UA96942C2 - Amino-piperidine derivatives as cetp inhibitors - Google Patents

Abstract

The present invention provides a compound of formula (I), wherein the variants R1, R2, R3, R4, R5, R6, R7 are as defined herein, and wherein said compound is an inhibitor of CETP, and thus can be employed for the treatment of a disorder or disease mediated by CETP or responsive to the inhibition of CETP.(I)

Description

haloalkyl, hydroxy group, halogen, nitro group, carboxy group, thio group, cyano group, NZO3--, alkoxy group, haloalkyl group, amino group, M-mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl) amino group; H2M-505-- and alkanoyl.

One embodiment of this invention relates to a compound of formula (I), in which one of KA and K5, preferably K5, represents hydrogen, and the other, preferably K4, represents a group defined in this invention that is not hydrogen.

One embodiment of this invention relates to a compound of formula (I), in which

Eb6 and 7 independently denote hydrogen, alkyl, haloalkyl, halogen, or an alkoxy group.

One embodiment of this invention relates to a compound of formula (I), in which

Eb6 and K7 represent hydrogen, alkyl or haloalkyl, such as trifluoromethyl.

The present invention also relates to compounds of formula (I), in which K1 denotes cycloalkyl, heterocyclyl, aryl, alkyl-O-C(O)-, alkanoyl, or alkyl, where each cycloalkyl, heterocyclyl, or aryl optionally contains from 1 to C substituents selected from the group consisting of alkyl, aryl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, HBOz-, cycloalkyl, alkenyl, alkoxy, cycloalkyl, alkenyloxy, alkyl-O-C(O)-, alkanoyl , carbamoyl, alkyl-5-, alkyl-50-, alkyl-5O2-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group, H2M-505- and heterocyclyl, Her where each alkanoyl . cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkyl-0O-C(O)-, alkanoyl, carbamoyl, alkyl-5-, alkyl-50-, alkyl-5O2-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group, H2M-505- and heterocyclyl;

K2 denotes an alkyl, cycloalkyl, cycloalkylalkyl or alkoxy group, where each alkyl, cycloalkyl or alkoxy group optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy or halogen;

KZ denotes К8-0О-С(0)-, (Н8В)(Н9)М-С(О0)-, А8-С(0)-, А8-5(0)2-, alkyl, cycloalkyl or arylalkyl-, wherein each alkyl, cycloalkyl or arylalkyl- optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, NZO3-, cycloalkyl, alkenyl, alkoxy, cycloalkyloxy, alkenyloxy , alkyl-0O-C(0)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-50"-, amino group, H2M-505-, heterocyclyl, where K8 and KU independently denote hydrogen, alkyl, cycloalkyl, aryl, arylalkyl- or cycloalkylalkyl-, where each alkyl, cycloalkyl, aryl, arylalkyl- or cycloalkylalkyl- optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen, nitro, carboxy, thio , cyano group,

NBZO3-, cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkyl-O-C(0)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-5O2-, amino group, NgM-505-, heterocyclyl ;

K4 and K5 independently denote hydrogen, alkyl, alkoxy group, cycloalkyl, aryl, heteroaryl, arylalkyl-, cycloalkylalkyl- and heteroarylalkyl-, where each alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl-, cycloalkylalkyl- and heteroarylalkyl- optionally contains from 17 to C substituents selected from the group consisting of alkyl, hydroxy, halogen, haloalkyl, nitro, carboxy, thio, cyano, NZOZ-, cycloalkyl, alkenyl, alkoxy, cycloalkyl, haloalkyl, alkenyloxy, alkyl-O-

C(0)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-5O-, alkyl-502-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group, H2M-50" -, heterocyclyl, provided that KA and K5 cannot simultaneously denote hydrogen;

Kb and K/ independently denote hydrogen, alkyl, haloalkyl, halogen, cyano group, nitro group, hydroxy group, amino group, dialkylamino group or alkyl group, haloalkyl group; or

Kb represents aryl, heteroaryl or alkyl-5(0)2-, where each aryl or heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, NZO3-, cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkyl-

O-C(O)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-505-, amino group, NaM-50»- heterocyclyl; or to a pharmaceutically acceptable salt thereof, or to an optical isomer thereof, or to a mixture of optical isomers, provided that, if Ka2 and E5 are independently alkyl and K4 is hydrogen, Kb or K7 cannot be hydrogen or an alkoxy group.

The present invention also relates to compounds of formula (I), in which K1 denotes cycloalkyl, heterocyclyl, aryl, alkyl-0O-C(0)-, alkanoyl, or alkyl, where each cycloalkyl, heterocyclyl, and aryl optionally contains from 1 to C substituents selected from the group consisting of alkyl, aryl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, HBOz-, cycloalkyl, alkenyl, alkoxy, cycloalkyl, alkenyloxy, alkyl-O-C(O)-, alkanoyl , carbamoyl, alkyl-5-, alkyl-50-, alkyl-5O2-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group, H2M-505- and heterocyclyl, and where each alkanoyl . cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkyl-0O-C(O)-, alkanoyl, carbamoyl, alkyl-5-, alkyl-50-, alkyl -5O2-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group, H2M-505- and heterocyclyl;

K2 represents an alkyl, cycloalkyl, cycloalkylalkyl or alkoxy group, where each alkyl, cycloalkyl and alkoxy group optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy or halogen;

KZ denotes К8-0О-С(0)-, (Н8В)(Н9)М-С(О0)-, А8-С(0)-, А8-5(0)2-, alkyl, cycloalkyl or arylalkyl-, wherein each alkyl, cycloalkyl and arylalkyl- optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, NZO3-, cycloalkyl, alkenyl, alkoxy, cycloalkyloxy, alkenyloxy , alkyl-0O-C(0)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-50"-, amino group, H2M-505-, heterocyclyl, where K8 and KU independently denote hydrogen, alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or non-aromatic heterocyclyl, wherein each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and non-aromatic heterocyclyl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen ) -, alkanoyl, kar bamimidoyl, alkyl-5-, alkyl-50-, alkyl-5O»2-, amino group, H2M-505- and heterocyclyl;

K4 and K5 independently denote hydrogen, alkyl, alkenyl, alkynyl, alkoxy group, cycloalkyl, aryl, heteroaryl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)--, dialkylamino-C(O)-- or dialkylamino- C(O)-alkyl--, where these two alkyl groups optionally form a ring and where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)- -, dialkylamino-C(O)-- or dialkylamino-C(O)-alkyl-- optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy group, halogen, haloalkyl, nitro group, carboxy group, thio group , cyano group, H5ZO3-, cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, haloalkyloxy group, alkenyloxy group, alkyl-O-C(0)-, alkanoyl, carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-50"-, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-)-amino group, H2M-505-, heterocyclyl, provided that KA and K5 cannot cyclize to form a ring;

Kb and K/ independently denote hydrogen, alkyl, haloalkyl, halogen, cyano group, nitro group, hydroxy group, amino group, dialkylamino group, alkyl group, haloalkyl group, aryl, heteroaryl or alkyl-5(0)2-, where each aryl and heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy group, halogen, nitro group, carboxy group, thio group, cyano group, NZO3-, cycloalkyl, alkenyl, alkoxy group, cycloalkyl group, alkenyloxy group, alkyl-0O-C(0)-, alkanoyl , carbamimidoyl, alkyl-5-, alkyl-50-, alkyl-502-, amino group, H2M-5052- heterocyclyl; or to a pharmaceutically acceptable salt thereof, or to an optical isomer thereof, or to a mixture of optical isomers.

One embodiment of this invention relates to a compound of formula (I), in which

K1 represents cycloalkyl, heterocyclyl, aryl, alkyl-O-C(0)-, alkanoyl or alkyl, where each cycloalkyl, heterocyclyl or aryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, aryl, haloalkyl ) , alkyl-5O2--, amino group, alkylamino group, H2M-502--, alkanoyl and heterocyclyl; and wherein each alkanoyl, alkyl-O-C(O)-, alkyl or heterocyclyl optionally additionally contains from 1 to 3 substituents selected from the group consisting of hydroxy, halogen, nitro, carboxy, thio, cyano, NZOzZ- - . alkanoyl and heterocyclyl;

K2 denotes an alkyl or alkoxy group;

KZ denotes К8-0-С(О)--, (АВ)(А9)М-С(О)--, АВ-С(О0)-, А8-5(0) 2--, alkyl, cycloalkyl or arylalkyl-;

C4 or C5 independently of each other denote hydrogen, aryl, alkyl, arylalkyl-, cycloalkyl, cycloalkylalkyl-, heteroaryl or heteroarylalkyl-, where each aryl, arylalkyl-, cycloalkyl, cycloalkylalkyl-, heteroaryl or heteroarylalkyl- optionally contains from 1 to From the substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, HeZO3- cycloalkyl, alkenyl, alkoxy, haloalkyl, cycloalkyl, alkenyloxy, alkoxycarbonyl, alkyl-5-, alkyl- 5O--, alkyl-5O2--, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group; H2M-505-- and alkanoyl;

Kb and K/ independently denote hydrogen, alkyl, haloalkyl, halogen, cyano group, nitro group, hydroxy group, dialkylamino group or alkoxy group; or

Kv denotes aryl, heteroaryl or K8-5(0)2-;;

E8 denotes hydrogen, alkyl, cycloalkyl, aryl, arylalkyl- or cycloalkylalkyl-; or to a pharmaceutically acceptable salt thereof, or to an optical isomer thereof, or to a mixture of optical isomers, provided that, when K2 and 5 are independently alkyl and 4 is hydrogen, Kb or K7 cannot be hydrogen or alkoxy.

One embodiment of the present invention relates to the compound of formula (I), in which K1 denotes alkyl-

O-C(O)- and heteroaryl, optionally containing from 17 to 3 substituents selected from the group consisting of halogen, heteroaryl, hydroxy, alkoxy, non-aromatic heterocyclyl, alkyl or dialkylamino, where each heteroaryl, alkoxy, alkyl and non-aromatic heterocyclyl optionally additionally contains 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, alkyl-O-C(0)-, carboxy, alkyl-505-, alkoxy, dialkylamino, and non-aromatic heterocyclyl and alkanoyl;

K2 denotes alkyl;

KZ denotes 8-C(0)- or K8-0-C(0)-, where K8 denotes alkyl, non-aromatic heterocyclyl or cycloalkyl, each alkyl, non-aromatic heterocyclyl or cycloalkyl optionally containing from 1 to 3 substituents selected from the group , which includes alkanoyl, alkyl-C(O)-O- and a hydroxy group;

K4 denotes arylalkyl-, alkyl or heteroaryl, each of which optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, halogen and hydroxy;

E5 denotes hydrogen or alkyl;

Eb6 and K7 independently denote haloalkyl, halogen, alkoxy group or alkyl-502-; or to a pharmaceutically acceptable salt thereof or to an optical isomer thereof or to a mixture of optical isomers.

One embodiment of this invention relates to the compound of formula (I), in which K1 denotes (C1-

C4)-alkyl-O-C(O)- or 5- to 7-membered heteroaryl, optionally containing from 1 to 3 substituents selected from the group consisting of halogen, 5- to 7-membered heteroaryl, (C1 -C4)-alkyl group, 5- - 7-membered non-aromatic heterocyclyl, (C1-C4)-alkyl or (C1-C4)-dialkylamino group, where (C1-C4)-alkyl is optionally substituted by one to three hydroxy groups, 5- - 7-membered non-aromatic heterocyclyl optionally substituted by one to three alkanoyl groups, and where each 5- to 7-membered heteroaryl and (C1-C4)- alkoxy group optionally additionally contains from 1 to 3 substituents selected from the group, which includes (C1-C4)-alkyl, hydroxy group, (C1-C4)-alkyl-0O-C(0)-, (C1-C4)-alkyl-5O2-, (C1-C4)-alkyl group, (C1- C4)- dialkylamino group and 5- - 7-lene non-aromatic heterocyclyl;

K2 denotes (C1-C4)-alkyl;

KZ denotes K8-C(0)- or K8-0O-C(0)-, where K8 denotes (C1-C4)-alkyl, 5- - 7-ene non-aromatic heterocyclyl or (C5-C7)-cycloalkyl, each (C1-C4)-alkyl, 5- - 7-lene non-aromatic heterocyclyl and (C5-C7)-cycloalkyl optionally contains from 1 to 3 substituents selected from the group including (C1-C4)- alkanoyl, ( C1-C4)-alkyl-C(O)-O- and a hydroxy group;

K4 denotes (C5-C9)-aryl-(C1-C4)-alkyl-, (C1-C4)-alkyl or 5- - 7-ene heteroaryl, each of which optionally contains from 17 to 3 substituents selected from the group including (C1-C4)-alkyl, halogen and hydroxy group;

K5 denotes hydrogen or (C1-C4)-alkyl;

Kb and 7 independently denote (C1-C4) haloalkyl, halogen, (C1-C4)-alkoxy group or (C1-C4)-alkyl-5O2g-; or to a pharmaceutically acceptable salt thereof or to an optical isomer thereof or to a mixture of optical isomers.

One embodiment of this invention relates to a compound of formula (I), in which

K1 denotes alkyl-O-C(0)-, alkanoyl or heteroaryl, where said heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of halogen, dialkylamino group, alkoxy group, heterocyclyl, where said heterocyclyl is optionally additionally contains from 1 to 3 substituents selected from the group consisting of a hydroxy group and an alkanoyl group,

K2 denotes alkyl;

KZ denotes alkyl-O-C(O)- or cycloalkyl-C(O)-;

E4 denotes arylalkyl-, optionally substituted with 1-C alkyls or halogens;

K5 denotes hydrogen; and

Kb and 7 independently denote a halogen, alkyl or alkoxy group, where the specified alkyl is optionally substituted with 1-C halogens.

One embodiment of this invention relates to a compound of formula (I), in which

CI denotes (C1-C7)alkyl-0O-C(O0)- or 5- or b-membered heteroaryl, where said heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of halogen, dialkylamino group, (C1 -

C7)-alkyl group and 5- or b-membered heterocyclyl, where said heterocyclyl optionally additionally contains from 1 to 3 substituents selected from the group including (C1-C7)alkanoyl or a hydroxy group;

K2 denotes (C1-C7)-alkyl;

KZ denotes (C1-C7)alkyl-O-C(O)- or 5- or b-membered cycloalkyl-C(O)-;

E4 denotes a 5- or 6-membered aryl optionally containing 1 to 3 substituents selected from the group consisting of alkyl and halogen;

K5 denotes hydrogen; and

Kb and 7 independently denote a halogen, (C1-C7)-alkyl or (C1-C7)-alkyl group, where the indicated alkyl is substituted by 1-C halogens.

The present invention also relates to the method of obtaining these compounds, to the use of these compounds and to pharmaceutical preparations containing such compound I in free form or in the form of a pharmaceutically acceptable salt.

Careful pharmacological studies have shown that compounds I and their pharmaceutically acceptable salts, for example, are characterized by pronounced selectivity of inhibition of BPHE (cholesteryl ester carrier protein). BIPHE is involved in the metabolism of any lipoprotein in living organisms and plays a major role in the circulation of the cholesterol transport system. In particular, BIPHE has attracted attention in connection with the mechanism of prevention of cholesterol accumulation in peripheral cells and prevention of arteriosclerosis. Due to the fact that HDL (high-density lipoprotein) plays an important role in this cholesterol transport system, a number of epidemiologic researchers have shown that a decrease in the content of XE (cholesteryl ester) contained in HDL in the blood is one of the risk factors development of coronary artery diseases. It has also been established that BPHE activity is different in different species of animals and that arteriosclerosis due to high cholesterol almost does not occur in animals with lower activity and, on the contrary, easily occurs in animals with higher activity, and that hyper-HDL-emia and hypo-LDLC (low-density lipoprotein)-emia occurs in the case of BPHE deficiency, which complicates the development of arteriosclerosis, which, in turn, leads to the conclusion about the importance of HDL content, as well as the importance of BPHE content, which mediates the transport of XE contained in LDL, in LDL contained in the blood. Although many attempts have been made in recent years to develop a drug that inhibits this activity of BPHE, a compound with satisfactory activity has not yet been obtained.

For purposes of this specification, the following definitions are used, and when appropriate, terms used in the singular include the plural, and vice versa.

As used herein, the term "alkyl" means a fully saturated branched or unbranched carbon moiety. Preferably, the alkyl comprises from 1 to 20 carbon atoms, more preferably from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 7 carbon atoms, or from 1 to 4 carbon atoms. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl , 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. If an alkyl group contains one or more multiple bonds, it can be called an alkenyl (double bond) or alkynyl (double bond) group. If the alkyl group can be substituted, it preferably contains 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, nitro, carboxy, thio, cyano, HBOz-- cycloalkyl, alkenyl, alkoxy, cycloalkyl, alkenyloxy, alkoxycarbonyl , carbamimidoyl, alkyl-5--, alkyl-5O--, alkyl-5O2--, amino group, H2M-505--, alkanoyl and heterocyclyl, more preferably - selected from the group including hydroxy group, halogen, nitro group, carboxy group, thio group, cyano group, alkoxy group and amino group.

The term "aryl" means monocyclic or bicyclic aromatic hydrocarbon groups containing 6-20 carbon atoms in the ring fragment. It is better if aryl means (Sn-Cio)-aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, most preferably phenyl, each of which may optionally contain 1-4 substituents such as alkyl, haloalkyl such as trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, alkyl-C (O)-O--, aryl-O--, heteroaryl-O--, amino group, acyl, thio group, alkyl-5--, aryl-5--, nitro group, cyano group, carboxy group, alkyl-O-C( О)-, carbamoyl, alkyl-5(0)-, sulfonyl, sulfonamide group, heterocyclyl, alkenyl, haloalkyloxy group, cycloalkyloxy group, alkenyloxy group, alkoxycarbonyl, alkyl-5O--, alkyl-5O2--, amino group, mono- or disubstituted ( alkyl, cycloalkyl, aryl and/or arylalkyl) amino group or H2M-505;.

Furthermore, the term "aryl" as used herein means an aromatic substituent which may be a single aromatic ring or multiple aromatic rings which are fused to each other, covalently bonded or linked to a common group such as a methylene or ethylene moiety. The common linking group can also be carbonyl, as in benzophenone, or oxygen, as in diphenyl ether, or nitrogen, as in diphenylamine.

As used in this invention, the term "alkyl group" means alkyl-O-, where alkyl is defined above in this invention. Typical examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. It is better if the alkoxy groups contain about 1-7, more preferably - about 1-4 carbon atoms.

As used herein, the term "acyl" means a K-C(O)- group containing from 1 to 10 carbon atoms, having a linear, branched or cyclic configuration, or a combination thereof, attached to the main structure through a carbonyl group. Such a group can be saturated or unsaturated and aliphatic or aromatic. It is better if K in the acyl residue denotes alkyl, or an alkoxy group, or aryl, or heteroaryl. If E denotes alkyl, then this fragment is called alkanoyl. It is also preferred if one or more carbon atoms in the acyl residue can be replaced by nitrogen, oxygen or sulfur, provided that attachment to the main structure through the carbonyl group is maintained. Examples include, but are not limited to, acetyl, benzoyl, propionyl, isobutyryl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Below acyl means acyl containing from 1 to 4 carbon atoms.

As used herein, the term "acylamino group" means acyl-MH--, where "acyl" is defined herein.

As used in this invention, the term "carbamoyl" means He»MC(O)-, alkyl-MHNO(O)-, (alkyl)»»MC(O)-, aryl-MHNO(O)-, alkyl(aryl) -MC(O)-, heteroaryl-MHO(O)-, alkyl(heteroaryl)-MC(O)-, arylalkyl-MHC(O)-, alkyl(arylalkyl)-MC(O)-, etc.

As used herein, the term "sulfonyl" means K-5052--, where K is hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl-O--, heteroaryl-O--, alkoxy, aryloxy, cycloalkyl, or heterocyclyl .

When used in this invention, the term "sulfonamide group" means alkyl-5(0)2-MH-, aryl-

C(0)2-MH-, arylalkyl-5(0)2-MH-, heteroaryl-5(0)2-MH-, heteroarylalkyl-5(0)2-MH-, alkyl-5(О0)2- M(alkyl)-, aryl-5(0)2-M(alkyl)-, arylalkyl-5(0)2-M(alkyl)-, heteroaryl-5(0)2-M(alkyl)-, heteroarylalkyl- 5(0)2-M(alkyl)- it.p.

As used in the present invention, the term "Alkoxycarbonyl" or "Alkyl-0O-C(0)-" means alkoxy-

C(O)-th, where the alkoxy group is defined in this invention.

As used herein, the term "alkanoyl" means alkyl-C(O)--, where alkyl is defined herein.

As used herein, the term "alkenyl" means a linear or branched hydrocarbon group containing from 2 to 20 carbon atoms and containing at least one double bond. Alkenyl groups preferably contain from about 2 to 8 carbon atoms.

As used herein, the term "alkynyl" means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to about 8 carbon atoms. The term alkynyl preferably means an alkyl group containing 1 or 2 carbon-carbon triple bonds and containing from 2 to b carbon atoms.

As used herein, the term "alkenyloxy" means alkenyl-O--, where alkenyl is defined herein.

As used herein, the term "cycloalkyl group" means cycloalkyl-O--, where cycloalkyl is defined herein.

As used herein, the term "heterocyclyl" means an optionally substituted, fully saturated or unsaturated aromatic or non-aromatic cyclic group, for example, a 4--7-membered monocyclic, 7--12-membered bicyclic or 10--15 - membered tricyclic ring system containing at least one heteroatom in at least one ring containing carbon atoms. Each ring of a heterocyclic group containing a heteroatom may contain 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also optionally be oxidized. A heterocyclic group can be attached to a heteroatom or a carbon atom.

Typical monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxazolidinyl, thiyl , piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl, 1,3 - dioxolane and tetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl, etc.

Типові біциклічні гетероциклічні групи включають індоліл, дигідроіндоліл, бензотіазоліл, бензоксазиніл, бензоксазоліл, бензотієніл, бензотіазиніл, хінуклідиніл, хінолініл, тетрагідрохінолініл, декагідрохінолініл, ізохінолініл, тетрагідроізохінолініл, декагідроізохінолініл, бензімідазоліл, бензопіраніл, індолізиніл, бензофурил, хромоніл, кумариніл, бензопіраніл, цінолініл, хіноксалініл , indazolyl, pyrrolopyridyl, furopyridinyl (such as furo|2,3-c|Ipyridinyl, furo3,2-B|-pyridinyl| or furo(2,3-b|pyridinyl), dihydroisoindolyl, 1,3-dioxo-1, 3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-

quinazolinil), phthalazinil, etc.

Typical tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl, and the like.

If the heterocyclyl is aromatic, then this moiety is called a "heteroaryl".

As used herein, the term "heteroaryl" means a 5- to 14-membered monocyclic or bicyclic or fused polycyclic ring system containing from 1 to 8 heteroatoms selected from the group consisting of M, O, and 5. Preferably, the heteroaryl represents is a 5- to 10-membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2, 3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2- pyrazinyl, 2-, 4- or 5-pyrimidinyl.

The term "heteroaryl" also means a group in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings in which the radical or position of attachment is in the heteroaromatic ring. Non-limiting examples include, but are not limited to, 1-, 2- , 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3 -, 4-, 6-, 7-, 8- or 9-quinolisinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5 -, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or b-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8- cinolinyl, 2-, 4-, 6- or 7-pteridinyl, 1- , 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- carbazolyl, 1 -, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10- phenanthridinyl, 1-, 2 -, C-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyrimidinyl, 2 -, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- benzisoquinolinyl, 2- , 3-, 4- or thieno(2,3-b|furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 - or 11-7H-pyrazine(2,3 -sicarbazolyl, 2-, 3-, 5-, 6- or 7-2H- furoyl3,2-B|-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido(2 ,3-4|-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo|4,3- a|-oxazolyl, 2-, 4- or 54H-imidazo|4,5-4| thiazolyl, 3-, 5- or 8-pyrazino|2,3-4|pyridazinyl, 2-, 3-, 5- or 6-imidazo|2,1-BI| thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo|3,4-s|cinolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 and 11-4H-pyrido(2,3-c|carbazolyl, 2-, 3-, 6- or 7-imidazo|(1,2-5111,2,Agriazinyl, 7-benzoiB|hyenyl, 2 -, 4-, 5-, 6- or 7- benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9- benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo|1,2-

BI(2I|benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5- , 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5B-, 6- or 7-benzoyl |hyenyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl .

The heteroaryl group can be mono-, bi-, tri- or polycyclic, preferably mono-, bi- or tricyclic, more preferably mono- or bicyclic.

The term "heterocyclyl" also means heterocyclic groups defined in this invention containing 1, 2 or C substituents selected from the group consisting of the following: alkyl; haloalkyl, hydroxy group (or protected hydroxy group); halogen; oxo group, i.e. 50; an amino group, a mono- or disubstituted (alkyl, cycloalkyl, aryl or arylalkyl) amino group, such as an alkylamino group or a dialkylamino group; an alkoxy group; cycloalkyl; alkenyl; carboxy group; a heterocyclooxy group, where a heterocyclooxy group means a heterocyclic group attached through an oxygen bridge; alkyl-0O-C(0)--; mercapto group; BUT"; nitro group; cyano group; sulfamoyl or sulfonamide group; aryl; alkyl-C(0)-0-; aryl-C(0)-O--; aryl-5--; a cycloalkyl group; alkenyloxy group; Alkoxycarbonyl; aryloxy group; carbamoyl; alkyl-5--; alkyl-5O--, alkyl-5O2--; formyl, i.e. HC(O)--; arylalkyl--; acyl such as alkanoyl; heterocyclyl and aryl substituted by alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O0)-MH--, alkylamino, dialkylamino or halogen.

As used herein, the term "cycloalkyl" means optionally substituted saturated or unsaturated, monocyclic, bicyclic or tricyclic hydrocarbon groups containing 3-12 carbon atoms, each of which may contain one or more substituents such as alkyl, halogen ) group, sulfamoyl, heterocyclyl, etc. Typical monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, and the like. Typical bicyclic hydrocarbon groups include bronyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo(2.1.1|hexyl, bicyclo|2.2.1|)heptyl, bicyclo(2.2.1|heptenyl, 6,6- dimethylbicyclo|3.1.1| heptyl, 2,6,b-trimethylbicyclo|3.1.1)heptyl, bicyclo(12.2.2|octyl, etc. Typical tricyclic hydrocarbon groups include adamantyl, etc.

When used in this invention, the term "sulfamoyl" means He2gM5(O)2-, alkyl-MHO(O)2-, (alkyl)i»M5(O0)2-, aryl-MHO(O)2-, alkyl(aryl )-М5(О)2-, (aryl)2М5(0)2-, heteroaryl-МНО(О)2-, arylalkyl-

МНО(О)2-, heteroarylalkyl-МНО(О)2-, etc.

As used herein, the term "aryloxy" means both --O-aryl and --O-heteroaryl, where aryl and heteroaryl are defined herein.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine.

As used herein, the term "haloalkyl" means an alkyl as defined herein substituted with one or more halide groups defined herein.

Preferably, haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can contain one atom of iodine, bromine, chlorine or fluorine in the alkyl group. Dihaloalkyl and polyhaloalkyl groups can contain two or more identical halogen atoms in the alkyl group or be a combination of different halide groups with alkyl.

It is better if the polyhaloalkyl contains up to 12, 10, or 8, or 6, or 4, or 3, or 2 halide groups.

Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,

dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhaloalkyl means an alkyl in which all hydrogen atoms have been replaced by halogen atoms.

As used herein, the term "monoalkylamino group" means an amino group substituted with one alkyl group.

As used herein, the term "dialkylamino group" means an amino group that is doubly substituted with alkyl, and the two alkyl groups may be the same or different. It is better if the dialkylamino group can contain the same alkyl substituents. Non-limiting examples of dialkylamino include dimethylamino, diethylamino, and diisopropylamino.

As used herein, the term "arylalkyl" is used interchangeably with the term "arylalkyl-", where aryl and alkyl are defined herein.

When used in this invention, the term "cycloalkylalkyl-" is used interchangeably with the term "cycloalkylalkyl", where cycloalkyl and alkyl are defined in this invention.

As used herein, the term "isomers" refers to different compounds having the same molecular formula. Furthermore, as used herein, the term "optical isomer" refers to each of the various stereoisomeric configurations that may exist for a given compound of the present invention, and includes geometric isomers. It should be understood that a substituent can be attached to a carbon atom that is a chiral center. Therefore, the present invention includes enantiomers, diastereoisomers and racemates of the compound. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of two enantiomers of a compound is called a "racemic" mixture.

This term is used to refer to a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other. The absolute stereochemical configuration is described using the 8-5 Kahn-Ingold-Prelog system. If the compound is a pure enantiomer, then the stereochemical configuration of each chiral carbon atom can be described as A or 5. Separated compounds whose absolute configuration is not established can be described using the symbols (g) or (-), depending on the direction in which they rotate the plane of light polarization at the wavelength of the О line of sodium (right-handed and left-handed). Some of the compounds described in this invention contain one or more asymmetric centers and therefore can form enantiomers, diastereoisomers and other stereoisomeric forms, the absolute stereochemical configuration of which can be designated as (H)- or (5)-. The present invention includes all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (A)- and (5)- isomers can be obtained with the help of chiral synthons or chiral reagents or isolated by conventional methods. If the compound contains a double bond, then the substituents can be in the E or 7 configuration. If the compound is a disubstituted cycloalkyl, then the cycloalkyl substituents can be in the cis- or trans-configuration. It is intended that the scope of this invention includes all tautomeric forms.

As used herein, the term "pharmaceutically acceptable salts" refers to salts which retain the biological efficacy and properties of the compounds of this invention and which are not biologically or otherwise undesirable. Non-limiting examples of salts include non-toxic inorganic or organic base or acid addition salts of compounds of the present invention. In many cases, the compounds proposed in this invention can form salts with an acid and/or a base due to the presence of amino groups and/or carboxyl groups or similar groups.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and with organic acids. Inorganic acids from which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be formed include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be formed include, for example, bases of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; ammonium, potassium, calcium and magnesium salts are especially preferred. Organic bases from which salts can be formed include, for example, primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, basic ion exchange resins, and the like, preferably such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Pharmaceutically acceptable salts proposed in this invention can be synthesized from the parent compound, basic or acidic fragment by conventional chemical methods. Usually, such salts can be obtained by reacting the free acid forms of these compounds with a stoichiometric amount of the corresponding base (such as hydroxide, carbonate, bicarbonate, etc.

Ma, Ca, Ma or K) or by the reaction of free basic forms of these compounds with a stoichiometric amount of the corresponding acid. such reactions are usually carried out in water or in an organic solvent or in a mixture thereof. Of course, if possible, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of additional suitable salts are given, for example, in the publication of Vetipdupier

RPpagtaseshisa! Zsieepsez5, 201 ed., Mask Ribriizpipd Sotrapu, Easiop, Ra., (1985), which is incorporated into the present invention as a reference.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersing media, coatings, surfactants, antioxidants, preservatives (eg, bactericidal agents, fungicidal agents), isotonic agents, retention agents absorption, salts, preservatives, drugs, drug stabilizers, binders, inert fillers, leavening agents, lubricating agents, sweeteners, flavorings, dyes, similar materials and combinations thereof, as would be known to one of ordinary skill in the art (see, e.g., the publication of Ketipdiopye Rpagtaseshis! Zsiepse5, 181p Ei. Mask Riipipd Sotrapu, 1990, pp. 1289-1329, which is incorporated herein by reference). Unless the usual carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended.

The term "therapeutically effective amount" of a compound of the present invention means an amount of a compound of the present invention that causes a biological or medical response in a subject, or alleviates symptoms, slows or delays the progression of a disease, or prevents a disease, etc. . In a preferred embodiment, an "effective amount" means an amount that inhibits or reduces the expression or activity of BPHE.

As used herein, the term "subject" means an animal. It is better if the animal is a mammal. Subject also means, for example, primates (eg humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

As used herein, the term "disorder" or "disease" means any disorder or abnormality of function; a painful physical or mental condition. See publication by Juopapa Shivigaiia

Meadis! Risiopagu, (M.V. Zaipayegv So. 271 ey. 1988).

As used in this invention, the term "inhibition" or "suppression" means weakening or suppressing a given pathological condition, symptom, or disorder, or disease, or a significant weakening of the original biological activity or process. Preferably, the pathological condition or symptom or disorder or disease is mediated by BPHE activity and responds to BPHE inhibition.

As used herein, the term "treating" any disease or disorder in one embodiment means ameliorating the course of the disease or disorder (ie, stopping or attenuating the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to the improvement of at least one physical parameter that may not be felt by the patient. In yet another embodiment, "treating" means altering the course of a disease or disorder, either physical (eg, stabilization of an ongoing symptom), or physiological (eg, stabilization of a physical parameter), or both. In yet another embodiment, "treating" means preventing or delaying the onset or development or progression of a disease or disorder.

When used in the present invention (especially in the claims), terms used in the singular include the plural, and vice versa, unless otherwise specified in the present invention and unless clearly inconsistent with the context. The designation of value ranges in the present invention is used simply to briefly refer to all individual values within that range. Unless otherwise specified herein, each individual value is included in the description as if it were specifically set forth herein. All techniques described in the present invention can be performed in any suitable order, unless otherwise specified in the present invention and unless clearly inconsistent with the context. The use of any and all examples or references to typical values (eg, "such as") herein is intended merely to better describe the invention and is not intended to limit the scope of the invention as defined by the claims. No expression in the specification should be construed as indicating an undisclosed element essential to the practical implementation of the present invention.

Below are the best implementation options for fragments and symbols of the formula | may be used independently of each other to replace more general definitions and thus define particularly preferred embodiments of the present invention, and other definitions may be left broadly as defined in the embodiments of the present invention defined above or below.

One embodiment of the present invention relates to a compound of formula I, in which

K1 represents heterocyclyl, aryl, alkoxycarbonyl, alkanoyl or alkyl, where each heterocyclyl or aryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, HBOz --, cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkoxycarbonyl, carbamoyl, alkyl-5--, alkyl-5O--, alkyl-502--, amino group, H2M-505--, alkanoyl and heterocyclyl; and wherein each alkanoyl, alkoxycarbonyl, or alkyl optionally contains from 17 to 3 substituents selected from the group consisting of hydroxy, halogen, nitro, carboxy, thio, cyano, HBO3-cycloalkyl, alkenyl, alkoxy, cycloalkyloxy, alkenyloxy, alkoxycarbonyl , carbamoyl, alkyl-5--, alkyl-5O--, alkyl-5O5--, amino group, H2M-505--, alkanoyl and heterocyclyl;

K2 denotes alkyl;

KZ denotes К8-0О-С(О)--, (АВ)(А9)М-С(О)--, АВ-С(О0)-, А8-5(0) 2--, alkyl, cycloalkyl or arylalkyl-;

C4 or C5 independently of each other represent hydrogen, arylalkyl-, cycloalkylalkyl- or heteroarylalkyl-, where each aryl, cycloalkyl or heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, halogen, nitro group, carboxy group, thio group, cyano group, NBZO3--, cycloalkyl, alkenyl, alkoxy group, haloalkyl group, cycloalkyl group, alkenyloxy group, alkoxycarbonyl, alkyl-5--, alkyl-5O--, alkyl-5O2--, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-)-amino group; H2M-505-- and alkanoyl;

Kb and K/ independently denote hydrogen, alkyl, haloalkyl, halogen, cyano group, nitro group, hydroxy group, dialkylamino group or alkoxy group; or

E6 denotes aryl or heteroaryl;

E8 denotes hydrogen, alkyl, cycloalkyl, aryl, arylalkyl- or cycloalkylalkyl-; or to a pharmaceutically acceptable salt thereof or to an optical isomer thereof or to a mixture of optical isomers.

