UA82091C2 - Diarylmethylidene piperidine derivatives, preparation thereof and use thereof - Google Patents

Abstract

Compounds of formula: (I) wherein R, R, R, Rand Rare as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.(IA)

Description

Description of the invention

The presented invention relates to new compounds, the method of their production, their use, and pharmaceutical 2 compositions containing new compounds. The novel compounds are useful in therapy, particularly in the treatment of pain, anxiety and functional gastrointestinal disorders.

The 5-receptor has been identified as playing a role in many bodily functions, such as the circulatory and pain systems. Ligands for the β5 receptor may therefore find potential applications as analgesic and/or antihypertensive agents. Ligands for the 5-receptor have also been shown to exhibit immunomodulatory activity. The identification of at least three distinct families of opioid receptors (y, b and k) is now well established and all three are present in the central and peripheral nervous systems of many species, including humans.

Analgesia has been observed in various animal models when one or more of these receptors are activated.

With few exceptions, the currently available selective opioid 5-ligands are peptide in nature and are /5 unsuitable for administration by systemic routes. One example of a non-peptide 5-agonist is ZMOS8O

IVIIizKU EU. hey ay., Uoigpa! oh RpagtasoYodu and Ehregitepia! Tpegaretsiisv, 273(1), pp. 359-366 (1995)).

Many of the 5-agonist compounds identified in the prior art have many disadvantages in that they have poor pharmacokinetics and are not analgesics when administered by systemic routes. Many of these 5-agonist compounds have also been documented to exhibit significant anticonvulsant effects when administered systematically. (U.S. Patent No. 187792 to Rayogte et al.| describes some 5-agonists. However, there is a need for improved 5-agonists.

Unless otherwise specified in this description, the nomenclature used in this description generally follows the examples and rules established in Motepsiaitge oi Ogdapis Spetivig, Zesiope A, B, C, O, E, E, and H,

Register of Chemical Structures, Ohio, 1979, provided as a reference for naming chemical structures and rules for naming chemical structures. at

The term "St" or "St group, alone or as a prefix, refers to any group having t-n carbon atoms.

The term "hydrocarbon", alone or as a suffix or prefix, refers to any structure containing only carbon atoms and hydrogen up to 14 carbon atoms. what:

The term "hydrocarbon radical" or "hydrocarbyl", alone or as a suffix or prefix, refers to any structure resulting from the removal of one or more hydrogens from a hydrocarbon. F

The term "alkyl", alone or as a suffix or prefix, refers to a linear and branched chain monovalent hydrocarbon radical containing approximately 1-12 carbon atoms.

The term "alkylene", alone or as a suffix or prefix, refers to a linear and branched chain divalent hydrocarbon radical containing approximately 1-12 carbon atoms that binds two carbon structures together.

The term "alkenyl", alone or as a suffix or prefix, refers to a monovalent linear and branched chain hydrocarbon radical having at least one carbon-carbon double bond and containing at least about 2-12 carbon atoms. "

The term "alkynyl", alone or as a suffix or prefix, refers to a linear and branched chain monovalent hydrocarbon radical having at least one carbon-carbon triple bond and containing at least about 2-12 carbon atoms. "" The term "cycloalkyl," alone or as a suffix or prefix, refers to a monovalent hydrocarbon radical having a ring containing at least about 3-12 carbon atoms.

The term "cycloalkenyl", alone or as a suffix or prefix, refers to a monovalent hydrocarbon (ox) radical having a ring having at least one carbon-carbon double bond and containing at least about 3-12 carbon atoms. The term "cycloalkynyl", alone or as a suffix or prefix, refers to a monovalent hydrocarbon radical having a ring having at least one carbon-carbon triple bond and containing about 7-12 carbon atoms. and The term "aryl", alone or as a suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having an aromatic character (eg, 4n-2 delocalized electrons) and containing about 5-14 atoms carbon

The term "arylene", alone or as a suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having an aromatic character (eg, 4n2 delocalized electrons) and containing approximately 5-14 carbon atoms, which bind the two structures together. iF) The term "heterocycle", alone or as a suffix or prefix, refers to a ring-containing structure or to a molecule having one or more multivalent heteroatoms independently selected from M, O, P and 5 as part of a ring structure containing at least about 3-20 ring atoms. The heterocycle may be saturated or unsaturated, contain one or more double bonds, and the heterocycle may contain more than one ring, when the heterocycle contains more than one ring, the rings may be fused or unfused. Condensed rings usually have at least two rings that share two atoms.

The heterocycle may or may not be aromatic.

The term "heteroaromatic", alone or as a suffix or prefix, refers to a ring-containing structure or 65 molecule having one or more multivalent heteroatoms independently selected from M, O, P, and 5 as part of a ring structure containing at least about 3-20 atoms in rings where the ring-containing structure or molecule has an aromatic character (for example, 4n12 delocalized electrons).

The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or "heterocyclo," alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removal of one or more hydrogens from it.

The term "heterocyclyl", alone or as a suffix or prefix, refers to a monovalent radical derived from a heterocycle by the removal of one hydrogen from it.

The term "heterocyclylene", alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens from it. which bind the two structures together. 70 The term "heteroaryl", alone or as a suffix or prefix, refers to heterocyclyls having an aromatic character.

The term "heterocycloalkyl," alone or as a suffix or prefix, refers to heterocyclyls that are not aromatic.

The term "heteroarylene", alone or as a suffix or prefix, refers to heterocyclylenes having a /5 aromatic character.

The term "heterocycloalkylene", alone or as a suffix or prefix, refers to heterocyclylenes that do not have an aromatic character.

The term "six-membered", used as a prefix, refers to groups having a ring containing six ring atoms.

The term "penta--lens", used as a prefix, refers to groups having a ring containing five ring atoms.

A five-membered heteroaryl is a heteroaryl with a ring having five ring atoms, wherein 1, 2, or C ring atoms are independently selected from M, O, and 5.

Examples of five-membered ring heteroaryls are thienyl. furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl , 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, (o) 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms, where 1, 2, or C ring atoms are independently selected from M, O, and 5. -- zo Examples of six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl,

The term "substituted", used as a prefix, refers to a structure, molecule or group where one or more hydrogens are replaced by one or more C. c-hydrocarbon groups, or by one or more chemical groups containing one or more heteroatoms selected from with M, O, 5, E, SI, Bg, I, and P. Examples of chemical groups containing one or more heteroatoms include -MO2. -OK. -СИ, -Вг, -И, -Р, -СЕз, -Ф(-О)К, -Ф(-ОО)ОН, -МН», -ЗН, с зв МНЕ, MK, -ЗК, -ЗОзЗН, -5OK, -5(ОЖК, «СМ, «ОН, -С(50)OK, -(5О)МК»о, -МКС(-О)К, oxo (750), imino (МК), so thio ( -5), and oximino (-M-OK), where each "K" is C. γ-hydrocarbyl, for example, substituted phenyl can refer to nitrophenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., where nitro, methoxy, chlorine, and amino groups can replace any suitable hydrogen on the phenyl ring.

The term "substituted", used as a suffix in relation to the first structure, molecule or group, " accompanied by one or more names of chemical groups, refers to a second structure, molecule or group that is the result of replacing one or more hydrogens of the first structure, molecule or group by one or more named chemical groups, eg "phenyl substituted nitro" refers to nitrophenyl. with Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, tirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, pyrazoline, dio-xolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, co-morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidia, 2,3,4,7-tetrahydro-1H-azepine, homopiperazine, 1,3-dioxepane, co 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide. o In addition, heterocycles include aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazane, pyrrole, imidazole, thiazole, oxazole, ppyrazole, isothiazole, isoxazole, se) 1,2,3-triazole, tetrazole , 1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, ha 1,3,4-triazole, 1,3,4-thiadiazole, and 1,3,4-oxadiazole.

In addition, heterocycles include polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxap. coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochromane, xanthene, phenoxathiene, thiantrene, indolizine, isoiindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, piperidine,

HF) phenanthridine, pyrimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene,

F benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthin, carbazole, carboline, acridine, pyrrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, polycyclic heterocycles where the ring condensation between two or more rings involves more than one bond common to both rings and more than two atoms common to both rings. Examples of such shunted heterocycles include quinuclidine, diazabicyclo|2,2,1)heptane, and 7-oxabicyclo|2,2,1)heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyl such as: aziridinyl, oxiranyl, thiiranyl, 65 azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl , tetrahydrofuranil, thiophanil, piperidinil,

1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl. 1,4-dioxanil, 1,3-dioxanil, dioxanil, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azerinyl, homopiperazinyl, 1,3-dioxeranil, 4,7-dihydro-1,3-dioxerinyl, and Hexamethylene Oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyl or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4 oxadiazolyl. 70 In addition, heterocyclyl encompasses polycyclic heterocyclyls (encompassing aromatic or non-aromatic) such as indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl. tetrahydroisoquinolinyl 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromenyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthazolyridinyl, quinoxalinyl, quinoxalinyl, .

In addition to the polycyclic heterocyclyls described above, heterocyclyl encompasses polycyclic heterocyclyls where the ring condensation between two or more rings involves more than one bond common to both rings and more than two atoms common to both rings. Examples of such shunted heterocycles include quinuclidinyl, diazabicyclo|2,2,1)heptyl; and 7-oxabicyclo|2,2,1|heptyl.

The term "Alkoxy", alone or as a suffix or prefix, refers to radicals of the general formula -O-K, where K is selected from the group: hydrocarbon radical. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy. and propargyloxy. high school

The term "amine" or "amino", alone or as a suffix or prefix, refers to radicals of the general formula -MAK, where K and K' are independently selected from hydrogen or a hydrocarbon radical. (8)

Halogen includes fluorine, chlorine, bromine and iodine. "Halogenated", used as a group prefix, means that one or more hydrogens on the group have been replaced by one or more halogens. In one aspect, the invention relates to a compound of the formula 1, its pharmaceutically acceptable salt, its diastereomers, its enantiomers, and mixtures thereof:

Kk, there is a sch p o t so "z! I,

M "( Z - with Kk ;" i M so mu 4 with Kk ("in") - the same M "Z V. 55 where

GF! B" is selected from the group: hydrogen, C. c-alkyl-O-C(-0)-, as an option, substituted C .. c-alkyl, as an option, substituted

C. c"cycloalkyl optionally substituted C blo-aryl optionally substituted C 2.o-heterocyclyl optionally substituted C o-aryl-C..3-alkyl and optionally substituted C" o-heterocyclyl-C 4.3-alkyl; n is 0, 1 or 2; t is 0, 1 or 2;

B, VZ and VC? independently selected from the group: hydrogen, as an option, substituted C 4-6 -alkyl, and, as an option, substituted C3-6-cycloalkyl; 25 and 2? independently selected from the group: -K, -MO», -OK, -SI, -Vg, -I, -E, -SEz, -FB(5O)K, -F(-O)OH, -MH», - ЗН, -МНЕ, -МЕ2, -ЗЕ, -5ОзН, -502к, -5(50)Б, -СМ, -"ОН, -С(-О)Ок, -С(5О)МК", -"МКОС (-ОЖК, and -МКС(-О)-ОК, where K independently 65 represents hydrogen or C..6-alkyl; and

B" is selected from the group: -H, -OH, as an option, substituted C -4.6-alkyl, as an option, substituted C 3.6-cycloalkyl, as an option, substituted Seo-aryl, as an option, substituted with C oz2o- heterocyclyl is optionally substituted

St. Lo-Aryl-S. c-alkyl, optionally substituted C» o-heterocyclyl-C 4 c-alkyl, -C(20)-MAZEU, -C(-0)-0-k8, -5(50)-K8, -(- 0)5-К8, -С(-0)-К8 and -803Н, where are КЗ and КЕ? are independently selected from the group: -H, optionally substituted C-6-alkyl, optionally substituted C-6-cycloalkyl, optionally substituted C-40-aryl, optionally substituted C-6-heterocyclyl, optionally substituted Co o-aryl-C. c-alkyl, and, as an option, substituted C o-heterocyclyl-C 4 c-alkyl.

In particular, the compounds of the present invention are compounds of formula I, where K' is selected from the group: hydrogen,

C. c-alkyl-O-C(-0)-, as an option, substituted C. c-alkyl, and, as an option, substituted C3-6-cycloalkyl;

B2 and EZ represent ethyl; then B" is selected from the group: hydrogen and C. 3-alkyl;

B" is selected from the group: -H, -OH, as an option, substituted phenyl, as an option, substituted C 3 -heterocyclyl, as an option, substituted phenyl-C 1-3-alkyl, as an option, substituted C 2 -heterocyclyl- C.-3-alkyl, alternatively, substituted C.-6-alkyl, alternatively, substituted C.sub.6-cycloalkyl, alternatively, substituted C.sub.6-cycloalkyl-C.4.3-alkyl, 75. 7b(50)-М-В ЗА, -с(50)-0-к8, -8(50)-К8, -5(50)5-К5, -с(50)-К8 and -"ВОЗН, where KZ and KU are independently selected from the group: -H, optionally substituted phenyl, optionally substituted C 6-heterocyclyl, optionally substituted phenyl-C 1-6-alkyl, optionally substituted C 6-heterocyclyl- C 4 3 -alkyl is optionally substituted C 3 -alkyl, optionally substituted C 3 -cycloalkyl, optionally substituted C 3 -cycloalkyl-C 3 -alkyl, and n and t are equal to 0.

More specifically, the compounds of the present invention are compounds of formula I, where

B" is selected from the group: hydrogen and C. b-alkyl-O-C(:0)-,

B2 and EZ represent ethyl;

B" is selected from the group: hydrogen and methyl;

B is selected from the group: -H, phenyl-C. c-alkyl, C3-cycloalkyl-C4 c-alkyl, C3-6-cycloalkyl, phenyl, as an option, with 29 substituted C. c-alkyl, -"C(-0)-M-B8b9, -8(-0 )5-88, and -C(-0)-K8, where KZ and KU are independently selected from the group: -H, He) phenyl-C..z-alkyl; C3-6-cycloalkyl-C-4-3-alkyl, C3-6-cycloalkyl, phenyl and optionally substituted C-6-alkyl and n and t are equal to 0.

In particular, the compounds of the present invention are compounds of the formula I, where Ge represents hydrogen; -

IN? and EZ represent ethyl; (22)

B" is selected from the group: hydrogen and methyl; o

B" is selected from the group: -H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(-0)-MH-B8, -B(50),-K8, and -C(-50)-K8 , where BZ is selected from the group: 2,2,2-trifluoroethyl, phenyl, benzyl or phenethyl, cyclohexyl, and cyclohexylmethyl; and c p and t are equal to 0.

In yet another aspect, the invention relates to a compound of formula IA, its pharmaceutically acceptable salt, its diastereomers, its enantiomers and their mixtures: "8) - c :" In

And | in | Also F so -a yu M ; at

F M

"With | IN! "K o M t you bo IA where

B' is selected from the group: hydrogen, C. v-alkyl-O-C(-O)-, C. v-alkyl, C. v. cycloalkyl, C. v. -aryl,

C, o-heterocyclyl, Svlo-aryl-C. c-alkyl and C o-heterocycle-C. c-alkyl; where Si are indicated. γ-alkyl, 65 C-cycloalkyl, C 10-aryl, C o-heterocyclyl, C 40-aryl-C. 3-alkyl and Co o-heterocyclyl-C. z-alkyl, as an option, substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Vg, -I, -E, -SEz, -FSH-ОШК,

-F("F)OH, -MH", -5H, -MNK, -MK»o, -ZK, -8OZN, -502K, -5(-0O)K, -SM, -OH, -FO)OK .

B, BZ and EK" are independently selected from the group: hydrogen, C1-6-alkyl and C3-6-cycloalkyl, where C1-6-alkyl and

C. d"cycloalkyl, as an option, substituted by one or more substituents selected from the group: -К, -МО5, -ОК, -СИ, -Вг, -И, -Е, -СЕз, -Ф(5О)К . , -FSH(5O)MK», -MKOS(-OK, and -MKS(-O)-OK, where K independently represents hydrogen or C. c-alkyl; and

B'/ selected from the group: OH, -OH, C-Ci-alkyl, C-Ci-cycloalkyl, C-Ci-aryl, C-Ci-heterocyclyl,

Selo-aryl-C, z-alkyl, Co.v-heterocyclyl-C.z-alkyl, -C(50)-MAZv9 -C(-0)-0-v8, -8(-0)-k8, - 8(50)5-88, -С(-0)-к8 then and -8О53Н, where are the КЗ and КУ? independently selected from the group: -H, C-C-alkyl, C-cycloalkyl, C-C-aryl,

C, o-heterocyclyl, S. lo-aryl-C..z-alkyl, and C. v-heterocyclyl-C..z-alkyl, where C.z.-alkyl are indicated,

C 2 -cycloalkyl, C 2 -aryl, C 2 -heterocyclyl, C 2 -aryl-C-3-alkyl, and C 2 -heterocyclyl-C. c-alkyl, used in definition 27, 88 or BE, as an option, substituted by one or more substituents selected from the y75 group: -K, -MO", -OK, -SI, -Bg, -I, -Э, - SEz, -F(O)K, -F(O)OH, "MN", -ZH, "MNE, -MKaz -ZK, -ZOZN, -5BOoK, -B(2O KK, -SM, -OH, - FSH-FO)OkK, -F(-O)MKo, -MKO(-O)Zh, and -MKOS(-O)-OK, where K independently represents hydrogen or

C. v-alkyl.

In one embodiment, the compounds of the present invention are represented by the formula IA, where EK" is selected from the group: hydrogen, C 1 -alkyl-O-C(-O)-, C 1-2 -cycloalkyl, benzyl and heteroarylmethyl, where C..v are indicated -alkyl, C1-6-cycloalkyl, benzyl, and Co-heteroarylmethyl, optionally substituted with one or more substituents selected from the group: C1-6-alkyl, halogenated C1-6-alkyl, -SE3, C-16- alkoxy, chlorine, fluorine, bromine, and iodine;

B2 and EZ represent ethyl;

B" is selected from the group: hydrogen and C. 3-alkyl;

B is selected from the group: -H, -OH, phenyl, C3-heterocyclyl, phenyl-C3-alkyl, C3-5-heterocyclyl-C4-alkyl, C3-79 C, alkyl, C3-cycloalkyl, C3-cycloalkyl-C c-alkyl, -С(50)-М-БеБ9, -с(50)-0-Б8, -8(50)-28, -8(-0)5-Б8, (3 -б(50)- 88 and -503Н, where КЗ and КО are independently selected from the group: -Н, phenyl, Са 5-heterocyclyl, phenyl-C.4 alkyl,

S. p-heterocyclyl-S. c-alkyl, C. c-alkyl, C3-cycloalkyl, C»-cycloalkyl-C3-alkyl, where phenyl,

Cz b-heterocyclyl, phenyl-C. z-alkyl, Cz 56-heterocyclyl-C..z-alkyl, Si. β-alkyl, C37-CYCLOALKYL, pr 30 C3--cycloalkyl-C..3-alkyl, used in definition 2", B8Ta KU, as an option, substituted by one or more substituents selected from the group: C. β-alkyl, halogenated C..v-alkyl, -SEz, C.v.-alkoxy, chlorine, fluorine, bromine, and Me, iodine. o

In another embodiment, the compounds of the present invention are represented by the formula IA, where B" is selected from the group: hydrogen, C1-6-alkyl-O-C(-0)-, C1-6-alkyl, C1-2-cycloalkyl, benzyl, thia -diazolylmethyl, pyridylmethyl, p

ZB thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and so

M-oxido-pyridylmethyl, where C..v.-alkyl, C.v.-cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and

M-oxido-pyridylmethyl is optionally substituted with one or more substituents selected from the group: C 4-6-alkyl, halogenated C 1-6-alkyl, -C 3 , C 6-alkyl, chlorine, fluorine, bromine, and iodine; « 40 B2 and EZ represent ethyl; - c B" is selected from the group: hydrogen and methyl;

From" B is selected from the group: -H, C. c-alkyl, phenyl-C.4 c-alkyl, C. -cycloalkyl-C. 3-alkyl, C3-6-cycloalkyl, phenyl,

C. v-alkyl, -C(50)-m-vve, -5(50)5-85, -C(50)-O-K2, and -C(-0)-KU, where is VK? and VK? independently selected from the group: -H, 45 phenyl-C. 3-alkyl, C 3 -cycloalkyl-C. 3-alkyl, C3-7-cycloalkyl-C4-3-alkyl, C3-7-cycloalkyl, phenyl, C3-alkyl, used in the definition of KE", 8 and KU, optionally substituted by one or more substituents selected from groups: C 4.6-alkyl, halogenated with C. 6'-alkyl, -C3, C6-6-alkyl, chlorine, fluorine, bromine and iodine. (a) In a further embodiment, the compounds of the presented invention are represented by the formula IA, where EK" selected from 50 groups: hydrogen, propyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, and triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and M-oxido-pyridylmethyl; "and B2 and EZ represent ethyl;

B" is selected from the group: hydrogen and methyl;

B" is selected from the group: -H, ethyl, phenyl, benzyl or phenethyl, naphthyl, fluorophenyl, chloro-phenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, -С(-0)-МН-К8, -5(- 0)5-К58, -С(50)-0О-К8, and

HF) -C(50)-85, where KZ is selected from the group: methyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, methylphenyl, t fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl.

It should be understood that when the compounds of the present invention contain one or more chiral centers, because the compounds of the invention can exist in enantiomeric or diastereomeric forms and be isolated as such or as a racemic mixture. The present invention covers any possible enantiomers, diastereomers, racemates or mixtures thereof of compounds of formula I or IA. Optically active forms of the compound of the invention can be I or IA. Optically active forms of the compound of the invention can be obtained, for example, by chiral chromatographic separation of the racemate, synthesis from optically active starting materials or asymmetric synthesis by the methods described below. 65 It should also be understood that some compounds of the present invention may exist as geometric isomers, for example, E and 7 isomers of alkenes. The present invention covers any geometric isomer of compounds of formula I or IA. It should also be understood that the present invention encompasses tautomers of compounds of formula I or IA.

It should also be understood that some compounds of the present invention can exist in solvated, for example, hydrated, as well as non-solvated forms. It should also be understood that the present invention encompasses all such solvated forms of compounds of formula I or IA.

The scope of the invention also includes salts of the compounds of the present invention, which can be prepared by standard methods well known in the art, for example, by the reaction of a sufficiently basic compound, for example, an alkylamine, with a suitable acid, for example, HCl or acetic acid, which gives a physiologically acceptable anion. It is also possible to form a suitable alkali metal (such as sodium, potassium, or lithium) 7/0 or alkaline earth metal (such as calcium) salt by treating a compound of the present invention with an appropriately acidic proton, such as a carboxylic acid or phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as an ethoxide or methoxide), or an appropriately basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification methods.

In one embodiment, a compound of formula I or IA above can be converted into a pharmaceutically acceptable salt or bolvate, particularly an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluenesulfonate.

The novel compounds of the present invention are useful in therapy, particularly in the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, rheumatoid arthritis pain, migraine, visceral pain, and the like. This list, however, is not complete.

The compounds of the invention are useful as immunomodulators, especially for autoimmune diseases such as arthritis, for skin grafting, organ transplantation and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumor agents and anti-viral agents.

The compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or involved in this paradigm. This may involve the use of isotope-labeled compounds of the invention in diagnostics and endoscopy, such as positron emission tomography (PET).

The compounds of the invention are useful in the treatment of diarrhea, depression, anxiety and stress-related (8) disorders such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobias, and obsessive-compulsive disorder, urinary incontinence, premature ejaculation , various mental illnesses, cough, pulmonary edema, various gastrointestinal disorders such as constipation, functional -- zo gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, disease

Parkinson's and other motor disorders, brain injury, stroke, cardioprotection after myocardial infarction, back injury, and drug dependence, including treatment for alcohol, nicotine, opioid and other drug abuse, and for sympathetic nervous system disorders such as hypertension.

The compounds of the invention are useful as analgesics for use in general anesthesia and controlled anesthesia. Combinations of agents with distinct properties are often used to achieve a balanced effect of co to maintain the state of anesthesia (eg, amnesia, analgesia, muscle relaxation, and sedation). Involved in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

Also within the scope of the invention is the use of any compound of formulas I or IA above for the manufacture of a medicament for the treatment of any of the above conditions. "

A further aspect of the invention is a method of treating a subject suffering from any of the above conditions, wherein an effective amount of a compound of formula I or IA above is administered to the patient in need of such treatment. with Therefore, the invention relates to the compound of formula I! or IA, or a pharmaceutically acceptable salt or solvate thereof, as defined above, for use in therapy.

In the next aspect, the presented invention relates to the use of the compound of formula I! or IA, or its oo of a pharmaceutically acceptable salt or solvate, as defined above, in the manufacture of a medicament for use in therapy. In the context of the present disclosure, the term "therapy" also includes "prophylaxis" unless otherwise specified. o The term "therapeutic" and "therapeutically" should be understood accordingly. The term "therapy" in the context of the present invention also encompasses the administration of an effective amount of a compound of the present invention (Ce) to alleviate a pre-existing disease state, acute or chronic or recurrent. This definition also covers prophylactic therapies to prevent recurrent conditions and ongoing therapies for chronic disorders.

