! o on shi s h y y s No ii y? o , o o Obtained as described in example 125 from preparation 1.

MS (CHIAT) 452/454 (MN) and "YAN NMR 5 (DMSO) 8.52 (1Н, c), 7.55 (1Н, 4), 7.31 (2Н, а), 7.31 (1Н , c), 7.07 (2H, 4), 7.03 (IN, a), 6.15 ka (IN, 0, 4.82-4.76 (1IN, t), 4.55-4, 45 (1H, t), 3.76-3.67 (1H, t), 3.36-3.32 (1H, t), 3.03-2.95 (1IN, t), 2.83- 2.712 (2H, t), 2.40-2.31 (4H, t), 2.27 (ЗН, в), 2.03-1.92 (2H, t), 1.75-1.61 ( 2H, t) b Example 127 with M-425)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-1-oxo-1,2- dihydroisoquinoline-4-k arboxamide » a "0 o yu Fiv: t a what. nn 60 o

Restrained as described in example 1 from preparation 9.

MS (HIAT) 504/506/508 (MAN)

TN nMR 5 (С0О500) 8.37 (IN, 4), 8.18 (IN, 4), 7.78 (IN, 0, 7.59 (IN, 8), 7.58 (IN, 9, 7 .37 (IN, 9), in 7.07 (1H. 4), 6.86 (IN, aa), 4.33-4.28 (1H, t), 3.60-3.45 (2H, t), 3.04-2.92 (2H, t), 2.60-2.45 (4H, t), 1.98-1.86 (2H, t), 1.72-1.60 ( 2H, t), 1.25 (ZH, c).

Example 128

M-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-2-oxo-1,2-dihydroquinoline-4-carb oxamide

LYA lekya D a o

Prepared as described in example 1 from preparation 9.

MS (HIAT) 504/506/508 (MAN)

TN NMR 5 (SOSI) 7.93 (1H, a), 7.53 (1H, O, 7.34-7.20 (4H, t), 6.98 (IN, a), 6.75-6 .69 (2H, t), 4.32-4.22 (1H, t), 3.68-3.40 (2H, t), 3.00-2.80 (2H, t), 2.70 -2.48 (4H, t), 2.00-1.86 (2H, t), 1.84-1.72 (2H, t), 1.26 (ZH, c).

Example 129

M-4(5)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxy-2-methylpropyloxy-3,4-dihydrophthalazine-1-carboxamide as o o o c) Men Ha si AK, NN (o)

Obtained as described in example 1 from preparation 9. (ee)

MS (HIAT) 505/507/509 (MN) p

TN NMR 5 (SOSIv) 10.18 (IN, B5), 9.15 (IN, a), 8.44 (IN, 4), 8.06 (IN, ra z), 7.89 (IN, O , 7.81 (IN, 0, 7.31 (IN, a), 7.01 (IN, a), 6.78 (1H, aa), 4.35-425 (1H, t), 3.58 -3.37 (2H, t), 3.04-2.82 (2H, t), 2.66-2.46 (4H, t), 2.06-1.96 (2H, t), 1 .94-1.80 (2H, t), 1.23 (ZH, 5). o

Example 130 3 (2kK)-m4-4(25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxy-2-methylpropyl)-2-hydroxy-2-phenethanamide (2 ,0) and 9 BUT What else? s a on 2» o

Prepared as described in example 1 from preparation 9.

MS (HIAT) 467/469/471 (MAN)

Co TN NMR 5 (SOCI3) 7.46-7.29 (6H, t), 6.98 (IN, a), 6.78 (IN, ra c), 6.75 (1H, a), 5, 8 (1H, c), av! 4.28-4.20 (1H, t), 3.71 (IN, ra 5), 3.35-3.20 (2H, t), 2.86-2.69 (2H, t), 2 .53-2.39 (2H, t), 2.31 (2H, c), 1.97-1.85 (2H, t), 1.82-1.70 (2H, t), 1.04 (ZN, c). o Example 131

Gee! 20 M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

IC e) 92 y o on M. go o no A. MA yu s zizity o 60

Prepared as described in Example 1 from preparation 10.

MS (HIAT) 470/472 (MN)

TN NMR 5 (C0500) 8.25 (IN, a), 8.08 (IN, 4), 7.67 (IN, 9, 7.48 (2Н, 9, 7.05-6.96 (2Н, t), 6.77 (1H, a), 4.36-4.25 (1H, t), 3.98-3.87 (1IN, t), 3.45 (1H, ad), 3.28 (1H, aa), 2.80-2.67 (2H, t), 2.49-2.34 (4H, t), bo 2.08 (ZH, B), 1.98-1.84 ( 2H, t), 1.78-1.64 (2H, t).

Example 132

M-42k)-3-14-(2-(Aminocarbonyl)-3,4-dichlorophenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisox inoline-4-carboxamide ? at. M, c sv) J o on to zu IF; at

The crude amine obtained from preparation 11 is redissolved in dichloromethane and treated with 75 g of diisopropylethylamine (0.85 ml) and 1-oxo-1,2-dihydroiso-dihydroquinoline-4-carbonyl chloride (0.40 g) at room temperature. The reaction is quenched with a saturated aqueous solution of sodium hydrogencarbonate and the mixture is concentrated in vacuo by distillation with toluene. Extraction of the solid residue with dichloromethane/methanol, filtration of the solids and chromatography on silica (dichloromethane:7H ammonia in methanol/15:2) afforded the desired compound as a white solid (0.31g).

MS (HIAT) 533/535 (MAN)

TN NMR 5 (C0500) 8.25 (IN, 4), 8.12 (IN, a), 7.69 (IN, t), 7.55 (1Н, 8), 7.49 (IN, t) , 7.44 (1H, 9), 7.05 (1H, a), 4.20 (1H, t), 3.55-2.96 (TON, t), 2.25-1.98 (AN , t).

Example 133

3-Cyano-M-(25)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)benzenesulfonamide with 7 ShK: o with Sky

F; che (ee) zo oo s

3- cyanobenzenesulfonyl chloride (0.127g, 0.63 mmol). After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo (a) and the residue was partitioned between 1095 aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with water, then brine, and dried over magnesium sulfate.The crude material was purified on silica gel (0 to 5965 7N ammonia in methanol/dichloromethane) to afford the title compound as a white foam (0.120 g).

MS (IER) 484/486 (MAN)

TN NMR 5 (DMSO) 8.22 (1H, a), 8.16-8.07 (2H, a), 7.82 (2H, 0, 7.50 (IN, a), 7.25 (1H , a), 6.97 (1Н, « aa), 4.71 (9, 71Нн), 447434 (1Н, t), 3.63-3.51 (IN, t), 2.93 (1Н, ach ), 2.71 (IN, aa), 2.69-2.55 (2Н, т), ХХ with 2.32-2.12 (АН, т), 1.95-1.79 (2Н, т ), 1.65-1.45 (2H, t), 1.65-1.45 (2H, t).

Example 134; t 5-(4(25)-3-14-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)amino)-sulfonyl)|-2-methoxybenzamide in a o o dev; ts a Mini 78: Mn, . oo o b 50 Y

Obtained as described in example 133 from preparation 7, using co 3-(aminocarbonyl)-4-methoxybenzenesulfonyl chloride.

MS (HIAT) 531/533 (MN)

TN NMR 5 (DMSO) 8.20 (IN, a), 7.87 (IN, a, 7.73 (2H, c), 7.55 (1IN, 8), 7.49 (IN, a), 7.32 (1H, 9), 59 7.25 (IN, a), 6.97 (IN, ad) 4.67 (IN, 4), 4.41 (IN, septet), 3.96 (ЗН , c), 3.58 (1H, a), 2.82 (1H, a),

HF) 2.68-2.57 (ZH, t), 2.30-2.16 (4H, t), 1.91-1.82 (2H, t), 1.60-1.49 (2H , t). Example 135

M-425)-3-I4-(3,4-dichloroarenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfone copper acetate 60 b5 ) Eat? (2K)-1-amino-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.15g) in operidine (2ml) is treated with 70. 1 -oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (0.11 g) and the mixture was stirred at external temperature for 18 hours. After addition of sulfonyl chloride (0.05 g), stirring for 24 hours, the solvent was evaporated. Purification by column chromatography and reversed -phase HPLC (Symmetric column C8 and acetonitrile/O.195 aqueous ammonium acetate), give the desired compound as a white solid product (0.06Hg).