Better definitions for K1

Better if K1! represents heterocyclyl, aryl, alkoxycarbonyl, alkanoyl, or alkyl, wherein each heterocyclyl or aryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, H5bOz- -, cycloalkyl, alkenyl, alkoxy group, cycloalkyloxy group, alkenyloxy group, alkoxycarbonyl, carbamoyl, alkyl-5--, alkyl-5O--, alkyl-502--, amino group, H2M-505--, alkanoyl and heterocyclyl; and wherein each alkanoyl, alkoxycarbonyl or alkyl optionally contains from 1 to 3 substituents selected from the group consisting of hydroxy, halogen, nitro, carboxy, thio, cyano, HBO3-cycloalkyl, alkenyl, alkoxy,

cycloalkoxy group, alkenyloxy group, alkoxycarbonyl, carbamoyl, alkyl-5--, alkyl-5O--, alkyl-5O5--, amino group, H2M-505--, alkanoyl and heterocyclyl. More is better if K! represents heterocyclyl, such as heteroaryl, alkanoyl, or alkoxycarbonyl, wherein each heterocyclyl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, NEO, cycloalkyl, alkenyl , an alkoxy group, a cycloalkyl group, an alkenyloxy group, an alkoxycarbonyl, a carbamoyl, an alkyl-5--, an alkyl-5O--, an alkyl-5O2--, an amino group, He2M-502--, alkanoyl and heterocyclyl, more preferably - an alkyl, a hydroxy group, a halogen, carboxy group, alkoxy group, amino group, alkanoyl or heterocyclyl. The best example of a heterocyclyl substituent of a heterocyclyl fragment for KI is a 5- - b--lene, preferably a fully saturated ring containing at least one heteroatom selected from the group consisting of 0, M and 5, preferably M, the most preferred being morpholinyl.

Mo | M

HA AK

The best value of the K1 group is heteroaryl, which is better described by the formulas, "M, M,

Hey, what's wrong -

Ж M o or pyridyl, better - » M o, which are unsubstituted or contain C-C4-alkyl as substituents, better - methyl or halogen, more better - Bg, or C-C4-alkoxycarbonyl, C-C4-alkylcarbonyl, or heterocyclyl such as piperidyl, piperazinyl or morpholinyl, preferably morpholinyl.

Better definitions for K2

It is better if K2 denotes a C-Cv-alkyl defined in this invention, having a linear or branched chain. Examples include methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl and sec-butyl, more preferably ethyl and isobutyl, most preferably ethyl.

Better definitions for short circuits

It is better if KZ denotes alkyl-O-C(O)--, cycloalkyl-O-C(O)--, arylalkyl-O-C(O)--, (alkyl)2M-C(O)--, alkanoyl, arylalkyl-C(O)-, alkyl-B(O)2--, aryl-5(O)2--, alkyl or arylalkyl-.

Preferred examples of alkyl-O-C(O)-- include fragments in which the alkyl is linear or branched chain alkyl, preferably branched chain, Ci-Cv-alkyl as defined herein, such as methyl, ethyl, isopropyl , isobutyl or tert-butyl, most preferably - isopropyl.

Preferred examples of cycloalkyl-0O-C2(O0)-- include fragments in which the cycloalkyl is a C3-C12-cycloalkyl as defined herein, such as cyclohexyl or adamantyl.

Preferred examples of arylalkyl-O-C(O)- include moieties in which the aryl is C1-C0-aryl as defined herein, such as phenyl or naphthyl, more preferably phenyl. Preferred examples of arylalkyl include benzyl, phenethyl, more preferably benzyl.

Preferred examples of (alkyl)2M-C(O)-- include fragments in which the alkyl is C1i-Cv-alkyl having a linear or branched chain, preferably a branched chain as defined in this invention, such as methyl, ethyl, isopropyl, isobutyl or tert-butyl, most preferably methyl or ethyl.

Preferred examples of alkanoyl include moieties wherein the alkyl is C1i-C6 alkyl having a straight or branched chain, preferably a branched chain as defined herein, such as methyl, ethyl, isopropyl, isobutyl or tert-butyl, most preferably - tert-butyl.

Preferred examples of arylalkyl-C(O)- include moieties in which the aryl is C1-C0-aryl as defined herein, such as phenyl or naphthyl, more preferably phenyl. Preferred examples of arylalkyl include benzyl, phenethyl, more preferably benzyl.

Preferred examples of alkyl-5(O0)2-- include fragments in which the alkyl is C1-C8-alkyl having a linear or branched chain, preferably a branched chain as defined in this invention, such as methyl, ethyl, isopropyl, isobutyl or tert-butyl, most preferably methyl.

Preferred examples of aryl-5(0)2-- include fragments in which the aryl is C1-C6-aryl as defined herein, such as phenyl or naphthyl, more preferably phenyl.

Preferred examples of alkyl include moieties in which the alkyl is a straight or branched chain alkyl, preferably a branched chain as defined herein, such as methyl, ethyl, isopropyl, isobutyl or tert-butyl.

Preferred examples of arylalkyl include moieties in which the aryl is C6-C0-aryl as defined herein, such as phenyl or naphthyl, more preferably phenyl. Preferred examples of arylalkyl include benzyl, phenethyl, more preferably benzyl.

It is most preferable if KZ denotes alkyl-O-C(O)- defined in this invention.

Better definitions for KA and K5

It is better if K4 or K5 independently of each other denote hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl-, cycloalkylalkyl- or heteroarylalkyl-, more preferably - hydrogen, arylalkyl-, cycloalkylalkyl- or heteroarylalkyl-, where each alkyl, neob' necessarily contains from 17 to 3 substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a carboxy group, a thio group, a cyano group, NZOzZ- -, cycloalkyl, alkenyl, an alkoxy group, a haloalkyl group, a cycloalkyl group, an alkenyloxy group, an alkoxycarbonyl, an alkyl-5--, alkyl-50--, alkyl-502--, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group; H2M-50O2-- and alkanoyl, and where each aryl, cycloalkyl or heteroaryl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thio, cyano, HBOz- -, cycloalkyl, alkenyl, alkoxy group, haloalkyloxy group, cycloalkyloxy group, alkenyloxy group, alkoxycarbonyl, alkyl-5--, alkyl-50--, alkyl-5O»2--, amino group, mono- or disubstituted (alkyl, cycloalkyl, aryl and/ or an arylalkyl-)-amino group;

H2M-505-- and alkanoyl.

It is better if KA or K5 independently of each other denote hydrogen, benzyl, or cycloalkyl-

SnHe--, where each benzyl or cycloalkyl optionally contains from 1 to 3 substituents selected from the group consisting of alkyl, haloalkyl, hydroxy group, halogen, nitro group, carboxy group, thio group, cyano group, NZO3--,

an alkoxy group, a haloalkyl group, an amino group, a mono- or disubstituted (alkyl, cycloalkyl, aryl and/or arylalkyl-) amino group; H2M-505-- and alkanoyl.

In one embodiment, one of K4 and K5, preferably K5, represents hydrogen, and the other, preferably H4, represents a group defined in this invention that is not hydrogen.

In another embodiment, both KA and E5 represent hydrogen.

It is best if KA denotes benzyl. It is also better if in this case K5 represents hydrogen.

Better definitions for Kb and K7

It is better if Kb and K7 independently denote hydrogen, alkyl, haloalkyl, halogen or an alkoxy group.

More preferably, Kb and K7 are independently hydrogen, alkyl or haloalkyl, such as trifluoromethyl.

In one embodiment, one of Kb and K7 represents hydrogen and the other represents a group defined in this invention that is not hydrogen.

In another preferred embodiment, both Kb and K7 are the same and as defined herein, most preferably trifluoromethyl.

The positions of Kb and K7 in the phenyl ring are better as follows: 87 c,

M.Sc

Vb

M

- in Z vi

Any asymmetric carbon atom in the compounds proposed in this invention can have (P)-, (5)- or (A,5)-configuration, preferably - (A)- or (5)-configuration. Substitutes of atoms forming a multiple bond, if possible, can be in the cis- (2)- or trans (E)-configuration. Therefore, the compounds proposed in this invention can be in the form of one of the possible isomers or in the form of their mixtures, for example, in the form of mainly pure geometric (cis- or trans-) isomers, diastereoisomers, optical isomers (antipodes), racemates or their mixtures

The best isomers of the compound proposed in this invention can be represented by the following formula: 87 nb te 2

M

- in Z for the better: 87 b te 2

M

- in z va

Any obtained mixtures of isomers using differences in the physical and chemical characteristics of the components can be separated into pure geometric or optical isomers, diastereoisomers, racemates, for example, using chromatography and/or fractional crystallization.

Any obtained racemates of final products or intermediates can be separated into optical antipodes by known techniques, for example, by separating the salts of their diastereoisomers obtained with an optically active acid or base, isolation of an optically active acidic or basic compound.

In particular, the imidazolyl moiety can be used in this way to resolve the compounds of the present invention into optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di- O,0'-p-toluene tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral sorbent.

In conclusion, we note that the compounds proposed in this invention are obtained in free form, in the form of a salt or in the form of their prodrug derivatives.

If the compounds proposed in this invention contain a basic group, then the compounds can be converted into addition salts with acids, in particular, into addition salts with acids on the imidazolyl fragment of the structure, preferably into their pharmaceutically acceptable salts. They are formed with inorganic acids or with organic acids. Suitable inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, and hydrohalic acid.

Suitable organic acids include, but are not limited to, carboxylic acids such as (C1-

Ca)alkanecarboxylic acids, which are, for example, unsubstituted or substituted by halogen, for example, acetic acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example, aspartic or glutamic acid, organic sulfonic acids, such as (C1i-C4)alkylsulfonic acids, for example, methanesulfonic acid; or arylsulfonic acids which are unsubstituted or substituted, for example, by halogen. Salts formed with hydrochloric acid, methanesulfonic acid, and maleic acid are preferred.

If the compounds of this invention contain an acidic group, the compounds can be converted into salts with pharmaceutically acceptable bases. Such salts include alkali metal salts such as sodium, lithium and potassium salts; salts of alkaline earth metals, such as calcium and magnesium salts; ammonium salts and salts with organic bases, for example, salts with trimethylamine, salts with diethylamine, salts with tris(hydroxymethyl)methylamine, salts with dicyclohexylamine and salts with methyl-O-glucamine; salts with amino acids such as arginine, lysine, etc. Salts can be obtained by conventional methods, preferably in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solution in the latter salt can be precipitated with simple ethers, for example, diethyl ether. The resulting salts can be converted into free compounds by treatment with acids. These and other salts can also be used to purify the resulting compounds.

If the same molecule contains both a basic group and an acidic group, then the compounds proposed in this invention can also form internal salts.

The present invention also relates to prodrugs of the compounds of the present invention that are readily converted to the compounds of the present invention. Prodrugs are an active or inactive compound that, after administration of prodrugs to the subject, chemically changes as a result of physiological effects of the drug, such as hydrolysis, metabolism, etc., with transformation into the compound proposed in this invention. Methods of preparation and use of prodrugs and their applicability are well known to specialists in this field of technology. By nature, prodrugs can be divided into two non-exclusive categories, prodrugs-biological precursors and prodrugs-carriers. See the publication of Te Rgasiise oi Medisipa! Spetivigh, Sleep. 31-32 (Ed. UUegtiiy,

Asadetis Rgez5, Zap Oiedo, Saiiii., 2001). Usually, prodrugs-biological precursors are compounds that are inactive or have low activity compared to the active drug compound, and contain one or more protective groups, and are converted into the active form due to metabolism or solvolysis. | the active form of the drug and any metabolic product released must have acceptably low toxicity.

The usual formation of an active medicinal compound involves a metabolic process or reaction belonging to one of the following types: 1. Oxidation reactions, such as oxidation of the oxy group, carbonyl and carboxy group, hydroxylation of aliphatic carbon atoms, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of double carbon-carbon bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative M-dealkylation, oxidative O- and 5-dealkylation, oxidative deamination, as well as other oxidation reactions. 2. Reduction reactions, such as reduction of carbonyl groups, reduction of hydroxy groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

C. Reactions without a change in the oxidation state, such as hydrolysis of simple and complex esters, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, formation of new bonds through dehydration reactions, hydrolytic dehalogenation, removal of a halogen molecule, and other such reactions .

Procarriers are drug compounds that contain a carrier moiety, for example, that improves absorption or localizes release at the site(s) of action. For such a prodrug carrier, it is preferable that the linkage between the drug moiety and the carrier moiety be covalent, the prodrugs are inactive or less active than the drug compound, and any carrier moiety released is reasonably non-toxic. In the case of prodrugs for which the carrier fragment is designed to enhance absorption, the release of the carrier fragment should usually be rapid. In other cases, it is better to use a fragment that provides a slow release, for example, some polymers or other fragments, such as cyclodextrins. See, Spepd ei aiI.,, 0520040077595, application Mo. 10/656838, which is incorporated herein by reference. Such prodrug carriers are often preferred for orally administered drugs. Prodrug carriers, for example, can be used to improve one or more of the following characteristics: increased lipophilicity, increased duration of pharmacological action, improved site-of-effect specificity, reduced toxicity and adverse reactions, and/or improved drug characteristics (e.g., stability, solubility in water, suppression of undesirable organoleptic or physicochemical characteristics). For example, lipophilicity can be increased by esterifying hydroxy groups with lipophilic carboxylic acids or carboxyl groups with alcohols, such as aliphatic alcohols. UMegtyshy, Te Rgasiise oi Meaisipa!

Spetivigu, SA. 31-32, Ed. UMegtish, Asadetis Rgezv, Zap Oyedo, Saiii., 2001.

Typical prodrugs are, for example, esters of carboxylic acids with 5-acyl- and O-acyl derivatives of thiols, alcohols and phenols, where acyl has the meaning defined in this invention. Pharmaceutically acceptable esters are preferred, which are converted into the original carboxylic acid by hydrolysis under physiological conditions, for example, below. alkyl esters, cycloalkyl esters, lower. alkenyl esters, benzyl esters, mono- or disubstituted lower. alkyl esters, such as o-(amino, mono- or di-lower. alkylamino-, carboxy-, lower. alkoxycarbonyl) y-lower. alkyl esters, o-(lower alkanoyloxy-, lower alkoxycarbonyl- or di-lower alkylaminocarbonyl)-lower alkyl esters, such as pivaloyloxymethyl ether, etc., which are commonly used in this field of technology. In addition, amines are masked by the formation of arylcarbonyloxymethyl derivatives, which are quickly cleaved by esterases with the release of free drug and formaldehyde (Vypadaaga, U. Med. Spet. 2503 (1989)). In addition, medicinal products containing an acidic MH group, such as imidazole, imidine, indole, etc., are masked with the help of M-acyloxymethyl groups (Vipiddaaga, YuOevidpoi Rgodishov, Eizemiegh (1985)). Hydroxy groups are masked by the formation of complex and simple esters. EP 039051 (5iIoap apa GishShe) discloses prodrugs that are Mannich bases of hydroxamic acids, their preparation and use.

Due to the close relationship between these compounds, compounds in the form of their salts and prodrugs, any reference to the compounds proposed in this invention should be understood as a reference to the corresponding prodrugs of the compounds proposed in this invention, if this is appropriate and appropriate.

In addition, the compounds proposed in this invention, including their salts, can also be obtained in the form of their hydrates or with the inclusion of other solvents used for their crystallization.

The compounds proposed in this invention have valuable pharmacological characteristics. The compounds proposed in this invention are used as cholesteryl ester carrier protein (CEP) inhibitors. BPHE is a glycopeptide with a molecular weight of 74 kDa, it is produced in the liver and is a key agent that facilitates the transfer of lipids between the various lipoproteins contained in the plasma. The main function of BPHE is the redistribution of cholesteryl esters (XE) and triglycerides between lipoproteins. See publication Az5tapp, about ei ai., "NOG. spoieziegoi apa rgoiesiime Tasiog5 ip aipegossiegoviv,"

Sigsshayop, 109: 1118-1114 (2004). Since most of the triglycerides in the plasma come from

LDL (very low-density lipoproteins) and the majority of XE will be formed in HDL particles (high-density lipoproteins) by a reaction catalyzed by lecithin:cholesterol acyltransferase, the activity of BPHE leads to the total transfer of the mass of triglycerides from LDL to LDL (low-density lipoproteins), LDL and HDL, and the total transfer of XE mass from the LVL to the LVL and LVL. Thus, BPHE potentially lowers the content

NOG-X increases the content of LDL-cholesterol (LDL-C) and reduces the size of HDL and LDL-C particles, and inhibition of BPHE may be a therapeutic agent for increasing the content of HDL-cholesterol (LDL-X), which affects the lipoprotein profile and reduces the risk of cardiovascular - vascular diseases. Accordingly, the compounds provided in the present invention as inhibitors of BPHE can be used to delay the progression and/or treat a disorder or disease that is mediated by BPHE or responsive to inhibition of BIPHE. Disorders, conditions and diseases that can be treated with the compounds of the present invention include, but are not limited to, hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular vascular disorder, coronary heart disease, coronary artery disease, coronary artery disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, heart attack such as myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, restenosis after angioplasty, hypertension, congestive heart failure , diabetes, such as type II diabetes, vascular complications in diabetes, obesity, infection with schistosomes or the development of their eggs, endotoxicosis, etc.

In addition, the present invention relates to: - the compound proposed in the present invention, described above in the present invention, intended for use as a medicinal product; - the use of a compound proposed in this invention, described above in this invention, for the preparation of a pharmaceutical composition intended for delaying the progression and/or treatment of a disorder or disease mediated by means of BPHE or responsive to inhibition of BPHE. - the use of the compound proposed in this invention, described above in this invention, for the preparation of a pharmaceutical composition intended for delaying the progression and/or treatment of a disorder or disease selected from the group including hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary heart disease, coronary artery disease, coronary artery disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, heart attack such as myocardial infarction, stroke, peripheral vascular disease , reperfusion injury, restenosis after angioplasty, hypertension, congestive heart failure, diabetes such as type II diabetes, vascular complications in diabetes, obesity and endotoxicosis, etc.

Compounds of formula (I) can be prepared by methods described in the following sections.

Typically, compounds of formula (I) can be prepared according to the following general procedures and schemes. In all of these schemes, the groups K1, K2, K3, K4, K5, Kb, K7 and K8 have the meanings given in the present invention, unless otherwise indicated. 1. General procedure A: use of piperidone A1 9) (AT) va ii 2 3 1.1. AI path, when KA and K5 denote hydrogen:

ome N Y food a OT B Ot

Oh no N

ІІ І Ш80--- Іі і, І і. A ai M h-- M ka sov Sol ke a-: SSO KV, pom KOMU, or a SSO RI then NOMH then KOKV yabo v-klry KV SVO, a-izho Vos u atk VeMH where K8 is defined in this invention, for example, 1I-Vy, i-Pg, Vp, 2,2,2-trichloroethyl, allyl, Mx denotes, for example, MoHg, Ma, MoSi, Gi, as well as a combination with ps".

At stage B) you can use standard conditions for 1,4-reduction, such as the use of Mo, alcohol; SesSiz, Mavna or catalytic hydrogenation. 1.2. The AIA path, when KA and K5 denote hydrogen:

OhMe Yi 7

H no 4 o a SHHI B c

A pt n y nyn r be

Kt n u va

So ka sorV a SI aa. then sdvidnykh reasent with aba a-2: svo; kat podridnykh reagent then KO B or re; At B - By, a-gayo Bos.O; then parid reassnt ; where KZ is defined in this invention, for example, I-Vy, i-Pt, Vp, 2,2,2-trichloroethyl, allyl. Suitable hydride reagents that can be used are those such as Mavn(OdAs)z, MavnzoM, Mavnae or I iVnNa,

K(OIRizVN, MaVIsn(SnNz)SeN5i|zN or MadIN(OSNoSNgOsnNZ)".

At stage B) standard conditions for 1,4-addition are used, such as the use of K2MOX (X-halogen), Sy! or K22211, catalysts containing Cy. 1.3. The AIIII path, when K5 represents hydrogen:

Ome y y

IN; and notes, including

C in XA; ram no I shchi inn with ok kA

Se stv vam vas sova sord-ne a: SSO vabulopm DOM, ba in-2: SSO RN enm KOMkh loti KONV, or a-Z: priya Ya x SVO, a-ovbo VoboO;svovm K2MH where K8 is defined in this invention, for example, И-Вы, иИ-Ри, Вп, 2,2,2-trichloroethyl, allyl, Мх means, for example, МоВг, Ма, МОСИ, Ги, and also the combination with 7псСи".

At stage B) standard conditions for 1,4-addition are used, such as the use of KAMAX (X:- halogen), Sy! or K4221, catalysts containing Cy. 1.4. The AIM path, when K5 denotes hydrogen: ome o Her i a m t v) V y she dy i me TO y vam A M ng y IZ zhd so;-ne So; НВ а: ССО КВ; pot MAMU, or, ag SSO Rirletn VAMkhnotzy KOM or aez:lvy KV - Vy, ahdabo NosOglopy KAMx where K8 is defined in this invention, for example, I-Vy, iI-RI, Vp, 2,2,2-trichloroethyl, allyl, Mx denotes, for example, MoVg, Ma, MoCI, Gi, as well as a combination with ps."

At stage B) standard conditions for 1,4-addition are used, such as the use of K2MaX (X:- halogen), Sy! or K2221, catalysts containing Cy. 1.5. The AM path, when KA denotes hydrogen:

oMe Her oh oh I with how vvs you "m M. I tav

Dream ve iz a tiasO v, t via Na SO od ebonauktd dreams 0 VZ SO Web hvprikhlyaa DREAM a, SSO NI oarchdikih realevt. lm KOVA, or shcha i x vk God How: Wu a-or Vorsosu lyut pdridny reznvyanu 8 where K8 is defined in this invention. Suitable hydride reagents that can be used

There are such as Mavn(OAs)i, MavVvVNz SM, MaVNa. or IVNa, K(OYIROzvnN, Mavrisn(СН3)С»Нь|Н or

MmaiINYUSnN»eSNngosnN Z)».

At stage 5) standard conditions for alkylation are used, such as the use of a strong base and halide; for example, DAV, KE5X or I NMO5 or KNMO5, K5X (X "- halogen or OM5, OT5, OT).

At stage c) standard conditions for 1,4-addition are used, such as the use of K2MyaaX (X-halogen), Sy! or K22211, catalysts containing Cy.

Short-circuit conversion can be carried out by standard methods of operations with functional groups, which are well known in the art or specifically described in the present invention. 1.6. AMI path, when KA denotes hydrogen:

A. in I B She ge Vot a Vb uiy I shi shi ne she ne

And YAN yur "to evscheesh Mt Kiy,

Zm x Moska Monet Mm'osyag sorp pa 3 3 ah SSO VV; then ZM or

BBC RIgpovm DaMmuloti KOVVaba a-Z:Pri KO x Vu, a-haba Vas uolatm. PeMX where K8 and KZ are defined in this invention; Mx denotes, for example, MoVg, Ma!, МОСсИ, Ги, as well as a combination with 2пСи".

At stage B), the short-circuit conversion can be carried out according to standard methods of operations with functional groups, which are well known in this field of technology or are specifically described in this invention.

At stage c) standard conditions for enamine alkylation are used, such as the use of K5X (X - halogen or OM5, OT5, OT); heating; or I" and using a base to give vinyl iodide followed by cross-coupling, such as the Suzuki, Stilley, Negishi, or Kumada reactions described, for example, in standard guidelines.

At stage a) you can use standard conditions for 1,4-addition, such as the use of Ma, alcohol; SesSiz, Mavna or catalytic hydrogenation. 1.7. The AMI Way!:

ОМе: а а о : и ; her

Z a g V Nv i. g byy More

Fit the shaft and key to groove 3

I x Sova kapoiksci Seh va SO vbo, chaerikped, SV shizh gu y a so Kvlotm KAM: or ves RA; Vey Kyamhusyam KOKO, voy a-ZPry VV EV, a-lvboVosyu:netm NAM where K8 and KZ are defined in this invention; Mx denotes, for example, MoVg, Ma!, МОСсИ, Ги, as well as a combination with 2пСи".

At stage 5) standard conditions for alkylation are used, such as the use of a strong base and halide; for example, DAV, KAH or I HMO5 or KHMO5, KAH (X "- halogen or OM5, OT5, OT).

At stage c) standard conditions for 1,4-reduction are used, such as the use of K5MaX (X:- halogen), Sy! or K5221, catalysts containing Cy.

At stage a), the short-circuit conversion can be carried out according to standard methods of operations with functional groups, which are well known in this field of technology or are specifically described in this invention.

Using each of the above-described АЙ - АМИЯ pathways, piperidone AT can be converted into a compound of formula (I) using one of the AMIЯ, АХХ, or АХ pathways described below. 1.8. AMI path:

vv ve 7 7

B in5 in MN lsh m' va M ag

All the best to you

VZ VZ

At stage a), standard methods of reductive amination are used, such as application

AgSNaMH", a hydride reagent (for example, Mavn(OAs)z, mMavnzoM, Mavne, IIVNae, VN»z, picolinborane, borane-pyridine complex; or Ti(OiRg)4; then a hydride reagent, such as Mavn(OAs)z, MaVvNz SM,

Mavnia, HIVna, borane, picolinborane, borane-pyridine complex, HyAlNe, 9-BBN, AlIripe borange, I iV(5-Vy)zH, and Iv(5ia)zH; or imine formation with or without acid catalysis followed by reduction with hydride reagents (see above).

At stage B) group K! introduced by conventional amino functional group operations such as alkylation, carbamate formation, urea formation, 5EM1 substitution, aryl amination, and reductive amination.

The KZ group can be modified at a suitable stage to obtain the required value specified in the claims, which is a standard protecting group of nitrogen atoms, as known in the art or described in the present invention. 1.9. AIH way:

Vb 87 o MN, nm" s v vam vi Mov vam tva, Fi

Az VZ Az vim vo

VZ

At stage a) standard methods of introduction of the primary amino group are used, such as: - the equivalent of МНз (for example, МНз/ЕУН, МНС, МНАОНИ, hydride reagent (for example, Мавн(оОдс)з,

MavVnNz CM or a combination of Ti(OIRg)4 with hydride reagents, such as Mavna - І) simultaneous or sequential treatment with the formation of imine using VpMn» with a hydride reagent (see above), ii) catalytic hydrogenation - treatment using VpMnH» according to conditions of catalytic hydrogenation - І) simultaneous or sequential treatment with the formation of an imine using РМВМН», a hydride reagent (see above), ии) SAM or DDH (oxidative debenzylation) or TFC - І) simultaneous or sequential treatment with the formation of an imine using Рп2ОНМН .” (benzhydrylamine), a hydride reagent (see above), i) removal of the protecting group using TFC/Eiz5in or catalytic hydrogenation - І) VOMN» (oxime formation), ii) Ma or ВНз or catalytic hydrogenation (for example, Ca-Mi, Ra-S, RI-S)

And reduction of oximay, where KE denotes, for example, benzyl, p-methoxybenzyl or allyl. - І) hydride reagent and reduction in alcohol, iii) Mitsunobu reaction using PP3, DEAD, Mz anion or mesylation using M5Cl and a base, then treatment with Mz anion or bromination using such reagents as МВ5/PPz, РВгз/ПРНз, СВга /PPyz, then treatment with Mz anion or with PBiz/PPyz, then treatment with M anion, her) PAZ or catalytic hydrogenation |reduction of azide|, where K denotes, for example, ethyl or phenyl.

In stages B) and c), the K1 group or the benzyl ring, respectively, is introduced by means of the usual operations with functional groups for the amino group, such as alkylation, carbamate formation, urea formation, ZKMI substitution, aryl amination and reductive amination for stage b) and preferably - alkylation and reductive amination for stage c).

The KZ group can be modified at an appropriate stage to obtain the required value specified in the claims, which is a standard nitrogen protecting group as known in the art or described herein.

AH path:

Ivye) (6) he still gave you Phi

Z Z Z da M to

Z where I o represents a leaving group such as mesylate, tosylate, triflate or bromide.

At stage a), standard methods of reducing the carbonyl group are used, such as the use of a hydride reagent, for example, MaVnNa or K-5eiIesipavye.

At stage p), standard techniques are used to convert the hydroxy group into a leaving group (I o; for example, mesylate, tosylate, or bromide). Techniques include the use of systems

M5Si/base or T5Si/base, or 5OSI", or MV5/RRPz, or SVg"/RRiz, or TRO under conditions well known in this field of technology.

At stage c), amino groups are introduced according to standard substitution reactions, for example, by using a secondary amine and a strong base, such as Man, KoiVy, and NMO5.

The KZ group can be modified at a suitable stage to obtain the required value specified in the claims, which is a standard protecting group of nitrogen atoms, as known in the art or described in the present invention. 2. General procedure B: using a Ritter-type reaction

A detailed description of the preparation of benzyl-substituted piperidine B1 is given in the publication Vioogdapis 85 Meaisai!

Spetivigh I eyege, Moi. b, Mo. 24, pp. 3029-3034, 1996. The methods described therein can be used similarly to the methods for obtaining substituted piperidines.

N

M

0 »

MH,

This piperidine can also be further reacted to give a compound of formula (I) by alkylation and nitrogen-protecting techniques as described above in Procedure A. 3. General Procedure C: Using the Dieckmann Reaction

Compounds of formula (I) can be obtained according to the synthesis scheme described in the publication doigpa! oh Meaisipai

Spitivigu, 2001, Moi. 44, Mo. 6, pp. 972-987, directly or similarly. 4. General procedure 0: using the Mannich reaction

Compounds of formula (I) can be obtained by the intramolecular Mannich reaction directly or similarly, and the obtained piperidone can be subjected to transformations according to the methods described above, for example, for the AMI, AIX or AX pathways. An illustrative example of this reaction is described in the publication Negegosusie5, 2002, Moi. 57, Mo. 10, 1807-1830. The asymmetric variant is described in the publication Ogdapis Geneg5, 2001, Moi. 3, Mo. 20, 3169-3171. 5. General procedure E: use of Michael's aza-reaction

Compounds of formula (I) can be obtained by the intramolecular Michael aza-reaction directly or analogously and the obtained piperidone can be subjected to transformations according to the methods described above, for example, for the AMIII, AIX or AX pathways. An illustrative example of this reaction is described in the publication Uoigpai! Oh, Ogdapis

Spetivigu, 2005, Moi. 70, pp. 169-174. 6. General procedure E: use of Michael's double aza-reaction for preparation from divinyl ketones

Compounds of formula (I) can be obtained by the intramolecular double aza-reaction of Michael directly or analogously, and the obtained piperidone can be subjected to transformations according to the methods described above, for example, for the pathways of AMIII, АЙХ or АХ. An illustrative example of this reaction is described in the publication

Washgpai oi Ogdapis Spetivighu, 1992, Moi. 57, pp. 5809-5810. 7. General procedure c: use of direct lithiation reaction

Compounds of formula (I) can be obtained by the direct lithiation reaction of piperidine directly or analogously, and the obtained piperidone can be subjected to transformations according to the methods described above, for example, for the AMIII, АЙХ or АХ pathways. An illustrative example of this reaction is described in the publication Woigpa! Oh, Ogdapis

Spitivigu, 1990, Moi. 55, pp. 2578-2580. The protected piperidone thus obtained can be readily converted to the corresponding piperidone by techniques well known in the art. 8. General procedure H: use of the Diels-Alder reaction

Compounds of formula (I) can be obtained according to the synthesis schemes described in the publication of Admapsei Zupipevi5 8

Saiya|uviv, 2006, Moi. 348, 2443-2448 or call us at Ategisap Spetis! Zosieiu, 2007, ABAR (M.O. UMShy ei ai. "KBedshiayop oi Oppodopa! ERipsiop5 ip a Otsa!/ Saiauzi Zuziet...") directly or similarly and subject the obtained piperidone to transformations according to the methods described above, for example, for the ways

AMII, AIH or AH. 9. General procedure !: production from substituted pyrone

Compounds of formula (I) can be obtained in a similar way from a substituted pyrone and the resulting pyridone subjected to transformations according to the methods described above, for example, for the AMI, AIX or AX pathways.

An illustrative example of obtaining piperidinol from pyrone is described in the publication doigpai! oh Ogdapis Spetivigh,

1950, My. 15, Mo. 2, pp. 337-342. The thus obtained piperidinol can be converted into the corresponding piperidone by methods well known in the art.

The obtained racemates and mixtures of diastereoisomers can be separated into pure isomers or racemates by known methods using differences in the physicochemical characteristics of the components, for example, by means of fractional crystallization or chiral chromatography or by HPLC using chiral stationary phases. The obtained racemates can be further separated into optical antipodes according to known methods, for example, by recrystallization from an optically pure solvent, chromatography using a chiral sorbent, with the help of suitable microorganisms, by cleavage with specific immobilized enzymes, by the formation of inclusion compounds, for example, using chiral crowns -esters with which only one enantiomer will form a complex, or by conversion into salts of diastereoisomers, for example, by reaction of the racemate of the main final compound with an optically active acid, such as a carboxylic acid, for example, tartaric or malic acid, or with a sulfonic acid, for example, camphorsulfonic acid, and with the separation of the mixture of diastereoisomers obtained in this way, for example, on the basis of different solubilities, into diastereoisomers, from which the necessary enantiomer can be isolated by treatment with suitable reagents. It is better to isolate the most active enantiomer.

The starting compounds and intermediates that are converted into the compounds of this invention by the methods described in this invention contain functional groups such as amino groups, thio groups, carboxy groups and hydroxy groups, which are optionally protected by conventional protecting groups, which are typical of preparative organic chemistry. Protected amino groups, thio groups, carboxy groups, and hydroxy groups are those that, under mild conditions, can be converted into free amino groups, thio groups, carboxy groups, and hydroxy groups without destroying the molecular structure and causing other undesirable side reactions.

The purpose of introducing protective groups is to protect functional groups from unwanted reactions with reactive components under the conditions used for chemical transformations.