The compounds of the present invention are useful in therapy, particularly in the treatment of various pain conditions including, but not limited to: chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.

GF) In the therapy of a warm-blooded animal, such as a human, the compounds of the invention can be used in their usual form

F pharmaceutical composition by any route, including oral, intramuscular, subcutaneous, local, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular, and joint injection.

In one embodiment of the invention, the route of administration can be oral, intravenous or intramuscular.

The dosage depends on the route of application, the severity of the disease, the age and weight of the patient and other factors usually taken into account by the doctor when determining the individual regimen and dosage level most acceptable 65 for a particular patient.

To obtain a pharmaceutical composition from the compound of the present invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid forms of drugs include powders, tablets, dispersible granules, capsules, sachets and suppositories.

The solid carrier may be one or more substances that may also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, or tablet disintegrators; and also as an encapsulating material.

In powders, the carrier is a finely divided solid material mixed with a finely divided compound of the invention or an active ingredient. In tablets, the active component is mixed with a carrier that has the necessary binding properties in a suitable proportion and pressed to the desired shape and size. 70 To obtain a suppository composition, a low-melting wax, such as a mixture of glycerides of fatty acids and cocoa butter is first melted and dispersed the active ingredient, for example, by stirring. The molten homogeneous mixture is then poured into a mold of suitable size and allowed to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc.

The term composition also encompasses the composition of an active ingredient with an encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, sachets are involved.

Tablets, powders, sachets and capsules can be used as solid dosage forms suitable for oral administration.

Liquid forms of the composition include solutions, suspensions and emulsions, for example, sterile aqueous or aqueous propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formed in a solution (in a water-polyethylene glycol solution.

Aqueous solutions for oral use can be obtained by dissolving the active component in water and adding suitable dyes, flavors, stabilizers and thickeners as needed. Aqueous suspensions for oral use can be obtained by dispersing the finely divided active ingredient in water together with a viscous material, such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the pharmaceutical art.

Depending on the mode of application, the pharmaceutical compositions preferably contain from 0.059565 to 9Omas.bo, more preferably from 0.10 to 5Omas.95, compounds of the invention.

A therapeutically effective amount for the implementation of the presented invention can be determined using (22) known criteria, including the age, weight and sensitivity of a particular patient, and interpreted in the context of the disease being treated or prevented by a specialist.

The scope of the invention covers the use of any compound of formulas | or IA, defined above, for the production of medicine. co

Also, the scope of the invention covers the use of any compound of formulas I or IA for the manufacture of a medicament for pain therapy.

Additionally, the use of any compound of Formulas I or IA is provided for the manufacture of a medicament for the treatment of various pain conditions including, but not limited to: chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain. - c A further aspect of the invention is a method of treating a subject suffering from any of the above. conditions, according to which the patient in need of such therapy is administered an effective amount of the compound of the formulas and? Y or IA above.

In addition, a pharmaceutical composition containing a compound of the formula | or | A, or its pharmaceutically acceptable salt in association with a pharmaceutically acceptable carrier. In particular, a pharmaceutical composition containing a compound of the formula | or | A, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for therapy, more specifically for pain therapy. o In addition, a pharmaceutical composition containing a compound of the formula is proposed or | A or its 5p pharmaceutically acceptable salt in association with a pharmaceutically acceptable carrier for use in any of (Ce) the above states. ha In the next aspect, the present invention relates to a method for obtaining a compound of formula I or IA.

In one embodiment, the invention relates to a method of obtaining a compound of the formula HER, which consists in:

F) ko 60 b5 da I ' o B and F

MA"

Goy i m t 1.s(- 10.s of the reaction of the compound of the formula P with X'-C(50)-K U: o a z | - zo Kk m F i Kk! o

KE o sh so p 8 s more. 7 M t so by IN o where (Ce) B is selected from the group: C. c-alkyl-O-C(-0)-3, as an option, substituted C 4 c-alkyl, as an option, substituted ha C. c "cycloalkyl, alternatively, substituted phenyl, optionally, substituted C 3 -C 5 -heterocyclyl, optionally substituted phenyl-C 3 -alkyl, and optionally, substituted C 3 5-heterocyclyl-C 4 -alkyl;

X! selected from the group: -ОВ "ОВ, -0-С(50)-8 7", -СИ, -Вг and -И, where В! - C. в-alkyl; 22В, ВЗ and В" independently selected from groups: hydrogen, as an option, substituted C 46-alkyl and, as an option, o-substituted C 3 b-cycloalkyl; and

BO is selected from the group: -H, optionally substituted phenyl, optionally substituted C with 5-heterocyclyl, optionally substituted phenyl-C. 3-alkyl, optionally substituted with C 5 -heterocyclyl-C. 3-alkyl, optionally substituted

C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl. 60 In particular, the invention relates to the method of obtaining the compound of the formula II described above, where B -

S. vd-alkyl-O-F(-0)-; x is selected from the group: -ОН, -СИ, -Вг and -Й; 2 and KZ represent ethyl; 7 represents hydrogen; and

VO is selected from the group: phenyl, phenyl-C. C-alkyl, C. C-alkyl C3-6-cycloalkyl and C-6-cycloalkyl-C. c-alkyl. 65 In the second embodiment, the presented invention relates to a method of obtaining a compound of formula IM, which consists in:

And B and Z | . 70 zu and s no E.

ДНА 13 и M х в и ни м 2 и: reactions of the compound of the formula M with B 72-Сс(50)-873 s 7 o 2 -

Kk; kt -nZ-zhh F and | about from he sch

Zo (ge) - s. and V g» M and d! where B is selected from the group: C. c-alkyl-0O-C(-0)-, as an option, substituted C. c-alkyl, as an option, substituted : : : - : : : - : : : - « se C. cycloalkyl, alternatively, substituted phenyl, optionally, substituted C.sub.5-heterocyclyl, alternatively, substituted phenyl-C..sub.-alkyl and, optionally, substituted C.5-heterocyclyl- C 4.z-alkyl;

IN? and KZ are independently selected from the group: hydrogen, optionally substituted C 4.3 -alkyl, and optionally substituted

C. d"cycloalkyl; a

B" and KZ are independently selected from the group: -H, optionally substituted phenyl, optionally substituted

C. β-heterocyclyl, alternatively, substituted phenyl-C.sub.1-alkyl, alternatively, substituted C.sub.5-heterocyclyl-C.sub.4-alkyl; alternatively, substituted C.sub.-alkyl and, alternatively, substituted C with β-cycloalkyl; or VK"? and KZ together form the C part of the C3.6-cycloalkyl ring or C3 5-heterocyclyl ring.

In particular, the invention relates to a method of obtaining a compound of the formula IM, where 60 B is Su c-alkyl-O-C(-0)-,

B2 and BZ represent ethyl; and

B" and KZ are independently selected from the group: -H, phenyl, phenyl-C3-alkyl, C. c-alkyl C3-cycloalkyl and

C. tetracyclyl-C 4.3-alkyl; or "2 and KZ together form the C3 part of the 6-cycloalkyl ring. 65 In the third embodiment, the presented invention relates to a method for obtaining a compound of formula MI, which consists in:

and h! about in F

N dr "you

And. reaction of the compound of formula M with B77-МСО: сч 7 о

VH. ch uh - and from | F

Kk r shchi o

She and and. with We, co

I - with in! . и У де со В" - Su c-alkyl-O-C(-0)-, as an option, substituted C 4.3-alkyl, as an option, substituted C with 6-cycloalkyl, as an option, substituted phenyl, as optionally substituted C 1 -C 5 -heterocyclyl, optionally substituted phenyl-C 1 -C 4 -alkyl, or optionally substituted C 3 5-heterocyclyl-C 4 -C 4 -alkyl; where B 1 and C 3 are independently selected from the group : hydrogen, as an option, substituted C 6 -alkyl and, as an option, substituted "se 20 C 6 -cycloalkyl; and chm B" is selected from the group: optionally, substituted phenyl, optionally, substituted C with 5-heterocyclyl, optionally, 7-substituted phenyl-C. 3-alkyl, optionally, substituted with C zv5-heterocyclyl-C.z- alkyl is optionally substituted

C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl.

In particular, the invention relates to a method of obtaining a compound of the formula MI described above, where BC 7 -

S. vd-alkyl-O-F(-0)-;

F) B2 and BZ represent ethyl; and co B" is selected from the group: phenyl, phenyl-C. 3-alkyl, C. 3-alkyl, C3-6-cycloalkyl and C3-6-cycloalkyl-C 4-6-alkyl.

In the fourth embodiment, the presented invention relates to a method of obtaining a compound of the formula MII, which 60 consists of: b5 cm | p ho to z i i i. 78 I went to

IN

MI reactions of compounds of the formula MP! with K19-X2.; with 7 o

M i, - ;

In F o

MN p

M - s; Are we? where

B' is selected from the group: C 1 -alkyl-O-C(-0)-, alternatively, substituted C 4 -alkyl, optionally, substituted (o| C, c)cycloalkyl, optionally, substituted phenyl, as optionally substituted C 3-5-heterocyclyl, optionally substituted phenyl-C 4-3-alkyl, and optionally substituted C 5-heterocyclyl-C 4-3-alkyl;

IN? and KZ are independently selected from the group: hydrogen, as an option, substituted C.43-alkyl and, as an option, substituted ("in C. b-"cycloalkyl; se 50 X2 is selected from the group: I, Bg and CI; chm B" 5 is selected from the group: -H, optionally, substituted phenyl, optionally, substituted C with 5-heterocyclyl, optionally, 7 substituted phenyl-C.3-alkyl, optionally, substituted with C zv5-heterocyclyl-C.z- alkyl is optionally substituted

C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl.

B"5 is selected from the group: alternatively, substituted phenyl-C 4 z -alkyl, optionally substituted C ..6-alkyl is optionally substituted

HF) C3 c-cycloalkyl and, optionally, substituted C3 6-cycloalkyl-C3-alkyl.

Ф In particular, the invention relates to the method of obtaining the compound of the formula МИЙ, which is described above, where

B - C. b-alkyl-O-C(:0)-; 60 X2? selected from the group: -SI, -Vg and -I;

B2 and EZ represent ethyl;

VE "5 is selected from the group: hydrogen and methyl; a

B "5 is selected from the group: phenyl, phenyl-C. 3-alkyl, C. 3-alkyl, C 3 -cycloalkyl and C 3 -cycloalkyl-C 4 -alkyl.

In the fifth embodiment, the presented invention relates to a method of obtaining a compound of formula IX, consisting of: b5

M o o : and m. PA de i

E 1 n 8 e/- 17. s of the reaction of the compound of formula PI with ХУ -5(-0)5-К 1: (8) s ? - eh

Vk Ge) about the village

From co

This is 2 p

Y. ;" M -5 so Sh ko de o B is selected from the group: C 1 -alkyl-O-C(-0)-, as an option, substituted C 4 -alkyl, as an option, substituted : : : - : : : - : : : - "se C. c" cycloalkyl, alternatively, substituted phenyl, alternatively, substituted C. 5-heterocyclyl, alternatively, substituted phenyl-C.. 5-alkyl and, optionally, substituted C". β-heterocyclyl-C 4.3-alkyl;

XZ is selected from the group: -OH, -OB, -SI, -Bg and -I, where B"! - C. c-alkyl;

B, B3, and B" are independently selected from the group: hydrogen, optionally, substituted C 46 -alkyl, and optionally,

Substituted C3-6-cycloalkyl; and

B" is selected from the group: -H, optionally substituted phenyl, optionally substituted C with 5-heterocyclyl, optionally, (F, substituted phenyl-C. z-alkyl, optionally substituted with C zv5-heterocyclyl-C .z-alkyl is optionally substituted

H0) C1-3-alkyl, optionally substituted C3-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-3-alkyl.

In particular, the invention relates to a method of obtaining the compound of formula IX described above, where B / - 60 C. z-alkyl-O-(:O).-; xz is selected from the group: -SI, -Vg and -I; 2 and C represent ethyl; c represents hydrogen;

B" is selected from the group: phenyl, phenyl-C-3-alkyl, as an option, substituted C-43-alkyl, Ca-cycloalkyl and

C. d"cycloalkyl-C.z-alkyl. 65 In another embodiment, the presented invention relates to a method of obtaining a compound of the formula PA, which consists in:

and in : r Shchi Ff r

IS

Я сх about the reaction of compounds of the formula ША with ЕЗ-СНо-Х or КЗ-СНО: о - that Ф с ' (he) . " action 7 t - s ;" so with Id ko o where X is a halogen;

B" is selected from the group: -С(-0)-0О-К8, -8(-0)-К8, -8(-0)5-88 and -С(-0)-К8, where КЗ is selected from the group : C. c-alkyl, and C. c-cycloalkyl, C. c-aryl, C. c-heterocyclyl, C. c- aryl-C.-c-alkyl and C. o-heterocyclyl-C.-c-alkyl, where C. c-alkyl are indicated .

Co o-heterocyclyl-C ..6-alkyl, optionally substituted by one or more substituents selected from the group: -K, -MO5, -OK, -SI, -Bg, -I, -E, -SEz, -F(5O)K, -FSH-O)OH, -MN», -ZN, -MNE, -MK»o, -ZK, -50О3Н, -502кК, -5(-О)К, -СМ, - ОН, -б(ихФО)ОВ, -С(О)ME», -МКОС(-О)К and -МКОС(-О)-ОК, where K independently represents hydrogen or C. в-alkyl; and about B? selected from the group: Cyclo-aryl and Co-heteroaryl, where the indicated Cyclo-aryl and Co-heteroaryl are optionally substituted with one or more substituents selected from the group: -K, -MO", -OK, -CI, -Bg, -I, -E, -SEz, -FSH-OJK, ko -F("F)OH, -MN", -5H, -MNK, -MK»o, -ZK, -8OZN, -50oK, -5(-O) K, -СМ, -ОН, -Ф(-О)OK, -С(-О)МК», -МКО(-ОК and -МКОС(-О)-ОК, where K independently represents hydrogen or С..в -alkyl.

AND

Example of the reaction of the compound of the formula MA with B "-X or VK 7-0-8 7. "-- and

M o s co

ИЙ « - s " M so m Vo o y MA (Se) khm where X is a halogen;

В is selected from the group: -С(-0)-ОО-28 and -С(-0)-КУ, where КЗ is selected from the group: С. 6-alkyl, С3 б-cycloalkyl, Св 4о-aryl,

Co o-heterocyclyl, S.lo-aryl-C.. v-alkyl and Co o-heterocyclyl-C. c-alkyl, where C are indicated. c-alkyl, dv C3-c-cycloalkyl, C-10-aryl, C o-heterocyclyl, C1-10-aryl-C. c-alkyl and C o-heterocyclyl-C..v-alkyl are optionally substituted with one or more substituents selected from the group: (F) -K, -MO", -OK, -CI, -Bg, -I . OK,

F -SM, -OH, -FSH-FO)OK, -F(-O)MK»o, -MKO(-O)K and -MKOS(-0)-OK, where K independently represents hydrogen or

C. c-alkyl; and in B? selected from the group: Cyclo-aryl and Co-heteroaryl, where the indicated Cyclo-aryl and Co-heteroaryl are optionally substituted with one or more substituents selected from the group: -K, -MO", -OK, -CI, -Bg, -I, -E, -SEz, -F(O)K5 -F("F)OH, -MN", -5H, -MNK, -MK»o, -ZK, -8OZN, -502K, -5(-0) K»5 -CM, -OH, -Ш(-О)OK, -С(-О)МК», -МКСО(-ОК and -МКОС(-О)-ОК, where K independently represents hydrogen or С. c-alkyl.

In a further embodiment, the presented invention relates to a method of obtaining a compound of formula MA. b5

S ok 70 in FI; 2, , c which consists in the reduction of the compound of the formula MIA, o a - ; at

In a swarm | счи со и - M, «- с "» Й - and their 45. | 1 со з ко о LA (Se) where - В is selected from the group: shydrogen, Su v-alkyl-O-C(-0)- , C - alkyl, C - cycloalkyl, C - aryl,

C,o-heterocyclyl, S-10-aryl-C,-c-alkyl and C o-heterocyclyl-C,-4-c-alkyl; where Si are indicated. β-alkyl,

C 3 -cycloalkyl, C 10 -aryl, C 10 -heterocyclyl, C 10 -aryl-C 10 -c -alkyl and C 10 -heterocyclyl-C. z-alkyl, optionally, 99 substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Vg, -I, -E, -SEz, -FSH-OJK, o - F("F)OH, -MH", -5H, -MNK, -MK»o, -ZK, -8OZN, -50oK, -5(-O)K, -SM, -OH, -F(-O )OK, -С(-О)МК», -МКО(-ОК and -МКО(-О)-ОК, where K independently represents hydrogen or C. в-alkyl; but B? and KZ are independently selected from the group: hydrogen, C. c-alkyl and Ca 6-cycloalkyl, where C c-alkyl and

C. β-cycloalkyl, as an option, substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, bo -Bg, -I, -E, -SEz, -FSH-O) K, -FSH-OON, -MN", -ZN, -MNK, -MK", -Z3K, -8OzH, -502K, -5(-:0)K, -SM, -OH, -FSH-FO) OK, -FSH(5O)MK", -MKOS(-O)K and -MKO(-O)-OK, where K independently represents hydrogen or C..in-alkyl.

In particular, the compounds of the present invention and the intermediates used for their production can be obtained by synthesis in Schemes 1-18. b5 kemyh s i po s dk. dough

Med KE and fe KZ I

Ve v. pa 70 -- ! ay She with vh Ya it

I. what. Co. iy th I sho sha she still ke I and there is also a child. is E i p their shi SHE WITH S in:

Zeaschykh Bas

KE and i pe

Sheryetsinka pn eriavvya: Zhitermedivki school in ; | M of the term: o z Shen lisa yani ny Biy rai f g m y. ; what and - what:

Her relatives Pera "Z ru ne t yah What h y di o Ves svy -y Zh S U o

Z toluvlvNY BO: y y

On t What in how s zv MBA schne no spennvnns so sana Internayikv: - p . a (og) ko («v se) - and ko 60 b5 and blame

Kg I in the village ZE... ptn t :ch zlu sih " zydryakh And groglit pyhreyuliktkyu beat so sia ak

PUT is new, BUT she is in good health.

Zh bab shh Nv 0 Kovoi 70 v ZE I z srifluvratstovy E y I and I and shob so In Shlopuka not and knoduka g name and STE A go tk: E: dog with Ge o p ke tka POSHY yvlukav: ns i o on the wife

Mei ve i) ii Ks sei oh gYaiy Her and I: skik eno she and s Mk sche nie

Zh. 2 St. SITTING "Yet

Pishi Sean nn, gzhkre t vysveatya; I yad 0 thermos "npolukavn chenykh compound teasnaii: reslvny I s hna y 8 . "» sh yiv 8) zh uh, m D. Where is everything from: eh tuyy y SHHI b - in gai "y Bo iy she yi V | what she YAN she sya yati o - Iv z Ey ce t Mai j WYNY i y V iv EV o | shi g rifiorat vva: KE sho

Fo WHAT What would be OV EK KD "a sne 7 odu se nt ss Nai pan ko 60 65 y vini

Kg I in the village ZE... ptn t :ch zlu sih " zydryakh And groglit pyhreyuliktkyu beat so sia ak

PUT is new, BUT she is in good health.

Zh bab shh Nv 0 Kovoi 70 v ZE I z srifluvratstovy E y I and I and shob so In Shlopuka not and knoduka g name and STE A go tk: E: dog with Ge o p ke tka POSHY yvlukav: ns i o on the wife

Mei ve i) ii Ks sei oh gYaiy Her and I: skik eno she and s Mk sche nie

Zh. 2 St. SITTING "Yet

Pishi Sean nn, gzhkre t vysveatya; I yad 0 thermos "npolukavn chenykh compound teasnaii: reslvny I s hna y 8 . "» sh yiv 8) zh uh, m D. Where is everything from: eh tuyy y SHHI b - in gai "y Bo iy she yi V | what she YAN she sya yati o - Iv z Ey ce t Mai j WYNY i y V iv EV o | shi g rifiorat vva: KE sho

Fo WHAT What would be OV EK KD "a sne 7 odu se nt ss Nai pan ko 60 65 y vini

Kg I in the village ZE... ptn t :ch zlu sih " zydryakh And groglit pyhreyuliktkyu beat so sia ak

PUT is new, BUT she is in good health.

Zh bab shh Nv 0 Kovoi 70 v ZE I z srifluvratstovy E y I and I and shob so In Shlopuka not and knoduka g name and STE A go tk: E: dog with Ge o p ke tka POSHY yvlukav: ns i o on the wife

Mei ve i) ii Ks sei oh gYaiy Her and I: skik eno she and s Mk sche nie

Zh. 2 St. SITTING "Yet

Pishi Sean nn, gzhkre t vysveatya; I yad 0 thermos "npolukavn chenykh compound teasnaii: reslvny I s hna y 8 . "» sh yiv 8) zh uh, m D. Where is everything from: eh tuyy y SHHI b - in gai "y Bo iy she yi V | what she YAN she sya yati o - Iv z Ey ce t Mai j WYNY i y V iv EV o | shi g rifiorat vva: KE sho

Fo WHAT What would be OV EK KD "a sne 7 odu se nt ss Nai pan ko 60 65

Shomab oi v: v te THAT we we I I m HOW. schu nev Z dk, or 170 I prp inno sksnivyuevokintu sen NV (Ve b; t KI and hovod onikninii NN

Vnotemenin in nulluva and Net; » MAM m pi Odesa same vn s ShK zhur ne y Bonya pu scha zh schi Shche Arkikh y ipe

Chi She: inn ze sk y u s, Kk; im ish shk: pi t- GIA What Ge)

GI about Vkrifluureinov; and and "

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E. I

(F) ko bo b5

Shomab oi v: v te THAT we we I I m HOW. schu nev Z dk, or 170 I prp inno sksnivyuevokintu sen NV (Ve b; t KI and hovod onikninii NN

Vnotemenin in nulluva and Net; » MAM m pi Odesa same vn s ShK zhur ne y Bonya pu scha zh schi Shche Arkikh y ipe

Chi She: inn ze sk y u s, Kk; im ish shk: pi t- GIA What Ge)

GI about Vkrifluureinov; and and "

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E. I

(F) ko bo b5

Shomab oi v: v te THAT we we I I m HOW. schu nev Z dk, or 170 I prp inno sksnivyuevokintu sen NV (Ve b; t KI and hovod onikninii NN

Vnotemenin in nulluva and Net; » MAM m pi Odesa same vn s ShK zhur ne y Bonya pu scha zh schi Shche Arkikh y ipe

Chi She: inn ze sk y u s, Kk; im ish shk: pi t- GIA What Ge)

GI about Vkrifluureinov; and and "

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E. I

(F) ko bo b5

In the y y vne b on i WE ! or and A with;

Z ZI re : iy she: i schu V I De. IB and Mk koe tin: her se M: "ay,

KI Msvshe soya chariana DY No. With pe Vana, like him, and in the stars I She

Zhermediyk 6 review of the NV as a ditch, yapoluka ot: Ko khaniv m , sa e Se (o) dl -y y rt za: V z R dyk svo vash a I ey i ey 5 lerifpuvuyetinya: write y Goshi ЙЙ ben - у zay behind MO ee

Who paid the fees for the 5 AK i pi ve In: zv Appeal of the povkva Pnpeornyujdbane era nysy so

In Teri tsi chi mshchi "

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Who paid the fees for the 5 AK i pi ve In: zv Appeal of the povkva Pnpeornyujdbane era nysy so

In Teri tsi chi mshchi "

Rol oi I In sei shchi I a wk with tk; scha z v y Z m. v she y M

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Intermediate b. 2. I'm in the middle of GB; yes, Yani

IJ

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Zo (ge)

Compound sb: Ky. liyachoD at mouth ng decree and OWL drank the same - . и» (ог) ио) (ав) (се) - и ио) бо b5

Sho Ts. Shchi t : zi: Yainsya "Norezhov a y i a re Riy za chit:

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With ! Her and her. and

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No, no. / rya i yo" this B

With ! Her and her. and

Also Ж chaviuev ay "compound Zh MV. vbluna ach 7 en

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That

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That

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G! with Co. F t as o 35 va tu tnknih ao she: shdvdvnes zhy p polova au sb koi i (ee) zspolyua iya; picoliridnya epoluka dv: Kene pirndnoye - ei t te 40 - m EV page N ya ra tn More V re - ЧИ вn "» : deya y s ya sin ra y y g y what More: y from Her y 45 ay Masses: M And "everything that is magnificent with her and what I eat; what are the walls of her and that I. sweat about B zoluey like 50 E- and Y

That

Sho zhpoluka li. There is irony: the zhnolukada veins propya enolukala Nieneirnki kpopuka in kieatridnya zpoluka And pchedridy live uyu in Nenoo nenykh (F) io) in 65

Khema V. and ru SM, liy gen 0000oizhe, 000 payayojurnako febonniai ; Essovr tn vet zhoOlolya those zhk Ai

Van Bebsproya: Kivertsi

Biological assessment

The compounds of the invention were found to be active in relation to 5-receptors of warm-blooded animals, for example, humans. In particular, the compounds of the invention were found to be effective ligands of the 5-receptor. ip migo studies, below, demonstrate these unexpected activities, particularly in terms of agonist potency and efficacy, as demonstrated in a rat brain functional study and/or a human M29 functional 5-receptor study. This feature may relate to IP mimo activity and may not correlate d) linearly with binding affinity. In these immunoassays, compounds are tested for their activity against 5-receptors and ICoos are obtained to determine the selective activity of a particular compound against 5-receptors. In the modern context, the ICBO usually refers to the concentration of the compound at which 50956 substitutions of the standard radioactive ligand of the 5-receptor are observed. The activities of the compounds in relation to K and M receptors are also measured in a similar study. Ge") added to Migo's ultura of cells

Human 293 Z cells, expressing cloned human k, 5, and c receptors and resistant to Neomycin Ce, are grown in suspension at 372С and 595 СО» in shake flasks containing calcium-free SO

OMEM'1095 EV5, 5906 VS, 0.195 Rishopis E-68 and bO0Omkg/ml geneticin.