MS (HIAT) 526/528 (MN)

TN NMR 5 (DMSO) 8.39 (1H, 4), 8.32 (IN, a), 7.95 (m, c), 7.86 (IN, aa), 7.64 (1H, 9, 7.39 (1H, o), 7.11 (IN, a), 6.89 (IN, aa), 4.45-4.39 (IN, t), 3.82-3.75 (IN, t), 3.34 (1H, 5), 2.97 (1H, ad), 2.92 (1H, ad), 2.81-2.72 (2H, t), 2.55-2.42 (2H, t), 2.02-1.92 (2H, t), 1.95 (ZH, 5, OAc), 1.82-1.72 (2H, t).

Example 136 2 M-425)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2,4-difluorobenzenesulfonamide a b

HA AHA iya an -6. sch k a a E o

Obtained as described in example 133 from preparation 7, using 2,4-difluorobenzenesulfonyl chloride.

MS (HIAT) 493/495 (MN) "YAN NMR 5 (DMSO) 7.94 (1Н, c), 7.86 (IN, 14), 7.55 (1Н, aa), 7.49 (1Н, a), 7.28 (1H, aa), 7.25 (1H, o), so 6.97 (IN, aa)5 4.69 (IN, 4), 4.42 (1H, septet), 3 .60 (IN, sextet), 2.96 (1H, aa) 2.81 (IN, ad), 2.68-2.58 «0 (2H, t), 2.34-2.16 (4H, t), 1.91-1.82 (2H, t), 1.60-1.49 (2H, t).

The following examples of the compounds of the invention, which were obtained as in example 133 from preparation 7, are presented in the following table. Example Name (MAN) (ав) " и " 2 ne s . g" со о з

Fu 2 so o yu bo

Mj 165 methyl 5-((25)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-amino)sulfonyl|-2-methyl-3-fursate

; I

I

; сч 2 о со зо ю сч о со "

WITH

-- iz» o

Fo yu b) o 520 (F) ko bo b5 i i

Example 185

M-K2)-3-I4-(3,4-dichlorophenoxy)-1-piperidinyl/|-2-hydroxypropyl)-1,4-dihydro-4-oxo-3-aminolinecarboxamide " | My syu zo oh oh so

Obtained as described in example 1 from preparation 7, using 4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

MS (HIAT) 490/492 (MN) o

TN NMR 5 (DMSO) 10.21 (5H, 0, 8.74 (6H, 8), 8.26 (BN, as), 7.74 (ION, aa), 7.68 (8H, a), 7.49 (11H, so a), 7.48-7.44 (11H, t), 7.25 (6H, a), 6.98 (6H, ach), 4.80 (4H, 5), 4.44 (6H, septet), 3.75 (6H, 5), 3.55 (7H, ada), 3.26-3.19 (20H, t), 2.78-2.68 (12H, t), 2.34 (20Н, а), 2.33-2.25 (24Н, т), 1.96-1.88 (12Н, т), 1.69-1.58 (12Н, т) ..

Example 186 "

M-4(25)-3-(4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1-2-dihydroisoquinoline-4-carbo ssh c xamide acetate and o b Aro i I I o in name)

Obtained as described in example 35 from preparation 10, using

Me (25)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate and 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

IR f) MS (HIAT) 470/472 (MAN)

TN NMR 5 (DMSO) 8.32 (IN, 0, 8.22 (2H, 4), 7.73 (IN, and), 7.52 (IN, 14), 7.52 (1IN, 8), 7.20 (1H, o), 7.14 (1H, ach), 698 (1H, 4), 4.38 (1H, septet), 3.81 (1H, quintet), 3.43-3.36 (IN, t), 3.18-3.11 (1IN, t), 2.15-2.63 (2Н, t), 2.42-2.28 (4Н, t), 2.14 (ЗН , 5), 1.94-1.84 (2H, t), 1.88 (ZH, 5, OAc), 1.70-1.555:5 (2H, t).

Example 187 o M-425)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl(-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide) a o H 60 n di n 6. 65 Prepared as described in example 35 from preparation 14 using 1-oxo-1,2-dipdroisoquinoline-4-carbonyl chloride.

MS (HIAT) 490/492/494 (MN)

TN nMR 5 (С0О500) 840 (IN, 4), 8.21 (IN, 4), 7.74 (IN, 0, 7.54 (IN, 0, 7.50 (IN, 58), 7.32 (1H, 9), 7.00 (IN, a), 6.76 (IN, ad), 4.36-4.24 (1H, t), 3.99-3.93 (1IN, a), 3.73-3.68 (1H, a), 3.33-3.28 (1IN, t), 2.96-2.84 (1H, t), 2.75-2.30 (5H, t ), 2.04-1.94 (2H, t), 1.88-1.76 (2H, c).

Example 188

M-425)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide Prepared as described in example 35 from preparation 15, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 504/506/508 (MAN)

TN NMR 5 (С0500) 8.38 (1Н, 4), 8.19 (IN, а)7.80 (IN, 0, 7.61 (IN, 0, 7.60 (IN, 0, 7.38 (1IN, 4), 7.09 (IN, 4), 6.87 (1H, ad), 4.37-4.30 (IN, t), 3.64 (1H, 4), 3.42 ( 1H, a), 3.03-2.83 (2H, t), 2.60-2.46 (4H, t), 1.96-1.86 (2H, t), 1.72-1, 60 (2H, t), 1.26 (ZH, c).

Example 189

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-Kmethylamino)sulfonyl|-1-oxo-1,2-dighydroisoquinoline-4- carboxamide sch ha still he o 7

HOM

Si chni eats so o Z ish! 7-KMethylamino)sulfonyl|-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.1g) in dimethylformamide (ml) is treated with M,M-carbonyldiimidazole (0.0bg) and the mixture heated at 55 2C for 45 minutes. ee (2K)-1-amino-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|Ipropan-2-ol (0.11 g) in dimethylformamide (1 ml) is added and the mixture is stirred at external temperature for 18 hours. 1 drop of water was added and the solvent was evaporated. Purification by reverse-phase HPLC (column C8) with acetonitrile/aqueous ammonium acetate as eluent afforded the title compound as a white solid (0.03g).

MS (HIAT) 583/585 (MH) s TN NMR 5 (DMSO) 8.59 (IN, c), 8.44 (1H, 4), 8.42 (IN, 0, 8.04 (IN, a, 7.73 (IN, 8), 7.62 (1H, 5), "» 7.49 (1H, 4), 7.25 (IN, a), 6.98 (IN, a), 4 .79 (IN, 5), 4.44 (1H, septet), 3.80 (1H, quintet), 3.45-3.37 " (IN, t), 3.18-3.11 (1H, t), 2.81-2.69 (2H, t), 2.42 (ZH, c), 2.39-2.25 (4H, t), 1.96-1.87 (2H, t) , 1.66-1.55 (2H, t).

Example 190

M-(42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-((2-hydroxyethyl)amino|sulfonyl)-1-0 (ee) xo- 1,2-Dihydroisoquinoline-4-carboxamide acetate c KH (4 o sa! ' ime) o uodevovoe cha chyn , so i Do ton

Z. And oh oh

Obtained as described in example 189 from preparation 7, using i) 1,2-dihydro-7-|(2-hydroxyethyl)amino|sulfonyl|-1-oxo-4-isoquinolinecarboxylic acid. co MS (HIAT) 613/615 (MEN)

TN NMR 5 (DMSO) 8.61 (1H, 5), 8.42 (1IN, 4), 8.42 (IN, 0, 8.07 (IN, a, 7.71 (IN, 5), 7 .49 (1H, 9), 60 7.25 (1H, 4), 6.98 (IN, ad) 4.44 (IN, septet), 3.81 (1H, quintet), 3.46-3, 37 (1IN, t), 3.35 (2Н, 9, 3.18-3.10 (1Н, t), 2.80-2.68 (2Н, t), 2.80 (2Н, 9, 2 ,42-2.25 (4H, t), 1.96-1.87 (2H, t), 1.88 (ZH, 5, OASc), 1.66-1.55 (2H, t).

Example 191 7-KCyclopropylamino)sulfonyl(|-M-(21K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1 65,2-dihydroisoquinoline- 4-carboxamide

Y Y o s Mk o

Prepared as described in example 189 from preparation 7, using 7-Ncyclopropylamino)sulfonyl/|-1,2-dihydro-1-oxo-4-isoquinolinecarboxylic acid.

MS (HIAT) 609/611 (MN)"

TN NMR 5 (DMSO) 8.64 (1H, 5), 8.44 (1IN, 4), 8.41 (IN, 0, 8.07 (IN, a, 7.72 (1H, 5), 7 .49 (1H, 9), 79 7.25 (1H, a), 6.98 (IN, ach), 4.78 (1H, 8), 4.44 (1H, septet), 3.81 (1H , quintet), 3.45-3.38 (1H, t), 3.18-3.10 (1H, t), 2.81-2.69 (2H, t), 2.42-2.25 (4H, t), 2.15-2.09 (1H, t), 1.96-1.86 (2H, t), 1.66-1.54 (2H, t), 0.50-0 .44 (2H, t), 0.38-0.32 (2H, t).