The necessity and choice of protective groups for a specific reaction are known to specialists in this field of technology and depend on the nature of the functional group being protected (hydroxy group, amino group, etc.), the structure and stability of the molecule, of which the substituent is a part, and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in the publications of MsOtie, "Rgoyesiime Sgoyr5 ip Ogdapis Spetivigu", Riepyt Rgez5, Hopdop, MM (1973); and Ogeepe apa uuciiv, "Rgoiesiime Stgoyrz ip Ogdapis Zupipeviv", dopp U/ieu apa 5opv, Ips., MM (1999).

The above reactions are carried out according to standard methods in the presence or absence of a diluent, preferably such as is inert with respect to the reagents and their solvents, condensing catalysts or other reagents, in an inert atmosphere, at low temperature, room temperature or elevated temperature, preferably at the boiling point of the solvents used, or a temperature close to it, at atmospheric or higher than atmospheric pressure. The best solvents, catalysts and reaction conditions are indicated in the accompanying illustrative examples.

The present invention additionally includes any variant of the described methods, in which the intermediate product obtained at any stage is used as a starting substance, and subsequent stages are carried out, or in which the starting substance is formed as a result of the reaction, or in which reaction components are used in the form of salts or optically pure antipodes.

The compounds of the present invention and intermediates can also be converted into one another by techniques that are well known.

Another object of the present invention is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared for specific routes of administration, such as oral administration, parenteral administration and rectal administration, and the like. In addition, the pharmaceutical compositions provided in the present invention can be prepared in solid form, including capsules, tablets, pills, granules, powders or suppositories, or in liquid form, including solutions, suspensions or emulsions. Pharmaceutical compositions may be subjected to conventional pharmaceutical processing such as sterilization and/or may contain conventional inert diluents, lubricating agents or buffering agents, and excipients such as preservatives, stabilizers, wetting agents, emulsifiers and buffering agents and etc.

It is better if the pharmaceutical compositions are tablets or capsules made of gelatin, including the active ingredient, as well as a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

B) lubricating agents, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminosilicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary a) leavening agents, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, dyes, flavors and sweeteners.

Film coating or enteric coating can be applied to tablets by techniques known in the art.

Compositions suitable for oral administration include an effective amount of a compound of the present invention in the form of tablets, cakes, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, or elixirs. Compositions intended for oral administration are prepared by any technique known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to to obtain pharmaceutically attractive and pleasant-tasting preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable inert excipients which are suitable for the manufacture of tablets. These inert fillers are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;

granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia gum; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets do not contain a coating, or they are coated according to known methods to delay disintegration and absorption in the gastrointestinal tract, which ensures a continuous effect for a longer period of time. For example, a retarding agent such as glyceryl monostearate or glyceryl distearate can be used.

Oral preparations may also be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.

Compositions for injections are preferably isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from emulsions or suspensions of fats. These compositions can be sterilized and/or excipients such as preservatives, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffering agents can be added to them. In addition, they may also contain other therapeutically valuable substances. These compositions are prepared by conventional mixing, granulation or coating techniques and contain approximately 0.1-7595, preferably approximately 1-50905, of the active ingredient.

Compositions suitable for transdermal administration include an effective amount of a compound of the present invention with a carrier. Preferred carriers include pharmacologically acceptable absorbable solvents that facilitate penetration through the recipient's skin. For example, transdermal delivery devices are a dressing that includes a protective layer, a reservoir containing the compound optionally with carriers, optionally a barrier that regulates the delivery of the compound through the recipient's skin at a predetermined rate over an extended period of time, and means of fixing the device on the skin.

Compositions suitable for topical administration, e.g. to the skin or eyes, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable compositions, e.g. for aerosol delivery, etc. Such topical devices are particularly suitable for exposure to the skin, e.g. for the treatment of skin cancer, e.g. for use as prophylactics in sunscreens, lotions, aerosol preparations, etc. Therefore, they are particularly suitable for use in topical agents, including cosmetics, well known in the art. They may contain solubilizers, stabilizers, tonicity-regulating agents, buffering agents, and preservatives.

The present invention also relates to anhydrous pharmaceutical compositions and dosage forms that include the compounds proposed in the present invention as active ingredients, since water can facilitate the decomposition of some compounds. For example, the addition of water (eg, 595) is widely used in pharmaceuticals as a means of improving long-term storage and determining characteristics such as shelf life and composition stability over time. See, for example,

Uepe T. Sageiepzep, Abomination of the Good: Riipsiriez 8 Rgasiise, 24. Ea., Magse! Oekkeg, MM, MM, 1995, pp. 379-800.

In fact, water and heat accelerate the decomposition of some compounds. At the same time, the influence of water on the composition can be more significant, since water and/or humidity usually affect the manufacture, circulation, packaging, transportation and application of drugs.

Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients under low-moisture conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if exposure to moisture is anticipated during manufacture, packaging and/or storage.

The anhydrous pharmaceutical composition should be prepared and stored so that it remains anhydrous.

Accordingly, anhydrous compositions are best packaged in materials known to be water resistant so that they can be included in suitable formulation kits. Examples of suitable packaging materials include, but are not limited to, hermetically sealed foil, plastics, single-dose containers (eg, vials), blister packs, and tape packs.

The present invention also relates to pharmaceutical compositions and dosage forms that include one or more agents that regulate the rate at which the compound proposed in the present invention as an active ingredient will be degraded. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH-adjusting buffering agents, and salt buffering agents, and the like.

The present invention also relates to the combination of a compound of the formula (I), (I A) or (I B), respectively, or its pharmaceutically acceptable salt with another active substance.

The combination can be prepared, for example, with the following active substances selected from the group including: (i) HMO-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, (i) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, (im) a calcium channel blocker or a pharmaceutically acceptable salt thereof, (M) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, (m) an aldosterone antagonist or a pharmaceutically acceptable salt thereof, (mi) dual angiotensin-converting enzyme/neutral endopeptidase inhibitor (ACE/NEP) or its pharmaceutically acceptable salt, (my) endothelin antagonist or its pharmaceutically acceptable salt, (their) renin inhibitor or its pharmaceutically acceptable salt, (x) diuretic or its pharmaceutically acceptable salt, ( xi) mimetic ApoA-!Y, and (xii) DHAT (diacylglycerol acyltransferase) inhibitor.

Antagonist of angiotensin receptor I or a pharmaceutically acceptable salt thereof means active ingredients that bind to the ATi subtype of the angiotensin II receptor, but do not lead to activation of the receptor. As a result of inhibition of the AT!| receptor these antagonists can, for example, be used as hypotensive agents or for the treatment of congestive heart failure.

The class of antagonists of the ATi receptor includes compounds having different structures, especially non-peptide compounds are preferred. For example, it is possible to note compounds that are selected from the group including valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tazosartan, telmisartan, a compound designated as E-1477 of the following formula

M and r» |!

I

M M

Soon, a compound designated as 50-52458 of the following formula

IN

Yi I

M

- pra ra sh -

MU mn x /

MM and the compound designated as 20-8731 of the following formula z, o e

MU sMmn x /

MM, or in each case a pharmaceutically acceptable salt thereof.

The best AT receptor antagonists; are commercially available, the most preferred being valsartan or a pharmaceutically acceptable salt thereof.

NMOe-Co-A reductase inhibitors (also called p-hydroxy-D-methylglutaryl-coenzyme A reductase inhibitors) are active agents that can be used to lower blood lipids, including cholesterol.

The class of NMO-Co-A reductase inhibitors includes compounds with different structures. For example, compounds selected from the group consisting of atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin or in each case a pharmaceutically acceptable salt thereof.

The preferred NMO-Co-A reductase inhibitors are those available commercially, most preferably fluvastatin and pitavastatin, or in each case a pharmaceutically acceptable salt thereof.

Stopping the enzymatic conversion of angiotensin in angiotensin II by so-called inhibitors

ACE inhibitors (also called angiotensin-converting enzyme inhibitors) are an effective option for blood pressure regulation and thereby provide a therapeutic approach to treating congestive heart failure.

The class of ACE inhibitors includes compounds with different structures. For example, we can note the compounds

which are selected from the group consisting of alazepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or in each case a pharmaceutically acceptable salt thereof.

The best ACE inhibitors are such products that are available for sale, the best ones are benazepril and enalapril.

The class of CCBs (calcium channel blockers) mainly includes dihydropyridines (DHPs) and non-DHPs such as

Diltiazem- and verapamil-type BCC.

The BCC used in said combination is preferably a representative of the DHP group selected from the group consisting of amlodipine, felodipine, riozidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and preferably a non-DHP member selected from the group consisting of flunarizine, prenilamine, diltiazem, fendiline, halopamil, mibefradil, anipamil, thiapamil and verapamil, and in each case a pharmaceutically acceptable salt thereof. All these BKK are used as medicines, for example, as hypotensive, antianginal or antiarrhythmic medicines.

Preferred BCCs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil, or, for example, depending on the particular BCC, a pharmaceutically acceptable salt thereof.

Amlodipine or its pharmaceutically acceptable salt is especially preferable as a DHP, its besylate is better.

A particularly preferred representative of the non-DHP group is verapamil or its pharmaceutically acceptable salt, preferably its hydrochloride.

Aldosterone synthase inhibitor is an enzyme that converts corticosterone to aldosterone by hydroxylating corticosterone to form 18-OH-corticosterone and converting 18-OH-corticosterone to aldosterone. The class of aldosterone synthase inhibitors known to be used to treat hypertension and primary aldosteronism includes steroidal and nonsteroidal aldosterone synthase inhibitors, the latter being the most preferred.

Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors approved for use by health authorities.

The class of aldosterone synthase inhibitors includes compounds with different structures. For example, mention may be made of compounds selected from the group consisting of the non-steroidal aromatase inhibitors anastrozole, fadrozole (including its (w)-enantiomer), and the steroidal aromatase inhibitor exemestane, or, in each case where applicable, a pharmaceutically acceptable salt thereof .

The best non-steroidal aldosterone synthase inhibitor is the (w)-enantiomer of fadrozole hydrochloride (patents O5 4617307 and 4889861) of the formula

M - 6 years

There is still

NSI and

The best steroid antagonist of aldosterone is eplerenone of formula c) and (c)

AD o SHI tone, o or spironolactone.

A preferred dual angiotensin-converting enzyme/neutral endopeptidase (ACE/NEG) inhibitor is, for example, omapatrilat (see EP 629627), fasidotril or fasidotril or, if applicable, a pharmaceutically acceptable salt thereof.

The best endothelin antagonist is, for example, bosentan (see EP 526708 A), in addition, tezosentan (see

UMO 96/19459) or in each case its pharmaceutically acceptable salt.

A renin inhibitor is, for example, a non-peptide renin inhibitor, such as a compound of formula sn. not sn o z Z on n.s sn, n

N.M, M ky mn, (c) (c) o

Nose about us sn, which has the chemical name 2(5),4(5),5(5),7(5)-M-(33-amino-2,2-dimethyl-3-oxopropyl)-2,7 -di(1-methylethyl)-4-hydroxy-5-amino-8-(14-methoxy-3-(3-methoxypropoxy)phenyl|-octanamide. This representative is specially disclosed in EP 678503 A. Especially preferable is its hemi- fumarate

A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide and chlorthalidone. Hydrochlorothiazide is most preferred.

AroA mimetic there is, for example, the OAE peptide, better - formulas O-M/-PE-K-A-E-U-0-K-M-A-E-K-E-K-E-A-E.

A DHAT inhibitor is, for example, one or more of the compounds described in UMO2005072740 and the previous application 0.5. Mo. 60/787859.

Preferably, the combined therapeutically effective amounts of the active agents included in the combination proposed in the present invention can be administered simultaneously or sequentially in any order, individually or in a fixed combination.

The structure of active agents described by generic or trade names is given in the latest edition of the standard reference book "pe Megsk Ipaeh" or in databases, for example, IM5 and eSusie (for example, IM5 Umopa Rybiysayop5). Their respective contents are incorporated herein by reference.

Any person skilled in the art is fully capable of identifying the active agents and, based on these references, is also capable of obtaining and investigating pharmaceutical indications and characteristics using standard models of both ip miigo and ip mimo.

In addition, the combinations described above can be administered to a subject by simultaneous, separate or sequential administration (application). Simultaneous administration (application) can be carried out in the form of one fixed combination of two or more active ingredients or by simultaneous administration of two, three or more compounds that are prepared in the form of separate preparations.

Sequential administration (application) preferably means the administration of one (or more) compounds or active ingredients of the combination at one point in time, other compounds or active ingredients at another point in time, i.e. in a chronologically alternating manner, preferably so that the combination exhibits greater efficacy than individual compounds administered independently (preferably synergistic). Separate administration (application) better means the administration of the compounds or active ingredients of the combination independently of each other at different times, better means that the two compounds are administered so that both compounds are not present in the blood in measurable amounts at the same time (no overlap).

Combinations of one, two, or more sequential, separate, and simultaneous administrations are also possible, preferably such that the compound-drug combination exhibits a combined therapeutic effect greater than that obtained when the compound-drug combinations are administered separately at intervals , so much larger that there is no mutual influence on the therapeutic effectiveness, especially the synergistic influence is better.

In addition, this invention relates to: - a pharmaceutical composition or combination proposed in this invention for use as a medicinal product; - the use of a pharmaceutical composition or combination proposed in this invention to delay the progression and/or treat a disorder or disease mediated by

BPHE or responsive to inhibition of BPHE; - the use of a pharmaceutical composition or combination proposed in this invention to delay the progression and/or treat a disorder or disease selected from the group including hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypertension , congestive heart failure, diabetes, such as type II diabetes, vascular complications in diabetes, obesity and endotoxicosis, etc.

The pharmaceutical composition or combination proposed in this invention may contain in a single dose approximately 1-1000 mg of active ingredients for a subject weighing approximately 50-70 kg, preferably approximately 5-500 mg of active ingredients. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof depends on the subject's body weight, age, and individual condition, disorder or disease being treated, and weight. A physician, clinician, or veterinarian with general training should readily determine the effective amount of each of the active ingredients necessary to prevent, treat, or inhibit the progression of a disorder or disease.

The above dose characteristics can be determined by ip migo and ip mmo studies, preferably using mammals such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds proposed in this invention can be used intravenously in the form of solutions, for example, better - aqueous solutions, and intravenously, parenterally, preferably intravenously, for example, in the form of a suspension or an aqueous solution. The dose of ip migo can be in the range of about 103 to 109 M. A therapeutically effective amount of ip mimo, depending on the route of administration, can be in the range of about 0.1-500 mg/kg, preferably about 1-100 mg/kg.

The ability of the compounds of this invention to inhibit BIPHE can be demonstrated using experimental models and studies known in the art. For example, in

EP111569581 describes studies on the activity of BPHE ip myo ip mimo, and its content is incorporated into the present invention by reference. In particular, the studies described below are used. (1) Study of BPHE ip myo:

The kit for the study of BPHE activity (KV-KERAK) was purchased from Koag Viospetisai, Ips. (Mem/ mok, MM, PERSON). 1.2 ng/well of the donor solution, 1 μl of the acceptor solution, and 5 μl of the compound solution diluted in 10095 DMSO in 38 μl of buffer containing 10 mM Ttgi5 (Tris (hydroxymethylaminomethane)), 150 mM Macia, 2 mM EDTC, pH 7.4.

The tablet is then sealed using a Tpetomei sealing device (co5iag 6524) and then mixed on a tablet shaker using a moving device

MISVORIATE MICHEA MRX-96 (IMMAKI) in power mode C for 10 s at room temperature. After incubation for 10 min at 37"C, the reaction is initiated by adding 5 μl of gpCETR solution (Sagaiomazsshag Tagdei, Mem" Mogk, MU, OA) and mixed on a device for shaking tablets for s, then the fluorescence intensity at the time of 0 min is measured using AKMO 5X (Regk

EIte!t, OA) at a disruption wavelength equal to 465 nm and an emission wavelength equal to 535 nm. After incubation for 120 min at 37"С, the intensity of fluorescence is measured again. Inhibition of activity

HISETR compound is calculated according to the following equation: Inhibition 95-51-(Е120-Е0)Д1И120-0)Х100). Where B: measured fluorescence intensity upon addition of the compound at time 0 or 120 min. 7 measured fluorescence intensity without compound at time 0 or 120 min.

ISvo values are determined based on the dose-effect relationship using the Ogidip software.

For the compounds proposed in this invention, or their pharmaceutically acceptable salts, better values

ICs were found to be from about 0.1 nM to about 50 µM. (2) Effects on plasma HDL content in hamsters:

The effect of compounds on the HDL-cholesterol content in hamsters was studied with some changes according to the previously described method (Eig, y). Rpatasoi, 466 (2003) 147-154). Briefly, the technique is as follows: male Syrian hamsters (5I C, Zpi2gooKa, darap) were given a high-cholesterol diet for 2 weeks. Then the animals were given a single dose of the compound suspended in a solution of carboxymethylcellulose. LDL-cholesterol content was determined using a commercially available kit (Uuako Ryge Spetisa!Y, Chucharap) after precipitation of lipoproteins containing apolipoprotein B (apoB) with 1395 polyethylene glycol 6000. (3) Preparation of rgo-apolipoprotein A! human (rho-aroAi)

cDNA (complementary DNA) rgo-aroA! (MSVI assayop pitreg: MM 000039) human cloned from human liver cDNA Opisk-Siopesm (Siopiesp, CA) and inserted into pET28a vector (Momadep, Segtapu) for bacterial expression. The expressed protein in the form of a fusion protein with a 6xNiz-tag at the M-terminus in VI-21 Xuyi (OEZ) (5igayedepe, CA) is purified by chelation with NiTgar (CE Neaipsage, ST). (4) Preparation of donor microemulsion

Microemulsion containing Rgo-aroAi! as a donor particle, prepared according to previous publications (9. Vioi. Spet., 280:14918-22). Glyceryl trioleate (62.5 ng, Zidta, MO), 3-zp-phosphatidylcholine (583 ng, MMako Riga Spetisai! Ipatsvigie5, Zarap) and cholesteryl VOOIRUZ RI. Si" (250 ng, Ipmigodep, SA) is dissolved in 1 ml of chloroform. The solution is evaporated, then the remaining solvent is removed under vacuum for another 1 hour.

The dried mixture of lipids is dissolved in 500 μl of buffer for analysis (50 mM Tris-HCl (gris(hydroxymethylaminomethane) |) (pH 7.4), containing 150 mM Masi and 2 mM EDTC (ethylenediaminetetraacetic acid)) and sonicated at 50" C using a microtip (MISKO5BOM M

OSTKAZOMIS SE. BIZKORTOK, Mizopih, Ragtipdaa!e, MU) at an output power of 006 for 2 min. After sonication, the solution is cooled to 40"C, 100 μg of human rgo-aroA! is added and sonicated at an output power of 004 for 5 min at 40"C. A solution containing a microemulsion

VOBIRU-XE as donor molecules is filtered through a filter made of polyvinylidene fluoride with holes of 0.45 μm and stored at 47C. (5) Study of the activity of BPHE in the plasma of the human ip mygo

Samples of human plasma with EDTC, taken from healthy people, are purchased from the company Mem Ogyd OeyemeIortepi

Vezeagsp Sepieg, Ips. The donor solution is prepared by diluting the donor microemulsion with a buffer for analysis. Human plasma (50 μl), buffer for analysis (35 μl) and the test compound dissolved in dimethylsulfoxide (1 μl) are added to each well of a 96-well flat-bottom plate, half of which is blackened. The reaction is initiated by adding the donor solution (14 μl) to each well. Fluorescence intensity is measured every 30 min at 37"C at an excitation wavelength equal to 485 nm and an emission wavelength equal to 535 nm. The activity of BPHE (fluorescence pulses/min) is determined as a change in fluorescence intensity during 30 to 90 min. Value ICho is obtained using the logistic equation (y-Voyot--(Tor-Voyot)/(1--(x/Svo)"Hill's slope) using the Ogidip software, Megsiop 7.5 53. Compounds of the formula | have an inhibitory activity characterized by with IC values in the range of approximately 0.001 to 100 μM, preferably from 0.01 to 10 μM.

The compounds of the present invention or their pharmaceutically acceptable salts have excellent ability to inhibit BPHE activity in mammals (eg, humans, monkeys, cattle, horses, dogs, cats, rabbits, mice, etc.) and can be used as inhibitors of BPHE activity. In addition, due to the excellent ability of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to inhibit the activity of BIPHE, the compounds of the present invention can be used as pharmaceutical agents effective in the prevention or treatment or retardation of the development of symptoms of diseases , in which BPHE is involved (for example, hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, coronary heart disease, coronary artery disease, coronary artery disease, angina pectoris , ischemia, cardiac ischemia, thrombosis, cardiac infarction such as myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, restenosis after angioplasty, hypertension, congestive heart failure, diabetes such as type I diabetes, vascular complications in diabetes, obesity or endotoxicosis, etc.), especially as preventive or therapeutic agents in hyperlipidemia or arteriosclerotic diseases.

Table 1

Inhibitory activity of compounds

BPHE in ISvo plasma

NM

2,4,6-cis-2-benzyl-4-|(5-bromopyrimidin-2-yl)-(3-methoxy-5-trifluoromethylbenzyl)-amino|-b-ethylpiperidine-1-carboxylic acid tert-butyl ether

Tert-butyl ether 2,4,6-cis-2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-dimethylaminopyrimidin-2-yl)-amino|I-b-ethylpiperidine-1-carbon acid

Tert-butyl ether 2,4,6-cis-4-((5-(4-acetylpiperazin-1-yl)-pyrimidin-2-yl|-(3,5-bis-trifluoromethylbenzyl)-amino|-2- benzyl-b-ethylpiperidine-1-carboxylic acid

Tert-butyl ether 2,4,6-cis-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-morpholine-ylpyrimidin-2-yl)-amino|-6-ethylpiperidin-1- carboxylic acid (2,4,6-Cys-2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6- ethylpiperidin-1-ylucyclopentylmethanone in Isopropyl 2,4,6-cis-2-benzyl-4-|(3-chloro-5-trifluoromethylbenzyl)-(5-furan-2-ylpyrimidin-2-yl)-amino1-b-ethylpiperidine-1-carboxylic acid ester

2,4,6-cis-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carboxylic acid tert-butyl ether in. 2,4,6-cis-4-((3-chloro-5-trifluoromethylbenzyl)-(5-methoxypyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether in Tert-butyl 2,4,6-cis-2-benzyl-4-(3,5-bis-trifluoromethylbenzyl)-|5-(2-hydroxyethoxy)-pyrimidin-2-ylamino)-b-ethylpiperidine-1-carboxylic acid acid

2,4,6-cis-2-benzyl-4-(3-chloro-5-trifluoromethylbenzyl)-|5-(1-methyl-1 H- in pyrazol-4-yl)-pyrimidin-2-yl isopropyl ether |I-amino)-6-ethylpiperidine-1-carboxylic acid

2,4,6-cis-2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-methoxycarbonylmethoxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether

2,4,6-cis-2-benzyl-4-(3-chloro-5-trifluoromethylbenzyl)-|5-(2-methanesulfonylethoxy)-pyrimidin-2-yl-aminos-b-ethylpiperidine-1-carboxylic acid isopropyl ether acid

2,4,6-cis-2-benzyl-4-(3-chloro-5-trifluoromethylbenzyl)-|5-(2-methoxyethoxy)-pyrimidin-2-yl1-amino)-6-ethylpiperidine-1- isopropyl ether carboxylic acid

2,4,6-cis-4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino!|-2-ethyl-6-(2-hydroxy-3-methylbutyl)-piperidine-1-carbonate tert-butyl ether acid

Tert-butyl ether 2,4,6-cis-4-I((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-methyl-2H-pyrazol-3-ylmethyl)-piperidine -1-carboxylic acid

Isopropyl ether (22K,4,65)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(3-16| ethoxycarbonylpropoxy)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine- 1-carboxylic acid 340 tan sheet benzite I TZ,B'bis trifluoromethylovnanl) (5 bromopyrimidine-?lu amino 6" ethylpiperidine-1-carbonyl-cyclohexyl ester of acetic acid (2,4,6-Cys-2-benzyl-4- |(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidin-1-yl"-(4-hydroxycyclohexyl)-methanone

Isopropyl ether pub cs With chloro-5 trifluoromethylbenznn) methoxycarbonylaminoM?! where ethyl-6-(2-ethyl-2H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid

Isopropyl ether svv vt e y'chloro b-trifluoronethylovnaic IB methyltilerazine vyl)-pyrimidin-2-ylI-amino)-2,6-diethylpiperidine-1-carboxylic acid

Isopropyl ether (22,48,65)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-imidazol-1-ylpyrimidin-2-yl)-amino1|-2,6-diethylpiperidine-1-carboxylic acid aa dis an benzna KO BV trifluoromethylbenant) (5 morpholine-japlirimidine'Yachil); acetic acid amino|-6-ethylpiperidine-1-carbonyl))-cyclohexyl ester

Abbreviations

Ac: acetyl

Ag: aromatic

BBN: borabicyclo!|3.3.1|nonane ara: dibenzylideneacetone

BINAF: bis(idiphenylphosphino)-1,1-dinaphthyl

Ex: benzyl

Vos: tert-butoxycarbonyl

SAM: cerium ammonium nitrate

KDI: 1,1"-carbonyldiimidazole

DCM: dichloromethane

DDH: 2,3-dichloro-5,6-dicyano-p-benzoquinone

DEAD: diethyl azodicarboxylate

DIPEA: M,M-diisopropylethylamine

DMAP: M,M-dimethylaminopyridine

DME: dimethoxyethane

DMME: Dimethoxymethane

DMF: M, M-dimethylformamide

DMSO: dimethyl sulfoxide arrg: 1,1-bisidiphenylphosphino)ferrocene

EDTC: ethylenediaminetetraacetic acid

IER: ionization by electrospray

EC ethyl

EC: ethyl acetate hrs.: hour(s)

NS: hydrochloric acid

HPLC: high performance liquid chromatography

IPS: 2-propanol (isopropyl alcohol)

IRg: isopropyl

IR: infrared

KNMO5: potassium hexamethyldisylamide

AHL: lithium aluminum hydride

LC: liquid chromatography

DAV: lithium diisopropylamide

NM: lithium hexamethyldisylamide

MHPBK: 3-chloroperbenzoic acid

Me: methyl min: minutes)

MS: mass spectrometry

M5: mesyl manmose5: sodium hexamethyldisylamide

MV: M-bromosuccinimide

NMR: nuclear magnetic resonance

RI: phenyl

PMB: p-methoxybenzyl

PTOH: preparative thin-layer chromatography rac: racemate

Wa-Mmi: Raney nickel

ZF: reversed phase

CT: room temperature 5-Vy: sec-butyl

Via: diazoamyl

HLC: supercritical liquid chromatography

TEA: triethylamine

TE triflat

TFC: trifluoroacetic acid

THFf: tetrahydrofuran

TLC: thin layer chromatography

TMS: trimethylsilyl

T8: tozyl

IVy: tert-butyl

I0!: tolyl

Examples

The following examples are intended to illustrate the present invention and should not be considered limiting. Temperatures are in degrees Celsius. Unless otherwise specified, all evaporations are carried out at reduced pressure, preferably at a pressure approximately equal to 15 mm Hg. Art. up to 100 mm Hg Art. (-20-133 mbar). The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, such as microanalysis and spectroscopic methods, such as MS, IR, NMR. Abbreviations used are as accepted in the art.

IC values for the compounds in the examples below range from about 0.1 n to about 10,000 n, or about 1,000 n for BPHE.

The conditions for measuring retention time are as follows:

Conditions A (HPLC)

Column: ASOSHITM SRI Stm VEN Siv 1.7 μm, 50x2.1 mm.

Flow rate: 0.5 ml/min

Mobile phase: A) TFC/water (0.1/100, v/v), B) TFC/acetonitrile (0.1/100, v/v)

Gradient mode: linear increase from 595 V to 10095 V in 2 min, then 100905 V in 1 min

Measurement: UV at 215 nm

Conditions B (HPLC)

Column: ASOSHITM SRI Stm VEN Siv 1.7 μm, 50x2.1 mm.

Flow rate: 0.5 ml/min

Mobile phase: A) TFC/water (0.1/100, v/v), B) TFC/acetonitrile (0.1/100, v/v)

Gradient mode: 595 V in 0.5 min, then linear increase from 595 V to 10090 V in 5.0 min, then 10095 V in 1.5 min

Measurement: UV at 215 nm

Conditions C (HPLC)

Column: Sotrissgeep O0O5-AM, 50 (4.6 mm).

Flow rate: 2.0 ml/min

Mobile phase: A) TFC/water (0.1/100, v/v), B) TFC/acetonitrile (0.1/100, v/v)

Gradient mode: linear increase from 595 V to 100905 V in 5 min, then 10095 V in 2 min

Measurement: UV at 215 nm

Conditions O (NRX)

Column: AXIS

Flow rate: With ml/min

Mobile phase: SOglodo DMME in IPS 100/7

Gradient mode: isocratic

Measurement: UV at 200 nm

Conditions E (HPLC)

Column: SpigaIrak AO-N, 25x0.46 cm.

Flow rate: 1.0 ml/min

Mobile phase: n-hexane//PS (95/5, v/v)

Gradient mode: isocratic

Measurement: UV at 220 nm

Conditions E (HPLC)

Column: SpigaIrak AO-N, 25x0.46 cm.

Flow rate: 1.5 ml/min

Mobile phase: heptane/zopropanol (90/10, vol./o6.)

Gradient mode: isocratic

Measurement: UV at 220 nm

Example 1: Synthesis of tert-butyl ether of 4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid

E E E E

E E E E er ber he still re. --

Y o y un or y o g pyridine, CT and

What else is that? -- M

To a solution of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (1.6 g, 3.1 mmol) in 10 ml of pyridine, cooled to 0"C, in the atmosphere Methyl chloroformate (1.7 mL, 22 mmol) was added dropwise to M2 over 5 min. The reaction mixture was warmed to room temperature and stirred for 14 h. The reaction was then quenched by adding 1N aqueous HCl (50 mL) and the aqueous layer was extracted with ethyl acetate (2x50 ml). The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed on a rotary evaporator. The residue was chromatographed to give tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2- ethylpiperidine-1-carboxylic acid; IER-MS ti/:: 513 (M.1)", retention time 2.35 min (conditions A).

Example 2: Synthesis of 4-(acetyl-(3,5-bis-trifluoromethylbenzyl)-amino|-2-ethylpiperidine-1-carboxylic acid tert-butyl ether

ET their g. debt TE kt zr - yad iy o i. "MN i r iy o triethylamine, DMAP, CT S

M m m shcha shchi what

A mixture of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (10 mg, 0.022 mmol), triethylamine (9 μl, 0.066 mmol) and a catalytic amount of M,M-dimethylaminopyridine is stirred at room temperature for 2 hours. The reaction is quenched with water, then the reaction mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure.

The residue is purified by 3F-HPLC and 4-(acetyl-(3,5-bis-)tert-butyl ether is obtained

trifluoromethylbenzyl)-amino|-2-ethylpiperidine-1-carboxylic acid; IER-MS t/2: 497 |MA1)", retention time 2.22 min (conditions A).

The following compound is obtained according to the method of example 2.

Me | IER-MS product t/2(Me1r | Retention time (min)

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

E E E E c)

KA about MN 1 bo 5.37 (conditions V cho Y ak 900

M M

Example 3: Synthesis of 4-|((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-2-ethylpiperidine-1-carboxylic acid tert-butyl ether

E E E E E E E E

E E E E

Ku u

MN sem a

S. KE, OIREA, OME, 80. es p.

M M

A mixture of 5-bromo-2-chloropyridine (21 mg, 0.11 mmol) and potassium fluoride (23 mg, 0.4 mmol) in M,M-dimethylformamide (0.5 ml) was stirred at 80°C for 3 hours. 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (45 mg, 0.1 mmol) and M,M-diisopropylethylamine (21 mg, 0.11 mmol) are added to the mixture. ). The mixture is stirred at 807C for 15 hours, then heated to 1157C. After stirring for three hours. the mixture is cooled to ambient temperature, then the reaction is stopped with a saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate. The combined organic layer is concentrated under reduced pressure. The residue is purified by 3ZF-HPLC and 3 mg of tert-butyl ether of 4-(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-2-ethylpiperidine-1-carboxylic acid is obtained; IER-MS ti/: 611 |M-A1G, retention time 2.59 min (conditions A).

Example 4: Synthesis of 4-|((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid ethyl ether

E E

E.. E in still iya g» y

Ve M a od i

X is not my Kon

MOTO 00 r g inMov, tn, -tv es dokt. |. AND

With Zsh7 I apple

Moto

In a two-necked flask, dissolve (3,5-bis-trifluoromethylbenzyl)-(2-ethylpiperidin-4-yl)-carbamic acid methyl ether (0.8 g, 1.9 mmol) in 3 ml of anhydrous THF. The solution is cooled to -78 20 and then /HMO5 (2.9 ml, 2.9 mmol) is added dropwise with stirring. After 30 min, ethyl chloroformate (0.31 mol, 3.0 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature.

The reaction is stopped with a saturated aqueous solution of ammonium chloride (40 ml) and the mixture is extracted with ethyl acetate (2x50 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified using flash chromatography, eluting with a mixture of hexane-ethyl acetate and obtaining the ethyl ether of //4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid; IR-MS t/:: 485 (MaА1)", retention time 2.21 min (conditions A).

Example 5: Synthesis of tert-butyl ether of 4-|(3,5-bis-trifluoromethylbenzyl)-(4-bromophenyl)-amino|-2-ethylpiperidine-1-carboxylic acid

E E sh c. Э Э ещ ч «R dy Veshe tvo OK t R

With Her | - In um KI in c

T -7 kro, mai, dmF, VO es t.

M a IV m schi

A mixture of 4-(4-bromophenylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (38 mg, 0.1 mmol), 1-bromomethyl-3,5-bis-trifluoromethylbenzene (22 μl, 0.12 mmol) ), potassium carbonate (69 mg, 0.5 mmol) and sodium iodide (30 mg, 0.2 mmol) in M,M-dimethylformamide (1 ml) are stirred at room temperature for 3 h. The mixture is heated to 8070 and 1-bromomethyl-3,5-bis-trifluoromethylbenzene (22 μL, 0.12 mmol) is added. After stirring the mixture at 80 °C for 15 h. the mixture is cooled to room temperature. The reaction is quenched with water, then the reaction mixture is extracted with ethyl acetate.

The organic layer is concentrated under reduced pressure. The resulting residue is purified by ZF-HPLC and 20 mg of tert-butyl ether of 4-(3,5-bis-trifluoromethylbenzyl)-(4-bromophenyl)-amino|-2-ethylpiperidine-1-carboxylic acid is obtained; IR-MS t/: 609 (M--1|", retention time 2.58 min (conditions A).