Rat brains are weighed and washed in ice-cold PB5 (containing 2.5 mM EDTA, pH 7.4). Brains are homogenized with a polytron for 30s (rats) in ice-cold lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with phenylmethylsulfonyl fluoride added immediately before use to 0.5 mM of a 0.5 M stock solution in a mixture of DMSO: ethanol) . with c Obtaining membranes

Cells are pelleted and resuspended in a lysis buffer (500 mM Tris, pH 7.0, 2.5 mM EDTA, with RMB5BE, added immediately before use to 0.1 mM of the 0.1 M stock solution in ethanol), incubated on ice for 15 minutes , then homogenize with a polytron for 30 seconds. The suspension is centrifuged at 10,000 (max) for 1 second at 45C. The supernatant is kept on ice and the pellets are resuspended and centrifuged

Go! as before Supernatants from both centrifugations are combined and centrifuged at 46,000g (max) for 30 minutes. Granules are resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and centrifuged again. The final granules are resuspended in membrane buffer (500 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots of (Iml) in polypropylene tubes are frozen in dry ice/ethanol and stored at -709C until use.

Protein concentrations are determined by a modified Lowry assay with sodium dodecyl sulfate. ix) Cell binding studies Membranes are thawed at 372, cooled on ice, passed 3 times through a 25-gauge needle and diluted with binding buffer (50 mM Tris, 3 mM MoSi 5, mg/ml VZA (Zidta A-7888), pH 7 ,4, |and stored at 49C after filtering through a 0.22m filter and adding bmkg/ml of aprotinin, TOmMm of bestatin, 10m of liprotin A, without OTT). Aliquots of 100 μl are added to ice-cooled 12x75 mm polypropylene tubes containing 100 μl of an acceptable radioligand and 1000 μl of the test compound at various concentrations. Total iF) (TV) and non-specific (M5) binding were determined in the absence and presence of 1 µM naloxone, respectively.

Kz The tubes are mixed and incubated at 259 for 60-75 minutes, after which the contents are quickly vacuum-filtered and washed with approximately 12 ml/tube of ice-cooled wash buffer (50 mM Tris, pH 7.0, 3 mM 60 Mass") through SR/V filters (MUpaitap ), pre-soaked for at least 2 hours in 0.195 polyethyleneimine.

Radioactivity on the filters is measured with a beta counter after soaking the filters for at least 12 hours in miniflasks containing b-7ml of scintillation liquid. If assays are performed in 96-well plates with deep cells, filtration is performed through 96-well polyethyleneimine-impregnated unifilters, which are washed with Zhiml washing buffer and dried in a cabinet at 5592 for 2 hours. for Filter tablets are counted in TorSoshp (RuskKaga) after adding 5 Омкл of scintillation liquid M5-20 per cell.

Functional research

Agonistic activity of compounds is measured by determining the degree to which the compound-receptor complex activates binding of STR to O-proteins to which the receptors bind. In the study of the binding of STR

OTRIMZ55 was combined with test compounds and membranes from NEK-2935 cells expressing cloned human opioid receptors or from homogenized rat and mouse brain. Agonists stimulate the binding of STRIA in these membranes. Values Emax and Emax of compounds are determined by dose-response curves. Rightward shifts of the dose-response curve with the delta antagonist naltrindole are performed to test whether the agonist activity is mediated by delta receptors. E wax values were determined relative to the standard 5-agonist ZMS80, i.e., 70 above 10095 indicates a compound with better efficacy than ZMS80.

Procedure for the brain of SOTR rats

Rat brain membranes are thawed at 372C, passed 3 times through a 25 gauge needle with a blunt end and diluted with STRUZ binder (50mM Nerez, 20mM Mahon, 100mM Masi, 1mM EDTA, 5mM Masi», pH 7 4, Add fresh: 1mM OT, 0.195 VBA). Finally, add 120 µM of SOF to the membrane dilutions. The value of ECo and

The Emax of the compounds is estimated by 10-point dose-response curves in ZOOmcl with an acceptable amount of membrane protein (2O0mcg per cell) and 100,000-130,000 bimp/min of STU per cell (0.11-0.14nM). Baseline and maximum stimulated binding are determined in the absence and presence of ZmkM ZMSO-80.

Analysis data

Specific binding (58) was calculated as TV-M5 and 5B in the presence of various test compounds and expressed as a percentage of the control ZV. IR values and Hill coefficient (pn) for ligands in the substitution of a specifically bound radioligand were calculated by logit transformation or curve fitting programs, such as Iidapa, sharpRai

Rgizvt, ZidtarRioi, or Keserioggii. The value of K was calculated according to the Cheng-Prussoff equation. ICvo-DiI., K, and pn values are presented for ligands tested in at least three displacement curves. high school

Based on the above testing, we found that the compounds of the present invention are active against the human 5-receptor. Of course, ICeo in relation to the human 5-receptor for most of the compounds (o) of the presented invention is within 0.48nM-17.9nM. ECo and 9oEux to the human 5-receptor for these compounds are typically in the range of 18.6nM-1724nM and 65-108, respectively. ICeo with respect to the human K and I receptors for the compound of the invention is usually in the range of 1317nM-9739NM and 261nM-9774NM, respectively. "-

Experiments on receptor saturation

The K 5 value of a radioligand is determined by conducting a binding study on cell membranes with (22 acceptable radioligands at a concentration ranging from 0.2 to 5 times the estimated K 5 (up to 10 times, if the amount of the required radioligand is real). Specific binding radioligand is expressed as pmol/mg of membrane protein. Values of K5 and Woodc from individual experiments were obtained by nonlinear fitting of specific bound (B) vs. free (E) radioligand from an individual according to a single-site model.

Determination of mechanoallodynia by von Frey testing

Testing is carried out between 08:00 and 16:00 hours in the manner described in |Spariap ei ai. (1994)). Rats are placed in Plexiglas cages with a wire bottom that allows access to the paws, and allowed to get used to it for 10-15 minutes. The area tested is the middle of the sole of the left hind paw, avoiding the less sensitive paw pads.

Paws are touched with a series of 8 von Frey hairs of logarithmically increasing stiffness (0.41, 0.69, 1.20, 2.04, ssh s 3.63, 5.50, 8.51, and 15.14g; Bioenipo, 111 , OYUOBA). The Von Frey hair is pushed from the bottom of the floor perpendicular to the surface of the sole with sufficient force to cause a slight bend of the paws and held for about 6-8 seconds. "» A positive response is noted if the paw is sharply withdrawn. Trembling immediately after removing the hair is also considered a positive response. Standing up is considered a dubious response and in such cases the stimulus is repeated. (se) Test protocol

Animals are tested on day 1 after surgery for the ESA-treated group. 5095 the threshold of withdrawal is determined using the up-down method of Dixon (1980). Testing begins with a hair of 2.04 g in the middle of the series. av | Stimuli are always applied sequentially, increasing or decreasing. In the absence of withdrawal of the paw as a response to the initially selected hair, a stronger stimulus is applied; in case of withdrawal of the paw, and the next weaker stimulus. The calculation of the optimal threshold in this way requires 6 responses in the immediate vicinity of the 5095 threshold, and the calculation of these responses begins when the first response change occurs, for example, the threshold is crossed for the first time. In cases where the thresholds are outside the stimuli, respectively, the value 15 .14 (normal sensitivity) or 0.41 (maximum allodynic). The resulting positive and negative feedbacks are grouped using conventional notations, X-no spiking: O-spiking and 5090 spiking threshold are interpolated by the formula: o BOZOg threshold- 100Chkeu10000io) where Chi-value of the last applied von Frey hair (log units), K-value

Ivid Spariap ei ai. (1994)| for positive/negative feedback; and 5-value of the difference between the stimuli (logarithmic 60 units). Here it is 5-0.224.

Von Frey's thresholds are expressed as a percentage of the maximum possible action (90 MPE), according to |(SNariap ei ai!. 1994).

The following equation was used to calculate 9oMPE: oBMPE - threshold during treatment Ggg) - threshold of allodynia (g) threshold of control (g) - threshold of allodynia (g bo Application of the test substance

Rats are injected (subcutaneously, intraperitoneally, intravenously, or orally) with the test substance before the von Frey test, the time between the application of the test compound and the von Frey test varying depending on the nature of the test compound.

Shrinkage test

Acetic acid induces abdominal contractions when administered intraperitoneally in mice, stretching their body in a typical pattern when analgesic drugs are applied, this described movement is observed less often and drugs are chosen as potentially good.

A full and typical writhing reflex is considered present only when the following elements are present: the animal does not move; the lower part of the back is weakly depressed; the soles of both paws are available for observation. In this study, compounds of the present invention demonstrate significant inhibition of twitch responses following oral administration of 1-100 µmol/kg. () Preparation of solutions

Acetic acid (ASON): 120 μl of acetic acid is added to 19.83 ml of distilled water to a final volume of 7/5 2Oml with a final concentration of 0.670 ASON. The solution is then mixed and used for injection.

Compounds (drugs): Each compound is prepared and dissolved in the most suitable vehicle by standard methods. (i) Application of solutions

The compound (drug) is administered orally, intraperitoneally, subcutaneously, or intravenously at 1 Oml/kg (taking into account the average body weight of mice) 20, 30, or 40 minutes (according to the class of the compound and its characteristics) before testing, when the compound is delivered centrally: intraventricularly or intrathecally, a volume of 5 μl is used.

AsoOnH is applied intraperitoneally in two areas at 1 Оml/kg (taking into account the average body weight of mice) immediately before testing, (ii) Testing with

The animal (mouse) is observed for 20 minutes and the number of cases (wiggle reflex) is recorded and compiled at the end of the experiment. Mice are kept in individual "shoebox" cages with contact (8) stacking. In total, 4 mice are usually observed at the same time: one control and three doses of drugs.

For anxiety and anxiety-like symptoms, efficacy was established in the rat conflict test

For symptoms of functional gastrointestinal disorders, efficacy may be established in --

From the study described by |Socippo ZM ei ai, in Ategisap ChWashgpa! oh Rpuzioiyudu -SavigoipiezNpa! 5 Pimeg Rpuzioiodu. 282(2):53 07-16,2002 Hrebi, in rats. (22)

Additional IP testing protocols by o

Subjects and accommodation

Untreated male Zrgadce Oamleu rats (175-200g) are divided into groups of 5 in a room with adjustable CM

With temperature (222C, 40-7096 humidity, 12 hours light/dark). Experiments are carried out during the light phase of the cycle. Animals have food and water ad libitum and are killed immediately after data collection.

Sample

Compound (drug) testing includes groups of rats that do not receive any treatment and others that are treated with E. soy lipopolysaccharide (IRB). For the 1st Rbo-experiment, 4 groups are injected with 1st RB, 1 of the 4 groups is then treated with a vehicle, and the other three groups are injected with drugs and their vehicle. The second series of experiments is carried out using five groups of rats; all of which do not receive I RB5 processing. The untreated group receives no compound (drug) or vehicle; the other 4 groups are treated with a vehicle with or without drugs. It is carried out to determine and? anxiolytic or sedative effect of drugs, which can contribute to the reduction of BM.

Application of I P5

Rats were allowed to get used to the experimental laboratory for 15-20 minutes before treatment. Inflammation

Go! induced by the use of ARZ (endotoxin of gram-negative bacteria serotype E. soii 0111:84, Zidta). I RZ (24 μg) is injected intracerebroventricularly), in a volume of 100 ml, using standard stereotaxic co-surgery under isoflurane anesthesia. The skin between the ears is moved rostrally and a longitudinal incision of about 1 cm is made to open the surface of the skull. The location of the puncture is determined by the coordinates: 0.8 mm behind the 5th crown, 1.5 mm to the left in relation to the lambda (sagittal seam) and 5 mm below the surface of the skull (vertically) in the lateral c ventricle. HRB is injected through a sterile stainless steel needle (26-05 3/8) 5 mm long attached to

MORE Hamilton's syringe with a 100-μl polyethylene tube (PE20; 10-15 cm). A 4 mm stopper made of a cut needle (20-5 b) is placed on top and isolated from the 26-53 needle with silicone glue to form the required depth of B5 mm.

After injection | The P5 needle is left for an additional 10s for compound diffusion, then removed. The incision is closed and the rat is returned to its cage and allowed to rest for a minimum of 3.5 hours before testing. (F) Experimental setup for air blast stimulation t Rats are left in the experimental laboratory after injection | P5 and use of compound (drugs). During testing, all rats are removed and placed outside the laboratory. One rat is transferred to the test laboratory and placed in a transparent box (9x9x18cm), which is then placed in a noise-absorbing ventilated box for measurement 62(w)x35(d)x4b(h)cm (INCLUDED ME, Oim. Tesp-Zegm Ips) . Blows of air through the outlet air nozzle О0.32cm are regulated by a system (Aiigoit, Zap Oiedo Ipigitepiv) capable of directing blows of air of fixed duration (0.2s) and fixed intensity with a frequency of 1 blow per 10s. A maximum of 10 blows are used, or until the voice is given , which goes first. The first blow of the air means the start of registration. 65 Experimental setup for ultrasonic registration

Voting is recorded for 10 minutes using microphones (S.K.A.5, Medraek, Oeptakgk)

placed on the side of each box and regulated by the I M5 program (I M5 SABA-X 3.58, Oaya Asdciziiop Mopiyog, Tgou,

Mispidap). Frequencies between 0 and 32000 Hz are registered, stored and analyzed by the same program (M SAVA-X 3.58,

Tite Oaiia Rgosezvipd Mopiog and ORA (Oveg Rgodgattipo and Apayuziv)).

Compounds (drugs)

All compounds (drugs) are adjusted to pH between 6.5 and 7.5 and used in a volume of 4 ml/kg. After the application of the compound (drug), the animals are returned to their cages until the time of testing.

Analysis

The registration is passed through a series of statistical and Fourier analyzes to the filter (between 20-24k Hz) and to calculate the required parameters. Data are expressed as CI values. Statistical significance was assessed using a t-test and one-way ANOVA followed by Dunnett's multiple comparison test (following) for drug efficacy comparisons between untreated and I Re-treated rats. A difference between groups is considered significant with a minimum p-value of less than 0.05. Experiments are repeated at least twice.

Examples

The invention is further described by the following examples, which describe ways in which the compounds of the present invention can be prepared, purified, analyzed and biologically tested, and which do not limit the invention.

Intermediate 1

A mixture of 4-(bromomethyl)benzoic acid methyl ester (11.2g, 49mmol) and trimethylphosphite (25ml) was heated at reflux under nitrogen for 5 hours. Excess trimethylphosphite was removed by co-distillation with toluene to give intermediate 1 in quantitative yield. "H-NMR (SOSI") 5 3.20 (8, 2H, 9U-22Hz, СНе), 3.68 (ad, ЗН 10.8Hz, OSН»a), 3.78 (a, ЗН, 11, 2Hz, OSN"), 3.91 (in,

ZN, OSN"), 7.38 (t, 2H, Ag-H), 8.00 (a, 2H, 9U-8Hz, Ag-H).

Intermediate 2: 4--4-Methoxycarbonyl-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester Ge

To a solution of intermediate 1 in dry tetrahydrofuran (200 ml), lithium diisopropylamide (32.7 ml of 1.5 M in hexanes, 49 mmol) was added dropwise at -782С. The reaction mixture was then allowed to warm to room temperature before addition of M-tert-butoxycarbonyl-4-piperidone (9.7b6g, 49mmol in 1700ml of dry tetrahydrofuran).

After 12 hours, the reaction mixture was quenched with water (3000ml) and extracted with ethyl acetate (33x3000ml). The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to give a crude product which was purified by flash chromatography to give intermediate 2 as a white solid (5.64g, 3595). b

ICH (Mass) 3424, 2974, 2855, 1718, 1688, 1606. 1427, 1362, 1276cm"; "H-NMR (SOSIi) 5 1.44 (z, 9H), 2.31 (5 9-5.5 Hz , 2H), 2.42 (B 9-5.5Hz, 2H), 3.37 (5 9U-5.5Hz, 2H), 3.48 o (B 9-5.5Hz, 2H), 3.37 (B, ZN, OSN"), 6.33 (B, 1H, CH), 7.20 (a 2-6.7Hz, 2H, Ag-H), 7.94(a, 7-6.7Hz, 2H, Ag-H); Ha 136 NMR (SOSIV5) 5 28.3, 29.2 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6, 166.8. co

Intermediate C: 4-Bromo-4-I(bromo-(4-methoxycarbonyl-phenyl)-methyl|-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of intermediate 2 (5.2g, 1bmmol) and potassium carbonate (1.0g) in dry dichloromethane (200ml) was added a solution of bromine (2.9g, 14mmol) in 30ml of dichloromethane at 02. After 1.5 hours at room temperature, the solution After filtering, the potassium carbonate thickened. The residue was then dissolved in ethyl acetate (200ml), washed with water (200ml), 0.5M NaOH (200ml) and brine (200ml) and dried over anhydrous magnesium sulfate. Removal of the solvents gave the crude product, which was recrystallized from methanol to give intermediate C as a white solid (6.07 g, 7895).

ICH (Mass) 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243cm"; "H-NMR (SOS) 5 1.28 (z, 9H), 1.75 (t, 1H), 1.90 (t, 1H), 2.1 (t, 2H), 3.08 (Bg, 2H), 3.90 (v, ZN, OSN»U), 4.08 (ee) (Bg, ZN), 7 .57 (a, U-8.4Hz, 2H, Ag-H) 7.98 (a, 9-8.4Hz, 2H, Ag-H); with 1ZS-NMR(SOSI") 5 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0, 130.3, 130.4, 141 ,9, 154.4, 166.3.

Intermediate 4: 4-I(bromo-(4-carboxyphenyl)-methylene|-piperidine-1-carboxylic acid tert-butyl ester ("c") A solution of intermediate C (5.4 g, 11 mmol) in methanol (30 Oml) and 2, 0 M Mahon (100 Oml) was heated at 402 C for 3 s 20 h. The solid product was collected by filtration and dried overnight under vacuum. The dry salt was dissolved in 4095 acetonitrile/water and adjusted to pH 2 using conc. NH. Intermediate 4 (3.8 g , 8795) was isolated - as a white powder by filtration. "YAN NMR (SOSIV) 5 1.45 (v, 9H, Vy), 2.22 (aa, 9-5.5Hz, b1Hz, 2H), 2.64 ( aa, 9uU-5.5Hz, 6b1GHz, 2H), 3.34 (aa, 9-5.5Hz, 6.1Hz, 2H), 3.54 (da, 9-5.5Hz, 6.1Hz, 2H) . 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3.

HF) Intermediate 5: 4-Ibromo-(4-diethylcarbamoyl-phenyl)-methylene|-piperidine-1-carboxylic acid tert-butyl ester

Isobutyl chloroformate (450 mg, 3.3 mmol) was added to a solution of intermediate 4 (1.0 g, 2.5 mmol) in dry dichloromethane (1 mL) at -209C. After 20 minutes at -202C, diethylamine (4 ml) was added and the reaction mixture was allowed to warm to room temperature. After 1.5 hours, the solvents were evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried with anhydrous magnesium sulfate. Removal of the solvents gave the crude product, which was purified by flash chromatography to give intermediate 5 as white needles (800 mg, 7390). 65 ICHS (Mass) 3051, 2975, 1694, 1633, 1416, 1281, 1168, 1115cm7;

TN-NMR (SOSIv) 5 1.13 (bg, ZN, СNa), 1.22 (bBg, ZN, СNa), 1.44 (v, 9Н, Vy), 2.22 (5 9-5.5Hz , 2H), 2.62 (i,

-5.5Hz, 2H), 3.33 (t, 4H), 3.55 (t, 4H), 7.31 (a, U-8.0Hz, 2H, Ag-H), 7.36 (a , U-8.0Hz, 2H, Ag-H);

ZS NMR (SOSIi) 5 12.71, 14.13, 28.3, 31.5, 34.2, 391, 43.2, 79.7, 115.9, 126.3, 129.3, 136, 8, 1371, 140.6, 154.6, 170.5.

Intermediate 6: 4-(2-aminophenyl)(4-(diethylamino)carbonyl|phenyl|methylene-1-piperidinecarboxylic acid 1,1-dimethylethyl ester

To a mixture of intermediate 5 (3.0g, 6.65mmol) and 2-aminophenylboronic acid (1.37g, 9.97mmol) in toluene (8bml) and ethanol (1/ml) was added 2.0M sodium carbonate (13ml). Palladium tetrakistriphenylphosphine (774 mg,

0.1 mmol) was added and the resulting mixture was heated overnight at 90 2C under nitrogen. The reaction mixture was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a silica gel column, eluting with a 7:3 E(Ac:hexanes) mixture to give intermediate 6 as a light brown solid (3.14 g, quantitative yield). 1.12 (Bg 8, ZN), 1.26 (rbg 5, ZN), 1.46 (z, 9H), 2.22 (t, 2H), 2.45 (t, 2H), 72 3, 28 (rg 8, 1H), 3.37 (t, ЗН), 3.54 (t, 4H), 3.66 (z, 2H), 6.69 (aa, 9-7.91, 0.88Hz , 1H), 6.73 (4, 9-7.42, 1.17Hz, yin), 6.95 (aa, 0-7.71, 146Hz, 1H), 7.09 (a, 9-7, 62, 1.56Hz, 1), 7.21 (a, 9-8.40Hz, 2H), 7.31 (a,

U-8.40Hz, 2H).

Compound 1: 4-((2-(benzoylamino)phenyl|-4-piperidinylidenemethyl/)-M,M-diethylbenzamide is p and 8 y. ; E and i (8) «-- mb her

N o

Triethylamine (0.3 bml,

Zo 2.Bdmmol) and then benzoyl chloride (13Zmg, 0.9b5mmol). The reaction mixture was stirred overnight at room temperature under nitrogen, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (2.5 ml) was added. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-4095 SNCM in water with a content of 0.196 trifluoroacetic acid), obtaining compound I (275 mgH, h 4696 yield) as trifluoroacetate. This material was lyophilized from CH with CM/water, obtaining a colorless solid and product. Purity (HPLC); 29995;

TN nMR (400 MHz, СО53О0) 5 1.06 (Her 9-6.64 Hz, ZN), 1.20 (5 9-6.74 Hz, ZN), 2.49-2.72 (t, 4H), 3 ,10-3.15 75 (t, 7), 3.20-3.31 (t, 4H), 3.31-3.40 (t, 1H), 3.43-3.55 (t, 2H ), 7.05 (a, 2-840Hz, 2H), 7.18 (a, 2-840Hz, so 2H), 7.27-7.31 (t, 1H), 7.37-7.43 ( t, ZN), 7.45 (a, 9-8.01Hz, 2H), 7.55 (B 9 -7.42, 1.37Hz, 1H), 7.66 (a, km U-7.23Hz , 2H). Found: C, 62.61; H, 5.92; M, 6.71. С з0Нзз3МаО»ох1,2СЕ5СО5НХ1,0Н2О has C, 62.52; H, 5.86; M, 6.75 90. o 50 Compound 2: M-(2-(C4-(diethylamino)carbonyl|phenyl|-4-piperidinylidenemethylphenyl)benzeneacetamide (Ce) and "- ; .

Y ) iya and iF) A and with 60 stitches b5 y

Method for compound 1 using intermediate 6 (400 mg, 0.3 mmol) and phenylacetyl chloride (13 µgHg,

0.95 mmol) gave compound 2 (381 mg, 6295 yield) as trifluoroacetate. This material was lyophilized from

SNZSM/water, obtaining a colorless solid product. Purity (HPLC): 29990;

TN nMR (400MHz, СО53О0) 5 1.09 (5 9U-6.74Hz, ZN), 1.22 (5 9-6.93Hz, ZN), 2.34-2.49 (t, ZN), 2 ,49-2.59 (t, 71Н), 2.95-3.04 (t, 1Н), 3.09-3.30 (t, 5Н), 3.47-3.58 (overlapping 4 and t , .-5.66 Hz, 4H), 6.89 (a,

U-820Hz, 2), 7.22 (a, U-820Hz, 2H), 7.26-7.42 (t, 9H). Found: C, 63.88: H, 6.13; M, 6.66.

СзоНз5МаО2х1:1СЕ5СО05НХ1.0НоО has C, 63.79: H, 6.14; M, 6.72 90.