Example 192 7-(Azetidin-1-ylsulfonyl)-M-4(2K)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2- dihydroisoquinoline-4-carboxamide acetate 2 H | and sch o s o s

Prepared as described in example 189 from preparation 7 using 7-(azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (HIAT) 609/611 (MN)" p

TN nMR 5 (DMSO) 8.53 (IN, 9, 8.52 (IN, 4), 8.44 (IN, 0, 8.09 (IN, a), 7.77 (1H, 5), 7 .50 (1H, 9), o 7.25 (IN, 4), 6.98 (IN, ad), 4.43 (IN, septet), 3.81 (1H, quintet), 3.69 (4H , 9, 3.47-3.37 (1H, t), 3.21-3.10 (IN, t), 2.83-2.68 (2H, t), 2.40-2.24 ( 4H, t), 2.05-1.86 (2H, t), 1.97 (2H, quintet), 1.88 (ZH, 8, 00

OAc), 1.68-1.53 (2H, t).

Example 193 7-(Aminosulfonyl)-M-(2K)-3-(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroiso" quinoline- 4-carboxamide and others. g" IF. On nor mi o so o M, . 5, o 5.o o Obtained as described in example 189 from preparation 7, using

Ge) 20 7-(aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. with MS (HIAT) 569/571 (MAN)

TN NMR 5 (DMSO) 8.65 (1H, c), 8.40 (1H, a), 8.39 (IN, 9, 8.09 (IN, a), 7.69 (1H, 8), 7.49 (1H, o), 7.50 (2H, 5), 7.25 (1H, a), 6.98 (1H, av), 4.77 (1H, c), 4.44 (1H , septet), 3.85-3.77 (1H, t), 3.41 (1H, ab, 3.14 (1H; 5 ayu, 2.81-2.69 (2H, t), 2.41 -2.25 (4H, t), 1.96-1.86 (2H, t), 1.67-1.54 (2H, t).

Example 194 (F) M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-Kdimethylamine)sulfonyl|)|-1-oxo-1, 2-di g hydroisoquinoline-4-carboxamide bo b5 c her ate I bo to Obtained as described in Example 189 from preparation 7, using 7-Kdimethylamino)sulfonyl|-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid .

MS (HIAT) 597/599 (MN)

TN NMR 5 (DMSO) 8.49 (1H, 5), 8.48 (1H, 4), 8.43 (IN, 0, 8.04 (1H, as), 7.75 (1IN, 5), 7.49 (1H, 9), 7.25 (1H, a), 6.98 (TOBTO, aa), 4.44 (1H, septet), 3.81 (1H, quintet), 3.46-3 .37 (1H, t), 3.18-3.11 (1IN, t), 2.82-2.69 (2H, t), 2.64 (6H, c), 2.42-2.26 (AN, t), 1.95-1.86 (2H, t), 1.89 (ZH, 5.OAc), 1.60 (2H, ayu.

Example 195

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(3-hydroxy-3-methylazetidin-1-yl)sulfonyl|-1-oxo -1,2-dihydroisoquinoline-4-carboxamide acetate t vaF on Ky? : | he m. AN a za i s o vi (o) bo

Obtained as described in example 189 from preparation 7, using 7-I-((3-hydroxy-3-methylazetidin-1-yl)sulfonyl|/|-1-oxo-1,2-dihydro!isoquinoline-4- carboxylic acid

MS (ARSI) 639/641 (MAN)" (Se)

TN NMR 5 (DMSO) 8.53 (1H, 4), 8.51 (IN, a), 845 (IN, 9, 8.08 (IN, a), 7.77 (1H, 8), 7, 49 (1H, o), ch 7.25 (1H, 4), 6.98 (IN, aa), 4.44 (1H, septet), 3.82 (1H, quintet), 3.60 (2H, a), 3.45 (2H, a), 3.45-3.40 (IN, t), 3.19-3.10 (IN, t), 2.81-2.69 (2H, t) , 2.42-2.25 (4H, t), 1.96-1.84 (2H, t), 1.88 (ZH, 5, OAc), F 1.66-1.55 (2H, t ).

Example 196

M-K2)-3-(4-13,4-Dichloro-2-((cyclopropylamino)carbonyl|phenoxy)piperidin-1-yl)-2-hydroxypropyl/)-1-oxo-1, 2-dihydroisoquinoline-4 -carboxamide acetate on H ((c) -0 ime) o 50 Obtained as described in example 35 from preparation C5, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

IR e) MS (HIAT) 573/575 (MAN)!

TN NMR 5 (СО30О0) 8.25 (1H, a), 8.09 (IN, a), 7.68 (IN, 0, 7.49 (1Н, 8), 7.48 (IN, 0, 7 .38 (1H, d), 6.97 (IN, 4), 4.54-448 (1H, t), 4.03-3.97 (1H, t), 3.44 (1H, ach) 3 .30 (IN, ad) 2.90-2.79 (2H, t), 29 2.76-2.58 (BN, t), 1.98-1.89 (2H, t), 1.87 -1.79 (2H, t), 1.85 (ZN, 5, OAc), 0.70-0.65 (2H, t), 0.52-0.48 (2H, t).

F! Example 197

M-42k)-3-I4-(3-chloro-4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbo xamide 60 - o o o m and hi and

CHE chary shy b5 o

Prepared as described in example 35 from preparation 24 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 481 (MAN)! "YAN NMR 5 (C0500) 8.36 (1H, ad), 8.19 (IN, 4), 7.86 (2H, a), 7.77-7.75 (2H, t), 7.57 (2H, 9), 7.12 (2H, a), 4.62-4.56 (1H, t), 4.07-4.01 (IN, t), 3.57 (IN, ad), 3.38 (IN, ach), 3.08 (ZN, 8), 2.98-2.88 (2H, t), 2.66-2.55 (4H, t), 2.12-2, 04 (2H, t), 1.92-1.83 (2H, t).

Example 198

M-(2K)-2-Hydroxy-3-14-(4--methylsulfonyl)phenoxy|piperidin-1-yl)propyl)-1-oxo-1,2-dihydroisoquinoline--4-k 70 arboxamide o o o «o, N.Y, An -e o o

Prepared as described in example 35 from preparation 25 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (CHIAT) 500 (MAN) "YAN NMR 5 (С0500) 8.36 (1Н, as), 8.19 (1Н, а), 7.86 (2Н, а), 7.77-7.75 ( 2H, t), 7.57 (2H, 1), 7.12 (2H, a), 4.62-4.56 (1H, t), 4.07-4.01 (IN, t), 3 .57 (IN, ad), 3.38 (IN, ach), 3.08 (ZH, 8), 2.98-2.88 (2H, t), 2.66-2.55 (4H, t ), 2.12-2.04 (2H, t), 1.92-1.83 (2H, t). s

Example 199 (o)

M-42k)-3-I4-(4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Her (Se)

Guy c "c) 3 Obtained as described in example 35 from preparation 26, using (2,0) 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 447 (MAN)! "IN YaMeR 5 (DMSO) 8.31 (1H, 0, 8.22 (2H, 4), 7.75-7.71 (ZH, y), 7.54-7.50 (2H, tu 7, 12 (2H, a), 4.80-4.73 (1H, « t), 4.56-4.49 (1H, t), 3.83-3.77 (1H, t)3 3.42 -3.35 (2H, t), 3.18-3.11 (1H, t), 2.81-2.71 (2H, t), 2.41-2.27 Z 70 (AN, t) , 1.98-1.91 (2H, t), 1.68-1.59 (2H, t). c Example 200 "with M-(2kK)-3-14-(2-(Aminocarbonyl)-4 -chlorophenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinol "in-4-carboxamide o nn, (ee) o "C on o o; " g. and MH

Han Pai (22) so o

Obtained as described in example 35 from preparation 33, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride. 59 MS (HIAT) 499 (MAN)

IN NMR 5 (СО500) 8.25 (1Н, 4), 8.08 (IN, sa), 7.78 (IN, 9), 7.67 (IN, m), 7.48 (IN, 0, 7.47 (1H, 5),

F) 7.35 (IN, ach), 7.08 (IN, 4), 4.56-4.50 (IN, t), 3.94-3.89 (IN, t), 3.46 ( 1H, aa), 3.27 (1H, aa), 2.79-2.70 o (2H, t), 2.46-2.36 (4H, t), 2.03-1.95 (2H , t), 1.82-1.73 (2H, t).