Example 6: Synthesis of tert-butyl ether of 4-(3,5-bis-trifluoromethylbenzyl)-cyclohexylamino|-2-ethylpiperidine-1-carboxylic acid

E E

E E g. R y. h and

FEE and

XX 2; at

From ov Her em bo, Ma, DMF, 80 es and 1

A. Shchy

In What And -- and

A mixture of 4-cyclohexylamino-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (31 mg, 0.1 mmol), 1-bromomethyl-3,5-bis-trifluoromethylbenzene (22 μl, 0.12 mmol), potassium carbonate (69 mg, 0.5 mmol) and sodium iodide (30 mg, 0.2 mmol) in M,M-dimethylformamide (1 ml) are stirred at room temperature for 3 hours. The mixture is heated to 8070 and 1-bromomethyl-3,5-bis-trifluoromethylbenzene (22 μL, 0.12 mmol) is added. After stirring the mixture at 80 °C for 15 h. the mixture is cooled to room temperature. The reaction is quenched with water, then the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure. The resulting residue is purified by ZF-HPLC and 7.6 is obtained

MG tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-cyclohexylamino|-2-ethylpiperidine-1-carboxylic acid; IER-MS m/:: 537 (Ma-1|", retention time 1.97 min (conditions A).

Example 7: Synthesis of the benzyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-ethylpiperidine-1-carboxylic acid (racemic)

E E

E E E and

E E r. ra i in sy ke tru IV

And in - Y o

Her "o

MN - veto from 1

And oh

DH Railway. DMAP, DEMOLITION OF KT "KA oto prom y o

To a solution of a racemic mixture of benzyl ether 2-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-6-

M,M-dimethylaminopyridine (0.034 mmol, 4.2 mg) and methyl chloroformate (0.042 mmol, 3.3 mg). After stirring for 1 hour. add methyl chloroformate (0.139 mmol, 11 ml) and

SneoSi" (0.7 ml). After another 1 hour. Methyl chloroformate (0.139 mmol, 11 mg) and M,M-dimethylaminopyridine (0.033 mmol, 4.0 mg) are added to the mixture. After 1.5 hours the reaction mixture is purified by preparative TLC and a racemic mixture of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-ethylpiperidine-1-carboxylic acid benzyl ether is obtained (8295, 8.9 mg); IER-MS t/27: 637 |M--1)", retention time 2.45 min (conditions A).

The following compounds are obtained according to the method of example 7.

And KE

E E

H

Mo in o 77 275 2 2 2 2 2 2 2 o o

MAG min 1 A 5 2.45 (conditions A)

UNTIL

2 A BA 2,A7 (conditions A) oo l racemic

K! A 621 5.35 (conditions B) od) t racemic g. 4 A. 621 2.74 (conditions A) od o)

A. racemic

OA 5.87 (conditions C) oo l racemic o 617 2.69 (conditions A) od o) l racemic

Z. 7 A v21 2.63 (conditions A) o7To l racemic obo

AH 637 2.7 (conditions A) o7To l racemic web and AH 639 2.62 (conditions A) oto lo racemic ovo 617 2.77 (conditions A) o7To

I racemic 11 905 633 2.83 (conditions A) 79 oo also racemic 12 CA 631 2.71 (conditions A) o7To t racemic rob 13 A 557 5.07 (conditions B) o7To l racemic 900 14 7 619 2.49 (conditions A)

N y | c -- I racemic

Fri, at 555 2.51 (conditions A) 7 t racemic K2CO3 instead of DMAP, THF instead

SNesSig" 16 ON 569 2.70 (conditions A)

AND

Example 8: Synthesis of tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (racemic)

E E E E and E E E my Bg take Re KE

Ah T still that M VG nm" m t ST

S Zh Ve Che zm

B Azh. Man, blows, kt SHHI and

I am! Ota H

Mother

AND.

A solution of a racemic mixture of 2-benzyl-4-(5-bromopyrimidine-2-ylamino)-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (0.076 mmol, 36 mg) in DMF (1 ml) was cooled to 0°C and Mann (6095 suspension in oil, 0.228 mmol, 5.5 mg) is added. The mixture is allowed to warm to room temperature and stirred for 30 min. The mixture is cooled to 0"C and 3,5-bis(trifluoromethyl)benzyl bromide (0.091 mmol , 27.9 mg). After stirring for 5 min, the solution is heated to room temperature and stirred for 2 h. The reaction is quenched with saturated brine and the mixture is extracted with ethyl acetate.

The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane/EOAc) to obtain a racemic mixture of tert-butyl ether /2-benzyl-4-|((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl) -amino|-6-ethylpiperidine-1-carboxylic acid (7.0 mg, 1395);

IER-MS ti/: 701 (Ma-1)", retention time 2.67 min (conditions A).

The following compounds are obtained according to the method of example 8

You are

Me |! 77777771 PER-MS t/s mat | Holding time (min)

Yii

IS

E M. 1,676 2.65 (conditions A)

And racemic

E E

E about 2,663 2.7 "(conditions A) and racemic

IS

IS

E SI

Z 667 6.22 (conditions B)

And racemic

E E

IS

4,633 2.89 (conditions A)

And racemic v. ooo

E 5. 711 2.7 (conditions A)

And racemic

Eh, meme

IS ! M

E U

715 2.73 (conditions A)

And racemic (about O.O and 7 683 6.31 (conditions B) and racemic

Example 9: Synthesis of isopropyl ether (25,4K,6k)-4-(5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-dimethylpiperidine-1-carboxylic acid

IS

E verchich miv jus nina nm7m -4 - i. she re Ve r

D sia i man, dmFf ri A

IM o"t'ua sh vi

A solution of (25,4E,6K)-4-(5-bromopyrimidine-2-ylamino)-2,6-dimethylpiperidine-1-carboxylic acid isopropyl ether (102 mg, 0.275 mmol) in DMF (1.5 mL) was cooled to 0"C and Man (6095 suspension in oil, 0.228 mmol, 5.5 mg) is added. The mixture is stirred at 0"C for 30 min and 3-chloro-5-trifluoromethylbenzyl bromide (113 mg, 0.412 mmol) is added. After stirring for 1 hour. the reaction is quenched with water and the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over

Mag25O4, filtered and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane/EthOAc) to obtain isopropyl ether (25,4K,6K)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino |-2,6-dimethylpiperidine-1-carboxylic acid (80 mg), IR-MS t/: 563 (Ma-1H", retention time 2.70 min (conditions A).

The following compounds are obtained according to the method of example 9.

Me | Product / | IER-MStudyMetg | Holding time (min)

and SI

U

Well, we have

Mohm 1 C 563 2.77 (conditions A)

GU M what X oo c) a A and Y SI and S le nebo mem o7 2 bo 619 2.44 (conditions A)

M

H obo c) Zh le

Example 10: Synthesis of 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (racemic)

Eh and

Because I love her - her

ШИ И E РАВШ вт ше Те то -о г | he o r shim she x M | My - ra(ara), morpholin den "I

As tolUurl, 100 s and her Ho

M. p

And eat

Tk) ov) vata -- I-

In a flask purged with M2, to a racemic mixture of tert-butyl ether 2-benzyl-4-

I(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (0.038 mmol, 27 mg) is added Raz(ava)z (0.0077 mmol , 7.0 mg), 2-(di-tert-butylphosphino)biphenyl (0.0154 mmol, 4.6 mg), sodium tert-butoxide (0.154 mmol, 14.8 mg), and morpholine (0.077 mmol, 0, 0067 ml). The flask is once again purged with Mg2, toluene (0.4 ml) is added and heated at 1007C for 4 h. The reaction is stopped with silicon dioxide and the crude product is purified by chromatography on a silica gel column to give a racemic mixture /tert-butyl ether /2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidine) -2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (0.0189 mmol, 13.37 mg, 50905); IER-MS m/: 708 (MaА1Г", retention time 2.55 min (conditions AND).

The following compounds are prepared according to the method of example 10, using the appropriate amines.

IER-MS ti/; | Time of maintenance and 8G0lyako0000 (boeereeuvenei deren

E E

E E

E SI to E si r u mm Ex 1 999 674 2.12 (conditions A) o

M M obo oo t racemic Ya shchi KE KE Shchi EE

E E | E E u u mem mm the sky is here

M M obo oo t racemic lo v. E schi y that C What in

M d g

M M u

Yes mm

M

A. M a 07 racemic de ve ge v. There is BE

E E E E d Vg s Sum mem MM 4 Sg, 623 5.57 (conditions B) post,

M M o7o oo i racemic le

E E shchi i KE AH E E

E EOM E E in m Vg in mem - 995 749 2.53 (conditions A) pot,

I) Moto oo t racemic t

E E

E E

E SI is E SI

MU that r Vg with ХУ

MM MM s v26 2.57 (conditions A) o ve m - M obo oo ac racemic cancer si gi si on Y

FI Su

In Moscow State University,

Su S

MM

7 chapter 612 2.17 (conditions A) bo

M

A obo (c) XX ac (nMO5 instead of IVOOM; THF instead of toluene)

And E blue yo

M M Vg

M

ХУ ХУ chapter 598 2.47 (conditions A) chapter

M

M oo AH

A ra what o) E what, Se what m Vg y

FI DU at 639 2.36 (conditions A) o

M M oo AH

Zh A

And E

What, si Y s

M M d Vg chapter 614 2.47 (conditions A) chapter

M

M oo AH

A ra gai SI gai otu y

M M Vg y

DU Z HU

11 chapter 626 2.37 (conditions A) o

M

M oo 4.

A A and: Zh

E E E Ii And what. 3 and E

M M d Ve 12 o'clock 632 2.41 (conditions A) chap

M

M oo Kh

A ra gi si shchi

E E SI

MU o, yo) Vg

M

FI DU

13 of 582 30.8 (conditions C) chapter

M

M oo 4

And A

J

E E

E E

E SI so E SI vu rmem i Sppog, What What and pog,

M M

E E

E E

E SI 7 E SI zh r me mem ob 611 2.17 (conditions A) chapter

M M

Example 11: Synthesis of tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-ethylpiperidine-1-carboxylic acid (racemic)

E E

2 And in yuk live

SH riy Y Z t tore y -x shchi che I t ee o

МН dДМАПОСНОСЯ. KK I and mine

Fe gu, tovetilsipan, Em se AKA trivtylamine, SNSI., VT and | railway you Z) Vos anhydride, VO E and M

S i oto with Z i A.

To a solution of a racemic mixture of 2-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-6-ethylpiperidine-1-carboxylic acid benzyl ether (0.064 mmol, 37.4 mg) in dry СНоСи» (10 ml) in an M2 atmosphere M,M-dimethylaminopyridine (0.128 mmol, 15.6 mg) and methyl chloroformate (0.128 mmol, 10.0 mg) are added at room temperature. After stirring for 14 h. the reaction mixture is filtered through a layer of silica gel and concentrated under reduced pressure to obtain benzyl ether /2-benzyl-4-|((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid, which is used in the following reaction without further purification. The flask containing the resulting residue and Rasi" (0.0064 mmol, 1.1 mg) is flushed with M". To the mixture is added triethylsilane (0.128 mmol, 14.9 mg), triethylamine (0, 0128 mmol, 1.3 mg) and dry SNeSi" (0.5 mol). After stirring for 1 hour, Rasig" (0.0576 mmol, 9.9 mg) and triethylamine (0.128 mmol, 13.1 mg) are added ). After stirring for 45 min, triethylsilane (0.250 mmol, 29 mg) was added to the mixture. The mixture was stirred for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: mixture

СНеСиг/methanol--100/1) and obtain the methyl ester of (2-benzyl-b-ethylpiperidin-4-yl)-(3,5-bis-trifluoromethylbenzyl)-carbamic acid, which is used in the next reaction. Bos anhydride (0.09 mmol, 19 mg) was added to the resulting residue. The mixture is stirred at 60"C for 11 hours, cooled to room temperature and purified by preparative TLC to obtain a racemic mixture of tert-butyl ether 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|- b -ethylpiperidine-1-carboxylic acid; IR-MS m/:: 603 (Ma-1|", retention time 2.50 min (conditions A).

The following compound is obtained according to the method of example 11.

Me| ///// Produst | IER-Mst/eMyur

E E

E E in E

E R E E

H

MTo MN 1 b21 2.54 (conditions A)

M M

Sho: what t is racemic

Example 12: Synthesis of tert-butyl ether of 5-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid

E E g iK E E E E tru teru nt o o i sy i

SG and INMOB, tgF, KT Suto a M - Ei a shchi p

In a two-necked flask, /5-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (22 mg, 0.04 mmol) was dissolved in 0.25 ml of anhydrous THF. The solution is cooled to -78"7C and then, with stirring, 1 NMOZ5 (0.05 ml, 0.05 mmol) is added dropwise. After a minute, methyl chloroformate (0.004 ml, 0.048 mmol) is added dropwise and the reaction mixture is allowed to warm to room temperature. The reaction is quenched with saturated aqueous ammonium chloride solution (20 ml) and the mixture is extracted with ethyl acetate (2 x 20 ml), dried over NaCl5O:x, filtered and evaporated to give the crude product. The resulting residue is purified by flash chromatography eluting with a mixture of hexane-ethyl acetate. and receive tert-butyl ether of 5-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid (yield 40905); IER-MS t/7: 603 Mat". retention time 2.46 min (conditions A).

Example 13: tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-methoxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (racemic)

E E

SU take - in G - 2 o. - 7 VI

AI - masme, Sci Ya

KK. sho 1pp9s and Her what se and a she A

A mixture of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (125 mg, 0.162 mmol) , sodium methylate (25 wt. 95 in methanol, 111 μl) and copper iodide (62 mg, 0.326 mmol) in DMF (1.5 ml) are stirred at 857C for 2.5 h. The mixture is cooled to room temperature and water and ethyl acetate are added. The mixture is filtered and the filtrate is washed with water and brine. The organic layer is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC to obtain tert-butyl ether 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-methoxypyrimidin-2-yl)-amino|- 6-ethylpiperidine-1-carboxylic acid (26 mg); IER-

MS t/: 653 |М-А-11", retention time 5.65 min (conditions B).

The following compounds are obtained according to the method of example 13.

Me | Product | ER-MS t/h MIT Retention time (min)

E E

What what what

Ve

M M o 9, 1 o 513 5.57 (conditions B) chap

M M o7o oz rok rak

E E

E eE iv; Hg

M - M

FI

ZI mem 2 ob 543 5.68 (conditions B) ob

M M oo oo

AJ A

Example 14: Synthesis of /1-(2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidin-1-ylyl2-cyclopentylethanone (racemic)

EY PE ke ee bor TE vahrya y t i MON 9 u shcha u a pog,

SI with DIPEA, DMF; you

Ov vi

H is not for her S

To a solution of 2-benzyl-b-ethylpiperidin-4-yl)-(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amine hydrochloride (50 mg, 0.078 mmol) in 1 ml of DMF at room temperature add diisopropylethylamine (54.6 μl, 0.313 mmol) and cyclopentylacetyl chloride (68 μl, 0.470 mmol). The solution is stirred at 607 for 18 hours. The mixture is purified by preparative HPLC and 1-(2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidin-1-yl)u is obtained .2-cyclopentylethanone (7.1 mg");

IER-MO ti/: 711 (Ma-1)", retention time 2.75 min (conditions A).

The following compounds are obtained according to the method of example 14.

E Y Y E

E E

M Vg

AND

MM

9905

Iv

Me| o FER-MS t/gIMa and )Retention time (min)| Reagents (base/solution). i (9 1 oo 673 2.66 (conditions A) iso . racemic I С82СО3 (SvgSO3/acetonitrile) i (9 2 in 671 2.83 (conditions A) and racemic (DIPEA/DMF)

I (9

Z 5 685 2.66 (conditions A) and racemic (DIPEA/DMF) x (9)

A ve 2.73 (conditions A) g racemic (DIPEA/DMF) z (9 c) c) 719 2.64 (conditions A) racemic (DIPEA/DMF) on 672 2.52 c racemic C (DIPEA/DMF) z AH 7 oo 687 2.78 (conditions A) oo ak racemic pe (DIPEA/DMF)

Example 15: Synthesis of 2-benzyl-4-|((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidin-1-ylcyclohexylmethanone (racemic) btrrya rya A in t tour VG still in ey sh-

AL t shi zm Sh sho sh a vn 1, i y St preg n i sypz NS

To a solution of 2-benzyl-b-ethylpiperidin-4-yl)-(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amine hydrochloride (50 mg, 0.078 mmol) in 1 ml of DMF at room temperature add triethylamine (110 μL, 0.78 mmol) and cyclohexanecarbonyl chloride (41 μL, 0.313 mmol). The solution is stirred in a microwave reactor at 150 C for 30 minutes. The mixture is purified by preparative HPLC to obtain 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidin-1-ylcyclohexylmethanone (25 mg); IER-MS t/2: 711 (Ma-1|), retention time 2.73 min (conditions A).

The following compounds are obtained according to the method of example 15.

E Y Y E

E E m Vg

AND

MM

9905

Iv

Me! 7777777 I PER-MS the same (9 1 (with 705 2.74 (conditions A) with racemic (TEA/DMF)

same (9 2 hu 697 2.80 (conditions A) same, racemic (TEA/DMF) i SI

From 073 683 2.76 (conditions A) 753 racemic (TEA/DMF) i SI 4 ssh 2.69 (conditions A) o racemic TEA/DMF w (9

F 754 2.57 ( А) o

Sho 357 (conditions 7

O racemic OO (TEA/DMF)

Example 16: Synthesis of isopropyl ether (25,4E,6K)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid

IS

IS

E E SI

IS

SI

E d Vg

Vg and

Su SISO, i-RG, KSO a xx - - I - - -k

And what about ob re

M

N ra |c)

To a solution of (5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-((25,4H8,68)-2,6-diethylpiperidin-4-yl)-amine (386 mg, 0.74 mmol) in acetonitrile (3 mL) at room temperature were added potassium carbonate (138 mg, 1.0 mmol) and isopropyl chloroformate (0.11 mL, 1.0 mmol). The solution is stirred at 100°C for 3 hours, and then a saturated aqueous solution of MnSOO3 is added. The mixture is extracted with ethyl acetate and the organic layer is dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue is purified by column chromatography with silica gel (eluent : n-hexane/ethyl acetate mixture) and obtain isopropyl ether (25,4E,6k)-4-(5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine -1-carboxylic acid (396 mg, 80905); IER-MS t/2: 519 (M--1|", retention time 6.00 min (conditions

IN).

Example 17: Synthesis of acetic acid 4-(2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carbonyl-cyclohexyl ester)

E E

R. E o ve E "IvOsI, mya i no To ya

Go) 2 iv E ge - ie NN FV

Still shchen, UVG Y 7 - M to sh- Shchi

BUT) o x M Y

WITH

WHERE

9 ob" from m

N sip from NSI

TEA

To a solution of 4-acetoxycyclohexanecarboxylic acid (73 mg, 0.392 mmol) in 1 ml of THF at room temperature is added thionyl chloride (143 μl, 1.69 mmol). The solution is stirred at room temperature for 18 hours. and concentrated under reduced pressure. A solution of 2-benzyl-b-ethylpiperidin-4-yl-(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amine hydrochloride (50 mg, 0.078 mmol) and triethylamine ( 110 μl, 0.78 mmol) in 2 ml of DMF. The solution is stirred in a microwave reactor at 1507 for 60 min. The mixture is cooled to room temperature and water and dichloromethane are added. The organic layer is washed with water and brine and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC to obtain /4-(2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carbonyl -cyclohexyl ester of acetic acid (2.7 mg), IR-MS m/:: 769 (Ma1|), retention time 2.75 min (conditions A).

The following compound is obtained according to the method of example 17.

E Y Y E

E E m Ve

AND

MM

Fo

Iv me | 77787717 PER-MS t/a Meter | Holding time (min) h on (c) (c) 1 i 769 2.16 (conditions A) more 6) 6) o. chny ac racemic

Example 18: Synthesis of /(2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino1|-6-ethylpiperidin-1-yl)-(4-hydroxycyclohexyl) -methanone in and - E E

She t this Ve E | y r G cotton

MOm 5M NOV 89

M z still o t og, y o) still he

To a solution of acetic acid 4-(2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino1|-6-ethylpiperidine-1-carbonyl-cyclohexyl ether (4, 3 mg, 0.00559 mmol) in 1 ml of 1,4-dioxane at room temperature add 1 ml of a 5 mol/l solution of hydrochloric acid. The solution is stirred at 1007"C for 3 hours. The mixture is cooled to room temperature and water is added.

Solvents are removed by lyophilization and 4(2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-b-ethylpiperidin-1-yl)-(4- hydroxycyclohexyl)-methanone (3.7 mg); IER-MS ti/l: 727 |MA1, retention time 2.64 min (conditions A).

The following compound is obtained according to the method of example 18.

E Y Y E

E E

M Ve

CA

MM

Fo

Iv me | 77778771 PMERAMS t/y Mat | Holding time (min)

(c) 1 o 727 2.62 (conditions A) oi

ON SHY racemic oh

Example 19: Synthesis of 4-(2-benzyl-4-I(3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carbonyl-cyclohexyl acetic acid ester

E Ii Y E

Е Е (c) о с что 18021, о00577-525-7 ММ 2

A. is E E O E E (v

A;

M

HU Fr

MM

(c) a

M

N

TEA

To a solution of 4-acetoxycyclohexanecarboxylic acid (753 mg, 4.05 mmol) in 5 ml of THF at room temperature is added thionyl chloride (1.48 ml, 20.2 mmol). The solution is stirred at room temperature for 18 hours. and then concentrated under reduced pressure. A solution of (2-benzyl-b-ethylpiperidin-4-yl)-(3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amine (492 mg, 0.81 mmol) and triethylamine (1.70 mL, 12.2 mmol) in 10 mL of DMF. The solution is stirred in a microwave reactor at 15077 for 60 min. The mixture is cooled to room temperature and water and dichloromethane are added. The organic layer is washed with water and brine and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC to obtain 4-(2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amino|-b-ethylpiperidin- 1- carbonyl cyclohexyl ester of acetic acid (163 mg), IER-MS t/l: 776 (Ma1|), retention time 2.39 min (conditions A).

Example 20: Synthesis of tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-methoxymethylpiperidine-1-carboxylic acid (racemic)

E E E E

E. E E E

S Iv mo tot y dO, Me - Y

Set SK osi sho oto p'bsa -y- A.

A mixture of 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino-1|-6-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ether (10.9 mg, 0.018 mmol), AdOH (20.8 mg, 0.090 mmol) and iodomethane (11.2 μl, 0.180 mmol) in 0.4 ml of DMF were stirred at 607C for 10 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give tert-butyl ether 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-methoxymethylpiperidine-1-carboxylic acid (2 mg); IER-MS m/:: 619 (Ma1)", retention time 2, 56 min (conditions A).

Example 21: Synthesis of tert-butyl ether of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-b-methylcarbamoylmethylpiperidine-1-carboxylic acid (racemic).

SE. SE.

SEU. ly and SR with TP with (or oya a IvySOesI still IRGOMEE "M A de

Mo t; 1 - 5 5 5 5 5 5 5 a Sh a memno HA

Kh. ZM ZM no M N AH

And here is autumn and A

And 7

To a solution of /4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-carboxymethyl-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (60 mg, 0.105 mmol) in THF (1 ml) is added IRg2MEI ( 0.02 ml, 0.116 mmol). To the solution cooled to 0"C, add SISOgiV (0.015 ml, 0.116 mmol) and

IRGgMEH (0.02 ml, 116 mmol), then a 2 M solution of MemN" in THF (0.5 ml, 0.525 mmol). The mixture was stirred at RT for 71 h, the reaction was quenched with water, the mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over Md5O4, and concentrated in vacuo to give a pale yellow oil. Crude oil is purified using chromatography on a column with silica gel (EIHUAS) and tert-butyl ether //4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-b-methylcarbamoylmethylpiperidine-1-carboxylic acid is obtained in the form colorless oil (40 mg, yield 65905) IER-

MS t/2: 584 (MaA1G", retention time 2.40 min (conditions A).

Example 22: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxo-2-pyrrolidin-1-ylethyl)-piperidine-1-carboxylic acid tert-butyl ether acid (racemic).

SE. SE

SEZ i and SE SCHI and skh z

M ia a y a roya WHEN, - mo pyrrolidine -- 4 - - « - 1 a 1 4 it, WHETHER tm on M

To a solution of tert-butyl ether /4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-carboxymethyl-b-ethylpiperidine-1-carboxylic acid (15 mg, 0.026 mmol) in 1, 2-dichloroethane is added 1, 1"-carbonyldiimidazole (6 mg, 0.034 mmol). After 1 h, pyrrolidine (0.011 mL, 0.13 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and directly purified by TLC (4:11 E(OAc-hexane) and obtain tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxo-2-pyrrolidin-1-ylethyl)-piperidine- 1-carboxylic acid in the form of a colorless oil (16 mg, yield 9790) LER-MS t/2: 624 (Ma-1)", retention time 2.56 min (conditions A).

The following compounds are obtained according to the method of example 22.

E Y Y E

E E

H

M7To7 oo in M ha y

Me | 77778771 MER-MS t/h Matt | Retention time (min) ze - 1 Her 598 2.53 (conditions A) Mn racemic rana p 2 Her 612 2.53 (conditions A) her racemic

Z AJ 626 2.60 (conditions A) An racemic

Example 23: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-hydroxy-3-methylbutyl)-piperidine-1-carboxylic acid tert-butyl ether (separate diastereoisomers , racemic).

E E E E E E

E E E E E E eru prut tsu? t i and Kh

HER -MusI To r

Kt tat G Go I. Fr

B A

A. y oretov Mt M

Ko Aa oo

To a solution of 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid tert-butyl ether (22 mg, 0.040 mmol) in THF ( 1.5 ml) at -40 6 add a 2 M solution of IRGIMOSI (0.22 ml, 0.436 mmol) and stir at -40"C for 1 hour. The reaction is stopped with a saturated aqueous solution of ammonium chloride, the mixture is extracted twice with ethyl acetate, washed with brine, dried over MBO and concentrated in vacuo The crude product mixture was purified by preparative TLC (3:1 hexane-COAc, twice) to give two diastereoisomers of tert-butyl 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino| -2-ethyl-6-(2-hydroxy-3-methylbutyl)-piperidine-1-carboxylic acid (more polar 8 mg, less polar 3 mg). Polar isomer: IER-MS t/l: 599 |M-- 1)", retention time 2.61 min (conditions A). Less polar isomer: IER-MS t/:: 599 (Ma1|), retention time 2.12 min (conditions A).

The following compound is obtained according to the method of example 23. and B1

IS

H

Maybe he

M

2

Me | 77777777 | and ER-MS of racemic A

Example 24: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1-methyl-1H-imidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether acid (racemic).

E E

E E E E

E E o od same -lh Shchv i S

S Ж «oh g I, man, me! do that

M M - TgF-DMF (31) M ZM

N A! SHHI 7 A

To a solution of 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-imidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (9 mg, 0.015 mmol ) in THF (0.3 ml) and DMF (0.1 ml)

Man (1 mg, 0.015 mmol) is added, followed by iodomethane (0.001 mL, 0.018 mmol). The mixture is stirred at room temperature for 2 hours, then the reaction is quenched with water, the mixture is extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. Purification by preparative TLC (EUAs 10095) gives tert-butyl ether 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1-methyl-1H-imidazol-2-ylmethyl)- of piperidine-1-carboxylic acid in the form of a colorless oil (5 mg, yield 5495) 1ER-MS ti/: 607 (Ma1|", retention time 2.23 min (conditions A).

Example 25: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-imidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (racemic) e g I E

E OE E E what I take she - СВ

ID 000 glyoxal yav 4 about them pl. meon i

Am and p DK

Nm " them

A. A-

To a mixture of tert-butyl ether 4-I((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid (18 mg, 0.0324 mmol) and 4095 glyoxal in water (0.017 mL, 0.117 mmol) add 7 N methanolic ammonia (1.5 mL). The mixture is stirred in a sealed tube at RT for 18 h. Additional glyoxal (0.005 mL, 0.034 mmol) is added and the mixture is stirred for another 1 h. Then the mixture is concentrated in a vacuum and directly purified with the help of preparative TLC (395 MeOon-SNesig) to obtain tert-butyl ether 4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6- (1H-imidazol-2-ylmethyl)-piperidine-1-carboxylic acid (23 mg, quantitative yield). EP-MS ti/:: 593 M--1|", retention time 2.25 min (conditions A) .

Example 26: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-hydroxybut-3-ynyl)-piperidine-1-carboxylic acid tert-butyl ether (separate diastereoisomers , racemic).

E E g. and there is r E that

E she E E I E ET se E o iy a H ma Ve - "ny di -O Ch che M a" ------zh . i. i AD. Shchy iy MD. n n domy i

And about that

F -- A-

Tert-butyl ether 4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6- of (2-oxoethyl)-piperidine-1-carboxylic acid in THF (2 mL). The mixture is stirred at RT for 1 h, then cooled again to 0"C and another portion of ethylmagnesium bromide (1 mL, 0.5 mmol) is added . The mixture is stirred for 15 min, then the reaction is stopped with a saturated aqueous MNaCl solution, the mixture is extracted twice with ethyl acetate, the combined organic layer is washed with brine, dried over sodium sulfate and concentrated in vacuo to obtain a diastereoisomeric mixture of tert-butyl ether /4-((3, 5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-hydroxybut-3-ynyl)-piperidine-1-carboxylic acid as a colorless foam (255 mg, quantitative yield). Then a small portion of the mixture was purified with the help of preparative TLC and two diastereoisomers are obtained (polar diastereoisomer: 7 mg, less polar diastereoisomer: 8 mg). Polar diastereoisomer: IER-MS t/l: 581 (Ma-1)", retention time 2.48 min (conditions

AND). Less polar diastereoisomer: IER-MS ti/l: 581 (M--1)", retention time 2.50 min (conditions A).

The following compounds are obtained according to the method of example 26.

E and E

E E

H

Why not?

Me! 77777771 PER-MS t/dumiur on

MoHg 1 ra 595 2.57 (conditions A) ra separate diastereoisomer A he Mav chBg 2 ra 595 2.55 (conditions A) ra separate diastereoisomer B

Example 27: Synthesis of tert-butyl ether 4-I((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-isoxazol-3-ylmethylpiperidine-i-carboxylic acid and tert-butyl ether /4-( 3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-isoxazol-5-ylmethylpiperidine-1-carboxylic acid (a mixture of two racemic compounds).

E E E E g to her shi E Bulls ex E that E she M s You to sg to 7 shk Mn;onNn, O my no - -jo 5 --2523- i

And t shk and g 8 g and A - and ato oto

And A. --

To a solution of 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxobut-3-ynyl)-piperidine-1-carboxylic acid tert-butyl ether (68 mg, 0.117 mmol ) in ethanol (1 ml) add 5095 aqueous solution of hydroxylamine (0.155 ml, 2.35 mmol). The mixture is stirred at RT for 10 min, then extracted twice with methylene chloride, the combined organic phase is washed with brine, dried over magnesium sulfate and concentrated. The crude oil is purified by preparative TLC (2:1 hexane-acetone) and a mixture of tert-butyl ether 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6b-isoxazol-3-ylmethylpiperidine- 1-carboxylic acid and tert-butyl ether of 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-isoxazol-5-ylmethylpiperidine-1-carboxylic acid in a 1:1 ratio (48 mg, output 6995). IER-MS t/2: 594 (Ma-1)", retention time 4.28 min (single peak, conditions C).

Example 28: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-methyl-2H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether acid (racemic).

E E

R. ch -E E these EE in E uy E

AI! and Oh TE as TE -y g

X 8 72 months; What?

N. v. EN, KoSO ( ke Mo

And from the bases of her river

FASHION ect M what re z m m m

Zh Ba g

To a solution of 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (20 mg, 0, 0337 mmol) and potassium carbonate (9 mg,

0.0674 mmol) in DMF (0.2 ml) add iodethane (0.008 ml, 0.101 mmol) and stir at RT for 20 h. Iodethane (0.1 mL, 1.25 mmol) was added to the mixture again. The mixture is heated at 60"C for 8 hours, then water is added. The mixture is extracted with methylene chloride using a phase separation device.

Purification by preparative TLC (1:11 EtOAc-hexane) gives two regioisomers: tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1-ethyl-1 H -pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid (9.3 mg, yield 4495). LER-MS t/2: 621 (MaА1Г", retention time 2.59 min (conditions

AND); 4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-ethyl-2H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (1.1 mg , 595 output) EP-MS t/2: 621 |Ma1|", retention time 2.57 min (conditions A).

The following compounds are obtained according to the method of example 28.

E and Y E

E E

H

May be

AND

What else 77777711 | ER-MS t/liMetg | Holding time (min)

Le 1 SA 607 2.51 (conditions A) with Zh

Example 29: Synthesis of 4-I-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (racemic) .

E E c. I Mr. Te

Y su I Also and tm Ah hydrazine ts M at a I EN, M m i S. e A is Ia t uto ato

To a solution of 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxobut-3-ynyl)-piperidine-1-carboxylic acid tert-butyl ether (117 mg, 0.202 mmol ) in ethanol (2 ml) add hydrazine monohydrate (0.196 ml, 4.04 mmol) and the mixture is stirred at RT for 2 h, then water is added.

The mixture is extracted twice with methylene chloride, dried over magnesium sulfate and concentrated to obtain tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-pyrazol-3-ylmethyl)- of piperidine-1-carboxylic acid in the form of a colorless foam (120 mg, quantitative yield). EP-MS ti/:: 593 Ma1|", retention time 2.36 min (conditions A).

Example 30: Synthesis of 4-((3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1-ethyl-1H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid isopropyl ether and isopropyl ether of 4-((3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-ethyl-2H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid (racemic).

k.i g. I take her and t that "si i t iRgMoVg Ko TI 7 th peryodinan mo it3-- "oh Dessa.- Martina in

Kh and SNOSI A

OV) tgF press an and 2772 OV)

ХК M. KA - nt 0? to KT ry M. and Yi et Yi sht on H hato Y ato aochye7ta ra ra r v. | EE in ru si vir og si

And there is o) o) What

MN.MNUN, O ne A dya EN, KSO, s noya o ----j wn bo--zt yaz schi yun MM diF MM 7 MM

MAK GO g mch "M y Moto o o o o Hory ra ry

To a solution of trimethylsilylacetylene (0.236 ml, 1.70 mmol) in THF (3 ml) at -78"C is added a 0.8 M solution of iRgMaYAVg (2.1 ml, 1.70 mmol), then isopropyl ether 4-((Z -chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid (430 mg, 0.848 mmol) in THF (3 mL). The mixture was heated to RT and stirred for From h. The reaction is stopped with a saturated aqueous solution of ammonium chloride, the mixture is extracted twice with ethyl acetate, and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated to obtain crude alcohol. To a solution of crude alcohol in methylene chloride (10 ml) at 0"C, add Dess-Martin periodinane (1.45 g, 3.42 mmol) and stirred for 3 h. The reaction mixture was diluted with diethyl ether, the reaction was quenched with a saturated aqueous solution of Mag5b2O4, then the mixture was extracted twice with diethyl ether, the combined organic layer was washed with a saturated aqueous solution MansSoOz, brine, dried over sodium sulfate and concentrated in c Purification by chromatography on a column with silica gel (ETAc-hexane) gives 4-(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxo-4-trimethylsilanylbut-3-ynyl) isopropyl ether )-piperidine-1-carboxylic acid in the form of a colorless foam (298 mg, yield 5890). EP-MS m/2: 603 (M--1|", retention time 2.51 min (conditions A).