Compound 3: 4-(2-Kcyclohexylcarbonyl)amino|phenyl)-4-piperidinylidenemethyl|-M,M-diethylbenzamide.

M Ek 7 o a z

By the method for compound I, using intermediate 6 (150 mg, 0.32 mmol) and cyclohexanecarbonyl chloride (52 mg, 0.35 mmol), compound C (159 mg, 8395 yield) was obtained as trifluoroacetate. This material was lyophilized from (o)

SNZSM/water, obtaining a colorless solid product. Purity (HPLC): 29990;

TN NMR (400MHz, CO5O0) 5 1.04-1.24 (t, b6H), 1.324-1.39 (t, 4H), 1.46 (494, 9U-12.33, 3.03Hz, 1H) , 1.58-1.91 (t, 5H), 2.22 (B 9U-128, 3.47Hz, 1H), 2.43-2.56 (t, 2H), 2.61 (a U- 14.84, 5.86Hz, 1H), 2.72 h- (a, 9-15.04, 6.05Hz, 1H), 3.15-3.33 (t, 6H), 3.47-3 .55 (t, U-6.83Hz, 2H), 7.19 (a, U-8.40Hz, 2H), 7.26-7.34 (t, 6H).

Revealed: C, 60.51; H, 6.33; M, 6.27. SzoNzoM3O»x1,6СЕ3СО5НЧО,2Н2О has C, 60.45; H, 6.26; M, 6.37905. b"

Compound 4: M-(2-((4-(diethylamino)carbonyl)phenyl)-4-piperidinylidenemethyl|phenyl|benzenepropanamid o ts sor fi Ff « | - s dich - y? 45 . o sa ya ko

The method for compound 1, using intermediate 6 (1500 mg, 0.32 mmol) and benzenepropanoyl chloride (bOmg, and 0.35 4 (157 79 J and iophiles 20 Zbmmol)) gave the compound (157 mg, /o yield) as trifluoroacetate. This material was lyophilized from (se) CHNSM/water to give a beige solid. Purity (HPLC): 29990; ha TN-NMR (400MGhCts, CO3O0) 5 1.07 (6 9-644Hz, ZN), 1.21 (5 9-6, 64Hz, ZN), 2.38-2.59 (t, 5H), 2.69 (a, 4-15.04, 5.66Hz, 1), 2.79-2.94 (t, 2H), 3.18-3.31 (t, 6H), 3.50 (Bbg a, 9U-6.51Hz, 2H), 7.07 (a, yu-8.20Hz, 2H), 7.15-7, 35 (t, 11H).

Revealed: C, 63.05; H, 5.89; M, 6.50. Szz3NaMaO»ox1,4СЕ3СО25НЧО,4НОО has C, 63.09; H, 5.96; M, 6.34905.

Compound 5: 4-(2-(Cyisohexylacetylamino|phenyl)-4-piperidinylidenemethyl/|-M,M-diethylbenzamide

F) ko 60 b5 and shchi and | M - everything

M

Diisopropylethylamine (0.14 ml, 0.8 mmol) was added to a solution of cyclohexylacetic acid (74 mg, 0.52 mmol) and NATIi (172 mg, 0.45 mmol) in dimethylformamide (7 mL), followed by intermediate 6 (150 mg, 0.32 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1N Mahon (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on a silica gel column, eluting with a mixture of 171 EOAc:hexanes, then redissolved in dichloromethane (LOml). Trifluoroacetic acid (ml) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase HPLC (gradient 10-4095 CHNaCl in water containing 0.195 DS: 1N trifluoroacetic acid) to give compound 5 (13mg, 6795 yield) as trifluoroacetate. This material was lyophilized from CH3SM/water to give a colorless solid. Purity (HPLC): 29990; "H-NMR (400 MHz, CO5O0) 5 0.90-1.06 (t, 2H), 1.05-1.33 (t, 9H), 1.61-1.80 (t, 6H), 1 .97 (aa, U-13.86, 7.23GHz, 1), 2.13 (da, 0-13.86, 6.64Hz, 1H), 2.51 (5 9U-5.96Hz, 2H) . ), 3.51 (a, U-664 Hz, 2H), 7.17 (a, 9-840 Hz, 2), z-- 7.24-7.37 (t, 6H). o

Found: C, 61.10; H, 6.47; M, 6.27. С34НА4Ма3О»ох1,6СЕ3СО5НХО,1Н20 has C, 61.13; H, 6.42; M, 6.2595.

Compound 6: M,M-diethyl-4-(2-K2-phenylethylamino|phenyl)-4-piperidinylidenemethyl|benzamide ("c") i c (ee)

UYU r i i i : - s i? She and | what is it?

Phenylacetaldehyde (156 mg, - 1.30 mmol) was added to a solution of intermediate 6 (ZOOmg, O0.b5mmol) in 1,2-dichloroethane (20ml), followed by glacial acetic acid (0.07ml, 1.30mmol) and Mavn(OAc) »z (Z44mg, 1.63mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred for another 4 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 20-4590 SNZSM in water containing 59 0.195 trifluoroacetic acid) to give compound 6 (181 mg, 4095 yield) as trifluoroacetate.This material

F! lyophilized from CH3CM/water to give a beige solid. Purity (HPLC): 29990;

TN-NMR (400 MHz, СО3О0) 5 1.08 (5 9-6.74 Hz, ZN), 1.21 (1 9-6.83 Hz, ZN), 2.19-2.36 (t, 2H), 2.56 (i, dc 3-6.05Hz, 2H), 2.84 (5 9U-6.64Hz, 2H), 2.96-3.05 (t, 1H), 3.06-3.14 (t, 1H), 3.13-3.21 (t, 2H), 3.20-3.30 (t, in 2H), 3.29-3.46 (t, 2H), 3.46- 3.56 (t, 2H), 6.63 (a, 9U-7.42, 0.98Hz, 1H), 6.73 (a, 9-8.20Hz, 1H), 6.89 (aa, 9 -7.42, 1.56Hz, 1H), 7.07 (a, 9-8.40Hz, 2H), 7.10-7.17 (t, 1H), 7.18-7.27 (t, 5H), 7.27-7.33 (t, 2H).

Found: C, 65.55; H, 6.48; M, 6.69, Cz4NaMa3Ox1,2СЕ53С05НХО,4Н2О has C, 65.58; H, 6.43; M, 6.8790.

Compound 7: 4-12-Kcyclohexylmethyl(amino|phenyl)-4-piperidinylidenemethyl()-M,M-diethylbenzamide b5 to : Fe n

To a solution of intermediate 6 (300mg, 0.bbmmol) in 1,2-dichloroethane (20ml) was added cyclohexanecarboxaldehyde (14bmg, 1.3bbmmol) followed by glacial acetic acid (0.07ml, 1.30mmol) and

Mavn(oOds)»z (344 mg, 1.63 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred for another 4 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogencarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase

HPLC (gradient of 20-5095 SNHZSM in water containing 0.195 trifluoroacetic acid) to give compound 7 (190 ug, in 43906 yield) as trifluoroacetate. This material was lyophilized from CH with CM/water to give a colorless solid. Purity (HPLC): 29995; (at)

TN-NMR (400MHz, СО3О0) 5 0.78-0.90 (t, 2Н), 1.05-1.25 (t, 10Н), 1.41-1.52 (t, 1Н), 1, 52-1.72 (t, 5H), 2.36-2.50 (t, 2H), 2.64-2.77 (t, 2 NO 2.88 (y, 9U-6.64Hz, 2H) , 3.12-3.38 (t. 5H), 3.46-5.55 (t, 2H), 6.59-6.66 (y, 2H), 6.96 (da, 9U-7, 42, 1.37Hz, 1H), 7.12 (ada, d-8.70, 7.42, 1.56HzC, 1H), 7.31 (v, 4H). "- zo Detected: C, 63, 61; H, 6.36; M, 6.92. CzoHl«Ma3Ox1.4СЕ5СО5Н has C, 63.61; H, 6.90; M, 6.78905.

Compound 8: M,M-diethyl-4-Ch2-(phenylmethyl)amino|phenyl)-4-piperidinylidenemethyl|benzamide (22) o - "c ) s aut o b s o 7 NO what c 2"

To a solution of intermediate 6 (309 mg, 0.7 mmol) in 1,2-dichloroethane (20 mL) was added benzaldehyde (140 µL, 1.3 mmol), followed by glacial acetic acid (3 mL, 0.6 mmol) and Mn(Ods) with (283 mg, 1.34 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. Trifluoroacetic acid 50% (2 ml) was added and the reaction mixture was stirred for another 4 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogencarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 20-5090 SNZSM in water containing 0.195 trifluoroacetic acid) to give compound 8 (203mg, 4595 yield) as trifluoroacetate. This material 59 was lyophilized from CH3CM/water to give a colorless solid. Purity (HPLC): 29990;

HF) TNA-NMR (400MHz, СО5О0) 5 1.11 (B, 9-7.62Hz, ZN), 1.24 (p, 9U-7.62Hz, ZN), 2.46-2.52 (t , 2H), t 2.64-2.79 (t, 2H), 3.17-3.37 (t, 6H), 3.49-3.58 (t, 2H), 4.34 (in, 2H), 6.54-6.57 (t, 1H), 6.61-6.66 (t, 1H), 6.96 (aa, 9-7.62, 1.56Hz, 1H), 7, 01-7.08 (t, 1H), 7.11-7.27 (t, 5H), 7.32-7.37 (t, 4H). It was revealed: C, 62.71; H, 5.89; M, 6.74. СзоНз5М3Ох1,5СЕ3СО05НЧО,4Н2О has C, 62.73; H, 5.95; M, 6.6590.

Compound 9: 4-((2-(cyclohexylamino)phenyl)-4-piperidinylidenemethyl/)-M,M-diethylbenzamide b5

. ik fi F r. : . 70 and what

N

To a suspension of intermediate 6 (200 mg, 0.4 mmol) and cyclohexanone (47 mg, 0.47 mmol) in MeonH (bml) was added decaborane (16 mg, 0.3 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated in vacuo. The residue was filtered through a thin layer of silica gel, eluting with a 1:1 mixture

EMOAzihexanes and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-40956 SNZSM in water containing 0.195 trifluoroacetic acid) to give compound 9 (207 mg, 7195 yield) as trifluoroacetate. This material was lyophilized from CH3CM/water to give a colorless solid. Purity (HPLC): 29990; si "YAN NMR (400 MHz, CO500) 5 0.69-0.82 (t, 1H), 1.05-1.38 (t, 11H), 1.47-1.61 (t, 2H), 1 .69 (a, uU-12.89Hz, 2), 1.93 (a, 9-11.72Hz, 1), 2.37-2.51 (t, 2H), 2.66-2.81 ( t, 2H), 3.08-3.17 (t, 1H), 3.17-3.38 (t, 5H), o 3.51 (rg a, 9U-6.45HCts, 2H), 6, 73-6.79 (t, 2H), 7.06 (yes, 2 -7.62,1.56Hz, 1H), 7.18 (ada, 9-8.25, 7.37,1.56Hz, 1H), 7.28-7.36 (t, 4H).

Found: C, 58.94; H, 6.47; M, 6.31. СгоНзоМазОх1,8СЕ3СО5НЧО,7Н2О has C, 59.01; H, 6.41; M, 6.3390. h-

Compound 10: M,M-diethyl-4-(2-((phenylamino)carbonylamino|phenyl)-4-piperidinylidenemethyl|benzamide

M. M. shsh with V.Y

And" Fr

A solution of intermediate 6 (200mg, O0.4mmol) and phenyl isocyanate (5mg, O0.47mmol) in 1,2-dichloroethane (10ml) was stirred overnight at 709C under nitrogen. The reaction mixture was then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and trifluoroacetic acid 20% (1.5 ml) was added. The reaction mixture was stirred for two hours at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-40956 CHNaCl in water containing 0.195 -. trifluoroacetic acid) to give compound 10 (235 mg, 9295 yield) as trifluoroacetate. This material was lyophilized from CHCl/water to give a colorless solid. Purity (HPLC): 29990;

TN nMR (400 MHz, СО3О0) 5 0.97 (B 9-6.74Hz, ZN), 1.17 (5 9-7.03Hz, ZN), 2.48 (5 9U-6.05Hz, 2H), 2.68 (a, U-5.60HZ, 2H), 3.04 (t, 2H), 3.15-3.27 (t, 4H), 3.39-3.53 (t, 2H), 6.98 (B -7.22, 1.17Hz, tn), "in,

HF) 9-7.42, 1.37HZ, 1), 7.20-7.28 (t, 6H), 7.28-7.30 (t, 1H), 7.30 (aa, 1-1 .76, 0.98Hz, 1), 7.33-7.34 (t, 1H), 7.34-7.37 (t, 1H), 7.60 (aa, 2-8.10, 0, 88 Hz, 1 N). ki Found: C, 57.39; H, 5.32; M, 7.87. SeoNzaMAaO»och1,9СЕ53СО025НХО,5Н2оО has C, 57.32; H, 5.25; M, 7.91905. in Compound 11: M,M-diethyl-4-12-(phenylamino)phenyl)-4-piperidinylidenemethyl|benzamide b5 o all | m

M

A mixture of intermediate 6 (30mg, 0.b5mmol), bromobenzene (13mg, 0.85mmol), Raz(ava)z (24mg, 0.02bmmol),

Mas'Vy (87 mg, 0.9 mmol), (4)-VIMAR (32 mg, 0.052 mmol) in toluene (3.7 mL) was placed in a microwave beaker. The flask was purged with nitrogen, sealed, and heated to 11093 for 10 minutes using microwave irradiation. The resulting mixture was cooled, concentrated in a vacuum, then purified by flash chromatography on a column with silica gel, eluting with a mixture of 2:3 EtOAc:hexanes. The product was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (2 ml) was added. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 15-40965 SNASM in water containing 0.195 trifluoroacetic acid) to give compound 11 (19 µg, 4495 yield) as c 29 trifluoroacetate. This material was lyophilized from CH3ZSM/water to give a colorless solid. Purity (9 (HPLC): x9995;

TN nMR (400 MHz, СО3О0) 5 1.01 (6 9-6.83 Hz, ZN), 1.19 (3-7.03 Hz, ZN), 2.48-2.58 (t, 2H), 2 ,58-2.76 (t, 2H), 3.03 (a, U-6.83HZ, 2H), 3.11-3.26 (t, 4H), 3.46 (a, 9U-7, 03Hz, 2H), 6.71-6.79 (t, ZN), 6.98 (aada, «- zo 9-7.62, 6.25, 2.34Hz, 1H), 7.05-7, 11 (t, 2H), 7.16-7.24 (t, 7H).

Found: C, 65.08; H, 6.11; M, 7.20. SouNzzMa3Ox1,1СЕ3СО05НХО, bno has C, 65.08: H, 6.18; M, 7, 3090. (22)

Compound 12: M,M-diethyl-4-(2--"methylphenylamino)phenyl|-4-piperidinylidenemethyl|benzamide o

And ch 35. s tu z i r M nd Zh « | - with zho and i | IF

M co

A mixture of intermediate 6 (225mg, 0.49mmol), bromobenzene (99mg, 0.bZmmol), Raz(ara)z (18mg, 0.019mmol), where MaOVy (b5mg, 0.b8mmol), (-) VIMAR (24mg, 0O .03 mmol) in toluene (2.9 mL) was placed in a microwave beaker. The flask was purged with nitrogen, sealed, and heated to 11093 for 10 minutes using microwave irradiation. The resulting mixture was cooled, concentrated in a vacuum, then purified by flash chromatography on a column with silica gel, eluting with a mixture of 2:3 EUAbs:xhexanes. The product (26bOmg, - 0.48mmol) was dissolved in dimethylformamide (11ml) and sodium hydride (46bmg, 1.1bmmol) was added. The reaction mixture was stirred for 1 hour at room temperature. Methyl iodide (171 mg, 1.21 mmol) was then added and the reaction mixture was stirred overnight at room temperature. After 18 hours, the reaction mixture was quenched with saturated ammonium chloride and extracted with dichloromethane. The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (LOml) and trifluoroacetic acid was added

Kz (1.5 ml). The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo.

The residue was purified by reverse-phase HPLC (gradient 20-5096 СNaАСМ in water with a content of 0.196 bo of trifluoroacetic acid), obtaining compound 12 (12bmg, 34956 yield over two steps) as trifluoroacetate. This material was lyophilized from SNUSM/water to give a pale yellow solid. Purity (HPLC): 9195 (215nm), 9395 (254nm), 86905 (280Ohm);

TN nMR (400 MHz, СО3О0) 5 1.04 (Bg 5, ZN), 1.19 (Bg 8, ZN), 2.38-2.57 (t, ZN), 2.57-2.72 (t , 4H), 2.93-3.18 (t, 5H), 3.20-3.33 (t, 71H), 3.48 (rg 5, 2H), 6.27 (a, 9-8, 20Hz, 2H), 6.60 (Her, 9-7.32Hz, 1), 6.92 bo (a, 9-8.01GHz, 2), 7.01 (6 9-7.81GHz, 2), 7.13 (9.9-7.62 Hz, 1), 7.16-7.23 (t, 2H), 7.34 (9-7.03 Hz, 1H),

7.43 (ad, 9-14.65, 7.42Hz, 2H).

Compound 13: M,M-diethyl-4-(2-((phenylsulfonyl)amino|phenyl)-4-piperidinylidenemethyl|benzamide 7 r ia F

M o and v

Benzenesulfonyl chloride (230mg, 1.300mmol) was added to a solution of intermediate 6 (30mg, 0.55mmol) in pyridine (110ml). The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (2 ml) was added. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase

HPLC (gradient 10-4095 CH3CM in water containing 0.195 trifluoroacetic acid) to give compound 13 (298 mg, 6390 yield) as trifluoroacetate. This material was lyophilized from CH3CM/water to give a yellow solid.

Purity (HPLC): 29996;

TN-NMR (400 MHz, СО3О0) 5 1.11 (5 9-6.64 Hz, ZN), 1.22 (5 9-7.03 Hz, ZN), 2.43-2.52 (t, 1H), 2.52-2.61..7-7 (t, 2H), 2.72-2.83 (t, 1H), 3.22-3.36 (t, 5H), 3.38-3, 48 (t, 1H), 3.47-3.60 (t, 2H), 6.64 (da, 9u-5.01, Fu 0.78hz, 1), 7.11 (ada, -8.01, 7 ,03.1.95Hz, 1H), 7.1-7.34 (t, 6H), 7.48-7.53 (t, 2H), 7.60 (K, 9-7.42.1, 37Hz, 1), 7.64-7.69 (t, 2H). at

Found: C, 58.37; H, 5.58; M, 6.46. Co5NazzMa3Oz5x1.1СЕ3С05НЧО,7Н2О has C, 58.40; H, 5.58; M, 6.5590. urine

Compound 14: M,M-diethyl-4-(2-Kphenylmethyl)sulfonyl|amino|phenyl)-4-piperidinylidenemethylylbenzamide so si k. - s r. 2» new (ee) her m ) o o . (Se) "-

The method for compound 13 using intermediate 6 (25mg, 0.54mmol) and benzylsulfonyl chloride (206mg, 1.08mmol) gave compound 14 (253mg, 6395 yield) as trifluoroacetate. This material was lyophilized from

HF) SNZSM/water, obtaining a beige solid product. Purity (HPLC): 29990; t TN nMR (400MHz, СО53О0) 5 1.02 (5 9U-6.83Hz, ZN), 1.20 (5 9-6.64Hz, ZN), 2.36-2.52 (t, 2H), 2.52-2.62 (t, 7), 2.74 (a O-15.38, 540Hz, 1H), 3.13-3.27 (t, 5H), 3.30-3.39 ( t, 1H), 3.42-3.55 (t, 2H), 4.13 (a, bo 3-13.86Hz, 1H), 4.25 (j, U-13.67Hz, 1H), 7 .17 (96 5-7.22, 1.17 Hz, 1H), 7.22-7.36 (t, 12 H).

Found: C, 58.87; N, 5.76; M, 6.91. SzoNz5M3Oz35x1.1СЕ3С05НЧО,8НоО has C, 58.82; H, 5.78; M, 6.3990.

Compound 15: M,M-Diethyl-4-(4-piperidinylidene(2-((2,2,2-trifluoroethyl)sulfonyl|amino|phenyl|methyl|benzamide))

Method for compound 13 using intermediate. 6 (203 mg, 0.44 mmol) and 2,2,2-trifluoroethanesulfonyl chloride (0.097 mL, 0.88 mmol) gave compound 15 (244 mg, 8995 yield) as trifluoroacetate. This material was lyophilized from CH3ZSM/water to give a pale yellow solid. Purity (HPLC): 29996; "NA-NMR (400 MHz, СО53О0) 5 1.11 (or -6.6 Hz, ZN), 1.23 (rg 5 9-7.0 Hz, ZN), 2.42-2.59 (t, ZN ), 2.73-2.82 (t, 1H), 3.19-3.40 (t, EN), 3.53 (a, U-6.8Hz, 2H), 3.95-4.15 (t, 2H), 7.26-7.44 (t, 8H).

Compound 16: 4-(2-(cyclopentylacetyl)amino|phenylUpiperidin-4-ylidene)methyl|-M,M-diethyl|benzam|d c

Compound 16 (180 mg, 8195) was obtained as trifluoroacetate by the procedure for compound 1 using intermediate 6 (175 mg, 0.377 mmol) and cyclopentyl acetyl chloride (b1 mg, 0.415 mmol). This material was lyophilized. with :z» SNZSM/water, obtaining colorless Purity (HPLC): 29990; "H-NMR (400 MHz, СО5О0) 5 1.06-1.26 (t, 8Н), 1.49-1.70 (t, 4H), 1.72-1.87 (t, 2H), 2.08-2.31 (t, ZN), 2.52 ( 9-5.96Hz, 2H), 2.56-2.66 ( t, 1H), 2.67-2.78 (t, 1H), 3.16-3.34 (t, 6H), 3.46-3.56 (rga, 9U-6.83Hz,

Go! 2), 7.17 (a, 20-8.40Hz, 2H), 7.26-7.37.

Found: C, 63.23; H, 6.84; M, 6.87. SzoNzoMa3Ozh1,1SEzSO5HHO,7HO has C, 63.23; H, 6.84; M, 6.87965. where Compound 17: 4-12-K(cyclopentylcarbonyl)amino|phenylpiperidin-4-ylidene)methyl/|-M,M-diethylbenzamide o

I. and "y ra r and Ff yu 60

The method for compound 1 using intermediate 6 (145 mg, 0.313 mmol) and cyclopentanecarbonyl chloride (4 mg, 0.344 mmol) gave compound 17 (141 mg, 7995) as trifluoroacetate. This material was lyophilized from

SNZSM/water, obtaining a colorless solid product. Purity (HPLC): 29990;

TNA-NMR (400 MHz, СО3О0) 5 1.10 (p, -6.35 Hz, ZN), 1.21 (p, 9U-6.35 Hz, ZN), 1.44-1.86 (t, 7Н) , 1.87-1.99 (t, 1H), 2.47-2.54 (t, 2H), 2.55-2.79 (t, ZH), 3.16-3.34 (t, 6H), 3.51 (rga, 9U-7.16Hz, 2H), 7.18

Ca, 2-8.40Hz, 2H), 7.27-7.35 (t, 6H).

Found: C, 60.05; H, 6.05; M, 6.71. SgoNaUMaO»och1,6СЕ3СО5НХО,1Н20 has C, 60.07; H, 6.07; M, 6.53905.

Compound 18: N,M-diethyl-4-(2-(3-phenylpropyl)amino|phenylpiperidin-4-ylidene)methyl|benzamide

She

7 AH

WITH

To a solution of intermediate 6 (200 mg, 0.4 mmol) in 1,2-dichloroethane (1 mmol) was added 3-phenylpropionaldehyde (9 mg, 0.69 mmol), followed by glacial acetic acid (3 mmol, 0.9 mmol) and Mn(OdAc) with ( 18Zmg, 0.8bmmol). with

The reaction mixture was stirred overnight at room temperature under nitrogen. Trifluoroacetic acid (U) (1.5 ml) was added and the reaction mixture was kept overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogencarbonate (1x). The layers were separated and the aqueous layer was additionally extracted with dichloromethane (2x). The combined organic phases were dried anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient - 20-5090 CH3CM in 0.195 trifluoroacetic acid water) to give compound 18 (112 mg, 3795 yield) as FU trifluoroacetate. This material was lyophilized from CH3CM /water to give a colorless solid. Purity (HPLC): x9996; o

TN nMR (400MHz, CO300) 5 0.99 (rg B 9-6.69Hz, ZN), 1.18 (bg 5, 9U-6.64Hz, ZN), 1.71-1.81 (t, 2H ), EM 2.37-2.56 (t, 4H), 2.64-2.79 (t, 2H), 3.00-3.27 (t, 7H), 3.30-3.37 ( t, 1H), 3.48 (Bg a, 9U-6.58Hz, 2H) 6.60 so (a, 0-7.71Hz, 71H), 6.66 (a 0-7.42, 0, 98Hz, 71H), 6.98 (yes, 9-7.47,1.61Hz, 1), 7.04-7.08 (t, 2H), 7.10-7.15 (t, 2H), 7.18-7.24 (t, 2H), 7.29-7.35 (t, 4H).