Example 201 60 M-K2k)-3-(4--4-Chloro-2-(Cmethylamino)carbonyl|phenoxy)piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinol in-4-carboxamide b5

0... and o o 10 o

Prepared as described in example 35 from preparation 32, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 513 (MH)7 15 "YAN NMR 5 (С0О500) 8.25 (1Н, а), 8.09 (1Н, а), 7.67 (1Н, 4), 7.63 (IN, 4), 7.48 (1H, 8), 7.48 (1H, Id), 7.33 (1H, aa), 7.07 (IN, 4), 4.59451 (IN, t), 4, 01-3.94 (IN, t), 3.46 (1H, ad), 3.28 (1H, aa), 2.91-2.80 (2H, t), 2.83 (ЗН, c) , 2.66-2.54 (4H, t), 2.05-1.94 (2H, t), 1.90-1.79 (2H, t).

Example 202

Methyl 20 5-chloro-2-C1-(2K)-2-hydroxy-3-((1-oxo-1,2-dihydroisoquinolin-4-yl)/carbonylamino)propyl)piperidin-4-yl|oxy)benzoate acetate oo c 25 " and c 30 o c

Obtained as described in example 35 from preparation C1, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride. with

MS (HIAT) 513 (MN)7 | "c) "YAN NMR 5 (C0500) 8.25 (1H, aa, 8.09 (IN, 4), 7.67 (IN, i), 7.60 (IN, a), 7.49 (IN , 5), 7.48 (1H, (9),

Zo 7.38 (IN, aa), 7.06 (IN, 4), 4.59-4.54 (1H, t), 4.05-3.99 (IN, t), 3.76 (ЗН , 8), 3.45 (IN, aa), 3.30 (1H, so ad), 3.03-2.92 (2H, t), 2.79-2.61 (4H, t), 2 ,00-1.86 (4H, t), 1.84 (ZH, 5, OAs).

Example 203

M-(2Kk)-3-4-(2-(Aminosulfonyl)-3,4-dichlorophenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroiso « quinoline-4-carboxamide trifluoroacetate 40 s | 2

I" 0:5:0 45 on so x. ((c) name)

Ge») 50 Obtained as described in Example 35 From preparation 40, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 569/571 (MN)"

TN nMR 5 (С0О500) 8.26 (IN, 4), 8.09 (IN, a), 7.71 (IN, 0, 7.62 (IN, 9), 7.52 (1Н, c), 7.48 (1H, 9, 7.18 (IN, 4), 5.02 (1H, 5), 4.23-4.15 (IN, t), 3.55 (IN, 0, 3.46 -3.33 (5H, t), 3.16-3.08 (2H, t), 2.26 (2H, 9, 2.15-2.00 (2H, t). (F; Example 204 g M-K2K)-3-(4-3,4-dichloro-2-(methylamino)sulfonyl|phenoxy)piperidin-1-yl)-2-hydroxypropyl|-1-oxo-1,2-dighydroisoquinoline-4- carboxamide acetate 60 b5

NM g 05529

Tan oh he oh I these. . a AK, x MN c)

Prepared as described in example 35 from preparation 41, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 583/585 (MN)"

IN NMR 5 (COO500) 8.25 (1H, 4), 8.08 (1H, 4), 7.69 (1H, i), 7.60 (IN, 9), 7.49. (1H, c), 7.48 (1H, yuyu), 7.16 (IN, 4), 4.73-4.68 (1H, t), 4.05-3.Р99 (1H, t), 3.44 (1H, ach) 3.30 (1H, ach), 3.15-3.04 (2H, t), 2.718-2.63 (4H, t), 2.52 (ZH, c), 2.07-1.93 (4H, t), 1.85 (ZH, 5, OAc).

Example 205

M-K2K)-3-(4-3,4-dichloro-2-(cyclopropylamino)sulfonyl|Ifenoxy)piperidin-1-yl)-2-hydroxypropyl/|-1-oxo-1,2-dihydroisoquinoline-4- carboxamide acetate with c 00:55:05 o 0 "so

And with

Prepared as described in example 35 from preparation 42, using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride. at

MS (HIAT) 609/611 (MN)" co

TN nMR 5 (С0О500) 8.25 (IN, 4), 8.08 (IN, 4), 7.68 (IN, 0, 7.61 (IN, 4), 7.49 (IN, 8), 7.47 (1H, 5, 7.17 (IN, 4), 4.72-4.665 (1H, t), 4.03-3.96 (1H, t), 3.44 (1H, ach) 3 .30 (1H, ach), 3.11-2.99 (2H, t), 2.73-2.58 (4H, t), 2.19-2.13 (1H, t), 2.04 -1.90 (4H, t), 1.83 (ZH, 5, OAc); 0.50-0.43 (4H, t). "

Example 206

M-42k)-3-I4-(3-chloro-4-cyanophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline- 4-carboxamide.

And" And. 0x5:3 t (ee) about others. o o » u; b 50 Me MAK, MN so c

Prepared as described in example 189 from preparation 24 using 7-(methylsulfonyl)-i-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (HIAT) 559 (MEN)"

F) "YAN NMR 5 (00500) 8.78 (1H, 4), 8.35 (1H, a), 8.14 (1H, as), 7.68 (1H, 5), 7.60 (1H , 4), 7.12 (1H, 9), ko 6.95 (1H, ad), 4.56-4.51 (IN, t), 4.01-3.95 (IN, t), 3 .47 (1H, aa) 3.28 (1H, ach), 3.10 (ZH, c), 2.94-2.85 (2H, t), 2.64-2.52 (4H, t) .

Example 207

M-4(2k)-3-4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxy-2-methylpropyl)-6-(methylsulfonyl)-1H-indole-

Z-carboxamide b5 o Y ' o; Phas oic Oma o 70 Obtained as described in example 189 from preparation 10, using β6-(methylsulfonyl)-1H-indole-3-carboxylic acid

MS (ARSI) 520/522/524 (MEN)" "YAN NMR 5 (С0500) 8.35 (1Н, 4), 8.19 (IN, 5), 8.07 (IN, 4), 7.69 (1H, a, 7.11 (IN, a), 7.08 (1H, ad), 6.88 (IN, a), 4.56-4.48 (1H, t), 4.20-4 ,12 (1H, t), 3.57 (IN, ad), 3.43 (IN, ach), 3.19-3.12 (5H, z), 75 3.03-2.98 (2H, t), 2.94 (1H, ad), 2.85 (1H, t), 2.18 (ZH, c), 2.16-2.08 (2H, t), 2.03-1.94 (2H, t).

Example 208

M-42k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-6--"methylsulfonyl)-1H-indole-3-carboxami d » a o ok X al 50 ,Ma s 25 7" o

Obtained as described in example 189 from preparation 8, using b-(methylsulfonyl)-

H-indole-3-carboxylic acid

MS (HIAT) 540/542/544 (MAN). so zo TN NMR 5 (С0500) 8.35 (IN, 4), 8.34 (IN, 8), 8.06 (1Н, 4), 7.69 (1Н, ach), 7.38 (1Н, 49), 7.09 (1H, 9), 6.87 (1H, ach), 4.50-4.43 (IN, t), 4.12-4.06 (IN, t), 3.57 (1H, aa) 3.41 (1H, ach), 3.13 (ZH, c), 3.07-2.99 ke, (2H, t), 2.81-2.68 (4H, t) , 2.12-2.04 (2H, t), 1.94-1.82 (2H, t). with

Example 209

M-42k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k o 35 arboxamide so ia oh he oh tni "

Pk chiy sh-v s g, o

And" and

Prepared as described in example 189 from preparation 7, using 7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. (ee) MS (HIAT) 508/510 (MN) about "YAN NMR 5 (DMSO) 11.73 (1H, c), 8.39-8.26 (2H, t), 7.88 (IN, aa ), 7.64 (1H, i), 7.54 (1H, c), 7.49 (1H, a), 7.25 (1H, a), 6.98 (IN, ach), 4.79 -4.71 (IN, t), 4.48-4.38 (1H, t), 3.85-3.75 (1H, t), 3.46-3.34 (1H, t), ko 3.19-3.09 (1H, t), 2.82-2.65 (2H, t), 2.43-2.23 (4H, t), 1.97-1.84 (2H, t ), 1.67-1.53 (2H, t). b» 50 Example 210

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-fluoro-1-oxo-1,2-dihydroisoquinoline co -4-carboxamide and o on Ko (F) MAK, t a 60 E

Prepared as described in Example 189 from Preparation 10 using 7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid,

MS (HIAT) 488 (MEN)! 65 TN NMR 5 (DMSO) 8.42-8.28 (2H, t), 7.88 (IN, a), 7.64 (IN, 19), 7.55 (1IN, c), 7.20 (1H, 49), 7.14 (IN, ad), 6.98 (1H, 4), 4.43-4.33 (1H, t), 3.85-3.75 (1H, t), 3.45-3.34 (1H, t), 3.20-3.08 (1H, t), 2.75-2.60 (2H,

t), 2.42-2.25 (4H, t), 2.14 (ZH, c), 1.94-1.81 (2H, t), 1.70-1.56 (2H, t) .