To a solution of 4-|(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxo-4-trimethylsilanylbut-3-ynyl)-piperidine-1-carboxylic acid (264 mg, 0.438 mmol) in ethanol (3.5 mL) add hydrazine monohydrate (0.425 mL, 8.76 mmol). The mixture is stirred for 2.5 hours, then the reaction is quenched with water, the mixture is extracted twice with ethyl acetate, the combined organic layer is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-((3-chloro-5-trifluoromethylbenzyl) isopropyl ether )-methoxycarbonylamino|-2-ethyl-6-(1H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid in the form of a colorless foamy substance (243 mg, quantitative yield) EP-MS t/: 545

IMA1G, retention time 2.10 min (conditions A).

To a solution of 4-((3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid isopropyl ether (243 mg, 0.446 mmol) in To THF (4.5 mL) and DMF (1.5 mL) at 0°C was added Mann (21 mg, ca. 0.147 mmol). The mixture was heated to 60 °C, then iodoethane (0.071 mL, 0.892 mmol) was added and stirred for 70 min, then the reaction is quenched with water. The mixture is extracted twice with ethyl acetate, washed twice with 595 aqueous Massey solution, once with brine, dried over magnesium sulfate, and concentrated. The crude product is purified first by silica gel column chromatography, then by preparative TLC (395 Meon -SNeSi") and two regioisomers are obtained: isopropyl ether 4-|(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(1-ethyl-1H-pyrazol-3-ylmethyl)-piperidine-1 -carboxylic acid (279 mg). IER-MS t/2: 573 |M1)", retention time 4.49 min (conditions C); 4-(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-ethyl-2H-pyrazol-3-ylmethyl)-piperidine-1-carboxylic acid isopropyl ether (18.2 mg). IER-MS t/2: 573 (Ma1|), retention time 4.38 min (conditions C).

Example 31: Synthesis of tert-butyl ether of 4-(3,5-ditrifluoromethylbenzylmethoxycarbonylamino)-2,6-trans-diisopropylpiperidine-1-carboxylic acid (racemic)

g A k.i Ky sh g ke oh TE

ШЭ de і o at you sisSOo Me "Shk

DMAP w on the nose of A

ZM tk 2 2 M y

And other A. I about: oto

And ry

To a mixture of 4-(3,5-ditrifluoromethylbenzylamino)-2,6-diisopropylpiperidine-1-carboxylic acid tert-butyl ether (0.034 mmol, 18.6 mg) and DMAP (0.068 mmol, 8.2 mg) in SNeoSig (0 .5 ml) at room temperature add methyl chloroformate (0.068 mmol, 5 μl). After stirring for 5 hours. at room temperature, the reaction mixture is purified using PTLC (eluent: n-hexane/ethyl acetate mixture) and 4-(3,5-ditrifluoromethylbenzylmethoxycarbonylamino)-2,6-trans-diisopropylpiperidine-1-carboxylic acid tert-butyl ether (17.3 mg, 5790); IR-MS t/: 569.00 (M--1I", retention time 2.71 min (conditions A).

Example 32: Synthesis of isopropyl ether 4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)-2,6 -trans-diisopropylpiperidine-1-carboxylic acid (racemic)

E E

KE. - E - and I take poshi o shchi and ooo nie eni ptn nnnntntnnnnntnnzr s RIRRIU, s v - manso, ee and A DME, BUT and AH a a Go) Go)

AK AJ.

In a Mg purged flask, to a mixture of 4-((3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-2,6-trans-diisopropylpiperidine-1-carboxylic acid isopropyl ether (0 .24 mmol, 148 mg) add Pa(RPPz)" (0.05 mmol, 75 mg), 1-methylpyrazole-4-boronic acid pinacone ester (0.36 mmol, 75 mg) and sodium bicarbonate (0.46 mmol , 40 mg) in DME and NgO. The reaction mixture is heated at 9570 for 2 h. After the separation of the aqueous layer, the organic layer is filtered, washed with brine and dried over Mag250O4. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of n-hexane /ethyl acetate) and obtain isopropyl ether 4-((3-chloro-5-trifluoromethylbenzyl)-I|5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)-2 ,6-trans-diisopropylpiperidine-1-carboxylic acid (107 mg, 72905);

IR-MS ti/: 621.94 (Ma-1G), retention time 2.59 min (conditions A).

Example 33: Synthesis of 4-|(3-chloro-5-trifluoromethylbenzyl)-(5-furan-3-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether. - IS

Ko and E

And how is Is: EL

I y and mech E Maya IF slya o v a ak shishsh e uv g 2. they i Zhde i SHHI i M ne i sh ne A mya what? Man, Ko! we mak: you but not shk she vo nina I

And A - and 7 sho and - ! ro; b M Y i oo ra

A mixture of 4-(5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino!-2,6-diethylpiperidine-1H-carboxylic acid isopropyl ether (0.1 mmol, 59 mg), 2 -furan-3-yl-4,4,5,5-tetramethyl-

I1,3,2Idioxaborolane (0.15 mmol, 29 mg), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11.5 mg/g) and sodium bicarbonate (0.2 mmol, 17 mg) in 1 ,2-dimethoxyethane (1 ml) and water (0.4 ml) are heated to 957C and stirred for 3 hours. The mixture is cooled to room temperature and then water is added. The mixture is extracted using SNeSi. The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EIOAc) and isopropyl ether 4-((3-

chloro-5-trifluoromethylbenzyl)-(5-furan-3-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (34 mg, 5995); IER-MO t/2: 579 (M--1)", retention time 2.60 min (conditions A).

The following compounds are obtained according to the method of example 33.

IS

IS

E VI me 2 yes

M M

M vi me! W! Her ve | ER-MS t/liMitr | Holding time (min) 6) o o /y 1 r; p; 611 2.54 (conditions A) o-B 7X 05.0 i t si M M 2 - DI; 579 2, A2 (conditions A) 4 and; o-B 7u?

AND

M.

SI h u

Z , AH 593 2, A49 (conditions A) o-B 7X

From that and their 4 "VI and M 675 2.21 (conditions A) In 7 M o-in 7X

M ich si M; 7

I hear 590 2.20 (conditions A) o-B 7x?

E ro. Sh re | - x ra 6o8 2.56 (conditions A) o-8 7X o0o-lk si 47 o. Х 7 is the ratio 620 2.73 (conditions A) о-8 7Х?

IS

IS

"V gu 607 2.62 (conditions A) " no-B on y 5 "7 DI; BOB 2.60 (conditions A) with . no-B on / o - (c) / U a YAZ 620 2.24 (conditions A) -- xx YM o-v food

And there are the same 5 11 Ka «x 590 2.20 (conditions A) o-8 7x?

J

Э Э syvyh shkne 12 times 624 2.12 (conditions A) o-B 7x?

The following compounds are obtained according to the method of example 33.

IS

And you had too

AND

MM

998 in me! IN! | Vg | OER-MS tudiMy Retention time (min) o o U // ro) - 1 . ri; ba 5.78 (conditions B) o-B

Well xx

SI p 2 i 641 5.97 (conditions B) o-8

7 more?

M. m si t u /

FROM, TO; 655 5.52 (conditions B) o-B 7X

Example 34: Synthesis of isopropyl ether (2K,4P,65)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-thiazol-2-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidin- 1-carboxylic acid

E E o se S Y sho i S

What SHY Z - M p B she M - v s se v sh Х

U. said, "

JH. then SHVY still tolusl D.

M E IM vi I vi

A mixture of isopropyl ether (25,4K,6K)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (100 mg . for 3 h at 13070. The mixture is cooled to room temperature and the obtained residue is purified by PTLC to give isopropyl ether (2kK,4k,65)-4-(3-chloro-5-trifluoromethylbenzyl)-(5-thiazole-2- ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (63 mg), IR-MS m/: 596 (Ma-1H", retention time 2.59 min (conditions A).

The following compounds are obtained according to the method of example 34.

Mmm Product / | 1ER-MS t/d im Retention time (min) and I Si p

МУ 5 ц Ж | in 1 hour 595 2.65 (conditions A) breath

M. Vi and I. Si

E su

Mk dm 2 sh. 5VO 2.56 (conditions A) breath

M. v

Example 35: Synthesis of isopropyl ether (2K,4,65)-4-(3-chloro-5-trifluoromethylbenzyl)-|5-(1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)- 2,6-dimethylpiperidine-1-carboxylic acid in. - as or GU E shchi with Z ! | y De She carts with -0k her m ra Shk G 8 K . T ra Y y M i I. u ty TU RAN iya m kove

Ku Y nos DY ME blue 5 Y 00 dmElШS |; Mk! S i lokh she young Ge mmM Ne Y "7 still I J she re m o i M i y 8 A shya shin, I oo el

A mixture of isopropyl ether (2K,A4Kk,65)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-dimethylpiperidine-1-carboxylic acid (54 mg , 0.0958 mmol), 1-(tetrahydropyran-2-yl)-4-(4,4,5,5-tetramethyl-(1,3,2|dioxaborolan-2-yl)-1H-pyrazole (0.144 mmol ), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11 mg) and sodium carbonate (0.2 mmol, 20 mg) in 1,2-dimethoxyethane (1 mL) and water (0.2 mL) are heated to 90"C and stirred for 6 h. The mixture was cooled to room temperature and then 2 M methanolic solution of NH was added. After stirring for 1 h, the mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Mag5O4, filtered and concentrated under reduced pressure. The obtained residue is purified by PTLC (eluent: a mixture of hexane/E(OAc) and isopropyl ether (2K,4Kk,65)-4-((3-chloro-5-trifluoromethylbenzyl)- I(5-(1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)-2,6-dimethylpiperidin-1-ka carboxylic acid (6 mg); IR-MS t/2: 551 (М-А1Г), retention time 2.29 min (conditions A).

The following compounds are obtained according to the method of example 35.

Me | Product | IER-MSt/gIMet g | Holding time (min)

E E

E E N E E E E

E E M E E

Y m sur Ku t i bob y Sh bo

M M di ri y E y si M Y si

E x E

I m "in bu" mm ех 2 С 551 2.23 (conditions A) St tm m iv: in

Example 36: Synthesis of isopropyl ether /(2K,4Kk,65)-4-(5-aminopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid g. s y Y SI ru A ru short VI add MN.

Iv A g MN S V

MOM pe radavra), BINAF (raci h. M they: - TsOMa, toluene A S

M n. in in

A mixture of isopropyl ether (2K,A4Kk,65)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-dimethylpiperidine-1-carboxylic acid (365 mg . After cooling the mixture to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over Mag50O»m, filtered and concentrated under reduced pressure. The resulting residue is dissolved in THF (4 ml) and 2 M aqueous solution of NS is added (4 mL). The mixture was stirred for 30 min and cooled to 070. A 5 M aqueous Mahon solution was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over

Mag25O4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/E(OAc) mixture) and isopropyl ether (28,48,65)-4-((5-aminopyrimidin-2-yl)-(3-chloro- 5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (253 mg); IER-MS t/g: 528 (Ma-1|", retention time 2.16 min (conditions A).

The following compound is obtained according to the method of example 36.

Me | Product | IER-MS t/gmMyH in Yi se k.e EE y y EE E

Kr schu mem mem 1 bob 562 2.09 (conditions A) bob

M M o v

Example 37: Synthesis of isopropyl ether (2K,4E,65)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-tetrazol-1-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidin- 1-carboxylic acid

E E Y y E E teg er SI cheh i p 2 re MN, I meh We

Hee hee

M m mam", triethylorto f or miat IOM

AH What ve "M Y M Z oo i r r

To a mixture of isopropyl ether (2K,4K,65)-4-|Y(5-aminopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid ( 74 mg, 0.140 mmol) in acetic acid (1 mL) was added triethoxymethane (35 μL, 0.2 mmol). After stirring the mixture at 7572; sodium azide (27 mg, 0.420 mmol) was added over 30 min and stirred at 807C for 3 h. After cooling the mixture to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over NaCl5O, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(As) and isopropyl ether (2K,4,65)-4-I(3-chloro-5-trifluoromethylbenzyl)-(5-tetrazole- 1-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (70 mg); IR-MS t/l: 581 (Ma1|", retention time 2.42 min (conditions A) .

The following compound is obtained according to the method of example 37.

Me | Product | 1ER-MS t/g (My|; g.i yiv shchi E

E vo0MeM E E

M in Ku

MK mm 1 bob 615 2.35 (conditions A) bob

M M

Example 38: Synthesis of isopropyl ether (2K,4K,65)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-

1,2,A)griazol-4-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid

E E and E

E ko; ra shi bi -k sh a | that

Ж Ш 2 Х N dor M ii Ж nesu A i

MOm not MM mon you A

She TM VSI, EBM, pyridine schi KK

M "M and more

And r

A mixture of isopropyl ether (28,48,65)-4-(5-aminopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (65 mg, 0.123 mmol), 1,2-diformylhydrazine (33 mg, 0.369 mmol), TMSOCI (156 μL, 1.23 mmol), and triethylamine (103 μL, 0.739 mmol) in pyridine (1 mL) were stirred at 95722 for 16 h. After cooling the mixture to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over Ma»5O»4, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of methanol/dichloromethane) and isopropyl ether (2kK,4Kk,65)-4-(3-chloro-

B5-trifluoromethylbenzyl)-(5-(11,2,A|griazol-4-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (51 mg); IR-MS t/2 : 580 (M.-1)", retention time 2.24 min (conditions A).

Example 39: Synthesis of isopropyl ether (2K,4P,65)-4-((3-chloro-5-trifluoromethylbenzyl)-|5-(2-oxoimidazolidin-1-yl)-pyrimidin-2-yl|-amino)- 2,6-diethylpiperidine-1-carboxylic acid g si E Y - o H

ET Mon E Mon SI 5th

In MN! We are 2 river om

Her 1 Gosmbtya i tm tolusl TMM re 23Man, dme ro

Go) and psyushigga

And r

A mixture of isopropyl ether (28,48,65)-4-(5-aminopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (74 mg, 0.140 mmol) and 2-chloroethyl isocyanate (34 μl) in toluene (1 ml) were stirred at room temperature for 1 h. Water is added to the mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over Ma»5O»4, filtered and concentrated under reduced pressure. The resulting residue is filtered through a layer of silica gel and the filtrate is concentrated under reduced pressure. The resulting residue was dissolved in DMF (1 mL) and sodium hydride (6095 in oil: b mg, 0.147 mmol) was added. After stirring for 1.5 hours. add water and extract with ethyl acetate. The organic layer is washed with brine, dried over NaCl5Ox, filtered and concentrated under reduced pressure to obtain isopropyl ether (2kK,4E,65)-4-(3-chloro-5-trifluoromethylbenzyl)-|5-(2- oxoimidazolidine-1 -yl)-pyrimidin-2-yl(amino)-2,6-diethylpiperidine-1-carboxylic acid; IER-MS t/2: 597

IMA1G, retention time 2.33 min (conditions A).

Example 40: Synthesis of isopropyl ether 4-(3-chloro-5-trifluoromethylbenzyl)-(5-(2-oxoxazolidin-3-yl)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1- carboxylic acid. ghai si MN gi s

ET nt - M 2 E shchy y so I V Ya nn, shchi - "I o ya mak VG y no S tk

M sta sY,Kkso, o x i yuyu re m-th 1,4-dioxane -- M N a - M

J. ra

A mixture of 4-(5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.05 mmol, 30 mg), oxazolidine- 2-one (0.05 mmol, 5 mg), copper iodide (0.05 mmol, 10 mg), trans-cyclohexane-1,2-diamine (0.05 mmol, 6 mg), and potassium carbonate (0.1 mmol, 14 mg) in 1,4-dioxane (0.3 ml) is heated to 110°C and stirred for 19 h. The mixture is cooled to room temperature and then an aqueous ammonia solution is added. The mixture is extracted with SNecSi.

The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on a silica gel column

(eluent: a mixture of n-hexane/E(OAc) and obtain isopropyl ether 4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(2-oxooxazolidin-3-yl)-pyrimidin-2-yl|-amino )-2,6-diethylpiperidine-1-carboxylic acid (26 mg, 8795); I EP-MS t/27: 598 |M-A1)", retention time 2.44 min (conditions A).

The following compounds are obtained according to the method of example 40.

IS

IS

E VI me B2

CA

IOM

M. v

Mmm in | weight MER-MS fluff Mir |Retention time (min) ze no ! Porridge 573 2.56 (conditions A) M I -proline instead of trans-cyclohexane-1,2-diamine in td Dt 2| MM 573 2.18 (conditions A) | NM Dimethylaminoacetic acid instead of trans-cyclohexane-1,2-diamine

N

NM ra o o ro 4. oon 812 2.33 (conditions A) non o o ro Y » yo; "OH 812 2.31 (conditions A) non

About 7 in (6) about "B - 637 2.31 (conditions A) A

I don't

SI Dt DI 7| is mae 611 2.43 (conditions A) NK (6) (6) on on roi АХ vi-0.44 і , m (hexane-EgOds-1:2) ny

МН МН с т прех "7 612 2.20 (conditions A) НМ 6) 6)

Example 41: Synthesis of tert-butyl ether 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-|5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-6-ethylpiperidin-1- carboxylic acid (racemic).

E E E E vv y

E ge E o nn -o M pe On i M- On

ХК | and he

MM Ом 7 АХ clearly precipitates Fe pan ly y to r

A mixture of 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (0.05 mmol, 32 mg), 2-bromomethanol (0.15 mmol, 12 μl) and potassium carbonate (0.3 mmol, 40 mg) in DMF (0.2 ml) were stirred at 60°C for 20 h and cooled to room temperature. Water was added to the mixture and the mixture was extracted with EtOAc. The combined organic layer was dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: a mixture of hexane/s(OAc) and receive tert-butyl ether) of 2-benzyl-4-(33-chloro-5-trifluoromethylbenzyl)-|5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-6-ethylpiperidine-1-carboxylic acid (23 mg, 6790); IER-MS t/:: 683 (Ma1|", retention time 2.61 min (conditions A).

Example 42: Synthesis of tert-butyl ether /2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-methoxycarbonylmethoxypyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carboxylic acid (racemic) .

E E E E

E Lya vn

E TE E | Te E a yan ON yari o y

Man, dmF and her H. what are you SS I I -- --

To a solution of tert-butyl ether of 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (0.05 mmol, 32 mg) in DMF (0.2 ml) at 0"C add sodium hydride (6095 suspension in oil, 0.06 mmol, 24 mg/g) and stir at room temperature for 15 min. Add to the mixture at 0"C bromoacetic acid methyl ether (0.15 mmol, 12 μL) and stirred at room temperature for 2 h. Saturated aqueous citric acid solution was added to the mixture and the mixture was extracted with EOAc. The combined organic layer was dried over Ma5Ox4, filtered and concentrated at The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EtOAc) and 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-methoxycarbonylmethoxypyrimidine-2) tert-butyl ether is obtained -yl)-amino|-b-ethylpiperidine-1-carboxylic acid (25 mg, 7095); IER-MO t/2: 711 (MaА1/", retention time 2.67 min (conditions A).

Example 43: Synthesis of tert-butyl ether /2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-carboxymethoxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (racemic) .

E E

R. E v.g le p NI her ore o yi rya i o. AH he nn | | m 9 IM Mao z. her t-77 sh M tgFf / Meon M ha ovo

To a solution of tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-methoxycarbonylmethoxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (0.028 mmol, 20 mg ) in

An aqueous solution of sodium hydroxide (1 M, 0.085 mmol, 85 μl) was added to THF (0.5 ml) and methanol (0.5 ml) at room temperature and stirred at room temperature for 15 h. An aqueous solution of hydrochloric acid (1 N.) is added to the mixture and the mixture is extracted with EtOAc. The combined organic layer is dried over Na»5O», filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and tert-butyl ether /2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-carboxymethoxypyrimidine-2 -yl)-amino|-6-ethylpiperidine-1-carboxylic acid (25 mg, 7095); IER-MS m/2: 697 (Ma1|", retention time 2.58 min (conditions A).

The following compound is obtained according to the method of example 43.

Me | TER-MS product t/h (Mate | Retention time (min) 6) 0)

E E -" E E Va

SI SI

E shko E -

Tk Tk 1 ob 623 2.18 (conditions A) ob

M M

Example 44: Synthesis of 2-benzyl-4-(33-chloro-5-trifluoromethylbenzyl)-|5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-6-ethylpiperidine-1-carboxylic acid isopropyl ether ( racemic).

E E

E E

E | ry and tan - in what ron v ko i and m A ri ta i o o --

A mixture of 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid isopropyl ether (0.12 mmol, 70 mg) , 2-bromoethanol (0.72 mmol, 50 μl) and potassium carbonate (0.72 mmol, 100 mg) in DMF (0.5 ml) were stirred at 60"C for 13 h and cooled to room temperature. To the mixture water is added and the mixture is extracted with EtOAc. The combined organic layer is dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/E(OAc) mixture) to give 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-1|5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-b-ethylpiperidine-1-carboxylic acid isopropyl ether (56 mg , 7495); IER-MS t/l: 635 |MA1), retention time 2.56 min (conditions

AND).

Example 45: Synthesis of isopropyl ether of 2-benzyl-4-(33-chloro-5-trifluoromethylbenzyl)-|5-(2-methanesulfonylethoxy)-pyrimidin-2-yl|-amino)-6-ethylpiperidine-1-carboxylic acid ( racemic). "IS

Co.

E m ke or S g. v

Y y y E She a GO rev Y I zho t: ey ЕРp. on polymeonamu no st i lo I sho ibzhohdichlon DEADOTTO fu g y i ev dyk zhi KO UUUUUUUUU U s dy" - --

I a and Ey and pr» i o o atza sht - Her and km ke zhu still

There is a myth about roads and even a poor M du (

To the mixture of isopropyl ether 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-

amino|-6-ethylpiperidine-1-carboxylic acid (0.05 mmol, 30 mg), 2-methylsulfonylethanol (0.075 mmol, 7 μl) and triphenylphosphine on a polymer support (1.41 mmol/g, 0.1 mmol, 71 mg ) in THF (0.5 ml) at room temperature, add DEAD (0.075 mmol, 34 μl) and then stir for 15 h. The mixture is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EthOAc) and isopropyl ether 2-benzyl-4-((33-chloro-

B5-trifluoromethylbenzyl)-(5-(2-methylsulfanylethoxy)-pyrimidin-2-yl|-amino)-b-ethylpiperidine-1-carboxylic acid (22 mg, 66965)

A solution of 2-benzyl-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(2-methylsulfanylethoxy)-pyrimidin-2-yl|-amino)-b6-ethylpiperidine-1-carboxylic acid isopropyl ether (0.033 mmol , 22 mg) in СНоСи" (1 ml) is cooled to 0"С and 3-chlorobenzenecarboperoxyacid (0.13 mmol, 23 mg) is added. The mixture is allowed to warm to room temperature and stirred for 2 hours. A saturated aqueous solution of hydrogen carbonate is added to the mixture of sodium and the mixture is extracted with СНоСі". The combined organic layer is concentrated under reduced pressure. The resulting residue is purified by column chromatography with silica gel (eluent: a mixture of hexane/EthOAc) to give isopropyl ether 2-benzyl-4-(3- chloro-5-trifluoromethylbenzyl)-I(5-(2-methanesulfonylethoxy)-pyrimidin-2-ylI-amino)-6-ethylpiperidine-1-carboxylic acid (21 mg, 9295); IER-MS t/2: 697 | M--11", retention time 2.58 min (conditions A).

Example 46: Synthesis of 2-benzyl-4-(33-chloro-5-trifluoromethylbenzyl)-|5-(2-methoxyethoxy)-pyrimidin-2-yl|1-amino)-b6-ethylpiperidine-1-carboxylic acid isopropyl ether (racemic).

IS

E E era Yasya si

And the matter is more

Ko ST retro km A max MOms s ia vya A E I i; shield t t M" -

A and I to wa de shi t

A mixture of 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid isopropyl ether (0.12 mmol, 70 mg) , 1-bromo-2-methoxyethane (0.72 mmol, 50 μL), sodium iodide (0.12 mmol, 18 mg), and potassium carbonate (0.72 mmol, 100 mg) in DMF (0.5 mL) were mixed for 15 h. Water was added to the mixture and the mixture was extracted with EtOAc. The combined organic layer was dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: a mixture of hexane/ E(OAc) and obtain isopropyl ether 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-|5-(2-methoxyethoxy)-pyrimidin-2-yl|-amino)-b-ethylpiperidine-1- carboxylic acid (7 mg, 995); IER-MS t/2: 649 |Ma1|", retention time 2.72 min (conditions A).

Example 47: Synthesis of 4-(3-chloro-5-trifluoromethylbenzyl)-(5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether. g. in 7 what and che - Po shchi chen t koso, di F "ya what ro and don - in oto oo more

A mixture of 4-|(3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.12 mmol, 64 mg), 2 -bromoethanol (0.72 mmol, 50 μl) and potassium carbonate (0.72 mmol, 100 mg) in DMF (1 ml) were stirred at 60°C for 16 h and cooled to room temperature. Water and a mixture were added to the mixture extracted with the help of SNeSi". The combined organic layer is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/w(OAc)) and 4-(3-chloro-5-trifluoromethylbenzyl) isopropyl ether is obtained )-I(5-(2-hydroxyethoxy)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (61 mg, 8995); IER-MO t/2: 573 (Ma- 1)", retention time 2.60 min (conditions A).

The following compounds are obtained according to the method of example 47. iMme| o Product | ER-MS t/e MAT | Holding time (min)

E E

E s c) in ve i 4 chapter 643 5.83 (conditions B) vky oh

M. v

IS

IS

E SI

Maybe

AND

IOM

2 o'clock 585 5.98 (conditions B) Ve it

M

7

IS

IS

E SI and !

With 557 5.78 (conditions B) 77 Man instead

K»SOz

M

7

Example 48: Synthesis of 4-(33-chloro-5-trifluoromethylbenzyl)-1|5-(2-methoxyethoxy)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether.

E Ii E

They ate in I am a PC. ET Shk: I am Mr. Shchi she yi r sh a

EI. | about the use of ERA on the polymeric surface of Sk Y v. E tgFf M still in B nal TT, Ya

I " i sr A

And aYta -e Shk M

To a mixture of 4-((3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.1 mmol, 53 mg), of 2-methoxyethanol (0.15 mmol, 12 μL) and triphenylphosphine on a polymer support (1.41 mmol/g, 0.2 mmol, 142 mg) in THF (1 mL) at room temperature was added DEAD (0.15 mmol, 68 μl) and then stirred for 15 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: a mixture of hexane/b(OAc)) to give isopropyl ether 4-(3-chloro- 5-trifluoromethylbenzyl)-I(5-(2-methoxyethoxy)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (51 mg, 8895); IER-MO t/2: 587 (Ma-1)", holding time 2.70 min (conditions A).

Example 49: Synthesis of 4-(3-chloro-5-trifluoromethylbenzyl)-(5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl1-amino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether .

and others: with

And HER and she and rr re Xia Z y

TE MU and sia V For o det nti si, , ih a VE; on popymernoy sublezhke Y sh || and Z

She ak m z chi s r y Z chn t Sh

To a mixture of 4-(3-chloro-5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.1 mmol, 53 mg), 2 -morpholin-4-yl-ethanol (0.15 mmol, 18 μl) and triphenylphosphine on a polymer support (1.41 mmol/g, 0.2 mmol, 142 mg) in THF (1 ml) at room temperature is added DEAD ( 0.15 mmol, 68 μl) and then stirred for 15 h. The mixture is filtered and the filtrate is concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of DXM/EUN) and isopropyl ether 4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(2-morpholine-4-ylethoxy)-pyrimidine- 2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (45 mg, 7095); IR-MS t/2: 642 (Ma-1)", retention time 2.18 min (conditions A).

The following compounds are obtained according to the method of example 49.

Me | // Product | 1ER-MStudyMetg | Time of keeping St.)

IS

IS

E Si o. what"

MM no. 1 ob 612 2.19 (conditions A) i

M. v

IS

IS

E SI

AND

MOM NU or 2 chapter 4.91 (conditions B) her

M. v

IS

IS

E SI uyu mm so no to live

From chapter 623 2.16 (conditions A) tu;

M. v

IS

IS

E Si (c) dulOon

MM no, 4 ob 612 2,13 (conditions A) Sy

M. v

Example 50: Synthesis of 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(4-ethoxycarbonyloxazol-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether

E E

E a- R Z en shi ono

NU M:

Shlya r y peren y da Chyny ve m

It is sl ra rya man, blows STILL OO

Eat 9 yo from the ravine where

To a solution of 2-benzyl-4-(4-ethoxycarbonyloxazol-2-ylamino)-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (0.63 mmol, 288 mg) in DMF (3 ml) at 0"C is added sodium hydride (6090 suspension in oil, 1.26 mmol, 50 mg) and stirred at room temperature for 20 min. 1-bromomethyl-3-chloro-5-trifluoromethylbenzene (0.94 mmol, 155 μl) and stirred at room temperature for 3 h. Water is added to the mixture and the mixture is extracted with EtOAc. The combined organic layer is dried over Na»5O», filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and tert-butyl ether 2-benzyl-4-|(3-chloro-5-trifluoromethylbenzyl)-(4-ethoxycarbonyloxazole-2- yl)-amino1|-6-ethylpiperidine-1-carboxylic acid (178 mg, 4395); IER-MS t/:: 650 (Ma1|", retention time 2.75 min (conditions

AND).

The following compound is obtained according to the method of example 50.

IS

Eh

KM vi

Me | IN! | 77777772 | OER-MS tams Retention time (min)

SI ot 0-7 4 - ra 5TA 2.69 (conditions A) « M o

Example 51: Synthesis of 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(4-hydroxymethyloxazol-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether

E E higher C plums

What is Bk in; o-k and ON ih Z . p

MM certain MM I from tgF EYUN tr

Zk M and M not about --

To a solution of tert-butyl ether of 2-benzyl-4-((3-chloro-5-trifluoromethylbenzyl)-(4-ethoxycarbonyloxazol-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (0.03 mmol, 20 mg) in THF (0.3 ml) and ethanol (20 μl) at 0"C, add a solution of lithium borohydride (2 M solution in THF, 0.15 mmol, 75 μl) and stir at room temperature for 3.5 h. Add to the mixture at room temperature

EYUODAs and stir for 10 minutes. The mixture is cooled to 0"C and then an aqueous solution of hydrochloric acid (1 N) is added dropwise. The mixture is extracted with dichloromethane. The combined organic layer is concentrated under reduced pressure. The resulting residue is purified by preparative TLC

(eluent: a mixture of hexane/e(OAc) and receive tert-butyl ether /2-benzyl-4-|(3-chloro-5-trifluoromethylbenzyl)-(4-hydroxymethyloxazol-2-yl)-amino|-b-ethylpiperidine -1-carboxylic acid (11 mg, 6395); IER-MS t/:2: 608 (Ma-1|", retention time 2.46 min (conditions A).

The following compound is obtained according to the method of example 51.

IS

E in : ;B1 m"

KM in me | in 777777 weights/ | ER-MS t/amMii Retention time (min) c) on

Example 52: Synthesis of 4-|(3-chloro-5-trifluoromethylbenzyl)-(4-methyloxazol-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether

E E

E E

SI

E si What about he about

M M M M

What is it?

M mesm Kh

Sh a

To a mixture of 4-(3-chloro-5-trifluoromethylbenzyl)-(4-hydroxymethyloxazol-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.05 mmol, 27 mg) and iodide sodium (0.5 mmol, 75 mg) in acetonitrile (0.2 ml), add trimethylsilyl chloride (0.5 mmol, 63 μl) and stir for 24 h. A saturated aqueous solution of sodium thiosulfate is added to the mixture. The mixture is extracted with EtOAc.

The combined organic layer is dried over Ma»5Ox4, filtered and concentrated under reduced pressure.

The resulting residue is purified by preparative TLC (eluent: hexane/EtOAc mixture) and 4-((3-chloro-5-trifluoromethylbenzyl)-(4-methyloxazol-2-yl)-amino|-2,6-diethylpiperidine isopropyl ether is obtained -1-carboxylic acid (5 mg, 2195); IER-MS t/: 516 (Ma-1|", retention time 2.12 min (conditions

AND).

Example 53: Synthesis of 4-I(3,5-bis-trifluoromethylbenzyl)-(2H-tetrazol-5-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether

E E in r E E in Z E she and. I'm Her MM ; MN m 00 Mom, MNASI V ne and dme Sho ao-sza a p

To a mixture of 4-I|(3,5-bis-trifluoromethylbenzyl)-cyanoamino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.365 mmol, 180 mg) and ammonium chloride (1.83 mmol, 100 mg) sodium azide (1.825 mmol, 120 mg) is added in DMF at room temperature. The mixture is heated to 60"C and stirred for 12 hours. Ammonium chloride (1.83 mmol, 100 mg) and sodium azide (1.825 mmol, 120 mg) are added to the mixture and stirred at 60"C for 9 hours. The mixture is cooled to room temperature and then water is added.

The mixture is extracted with EtOAc. The combined organic layer was dried over Na»5O»m, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: a mixture of DXM/Meon) and 4-(3,5-bis-trifluoromethylbenzyl)-(2H-tetrazol-5-yl)-amino|-2,6 isopropyl ether is obtained -diethylpiperidine-1-carboxylic acid (85 mg, 4395);

IER-MS ti/: 537 (Ma-1)", retention time 2.49 min (conditions A).

Example 54: Synthesis of isopropyl ether 4-Y((3,5-bis-trifluoromethylbenzyl)-(5-methyl-(1,3,4|oxadiazol-2-yl)-amino|-2,6-diethylpiperidine-1- carboxylic acid

E E still -E g r o t TE ET Still E ne mM yo M nku s A r acetic anhydride

Z mesm 7 m M ese oo

A solution of 4-((3,5-bis-trifluoromethylbenzyl)-(2H-tetrazol-b-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.056 mmol, 30 mg) and acetic anhydride (0.28 mmol, 27 μl in acetonitrile (0.5 ml) is stirred in a microwave reactor at 120 C for 1 h. The solution is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/hBiOAc ( 11 mg, 3695); IER-MS t/2: 551 (Ma1|", retention time 2.51 min (conditions A).