Found: C, 62.11; H, 5.88; M, 5.69. SzoNzoMaOx1.8СЕ3СО5НЧО,1Н20 has C, 62.08; H, 6.00; M, 6,109.

Compound 19: 4-(2-(2-cyclohexylethyl)amino|phenylIpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide « - - ? . 2» ak: so A po te

F

N ; (Se) ; and "-

To a solution of intermediate 6 (175mg, 0.377mmol) in 1,2-dichloroethane (12ml) was added cyclohexylacetaldehyde (57mg, 0.453mmol) followed by glacial acetic acid (2bml, 0.453mmol) and Mavn(OdAs) with (16Omg, O0 ,755mMmol). The reaction mixture was stirred overnight at room temperature under nitrogen. Trifluoroacetic acid (1.5 ml) was added and the reaction mixture was kept overnight at room temperature. The reaction mixture 60 was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (1x). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 20-5095 CHZSM in water containing 0.195 trifluoroacetic acid) to give compound 19 (89 mg, 3495 yield) as trifluoroacetate. This material was lyophilized from CHCl3/water to give a colorless solid. Purity (HPLC): 29996;

TN NMR (400MHz, CO53O0) 5 0.85-0.98 (t, 2H), 1.10 (rg 6 9-6.25Hz, ZN), 1.04-1.32 (t, 4H), 1 ,21 (By,

U-7.08Hz, ZN), 1.32-1.44 (t, 2H), 1.59-1.75 (t, 5H), 2.35-2.48 (t, 2H), 2, 63-2.76 (t, 2H), 3.01-3.36 (t, 8H), 3.48-3.56 (t, 2H), 6.62-6.68 (t, 2H), 6.94 (aa, 9-7.37, 1.32 Hz, tn), 7.14 (ada, o-8.30, 7.42, 1.66 Hz, 1H), 7.29-7.35 ( t, 4 H).

Found: C, 64.57; H, 7.10; M, 6.95. Cz4NazMa3Ox1,3СЕ3СО5НХО,2Н2О has C, 64.52; H, 7.20; M, 6.7290.

Compound 20: 4-((2-(cyclopentylamino)phenyl)((piperidin-4-ylidene)methyl/|-M,M-diethylbenzamide

S. r and Ff

A method for compound 9 using intermediate 6 (200 mg, 0.4 mmol) and cyclopentanone (40 mg, 047 mmol) afforded compound 20 (210 mg, 7495) as trifluoroacetate. This material was lyophilized from CH3SM/water to give a colorless solid. Purity (HPLC): 29996;

TNA-NMR (400 MHz, CO3O0) 5 1.05-1.26 (t, 1H), 1.09 (ry, 9U-6.06 Hz, ZN), 1.21 (5 9 -6.64 Hz,. ZN ),

Y30-1.67 (t, 5H), 1.71-1.81 (t, 1H), 1.90-2.02 (t, 1H), 2.36-2.52 (t, 2H), 2.65-2.79 (t, 2H), 3.14-3.36 (t, b6H), 3.47-3.55 (t, 2H), 3.66-3.74 (t, 1H ), 6.69-6.76 (t, 2H), 7.02 (da, u0-7.32, 1.27Hz, 1), 7.16 (ada, in the same 8.45, 7.18, 1.76 Hz, 1H), 7.27-7.35 (t, 4H). b

Found: C, 56.62; H, 5.62; M, 6.30. SovNaM3Ox2,2СЕ53С05НЧО,2Н2О has C, 56.72; H, 5.82; M, 6.1290.

Compound 21: 4-(2-(cycloheptylamino)phenyl)(piperidin-4-ylidene)methyl|-M,M-diethylbenzamide (α) c

Compound 21 ( 241mg, 8195) as trifluoroacetate. This material was lyophilized from CH3SM/water, (Ce) - i.r.: obtaining a colorless solid. Purity (HPLC): 29990; -. TN nMR (400MHz, CO53O0) 5 1.05-1 .25 (t, 4H), 1.21 (5 9-7.03 HZ, ZN), 1.25-1.70 (t, 11H), 1.8-1.98 (t, 1H), 2 36-2-49 (t, 2H), 2.67-2.80 (t, 2H), 3.13-3.38 (t, EN), 3.51 (a, U-6.70Hz, 2H ), 6.73 (a, 9U-8.01Hz, 1H), 6.77 (a o-7.42, 1.17Hz, 1H), 7.06 (aa, 2-7.32, 1.27Hz , 1), 7.16 (yes, U -8.45, 7.18, 1.76 Hz, 1H), 7.27-7.35 (t, 4H). 25 Found: C, 57.47; H , 5.91; M, 5.76. CzoHl«M3Ox2,3CE3CO5HHO, 1 NoO has C, 57.42; H, 6.06; M, 5.81905. o Compound 22: A-(2-(benzylamino) carbonylamino)phenyl(piperidin-4-ylidene)methyl-M,M-diethylbenzamide ko 60 b5 i i

M o

The method for compound 10 using intermediate b (200 mg, 0.4 µmol) and benzyl isocyanate (bZmg, 0.47 mmol) provided compound 22 (193 µg, 74965) as trifluoroacetate. This material was lyophilized from CH with CM/water to give a beige solid. Purity (HPLC): 29996;

TNA-NMR (400 MHz, СО3О0) 5 1.08 (6 -6.64 GHz, Z), 1.23 (5 9-6.64 Hz, ЗН), 2.44 (5 9-6.05 Hz, 2Н), 2.55-2.68 (t, 2H), 3.12-3.27 (t, 6H), 3.51 (g a, 9U-6.44Hz, 2H), 4.23-4.36 ( t, 2H), 7.13 (a 9-7.42, 1.37Hz, 1H)U, 7.17-7.21 (t, ЗН), 7.22-7.36 (t, 8H), 7.56 (yes, 9U-8.20, 0.78Hz, 1H). Found: C, 62.35; H, 5.96; M, 8.73.

С31Нз6МаО»х1,2СЕ3СО02НХО,5НоО has C, 62.44; H, 5.99; M, 8.72905. with

Compound 23: N,M-diethyl-4-((2-(1-naphthylamino)phenylpiperidin-4-ylidene)methyl|benzamide o «--

And r |! with | M (ge) 4 1 "

M i - s Mixture of intermediate 6 (200 mg, 0.4 mmol), bromonaphthalene (116 mg, 0.5 mmol), Raz(adva)z (1 mg, 0.017 mmol), ;z» Mmas'Vy (58 mg, 0.bOmol), (4)-VIMAR (21 mg, 0.034 mmol) in toluene (2.4 mL) was placed in a microwave beaker. The flask was purged with nitrogen, capped, and heated to 110 °C for 5 mm using microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, then purified (se) by flash chromatography on a silica gel column, eluting with a 1:1 E(OAc:hexanes) mixture. The product was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1.33 mL) was added. the mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient o 20-4595 CH32SM in water containing 0.190 trifluoroacetic acid) to afford compound 23 (13 µg, 4595 yield) as trifluoroacetate. This material lyophilized from CH3SM/water to give a beige solid. Purity (HPLC): 29996; "- "H-NMR (400MHz, CO5O0) 5 1.00 (5 9-6.54Hz, ZN), 1.19 (5 9-6.74 Hz, ZN), 2.54-2.75 (t, 4H), 3.08-3.21 (t, 4H), 3.23-3.31 (t, 2H), 3, 42-3.53 (t, 2H), 6.78 (ad, U-8.01, 0.98Hz, 1H), 6.88 (yes, 9-7.42, 0.98Hz, MH), 6 ... -6.83, 1.17Hz, 71), 7.47 (а, у-8.20Hz, 1Н), 7.56 (а, У-8.40Hz, 1Н), 7.80 (а, 9 -8.20 Hz, 1H). o Revealed: C, 66.35; H, 5.04; M, 6.65. SzzNa5MaOx1.4СЕ5СО5Н has C, 66.22; H, 5.65; M, 6.47905.

Compound 24: M,M-diethyl-4-K2-(3-fluorophenyl)amino|phenylUpiperidin-4-ylidene)methyl|benzamide ko 60 b5 -BO0-

what | . 8 M and? shi

A mixture of intermediate b (200 mg, 0.4 mmol), Z-fluoroiodobenzene (124 mg, 0.5 mmol), Raz(ara)z (1 mg, 0.017 mmol), MaO!Vy (58 mg, 0. mmol), (43-VIMAR ( 21 mg, 0.034 mmol) in toluene (2.4 mL) was placed in a microwave beaker. The flask was purged with nitrogen, capped, and heated to 1102 for 25 min using microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, then purified by flash column chromatography with silica gel, eluting with a 1:1 mixture of E(OAc/hexanes. The product was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1.33 mL) was added. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient si ov 1715-4090 SNUSM In water containing 0.196 trifluoroacetic acid) affording compound 24 (99mg, 3495 yield) as trifluoroacetate. This material was lyophilized from SNSSM/water to give a light crude solid. Purity (i) (HPLC ): x9595; "YAN nNMR (400 MHz, CO53O0) 5 1.00 (5 9-6.83 HC, ZN), 1.18 (5 9U-6.83HC, HC), 2.47-2.74 (t, 4H), 3.01 (ad, 3-6.83HC, 2H), 3.14 -3.27 (t, 4H), 3.46 (a, U-5.86Hz, 2H), 6.32-6.39 (t, 2H), 6.46-6.50 (t, 1H) , 6.97-7.05 (t, part 1H), 7.07-7.32 (t, 8H).

Found: C, 62.96; H, 5.62; M, 7.17. SgoaNzaeMa3Ox1,2СЕ3СО5НХО, 2Н.О has C, 63.07; H, 5.66; M, 7.0390. F

Compound 25: 4-N2-(4-chlorophenyl)amino|phenyl)piperidin-4-ylidene)methyl-N,N-diethylbenzamide ester so r (I F them: " - p

I" Mich and ; so -oto ko o Mixture of intermediate b (200 mg, 0.4 mmol), 4-bromochlorobenzene (107 mg, 0.5 mmol), Raz(ara)z (16 mg, 0.017 mmol), Mas'Vy (58 mg, 0. mmol), (4)-VIMAR (21 mg, 0.034 mmol) in toluene (2.4 mL) was placed in a beaker x) for microwave treatment. The flask was flushed with nitrogen, closed and heated to 110 9C for 5 min using microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, then purified by flash chromatography on a silica gel column, eluting with a 2:3 E(Ac:hexanes) mixture. The product was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1.33 mL) was added. The reaction mixture was stirred for overnight at room temperature, then concentrated in vacuo.The residue was purified by reverse phase

HPLC (gradient 20-5095 CH3SM in water containing 0.195 trifluoroacetic acid) to give compound 25 (139 mg, (F) 4696 yield) as trifluoroacetate. This material was lyophilized from CH with CM/water to give a beige solid. Purity (HPLC): 29995; "NA-NMR (400MHz, CO300) 5 1.01 (5 9U-6.83Hz, ZN), 1.18 (5 9-6.83Hz, ZN), 2.46-2.75 (t, 4H) . .69 (y, 2H), 6.98-7.03 (t, 2H), 7.06 (a 9-7.37, 1.27HZ, 1H), 7.15-7.21 (t, 5H ), 7.23-7.28 (t, 2H).

Found: C, 60.39; H, 5.29; M, 6.65. SooNzaSIMazOx1.4СЕ5СО5Н has C, 60.28; H, 5.31; M, 6.63905.

Compound 26: 4-(2-I(Icyclohexyl(methyl)amino|phenyl)hpiperidin-4-ylidene)methyl)-M,M-diethylbenzamide b5 h

M

To a suspension of intermediate 6 (175 mg, 0.3–8 mmol) and cyclohexanone (41 mg, 0.42 mmol) in MeonH (5 ml) was added decaborane (14 mg, 0.11 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated in vacuo. The residue was filtered through a thin layer of silica gel, eluting with a 1:1 mixture

EtOAc:hexanes and concentrated in vacuo. To a solution of the product (20 mg, 0.38 mmol) in Meon (4 mL) was added formaldehyde (3795 in water, 0.084 mL, 1.13 mmol). The reaction mixture was stirred for 30 minutes at room temperature. Decaborane (28 mg, 0.23 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature under nitrogen, then concentrated in vacuo. The residue was filtered through a thin layer of silica gel, eluting with a 1:1 mixture of E(OAc:xhexanes) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1.2 mL) was added. The reaction mixture was stirred overnight at room temperature , then concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 5-30956 CHZaCM in water containing 0.195 trifluoroacetic acid) to afford compound 26 (181 mg, 7090 yield) as trifluoroacetate. This material was lyophilized from CH3CM/water to give a solid . Purity (HPLC): 29990; ch: "NA-NMR (400MHz, СО53О0) 5 0.95 (Bg in, ZN), 1.08 (rg B 9-6.35Hz, ZN), 1.21 (Bg 6 9-644 Hz, ЗН), b 1.18-1.25 (t, 2Н), 1.45-1.63 (t, ЗН), 1.70 (rgv, 2Н), 2.39-2, 54 (t, 2H), 2.71-2.93 (t, 5H), 3.02 (Bg 8, 1H), 3.07-3.21 (t, 2H), 3.22-3.43 (t, 4H), 3.51 (Bg a, U-6.64Hz, 2H), 7.35 (8, 5H), 7.50 (rgv, ЗН). o

Revealed: C, 52.62; H, 6.35; M, 5.00. SzoNa«Ma3Ox2,5СЕ53СО5НХЗ,ОН2оО has C, 52.63; H, 6.25; M, 5.2690. with

Compound 27: N,M-diethyl-4-(2-X(4-methylphenyl)sulfonyl|iamino)phenyl)(piperidin-4-ylidene)methyl|benzamide co | and - with -E

And" | and

J is so Y I g "sh

Me 1 nk

And in the same manner as for compound 13, using intermediate 6 (175 mg, 0.3 mmol) and p-toluenesulfonyl chloride (144 g, 0.7 mmol), except that the residue was purified by reverse-phase HPLC (gradient 15-4095 SNUSM in water with a content of 0.196 trifluoroacetic acid), compound 27 (181 mg, 7695 yield) was obtained as trifluoroacetate.

This material was lyophilized from SNUSM/water to give a beige solid. Purity (HPLC): 29996; "NA-NMR (400MHz, СО5300) 5 1.11 (p, 9U-6.64GHz, ZN), 1.22 (B 9 -7.03Hz, ZN), 2.40 (z, ZN), 2, 42-2.51 (t, 1), 2.51-2.61 (t, 2H), 2.73-2.82 (t, 1H), 3.22-3.34 (t, 5H), 3.39-3.47 (t, 1H), 3.49-3.57 (t, 2H), 6.67

IF) (aa, o-7.81, 0.98Hz, 1), 7.11 s (ada, o-7.81, 7.03, 1.95Hz, 71H), 7.19-7.29 ( t, 4H), 7.31 (a, 2-820Hz, 4H), ke 7.53 (a, 9-8.40Hz, 2H).

Found: C, 57.97; H, 5.36; M, 6,931. SzoNz5Ma3Oz5x1.4СЕ53СО05НЧО,1Н20 has C, 58.01; H, 5.43; M, 6,199. 60 Compound 28: M,M-diethyl-4-(2--(2-fluorophenyl)sulfonyl|amino)srenyl)(piperidin-4-ylidene)methyl|benzamide b5

And - and ray and 7 | E chat, M and ! and Z shch sa!

The method for compound 13 using intermediate b (175 mg, 0.3 mmol) and 2-fluorobenzenesulfonyl chloride (147 mg, 0.7 mmol) gave compound 28 (121 mg, 5195 yield) as trifluoroacetate. This material was lyophilized from SNUSM/water to give a beige solid. Purity (HPLC): x9995;

TN-NMR (400 MHz, СО300) 5 1.11 (B, 1-6.64 Hz, ZN), 1.23 (p, 9U-6.83 Hz, ZN), 2.43-2.61 (t, ZN ), 2.713-2.81 (t, 1H), 3.22-3.35 (t, 5H), 3.39-3.48 (t, 1H), 3.53 (rg 4, U-6, 96Hz, 2H), 6.71 (а, ю9-7.42HzC, 1H), c re TL12 (аа, 9-7.91, 6.93, 2.15Hz, 1H), 7.23-7.33 (t, 8H), 7.63-7.68 (t, 1H), 7.70 (and U-7.03, 1.76Hz, 1H).

Found: C, 56.89; H, 5.08; M, 6.33. SgoNaz»EMa3Oz35x1.2СЕ5СО05НЧО,2НО has C, 56.96; H, 5.12: M, 6.3590. at

Compound 29: 4-(2-Kbutylsulfonyl)-amino|phenyl(piperidin-4-ylidene)methyl|-M,M-diethylbenzamide i.) h- ! Fra o r so | (uh)

M. g /Y water « o -v s I;» " The method for compound 13, using intermediate 6 (208mg, 0.449mmol) and butane-1-sulfonyl chloride (0.12ml, 0.93mmol) gave compound 29 (95.7mg, 3b9o yield) as trifluoroacetate. This material was lyophilized from CNaCM/ water, obtaining a pale whitish solid product. Purity (HPLC): 294965; so 1n MMK (400MHz, СО500) 5 0.91 (5 9-74Hzc, ZN), 1.12 (g B 9U-6.9HzC, ZN ), 1.23 (B, 9U-7.1hz, ZN), t 1.35-1.46 (t, 2H), 1.65-1.74 (t, 2H), 2.40-2, 62 (t, ZN), 2.73-2.82 (t, 1H), 2.85-3.02 (t, 2H), 3.18-3.42 (t, 6H), 3.53 ( Bha, U-7.2Hz, 2H), 7.28-7.39 (t, 8H). o Found: C, 55.52; H, 5.90; M, 6.73. C27NaUMa3Oz5x1.4СЕ53СО05НЧО,1Н20 has C, 55.48; H, 6.03; M, 6.5190. "c 50 Intermediate (7: 4-(C4-Kdiethylamino)carbonylphenyl|(2-nitrophenyl)methylene-1-piperidinecarboxylic acid 1,1- dimethyl ethyl ester "-. 2.0 M sodium carbonate (4.4 ml) was added to a mixture of intermediate 5 (100 mg, 2.22 mmol) and 2-nitrophenylboronic acid (556 mg, 3.3 mmol) in toluene (28 ml) and ethanol (b. ).Palladium tetrakistriphenylphosphine (257mg, 0.22mmol) was added and the resulting mixture was heated overnight at 9029 under nitrogen. The reaction mixture was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a silica gel column, eluting with a 1:1 mixture of E(Ac:hexanes) to give intermediate 7 as a brown oil (244 mg, 2290 yield). in TN nMR (400 MHz, SOSi3) 5 1.12 (bg 8, ZN), 1.22 (bg 85, ZN), 1.45 (in, 9H), 2.07-2.15 (t, 2H), 2.26-2.36 (t, 71), 2.41-2.50 (t, 1H), 3.20-3.43 (t, 4H), 3.45-3.62 (t, 4H), 7.22 (a, 2-8.20Hz , 2H), 7.30 (a, 2-8.20Hz,

ZN), 7.40-7.46 (t, 1H), 7.58 (a, 9-7.62, 1.17Hz, 1H), 7.90 (da, 2-8.10, 1.07Hz , 1H).

Intermediate 8: 4-(1-benzylpiperidin-4-ylidene)(2-nitrophenyl)methyl/)|-M,M-diethylbenzamide

Trifluoroacetic acid b (1.3 ml) was added to a solution of intermediate 7 (244 mg, 0.049 mmol) in dichloromethane (10 ml). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo.

The residue was redissolved in dichloromethane and washed with saturated aqueous Manceau (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue and benzaldehyde (0.101 mL, 0.99 mmol) were dissolved in 1,2-dichloroethane (13 mL). Glacial acetic acid (57 μl, 0.99 mmol)) was added to the reaction mixture and then

Mavn(OdAc)z (262mg, 1.24mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, redissolved in dichloromethane and washed with saturated aqueous Manceau (1x).

The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by filtration through a thin layer of silica gel, eluting with a gradient mixture of 10095 dichloromethane to 1:9 MeOH/dichloromethane, 7/0 to give intermediate 8 as a dark yellow oil (238 mg, 9395 yield).

TN-NMR (400 MHz, SOSIia) 5 1.10 (rg 8, ZN), 1.24 (Bg in, ZN), 2.09-2.23 (t, 2H), 2.31-2.55 ( t, 6H), 3.24 (bho8, 2H), 3.46-3.57 (t, 4H), 7.20-7.34 (t, 8H), 7.36-7.43 (t, ZN), 7.55 (a 9-7.52, 1.37Hz, 1H), 7.87 (aa, 5-8.20.1, 17Hz, 1H).

Intermediate 9: 4-((2-aminophenyl)/(4-((diethylamino)carbonyl|phenyl)imethylene)piperidine-1-tert-butyl carboxylate

2.0 M sodium carbonate (4.8 ml) was added to a mixture of intermediate 5 (1080 mg, 2.39 mmol) and 2-aminophenylboronic acids (426 mg, 3.11 mmol) in toluene (3 ml) and ethanol (b.2 ml). Palladium tetrakistriphenylphosphine (27 mg, 0.24 mmol) was added and the resulting mixture was heated overnight at 902° under nitrogen. The reaction mixture was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a silica gel column, eluting with a mixture of 7:3 E(Ac':hexanes) to give intermediate 9 as a brown solid (103mg, 9495 yield).

H NMR (400 MHz, SOSIz) 5 1.12 (Bg 8, ZN), 1.23 (bg 8, ZN), 1.46 (v, 9H), 2.15-2.27 (t, 2H) , 2.40-2.51 (t, 2H), 3.22-3.44 (t, 4H), 3.46-3.78 (t, 6H), 6.69 (a, 9-7, 81GHz, 1), 6.73 (a 0-7.47, 1.07Hz, 1H), 6.95 (aa, y-7.52, 1.46Hz, 1H), 7.09 (ak yu-7 ,62,1.56Hz, 1), 7.21 (a, 2-8.20Hz, 2H), 7.31 (a, 2-8.20Hz, 2H). with

Compound 31:4-((2-(acetylamino)phenyl|(piperidin-4-ylidene)methyl/|-M,M-diethylbenzamide o

To a solution of intermediate 9 (250 mg, 0.54 mmol) in dichloromethane (1 bml) was added triethylamine (225 μl, 1.62 mmol), followed by acetyl chloride (50 ri, 0.70 mmol). The reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and washed with saturated aqueous Manceau (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (1.7 mL) was added. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The residue was purified in reverse by -phase HPLC (gradient 5-30956 CHZSM in se water with a content of 0.195 trifluoroacetic acid). The product was dissolved in dichloromethane and washed with saturated aqueous ManNnsSoOz (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined

The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 31 as a colorless solid (13 mg, 6195 yield).

TNA-NMR (400 MHz, SOSIZ) 5 1.11 (bgv, ZN), 1.23 (biv, ZN), 2.07 (z, ZN), 2.09-2.25 (t, 2H), 2 ,51 (bg i,

U-547HzC, 2H), 2.90 (5 9-5.57Hz, 2H), 2.96 (rg b 9-547Hzc, 2H), 3.26 (Bg 85, 2H), 3.53 (rg in , 2H), 7.06-7.13 " (t, 2H), 7.15 (a, U-8.20Hz, 2H), 7.27-7.35 (t, 4H), 8.22 ( a, 9-8.40Hz, 1H). 70 Compound 32: methyl 2-(4-(diethylamino)carbonyl)phenyl)(piperidin-4-ylidene)methyl|phenylcarbamate o, c A mixture of zinc powder (30mg, 0.59mmol) and methyl chloroformate (4bml, 0.509mmol) in toluene (2ml) was stirred for 1 hour at room temperature. A solution of intermediate 9 (250mg, 0.54mmol) in toluene (4ml) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature, diluted with SNiSiIa, filtered and then washed with 1N Manceau from (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a silica gel column, eluting with 3:11 E(Ac/hexanes). The product was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (1.7 mL) was added. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with sat. as a dark yellow oil (88 mg, 36905 yield). "H-NMR (400 MHz, SOCIi) 5 1.11 (g 5, ZN), 1.23 (Bg 5, ZN), 2.11-2, 22 (t, 2H), 2.50 (5 9-5.66Hz, 2H), 2.94 (d4, 9-24.85, 4.93Hz, 4H), 3.26 (rg 5, 2H), 3.53 (Bg 8, 2H), 3.74 (v, ZN), 6.84 (rg 8, 1H), 7.01-7.07 (t, 2H), 7.15 (a, U- 8.40Hz, 2H), 7.27-7.33 (t, 4H), 8.07 (a, 9-7.42Hz, 1H).

HF) Intermediate 10: M,M-diethyl-4-(2-nitrophenyl)hpiperidin-4-ylidene)methyl|benzamide

To a mixture of intermediate 5 (5.16g, 11.7mmol) and 2-nitrophenylboronic acid (2.93g, 17.5mmol) in toluene (125ml) and ethanol (25ml) was added 2.0M sodium carbonate (14.bml). Palladium tetrakistriphenylphosphine (1.35 g, in 1.17 mmol) was added and the resulting mixture was heated overnight at 909C under nitrogen. The reaction mixture was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with two portions of E(Ac.

The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a column with silica gel, eluting with a 1:11 mixture of E(Ac:hexanes.