Example 211

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide du IF; be yu "1 We o - 0:5:0

AND

Prepared as described in example 189 from preparation 10, using b6-(methylsulfonyl)-i-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (HIAT) 548 (MEN)! "YAN NMR 5 (DMSO) 11.98 (1H, c), 8.89 (1H, a), 8.44 (1H, 4), 8.42 (IN, 0, 8.01 (1H, as) , 7.76-7.72 (1H, t), 7.20 (1H, a), 7.14 (1H, aa), 6.98 (1H, 4), 4.77 (IN, a), 443434 (1H, t), 3.86-3.77 (1IN, t), 3.42 (1H, 14), 3.28 (ZH, 8), 3.17 (1H, quintet), 2.77 -2.63 (2H, t), 2.42-2.29 (4H, t), 2.14 (ZH, 58), 1.95-1.84 (2H, t), 1.71-1 .58 (2H, t).

Example 212 p

M-42k)-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-(methylsulfonyl)-1-oxo-1,2-diHe ) hydroisoquinoline-4-carboxamide o: Y c) so i on n ; s s ny sch o o d), 0:5:0

Example 213

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroiso « 20 quinoline-4 -carboxamide acetate - with M; 9 o on o a M - sh (o) o Ku (av) b o ime) o 50 Obtained as described in example 189 From preparation 7, using 7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline- 4-carboxylic acid. with MS (ARST) 568/566 (MN)

TN NMR 5 (DMSO) 8.70 (1H, 5), 8.46 (IN, 4), 8.16 (IN; aF, 810 (IN, 0, 7.70 (IN, 5), 7.45 (1H, 9), 7.18 (IN, a), 6.94 (IN, aa), 4.39 (1H, septet), 3.82 (1H, quintet), 3.42 (1H, ayu, 3.30-3.09 (1IN, t), 3.22 (ЗН, 5), 2.82-2.67 (2Н, t), 2.45-2.27 (4Н, t), 1, 99-1.80 (2H, t), 1.89 (ZH, 5, OAc), 1.72-1.53 (2H, t). o Example 214

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4- carboxamide acetate 60 b5

N y 70 " o She

Prepared as described in example 189 from preparation 10 using 7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid, 75 MS (HIAT) 548/550 (MN)

TN NMR 5 (DMSO) 8.68 (1H, 4), 8.48 (IN, a), 843 (IN, 9, 8.20 (IN, a, 7.76 (IN, 8), 7.21 (IN, o), 7.15 (IN, aa), 6.98 (1H, a), 4.84-4.72 (1H, t), 4.46-4.31 (1IN, t), 3.88-3.74 (1H, t), 3.49-3.34 (IN, t), 3.28 (ЗН, в), 3.22-3.08 (1H, t), 2, 78-2.60 (2H, t), 2.44-2.24 (AN, t), 2.14 (ZH, c), 1.98-1.79 (2H, t), 1.74- 1.54 (2H, t).

Example 215 20 M-42k)-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-7-(methylsulfonyl)-1-oxo-1,2 -dihydroisoquinoline-4-carboxamide acetate 7 c. o o o z I so o Te)

Obtained as described in example 189 from preparation 13, using c 7-(methylsulfonyl)-i-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. at

MS (HIAT) 582/584 (MH) 3o TN NMR 5 (DMSO) 8.68 (1H, 4), 8.47 (1H, a), 8.44 (IN, 0, 8.20 (1H, aa ), 7.76 (1H, 5), 7.35 (1H, o), so 7.10 (IN, a), 4.53-4.44 (IN, t), 3.81 (IN, quintet ), 3.42 (1H, ayu, 10 3.20-3.09 (1H, t), 2.77-2.65 (2H, t), 2.40 (ZH, c), 2.39- 2.28 (4H, t), 1.95-1.85 (2H, t), 1.87 (ZH, 5, OAc), 1.73-1.61 (2H, t).

Example 216 "

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-(methylsulfonyl)-1-oxo-1,2-dihydroiso C 40 quinol in- 4-carboxamide with . z a on J o «z m. bo ' o o z 02:25:20 b 50 s Obtained as described in example 189 from preparation 7, using b-(methyl sulfonyl)-1-oxo-1,2- dihydroiso-1H-quinolinine-4-carboxylic acid.

MS (IER) 568/570 (MAN)

Example 217

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k

F, arboxamide ime) 60 b5

IS

Prepared as described in example 189 from preparation 7, using b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (ARO) 508/510 (MAN) "YAN NMR 5 (DMSO) 11.70 (1H, 4), 8.34 (1IN, 0, 8.28 (1H, ach), 8.03 (1H, aa ), 7.64 (1H, 4), 7.49 (1H, 9), 7.38 (IN, 4), 7.25 (IN, 4), 6.98 (IN, ad), 4.80 -4.70 (1H, t), 4.44 (IN, septet), 3.87-3.73 (1H, t), 3.45-3.36 (1H, t), 3.14 (1H , quintet), 2.84-2.66 (2H, t), 2.43-2.21 (4H, t), 1.99-1.84 (2H t), 1.69-1.51 ( 2H, t).

Example 218

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide M. to m. A.M. iy a an o . at

E s "co

Obtained as described in example 189 from preparation 10, using sc b-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (IER) 488/490 (MAN) | "in)

Example 219

Zo M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-oxo-4-trifluoromethyl)-1,2-dihydro so pyrimidine-5 -carboxamid o M ikh on o shi s h. h and "who is her i?

With bo Obtained as described in example 35 from preparation 10, using o 2-oxo-4-trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (IER) 489/491 (MAN) ko Example 220 b 20 M-(2k)-3-I(4-(2,4-dichloro-3-methylphenoxy)piperidin-1-ylI-2-hydroxypropyl)-2 -oxo-4-trifluoromethyl)-1,2-dighydropyrimidine-5-carboxamide

IR e) zv On ; M lo : name) 60 z

Obtained as described in example 35 From preparation 13, using 2-oxo-4-trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (IER) 523/525 (MAN)

Example 221 65 M-(2K)-3-14-13,4-dichloro-2-(methylsulfonyl)phenoxy|piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4 -carboxamide acetate y y I " c

In o on 0 o

Prepared as described in example 35 from preparation 48 using 1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 568/570 (MAN)

TN nMR 5 (С0О500) 8.35 (IN, 4), 8.18 (IN, 4), 7.78 (IN, 0, 7.76 (IN, 4), 7.58 (IN, 8), 7.57 (1H, 9, t 7.28 (1H, a), 4.87-4.80 (1H, t), 4.13-4.07 (1H, t), 3.54 (IN, aa), 3.40 (IN, aa), 3.35 (ZN, c), 3.16-3.06 (2H, t), 2.85-2.69 (4H, t), 2.16 -2.00 (4H, t), 1.94 (ZH, 5).

Example 222

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-oxo-4-trifluoromethyl)-1,6-dihydropyridine-3-carboxamide acetate oh che SHE as with z

Prepared as described in Example 35 from preparation 7, using co b-oxo-4-trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride, which is obtained by hydrolysis with sodium hydroxide followed by treatment with thionyl chloride of commercially available b-chloro-4 -trifluoromethyl methyl nicotinate). (Se)

MS (HIAT) 508/510 (MN) sch

TN NMR 5 (DMSO) 8.35 (IN, 9, 7.77 (1IN, 85), 7.49 (1H, 4), 7.25 (1H, a), 6.98 (1H, aa), 6.72 (1H, z), 4.43 (1H, septet), 3.71 (1H, quintet), 3.29 (IN, ad, 3.06 (IN, a, 2.78-2.66 (2H, t), 2.36-2.24 (4H, t, F 1.95-1.86 (2H, t), 1.90 (ZH, c), 1.65-1.54 (2H , t).

Example 223

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-6-oxo-4-trifluoromethyl)-1,6-dihydro pyrimidine-3-carboxamide acetate «, o and o Z I su IF. and? Gene | i am 45 SE, so!

Obtained as described in example 35 from preparation 10, using o b-oxo-4-trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride. co MS (HIAT) 488/490 (MN)

TN nMR 5 (DMSO) 8.35 (IN, 0, 7.77 (IN, 8), 7.20 (IN, 5), 7.15 (IN, aa), 6.98 (IN, 4), 6.73 (1H, c), b 4.42-4.34 (1H, hl), 3.72 (1H, quintet), 3.33- 3.27 (1H, t), 3.06 (1H , ayu, 2.71-2.61 (2H, t), 2.37-2.25 (AN, so t), 2.14 (ZH, c), 1.93-1.84 (2H, t ), 1.91 (ZH, c), 1.69-1.58 (2H, t).