Example 55: Synthesis of 4-(3,5-bis-trifluoromethylbenzyl)-(2-(2-methoxyethyl)-2H-tetrazol-5-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether

A la

E HO TE mountain TE -sh- MM, to M shko -.MN me B) more Naltyaya mm and to ER» on a polymer carrier t " - EAD, THF A tk DEAD m oo ota

To a mixture of isopropyl ether /4-(3,5-bis-trifluoromethylbenzyl)-(2H-tetrazol-5-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (0.1 mmol, 54 mg), of 2-methoxyethanol (0.15 mmol, 12 μL) and triphenylphosphine on a polymer support (1.41 mmol/g, 0.2 mmol, 142 mg) in THF (1 mL) at room temperature was added DEAD (0.15 mmol, 68 μl) and then stirred for 15 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and isopropyl ether 4-(3,5-bis-trifluoromethylbenzyl)-(2-(2-methoxyethyl)-2H-tetrazole-b5 is obtained -yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (41 mg, 9195); IER-MO t/2: 595 (M.-1)", retention time 2.63 min (conditions A) .

Example 56: Synthesis of 4-(3,5-bis-trifluoromethylbenzyl)-|(2-(2-hydroxyethyl)-2H-tetrazol-5-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether

E E E E

E E E. E rya r v su - MAM, -t MM, - MN t M - you p on re Mao", dme / ma u r v

A mixture of 4-((3,5-bis-trifluoromethylbenzyl)-(2H-tetrazol-b-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.1 mmol, 54 mg), 2 -bromoethanol (0.5 mmol, 35 μl) and potassium carbonate (0.5 mmol, 70 mg) in DMF (1 ml) are stirred at 60"C for 2 hours, then cooled to room temperature. Add to the mixture. . and the mixture is extracted with EtOAc. The combined organic layer is dried over Ma»5O4 and then concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: a mixture of hexane/E(OAc)) to give isopropyl ether 4 -(3,5-bis-trifluoromethylbenzyl)-|2-(2-hydroxyethyl)-2H-tetrazol-5-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (49 mg, 8495); IER -MS t/:: 581 |МА1)", retention time 2.51 min (conditions

AND).

Example 57: Synthesis of isopropyl ether 4-Y((3,5-bis-trifluoromethylbenzyl)-(1-methyl-1H-(I1,2,A|griazol-

3-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid

E E

E uk c. E E 4 r kt I Me -b7 pk that M- zd: M, VNa tgF tk

WITH

I you va popShschptta still ry AK

To a solution of isopropyl ether 4-|(3,5-bis-trifluoromethyl-benzoyl)-(1-methyl-1 H-(1,2,4Hriazol-3-yl)-amino|-2,6-diethylpiperidine-1- carboxylic acid (0.28 mmol, 160 mg) in THF at room temperature is added borane complex with tetrahydrofuran in THF (1.17 M, 1.4 mmol, 1.2 mol).The mixture is heated to 5070 and stirred for 5 h. The mixture is cooled to room temperature, and then methanol is added at 0"C and stirred at 40"C for 30 min. The mixture is concentrated under reduced pressure. The resulting residue is purified by chromatography on a silica gel column (eluent: dichloromethane/MMeOH mixture) and isopropyl ether 4-|(3,5-bis-trifluoromethylbenzyl)-(1-methyl-1 H-

I1,2,A)Hygriazol-3-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (42 mg, 2790); IER-MS t/2: 550 (Ma-1|), retention time 2.53 min (conditions A).

The following compounds are obtained according to the method of example 57.

IS

E about mg o in me | uti | 77777/va/////// | EP-MS topics Retention time (min)

E Mem

IS

1 "M-551 2.63 (conditions of A

An bell 2 550 2.69 (conditions A ra Zhe (conditions A)

Example 58: Synthesis of tert-butyl ether /2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carboxylic acid

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

E E E E

M o u

Ai o

IOM loeros meon

M. Mara

A mixture of tert-butyl ether 2-benzyl-4-|(5-benzyloxypyrimidin-2-yl)-(3,5-bis-trifluoromethylbenzyl)-

of amino|-6-ethylpiperidine-1-carboxylic acid (0.41 mmol, 300 mg) in methanol is stirred in a hydrogen atmosphere at room temperature for 1 hour. The mixture is filtered and the resulting solution is concentrated under reduced pressure to obtain tert-butyl ether 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-b-ethylpiperidin-1 -carboxylic acid (250 mg, 9595); IR-MS t/:: 639 (Ma-1|), retention time 2.59 min (conditions A).

Example 59: Synthesis of isopropyl ether //2-benzyl-4-|(3-chloro-5--trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-b-ethylpiperidine-1-carboxylic acid

I am E and E

E SI kA and si u u t-x ALL"; SNeSI" meme 0

M M

Zh S

To a solution of 2-benzyl-4-I((5-benzyloxy-pyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-6-ethylpiperidine-1-carboxylic acid isopropyl ether (0.72 mmol , 490 mg) in dichloromethane at 0"C, add a solution of boron trichloride in dichloromethane (1 M, 1.1 mmol, 1.1 mol) and stir at 0"C for 4 hours. Add a solution of boron trichloride to the mixture at 0"C in dichloromethane (1 M, 1.1 mmol, 1.1 ml) and stirred at 0"C for 1 h. Methanol (1 ml) was added dropwise to the mixture at 0"C. Water was added to the mixture and the mixture was extracted with dichloromethane. The combined organic layer was dried over Mabose, filtered and concentrated under reduced pressure. 5-trifluoromethylbenzyl)-(5-hydroxypyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid (417 mg, 9895); IER-MO t/2: 591 (M.-1|", time retention 5.34 min (conditions B).

The following compound is obtained according to the method of example 59.

IS

E about -B82

M o v

Me | VEE! HER 77777777 v2 | ER-MS tami Retention time (min) d on 1 "v u 529 2.60 (conditions A) "TM

Example 60: Synthesis of tert-butyl ether of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-cyclopropylpiperidine-1-carboxylic acid

E E E E E E

E E E E E and 9 Her. Shsh s o no Ge) de | t s Mn; "MN so zo

Z Mavn(osa SHY - obliquely, TgF S s to KK

A. dichloroethane rea t re y re y A Y

To a mixture of 2-benzyl-6-cyclopropyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (50 mg,

0.152 mmol) and 3,5-bis(--trifluoromethyl)benzylamine (45 mg, 0.167 mmol) in 1,2-dichloroethane (0.5 ml) under M2 atmosphere at room temperature add acetic acid (0.1 ml, 1 .74 mmol) and Mavn(OAds)»z (64 mg, 0.30 mmol). The mixture is stirred for 18 hours. and then the reaction is stopped with a saturated aqueous solution

MansoOz. The layers are separated and the aqueous layer is extracted with EOAc. The combined organic layer is washed with brine, dried over Mag5O4, filtered and concentrated under reduced pressure, and the crude product is used in the next step without purification.

Methyl chloroformate (0.023 mL, 0.3 mmol) was added to a solution of the crude mixture mentioned above and potassium carbonate (41.4 mg, 0.3 mmol) in THF (2.0 mL) under Mg atmosphere at room temperature. The mixture is stirred for 1 day and then the reaction is quenched with water. The layers are separated and the aqueous layer is extracted with EAs. The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to obtain 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-cyclopropylpiperidine-1-carboxylic acid tert-butyl ether (23 mg) with a yield of 2595 (in 2 x stages); IER-MS t/: 615 (MaА1|), retention time 5.63 min (conditions B).

Example 61: Synthesis of isopropyl ether /(25,48,6H8)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-cyanopyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carbon acid

E E z si ch s i shi ch M g b - t - dLOMRO(РРН,), --333333НННнНнН6Н ИЯ--Ш-ОО-йО nya o: Й

M sia 73 ono

A mixture of isopropyl ether (25,48,6H8)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (120 mg , 0.20 mmol), zinc cyanide (23.5 mg, 0.20 mmol) and

RA(PP3)a (12 mg, 0.01 mmol) in DMF (2 ml) in a nitrogen atmosphere was stirred at 1107C for 3.5 h.

The mixture is cooled to room temperature and the reaction is stopped with saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the organic layer is washed with brine, dried over Mag»50Ox, filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (hexane-ethyl acetate) to obtain isopropyl ether (25.4K,6K)-4-

I(3-chloro-5-trifluoromethylbenzyl)-(5-cyanopyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (100 mg); IER-MS etc/2: 537 (M--1)", retention time 5.05 min (conditions B).

Example 62: Synthesis of isopropyl ether (25,48,6H8)-4-(3-chloro-5-trifluoromethylbenzyl)-I|5-(2n-tetrazol-5-yl)-pyrimidin-2-yl|-amino)- of 2,6-diethylpiperidine-1-carboxylic acid with su z shk shi si i 2 i Y M

They and nya TI tim A

A. mam, MNusI MM

Art d

Mch Kha. I'm M

Still you

To a mixture of isopropyl ether (25.4K, 6kK)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-cyanopyrimidin-2-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (87 mg, 0.16 mmol) and ammonium chloride (86 mg, 1.6 mmol) in

Sodium azide (104 mg, 1.6 mmol) was added to DMF (1 mL). The mixture is stirred in a nitrogen atmosphere at 1007C for 5 hours. and cooled to room temperature. Water is added to the mixture and filtered and washed with a mixture of diethyl ether and hexane (1:11). The obtained residue is purified by chromatography on a column with silica gel (hexane-ethyl acetate) and isopropyl ether (25.4K,6K)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-(2H-tetrazole-5- yl)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (82 mg); IR-MS t/:: 580 (M.-1)", retention time 4.9 min (conditions B).

Example 63: Synthesis of isopropyl ether (25,48,6H8)-4-((3Z-chloro-B5-trifluoromethylbenzyl)-|5-(1H-imidazol-4-yl)-pyrimidin-2-yl|-amino) -2,6-diethylpiperidine-1-carboxylic acid

IS

IS

E sh M o, and SI

Zh s E MAX tr r s pe A ob a4M NS, ASON ob

And Y

And and

To a mixture of isopropyl ether (25.4K, 6kK)-4-(3-chloro-5-trifluoromethylbenzyl)-I|5-(1-trityl-1H-imidazol-4-yl)-pyrimidin-2-yl|- amino)-2,6-diethylpiperidine-1-carboxylic acid (170 mg, 0.20 mmol) in acetic acid (3 ml) at 0"С, a 4 M solution of HCl in ethyl acetate is added. The mixture is stirred at room temperature for 2.5 h and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and dichloromethane and the organic layer was washed with brine, dried over Mg5O", filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane) to give isopropyl ether (25,4E,6K)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1H-imidazol-4-yl)-pyrimidin-2-ylI-amino)-2,6- of diethylpiperidine-1-carboxylic acid (30 mg); IER-MS t/2: 579 (Ma-1)", retention time 4.11 min (conditions B).

Example 64: Synthesis of isopropyl ether (25,48,6H8)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1-isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl| -amino)-2,6-diethylpiperidine-1-carboxylic acid

IS

E N and U-v. that and M and still M re M | What else do they need?

And AH u

DM Yat g

I hak 9 Ii o7to t AJ

A mixture of isopropyl ether /(25,4H8,68)-4-((3-Chloro-5-trifluoromethylbenzyl)-I|5-(1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)- 2,6-diethylpiperidine-1-carboxylic acid (30 mg, 0.05 mmol), isopropyl iodide (15 μL, 0.15 mmol), and potassium carbonate (14 mg, 0.10 mmol) in DMF (0.5 mL) stirred at room temperature for 16 h. Water is added to the mixture and the mixture is extracted with dichloromethane. After concentrating the mixture under reduced pressure, the residue is purified by chromatography on a column with silica gel (hexane/ethyl acetate) and isopropyl ether (25.4K,6K)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1 -isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (8.4 mg); IER-MS ti/: 621 (MaA1)", retention time 2.59 min (conditions A).

The following compounds are obtained according to the method of example 64

E E

E E N

E a M E shchi MM

Her M I m mem m 1 o 595 5.02 (conditions B) Methyl iodide o

M M e E

IS

E a m- and s m-M

Im im ur br me - 2 ob 595 5.33 (conditions B) Methyl iodide bo

M M e E

E E

E tm E s Me hu M -- MN

Cr Cr

MK Methyliodide M

With 593 4.05 (conditions B) (Mann instead

K»COz)

M M in vi

IS

Y si g s

E Mah E Me fun - MN

MU and Kur

Mk Methyl iodide Mk 4 593 4.05 (conditions B) (Man instead of

K»COz)

ММ оо обо ра рач

Example 65: Synthesis of isopropyl ether (25,4H8,68)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1,1-dioxo-1-thiomorpholin-4-yl)-pyrimidin-2- ilI-amino)-2,6-diethylpiperidine-1-carboxylic acid

E company Shk t Geo r more

MkhpeKk is still in Shk Sho

Shi m g vi

To a solution of isopropyl ether (25,4H8,6H8)-4-((3-chloro-5-trifluoromethylbenzyl)-(5-thiomorpholin-4-ylpyrimidin-2-yl)-amino|-2,6-diethylpiperidin-1- of carboxylic acid (80 mg, 0.13 mmol) in dichloromethane (4 mL) at room temperature was added MHPBC (2.4 g, 0.31 mmol) and stirred for 16 h. The mixture was washed with saturated sodium bicarbonate solution and brine. Organic layer dried over Mdzoh, filtered and concentrated under reduced pressure. The resulting residue was purified by PTLC (Mn silica) to give isopropyl ether (25.4K,6Kk)-4-(3Z-chloro-5-trifluoromethylbenzyl)-|5-( 1,1-dioxo-1-thiomorpholin-4-yl)-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (3.87 mg); IER-

MS t/:: 646 (MaА1Г", retention time 2.02 min (conditions A).

Example 66: Synthesis of tert-butyl ether 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-|5-(4-carboxypiperidin-1-yl)-pyrimidin-2-yl|-amino)-6- ethylpiperidine-1-carboxylic acid (racemic)

ET Uk Dt v i t og TE FI dya E" sut su - t sho tr - mim is: r MM E. 1 YY ON tot still XX. zhi M sh- i what - oo oo -- -і-

A mixture of tert-butyl ether 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-|5-(4-ethoxycarbonylpiperidin-1-yl)-pyrimidin-2-yl|-amino)-b-ethylpiperidin-1 -carboxylic acid (35 mg, 0.05 mmol) in a mixture of EUN and THF in a ratio of 1:11 is stirred at room temperature for 13 hours. The mixture is concentrated under reduced pressure, acidified with a 1 M aqueous solution of NOSI and extracted with ethyl acetate. The mixture is concentrated under reduced pressure to obtain tert-butyl ether 2-benzyl-4-(3,5-bis-trifluoromethylbenzyl)-I(5-(4-carboxypiperidin-1-yl)-pyrimidin-2-yl|-amino) -6-ethylpiperidine-1-carboxylic acid (26 mg); IER-MS ti/l: 750 |MA1 |, retention time 2.39 min (conditions A).

The following compound is obtained according to the method of example 66.

Me| Product PER-MS t/2 (MAT | Retention time (min)

E E

Ri liv a Ri lu o ron ryu mem mem 1 ob 595 5.02 (conditions B) ob

M M

Example 67: Preparation of tert-butyl ether (25,45,68)-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-ethylpiperidine-1-carboxylic acid (enantiomer)

IS

E and E

E E

H

M7to7 zo

AND

Tert-butyl ether (25,45,6K)-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid is separated from racemic tert-butyl ether 2-benzyl -4-

I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid with the help of preparative NRH (column: OSI 7 μm, 21.2x250 mm; flow rate: 50 g/min; mobile phase: CO ", 1095

DMMELAPOS 100:7 isocratic); IER-MS t/l: 602 (М-А1|), retention time 2.57 min (conditions A), 5.16 min (conditions 0).

Example 68: Preparation of tert-butyl ether (25,45,68)-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(B-morpholin-4-ylpyrimidin-2-yl)-amino|- b-ethylpiperidine-1-carboxylic acid (enantiomer)

IS

E and E

E E ke

AND

MM

Sg

Tert-butyl ether (25,45,6)-2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amino|-6-ethylpiperidin- 1-carboxylic acid is separated from racemic tert-butyl ether 2-benzyl-4-((3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-ylpyrimidin-2-yl)-amino|-b-ethylpiperidin-1 - carboxylic acid using preparative chiral HPLC (column: Spigairak AO 20 μm 5x5 cm; flow rate: 100 ml/min; mobile phase: n-hexane/IPS 95:5); IR-MS ti/: 708 (Ma-1 /", retention time 2.57 min (conditions A), 8.06 min (conditions E).

Example 69: Preparation of isopropyl ether (25,45,65)-4-((3-chloro-5-trifluoromethylbenzyl)-15-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|- amino)-2,6-diisopropylpiperidine-1-carboxylic acid (enantiomer)

IS

IS ! /

E about M

Them

M

AND

IOM about vi

Isopropyl ether (25,45,65)-4-((3-chloro-5-trifluoromethylbenzyl)-I(5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino )-2,6-diisopropylpiperidine-1-carboxylic acid is separated from racemic isopropyl ether 4-(33-chloro-5-trifluoromethylbenzyl)-15-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2- yl|-amino)-2,6-diisopropylpiperidine-1-carboxylic acid using preparative chiral HPLC (column:

SpigaIrak AO 20 μm 5x50 cm; flow rate: 70 ml/min; mobile phase: heptane/2-propanol 90:10); YIER-MS t/27: 621 |МА1)", retention time 2.59 min (conditions A), 16.2 min (conditions P).

Example 70: Preparation of isopropyl ether (25,48,65)-4-((3-chloro-5-trifluoromethylbenzyl)-|5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl| -amino)-2,6-diisopropylpiperidine-1-carboxylic acid (enantiomer)

IS

IS ! /

E about M

Them

M

AND

IOM v

Isopropyl ether (25,4K,65)-4-(3-chloro-5-trifluoromethylbenzyl)-I(5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl|-amino) -2,6-diisopropylpiperidine-1-carboxylic acid is separated from racemic isopropyl ether 4-(33-chloro-5-trifluoromethylbenzyl)-15-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl |-amino)-2,6-diisopropylpiperidine-1-carboxylic acid using preparative chiral HPLC (column:

SpigaIrak AO 20 μm 5x50 cm; flow rate: 70 ml/min; mobile phase: heptane/2-propanol 90:10); IER-MS t/27: 621 |МА1)", retention time 2.59 min (conditions A), 9.91 min (conditions P).

Example 71: Preparation of starting substances can be carried out in the following way. 1) Synthesis of tert-butyl ether of 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid. KT g I. tgF,-25 С M 7 then 1M NSI M and - m you. r shch wa osa

To a solution of 4-aminopiperidine (15.6 g, 143 mmol) in dry THF (1 L) cooled to -35"С, add

SISSORI (22.7 g, 144 mmol). After stirring the suspension for 1 hour. EIMOVg (150 mL, 150 mmol) is slowly added over 30 min. The mixture is heated at 10"C for 2 hours, then the reaction is stopped with H2O. The reaction mixture is extracted twice with EO (1 L), the combined organic layer is dried over Mag50Ox, and the solvent is removed under reduced pressure. To a solution of the obtained colorless oil I-VyOK (64 g, 572 mmol) is added to dry THF (500 ml) at -78"C. The reaction mixture was stirred overnight and warmed to room temperature. The reaction mixture is diluted with EBO, the reaction is stopped with ice, the phases are separated and the organic layer is washed three times with 1.5 N. with an aqueous Mahon solution and then with brine, dried over Md5Oa and concentrated under reduced pressure to obtain tert-butyl ether of 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid in the form of a pale yellow oil ( 27.8 g, output 8696); IER-MS t/h: 226 (Ma1)", retention time 1.64 min (conditions A).

The following compounds are obtained according to the method described above. (6) district;

Isopropyl ether h-ethyl-4-oxo-3,4-dihydro-2H- with SISO»iRg instead of SISOORP pyridine-1-carboxylic acid A

AND

6)

Isopropyl ether 2-ethyl-4-oxo-3,4-dihydro-2H-C SISO»iRg instead of SISO2RY, MemavVg of pyridine-1-carboxylic acid X instead of EIMOVg

AND

2). Synthesis of 2-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-b-ethylpiperidine-1-carboxylic acid benzyl ether. I. What is the difference between Я and М to мн MN ny

A. by, Eimavg, VE ZEO g 2 alta -- 2 -Sht-- yataro ---- I LA I se 1 tgoF,- V S doc OO AsSON, Mavngods) with SO s SISNOSNOSI, Kt dO m --

Her and Mr

In a flask blown with M2, to Sy! (1.0 mmol, 190.5 mg) at -78"C, add a 0.86 M solution of EIMOoVg in tetrahydrofuran (1.0 mmol, 1.2 mol). After stirring the suspension for 10 min, add VEz'ESO (0, 5 mmol, 70.6 mg) and stir for 10 min at the same temperature. A solution of 2-benzyl-4-oxo-3,4-dihydro-2H-pyridine-1-carbonate benzyl ether is added to the suspension at -78"C acid (0.5 mmol, 160.7 mg) in tetrahydrofuran (3.8 ml), then the mixture was stirred for 1 h. and then gradually heated to room temperature and stirred for 13 h. The reaction is stopped with a saturated aqueous solution of MNeCl and the mixture is extracted with EOAc. The combined organic layers are washed with brine, dried over Md5O", filtered, concentrated under reduced pressure, and purified by chromatography on a silica gel column (eluent: a mixture of hexane/B(As-4/1)) to give 2-benzyl benzyl ether -β6-ethyl-4-oxopiperidine-1-carboxylic acid (57 mg, 3295); IER-MS t/g: 352

IMA1G, retention time 2.12 min (conditions A).

To a solution of 2-benzyl-b-ethyl-4-oxopiperidine-1-carboxylic acid benzyl ether (0.16 mmol, 57.0 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.2 mmol, 48.6 mg) in 1,2-dichloroethane (0.3 ml) in an M2 atmosphere at room temperature add acetic acid (0.2 mmol, 12 mg) and Mavn(OAc)z (0.4 mmol, 84.8 mg). The mixture is stirred for 15 hours. and then alkalinize 1 n. with an aqueous Mason solution to a pH of approximately 10. The layers are separated and the aqueous layer is extracted with CH2oSi." The combined organic layer is washed with brine, dried over Ma5Om, filtered and concentrated under reduced pressure and purified by silica gel column chromatography (eluent: a mixture of hexane/E(OAc-4:1)) to give 2-benzyl-4 benzyl ether -(3,5-bis-trifluoromethylbenzylamino)-b-ethylpiperidine-1-carboxylic acid

(47.4 mg, 5195); IER-MS t/: 579 MaА1|", retention time 2.01 min (conditions A). 3). Synthesis of tert-butyl ether of 2,6-diethyl-4-oxopiperidine-1-carboxylic acid (racemic) o) c s g A I sy, EMV, VE OBESO st.

In a flask blown with M2, to Sy! (0.82 mmol, 156 mg) at -78"C, add a 1.00 M solution of EIMOVg in tetrahydrofuran (0.82 mmol, 0.82 mol). After stirring the suspension for 30 min, add БезЕСО (0.41 mmol, 57 .9 mg) and stir for 10 minutes at the same temperature. A solution of 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether is added to the suspension at -78"C ( 0.41 mmol, 92.7 mg) in tetrahydrofuran (3.3 ml), then the mixture was stirred for 1.5 h. and then stirred at -40"C for 2 h. The mixture was heated to room temperature and the reaction was quenched with a saturated aqueous solution of MNeCl and the mixture was extracted with EOAc. The combined organic layers were washed with brine, dried over Ma5O", filtered, concentrated under reduced pressure and purified by chromatography on a column with silica gel (eluent: a mixture of hexane/HBUAs-10/1) and the cis- and trans-isomers of the racemic tert-butyl ether of 2,6-diethyl-4-oxopiperidine-1-carboxylic acid (cis : mg, 5095); IER-MS t/2: 200 (M-Vy--2", retention time 3.51 min. (trans: 13 mg, 1395); IER-MS t/2: 200 (M-

IVy--2G, retention time 3.53 min (conditions A).

The following compounds are obtained according to the method described above.

Structure (6) 6)

Isopropyl ether (2K,65)-2,6-diethyl-4-bozo oxopiperidine-1-carboxylic acid AA ra Y ra Y (6) 6)

Isopropyl ether (2K,65)-2,6-dimethyl-4-dach Oxopiperidine-1-carboxylic acid A. A oso oso rah Bak Memovg instead of EMOVg (6) 6)

2,6-trans-dimethyl-4-pok CH isopropyl ether. of oxopiperidine-1-carboxylic acid " A. A oso oso rah Bak Memovg instead of EMOVg (6) (6)

M M

Isopropyl ether (25,35,6K)-2,6-diethyl-3-MM methyl-4-oxopiperidine-1-carboxylic acid AA ra Y ra Y 4). Synthesis of 4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethylpiperidine-1-carboxylic acid tert-butyl ether (2,6-cis-isomer)

g Kusha PUE rod poison kish S

Yes, I do

Met ro

A. ASON, MaVN(OAS) with also KhM. oo SsIiSN.SNoSI, kt M yo

And oh

AND.

To a solution of a racemic mixture of tert-butyl ether (cis)-2,6-diethyl-4-oxopiperidine-1-carboxylic acid (0.21 mmol, 53 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.25 mmol , 61.3 mg) in 1,2-dichloroethane (0.5 ml) in an M2 atmosphere at room temperature add acetic acid (0.25 mmol, 15 mg) and Mavn(OAc)z (0.42 mmol, 89 mg ). The mixture is stirred for 20 hours. and then alkalinize 1 n. with an aqueous solution of Mmaon to a pH equal to approximately 10. The layers are separated and the aqueous layer is extracted using СНоСи». The combined organic layer is washed with brine, dried over Mag5O.4, filtered and concentrated under reduced pressure and purified by preparative TLC (eluent: a mixture of hexane/EUAs-2:1) to obtain tert-butyl ether 4-(3,5 -bis-trifluoromethylbenzylamino)-2,6-diethylpiperidine-1-carboxylic acid (20.8 mg, 2096); UIER-MS t/g: 483 (Ma-1)", retention time 1.92 min (conditions A). 5). Synthesis of tert-butyl ether 4-(3,5-bis-trifluoromethylbenzylamino)-2,6- diethylpiperidine-1-carboxylic acid (2,6-trans-isomer, racemic) in. Te shcha Tv 7 koor 0 - schle re "MH. "MN 4 ASON, MaVN (OASI of Fe ogo SISNUSNoSI, Kt. chen

Same o2cho

AND.

To a solution of a racemic mixture of tert-butyl ether (trans)-2,6-diethyl-4-oxopiperidine-1-carboxylic acid (0.052 mmol, 13.3 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.062 mmol, 15 .1 mg) in 1,2-dichloroethane (01 ml) in an M2 atmosphere at room temperature, add acetic acid (0.062 mmol, 3.7 ml") and

Mavn(Ods)z (0.104 mmol, 22 mg). The mixture is stirred for 20 hours. and then alkalinize 1 n. with an aqueous Mahon solution to a pH of approximately 10. The layers are separated and the aqueous layer is extracted using

SNesi". The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The residue is purified by preparative TLC (eluent: a mixture of hexane/COAc-2:1) and a racemic mixture of 4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethylpiperidine-1-carboxylic acid tert-butyl ether is obtained (8 .6 mg, 3495); IER-MS t/2: 483

IMA1G, retention time 1.93 min (conditions A). 6). Synthesis of tert-butyl ether (25,32,45,6kK)-4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethyl-3-methylpiperidine-1-carboxylic acid (2,6-cis-isomer, racemic) vebe i ov

E E

E E

(6)

M MN

MN, Fri

M pi I

And mavn, that's meon A

WHAT J

To a solution of a racemic mixture of isopropyl ether (25,35,68)-2,6-diethyl-3-methyl-4-oxopiperidine-1-carboxylic acid (0.193 mmol, 52 mg) and 3,5-bis(trifluoromethyl)benzylamine ( . , 0.16 mmol) and stirred at 100"C for 1 hour. After cooling to room temperature, water is added to the mixture and the mixture is extracted with dichloromethane. The organic layer is washed with saturated sodium bicarbonate, dried over

Ma5oO", filter and concentrate under reduced pressure. The residue is purified by 3F-HPLC and a racemic mixture of tert-butyl ether (25,3,45,6H8)-4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethyl-3-methylpiperidine-1-carboxylic acid is obtained acids (14 mg); IR-MS m/2: 497 IMaА1|", retention time 2.19 min (conditions A). 7). Synthesis of 2-benzyl-4-(5-bromopyrimidin-2-ylamino)-b-ethylpiperidine tert-butyl ether -1-carboxylic acid o a | 7 c c i. THI 4 that

AD she iy

M" sy, E2MoVg, VE ZEBO "M mn. Z SG i tgF,-79 C to KT oo ASON, Mavn(sAs) THE SAME

A. A SISSNSNSI, KT A.

MN M tr 2 - VG A i iy TP nm m

Ra, No, MEON sg. sim So I -- shchi IDIPEA, DMF 120 s r - t Her th

In the flask, which is blown with the help of M", to Sy! (83.6 mmol, 15.9 g) at -78"С add a 1.00 M solution

EIMOoVg in THF (83.6 mmol, 83.6 ml). After stirring the suspension for 10 min, add VEzEBO (41.8 mmol, 5.9 g) and stir for 10 min at the same temperature. A solution of 2-benzyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (41.8 mmol, 12.0 g) in tetrahydrofuran (125 .4 ml), then the mixture is stirred for 2 h. The reaction is quenched with a saturated aqueous solution of MNACI and the mixture is extracted with EOAc. The combined organic layers are washed with brine, dried over Ma»5O4, filtered, concentrated under reduced pressure and purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and receive tert-butyl ether of 2-benzyl-6-ethyl-4-oxopiperidine-1-carboxylic acid (8.19 g, 6295); IR-MS t/ 2: 262 |M -IVy-1)", retention time 2.14 min (conditions A).

To a solution of tert-butyl ether of 2-benzyl-b-ethyl-4-oxopiperidine-1-carboxylic acid (25.8 mmol, 8.19 g) of its benzylamine (28.4 mmol, 3.04 g) in 1.2 -dichloroethane (65 ml) under a Ma atmosphere at room temperature add acetic acid (28.4 mmol, 1.76 g) and Mavn(OAc)z (51.6 mmol, 10.9 g). The mixture is stirred for 12 hours. and then alkalinize 1 n. with an aqueous solution of Mahon to a pH of approximately 10. The mixture is extracted with SNeSi. The combined organic layer is washed with brine, dried over

Mag5O»4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/ETOAc) to obtain tert-butyl ether of 2-benzyl-4-benzylamino-b-ethylpiperidine-1-carboxylic acid (9.55 g, 9195); IER-MS t/:: 409 (Ma1|), retention time 1.85 min (conditions A).

The flask is filled with a solution of 2-benzyl-4-benzylamino-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (23 mmol, 9.4 g in Meon (94 ml)) and then purged with nitrogen. 1095

Ra on charcoal (moisture 5095) (2.3 mmol, 940 mg). After stirring for 30 minutes, the flask is purged with hydrogen. The mixture is stirred for 4 hours. at room temperature and then within 3 h. at 40"C.

The mixture is filtered and concentrated under reduced pressure. Tert-butyl ether of 4-amino-2-benzyl-6-ethylpiperidine-1-carboxylic acid (6.8 g, 9395) is used in the next stage without additional purification; IER-MS ti/: 319 (M-1|), retention time 2.88 min (conditions B).

A solution of 4-amino-2-benzyl-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (0.1 mmol, 31.9 mg), 5-bromo-2-chloropyrimidine (0.15 mmol, 29.0 mg ) and M,M-diisopropylethylamine (0.2 mmol, 25.8 mg) in DMF (0.3 ml) are heated to 120°C and stirred for 4 hours. The mixture is cooled to room temperature, then the reaction is stopped with 51iO " and the mixture is filtered through a layer of silica gel. The mixture is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/EIOAc mixture) to give 2-benzyl-4-(5-bromopyrimidine-2-tert-butyl ether) -ylamino)-6-ethylpiperidine-1-carboxylic acid (36 mg, 7695); IR-MS t/2: 475 (Ma1|", retention time 2.40, 2.45 min (conditions B).

The following compound is obtained according to the method described above.

- M o

Tert-butyl ps c ether 2,4,6-cis-2-nm mo benzyl-6b-ethyl-4-(4-bo X methoxypyrimidine-2- 427 2,13 (conditions A) otoylamino)-piperidine- X is 1-carboxylic acid, i.e. 2-Chloro-4-methoxy-acid A-pyrimidine instead of 5-bromo-2-chloropyrimidine 8). Synthesis of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-(4-fluorobenzyl)-piperidine-1-carboxylic acid tert-butyl ether (2,4-cis- and 2,4-trans isomers )

Go) 1) SISO RA then Es A dl p.fluorobenzylmagnesium bromide with 23 vyk that M Sy, EIMavg, VEZBBO a Y o Z a (Z tge,-452C to Kt alto 0 tgF,-78"C to kt

M -

E E bobu tru -E that on her mn, MN chn

Yi sha uh v. ra

AH. se and also 0 ASON, Mavn(Ols) not Ts X,

A. SISN.SN.SI, Kt -sh g i sa nai

And shre -4-

Phenyl chloroformate (12.1 mmol, 1.89 g) was added to a solution of 4-methoxypyridine (12 mmol, 1.31 g) in THF cooled to -45"C under a nitrogen atmosphere. The solution was allowed to warm to -25"7C and stir for min. A 0.25 M solution of p-fluorobenzylmagnesium bromide in

THF (12.5 mmol, 50 ml) and stirred for 1 h. The mixtures are allowed to warm to room temperature and after stirring for 2 hours. the reaction is quenched with ice and then with HgO and the mixture is extracted with Eb25O. The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. THF (100 mL) was added to the residue and the solution was cooled to -45°C and IVOOC (48 mmol, 5.39 g) was added. The solution was allowed to gradually warm to room temperature and stirred for 15 h. The reaction was quenched with ice and then with NgO and the mixture is extracted with EC 2 O. The combined organic layer is washed three times with 1 N aqueous Mahon solution and then three times with 1 N aqueous HCl. The mixture is dried over Mag 5 O 4 , filtered and concentrated under reduced pressure. The residue is purified by chromatography on column with silica gel (eluent: a mixture of hexane/EiOAc, then a mixture of MeOH/CHnesSi") and receive tert-butyl ether of 2-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (495, 150 mg); IER-MS t/2: 306 (Ma-1)", retention time 1.97 min (conditions A).

In a flask blown with M2, to Sy! (0.556 mmol, 106 mg) at -78"С, a 1.00 M solution of EIMOVg in tetrahydrofuran (0.556 mmol, 0.556 ml) is added. After stirring the suspension for 15 min, VEz.ESO (0.278 mmol, 39.2 mg) is added and stirred for 10 min at the same temperature. A solution of 2-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (0.278 mmol, 93.4 mg) in tetrahydrofuran (0.2 ml), then the mixture was stirred for 1 h. After heating the mixture to room temperature and stirring for 2 hours. the reaction is stopped with saturated aqueous MNACI and the mixture is extracted with EtOAc.

The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/EOAc mixture) and 2-ethyl-6-(4-fluorobenzyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ether is obtained (63.8 mg, 6890); IR-MS t/2: 280 (M-IVy--21", retention time 2.14 min (conditions A).