The material was dissolved in dichloromethane (200 ml) and trifluoroacetic acid (bml) was added. The reaction mixture 65 was stirred overnight at room temperature and saturated aqueous sodium hydrogencarbonate was added.

The phases were separated and the aqueous phase was extracted with two portions of dichloromethane. The combined organic phases were dried -B4-

anhydrous sodium sulfate, filtered and concentrated in vacuo to give intermediate 10 as a brown solid (1.50g, 30905). "H-NMR (400 MHz, SOSIi) 5 1.06-1.16 (t, ЗН), 1.18-1.29 (t, ЗН), 2.29-2.39 (t, 1Н), 2 ,42-2.53 (t, 1H), 2.54-2.73 (t, 2H), 2.99-3.10 (t, 2H), 3.16-3.29 (t, 4H) , 3.47-3.59 (t, 2H), 7.20 (a, 9-8.40 Hz, 2H), 7.29-7.33 (t, ZN), 7.47 (davd, 9- 8.20, 7.62, 1.56Hz, 1H), 7.61 (a, 9U-7.62, 1.37Hz, 1H), 7.92 (aa, 2-8.20, 1.17Hz, 1H).

Intermediate 11: 4-I(bromo(1-butylpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide

Trifluoroacetic acid (15ml) was added to intermediate 5 (5000mg, 11.08mmol) in dichloromethane (10ml) at room temperature. The resulting mixture was stirred at room temperature for 4 hours under nitrogen. 70 The reaction mixture was then concentrated in vacuo and the residue was diluted with saturated aqueous ManSO 3 . The aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. To this crude product in dichloroethane (50 mL) was added butylaldehyde (878 mg, 12.2 mmol) followed by Mavn(OAc)z (3520 mg, 16.62 mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, redissolved in dichloromethane 75 and washed with 2M Mahon solution (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x).

The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a gradient mixture of 9:11 dichloromethane/HOAc - 3:2 dichloromethane/E(OAc) to give intermediate 11 as a pale yellow oil (1807 mg, 4095 yield). ) 5 0.92 (B 9-7.32Hz, ЗН), 1.07-1.19 (t, ЗН), 1.20-1.39 (t, 4Н), 1.42-1.54 ( t, 2H), 1.57-1.64 (t, 1H), 2.24-2.39 (t, 6H), 2.55 (5 9-5.86Hz, 2H), 2.70 (1 , 9U-8.00Hz, 2H), 3.23-3.36 (t, 2H), 3.48-3.62 (t, 2H), 7.31 (a, U-8.00Hz, 2H) 7.35 (a, 9U-8.00, 2H).

Intermediate 12: 4-I(bromo|1-(pyridin-4-ylmethyl)piperidin-4-ylidenemethyl/|-M,M-diethylbenzamide

The method for intermediate 11 using intermediate 5 (b00mg, 13.mmol) and 4-pyridinecarboxaldehyde (3242mg, 9.24mmol) gave intermediate 12 (3675mg, 9095 yield) as a pale yellow solid. c 29 "H-NMR (400 MHz, CO500) 5 1.12 (5 9-6.83 Hz, ZN), 1.23 ( 9U-6.93 Hz, ZN), 2.27-2.33 (t, 2H ), 2.38-2.43 Ge) (t, 2H), 2.57 (5 9-5.76HzC, 2H), 2.69-2.75 (t, 2H), 3.24-3, 34 (t, ZN), 3.53 (a, 9U-7.23HZ, 1H), 3.59 (c, 2H), 7.36 (c, AN), 7.42-7.46 (t, 2H), 8.43-8.47 (t, 2H).

Intermediate 13: 4-Ibromo|1-Ipyridin-3-ylmethyl)piperidin-4-ylidenemethyl/|-M,M-diethylbenzamide

The method for intermediate 11 using intermediate 5 (4000mg, 8.87mmol) and Z-pyridinecarboxaldehyde (531.3mg, 4.9bmmol) gave intermediate 13 (205mg, 9390 yield) as a light dgeep oil. b

TN-NMR (400 MHz, СО500) 5 1.12 (5 9-7.23 Hz, ZN), 1.23 (5 9-7.23 Hz, ZN), 2.25-2.31 (t, 2H), 2.37-2.44 (t, 2), 2.57 (5 9-5.76Hz, 2H), 2.67-2.74 (t, 2H), 3.24-3.34 (t, ZN), 3.48-3.57 (t, 1H), 3.59 (v, 2H), 7.36 o (85, 4H), 7.38-7.43 (t, 1H), 7, 80-7.87 (t, 1H), 8.43 (ad, 9-4.88, 1.56Hz, 1H), 8.49 (a, 9-1.56Hz, 1H). with

Intermediate 14: 4-Ibromo|1-(pyridin-2-ylmethyl)piperidin-4-ylidenemethyl)-M,M-diethylbenzamide co

The method for intermediate 11 using intermediate 5 (500mg, 11.00mmol) and 2-pyridinecarboxaldehyde (114mg, 10.7mmol) gave intermediate 14 (4096bmg, 8790 yield) as a pale yellow solid.

TN nMR (400MHz, СО3О0) 5 1.12 (5 9-6.93Hz, ЗН), 1.23 (5 9U-7.03Hz, ЗН), 2.26-2.32 (t, 2Н), 2 ,40-2.46 (t, 2H), 2.60 (65 20-566Hz, 2H), 2.67-2.75 (t, 2H), 3.24-3.35 (t, ЗН), 3.53 (a, 9U-6.96Hz, 1), 3.66 (v, 2H), « 400728-7.33 (t, 1H), 7.36 (v, 4H), 7.54 (a , U-7.81 Hz, 1H), 7.78-7.84 (t, 1H), 8.44-8.48 (t, 1H). - with Compound 30: 4-((2-aminophenyl)(1-benzylpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide :» salt

F) p ko 60

Iron powder (275mg, 4.92mmol) was added to the solution of intermediate 8 (238mg, 0.049mmol) in a mixture of 4:2:1:11 EUN/hetrahydrofuran/water/Mn.SiI(aqueous). The reaction mixture was microwaved at 1409 for 1 min and then filtered through brownmillerite. Brownmillerite was washed with Eas. The filtrate was concentrated in vacuo, redissolved in EtOAc and washed with saturated aqueous Manceau with (1x) and brine b5 and y and y. (1x). The organic phase was collected and the aqueous phase was extracted with EtOAc (1x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-4095 SNZSM in water with a content of 0.195 trifluoroacetic acid), obtaining compound ZO (118 mg, 3590 yield) as trifluoroacetate. This material was lyophilized from CH 33SM/water to give a beige solid.

Purity (HPLC): 29996;

TN nMR (400MHz, СО3О0) 5 1.09 (rg B -6.64Hz, ZN), 1.21 (Bg B 9-6.83Hz, ZN), 2.30-2.63 (t, ZN), 2.84-2.96 (t, 1H), 3.00-3.32 (t, 4H), 3.51 (rg a, 9U-6.77Hz, 4H), 4.32 (v, 2H) , 6.70 (in, 1H), 6.80-6.89 (t, 2H), 7.03-7.19 (t, 1H), 7.31 (in, 4H) 7.48 (in, 5H).

Found: C, 60.57; H, 6.01; M, 6.60. SzoNz5Ma3Ox1.5СЕ3СО5НХ1.6Н2О has C, 60.65; H, 6.12; M, 6.4390. 70 Compound 33: 4-(2-(adacetylamino)phenyl)(1-benzylpiperidin-4-ylidene)methyl/)|-M,M-diethylbenzamide

She

AND I; fi F 20. | and

Master's degree 25 o "-- 30 (2)

To a solution of compound 31 (133mg, 0.3mmol) and benzaldehyde in 1,2-dichloroethane (Chuml) was added glacial acetic acid (30mCl, 0.bbmmol), followed by Mavn(OAc)z (174mg, 0.82mmol). The reaction mixture was stirred and concentrated under vacuum overnight at room temperature, re-dissolved in dichloromethane and washed with saturated aqueous MnSO 3 (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x).

The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. co

The residue was purified by reverse-phase HPLC (gradient 10-4095 СNaАСМ in water containing 0.196 trifluoroacetic acid) to give compound 33 (127mg, 64956 yield) as trifluoroacetate. This material was lyophilized from

SNZSM/water, obtaining a colorless solid product. Purity (HPLC): 29990; " "H-NMR (400 MHz, SOZOB) 5 1.09 (Bg in, ZN), 1.20 (i, 9U-6.64Hz, ZN), 1.89 (a, 9-17.18Hz, ZN) 5 2.30-2.54 (t, 1H), C s 2.55-2.72 (t, 1H), 2.83-3.09 (t, 71H), 3.10-3.30 ( t, 5H), 3.43-3.63 (t, 4H), 4.34 (a, 9-13.28Hz, 2H), 7.11 (a,

U-7.62Hz, 1), 7.17 (a, 90-7.62Hz, 1), 7.25-7.39 (t, 6H), 7.45-7.54 (t, 5H). :z" Revealed: C, 61.21; H, 5.68; M, 6.00. Сз2На7М3О2х1.7СЕ3СО5НХО,ЗНоО has C, 61.19; H, 5.70; M, 6.0595.

Compound 34: methyl 2-((1-benzylpiperidin-4-ylidene)(4-(diethylamino)carbonyl)phenyl)methyl)phenylcarbamate

Why? yu IYA oh ah

Ф in "- " in y --

F) 0. And he) CHU and 60 | ) bo Method for compound 33, using compound 32 (88mg, 0.21mmol) and benzaldehyde (44mg, 0.42mmol) -58v-

obtained compound 34 (81 mg, 6295 yield) as trifluoroacetate. This material was lyophilized from CH with CM/water to give a colorless solid. Purity (HPLC): 29990;

TN nMR (400 MHz, CO53O0) 5 1.08 (B -6.93 Hz, ZN), 1.20 (p, 9U-6.83 Hz, ZN), 2.36-2.64 (t, ZN), 2 .81-3.00 (t, 1H), 3.00-3.18 (t, 2H), 3.20-3.30 (t, 2H), 3.45-3.55 (t, 4H) , 3.57 (in, ZN), 4.33 (rga,

U-7.03 Hz, 2H), 7.14-7 24 (t, 4H), 7.26-7.40 (t, 4H), 7.48 (v, 5H).

Found: C, 60.84; H, 5.67; M, 6.17. Cz2NaUMa3Ozh1.5СЕ3СО025НЧО,4НО has C, 60.93; H, 5.74; M, 6.09905.

Compound 35: 4-((2-aminophenyl)|1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene|methyl)-NM-diethylbenzamide

MO čne v

M si 7

A solution of intermediate 10 (0.760g, 1.93mmol), 4-chloromethylthiazole hydrochloride (0.493g, 2.90mmol) and potassium carbonate (0.533g, 3.8bmmol) in dry dimethylformamide (20ml) was stirred for 18 hours at room temperature. F" temperature under nitrogen. The mixture was concentrated in vacuo, then diluted with dichloromethane. The solution was washed with one portion of saturated aqueous sodium bicarbonate and one portion of brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a mixture of 4:2:1:1 with

EUN/tetrahydrofuran/water/MH Asi (aq) (4ml) in a microwaveable beaker. Iron powder (1.08Hg, SO 19.3mmol) was added and the reaction mixture was heated in the microwave at 1502 for 20min and then filtered through brownmillerite. Brownmillerite was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with a mixture of 190-596 methanol in dichloromethane to give the product as a yellow solid (0.321g, 3690). A portion of the product (115 mg, 0.249 mmol) was purified by reverse-phase HPLC (gradient 10-45976 SNUSM in water containing 0.196 trifluoroacetic acid) to give compound 35 (89 mg, 1990 s yield) as trifluoroacetate. This material was lyophilized from CH with CM/water to give a yellow solid.

TOP Purity: 295965 (215nm); 29395 (254nm); 299905 (280 nm); . "» TNA-NMR (400MHz, CO5O0) 5 1.11 (p, -644Hz, ZN), 1.23 (p, 9-742Hz, ZN), 2.47-2.59 (t, 2H), 2 .64-2.76 (t, 1H), 2.84-2.98 (t, 1H), 3.24-3.33 (t, 4H), 3.48-3.59 (t, 4H) , 4.53 (in, 2H), 6.86-6.97 (tv2H), 7.10-7.21 (t, 2H), 7.30-7.37 (t, 4H), 7.85 (a, 9-1.95Hz, 1H), 9.11 (a, 9-1.95Hz, 1H).

Go | Revealed: C, 52.11; H, 5.21; M, 7.66. С27НзаМОзХ2.1СЕ3СО5НХ1.1Н20 has C, 52.05; H, 5.08; M, 7.7890. from Compound 36: 4-((2-aminophenyl)|(1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyl|-N,M-diethylbenzamide o

Fr ga is lk and she!

And I

GF! with ko vo te hav ki b5 M

To a solution of intermediate 10 (0.717 ipu, 1.82 mmol) and thiazole-5-carboxaldehyde (0.717 g, 1.82 mmol) in 1,2-dichloroethane (40 mL) was added Mavn(OAc)»z (0.656 bmg, C, 09 mmol) . The reaction mixture was stirred overnight at room temperature and then washed with saturated aqueous Manso" (1x). The organic phase was collected and

The aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a 4:2:1:1 mixture

EUN/tetrahydrofuran/water/MH aSi(aq) (4 mL) in a microwavable beaker. Iron powder (1.08g, 19.3mmol) was added and the reaction mixture was heated in the microwave at 1509 for 20min and then filtered through brownmillerite. Brownmillerite was washed with ethyl acetate and the filtrate was concentrated. The residue 70 was purified by flash chromatography, eluting with a mixture of 196-590 methanol in dichloromethane to give the product as an orange solid (0.503g, 6495). Part of the product (150 mg, 0.32 mmol) was purified by reverse phase

HPLC (gradient 10-4595 CH3CM in water containing 0.195 trifluoroacetic acid) to give compound 36 (108 mg, 3090 yield) as trifluoroacetate. This material was lyophilized from CH3CM/water to give a yellow solid.

HPLC-purity: 297965 (215nm); 294965 (254 nm); 29995 (28Ohm);

TNA-NMR (400MHz, СО5О0) 5 1.11 (B, 9-7.03Hz, ЗН), 1.22 (р, 9-7.03Hz, ЗН), 2.41-2.59 (t, 2Н ), 2.63-2.88 (t, 2H), 3.24-3.33 (t, 4H), 3.33-3.48 (t, 2H), 3.48-3.57 (t , 2H), 4.71 (v, 2H), 6.72-6.79 (t, MH), 6.83 (aa, 9-8.01, 0.78Hz, 71H), 6.91-7 ... ,20 (in, 1H).

Found: C, 51.64; H, 5.14; M, 7.67. С27Наз»2МаО»ох2 1СЕ3СО05НХ1.4Н2О has C, 51.67; H, 5.13; M, 7.7290

Compound 37: 4-(2-(acetylamino)phenyl)|1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyl|-M,M-diethylbenzamide s shin SG i o ) shi sonya, t - more - t h;

Mdy Fyo o ; with

M so i i n «| « 5 - s a A solution of compound C5 as a free base (10 µg, 0.224 mmol), acetyl chloride (32 µl, 0.448 mmol) and "» triethylamine (11 µl, 0.72 mmol) in dichloroethane (1 µl) was stirred overnight at room temperature. The solution was diluted dichloromethane and washed with sat.

SNUSM in water containing 0.195 trifluoroacetic acid) to give compound 37 (8mg, 5895 yield) as ditrifluoroacetate. This material was lyophilized from SNUSM/water to give a yellow solid. Purity: 29795 av | (215nm); 294965 (254nm); 29995 (28Ohm); "cho" H-NMR (400MHz, CO300) 5 1.11 (B, 9U-6.64Hz, ZN), 1.23 (B, 9U-6.64Hz, ZN), 1.92 (in, ZN) , 2.36-2.61 (t, 2H), 2.63-2.74 (t, 2H), 3.21-3.532 (t, 6H), 3.48-3.57 (t, 2H) , 4.55 (in, 2H), 7.11-7.23 (t, 2H), 7.28-7.39 "y (t, 6H), 7.86 (in, 1H), 9.12 (a, 9U-1.76Hz, 1H).

Revealed: C, 54.55; H, 5.48; M, 7.91. СгоНзаМаОозх1.6СЕзСО2НХ1.3 But has C, 54.59; H, 5.43; M, 7.9196.

Compound 38: methyl 25 2-CA-((diethylamino)carbonyl|phenyl1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene|methyl)phenylcarbamate

F) ko 60 b5

. | Shock r t- r 5

A mixture of zinc powder (15 mg, 0.22 mmol) and methyl chloroformate (17 ri, 0.22 mmol) in toluene (1 mL) was stirred for 1 min at room temperature. A solution of compound 35 (10 µg, 0.22 mmol) in toluene (bml) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and washed with saturated aqueous Manso with (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-4595 CH3SM in water containing 0.195 trifluoroacetic acid) to give compound 38 (2 mg, 1895 yield) as trifluoroacetate. This material was lyophilized from SNUSM/water to give a yellow solid. Purity: 28790 che: (215nm); 281965 (254nm); 286905 (280 Ohm); Fo

TN nMR (400 MHz, СО5О0) 5 1.11 (B -6.64 Hz, ZN), 1.23 (p, 9U-6.64 Hz, ZN), 2.38-2.60 (t, 2H), 2 ,63-2.73 (t, 2H), 3.21-3.30 (t, b6H), 3.50-3.56 (t, 2H), 3.60 (v, ЗН), 4.56 (c, 2H), 7.11-7.23 (t, 2H), F 7.29-7.39 (t, 6H), 7.86 (z, 1H), 9.11 (a, 9- 1.76Hz, 1H). high school

Revealed: C, 54.55; H, 5.48; M, 7.91. SguNzaAMaOozh1,6СЕ3СО5НХ1,3Н2оО has C, 54.59; H, 5.43; M, 7.9190.

Zo Compound 39: 4-(2-(acetylamino)phenyl)|1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyl|-M,M-diethylbenzamide co v « 1 Vk: With c r ;" ; :

NK o so -. z o A (Se) sa s

M

HF) To a solution of compound 31 (0.289g, 0.71 mmol) and thiazole-5-carboxaldehyde (0.129g, 1.14 mmol) in 1,2-dichloroethane (20 ml) was added Mavn(Ods)" (0.257g, 1, 21 mmol). The reaction mixture was stirred overnight at room temperature and washed with saturated aqueous MansSO 2 (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-4596 CHZSM in water containing 0.195 trifluoroacetic acid) to give compound 39 (187 mg, 4395 yield) as trifluoroacetate.

This material was lyophilized from CH3CM/water to give a white solid. Purity (HPLC): 29990;

TN nMR (400MHz, СО53О0) 5 1.11 (B 9-7.03Hz, ZN), 1.23 (p, 9-6.64Hz, ZN), 1.92 (z, ZN), 2.50- 2.73 65 (t, 4Н), 3.22-3.32 (t, ЗВ), 3.45-3.58 (t, ЗН), 4.74 (в, 2Н), 7.13-7 ,19 (t, 2H), 7.20-7.28 (t, 1H), 7.31 (a,

U-8.40 Hz, 2H), 7.32-7.38 (t, ЗН), 8.09-8.11 (t, 1H), 9.19-9.21 (t, 1H).

Found: C, 53.46; H, 5.22; M, 7.30. SguNzaAMaO25х1.9СЕ53СО05НХ1.0Н2оО has C, 53.43; H, 5.18; M, 7.6090.

Compound 40: methyl 2-Ch4-((diethylamino)carbonyl|phenyl)|(1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyliphenylcarbamate 70 μh M y: and '

She x Yi o. and. shi s

M o

The method for compound 39, using compound 32 (0.172g, 0.408mmol) and thiazole-5-carboxaldehyde (74mgH, 0O.b5mmol) gave compound 40 (0.239mg, 93956 yield) as trifluoroacetate. This material was lyophilized from

SNZSM/water, obtaining a whitish solid product. Purity (HPLC): 29996: "H-NMR (400MHz, CO3O0) 5 1.11 (B, 9U-6.25Hz, ZN), 1.23 (bg b 9-7.03Hz, ZN), 2.51 -2.62 (t, 2H), 7-7 2.63-3.08 (t, 2H), 3.20-3.35 (t, 5H), 3.46-3.57 (t, ZN ), 3.60 (in, ЗН), 4.73 (in, 2Н), 7.18-7.27 (t, 48), F 7.27-7.36 (t, ЗН), 7.38 -7.49 (t, 1H), 8.07-8.14 (t, 1H), 9.18-9.23 (t, 1H).

Revealed: C, 52.95; H, 5.28; M, 7.48. SguNzaAMaOzZx1.7СЕ3СО5НХ1.3Н2оО has C, 52.88; H, 5.25; M, 7.6190. at

Compound 41: 4-((2-(acetylamino)phenyl)(1-butylpiperidin-4-ylidene)methylI-M,M-diethylbenzamide sech so a : « y - s | Shk . » i wn, p so i ko o (Se) "- I

To a mixture of intermediate 11 (1.80g, 4.44mmol) and 2-aminophenylboronic acid (792mg, 5.78mmol) in toluene (bOml) and ethanol (13ml) was added 2.0M sodium carbonate (100ml). Palladium tetrakistriphenylphosphine (514mg, about 0.445mmol) was added and the resulting mixture was heated overnight at 9092 using a pressure vessel.

The reaction mixture was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2X). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

The crude product was purified by flash chromatography on a silica gel column, eluting with a 3:2 gradient mixture of 60 EtOH/dichloromethane - 10095 EOAc to give compound 41 as a pale yellow oil (1769 mg, 9595 yield). The oil (200 mg) was again purified by reverse-phase HPLC (gradient 10-7096 CHZSM in water containing 0.195 trifluoroacetic acid) to give compound 41 (130 mg) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN nMR (400MHz, SOSIi) 5 0.98 (B 9U-7.03Hz, ZN), 1.04-1.16 (t, ZN), 1.17-1.30 (t, ZN), 1, 33-1.51 (t, bo 2H), 1.61-1.82 (t, 2H), 2.29-2.72 (t, 2H), 2.83-3.07 (t, 2H) , 3.07-322 (t, ZN), 3.23-3.39 (t, ZN),

3.42-3.71 (t, 4H), 6.79-7.05 (t, 2H), 7.08-7.27 (t, 2H), 7.33 (v, 4H).

Found: C, 58.08; H, 6.05; M, 6.63. С27НаМа3Ох1.90С2НО»Р» has C, 58.14; H, 6.16; M, 6.6090

Compound 42: 4-((2-aminophenyl)|1 -(pyridin-4-ylmethyl|piperidin-4-ylidene|methyl)-M,M-diethylbenzamide a | f - МН, ; c

Another 20. M -

Method for compound 41 using intermediate 12 (1.31g, 2.p95mmol), 2-agpipophenylboronic acid (526mg, 3.864mmol), palladium tetrakistriphenylphosphine (341mg, 0.295mmol), toluene (30ml), ethanol (bml) and 2, 0M sodium carbonate (bml) afforded compound 42. The crude product was purified by flash chromatography on a silica gel column eluting with EtOAc to afford compound 42 as a pale yellow solid (1.32g, 9895 g yield). The solid product (400 mg) was again purified by reverse-phase HPLC (gradient 10-6096 SNUSM in water containing 0.195 trifluoroacetic acid) to give compound 42 (456.7 mg) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN NMR (400MHz, SOSIz) 5 0.96-1.36 (t, 6H), 2.33-2.63 (t, 2H), 2.67-2.91 (t, 2H), 3.15 -3.63 (t, TON), w

AdA (z, 2H), 6.88-7.00 (t, 2H), 7.08 (0.9-7.22Hz, 1H), 7.14-7.23 (t, 1H), 7, 26-7.40 (t, 4H), 7.74 (a, b -2.93 Hz, 2H), 8.77 (8, 2H).

Revealed: C, 55.54; H, 5.05; M, 7.81. SgoNzaMaOx2,4С2НО»РзхХО,1Н20 has C, 55.61; H, 5.05; M, 7.6790 ("v

Compound 43: 4-T2-aminophenyl)|1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide c is (he) x a and ay a « | | 50 Method for compound 41 using intermediate 13 (2.05 g, 4.64 mmol), 2-aminophenylboronic acid (826 mg, 6.0 mmol), palladium tetrakistriphenylphosphine (53 mg, 0.464 mmol), toluene (bOml), ethanol (12ml), and 2.0M sodium carbonate (1Oml) afforded compound 43. The crude product was purified by flash chromatography on a silica gel column, eluting with a mixture of EAs, to afford compound 43 as a pale yellow solid product (1.79g, 8590 yield). This solid product (400mg) was purified by reverse-phase HPLC (gradient 10-6095 CH3SM in water containing 0.195 trifluoroacetic acid 99) to give compound 43 as trifluoroacetate. This material was lyophilized

F! from water to give a colorless solid. Purity (HPLC): 299960; 5 TN NMR (400 MHz, SOCI3) 5 0.96-1.33 (t, 6H), 2.36-2.61 (t, 2H), 2.65-2.92 (t, 2H), 3, 16-3.66 (t, 1OH), 4.35-4.55 (v, 2H), 6.99 (a, U-820Hz, 2), 7.11 (a, 9-644Hzc, 1H), 7.21 (5 9-7.71 Hz, 1), 7.28-7.39 (t, 4H), in 7.67 (ad, 9-7.71, 5.17 Hz, 1), 8.15 (a, 9U-8.01Hz, 1H), 8.74 (a, 9-23.43Hz, 2H).