Example 224

M-42k)-3-I(4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-b-oxo-4--trifluoromethyl)-1,6-dig hydropyrimidine-3-carboxamide B 60 Han ev k o SE,

Prepared as described in example 35 from preparation 13, using 65 8-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride.

MS (HIAT) 522/524 (MN)

"YAN NMR 5 (DMSO) 8.32 (1H, 0, 7.79 (1H, c), 7.35 (1H, 4), 7.10 (1H, 49), 6.69 (1H 5), 4.49 (1H, septet), 3.72 (1H, quintet), 3.30 (IN, ayu, 3.07 (IN, ayu, 2.74- 2.64 (2H, t), 2.40 (ZH, 8), 2.37-2.25 (4H, t), 1.94-1.84 (2H, t), 1.89 (ZH, c), 1.71-1.61 (2H , t).

Example 225

M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-(2-oxoquinoxalin-1-(2H)-yl)acetamide

Obtained as described in example 1 from preparation 7, using (2-oxoquinoxalin-1-(2H)-yl)acetic acid.

MS (HIAT) 505/507 (MN)

TN NMR 5 (SOCI3) 8.37 (1H, 85), 7.92 (1IN, 4), 7.61 (IN, 09, 7.49 (1H, a), 7.40 (IN, 0, 7 .32 (1H, 9), 6.99 (1H, 4), 6.74 (1H, aa), 6.72 (IN, Ba 5), 4.91 (2H, t), 4.36-4 .26 (IN, t), 3.86-3.76 (IN, t), 3.52-3.42 (IN, t), 3.26-3.18 (IN, t), 2.88 -2.80 (1IN, t), 2.63-2.53 (2Н, t), 2.40-2.26 (ЗН, t), 2.06-1.92 (2Н, t), 1 .87-1.73 (2H, t).

Example 226

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-ylI|-2-hydroxypropyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide o he Ge (o) 7 i. and d) "co

Obtained as described in example 35 from preparation 7, using

Z-oxo-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride. with

MS (ARSTI) 505/507 (M.-NI" o

TN NMR 5 (SOSIv) 8.26 (IN, 8), 7.43 (IN, 4), 7.31 (IN, a), 7.19-7.09 (IN, t), 6.99 ( IN, a), 6.94 (1H, a), 6.75 (1H, a), 5.72 (1H, 9, 4.44 (2H, 8), 4.30-4.22 (1H, t), 3.88-3.81 (1H, t), 3.58-3.52 (IN, t), so 3.17-3.11 (IN, t), 2.93-2.85 (IN, t), 2.67-2.61 (1IN, t), 2.57-2.53 (1Н, t), 2.44-2.40 (1Н, t), 2.36-2 .29 (2H, t), 2.00-1.90 (2H, t), 1.80-1.70 (2H, t).

Example 227 "

M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-ylI-2-hydroxypropyl)-3--trifluoromethyl)-1H-pyrazole-4-carboxamido) with IF: and M

F O se, o Obtained as described in example 1 from preparation 10, using

Gee! 20 C-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. with MS (HIAT) 460/462 (MN)

TN NMR 5 (DMSO) 8.41 (1H, 8), 8.15 (IN, 0, 7.20 (1H, 4), 7.14 (1H, as), 6.98 (1H, a), 4.42-4.36 (1H, t), 3.77-3.71 (IN, t), 3.39-3.33 (1TN, t), 3.10-3.04 (1IN, t ), 2.73-2.63 (2H, t), 2.36-2.26 (4H, t), 2.14 (ZH, 8), 1.92-1.82 (2H, t), 1.70-1.60 (2H, t).

Example 228

HF) M-42k)-3-I(4-(-2,4-dichloro-3-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-3-trifluoromethyl)-1H-pyrazole-4-k

HF arboxamide 60 o H b5 o sg,

Obtained as described in example 1 from preparation 13, using, using

C-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.

MS (HIAT) 495/497 (MN) "YAN NMR 5 (DMSO) 8.41 (1H, 8), 8.15 (IN, 9, 7.34 (IN, a), 7.09 (IN, aa ), 4.50-4.42 (1H, t), 3.77-3.71 (IN, t), 3.37-3.33 (1H, t), 3.10-3.04 (1H , t), 2.74-2.64 (2Н, t), 2.39 (ЗН, в), 2.36-2.26 (4Н, t), 1.96-1.86 (2Н, t ), 1.69-1.62 (2H, t).

Example 229

M-42k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl)-2-hydroxypropyl)-1-oxo-1,2-dihydro-2-methylisoquinoline-4-k 70 arboxamide o on She 7 o'clock; Fe and s, o

Prepared as described in example 1 from preparation 7, using 2-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (HIAT) 504/506/508 (MAN)!

TN NMR 5 (SOSIi) 847 (1H, a), 8.14 (IN, a), 7.70 (IN, 9, 7.61 (IN, 8), 7.53 (1IN, 0, 7.33 (1H, o), 7.00 (IN, a), 6.76 (1H, aa), 6.58 (IN, ra 9, 4.42-4.32 (1H, t), 4.06- 3.96 (1H, t), 3.80-3.70 (1H, t), 3.63 s 29 (ZH, 8), 3.44-3.34 (IN, t), 3.02- 2.92 (1H, t), 2.78-2.68 (2H, t), 2.59- 2.45 (ZH, t), 2.16-2.00 (2H, t, (3 1 .96-1.80 (2H, t).

Example 230

M-(2k)-3-4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-oxo-1,2-dihydro-1-methylquinoline-4-carb oxamide so «so si o "Ma s, clothes I

MA M so s act o "

Obtained as described in example 1 Kk! preparation 7, using 1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid. t s MS (HIAT) t/2 504/506/508 (MAN) 7 "» TN NMR 5 (SOCI5) 7.97 (IN, a), 7.62 (IN, 0, 7.40 (IN, a ), 7.32 (IN, 4), 7.28 (IN, 0, 7.00 (IN, o), " 6.83 (1IN, c), 6.76 (1H, ad), 6.72 (1H, 9, 4.39-4.31 (1H, t), 4.04-3.94 (1H, t), 3.78-3.70 (1H, t), 3.72 (ЗН, 8), 3.47-3.37 (1H, t), 3.00-2.90 (1H, t), 2.75-2.67 (2H, t), 2.56-2.42 ( ZH, t), 2.10-1.94 (2H, t), 1.94-1.78 (2H, t).

Example 231 bo M-42k)-3-I(4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-k aw! arboxamide o. b 50 a o he Y o

E: M so Z Mi g o

GF) Obtained as described in example 35 from preparation 7, using 8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (HIAT) 508/510 (MN)

Example 232 60 M-42k)-3-I4-(4-chloro-2-methylphenoxy)piperidin-1-yl|-2-hydroxypropyl)-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide b5 ko o 70 Obtained as described in example 35 From preparation 10, using 8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (ARO) 488/490 (MAN)

Example 233

M-42k)-3-I4-(3,4-dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-2-oxo-4--trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide ether von p seam b

Obtained as described in example 35 from preparation 7, using 2-oxo-4-trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride. at

MS (ERSI) 509/511 (MAN)"

Example 234

M-42k)-3-I4-(3,4-Dichlorophenoxy)piperidin-1-yl|-2-hydroxypropyl)-4-methyl-2-oxo-1,2-dihydropyrimidine-5-carboxamide so "so" as in iy a , d) o E

Obtained as described in example 35 from preparation 7, using "4-methyl-2-oxo-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (ERSI) 455/457 (MAN)" t s Example 235 h" Pharmacological analysis: study of calcium flux (Ca? |i " Human eosinophils

Human eosinophils are separated from anticoagulated EDTA peripheral blood as previously described in Chapters 9. Etc. Meijosdiz, 1991, 145, 105-110). Cells are resuspended (5x1Obcl/ml) and loaded with 5μM of EOO-3Z/"AM. Rishgopis E127 2.2μl/ml (Moyesshag Rgorevs) in a solution with a low potassium content (I K5; Mass 118mM, o Mao, 0.8MM; glucose 5.5mM, sodium carbonate 8.5mM, KSI 5mM, HEPES 20mM, Sasi» 1.8mM, BSA 0.195, pH7 4) for 1 hour at room temperature. After loading, the cells are centrifuged at 2009 for 5 minutes and resuspended in YK5 at 2.5x10 bcl/ml Cells are then transferred to 96-cell EPIRg plates

Ge») 20 (Roiu-O-I uzipe from Vesiop Oiscipzop, pre-incubated with BM fibronectin) at 25 μl/cell. The tablet is centrifuged at 2009 for 5 minutes and the cells are washed twice with 1 KZ (200(0.1; room temperature). The compound from the examples is pre-dissolved in DMSO and added to the final volume fraction of DMSO 0.195.