To a solution of 2-ethyl-6-(4-fluorobenzyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ether (0.19 mmol, 63.8 mg) and 3,5-bistrifluoromethyl)benzylamine (0.266 mmol, 64 .7 mg) in 1,2-dichloroethane (0.4 ml) under M2 atmosphere at room temperature add acetic acid (0.266 mmol, 16 mg) and Mavn(OAc)z (0.40 mmol, 84.8 mg). The mixture is stirred for 22 hours. and then alkalinize 1 n. with an aqueous Mahon solution to a pH of about 10. The layers are separated and the aqueous layer is extracted with СНоСи». The combined organic layer is washed with brine, dried over Mag5O.4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EiOAc) and a racemic mixture of tert-butyl ether 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-(4-fluorobenzyl)-piperidine is obtained -1-carboxylic acid (2,4-cis-isomer: 35.3 mg, 3395); IER-MS t/: 563

IMATH, retention time 2.03 min (conditions A), (2, trans isomer: 14.0 mg, 1395); IER-MS t/2: 563 (Mat, retention time 2.04 min (conditions A).

The following compounds are obtained according to the method described above.

ITER-MS t/2 (M.A. College of EE Unit

Tert-butyl ether 4-(3,5-bis-MH trifluoromethylbenzylamino)-2-ethyl-6b-(2-fluorobenzyl)-piperidine-1- and 621 2.54 min (conditions A) carboxylic acid M v.i M KE unit

Tert-butyl ether 4-(3,5-bis-E MH trifluoromethylbenzylamino)-2-ethyl-6b-(3-fluorobenzyl)-piperidine-1- 621 2.63 min (conditions A) carboxylic acid M

E Y Y E because

Tert-butyl ether 4-(3,5-bis-MH trifluoromethylbenzylamino)-2-ethyl-6b- 817 2.69 min (conditions A) (3-methylbenzyl)-piperidine-1-' U carboxylic acid

M

E and Re E unit

Tert-butyl ether 4-(3,5-bis-MH trifluoromethylbenzylamino)-2-(4-chlorobenzyl)-6b-ethylpiperidine-1-s 637 2.10 min (conditions A) of carboxylic acid

M in Oh yeah

Tert-butyl ether 4-(3,5-bis-E MH trifluoromethylbenzylamino)-2-(3,4-difluorobenzyl)-6b-ethylpiperidine-1- and 639 2.62 min (conditions A) of carboxylic acid

M

E Y Y E od

Tert-butyl ether 4-(3,5-bis-MH trifluoromethylbenzylamino)-2-ethyl-6b-(2-methylbenzyl)-piperidine-1- 617 2.11 min (conditions A) carboxylic acid

M

E Y Y E

Tert-butyl ether 4-(3,5-bis-MH trifluoromethylbenzylamino)-2-(2,6-dimethylbenzyl)-b-ethylpiperidine-1- 631 2.11 min (conditions A) carboxylic acid

M

E Y Y E what

Tert-butyl ether 4-(3,5-bis- | MH trifluoromethylbenzylamino)-2-ethyl-6b-(2-methoxybenzyl)-piperidine-1- o 633 2.63 min (conditions A) of carboxylic acid

M

9). Synthesis of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether

E -Y Y E

E E g E E E

E TE o su: s Y "Mn yan sht

A. mavn u, kt che kt ogo methanol / SISSNOSNOSI A - 0 A

A solution of 2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (1 g, 4.4 mmol), 3,5-bis(trifluoromethyl)benzylamine (1.4 g, 4.84 mmol) and titanium isopropoxide (catalytic amount, Z drops) in 7.5 ml of methanol and 7.5 ml of dichloroethane under a nitrogen atmosphere was stirred with Mavna (183 mg, 4.84 mmol) at room temperature for 6 h. The reaction is stopped by adding a saturated aqueous solution of ammonium chloride and the mixture is filtered and the precipitate is washed with ethyl acetate. The mixture is extracted with ethyl acetate (2x50 ml). The organic layer is washed with brine, dried over anhydrous sodium sulfate, and then concentrated to obtain 1.7 g (7695) of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether; IER-MS t/: 455 |Ma1|", retention time 1.75 min (conditions A). 10). Synthesis of (3,5-bis-trifluoromethylbenzyl)-(2-ethylpiperidin-4-yl)-carbamine methyl ether acid

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To a solution of /4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethylpiperidine-1-carboxylic acid tert-butyl ether (1.2 g, 2.3 mmol) in 2 ml of ethyl acetate in an M2 atmosphere for 5 min drop by drop add 4 n. a solution of NCI in ethyl acetate (10 ml, 40 mmol). The reaction mixture is stirred for 4 hours. Then the reaction mixture is concentrated and then the reaction is stopped by adding a saturated aqueous solution of sodium bicarbonate (50 ml) and the aqueous layer is extracted with ethyl acetate (2x50 ml). The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, and then concentrated to give 0.8 g (8495) of (3,5-bis-trifluoromethylbenzyl)-(2-ethylpiperidin-4-yl)-carbamic acid methyl ether; IER-MS ti/l: 413 (M--1", retention time 1.67 min (conditions A). 11). tert-butyl ether 5-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-2 -ethylpiperidine-1-carboxylic acid g ES in Ee

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A mixture of 2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (610 mg, 2.7 mmol), pyrrolidine (287 mg, 4.0 mmol), and 5 mL of toluene was refluxed overnight at using the Dean-Stark apparatus. The mixture is evaporated and a dark residue is obtained, which is directly used in the next stage. To this dark residue was added benzyl bromide (2 mL, 17 mmol) and stirred at room temperature for 2 days. The reaction was quenched with a saturated aqueous ammonium chloride solution (40 mL) and the mixture was extracted with ethyl acetate (2x50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using flash chromatography on silica gel eluting with hexane-ethyl acetate mixtures and obtaining 5-benzyl-2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether with a yield of 2095; IER-MS t/2: 262 |M-55|", retention time 2.10 min (conditions A).

A solution of 5-benzyl-2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (127 mg, 04 mmol), 3,5-bis(trifluoromethyl)benzylamine (117 mg, 0.484 mmol) and titanium isopropoxide (catalytic amount, Z drops) in 0.5 ml of acetic acid, 1 ml of methanol and 1 ml of tetrahydrofuran was stirred with MavNa (18 mg, 0.484 mmol) at room temperature for 1 day under a nitrogen atmosphere. The reaction is stopped by adding saturated aqueous ammonium chloride, the mixture is filtered and washed with ethyl acetate.

The mixture is extracted with ethyl acetate (2x50 ml). The organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated to give the crude product. The resulting residue is purified using flash chromatography on silica gel, eluting with hexane-ethyl acetate mixtures, and tert-butyl ether of 5-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-2-ethylpiperidine-1-carboxylic acid is obtained with a yield of 1595; IER-MS t/: 545 (Ma-1)", retention time 2.00 min (conditions A). 12). Synthesis of 4-(4-bromophenylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether VG a - VG XX century

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A mixture of 2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (114 mg, 0.5 mmol), p-bromoaniline (95 mg, 0.55 mmol), sodium triacetoxyborohydride (111 mg, 0.525 mmol) and of acetic acid (34 μl, 0.6 mmol) in 1,2-dichloroethane (0.8 ml) was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (111 mg, 0.525 mmol) was added to the mixture. Then the mixture is stirred at room temperature for 20 hours. The mixture is made alkaline by 1 n. aqueous sodium hydroxide solution to pH 10, then extracted with 1,2-dichloroethane. The organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: a mixture of ethyl acetate/n-hexane-1/4) and 93 mg of 4-(4-bromophenylamino)-2-ethylpiperidine-1-carboxylic acid tert-butyl ether is obtained; IER-MS t/2: 383

IMA1G, retention time 2.18 min (conditions A). 13). Synthesis of tert-butyl ether of 4-cyclohexylamino-2-ethylpiperidine-1-carboxylic acid

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A mixture of 2-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (114 mg, 0.5 mmol), cyclohexylamine (63 μl, 0.55 mmol), sodium triacetoxyborohydride (111 mg, 0.525 mmol), and acetic acid (34 μl, 0.6 mmol) in 1,2-dichloroethane (0.8 ml) was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (111 mg, 0.525 mmol) was added to the mixture. Then the mixture is stirred at room temperature for 20 hours. The mixture is made alkaline by 1 n. aqueous sodium hydroxide solution to pH 10, then extracted with 1,2-dichloroethane. The organic layer is concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of methanol/dichloromethane-1/10) and 124 mg of tert-butyl ether of 4-cyclohexylamino-2-ethylpiperidine-1-carboxylic acid is obtained; IER-MS t/: 311 (Ma-1|", retention time 1.63 min (conditions A). 14). Synthesis of (3-chloromethyl-5-trifluoromethylphenyl)-dimethylamine

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A solution of 5-nitro-3-trifluoromethyl)benzoic acid (2.35 g, 10 mmol) and H»5O»4 (53 μl, 1 mmol) in methanol (30 ml) was heated under reflux and stirred for 20 h. The mixture is cooled to room temperature, then concentrated under reduced pressure. The resulting residue is neutralized with a saturated aqueous solution of MansSoz. The mixture is extracted using SNeSi. The combined organic layer is washed with brine, dried over Mag5O.4, filtered and concentrated under reduced pressure to give 3-nitro-5-trifluoromethylbenzoic acid methyl ester (2.15 g, 86905), which is used in the next step without additional purification .

A solution of methyl ester of 3-nitro-5-trifluoromethylbenzoic acid (8.6 mmol, 2.15 g) and tin dihydrochloride (25.8 mmol, 5.82) in ethanol (40 ml) is heated to 60"C and stirred for 4 h .

The mixture is cooled to room temperature, then concentrated under reduced pressure. The resulting residue is neutralized with a saturated aqueous solution of ManHsCO3. The mixture is filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and the methyl ester of 3-amino-5-trifluoromethylbenzoic acid is obtained (7496, 1.4 u); IR-MS t/: 220 ( M.A1)", retention time 1.81 min (conditions A).

A solution of 3-amino-5-trifluoromethylbenzoic acid methyl ester (2 mmol, 438 mg) in THF was added dropwise to a suspension of lithium aluminum hydride (4 mmol, 152 mg) in THF (5 ml), cooled to 0"C, in a nitrogen atmosphere (1 mL). The solution was allowed to warm to RT and stirred for 2 h. Diethyl ether (6 mL) was added to the solution, then the reaction was quenched with sodium sulfate decahydrate and brine. After decantation, the solution was dried over Mag25O4, filtered and concentrated under reduced pressure to give (3-amino-5-trifluoromethylphenyl)-methanol (quantitative yield), used in the next stage without additional purification); IR-MS t/2: 192 (M.-1)", retention time 1.30 min (conditions AND).

Acetic acid was added to a solution of (3-amino-5-trifluoromethylphenyl)-methanol (1 mmol, 191 mg) and a 3795 aqueous solution of formaldehyde (5 mmol, 372 μl) in acetonitrile (2.5 ml) under a nitrogen atmosphere at 0"C. (5.5 mmol, 315 μl) and Mavn(OAc)z (0.40 mmol, 84.8 mg). The mixture was stirred for 30 min at

OS and then alkalinize 1 n. with an aqueous Mahon solution to a pH of approximately 10. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layer is washed with brine, dried over

Mag5O»4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and (3-dimethylamino-5-trifluoromethylphenyl)-methanol (128 mg, 5895); IR-MS t/2: 220 (Ma- 1|", holding time 1.55 min (conditions A).

To a solution of (3-dimethylamino-5-trifluoromethylphenyl)-methanol (0.15 mmol, 33 mg) in dichloromethane (1 ml), cooled to 0"С, under a nitrogen atmosphere, thionyl chloride (0.3 mmol, 21 μl) was added dropwise ).

The solution is allowed to heat up to room temperature and stirred for 1 hour. A saturated aqueous solution of MansSoOz is added to the solution. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layer is washed with brine, dried over Ma»5O», filtered and concentrated under reduced pressure to give (3-chloromethyl-5-trifluoromethylphenyl)-dimethylamine (quantitative yield); IER-MS t/2: 238 |Ma-1|", retention time 2.14 min (conditions A). 15). Synthesis of 1-bromomethyl-3-methoxy-5-trifluoromethylbenzene

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Methyl iodide (1.09 mol, 17 .5 mmol), the mixture is heated to 40"C and stirred for 20 h. The mixture is cooled to room temperature, then water is added. The mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over Ma»5O4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EIOAc) and the methyl ester of //3-methoxy-5-trifluoromethylbenzoic acid is obtained (1.11 g, 9595); IR-MS m/: 235 ( Ma1|", retention time 2.06 min (conditions A).

To a suspension of lithium aluminum hydride (9.48 mmol, 360 mg) in THF, cooled to 0"C, in a nitrogen atmosphere, a solution of methyl ester of 3-methoxy-5-trifluoromethylbenzoic acid (4.74 mmol, 1.11 g) is added dropwise. in THF. The solution is allowed to warm to RT and stirred for 2 h. Diethyl ether is added to the solution, then the reaction is quenched with sodium sulfate decahydrate and brine. After decantation, the solution is dried over Ma»5Ox, filtered and concentrated under reduced pressure to give (3-methoxy -5- trifluoromethylphenyl)-methanol (960 mg, 9895), used in the next stage without additional purification.

To a solution of (3-methoxy-5-trifluoromethylphenyl)-methanol (1 mmol, 206 mg) and triphenylphosphine (1.5 mmol, 392 mg) in dichloromethane (10 ml), cooled to 0"C, under a nitrogen atmosphere, add MV5 ( 1.5 mmol, 266 mg). The solution was allowed to warm to RT and stirred for 1 h. Water was added to the solution, then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NaCl, filtered and concentrated under reduced pressure The residue is purified by silica gel column chromatography (eluent: hexane/E(OAc) mixture) to give 1-bromomethyl-3-methoxy-5-trifluoromethylbenzene (245 mg, 9195); IER-MS t/l: 189 (M -Vg--1)", holding time 1.76 min (conditions A). 16). Synthesis of 1-bromomethyl-3-methanesulfonyl-5-trifluoromethylbenzene

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To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (5 mmol, 1.35 g) in THF (8 mL) under a nitrogen atmosphere was added a 1 M solution of borohydride in THF (16 mmol, 16 mL). The solution is heated to 65"7C and stirred for 2 hours. The mixture is cooled to room temperature, then poured into a saturated aqueous solution

MansoOz. The mixture is extracted with EtOAc. The combined organic layer was washed with brine, dried over Na»5O», filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EB(OAc) mixture) to give (3-bromo-5-trifluoromethylphenyl)-methanol (418 mg, 6905).

To a solution of (3-bromo-5-trifluoromethylphenyl)-methanol (2 mmol, 613 mg), I-proline sodium salt (0.4 mmol, 55 mg), copper iodide (0.2 mmol, 38 mg) in DMSO ( 4 ml) in a nitrogen atmosphere add sodium methanesulfinate (2.4 mmol, 245 mg). The solution is heated to 9570 and stirred for 20 hours. The mixture is cooled to room temperature, then water is added. The mixture is extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na»5O», filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/E(OAc) mixture) to give (3-methanesulfonyl-5-trifluoromethylphenyl)-methanol (418 mg, 6995); IR-MS t/g: 255 Mat". retention time 1.64 min (conditions A).

To a solution of (3-methanesulfonyl-5-trifluoromethylphenyl)-methanol (0.8 mmol, 203 mg) and triphenylphosphine (1.2 mmol, 315 mg) in dichloromethane (8 ml), cooled to 0"C, under a nitrogen atmosphere, add MW5 (1.2 mmol, 214 mg). The solution was allowed to warm to RT and stirred for 1 h. Water was added to the solution, then extracted with dichloromethane. The combined organic layer was washed with brine, dried over Mag5Ox, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/EOAc mixture) and 1-bromomethyl-3-methanesulfonyl-5-

trifluoromethylbenzene (228 mg, 9095). 17). Synthesis of 1-(3-bromomethyl-5-trifluoromethylphenyl)-5-methyl-1H-tetrazole

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To a solution of (3-amino-5-trifluoromethylphenyl)-methanol (210 mg, 1.1 mmol) in acetic acid (1.6 mL) was added triethyl orthoacetate (282 μL, 1.54 mmol). The mixture is heated to 75"C and stirred for 45 min, then sodium azide (215 mg, 3.3 mmol) is added at 757"C and stirred for 3 h. The mixture is cooled to room temperature, then water is added. The mixture is made alkaline by 1 n. aqueous solution

Mahon to a pH of about 10, then extracted with dichloromethane. The combined organic layer is washed with brine, dried over Mag25O4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and obtain

13-(5-methyltetrazol-1-yl)-5-trifluoromethylphenyl]-methanol (94 mg, 3395); IER-MS t/2: 259 |MaА1|", retention time 1.70 min (conditions A).

To a solution of |3-(5-methyltetrazol-1-yl)y-5-trifluoromethylphenyl|-methanol (0.23 mmol, 60 mg) and triphenylphosphine (0.95 mmol, 92 mg) in dichloromethane (2.5 ml) , cooled to 0"C, MB5 (0.35 mmol, 62 mg) is added under a nitrogen atmosphere. The solution is allowed to warm to room temperature and stirred for 4 h. Water is added to the solution, then extracted with dichloromethane. The combined organic layer is washed with brine, dried over Ma"5O", filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: a mixture of hexane/E(OAc)) to give 1-(3-bromomethyl-5-trifluoromethylphenyl)-5-methyl -1 H-tetrazole (72 mg, 9695); IR-MS t/7: 320 (Ma1|", retention time 2.08 min (conditions A). 18). Synthesis of 1-bromomethyl-3-chloro-5- trifluoromethoxybenzene

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To a solution of (3-chloro-5-trifluoromethoxyphenyl)-methanol (1 mmol, 226 mg) and triphenylphosphine (1.5 mmol, 392 mg) in dichloromethane (10 ml), cooled to 0"C, under a nitrogen atmosphere, add MV5 ( 1.5 mmol, 266 mg).

The solution is allowed to heat up to room temperature and stirred for 1 hour. Water is added to the solution, then extracted with dichloromethane. The combined organic layer was washed with brine, dried over Mao', filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EOAc mixture) to give 1-bromomethyl-3-chloro-5-trifluoromethoxybenzene (257 mg, 899). 19). Synthesis of 4-(3,5-bis-trifluoromethylbenzylamino)-2-cyclohexylmethyl-6b-ethylpiperidine-1-carboxylic acid tert-butyl ether (2,4,6-cis-isomer)

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Phenyl chloroformate (10.6 mmol, 1.33 ml) was added to a solution of 4-methoxypyridine (9.6 mmol, 1.05 g) in THF (75 ml), cooled to -40°C, under a nitrogen atmosphere. After stirring for A 0.7 M solution of cyclohexylmethylmagnesium bromide in THF (10.08 mmol) was slowly added over 20 min. The mixture was allowed to warm to room temperature and after stirring for 2 h, the reaction was quenched with ice and then with HO and the mixture was extracted with E 2 O. The combined the organic layer is washed with brine, dried over Ma5Ox, filtered and concentrated under reduced pressure. THFf (30 ml) is added to the residue and the solution is cooled to -78"C and IVSHOK (38.4 mmol, 4.3 g) is added. The solution is allowed to gradually warm to room temperature. The reaction is quenched with ice and then with H2O and the mixture is extracted with Eb25O. The combined organic layer is washed three times with 1 n. aqueous Mahon solution and then three times 1 n. aqueous solution of NSI. The mixture is dried over Mo5O5, filtered and concentrated under reduced pressure.

The obtained residue is purified by chromatography on a silica gel column (eluent: n-hexane/ethyl acetate mixture) and 2-cyclohexylmethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether is obtained (1595 , 0.43 g); IR-MS t/:: 294 (Ma-1|), retention time 2.29 min (conditions A).

In the flask, which is blown with the help of M»2, to Sy! (1.0 mmol, 191 mg) and THF (4 ml) at -78"C, add a 1.00 M solution of E(MOVg in tetrahydrofuran (1.0 mmol, 1.0 ml). After stirring the suspension for 10 min, add БезЕбСО (1.0 mmol, 1.0 mg) and stir for 10 min at the same temperature. A solution of tert-butyl ether 2-cyclohexylmethyl-4-oxo-3,4-dihydro-2H is added to the suspension at -78"С -pyridine-1-carboxylic acid (0.5 mmol, 119.7 mg) in tetrahydrofuran (5 ml), then the mixture is stirred for 1 h. After heating the mixture to room temperature and stirring for 2 h, the reaction is stopped with a saturated aqueous solution of MNEeSi and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Mag5O"4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/"ethyl acetate) and obtain cis-2-cyclohexylmethyl-b-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (108 mg, 6795); IER-MS ti/: 2 68 (M-Vy--2/", retention time 2.44 min (conditions A).

To a solution of cis-2-cyclohexylmethyl-b-ethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (0.21 mmol, 68 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.25 mmol, 60 .8 mg) in 1,2-dichloroethane (0.4 ml) at room temperature add acetic acid (0.25 mmol, 13.7 μl) and Mavn(OAc)z (0.42 mmol, 89 mg). The mixture is stirred for 7.5 hours. and then alkalinize 1 n. with an aqueous Mahon solution to a pH of approximately 10. The mixture is extracted with СНеСи» and the combined organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) and a racemic mixture of tert-butyl 4-(3,5-bis-trifluoromethylbenzylamino)-2-cyclohexylmethyl-b-ethylpiperidine-1-carboxylic acid ester is obtained acids (2,4,6-cis isomer: 88.0 mg, 7695); IER-MSO t/g2: 551 |Ma1|", retention time 2.21 min (conditions A). 20). Synthesis of 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino tert-butyl ether |-6- hydroxymethylpiperidine-1-carboxylic acid (2,4,6-cis-isomer)

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Phenyl chloroformate (105 mmol, 13 ml) was added to a solution of 4-methoxypyridine (100 mmol, 10 ml) in THF (390 ml) cooled to -40°C under a nitrogen atmosphere. After stirring for 20 min, slowly add 1.0 M a solution of benzylmethylmagnesium bromide in THF (110 mmol). The mixtures are allowed to warm to room temperature and after stirring for 2 hours, the mixture is cooled to -40"C and IVONOK (250 mmol, 28.1 g) is added. The solution is allowed to gradually warm to room temperature and stirred for 14 hours. The reaction is quenched with ice and then with H2HO and the mixture is extracted with ESO.

The combined organic layer is washed three times with 1 n. aqueous Mahon solution and then three times 1 n. aqueous solution of NOSI. The mixture is dried over Ma5O", filtered and concentrated under reduced pressure. The obtained residue is filtered through a layer of silica gel and concentrated under reduced pressure to obtain a crude product, which is used in the next stage without additional purification.

In a flask blown with Mg2, to Sy! (98.8 mmol, 18.8 g) and THF (200 ml) at -60"C for 30 min. add a 1.00 M solution of vinylmagnesium bromide in tetrahydrofuran (98.8 mmol, 98.8 ml). After stirring the suspension for After 15 min, add VEzEbBO (49.4 mmol, 6.2 ml) and stir for 15 min at the same temperature. A solution of the crude product in tetrahydrofuran (200 ml) is added to the suspension at -407"C, then the mixture is stirred for 2 h. After heating the mixture to room temperature and stirring for 2 hours. the reaction is stopped with a saturated aqueous solution of MNeCl and the mixture is extracted with EAs. The combined organic layer is washed with brine, dried over Mda5O", filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to obtain a diastereometric mixture of 2-benzyl-4-oxo-b-vinylpiperidine-1-carboxylic acid tert-butyl ether (4.29 g, 1495 in 2 stages); IER-MS t/:: 260

IM-Vy--2|", retention time 2.17 min (conditions A).

A mixture of 2-benzyl-4-oxo-b-vinylpiperidine-1-carboxylic acid tert-butyl ether (13.6 mmol, 4.29 g), Atrepuvy 9 15 (680 mg), triethoxymethane (109 mmol, 18 mL) and of ethylene glycol (136 mmol, 7.5 ml) is stirred for 24 h. at room temperature. After mixing with additional amt

AtrBrepuvi? 15 (136 mg) within 4 hours. the mixture is filtered through a layer of silica gel and washed with ethyl acetate.

The mixture is washed with a 0.1 M aqueous solution of HCl, a saturated aqueous solution of MansSoOz, and brine.

The organic layer is dried over Mag5O4, filtered and concentrated under reduced pressure to obtain a diastereometric mixture of tert-butyl ether 7-benzyl-9-vinyl-1,4-dioxa-8-azaspiro(4.5|decane-8-

carboxylic acid (4.72 g, 9795); IER-MS ti/l: 304 (M-Vy--21", retention time 2.33 min (conditions A).

To a mixture of tert-butyl ether of 7-benzyl-9-vinyl-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid (13.1 mmol, 4.72 g)) and Manso" (26 2 mmol , 2.20 g) in methanol (70 ml) at -78"С for 1 hour, add Oz to

O" (100 Nl/hour, 60 revolutions). After passing OH over 30 min, dimethyl sulfide (78.6 mmol, 5.8 mL) was added and the reaction mixture was stirred for 30 min at the same temperature and allowed to warm to room temperature. CoCO3 (15.7 mmol, 2.17 g) was added to the mixture and stirred for 11 h. Water is added to the mixture and the organic product is extracted with diethyl ether. The organic layer is washed with a saturated aqueous solution of MNaCl and brine, dried over Mag25O.:, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of n-hexane/ethyl acetate) and a diastereometric mixture of tert-butyl ether 7-benzyl-9-formyl-1,4-dioxa-8-azaspiro(4.5|decane) is obtained -8-carboxylic acid (2.06 g, 4495); IER-MS t/:2: 306 (M-

IVy--21", retention time 2.18 min (conditions A).

To a mixture of 7-benzyl-9-formyl-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid tert-butyl ether (3.0 mmol, 1.08 g) in methanol (30 mL) and in dichloromethane (10 ml) at 0"C is added Mavna (9.0 mmol, 340 mg). The mixture is stirred for 1.5 h at room temperature, quenched with a saturated aqueous solution of MNaCl and extracted with dichloromethane. The organic layer is washed with brine, dried over Ma5Om , filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of n-hexane/"ethyl acetate) and a diastereoisomeric mixture of 7-benzyl-9-hydroxymethyl-1,4-dioxa tert-butyl ether is obtained -8-azaspiro(4.5|decane-8-carboxylic acid (890 mg, 8295); IR-MS m/:: 364 (Ma1)", retention time 3.73 (2, 6-cis), 3.85 ( 2, b-trans) min (conditions B).

A mixture of 7-benzyl-9-hydroxymethyl-1,4-dioxa-8-azaspiro|(4.5|decane-8-carboxylic acid tert-butyl ether (2.45 mmol, 890 mg) and Atrepuvzi? 15 (2.9 g ) in acetone (25 ml) and water (5 ml) are stirred at 6020.

The mixture is stirred for 2 days at 60"C and filtered. The mixture is washed with ethyl acetate and dichloromethane, then concentrated under reduced pressure. The resulting residue is mixed with ethyl acetate, washed with brine, dried over Md5O", filtered and concentrated under reduced pressure. The resulting residue is filtered through a layer silica gel (eluent: dichloromethane/methanol mixture) and the crude product (360 mg) is obtained, which is used in the next step without further purification.

To a mixture of crude product (360 mg), 3,5-bis(trifluoromethyl)benzylamine (1.70 mmol, 413 mg/g) and acetic acid (1.70 mmol, 93 μL) in dichloroethane (5 mL) at room temperature add Mavn(OdAc)z (3.40 mmol, 721 mg). The mixture is stirred for 13 hours. and then the reaction is stopped with 1 M aqueous solution of maon. The mixture is extracted with dichloromethane and the organic layer is concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of dichloromethane/methanol, then a mixture of n-hexane/ethyl acetate) and tert-butyl ether cis-2-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)- 6-hydroxymethylpiperidine-1-carboxylic acid (216 mg, 11 95 in 2 stages); IER-MS t/g2: 547 (Ma-1|), retention time 3.73 min (conditions B).

To a mixture of 2-benzyl-4-(3,5-bis-trifluoromethylbenzylamino)-6-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ether (0.05 mmol, 28.0 mg) and KgSO3 (0.50 mmol, 69 mg) in THF (0.5 ml) at room temperature add methyl chloroformate (0.15 mmol, 10.6 μl). After stirring for 2 hours. at room temperature, water is added and the mixture is extracted with EtOAc.

The organic layer is washed with brine, dried over Mag5O4, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of n-hexane/"ethyl acetate) and tert-butyl ether 2-benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-b-hydroxymethylpiperidine is obtained -1-carboxylic acid (17.3 mg, 57905); IER-MS t/;: 605

IMA1G, retention time 2.41 min (conditions A). 21). Synthesis of 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-((A)-hydroxyphenylmethyl)-piperidine-1-carboxylic acid tert-butyl ether (2,4,6-cis-isomer)

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To Si! (10.0 mmol, 1.90 g) in THF (20 ml) at -78"С under a nitrogen atmosphere, slowly add a 1 M solution of vinylmagnesium bromide in THF (10.0 mmol, 10 ml). To the resulting mixture, add VEzEBO (5 .0 mmol, 624 μl), then a solution of 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (5.0 mmol, 1.13 g) in THF ( 20 ml). After stirring for 3 hours at room temperature, a saturated aqueous MNaCl solution is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over Ma»5O», filtered and concentrated under reduced pressure. The resulting residue is purified using column chromatography with silica gel (eluent: a mixture of n-hexane/ethyl acetate) and obtain a diastereometric mixture of 2-ethyl-b-isopropynyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (1.15 g, 9195); IR-MS ti/ : 198 (M-Vy--21", retention time 2.06 min (conditions A).

A mixture of tert-butyl ether 2-ethyl-b6-isopropynyl-4-oxopiperidine-1-carboxylic acid (17.4 mmol, 4.41 g), Atrepusi 2 15 (1 g), triethoxymethane (122 mmol, 20.3 ml ) and ethylene glycol (174 mmol, 9.6 ml) were stirred for 18 h. at room temperature. The mixture is filtered through a layer of silica gel and washed with ethyl acetate, and the collected solution is washed with 0.1 M aqueous solution of HCl and saturated aqueous solution of Mansoz. The organic layer is dried over Mag5O", filtered and concentrated under reduced pressure to obtain tert-butyl ether of 7-ethyl-9-isopropynyl-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid (4.83 g , 9395); IER-MS ti/: 242 |M-Vy--2G", retention time 2.31 min (conditions A).

To a solution of 7-ethyl-9-isopropynyl-1,4-dioxa-8-azaspiroI(4.5|decane-8-carboxylic acid tert-butyl ether (3.36 mmol, 1.00 g) in methanol (34 mL) at -78"C for 45 minutes, add Oz (100 Nl/hour, 60 rpm).

After passing OO», dimethyl sulfide (27.2 mmol, 2 mL) was added over 15 min at the same temperature, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture is concentrated and diethyl ether is added. The mixture was washed with water and brine, and the organic layer was dried over Na»5O», filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of n-hexane/ethyl acetate) and tert-butyl ether 7-ethyl-9-formyl-1,4-dioxa-8-azaspiro(4.5|decane-8- carboxylic acid (517 mg, 5190); IER-

MS ti/: 244 |M-Vy--2)", retention time 2.07 min (conditions A).

To a solution of 7-ethyl-9-formyl-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid tert-butyl ether (1.0 mmol, 299 mg) in THF (9 mL) at -78 To C, 1 M phenylmagnesium bromide in THF (2.0 mmol, 2.0 mL) is added. The mixture is stirred at room temperature for 1 h and then stirred for 1 h with an additional 1 M solution of phenylmagnesium bromide in THF (1.0 mmol , 1.0 ml). A saturated aqueous solution of MNACI is added to the mixture and extracted with ethyl acetate. The mixture is washed with water and brine, and the organic layer is dried over Mag5O4, filtered and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (eluent: mixture of n-hexane/ethyl acetate) and obtain tert-butyl ether of 7-ethyl-9-(B)-hydroxyphenylmethyl)-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid (131.7 mg, 3595); IER-MS t/:: 378 |MA1G, retention time 4.35 min (conditions B).

A mixture of tert-butyl ether of 7-ethyl-9-(B)-hydroxyphenylmethyl)-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid (0.25 mmol, 95.1 mg) and monohydrate p -toluenesulfonic acid (0.25 ml, 43 mg) in acetone (9 ml) is stirred at 50"С for 14 hours and then a saturated aqueous solution of MansSoz is added.

The mixture is extracted with ethyl acetate and the organic layer is dried over Mag5O", filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) and 2-ethyl-6-((A)-hydroxyphenylmethyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ether is obtained (36 mg, 4395); IER-MS t/: 278 (M-Vy--21", retention time 2.08 min (conditions

AND).

To a mixture of 2-ethyl-6-(HA)-hydroxyphenylmethyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ether (0.11 mmol, 36 mg), 3,5-bis(trifluoromethyl)benzylamine (0.17 mmol, 41 mg/g) and acetic acid (0.19 mmol, 10.4 μl) in dichloroethane (1.1 ml) at room temperature was added Mavn(ods)z (0.34 mmol, 72 mg).

The mixture is stirred for 13 hours. and then the reaction is stopped with 1 M aqueous Mahon solution. The mixture is extracted with dichloromethane and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) and a diastereometric mixture of tert-butyl ether 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-(A)- hydroxyphenylmethyl)-piperidine-1-carboxylic acid (41.4 mg, 6795, 2,4,6-cis/2,6-cis-4-trans-1/6);

IR-MS ti/: 561 (Ma-1)", retention time 2.06 min (conditions A). 22). Synthesis of tert-butyl ether 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6 - methoxymethylpiperidine-1-carboxylic acid (2,4,6-cis-isomer) -ke 11MaBN., mes, PS to CT KO n "a SH. ZMI DIPEA Aa I E a: kit XX.

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To a solution of 7-ethyl-9-formyl-1,4-dioxa-8-azaspiro(4.5|decane-8-carboxylic acid tert-butyl ether (1.0 mmol, 299 mg) in methanol (10 mL) at 0" C was added MavVNa (3.0 mmol, 113 mg). After stirring for 1.5 h at room temperature, a saturated aqueous solution of MNACI was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Md5Oah, filtered and concentrated under reduced pressure. To the resulting residue in DMF (5 mL) at room temperature was added DIPEA (3.0 mmol, 523 μL), AdHgO (3.0 mmol, 493 mg), and Me! (19 mmol, 1.2 mL). After stirring for 24 hours at 50"C, the mixture is filtered and washed with ethyl acetate. A saturated aqueous solution of MNeCl is added to the collected solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over Md5O, filtered and concentrated under reduced pressure. To the obtained residue in acetone (10 ml) p-toluenesulfonic acid monohydrate (1.0 mmol, 172 mg) is added and the mixture is stirred at 50°C for 14 hours A saturated aqueous solution of MansSOO was added to the mixture and then extracted with ethyl acetate. The organic layer is washed with brine, dried over Md5O, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to give 2-ethyl-6-methoxymethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (30 mg, 1195 in 3- x stages); IR-MS ti/: 216 (M-Vy-2g, retention time 1.95 min (conditions A).