Revealed: C, 55.94; H, 5.11; M, 7.91. SguNzaMaOx2,3С2НО»РзхХО,2Н2О has C, 56.01; H, 5.13; M, 7.7890

Compound 44: 4-(2-aminophenyl)|1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide b5 schi ! | N

Method for compound 41 using intermediate 14 (4.08g, 9.27mmol), 2-aminophenylboronic acid (1.65g, 12.0mmol), palladium tetrakistriphenylphosphine (1.07g, 0.927mmol), toluene (120ml), ethanol ( 24ml) and 2.0M

Ma»SO» (20 ml). The crude product was purified by flash column chromatography, eluting with E(Ac) to give compound 44 as a dark yellow solid (3.10 g, 7495 yield). This solid (500 mg) was purified by reverse-phase HPLC (gradient 10-70956 SNZASM in water containing 0.195 trifluoroacetic acid) to give compound 44 (487 mg) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29995; s

TN NMR (400 MHz, SOSIia) 5 0.97-1.39 (t, 6H), 2.40-2.65 (t, 2H), 2.69-2.91 (t, 2H), 3.16 -3.64 (t, 1OH), o 4.38-4.57 (t, 2H), 6.70-6.91 (t, 2H), 6.98 (5 -6.93HZ, 1), 7.06-7.19 (t, 7H), 7.28-7.38 (t, 4H), 7.39-7.54 (t, 2H), 7.81-7.97 (t, 1H ), 8.58-8.74 (t, 1H).

Found: C, 58.75; H, 5.36; M, 8.62. СгоНаз5МаОх1,8С2НО»РзхХО,3НоО has C, 58.86; H, 5.52; M, 8.4290.

Compound 45: 4-12-(acetylamino)phenyl)(1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide - (2)

Nnch - s 2 Me and

Ex o Method for compound 41, using intermediate 12 (590 mg, 1.333 mmol), 2-acetylaminophenyl)boronic acid (310 mg, 1.735 mmol), palladium tetrakistriphenylphosphine (154 mg, 0.1333 mmol), toluene (20 mL ), ethanol (Bml) and 2.0M NaClCO (3.5ml) afforded compound 45. The crude product was purified by flash chromatography on (a) column eluting with EOAc to afford compound 45 as a pale yellow oil (b3Omg, 9595 outputs). This oil from 20 was purified by reverse-phase HPLC (gradient 10-6095 CNaLCM in water containing 0.195 trifluoroacetic acid) to give compound 45 (443 mg) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN nMR (400 MHz, SOSIz) 5 0.90-1.37 (t, 6H), 1.91 (in, ЗН), 2.38-2.97 (t, 4H), 3.09-3.71 (t, 8H), 4.45 (85, 2H), 7.17 (9, 9-8.01 Hz, 2H), 7.23-7.48 (t, 7H), 7.71 (in, 2H ), 8.73 (in, 2H). 25 Compound 46: 4-12-(acetylamino)phenyl/i|1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl|-M,M-diethylbenzamide

F) ko 60 b5 ra : b tu | that t-di in

Method for compound 41 using intermediate 13 (590 mg, 1.333 mmol), 2-acetylaminophenyl)boronic acid (310 mg, 1.735 mmol), palladium tetrakistriphenylphosphine (154 mg, 0.1333 mmol), toluene (20 mL), ethanol (5Bml) and 2.0M sodium carbonate (3.5ml) afforded compound 46. The crude product was purified by reverse-phase HPLC (gradient 10-4095 SNZSM in water containing 0.195 trifluoroacetic acid) to afford compound 46 (650mg, 8090 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid.

Purity (HPLC): 29696; Ge

TN nMR (400MHz, SOSI) 5 1.02 (6 9-644Hz, ZN), 1.14 ( 9-6.35Hz, ZN), 1.83 (v, ZN), 3.10-3.28 ( t, o 1OH), 3.35-3.52 (t, 2H), 4.37 (v, 2H), 7.07 (a, y9-7.42H, 1H), 7.18-7.34 (t, TON), 7.47-7.66 (t, 1H), 7.97 (a, 9-7.62 Hz, 1H).

Revealed: C, 49.11; H, 4.53; M, 6.54. С34НзвМаО»ох3.5С2НО»Г»зХ1.8Н2О has C, 49.17; N, 4.68; M, 6,049

Compound 47: 4-(2-(acetylamino)phenyl-butylpiperidin-4-ylidene)methyl-N,M-diethylbenzamide - (2) . o i s (ge) u y " o pt s ;" To a solution of compound 41 (500mg, 1.19mmol) and triethylamine (18mg, 1.78mmol) in dichloromethane (ml) was added acetyl chloride (110μl, 1.54mmol) at 09С. The mixture was stirred overnight at room (C) temperature. The solution was washed with water. The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse-phase HPLC (gradient 10-7096 SNHCM in water containing 0.190 trifluoroacetic acid) to give compound 47 (267 mg, 4995 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): »9995; "H-NMR (400 MHz, SOSIi) 5 0.94-1.04 (t, ZN), 1.05-1.15 (t, ZN), 1.17-1.28 (t, ZN), 1 ,35-1.50 (t, 2H), (F, 1.66-1.80 (t, 2H), 1.92 (40, 9-15.04 HZ, ZN), 2.31-2.78 (t, 2H), 2.82-3.20 (t, ЗН), 3.21-3.35 (t, 5H), ka 3.44-3.75 (t, 4H), 7.09- 7.22 (t, 2H), 7.27-7.39 (t, 6H).

Revealed: C, 60.51; H, 6.50; M, 6.43. SooNazoMa3O»x1.5С02НО»2Р»z has C, 60.75; H, 6.45; M, 6,640. 60 Compound 48: 4-12-(acetylamino)phenyl)(1-(pyridin-2-ylmethyl)piperidin-4-ylidenemethyl)-M,M-diethylbenzamide b5

5. , and o. Tr

The method for compound 47 using compound 44 (502 mg, 1.10 mmol), acetyl chloride (95 mg, 1.21 mmol) and triethylamine (122 4 mg, 1.21 mmol) gave compound 48 (111 mg, 2095 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29690;

TN nMR (400 MHz, SOSIi) 5 0.98-1.36 (t, bH), 1.94 (z, ЗН), 2.50-2.98 (t, 4H), 3.14-3.68 (t, 8H), 4.40-4.62 (t, 2H), 7.17 (0.9-7.81Hz, 2H), 7.24-7.40 (t, 7H), 7.41 -7.56 (t, 2H), 7.90 (i 90-7.71Hz, 1H), 8.69 (a, 9-4 10Hz, 1H).

Revealed: C, 60.91; H, 5.54; M, 8.46. С34НзвМиО»2х1.5С02НО02РзхО,1Н20 has С, 61.00; H, 5.68; M, 8.37905. si

Compound 49: methyl (2-(1-butylpiperidin-4-ylidene4((diethylamino)carbonyl|phenyl)imethyl)phenyl|carbamate in h-30.; E t p (e)

T g s i ni so a "- s ;"

A mixture of zinc powder (17.4 mg, 0.267 mmol) and methyl chloroformate (41 μL, 0.534 mmol) in toluene (2 mL) was stirred for 1 hour at room temperature. A solution of compound 41 (112 mg, 0.267 mmol) in dichloromethane was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at 802, diluted with dichloromethane, filtered and then washed with 1N Manceau from (1x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (1x). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by thin-layer preparative chromatography with a mixture of 1:11 ethyl acetate/hexanes to give a colorless oil. This oil was purified by reverse-phase HPLC (gradient 10-6096 SNZASM in water containing 0.195 trifluoroacetic acid) to give compound 49 (26.mg, 1795 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN-NMR (400 MHz, SOSIz) 5 0.934.03 (t, ZN), 1.04-1.15 (t, ZN), 1.17-1.26 (t, ZN), 1.35-1, 49 (y, 2H), 29 1.63-1.81 (t, 2H), 2.34-2.70 (t, 2H), 2.79-3.19 (t, ЗН), 3.20 -3.33 (pp, 5H), 3.43-3.74 (t, 7H), 7.17-7.26 (t, o ZN), 7.26-7.36 (t, 4H), 7.46 (ad, 9U-33.4, 7.81 Hz, 1).

Found: C, 52.36: H, 5.77; M, 5.77. Со9НзоМа3Озх2,7С2НО»Р» has C, 52.60; H, 5.35; M, 5.3590. io) BO compound: methyl (2-I(4-Kdiethylamino)carbonyl|phenyl-1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)phenyl)carbam at 60 b5 and a ; and third

By the method for compound 49, compound 50 was obtained using compound 42 (400 mg, 0.8 mmol), methyl chloroformate (166 mg, 1.7 mmol) and zinc powder (57.5 mg, 0.688 mmol) at 509C. The crude product was purified by flash chromatography on column, eluting with 1:11 E(dArs/heptane) to give compound 50 (282 mg, 6290 yield). This compound was purified by reverse-phase HPLC (gradient 10-6096 SNHCM in water containing 0.190 trifluoroacetic acid) to give compound 50 as trifluoroacetate This material was lyophilized from water to give a colorless solid Purity (HPLC): 29990;

TN nMR (400 MHz, SOSIi) 5 1.09 (5 9-6.35 Hz, ZN), 1.16-1.30 (5 9-5.76 Hz, ZN), 2.46-2.60 (t, 2H), c ov 262-287 (t, 2H), 3.15-3.56 (t, 8H), 3.59 (v, ЗН), 4.36454 (t, 2H), 7.14-7 .36 (t, 7H), 7.44 (a, 9-7.81Gu, 1), 7.72 (a 2-4.49Hz, 2H), 5.59-5.92 (t, 2H). and)

Found: C, 54.48: H, 4.85; M, 7.95. Cz4NzoMaOzh2,2C2HO»PzhO,80H.O has C, 54.66: H, 5.16; M, 7,2090.

Compound 51: methyl (2-(4-(diethylamino)carbonyl|phenyl-1-(pyridin-3-ylmethyl)piperidin-4-ylidenemethyl)phenyl)carbam

E zhk n ; at

And ia and her; With so uh h«

Tu - c. 2) I and (se) Compound 51 was obtained by the method for compound 49 using compound 43 (500 mg, 1.10 mmol), methyl chloroformate (208 mg, 2.20 mmol) and zinc powder (71.9 mg, 1.10 mmol) at 509C. The crude product was purified by reverse-phase HPLC (gradient 10-5096 SNZASM in water containing 0.195 trifluoroacetic acid) to give (ab) compound 51 as trifluoroacetate (335.4 mg, 5995 yield). This material was lyophilized from water to give a colorless solid product. Purity (HPLC): 29790;

TN nMR (400MHz, SOSIz) 5 0.95-19U6 (t, 6H), 2.45-2.60 (t, 2H), 2.64-2.88 (t, 2H), 3.20-3 .57 (t, 8H), ". 3.60 (c, ZN), 4.39-4.56 (t, 2H), 7.15-7.36 (t, 8H), 7.44 (a , 0-11.13 Hz, 1), 7.62-7.76 (t, 1H), 8.16 (a,

U-7.62Hz, 1H), 8.24 (v, 1H), 8.62-8.97 (t, 1H).

Found: C, 56.77; H, 5.17; M, 7.73. Cz1NzeMaOzh2.0C2HO» P» has C, 56.76; H, 5.17; M, 7,560. 52 Compound 52: methyl o (2-c4-IIdiethylamino)carbonyl)phenyl 1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)phenyl)carbamate co 60 b5

Eat

By the method for compound 49, using compound 44 (500 mg, 1.10 mmol), methyl chloroformate (208 mg, 2.20 mmol) and zinc powder (71.9 mg, 1.10 mmol) at 509C, compound 52 was obtained. The crude product was purified by flash chromatography on the column, eluting with 4:11 E(SAc/heptane) to give compound 52 (156.7 mg, 2890 yield). This compound was purified by reverse-phase HPLC (gradient 10-6096 CNHCM in water containing 0.190 trifluoroacetic acid) to give compound 52 (134mg) as trifluoroacetate This material was lyophilized from water to give a colorless solid Purity (HPLC): 29790;

TN nMR (400 MHz, SOSIi) 5 1.10 (5 9-8.00 Hz, ZN), 1.22 (5 9-7.23 Hz, ZN), 2.59 (5 -6.05 Hz, 2H), s 2.67-2.93 (t, 2H), 3.16-3.57 (t, 8H), 3.59-3.72 (t, ZH), 4.37-4.62 (y, 2H ), 7.17-7.38 (t, 7H), 7.39-7.558 (t, OO)

ZN), 7.82-7.98 (t, 1H), 8.24 (8, 1H), 8.68 (a, 9-4 .88Hz, 1H).

Found: C, 58.25; H, 5.72; M, 8.03. Cz4NzeMaOzh1.5C02HO2Pzh1.0H2O has C, 58.20; H, 5.67; M, 7.98905.

Compound 53: 4-(1-butylpiperidin-4-ylidene)|(2-(ethylamino)phenyl|methyl)-M,M-diethylbenzamide - (2) o

A i i i so « - s ;» Co. To a solution of compound 41 (190 mg, 0.452 mmol) and acetylaldehyde (20 mg, 0.452 mmol) in 1,2-dichloroethane (ml) t was added Mavn(oAc)" (144 mg, 0.678 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, washed with 2M Mahon solution (2x). The organic phase was collected and the aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over anhydrous magnesium sulfate, filtered through 20°C, and concentrated in vacuo. The residue was purified by reverse-phase HPLC (gradient 10-6596 CNaCM in water containing 0.196 trifluoroacetic acid) to give compound 53 (100 mg, 4895 yield) as trifluoroacetate. This "-. material was lyophilized from SNSM/water, obtaining a colorless solid product. Purity (HPLC): 29996; "H-NMR (400 MHz, СО5О0) 5 0.94-1.02 (t, ЗН), 1.02- 1.16 (t, 6H), 1.16-1.27 (t, ZH), 1.33-1.50 (t, 2H), 1.64-1.81 (t, 2H), 2, 30-2.73 (t, ZN), 2.84-3.37 (t, TON), 3.43-3.71 (t, 4H), 6.61-6.77 (t, 2H), 6.97 (aa, -62.58, 7.71Hz, 1H), 7.16 (a, U-7.88Hz, 1H), 7.27-7.38 (t, 4H).

GF) Revealed: C, 62.90; N, 7.33; M, 6.99. SooNl"MzOxH1,4С2НО" ГГ" has C, 62.89; N, 7.04; M, 6.9290. compound 54: M,M-diethyl-4-42-(ethylamino)phenyl)|1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)benzamide 60 b5

Method for compound 53 using compound 42 (231.1mg, 0.508mmol), acetylaldehyde (22.4mg,

0.508 mmol) and Mavn(OAc)z (161.b6 mg, 0.7633 mmol) gave compound 54. The crude product was purified by reverse-phase HPLC (gradient 10-4095 CH3SM in water containing 0.195 trifluoroacetic acid) to give compound 54 (164 .7mg, 6795 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN nMR (400MHz, SOSIV) 5 1.02-1.16 (t, 6H), 1.23 (5 9U-6.54Hz, ZN), 2.51 (5 uU- 5.96Hz, 2H), 2 .71-2.89 (t, 2H), 2.93-3.05 (t, 1H), 3.07-3.20 (t, 1H), 3.21-3.61 (t, 9H) , 4.37453 (t, 2H), 6.71-6.88 (t, 2H), 7.04 s 29 (a, 2-6.83Hz, 1H), 7.16-7.26 (t, 1H), 7.29-7.43 (t, 4H), 7.74 (a, 2-4.10Hz, 2H), 8.56-9.00 (t, 2H). Gee)

Found: C, 56.23; H, 5.56; M, 7.54. Сз4НзаМ.Ох2,30С2НО»РзхХО,80Н-О has C, 56.31; H, 5.56; M, 7,380.

Compound 55: N,M-diethyl-4-12-(«ethylamino)phenyl(1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl)benzamide. ch- r. in Fe school; cha p

What: co

T " she - I (5 z

By the method for compound 53, compound 55 was obtained using compound 43 (ZbOmg, 0.792 mmol), acetyl aldehyde (34.Omg, 75 0.792 mmol) and Mavn(OAc)z (251.5 mg, 1.18 mmol). The crude product was purified with reverse-phase HPLC (gradient 10-6096 SNZASM in water with a content of 0.195 trifluoroacetic acid), obtaining

H0) compound 55 (85 mg, 1595 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996; at 50 TN iNMR (400MHz, SOSIv) 5 1.03-1.14 (t, 6H), 1.23 (5 9-6.93Hz, ZN), 2.45-2.56 (t, 2H), 2.72-2.88 (t, (Ce) 2H), 2.90-3.18 (t, 2H), 3.20-3.60 (t, 9H), 4.38-4.55 ( t, 2H), 6.78-6.90 (t, 2H), 7.08 (a, 9-7.81 HZ, МН), x 7.19-7.27 (t, 1H), 7.30 - 7.40 (t, 5H), 7.62-7.79 (t, 1H), 8.16 (a, 9-7.81Hz, 1H), 8.62-8.98 (t, 1H) . 7 Found: C, 55.54; H, 5.59; M, 7.51. Cz4NzaM.Ox2.30C2HO»P»zhX1.40H20 has C, 55.52; H, 5.64; M, 72790.

Compound 56: N,M-diethyl-4-((2-(ethylamino)phenyl|p-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)benzamide

F) ko 60 b5

(y rik b cha y za

Compound 56 was obtained by the method for compound 53 using compound 44 (ZbOmg, 0.792 mmol), acetyl aldehyde (34.Omg, 0.792 mmol) and Mavn(OAc)z (251.8 mg, 1.13 mmol). The crude product was purified by reverse by phase HPLC (gradient 10-6096 CNaUSM in water with a content of 0.196 trifluoroacetic acids), obtaining the same compound 56 (220 mg, 3995 yield) as trifluoroacetate. This material was lyophilized from water to give a colorless solid. Purity (HPLC): 29996;

TN-NMR (400MHz, SOSIv) 5 1.04-1.16 (y, 6H), 1.23 ( 9-6.54Hz, ZN), 2.54 (and 9- 5.96Hz, 2H), 2 .73-2.93 (t, 2H), 2.97-3.21 (t, 2H), 3.21-3.61 (t, 9H), 4.50 (in, 2H), 6.70 -6.84 (t, 2H), 7.02 (a, 9U-6.82Hz, 1H), with two 07.13-7T.24 (t, 1H), 7.34 (v, 4H), 7.40 -7.50 (t, 2H), 7.82-7.95 (t, 2H), 8.68 (a, 9-4.30 Hz, 1H).

Found: C, 62.22; H, 6.22; M, 8.56. С34НзаМ.Ох1.50С2НО»Рзх0.70Н-О has C, 62.19; H, 6.19; M, 8.4196. at

Claims (1)