The study is initiated by adding the concentration of A to eotaxin and monitoring the short-term increase in fluorescence of Bricho-Z3 (5456-49O0nm and X80-92Onm) using RIIRK (Tablet reader 59 fluorometric display, MoiIestag JuOemisez, Zippumaie, O.5.A.).

HF) The compounds of the examples were found to be antagonists if the increase in fluorescence induced by teotaxin (a selective agonist of SSKZ) is inhibited in a concentration-dependent manner. The concentration of antagonist required to inhibit fluorescence at 5095 can be used to determine the IR 50 for an antagonist of the SSKZ receptor. 60 Example 236 Chemotaxis of human eosinophils

Human eosinophils are separated from anticoagulated EDTA peripheral blood, as previously described by INapzei ei AI., U. Ittipoi. Meijodz, 1991, 145, 105-110). Cells are resuspended at 10x10 Ucl/ml in ERMI containing 200

IU/ml of penicillin, 200mcg/ml of streptomycin sulfate and supplement with 1095 NIES5Z at room temperature. c5 Eosinophils (70μl) are pre-incubated for 15 minutes at 372C with 7μl of filler or compound (100x required final concentration in 10956 DMSO). Tablet for chemotaxis (StemoTx, pores Zmkm, Meigorgore)

load by adding 28 μl of a concentration of eotaxin from 0.1 to TO0NM (a selective agonist of SSKZ in these concentration ranges), containing a concentration of the compound from the examples or a solvent, to the lower cells of the tablet for chemotaxis. The filter is then placed on top of the cells and 25 µl of the eosinophil suspension is added to the top of the filter. The tablet is incubated for 1 hour at 372C in a humidified incubator with an atmosphere of 95965 air/596 CO» for the course of chemotaxis.

The medium containing non-migrated cells is carefully aspirated from the filter and discarded. The filter is washed once with phosphate-buffered saline (PB5) containing MM EDTA to remove any adherent cells. Cells that have migrated through the filter are pelleted by 7/0 centrifugation (300x for 5 minutes at room temperature) and the filter is removed and the supernatant transferred to each cell of a 96-well plate (Soziag). Pelleted cells are lysed by adding 28 μl of PB5 containing 0.590

Tritonx100, and 2 freeze/thaw cycles are carried out. The cell lysate is then added to the supernatant.

The number of migrated eosinophils is analyzed by the method |Zigaiy ei ai., U. Ittipoi. Meiyoadz, 1985, 83, 2091 by measuring the peroxidase activity of eosinophils in the supernatant.

The example compounds were found to be antagonists of eotaxin-mediated chemotaxis of human eosinophils if the concentration response to eotaxin shifted to the right of the control curve.

Measurement of the desired concentration of eotaxin that gives 5095 chemotaxis in the presence or absence of the compounds allows the calculation of the affinity of the compound for the SSC, or the assay can be used to determine the activity of the compounds at various concentrations of the compound against a predetermined concentration of 20 eotaxin. сч го о со зо о сч о з5 111118 со «

Example 237 Isolated tracheas of guinea pigs - see, for example, Naigtivzop, K.MU.5., Sagvumei, N. 5 Moipo, 9.M. (1984) Eigoreap 9. Riaptasoi., 106, 405-409. a Male YuipKkip-Napieu white guinea pigs (250 g) are killed by decapitation and the tracheas are completely removed. "» After cleaning from the connective tissue, the trachea is cut into six annular segments, each with a width of three cartilage bands, and then suspended in a bath for organs of 20 ml containing a Krebs-Hensleit solution of the following composition (MM): Mass 117.6, sodium dihydrogen phosphate 0.9, sodium bicarbonate 25.0, MAO, 1.2, KSI 5.4, Sasi" 2.6, and glucose (ee) 11.1. The buffer is maintained at 372C and purged with 595 CO" in oxygen. Indomethacin (2.8 μM) is added to the Krebs solution to prevent the development of smooth muscle tone due to the synthesis of cyclooxygenase products.

The tracheal rings are suspended between two parallel tungsten wire hooks, one of them attached to a bar isometric Ogtted force transducer and the other to a stationary bracket in the bath for

Phew 50 organs. Changes in isometric force are recorded on a Zekopis 2-channel recorder.

Experimental protocols and42) At the beginning of each of the experiments, a force of 1 g is applied to the tissue and this is maintained during the equilibration period of 60 minutes, until they reach a stable tone at rest. Then set the curve of action of cumulative concentration of histamine (ELAI) with increments in logarithmic units of 0.5 in each tissue.

The tissues are then washed and approximately 30 minutes later the test compound or vehicle (20956 DMSO) is added. o After an incubation period of 60 minutes, a second ELA curve for histamine is established.

Contraction reactions are recorded as a percentage of the maximum of the first curve. eat) Analysis data

The experimental data of the E/LA curve) are analyzed to estimate the potency (pIA 5o| value) of histamine in the absence and presence of the test compound. The affinity (rAzo) of the test compounds is then calculated using the equation:

Iod(r-)-1od(VIkrA" where r-|A|5o in the presence of the test compound/(A| bo in the absence of an antagonist, and (B| represents the concentration of the test compound. The compounds of the examples, as it was found, are antagonists NO.

Example 238. 65 The activity of the compounds of the invention in relation to the binding of the NO histamine receptor is evaluated by competitive displacement of 1 nM IZNI-pyrylamine (Ategenat, Vyske, code TEK 608, with specific activity ZOKi/mmol) on 2 μg of membranes,

obtained from recombinant SHO-K!I cells expressing the human NO receptor (Eyigozsgeep ZA, Vgizzzei58,

Veidiite, code E5-390-M) in the research buffer (50 mM Tris pH7.4, containing 2 mM MoSi, 250 mM sucrose and 100 mM mass) for 1 hour at room temperature. o iv vv vv vv with

Claims (1)

The formula of the invention of 1. Compound of formula (1): Shan: Mossvyusna sten ve -2--- 1383 o Kk v s where: o X represents CH», O, 5(0)» or MAO; c XM represents a bond, CHno, MEZ5, CHNOMH, CHNOMH(o), CH(OH), CH(MNSTsov), sn(MHO(028, CHNO or cHnoz; 7 represents C(O) or, when U represents a bond "bond, 7 may also represent 5(O) 2; "B" represents optionally substituted aryl, optionally substituted heterocyclyl or C/C cycloalkyl, fused with a benzene ring; C with B" represents hydrogen, C. alkyl (optionally substituted with C 3 -cycloalkyl) or C 3 -cycloalkyl; Is" 22, BZ, c", 85, B and KZ represent, independently, hydrogen, C 1 -alkyl or C 3 -cycloalkyl; m and n are, independently, 0 or 1; 415 BE? represents optionally substituted aryl or optionally substituted heterocyclyl; co "9, 232 and EZ5 represent, independently, hydrogen, C 1 alkyl or C 3 c cycloalkyl; BZ and KZ" represent C 1 alkyl or C 6 cycloalkyl; o where the above-mentioned aryl and heterocyclyl, where possible, optionally substituted with a substituent selected from the group: IF) halogen, cyano, nitro, hydroxy, oxo, (0.82, oOS(OME Zv, MAV MA C(ОВ8, MA' C(OMA V, Fu 50 5(0), MA v, M А 5(0)2825, С(ОМА?бВ?, с(0ОВК?8, Sov? MAZSOoV, C. valkyl (itself, as an option, monosubstituted by MHC(O)phenyl), C. haloalkyl, C. valoxy(C-4 c) alkyl, C. valkoxy, C. haloalkoxy, co Si valoxy(C- c) dalkoxy, C. valkylthio group, Sovalkenyl, Sovalkynyl, C3.ocycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C.-l)alkyl, phenoxy, phenylthio group, phenyl(C.- /)alkoxy, morpholinyl, heteroaryl, heteroaryl(C. .4) alkyl, heteroaryloxy or heteroaryl(C..4) alkoxy, where any of the above 22 phenyl and heteroaryl is optionally substituted with the following substituent: halogen, hydroxy, nitro, 5(0) DS .dalalkyl), F ! З(0)2МН»о, З(О)2МН(С. далкіл),, 5(0)2М(С.. далкіл)о, cyano, Сі далкіл, Сі lalkoxy, С(О)МН», С( OMN(S. dalkil), SON, СО5(С.u dalkil), MНС(ОХС. g are independently equal to 0, 1 or 2; ВЗ, в, в, Вб в, ВВ в Ов, в, ВЗ В, dob, до, ВZ and КО, independently, represent 60 hydrogen, S.i.valkyl (as variant substituted by halogen, hydroxy or C isocycloalkyl), CNa(C" valkenyl), C3.vcycloalkyl, phenyl (itself optionally substituted with halogen, hydroxy, nitro, MH 5, MH(C). dalalkyl), MH(C. dalalkyl)", З(0)5(C4 ralalkyl), З(О )2MH", 5(0)2MH(C 4 dalalkyl), C(0)2M(C.alalkyl)", cyano, C..alalkyl, Si daloxy, C(O)MH", C(O)MH( S. dalkilom), S(O)M(S. dalkilom)", SON, SOS. dalalkyl), MNO(OX(C. dalalkyl), MNO(O)2(C dalalkyl), and C(O)(C dalalkyl), CEz or ОС) or heterocyclyl (itself, as an option, substituted with halogen, hydroxy, nitro, MH, MH (Sialkyl), M(C-alkyl)", Z(0)5(Sialalkyl), /5(O)2MH", C(0)2MH(C..alkyl), 5(0)2M(C.4.alkyl)o, cyano, C.-.alkyl, C.alkoxy, C(O)MH»o, C(O)MH (S. dalkylom), С(ОМ(С. dalkylom)», СО2Н, СОС. ldalkylom), МНО(ОХ(С. dalkylom), MNU(O)5(С. lalkylom), С(О)Х С. by far), SEz or OSE"); alternatively, ME"ZV"Ya, MAV 716, Me2082!, MAV, MAK29827 can independently form a 4-7-membered heterocyclic ring selected from the group: azetidine (itself optionally substituted with hydroxy or C 4 alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted with C 4alkyl on the distal nitrogen atom; B", 5, 28 and KZ! represent, independently, C 1. alkyl (optionally substituted by halogen, hydroxy or 70. C. uocycloalkyl), CNa(Co-valkenyl), phenyl (itself, alternatively, substituted by halogen, hydroxy, nitro, MH 2, MH(C. dalalkyl), M(Ci dalalkyl)" (these alkyls can be combined with formation of a ring, as described for VK "Z and B"! above), З(О)5(C-alkylom), З(О)2МНо, 5(О)2МН(С. олalkyl), З(О)2М( C- dalalkyl)" (these oalkyls can combine to form a ring, as described for B "Z" and E"" above), cyano, C. dalalkyl, C. 4-alkyl, C(O)MN", C(OMN(C y dalalkyl), С(О)М(С. lalalkyl)o (these alkyls can combine to form a ring as described in 79 for Vis tay above), СОН, СО4(Si dalalkyl), MHC(O)(Si dalalkyl), MNU (O)5(Si dalalkyl), C(OX(Si dalalkyl), CEz or OSE)") or heterocyclyl (itself, alternatively, substituted with halogen, hydroxy, nitro, MH 5", MH(C. dalalkyl), M (Si dalalkyl)o (these alkyls can combine to form a ring as described for K 3 and BK"? above), З(0)4(С, dalalkyl), З(О)2МН», З(0)2МН( C. dalkylom), З(О)2М(С. dalkylom)o (these alkyls can combine to form a ring, as described for B C and VK" above), cyano, Sidalkylom, S.ylalkyloxy, C(O)MH", C(O)MH(C dalkylom), C(O)M(S. dalalkyl)o (these alkyls can combine to form a ring, as described for KZ and E"" above), SON, COX(Si with dalalkyl), MHC(O) Su with alkyl), MNUZ(O)5(Si with alalkyl), C (ОХХ(Si dalkilom), SEz or ОСЕ"); provided that when X represents CM" and t and n are equal to 0, then M does not represent MAZ5; or its M-oxide; or a pharmaceutically acceptable salt, solvate or salt solvate thereof. p. 29 2. Compound according to claim 1, where: X represents O; U represents a bond, CH o, Me, СНо.МН, СН(ОН), He) СН(МНС(ОВ З), СН(МНИ(О28У) or СНО; 7 represents С(О) or, when У represents bond, 7 may also represent 5(0)"; B! represents optionally substituted phenyl; B" represents hydrogen or C 1alkyl; K?, BZ, 5, 59, c and 8, all, if present, C is hydrogen; t and n are independently 0 or 1; He is optionally substituted aryl or optionally substituted heterocyclyl; B32 and BZ are independently hydrogen or C alkyl; KZZ and Dya are C . alkyl; where the above-mentioned phenyl, aryl and heterocyclyl, where possible, optionally substituted with the following substituent: halogen, cyano, hydroxy, oxo, (02812, MA"9B76, MA'7c(O)88, 5(0)DMvv , MA 5(0)D,85, (with c(Ome ev?" SOU, S. valkyl (itself, as an option, monosubstituted by MHC(O)phenyl), SEz, phenyl or heteroaryl; where any of the above-mentioned phenyl and heteroaryl optionally substituted with the following substituent: halogen, 09 S. lalkil, Si. lalkoxy or Cg"; В, Вб, в ВВ, В, З, т, доб, В" and КЗ represent, independently, hydrogen, C 1 alkyl (optionally substituted by hydroxy) or C 3 vcycloalkyl; alternatively, MK?В?З may form an azetidine ring (same as "variant substituted by hydroxy or C. .alkyl); -o c B"? and E?5 represent, independently, C. alkyl or phenyl; or a pharmaceutically acceptable salt thereof. and C. The compound according to claims 1 or 2, where Ge represents phenyl, optionally substituted with halogen, cyano, C 4.4 alkyl, "» C. dalkoxy, C(0)5(C. lalalkyl), C(0)2MH" . . 4. The compound according to claim 1 or 3, where X represents 0. (og) 5. The compound according to claims 1, 2, C or 4, where Y represents a connection. o 6. The compound according to claims 1, 2, 3, 4 or 5, where 7 represents C(O). 7. A compound according to any of the previous points, where both t and n are equal to 0. ime) 8. A compound according to any of the previous points, where BC 2, КZ, 7, 5, 9, вк and КВ, all, if present, b 20 represent hydrogen. 9. The compound according to any of the previous clauses, where it is substituted, as an option, by heterocyclyl; where co is heterocyclyl: thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl, 1,6-dihydropyridinyl, pyrimidinyl, indolyl, indazolyl, 2,3-dihydro-1H-indazolyl , imidazopyridinyl, 2,1,3-benzothiadiazolyl, quinoxalinyl, quinolinyl, 52 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, isoquinolinyl, 1,2-dihydroisoquinolinyl, cinolinyl, HF) Z,4-dihydrophthalazinyl, 2,3- dihydro-4H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 1,3-dihydro-2H-isoindolyl, pyrazolotriazinyl, pyrazolopyrimidinyl, imidazobenzothiazolyl, imidazopyrimidinyl, o or /2,1,3 -benzoxadiazolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, 4,5,6,7-tetrahydroindazole or 2,3-dihydro-1H-benzimidazole; where heterocyclyl is unsubstituted or substituted by one or more substituents: oxo (where 60 is possible), halogen, Si. dalalkyl, CEz, Si dalkoxy, 5(0)5(C..lalkyl), 5(F0)2MH", 5(0)2MH(C 4 dalalkyl), 5X0)2M(C..lalkyl) or OSE". 10. The method of obtaining the compound according to claim 1, in which the reaction of the compound of the formula (II): b5 an, H in! se2nI--- (SNapi sSeze-- (SET), shi ik razg SI where X, B", 2, 23, B", 5 5, B", v8, 32, t and n are defined above, as follows: 70 (i) when U represents a bond, CHO, ME? СНоМН, СНоМНС(О), СН(ОН), СН(ИМНСОВ ЗУ), СН(МНВЗО»ВУ, СНО or СН»2В, 7 represents С(О) . variant, with the presence of a coupling agent; (ii) when M represents MH, and 2 represents C(O), with a compound of the formula (NAME): оБВБ----52БЗ--М where KE? is defined above; or ) when M represents a bond, and 7 represents 5(0)", with the compound of the formula (Ps): 1. - And (about Z ss ' where KE? is defined above, and "I" represents a leaving group, if there is a base. 11. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate or a salt solvate according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier. d) 12. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or salt solvate according to claim 1, for use in therapy. 13. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or salt solvate according to claim 1 in the production of a medicament for use in therapy. co 14. A method of treating a chemokine-mediated disease in a mammal suffering from said disease or at risk of developing said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or salt solvate thereof for c claim 1. o Zo Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuit microcircuits", 2007, M 14, 10.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. shi s ;" (ee) ((c) name) b 50 IR e) F) name) 60 b5