The formula of the invention "-- 1. The compound of the formula IA, its pharmaceutically acceptable salt, diastereomers, enantiomers or their mixtures: Ge") "A o o ve - | s de | and where 45 B is selected from the group: s-hydrogen, C-alkyl-O-C(-0)-, C-alkyl, C-cycloalkyl, C-aryl, o-C, o-heterocyclyl, C-al-aryl-C ..3-alkyl and Co-o-heterocyclyl-C.4 c-alkyl, where C-6-alkyl, C3-6-cycloalkyl, C-10-aryl, Co-heterocyclyl, C-10-aryl-C are indicated. 4 c-alkyl and C o-heterocyclyl-C c-alkyl are optionally substituted with one or more substituents selected from the group: -K, -MO", -OK, -SI, -Bg, -I, -E , -SEz, -FSH-OJK, o -F("F)OH, -MN", -5H, -MNK, -MK»o, -ZK, -8OZN, -50oK, -5(-O)K, -СМ, -ОН, -Ф(-О)OK, -С(-О)МК», -МКО(-ОК and 50 -МКС(-О)-ОК, where K independently represents hydrogen or С..в- alkyl; 1-0 B, BZ and VK" are independently selected from the group: hydrogen, C1-6-alkyl and C3-6-cycloalkyl; where C1-6-alkyl are indicated. and - C. d"cycloalkyl, as an option, substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Bg, -I, -E, -SEz, -FSH-O) K, -FSH-OON, -MN", -ZN, -MNK, -MK", -Z3K, -8OzH, -502K, -5(-:0)K, -SM, -OH, -FSH-FO) OK, -FSH(5О)МК», -МКОС(-О)К and -МКО(-О)-ОК, where K independently represents hydrogen or C..6-alkyl; B'/ is selected from the group: -Н -OH, o C-alkyl, C-cycloalkyl, C-aryl, C-heterocyclyl, He! C-aryl-C, c-alkyl, C-o-heterocyclyl-C 4.c-alkyl, -C(x0) -М-К в, -С(50)-0-в8, -8(50)-к8, -8(х0)5-288, -с(50)-в8 t and -80О3Н, where КЗ and КО are independent selected from the group: -H, Cz-alkyl, Czc-cycloalkyl, Czc-aryl, C. o-heterocyclyl, C.v.-aryl-C.i.v.-alkyl, Co. o-heterocyclyl-C.i.v.-alkyl, where C. v.-alkyl, C.v.-cycloalkyl, 60 C.v.-aryl, C.i.v.-heterocyclyl , St. 4o-aryl-S. γ-alkyl, Co o-heterocyclyl-C. β-alkyl, used in definitions 2", 8 and B, optionally substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Bg, -M -E, -SEz , -F(-5O)K, -F(-O)OH, -MNo, -ZN, -MNEK, -MKo, -3K, -ZOzH, -5O»K, -5(-O)K, -SM . 2. The compound according to claim 1, because where K' is selected from the group: oxyhydrogen, C.sub.-alkyl-O-C(-0)-, C.sub.-alkyl, C.sub.-cycloalkyl, benzyl and C, C-heterocyclyl, where C-1-C-alkyl, C-C-6-cycloalkyl, benzyl and C-C-heterocyclyl are optionally substituted with one or more substituents selected from the group: C-C-C-alkyl, halogenated C..in-alkyl, -C3, C.in.-alkyl, chlorine, fluorine, bromine and iodine; IN? and EZ represent ethyl; B" is selected from the group: hydrogen and C. 3-alkyl; B is selected from the group: -H, -OH, phenyl, C3-heterocyclyl, phenyl-C3-alkyl, C3-5-heterocyclyl-C 4 c-alkyl, C. c-alkyl, C3-cycloalkyl, C3-7-cycloalkyl-C4.3-alkyl, -C(50)-M-ZuU, -0(-0)-0-k8, -8(-0)-29, -8(-0)5-А8, 70 -б(50)-88 and -5О3Н, where are КЗ and КЕ? independently selected from the group: -H, phenyl, C3.5-heterocyclyl, phenyl-C. c-alkyl, S. p-heterocyclyl-S. c-alkyl, C. c-alkyl, C3-cycloalkyl, C»-cycloalkyl-C3-alkyl, where phenyl, C3-b-heterocyclyl, phenyl-C are indicated. z-alkyl, Cz 56-heterocyclyl-C..z-alkyl, Si. β-alkyl, C3-cycloalkyl, C3-cycloalkyl-C. c-alkyl, used in definitions 27, 8 and VU, as an option, substituted by one or more substituents selected from the group: fluorine, bromine and iodine. Z. The compound according to claim 1, where He is selected from the group: hydrogen, C..i.-alkyl-O-C(-0)-, C.i.i.-alkyl, C.sub.6-cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and M-oxidopyridylmethyl, where C-C-alkyl, C-Cv-cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and M-oxidopyridylmethyl are indicated, as an option, substituted by one or more substituents selected from the group: C 4-6 alkyl, halogenated C 6 alkyl, -C3, C 4-alkyl, chlorine, fluorine, bromine and iodine; IN? and EZ represent ethyl; c B" is selected from the group: hydrogen and methyl; Ge) B is selected from the group: -H, C. c-alkyl, phenyl-C. c-alkyl, Ca-cycloalkyl-C. c-alkyl, Ca-c-cycloalkyl, phenyl, C. v-alkyl, -C(x0)-M-Keve, -5(50)5-K8, -C(t0)-0-88 and -C(x0)-K8, where VK? and KU are independently selected from the group: -H, phenyl-C. c-alkyl, C3-cycloalkyl-C3-alkyl, C3/7-cycloalkyl, phenyl and C3-alkyl, where phenyl-C. 3-alkyl, "- C3-t-cycloalkyl-C3-3-alkyl, C3-7-cycloalkyl, phenyl, C1-6-alkyl, used in the definition of "ve and KU, as an option, substituted by one or more substituents, selected from the group: C..c-alkyl, halogenated C..c-alkyl, -SEz, b" Si. β-Alkoxyl, chlorine, fluorine, bromine and iodine. at 4. Compound according to claim 1, where B! selected from the group: hydrogen, propyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, c imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and M-oxidopyridylmethyl; co B2 and EZ represent ethyl; B" is selected from the group: hydrogen and methyl; B" is selected from the group: -H, ethyl, phenyl, benzyl or phenethyl, naphthyl, fluorophenyl, chlorophenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, -C(-0) -МН-К8, -5(-0)5-К58, -С(50)-0-К8 and 70 -с(50)-К8, where KZ is selected from the group: methyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, methylphenyl, in c fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl. of 5. The compound according to claim 1, which is selected from the group: COMPOUND 1: 4-((2-(benzoylamino)phenyl|-4-piperidinylidenemethyld|-M,M-diethylbenzamide; COMPOUND 2: M-(2-(4- Cdiethylamino)carbonyl|Iphenyl)|-4-piperidinylidenemethyl|phenyl|benzeneacetamide; 15 COMPOUND 3: 4-((2-Ccyclohexylcarbonyl)amino|phenyl)-4-piperidinylidenemethyl|)|-M,M-diethylbenzamide; co COMPOUND 4: M-(2-(C4-Kdiethylamino)carbonyl|Ifenyl)|-4-piperidinylidenemethyl|phenyl|benzenepropanamide; Kz COMPOUND 5: 4-((2-((cyclohexylacetyl)amino|phenyl|-4-piperidinylidenemethyl|-M, M-diethylbenzamide; COMPOUND 6: M,M-diethyl-4-((2-(2-phenylethyl)amino|phenyl)-4-piperidinylidenemethyl|benzamide; o COMPOUND 7: 4-(2-(cyclohexylmethyl)amino|phenyl) |-4-piperidinylidenemethyl/)-M,M-diethylbenzamide; se 50 COMPOUND 8: M,M-diethyl-4-((2-(phenylmethyl)amino|phenyl)-4-piperidinylidenemethyl|-benzamide; COMPOUND 9: 4 -((2-(cyclohexylamino)phenyl)-4-piperidinylidenemethyl|)|-M,M-diethylbenzamide; "- COMPOUND 10: M,M-diethyl-4-(2-((phenylamino)carbonyl|amino|phenyl )-4-piperidinylidenemethyl|benzamide; COMPOUND 11: M,M-diethyl-4-((2-(phenylamino)phenyl|-4-piperidinylidenemethylibSenzamide); COMPOUND 12: M,M-diethyl-4-((2-(methylphenylamino)phenyl)-4-piperidinylidenemethyl|benzamide; COMPOUND 13: M,M-diethyl-4-((2-Cphenylsulfonyl)amino|phenyl|-4 -piperidinylidenemethylbenzamide; F! COMPOUND 14: M,M-diethyl-4-(2-((phenylmethyl)sulfonyl|amino|phenyl)-4-piperidinylidenemethyl|benzamide; COMPOUND 15: ki M,M-diethyl-4-I( 4-piperidinylidene(2-((2,2,2-trifluoroethyl)sulfonyl|amino|phenyl|methyl|bSensamide; COMPOUND 16: 4-K2-(cyclopentylacetyl)amino|phenylpiperidin-4-ylidene)methyl|/|-M ,M-diethylbenzamide; 60 COMPOUND 17: 4-(2-Ccyclopentylcarbonyl)amino|phenylUpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide; COMPOUND 18: M,M-diethyl-4-((2-(Z -phenylpropyl)amino|phenylUpiperidin-4-ylidene)methyl|bSenzamide; COMPOUND 19: 4-(2-((2-cyclohexylethyl)amino|phenylpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide; COMPOUND 20: 4 -((2-(cyclopentylamino)phenylI(piperidin-4-ylidene)methyl/)|-M,M-diethylbenzamide; COMPOUND 21: 4-((2-(cycloheptylamino)phenylI(piperidin-4-ylidene)methyl|- M,M-diethylbenzamide; for COMPOUND 22: 4-(2-«(benzylamino)carbonyl amino)phenyl)(piperidin-4-ylidene)methyl/|-M,M-diethylbenzamide; COMPOUND 23: M,M-diethyl-4-((2-(1-naphthylamino)phenyl(piperidin-4-ylidene)methyl|bSenzamide; COMPOUND 24: M,M-diethyl-4-((2-(KZ- fluorophenyl)amino|phenylpiperidin-4-ylidene)methyl|bSensamide; COMPOUND 25: 4-(2-(4-chlorophenyl)amino|phenylUpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide; COMPOUND 26: 4-( (2-(cyclohexyl(methyl)amino|phenylpiperidin-4-ylidene)methyl|-M,M-diethylbenzamide; COMPOUND 27: M,M-diethyl-4-((2-((4-methylphenyl)sulfonylamino)phenyl) (piperidin-4-ylidene)methylbenzamide; COMPOUND 28: M,M-diethyl-4-(2-X1(2-fluorophenyl)sulfonyl|amino)phenyl)(piperidin-4-ylidene)methylbenzamide; COMPOUND 29: 4-K2 -Kbutylsulfonyl)amino|phenylpiperidin-4-ylidene)methyl|/|-M,M-diethylbenzamide; COMPOUND 31: 4-((2-(acetylamino)phenyl|(piperidin-4-ylidene)methyl/|-M,M -diethylbenzamide; 70 COMPOUND 32: methyl 2-KA-((diethylamino)carbonyl|phenylpiperidin-4-ylidene)methyl|phenylcarbamate; COMPOUND 30: 4-((2-aminophenyl)(1-benzylpiperidin-4-ylidene)methyl| -M,M-diethylbenzamide; COMPOUND 33: 4-((2--acetylamino)phenyl)(1-benzylpiperidin-4-ylidene)methyl/ |-M,M-diethylbenzamide; COMPOUND 34: methyl 2-(1-benzylpiperidin-4-ylidene)/4-(diethylamino)carbonyl|phenyl)methyl)phenylcarbamate; COMPOUND 35: 4-(2-aminophenyl)|1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND 36: 4-(2-aminophenyl)|1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND 37: 4-(2-(acetylamino)phenyl|(1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND C8: methyl 2-CCH4- ((diethylamino)carbonyl|phenyl)|(1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene|methyl)phenylcarbamate; COMPOUND 39: 4-(2-(acetylamino)phenyl|(1-( 1,3-thiazol-5-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND 40: methyl 2-CH4-((diethylamino)carbonyl|phenyl)|(1-(1,3- thiazol-5-ylmethyl)piperidin-4-ylidene|methyl)phenylcarbamate; COMPOUND 41: 4-((2-aminophenyl)(1-butylpiperidin-4-ylidene)methyl/|-M,M-diethylbenzamide; c COMPOUND 42: 4-(2-aminophenyl)|1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND 43: 4-(2-aminophenyl)|1-(pyridin-3- ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; (8) COMPOUND 44: 4-(2-aminophenyl)|1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)-M ,M-diethylbenzamide; COMPOUND 45: 4-12-(acetylamino)phenyl/1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; COMPOUND 46: 4-12-(acetylamino)phenyl/1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; -- from COMPOUND 47: 4-((2-(acetylamino)phenyl)|(1-butylpiperidin-4-ylidene)methyl/)|-M,M-diethylbenzamide; COMPOUND 48: 4-12-(acetylamino)phenyl/1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)-M,M-diethylbenzamide; b» COMPOUND 49: methyl |2-(1-butylpiperidin-4-ylidene)(4((diethylamino)carbonyl|Iphenyl)methyl)phenylI|carbamate; o COMPOUND 50: methyl (2-CH4-(diethylamino)carbonylIphenyl1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)phenyl)carbamate; c COMPOUND 51: methyl co (2-CH4-(diethylamino)carbonylphenyl1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl)phenyl)carbamate; COMPOUND 52: methyl (2-CH4-(diethylamino)carbonylIphenyl1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)phenyl)carbamate; COMPOUND 53: 4-(1-butylpiperidin-4-ylidene)|(2-(ethylamino)phenyl|methyl)-N,M-diethylbenzamide; " COMPOUND 54: N,M-diethyl-4-H2-(ethylamino)phenyl)|(1-(pyridin-4-ylmethyl)piperidin-4-ylidene|methyl)benzamide; from c COMPOUND 55: N,M-diethyl-4-H2-(ethylamino)phenyl)|(1-(pyridin-3-ylmethyl)piperidin-4-ylidene|methyl)benzamide; COMPOUND 56: N,M-diethyl-4-Ch2-(ethylamino)phenyl)|(1-(pyridin-2-ylmethyl)piperidin-4-ylidene|methyl)benzamide; with and their pharmaceutically acceptable salts. 6. A compound according to any one of claims 1-5 for use as a medicament. 7. Use of a compound according to any one of claims 1-5 in the manufacture of a medicament for the treatment of pain, anxiety or functional gastrointestinal disorders. 8. A pharmaceutical composition containing a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier. 9. A method of treating pain in a warm-blooded animal, in which a therapeutically effective amount of the compound according to any one of claims 1-5 is administered to said animal in need of such therapy. 10. A method of treating functional gastrointestinal disorders in a warm-blooded animal, in which a therapeutically effective amount of the compound according to any one of claims 1-5 is administered to said animal in need of such therapy. ha 11. The method of obtaining the compound of the formula PA o ; PA vom | Be still about NM zho 60 A eh? 65 in which: the compound of the formula SHA is reacted with К?-СНо-Х or К?-СНО: about; ША mash: The same GI k-t no so NM - in MN where X is a halogen; B is selected from the group: -С(-0)-ОО-К8, -8(50)-88, -5(50)5-883 and -С(50)-88, BZ is selected from the group: C in alkyl , Са в-cycloalkyl, Сё-aryl, Сё-heterocyclyl, Сё-aryl-C. γ-alkyls and C. o-heterocyclyl-C; C-alkyl, where C-C-alkyl, C-C-cycloalkyl, C-C-aryl, C-C-o-heterocyclyl, Sv.lo-aryl-Ci v-alkyl and Co o-heterocyclyl-C. 6C-alkyl optionally substituted with one or more substituents selected from the group: -K, -MO", OK, -SI, -Bg, -I, -E, -SEz, -FSH-O)K, -F (-O)OH, -MH", -5H, -MNE, -MK", -ZK, -5OZN, -5021, -5(-O)B, -SM, -OH, -F(-5F)Ok . and B? selected from the group: Cyclo-aryl and Co-heteroaryl, where the indicated Cyclo-aryl and Co-heteroaryl are optionally substituted with one or more substituents selected from the group: -K, -MO", -OK, -CI, -Bg, -I, -E, -SEz, -FOJ, -F("F)OH, -MN", -5H, -MNK, -MK»o, -ZK, -8OZN, -50oK, -5(-0O)K, - CM, -OH, -F(-O)OK, -C(-O)MK", -MKO(-OK) and -MKOS(-O)-OK, where K independently represents hydrogen or C..in-alkyl. urine 12. The method of obtaining the compound of the formula PA o o ; PA te po kt shi i y - - (o) NM -- r? o s M A so e? in which: "compounds of the MA formula are reacted with K"-X or K7-0-B" Ge! , MA - with khz» our | zhe a rya - co Mn, co o MA (Ce) 5 "- and where X is a halogen; B" is selected from the group: -С(-0)-О-28 and -С(-0)-К8, where BZ is selected from the group: C 10 -alkyl, C 10 -cycloalkyl, C 10 -aryl, C 10 -heterocyclyl, C 10 -aryl-C 10 -alkyl and C 10 -heterocyclyl-C. c-alkyl, where C are indicated. β-alkyl, C3 β-cycloalkyl, C10-aryl, C0-heterocyclyl, C10-aryl-C4 c-alkyl and C0-heterocyclyl-C. .beta.-alkyl, optionally substituted by one or more substituents selected from the group: kz -K, -MO", -OK, -SI, -Bg, -I, -E, -SEz, -FSH(-OK, - FSH(-О)OH, -МН», -ZN, -MNE, -MK», -ZK, -8ОзН, -502K, -5(:OK, -SM, -OH, -FSH-FO)OK, - Ф(-О)МК»о, -МКО(-О)К and -МКОС(-0)-ОК, where K independently represents hydrogen or 60 C. в-alkyl, and B? is selected from the group: Sbvlo-aryl and Sovheteroaryl where Svo-aryl and Sovheteroaryl are indicated, as an option, substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Vg, -I, -E, -SEz, -FSH- ОЖК, -ФО)ОН, -МН», -5Н, -МНК, -МК»о, -ЗК, -5ОзН, -502К, -5(-:О)К, -СМ, -ОН, -Ф(- O)OK, -С(-О)МК», -МКО(-О)К and -МКОС(-О)-ОК, where K independently represents hydrogen or С..в.-alkyl. bo 13. The method of obtaining the compound of formula MA (8) MA reg Zm -kh yat I ez she | eh MN. Yay in! in which the compound of the formula MIA O, MA reg Zm is reduced -kh yat r -4 y: Mo. MI with in! (8) where B' is selected from the group: C-hydrogen, C-alkyl-O-C(-0)-, C-alkyl, C-cycloalkyl, C-cycloalkyl, C, o-heterocyclyl, C-cyclo-aryl- C..3-alkyl and Co. o-heterocyclyl-C.4-alkyl; where C10-alkyl, C10-cycloalkyl, C10-aryl, C0-heterocyclyl, C10-aryl-C10-alkyl and C0-heterocyclyl-C are indicated. C-alkyl, optionally, F is substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, -Bg, -I, -E, -SEz, -FSH-ОШК, -С ("FON, -MN", -ZN, -MNE, -ME", -58, -8О3Н, -5028, -5(-0)8, -СМ, "ОН, -С(-О)ОВ, - C(-O)ME»o, -MAS(-O)B and F -MKS(-O)-OK, where K independently represents hydrogen or C. c-alkyl; c B? and BZ are independently selected from the group: hydrogen , C. 6-alkyl and C-C-cycloalkyl, where C. c-alkyl and C. d"cycloalkyl, as an option, substituted by one or more substituents selected from the group: -K, -MO", -OK, -SI, co -Bg, -I, -E, -SEz, -FSH-O) K, -FSH-OON, -MN", -ZN, -MNK, -MK", -Z3K, -8OzH, -502K, -5(-:0)K, -SM, -OH, -FSH-FO) OK, -F(5O0)MK", -MKO(ЗОЖК and -МКС(О)-OK, where K independently represents hydrogen or C. .v-alkyl. 14. The compound of formula I, its pharmaceutically acceptable salt, its diastereomers, its enantiomers, and their mixtures: "5 in 20 o Ex, Eto - v2 s shk m MI y g" SHY 3 dO I: | M so |" in th IR o so 50 in! C where B" is selected from the group: hydrogen, C. in-alkyl-O-C(-0)-, as an option, substituted C .. in-alkyl, as an option , substituted C. c" cycloalkyl optionally substituted C blo-aryl optionally substituted C 2.o-heterocyclyl optionally Substituted C. 41o-aryl-C. 3-alkyl and optionally substituted C o-heterocyclyl -C 4 z-alkyl; n is 0, 1 or 2; (F; t is 0, 1 or 2; H0) B, BZ and VK" are independently selected from the group: hydrogen, as an option, substituted by C 4.c- alkyl and optionally substituted C3-cycloalkyl; 60 25 and 2? independently selected from the group: -K, -MO», -OK, -SI, -Vg, -I, -P, -SEz, -FSH-О)К, -Ф(-О)ОН, -МН», - ZN, -MNE, -ME", -3K, -"8OZN, -5021K, -5(-O)K, -SM, -"OH, -F(-O)OK, -F(-O)M" , -"MKO(OK) and -МКС(-О)-OK, where K independently represents hydrogen or C-C-alkyl; and B" is selected from the group: -H, -OH, optionally substituted with C -4. β-alkyl, optionally substituted C 2 -C 6 -cycloalkyl, optionally substituted C 0 -aryl, optionally substituted C 2 O -heterocyclyl, optionally substituted 62 C 60 -aryl-C 6 -alkyl, optionally, substituted C»v-heterocyclyl-C4.v-alkyl, -C(20)-МА8А?, -С(х0)0-К8, -8(50)-К8, -(-0)5-88, -с(50)-К8 and -5О3Н, where are КЗ and ВЕ? are independently selected from the group: -H, optionally, substituted C.sub.6-alkyl, optionally, substituted C.sub.3-8-cycloalkyl, optionally, substituted C.sub.40-aryl, optionally, substituted C.sub.3-o-heterocyclyl, as variant, substituted by Ce 1o-aryl-C..in-alkyl, and, as an option, substituted by Ce o-heterocyclyl-C 4.in-alkyl. 15. The compound according to claim 14, where B is selected from the group: hydrogen, C 1 -alkyl-O-C(0)-, alternatively, substituted C 4 -alkyl, and, optionally, substituted C 3 -cycloalkyl; B2 and EZ represent ethyl; B" is selected from the group: hydrogen and C. 3-alkyl; B" is selected from the group: -H, -OH, as an option, substituted phenyl, as an option, substituted C 3-heterocyclyl, as an option, substituted phenyl-C.- .3-alkyl, optionally substituted C 2 -heterocyclyl-C 1-6 -alkyl, optionally substituted C 1-6 -alkyl, optionally substituted C 1-6-cycloalkyl, optionally substituted C 3 6-cycloalkyl-C.4.z-alkyl, -с(50)-м-в 889, -сС(-0)-0-28, -8(50)-К8, -5(-0)5- 85, -С(-0)-28 and -БО3ЗН, where are КЗ and КЕ? independently selected from the group: /5 -H, optionally substituted phenyl, optionally substituted IF; c-C-heterocyclyl optionally substituted phenyl-C..c-alkyl optionally substituted C with c5-heterocyclyl-C. 3-alkyl, optionally substituted C 4,6-alkyl, optionally substituted C 3 6-cycloalkyl, optionally substituted C 3-6-cycloalkyl-C. c-alkyl; and n and t are equal to 0. 16. The compound according to claim 14, where KE" is selected from the group: hydrogen and C. v-alkyl-O-C(:0)-; B2 and EZ represent ethyl; B" is selected from the group: hydrogen and methyl; B is selected from the group: -H, phenyl-C. c-alkyl, C3-cycloalkyl-C4 c-alkyl, C3-6-cycloalkyl, phenyl, alternatively, substituted C3-alkyl, -C(-0)-M-B889, -8(50)5-28 and -C(50)-KZ, where KZ and KO are independently selected from the group: -H, CM phenyl-C..3-alkyl, C3.6-cycloalkyl-C4.3-alkyl, C3.6-cycloalkyl, phenyl, and, as an option, substituted C..c.-alkyl; and o n and t are equal to 0. 17. The compound according to claim 14, where Ge represents hydrogen; IN? and EZ represent ethyl; - B" is selected from the group: hydrogen and methyl; He") B is selected from the group: -H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(-0)-MH-B8, o -5(20), -к8 and -С(50)-28, where BZ is selected from the group: 2,2,2-trifluoroethyl, phenyl, benzyl or phenethyl, cyclohexyl and cyclohexylmethyl, and c p and t are equal to 0. со 18. The method of obtaining the compound of formula II (8) III reg Mt -x dO h | | | with s Ez pon poh - oo. o M she so ko E! in which: the compound of formula PI is reacted with X-C(-0)-879; yin (8) AI - and reg tk | - to This so ee about MN tyu in the 60s! where B is selected from the group: C 1 -alkyl-O-C(-0)-, optionally, substituted C 4 -alkyl, optionally, substituted C 4 -cycloalkyl, optionally, substituted phenyl, optionally, substituted C 2.5-heterocyclyl, optionally substituted phenyl-C 4.3-alkyl and optionally substituted C 5-heterocyclyl-C 4.3-alkyl; X! is selected from the group: -"OH, "OK, -0-С(-0)-8 7, -СИ, -Bg and -I, where B is C. c-alkyl; B, BZ and KK" are independently selected from the group: hydrogen, optionally substituted C 4 c-alkyl and, as an option, substituted C3.c-cycloalkyl; and BO is selected from the group: -H, optionally substituted phenyl, optionally substituted C with 5-heterocyclyl, optionally substituted phenyl-C. 3-alkyl, optionally substituted with C 5 -heterocyclyl-C. 3-alkyl, optionally substituted C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl. 19. The method of obtaining the compound of the formula IM a , M regsha te - and viz St MA ry: in which: the reaction of the compound of the formula M with B 72-C(50)-8 73 is carried out; a M s vg (8) S s r ot ! with, - chn. b" and o MI c 3o E (he) where B is selected from the group: C 1 -alkyl-O-C(-0)-, alternatively, substituted C 4 -alkyl, optionally, substituted C. c" cycloalkyl, alternatively, substituted phenyl, optionally, substituted C, 5-heterocyclyl, optionally, substituted " 40. phenyl-C 1-3 -alkyl and, as an option, substituted C 3 5-heterocyclyl-C 1-3-alkyl; with with B? and KZ are independently selected from the group: hydrogen, as an option, substituted C 4.6-alkyl and, as an option, also substituted C. d"cycloalkyl; and -" B"? and KZ independently selected from the group: -H, optionally substituted phenyl, optionally substituted C. c-"heterocyclyl, optionally substituted phenyl-C 4.3-alkyl, optionally substituted C c.5-heterocyclyl-C.3-alkyl, optionally substituted C c-alkyl, optionally substituted C c.6 -cycloalkyl and, as an option, substituted with Cα-cycloalkyl-Ci3-alkyl, or КВК? and Б'З together form part of a C3-cycloalkyl ring or a C3-heterocyclyl ring. 20. The method of obtaining a compound of the formula Mi, in which: o a MI (Ce) E2 - "WITH IT | She she with me | t N NM M. F) y ve ke) Y o bo v! carry out the reaction of the compound of the formula M with K"7-МСО: b5 (8) M reg --- . M She and I rt dn! with, MN. M A in! where B is selected from the group: C 1 -alkyl-O-C(-O)-, optionally substituted C 46 -alkyl, optionally substituted C. c"cycloalkyl, optionally substituted phenyl, optionally substituted C.sub.5-heterocyclyl, optionally substituted phenyl-C..sub.-alkyl and optionally substituted C.5-heterocyclyl-C 4 .C-alkyl; B? and C-C are independently selected from the group: hydrogen, optionally substituted C .-C-alkyl and optionally substituted C. d"cycloalkyl; and and and Y and and and Y and and B" is selected from the group: as an option, substituted phenyl, as an option, substituted C with 5-heterocyclyl, as an option, 3-5 substituted phenyl-C. 3-alkyl, optionally substituted with C 5 -heterocyclyl-C. 3-alkyl, optionally substituted C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl. 21. The method of obtaining the compound of the formula МИЙ сч Го ; MI vg (8) -- . And | More SHO ez nn son "- M Ge; At 5 o'clock IR with in! so in which: the reaction of the compound of the formula MP! with K76-X2; about; M " 40. in o, --- . with M She and . And what happened to her too! (Ce) where B is selected from the group: C 4 -alkyl-O-C(-0)-, alternatively, substituted C 4 -alkyl, optionally, substituted C. c" cycloalkyl, optionally substituted phenyl, optionally substituted C 5-heterocyclyl, optionally substituted phenyl-C 5-heterocyclyl, and optionally substituted C 5-heterocyclyl-C 4 c-alkyl ; 59 B? and KZ are independently selected from the group: hydrogen, as an option, substituted C 4.6-alkyl and, as an option, substituted with C. d"cycloalkyl; with X2 selected from the group: I, Vg and SI; B"5 is selected from the group: -H, as an option, substituted phenyl, as an option, substituted C with 5-heterocyclyl, as an option, substituted phenyl-C. z-alkyl, as an option, substituted with C zv5-heterocyclyl-C. C-alkyl is optionally substituted C. 6-alkyl, as an option, substituted C3-6-cycloalkyl and, as an option, substituted C3.6-cycloalkyl-C3-6-alkyl; and B" is selected from the group: optionally, substituted phenyl-C / 3-alkyl, optionally, substituted C with 5-heterocyclyl, optionally, substituted C 2 -heterocyclyl-C.i.3-alkyl, optionally, substituted with C ..6-alkyl is optionally substituted C3.6-cycloalkyl and, as an option, substituted C3.-cycloalkyl-C4.3-alkyl. 65 22. The method of obtaining the compound of formula IX (8) Their reg Mt -x dO only r schu with | and hello to M a v! in which: the compound of formula PI is reacted with ХЗ-5(-0)5-877 о; p: "those with more | c her in M c 7 | o c! where B is selected from the group: Ci c-alkyl-O-C(-O)-, as an option, substituted C 46-alkyl, as an option, substituted h- C. c" cycloalkyl, optionally substituted phenyl, optionally substituted C. 5-heterocyclyl, optionally substituted F phenyl-C.. 3-alkyl and optionally substituted C. 5-heterocyclyl-C 4. z-alkyl; XZ is selected from the group: -OH, -OK7, -SI, -Bg and -I, where EC! - C. b-alkyl; and- B, BZ and KK" are independently selected from the group: hydrogen, as an option, substituted C 4 c-alkyl and, as an option, Ge substituted C 3 b-cycloalkyl; and so B" is selected from the group: -H, alternatively, substituted phenyl, optionally, substituted C z.5-heterocyclyl, optionally, substituted phenyl-C. z-alkyl, optionally, substituted C zv5-heterocyclyl-C .z-alkyl is optionally substituted C1-6-alkyl, optionally substituted C1-6-cycloalkyl and optionally substituted C3-6-cycloalkyl-C1-6-alkyl. "Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 05, 11.03.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. . and? so ko o (Se) "- ko 60 b5