To a mixture of 2-ethyl-b-methoxymethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (0.11 mmol, 30 mg), 3,5-bis(trifluoromethyl)benzylamine (0.16 mmol, 38.9 mg) and acetic acid (0.16 mmol, 8.7 μl) in dichloroethane (0.3 ml) at room temperature was added Mavn(Ods)z (0.32 mmol, 67.8 mg). The mixture is stirred for 13 hours. and then the reaction is stopped with 1 M aqueous solution of Mmaon. The mixture is extracted with dichloromethane and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) and 4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-methoxymethylpiperidine-1-carboxylic acid tert-butyl ether is obtained (2,4,6-cis-isomer) (17.5 mg, 32905); IER-MS m/2: 499 (M.A1)", retention time 1.95 min (conditions A). 23). Synthesis of 2-benzyl-b-ethylpiperidin-4-yl)-(3,5-bis- trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amine hydrochloride (2,4,6-cis-isomer)

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2-Benzyl-4-|(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (2,4,6-cis -isomer) (1.29 mmol, 900 mg) is dissolved in a 4 M solution of HCl in ethyl acetate. The mixture is stirred for 4 hours. at room temperature, then concentrated under reduced pressure. Diethyl ether is added to the obtained residue and filtered to obtain 2-benzyl-6-ethylpiperidin-4-yl)-(3,5-bis-trifluoromethylbenzyl)-(5-bromopyrimidin-2-yl)-amine hydrochloride (2,4,6 -cis- isomer) (771 mg); IER-MS t/2: 601 (MeNI), retention time 2.14 min (conditions A).

The following compound is obtained according to the method described above.

The structure of IER-MS pu/g (METI

E Y Y E

E E Ho) 2-Benzyl-b-ethylpiperidin-4-yl)-(3,5-bis-IF trifluoromethylbenzyl)-(5-m 6o8 1.99 min (conditions A) morpholin-4-ylpyrimidin-2- il)- M

M

N

24). Synthesis of tert-butyl ether (28,48,65)-4-(3,5-bis-trifluoromethylbenzylamino)-2,6-dipropylpiperidine-1-carboxylic acid o! I am V. B

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To a mixture of (5)-(--)-p-toluenesulfinamide (6.0 mmol, 931 mg) and (E)-but-2-enal (7.2 mmol, 597 μL) in dichloromethane (80 mL) at room (30 mmol, 6.3 mol). The mixture is stirred for 4.5 hours at 50"C and then cooled to room temperature. The mixture is poured into water and filtered. The filtered precipitate is washed with dichloromethane. The filtrate washed with water and brine, dried over Ma95O»x, filtered and concentrated under reduced pressure to obtain ME)-but-2-ene-(E)-ylideneamide of 4-methylbenzylsulfinic acid (1.16 g, 9495), which can be used without additional purification; IER-MS ti/:: 208.00 (Ma-1G", retention time 2.17 min (conditions A).

Methyl acetate (28 mmol, 28 mL) in THF (20 mL) at -78"C is added to a 1 M solution of

2.23 ml). The mixture is stirred for 1 hour. and at -78"C, |(E)-but-2-ene-(E)-ylideneamide of 4-methylbenzylsulfinic acid (5.6 mmol, 1.16 g) is added. The mixture is stirred, slowly increasing the temperature. After approximately 5 h at -18"C, add a saturated aqueous solution of MNaCl. The mixture is extracted with ethyl acetate and the organic layer is washed with water and brine, dried over Md5Ox, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/(ethyl acetate-1/1) and methyl ether (E)-(A)-3-oxo-5-(toluene-4-sulfinylamino)-oct is obtained -6-enoic acid (0.92 g, 5195); IER-MS t/: 323.93 (M.-1)", retention time 2.07 min (conditions A).

To a solution of (E)-(H)-3-oxo-5-(toluene-4-sulfinylamino)-oct-b-enoic acid methyl ester (1.3 mmol, 420 mg) in methanol (13 mL) at room temperature add TFC (0.48 mmol, 6.5 ml) and stir for 30 min. The mixture is concentrated under reduced pressure and the obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/ethyl acetate 4/1, then methanol).

The obtained substance is dissolved in dichloromethane (25 ml) and butyric aldehyde (13.3 mmol, 1.2 ml) is added.

The mixture is stirred for 1 hour. at room temperature, dilute with ethyl acetate, then add a saturated aqueous Mansoz solution. The organic layer is washed with brine, dried over NaCl, filtered and concentrated under reduced pressure to obtain (28,38,6НА)-4-oxo-6-(E)-propenyl)-2-propylpiperidine-3-carboxylic acid methyl ester (280 mg, 8095); IR-MS t/2: 240.08 (Ma1|), retention time 1.81 min (conditions A).

A mixture of (2K,3,6)-4-oxo-6-(E)-propenyl)-2-propylpiperidine-3-carboxylic acid methyl ester (137 mmol, 327 mg) and 1095 Ra/C (145 mg) in ethyl acetate (13 ml) is stirred in a hydrogen atmosphere for 1.5 hours. at room temperature. The mixture is filtered and concentrated under reduced pressure to obtain (28,38,65)-4-oxo-2,6-dipropylpiperidine-3-carboxylic acid methyl ester (361 mg); IER-MS t/:: 242.08

IMA1G, retention time 1.55 min (conditions A).

To a solution of (2K,3,65)-4-oxo-2,6-dipropylpiperidine-3-carboxylic acid methyl ether (0.62 mmol, 150 mg) in THF (4 ml) at room temperature is added a solution of GION monohydrate (6 .2 mmol, 236 mg) in HgO (20 ml). The mixture is stirred at 1007C for 2 hours. and cooled to room temperature.

A saturated aqueous solution of MNASI is added to the mixture and extracted with dichloromethane. The organic layer is dried over Na500, filtered and concentrated under reduced pressure to give (28,65)-2,6-dipropylpiperidin-4-one (93 mg), which is used in the next step without additional.

A mixture of (2K,65)-2,6-dipropylpiperidin-4-one (0.51 mmol, 93 mg) and BOC anhydride (166 mg) in dichloromethane (2 ml) was stirred at 60°C for 1.5 h and cooled to room temperature. Water was added to the mixture and extracted with dichloromethane. The organic layer was dried over Md5O", filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate mixture) to give tert-butyl (28.65)-4-oxo-2,6-dipropylpiperidine-1-carboxylic acid ester (46 mg); IR-MS t/g: 228.10 (M--1)", retention time 2.25 min (conditions A).

A mixture of (28,65)-4-oxo-2,6-dipropylpiperidine-1-carboxylic acid tert-butyl ether (0.091 mmol, 26 mg), 3,5-bis(trifluoromethyl)benzylamine (0.11 mmol, 33, 5 mg), Mavn(OAc)»z (0.184 mmol, 39 mg/g) and acetic acid (0.11 mmol, b μl) in dichloromethane (0.4 ml) were stirred under a nitrogen atmosphere at room temperature for 16 h. A 0.5 M aqueous solution of Maoson is added to the mixture and extracted with dichloromethane.

The organic layer is dried over Mag50O", filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/ethyl acetate) to obtain tert-butyl ether (2K,48,65)-4-(3,5-bis-trifluoromethylbenzylamino)-2,6-dipropylpiperidine- 1- carboxylic acid (16.2 mg, 34905); IER-MS t/g2: 511.01 (Ma1|", retention time 2.21 min (conditions A). 25). Synthesis of tert-butyl ether /4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino| -2- carboxymethyl-b-ethylpiperidine-1-carboxylic acid (racemate).

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To a solution of 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid tert-butyl ether (104 mg, 0.187 mmol) in 1- VION (3.5 mL) and 2-methylpropylene (0.5 mL) were added at 0"C to a cooled solution of MaciOx (34 mg, 0.375 mmol) and MaNgRoOx (0.112 mg, 0.935 mmol) in water (3.5 mL). The mixture is stirred at 0"C for 5 min and the reaction is stopped with a saturated solution of MagogOx.

The mixture is extracted twice with ethyl acetate and the combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl ether 4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-carboxymethyl-b -ethylpiperidine-1-carboxylic acid in the form of a colorless foamy substance (119 mg) LER-MS t/2: 571 (MA1)", retention time 2.42 min (conditions A). 26). Synthesis of tert-butyl ether 4- I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxobut-3-ynyl)-piperidine-1-carboxylic acid (racemic).

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To a solution of tert-butyl ether of 4-I(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-hydroxybut-3-ynyl)-piperidine-1-carboxylic acid (145 mg, 0.250 mmol ) in methylene chloride (3 ml) at 0"C, add Dess-Martin periodinan (265 mg, 0.624 mmol) and stir at RT for 1 h. Add an additional amount of Dess-Martin periodinan (86 mg, 0.202 mmol) and stir the mixture for another 1 h. Water and a saturated aqueous solution of Mago2O4 are added to the mixture. The mixture is extracted twice with diethyl ether, washed with brine, and the combined organic layer is dried over magnesium sulfate and purified by silica gel column chromatography to obtain tert-butyl ether 4-|( 3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxobut-3-ynyl)u-piperidine-1-carboxylic acid in the form of a colorless oil (194 mg) LER-MS t/l: 579 |Ma-1|", retention time 1.57 min (conditions A).

The following compounds are obtained according to the method described above.

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4-((3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxobut-3-ynyl)-piperidine-1-ocarboxylic acid isopropyl ether

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To a solution of 2-allyl-4-(3,5-bis-trifluoromethylbenzylamino)-b-ethylpiperidine-1-carboxylic acid tert-butyl ether (1.1 g, 2.22 mmol) in methylene chloride (5 ml) was added saturated aqueous solution of ManSoz (10 ml), then methyl chloroformate (0.190 ml, 2.4 mmol) and stirred at RT for 1 h.

The methylene chloride layer is extracted using a phase separator and the solvent is removed in vacuo to give 2-allyl-4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether as colorless oil (989 mg, 8195 yield). ER-MS t/;: 553

IMA1G, retention time 2.65 min (conditions A).

A solution of /2-allyl-4-((3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (677 mg, 1.22 mmol) in methylene chloride (8 mL) and methanol (2 ml) at -78"С for 5 min is treated with ozone (purging). After purging the solution with oxygen, triphenylphosphine (962 mg, 3.67 mmol) is added. The solution is heated to RT, concentrated in vacuo and purified by column chromatography with silica gel to obtain 4-(3,5-bis-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (642 mg, 9595 yield) LER-MS t/2: 499 (M-AIVy--1G, retention time 2.48 min (conditions A). 28). Synthesis of 4-|(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino isopropyl ether |-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid (racemic).

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A saturated aqueous solution is added to a solution of 2-allyl-4-(3-chloro-5-trifluoromethylbenzylamino)-b-ethylpiperidine-1-carboxylic acid isopropyl ether (0.846 mg, 1.89 mmol) in methylene chloride (5 ml)

Mansose (10 mL), then methyl chloroformate (0.161 mL, 2.08 mmol) and stirred at RT for 15 min.

The methylene chloride layer is extracted using a phase separator and the solvent is removed in vacuo to give 2-allyl-4-|(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-b-ethylpiperidine-1-carboxylic acid isopropyl ether as a colorless oil (954 mg, quantitative yield). yER-MS t/:

505 |M--11", retention time 2.47 min (conditions A).

A solution of /2-allyl-4-((3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-6-ethylpiperidine-1-carboxylic acid isopropyl ether (954 mg, 1.89 mmol) in methylene chloride (8 mL) and methanol ( 2 ml) at -78"C for 7 min treated with ozone (purging). After purging the solution with oxygen, triphenylphosphine (1.48 g, 5.57 mmol) was added. The solution was heated to RT, concentrated in vacuo and purified by column chromatography with silica gel and obtain a colorless oil isopropyl ether 4-|(3-chloro-5-trifluoromethylbenzyl)-methoxycarbonylamino|-2-ethyl-6-(2-oxoethyl)-piperidine-1-carboxylic acid in the form of a colorless oil (834 mg, 8795 output) and EP-MS t/: 506 (MA1)", retention time 2.28 min (conditions A). 29). Synthesis of tert-butyl ether of 4-(3,5-bis-trifluoromethylbenzylamino)-2,6-trans-diisopropylpiperidine-1-carboxylic acid (racemic))-mog 1

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M y nn I oho Mavn (Ods) from ASON G me

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AND:

To a solution of 4-methoxypyridine (10 mmol, 1.02 g) in THF (39 mL) at -407C under a nitrogen atmosphere is slowly added a 0.76 M solution of isopropylmagnesium bromide (11 mmol, 14.5 mL) in THF. After stirring for 1 min at -40°C, phenyl chloroformate (10.5 mmol, 1.33 ml) was added and a pale gray suspension was obtained.

The cooling bath is removed after stirring for 2 hours. the mixture is cooled to -40"C, IIVNOK (40 mmol, 4.5 g) is added in one portion and a yellow suspension is obtained. After stirring for 10 min at -40"C, the cooling bath is removed and the mixture is vigorously stirred for another 4 hours. The reaction is quenched with 31 mol HgO and the mixture is extracted with EBO. The combined organic layer is washed once with 1 n. aqueous solution of Mmaon and then three times 1 n. aqueous solution

NOSE After washing with brine, the organic layer is dried over Mda5O»x, filtered and concentrated under reduced pressure to obtain 2-isopropyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (957 mg, 4095 ), used in the next stage without additional purification. IER-MO t/: 240

IMA1G, retention time 2.27 min (conditions A).

To the suspension of Si! (8 mmoles, 1.52 g) in THF (40 ml) at -78"C under a nitrogen atmosphere, slowly add a 0.76 M solution of isopropylmagnesium bromide (8 mmoles, 10.5 ml) in THF. After stirring for 10 min dropwise at -70"С, add БЕзЕСО (4.8 mmol, 0.48 ml) and the gray suspension is vigorously stirred for 1 hour. at the same temperature. A solution of 2-isopropyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (4 mmol, 957 mg) in THF (5 ml) is added to the suspension at -78"C. allowed to warm to room temperature overnight and the reaction quenched with ice, sat.

Ma5oO", filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to give 2,6-trans-diisopropyl-4-oxopiperidine-1-carboxylic acid tert-butyl ether (164 mg, 2095); IER-MS t/;: 228.04 |M-

IVy--21", retention time 2.44 min (conditions A).

To a solution of tert-butyl ether of 2,6-trans-diisopropyl-4-oxopiperidine-1-carboxylic acid (0.15 mmol, 42 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.18 mmol, 55 mg) in 1,2-dichloroethane (1 ml) at room temperature add acetic acid (0.3 mmol, 17 μl) and Mavn(OAc)z (0.3 mmol, 64 mg). The mixture is stirred overnight and then diluted with H2O, made alkaline by 1 n. aqueous solution

Mahon, neutralize to pH 7 with a saturated MNaCl solution. The mixture is extracted using SN and the combined organic layer is concentrated under reduced pressure. The residue is purified by preparative TLC (eluent: n-hexane/ethyl acetate mixture) and a racemic mixture of tert-butyl ether /4-(3,5-bis-trifluoromethylbenzylamino)-2,6-trans-diisopropylpiperidine-1-carboxylic acid is obtained (2,6- trans isomer: 18 mg, 2495); IER-MS ti/l: 551.01 (MaА1Г", retention time 2.33 min (conditions A). 30). Synthesis of isopropyl ether 4-((5-bromopyrimidin-2-yl)-(3-chloro-5 --trifluoromethylbenzyl)-amino|-2,6- trans-diisopropylpiperidine-1-carboxylic acid (racemic).

; ! them about FRYUSOSI A sy, i-RIMOVg 1uvAmn, n g iRMoV shcha Y ve, | VE zOE, - tgF M zchavn that oo and dya mata, sho m r A ono r

It's still a vei -e maku si yin, "In Her | not what In o en o NI No

RShS, EN and me es y. s mem -- :-tl - 25 Й' '- at M nn - -ж- -ж5233- 1 4 whatever man, dm C about her A I A for M

AH 7 o

A 0.76 M solution of isopropylmagnesium bromide (76 mmol, 100 mol) in THF was slowly added through a cannula to a solution of 4-methoxypyridine (70 mmol, 7 mL) in THF (300 mL) at -40"С under a nitrogen atmosphere. After stirring for 20 isopropyl chloroformate (73 mmol, 8.36 mL) was added for 1 min at -507 C to give a pale gray suspension. 5O. The combined organic layer is washed three times with 50 mol of 1 N aqueous solution of HCl. After washing with brine, the organic layer is dried over Ma5O", filtered and concentrated under reduced pressure to give 2-isopropyl-4-oxo-3 isopropyl ether ,4-dihydro-2H-pyridine-1-carboxylic acid (15 g, 9595), which is used in the next stage without additional purification. EP-MS t/2: 226.04 Mat", retention time 1.84 min (conditions AND).

To the suspension of Sy! (70 mmol, 13.3 g) in THF (250 ml) at -78"С under a nitrogen atmosphere slowly add 0.76

M solution of isopropylmagnesium bromide (70 mmol, 92 ml) in THF. After stirring for 10 min at -707C, ВЭЭСО (42 mmol, 4 mL) was added dropwise, and the gray suspension was vigorously stirred for 1 h. at the same temperature. A solution of 2-isopropyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid isopropyl ether (35 mmol, 8.56 g) in THF (15 ml) is added to the suspension at -78"C. the vigorously stirred mixture is allowed to warm to room temperature overnight and the reaction is quenched with ice, sat. chromatography on a column with silica gel (eluent: a mixture of n-hexane/ethyl acetate) and obtain isopropyl ether of 2,6-trans-diisopropyl-4-oxopiperidine-1-carboxylic acid (1.75 g, 1995);

IR-MS ti/: 270.12 |(Ma1H, retention time 2.13 min (conditions A).

Benzylamine (9.75 mmol, 1.07 mol) and boron trifluoride etherate (0.065 mmol, 8 μl) and the resulting mixture is refluxed at 137"С for 30 min. After cooling to RT, toluene is removed under reduced pressure and the crude imide is used without further purification. To the crude imide sodium borohydride (4.7 mmol, 173 mg) is added to 85 mL of MeonH under M2 atmosphere. After heating to RT, the MeoOH is removed under reduced pressure and a saturated aqueous solution of MNACI is added. The aqueous layer is extracted with dichloromethane. The organic layer is washed with

NgO, brine, dried over Mag5O4, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to give 4-benzylamino-2,6-trans-diisopropylpiperidine-1-carboxylic acid isopropyl ether (2.09 g, 8995). IER-MS t/: 361.10

IMA1G, retention time 1.88 min (conditions A).

To a mixture of isopropyl ether of 4-benzylamino-2,b6-trans-diisopropylpiperidine-1-carboxylic acid (2.77 mmol, 1 g) in ethanol (80 ml) under an atmosphere of M" was added Ra/C (100 mg). Then nitrogen is replaced with hydrogen (1 atm.) and the reaction mixture is stirred at 60"C for 7 hours. After cooling to room temperature, filtration and evaporation gives isopropyl ether of 4-amino-2,6-trans-diisopropylpiperidine-1-carboxylic acid (0. 75 g, 10095), which is used without additional purification. IR-MS t/2: 271.12 (M--1G", retention time 1.68 min (conditions A).

5-Bromopyrimidine (3.9 mmol, 754 mi) and diisopropylethylamine (5.2 mmol, 0.91 mol). The reaction mixture is stirred at 120"C for 4 hours. After cooling, brine and H2O are added to the CT, and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of ammonium chloride and then dried over Mdzoh.

The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) and 4-(5-bromopyrimidine-2-ylamino)-2,6-trans-diisopropylpiperidine-1-carboxylic acid isopropyl ether is obtained (0 .66 g, 6095). IR-MS t/7: 426.99 (MaА1)", retention time 2.45 min (conditions A).

Sodium hydride (3.08 mmol, 123 mg), then the ice bath is removed. After stirring for 20 min at room temperature, the reaction mixture is cooled to 4°C and 3-chloro-5-trifluoromethylbenzyl bromide (2.31 mmol, 375 μl) is added. The ice bath is removed, and then the reaction mixture is stirred at room temperature for 2 h. Add H2HO and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Mag5O4, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to give isopropyl ether 4-(5 -bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-trans-diisopropylpiperidine-1-carboxylic acid (435 mg, 46905). IR-MS t/27: 620.87 |M--17", holding time 2.85 min (conditions A). 31). Synthesis of 2-benzyl-4-(4-ethoxycarbonyloxazol-2-ylamino)-b-ethylpiperidine-1-carboxylic acid tert-butyl ether

Oo- ak -h but they would o she SI M v y s KM Z | And its DIPEA, DMFO shshch

And about I

A solution of 4-amino-2-benzyl-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (1 mmol, 318 mg), 2-chloro-oxazole-4-carboxylic acid ethyl ether (3 mmol, 527 mg) and M ,M-diisopropylethylamine (2 mmol, 348 μl) in DMF (4 ml) is heated to 1107 and stirred for 24 h. The mixture is cooled to room temperature, then water is added. The mixture is extracted with EAs. The combined organic layer is dried over Na»5O», filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and 2-benzyl-4-(4-ethoxycarbonyloxazol-2-ylamino)-6-ethylpiperidine-1-carboxylic acid tert-butyl ether is obtained (288 mg, 6395); IER-MSO t/g: 458 |Ma1|", retention time 2.46 min (conditions A).

The following compound is obtained according to the method described above.

Structure c) X o-/

AND.

NM M o

Isopropyl ether of 4-(4-ethoxycarbonyloxazol-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid M to 32). Synthesis of 4-(3,5-bis-trifluoromethylbenzyl)-cyanoamino|-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether

E E is E E E (6)

IS"

MN, MN SMVe, Ma, SO M

M -- ----she-- ----232385-2

A TI(OIRI),, Mavn, meon oo meon ra m H ke va

A solution of 2,6-diethyl-4-oxopiperidine-1-carboxylic acid isopropyl ether (10 mmol, 2.41 g), 3,5-bistrifluoromethyl)benzylamine (15 mmol, 3.65 g) and titanium isopropoxide (12 mmol, 3.55 ml) in 20 ml of methanol is stirred at room temperature for 17 hours. Add to the mixture at 0"C in portions

Mavna (15 mmol, 570 mg) and stirred for 3 hours. The reaction is stopped by adding water and the mixture is stirred at room temperature for 1 hour. The suspension is filtered and washed with ethyl acetate. The solution is concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and isopropyl ether of 4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethylpiperidine-1-carboxylic acid (3.02 g, 64905).

To a mixture of 4-(3,5-bis-trifluoromethylbenzylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (0.6 mmol, 280 mg) and sodium carbonate (1.2 mmol, 127 mg) in methanol at cyanide bromide (0.9 mmol, 95 mg) is added at room temperature and stirred for 3 h. The mixture is filtered and the resulting solution is concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/hy(OAc) and isopropyl ether of 4-(3,5-bis-trifluoromethylbenzyl)-cyanoamino|-2,6-diethylpiperidine-1-carboxylic acid is obtained ( 265 mg, 9095); IER-MS ti/l: 494 |MA1T", retention time 2.52 min (conditions A).

33). Synthesis of isopropyl ether 4-|((3,5-bis-trifluoromethyl-benzoyl)-(1-methyl-1 H-(1,2,4|griazol-3-yl)-amino|-2,6-diethylpiperidine- 1-carboxylic acid

E E

E E E E

IS

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How - and I ik- - "M Nam shchi ol o still

A mavnghos a, ASON M pyridine o 0 z Arlin no m r ogo ro

To a solution of isopropyl ether of 2,6-diethyl-4-oxopiperidine-1-carboxylic acid (1 mmol, 240 mg), 1-methyl-1H-(1,2,4|griazol-3-ylamine (2 mmol, 200 mg) ) and acetic acid (2 mmol, 114 μL) in dichloroethane (2 mL) at room temperature was added sodium triacetoxyborohydride (2 mmol, 424 mg) and stirred for 15 h. The reaction was stopped by adding a saturated aqueous solution of sodium bicarbonate.

The mixture is extracted with dichloromethane and the combined organic layer is concentrated under reduced pressure.

The resulting residue is purified by silica gel column chromatography (eluent: Dhy/mMeon mixture) and 2,6-diethyl-4-(1-methyl-1H-(1,2,griazol-3-ylamino)-isopropyl ether is obtained of piperidine-1-carboxylic acid (168 mg, 5295); IER-MS t/g: 324 |MaА1Г", retention time 2.06 min (conditions A).

To a solution of 2,6-diethyl-4-(1-methyl-1H-(1,2,4|griazol-3-ylamino)-piperidine-1-carboxylic acid isopropyl ether (0.28 mmol, 90 mg) in pyridine (1 ml) at 0"C add 3,5-bis-trifluoromethylbenzoyl chloride (0.42 mmol, 77 μl) and stir for 1 hour at room temperature.

3,5-bis-trifluoromethylbenzoyl chloride (0.42 mmol, 77 μL) was added to the mixture at 0"C and stirred for 17 h at room temperature. A saturated aqueous solution of MNEeSi was added to the mixture and then extracted with DCM. The combined the organic solution is concentrated under reduced pressure.

The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EOAc) and 4-(3,5-bis-trifluoromethyl-benzoyl)-(1-methyl-1H-) isopropyl ether is obtained

1,2,A)Hygriazol-3-yl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (160 mg, quantitative yield); IER-MS ti/l: 564 |M.--11", retention time 2.48 min (conditions A).

The following compounds are obtained according to the method described above.

ITER-MS t/2 (MAG

E her and E

E E

I - I I MEME

Isopropyl ether 4-|(3,5-bis-M trifluoromethylbenzoyl)-(2-methyl- o What 2H-tetrazol-5-yl)-amino|-2,6- 565 2.59 (conditions A) diethylpiperidine- 1-carboxylic acid Sho

M

Ba

E Y and E

E E isopropyl ether 4-I(3,5-bis-9 trifluoromethylbenzoyl)-(5- o o- methylisoxazol-3-yl)-amino|-2,6- 564 2.59 (conditions A) diethylpiperidine-1- carboxylic acid

M ra 34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-|(1,3,2|dioxaborolan-2-yl)-pyrimidine that and v. vk (tu) aV, pon that ze 8-7

There is g tolusl Y TGgF che. Won na on V t pntvityzhchzhchnchzhchnyzhnchaaoyayavchnnnn NN, yan - cm -i8 s Su MabOdotoluslo MU | about em I. si

To a solution of 5-bromo-2-chloropyrimidine (10 mmol, 1.93 g) and triisopropylborate (12 mmol, 2.8 ml) in toluene (16 ml) and THF (4 ml) at -787C dropwise over 45 min add n-butyllithium in hexane (1.58 M, 12 mmol, 7.6 ml) and stirred at -78"C for 1 hour. The mixture was heated to -20"C, then an aqueous solution of hydrochloric acid (1 M, 20 mol ). The mixture is heated to room temperature. The precipitate was collected and washed with hexane to give a colorless powder (808 mg, 5195). A mixture of the powder (3.63 mmol, 575 mg), pinacone (3.81 mmol, 450 mg) and Md5Ox (18.15 mmol, 2.2 g) in toluene (10 mL) was stirred at room temperature for 15 h. The mixture is filtered and the solution is concentrated under reduced pressure. The resulting solid was washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-(1,3,2|dioxaborolan-2-yl)-pyrimidine (875 mg, quantitative yield); IR-MS t/2: 159 (M 1-pinaconi", retention time 1.75 min (conditions A). 35). Synthesis of 4-((5-benzyloxypyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl) isopropyl ether )-amino|-2,6-diethylpiperidine-1-carboxylic acid, 2 parts

ХК but A. g and is A IRGBIM NAM ad. BUT,

M nn va -- 2 « :-- - I '('«'-'I-Z

Her di tgF still oto Ж r rech ayao at ra det t» donya, in Y g si A

Y i reno that i mya o Y T r. che IV

A. Her C SI

NM m mm

Vpvg, KaSsOu g diF still man, dif shchi i

A solution of 4-amino-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (3.3 mmol, 800 mg), 2-chloro-5-(4,4,5,5-tetramethyl-(1,3,2 |dioxaborolan-2-yl)-pyrimidine (3.74 mmol, 900 mg and M,M-diisopropylethylamine (6.6 mmol, 1.15 mol) in DMF (10 ml) is heated to 120"C and stirred for 3 h The mixture is cooled to room temperature, then water is added.The mixture is extracted with

EUAs. The combined organic layer is dried over Ma»5O5, filtered and concentrated under reduced pressure.

The obtained residue is dissolved in THF (12 ml) and at room temperature an aqueous solution of HgO" (3595, 3.8 ml) is added. The mixture is stirred at room temperature for 2 hours. The mixture is cooled to 0"C and the reaction is stopped with a saturated aqueous solution of sodium thiosulfate. The mixture is extracted using

EUAs. The combined organic layer is dried over Ma50", filtered and concentrated under reduced pressure.

The resulting residue is purified by silica gel column chromatography (eluent: hexane/EOAc mixture) and 2,6-diethyl-4-(5-hydroxypyrimidin-2-ylamino)-piperidine-1-carboxylic acid isopropyl ether is obtained (580 mg, 5395); IR-MS t/:: 337 (Ma1G), retention time 3.94 min (conditions B).

To a mixture of 2,6-diethyl-4-(5-hydroxypyrimidin-2-ylamino)-piperidine-1-carboxylic acid isopropyl ether (1.72 mmol, 580 mg/g) and potassium carbonate (3.44 mmol, 475 mg ) in DMF (6 ml) at room temperature, add benzylamine (1.89 mmol, 225 μl) and stir for 13 h. Water is added to the mixture, then extracted with EOAc. The combined organic layer is dried over Ma?»5O»4, filtered and concentrated under reduced pressure. The resulting residue is washed with n-hexane to give 4-(5-benzyloxypyrimidine-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (635 mg, 8796); YIER-MS t/g2: 427 (Ma1)", retention time 2.33 min (conditions A).

Sodium hydride (6095 suspension in oil, 3 mmol, 120 mg) and stirred at room temperature for 20 min. 1-bromomethyl-3-chloro-5-trifluoromethylbenzene (2.25 mmol, 370 μl) was added to the mixture at 0"C and stirred at room temperature temperature for 5 hours

Water is added to the mixture and the mixture is extracted with EtOAc. The combined organic layer is dried over

Mag25O4, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/EIOAc) and 4-(5-benzyloxypyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2 isopropyl ether is obtained. 6-diethylpiperidine-1-carboxylic acid (705 mg, 7695); IER-MO t/2: 619 (M.-1|", retention time 2.78 min (conditions A).

The following compounds are obtained according to the method described above.

MA min

E E E E MN,

Tert-butyl ether E E boh, 2-benzyl-4-(5-me o. C Z benzyloxypyrimidine-g De; 2-yl)-(3,5-bis- mm ta vo -- /00 (conditions B) trifluoromethylbenzyl)-ba 1-Bromomethyl-3,5-bisamino)|-6-M trifluoromethylbenzene ethylpiperidine-1-oo instead of 1-bromomethyl-carboxylic acid A 3-chloro-5-trifluoromethylbenzene

Tert-butyl ether E c 2-benzyl-4-|(5- ma o. C Mn, benzyloxypyrimidin- g be 2-yl)-(3-chloro-5-Mom trifluoromethylbenzyl)-ba 695 6.06 (conditions B ) va amino|-6-MA-ethylpiperidine-1-A. carboxylic acid ra o

Zb). Synthesis of 2-benzyl-4-((5-benzyloxypyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-6-ethylpiperidine-1-carboxylic acid isopropyl ether

E sn o y vashchih S Els y r

What if I - I will go | And in, su; M TUNOII, 1,4-dioxane as pnypttTtTtTtlpipinshchich

C C 21 isopropyl chlorformiate I Y be t Sv.cOz, SNaSM what em

Kg

To a solution of 2-benzyl-4-((5-benzyloxypyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-6-ethylpiperidine-1-carboxylic acid tert-butyl ether (0.974 mmol, 677 mg ) in 1,4-dioxane (5 ml) at 0"C, add a solution of hydrochloric acid (4 N solution in 1,4-dioxane, 5 ml) and stir for 1 hour. The mixture is concentrated under reduced pressure. To the residue, add aqueous sodium hydroxide solution (1N) and extracted with dichloromethane.The combined organic layer was concentrated under reduced pressure.

To a mixture of the resulting residue and cesium carbonate (9.74 mmol, 3.2 g) in acetonitrile (5 mL) at room temperature is added isopropyl chloroformate (9.74 mmol, 1.12 mL). The mixture is heated to 607 and stirred for 3 hours. The mixture is cooled to room temperature and then water is added. The mixture is extracted with EtOAc. The combined organic layer is dried over Na?»b5Ox4, filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and isopropyl ether 2-benzyl-4-|(5-benzyloxy-pyrimidin-2-yl)-(3-chloro-5- trifluoromethylbenzyl)-amino|-b-ethylpiperidine-1-carboxylic acid (540 mg, 8195); IER-MS t/g: 681

IMA1G, retention time 5.94 min (conditions B). 37). Synthesis of tert-butyl ether of 2-ethyl-6-(hydroxyphenylmethyl)-4-oxopiperidine-1-carboxylic acid

KY Lo tevnv, sov u Su tvonlyaluva 7 ry t ya

IN; g l san I Me dichloroethane, MBO, day, bo

Z t ni and N i

Mesn Si on, 72. V-T5ON, tolui wa be n Ya

NO D9) yet) ! pu še s Ti i oso i s tuo acetone Che ak; vo i o i: -e -k

To a solution of 5-phenyl-3-penten-2-one (4.8 g, 30 mmol) in ethyl acetate (50 ml) with stirring, add phthalimide (4.4 g, 30 mmol) and a 4095 solution of Thiiyop? B in methanol (2 ml). The resulting solution is heated under reflux until the phthalimide is completely consumed. Then the mixture is allowed to cool to room temperature. Evaporation of the solvent and subsequent recrystallization from ethanol gave 2-(1-benzyl-3-oxobutyl)-isoindole-1,3-dione (4.0 g, 4390) as a white solid. IR-MS t/2: 308.01 (MaА1)", retention time 3.59 min (conditions B).

In a round-bottom flask connected to a Dean-Stark apparatus, to a solution of 2-(1-benzyl-3-oxobutyl)-isoindole-1,3-dione (4.0 g, 13.0 mmol) in toluene ( 50 ml), add freshly distilled ethylene glycol (0.87 mol, 15.6 mmol) and p--5OH (495 mg, 2.6 mmol). The mixture is refluxed for 5 hours, then cooled to room temperature and treated with a saturated solution of MansSoOz. The two layers are separated and the aqueous phase is extracted several times with ethyl acetate. The combined organic layers were washed with brine and then dried over Mag25O4. After evaporation of the solvent, the residue is purified by chromatography on silica gel (eluent: a mixture of hexane/ethyl acetate, 5/1) to obtain 2-|1-benzyl-2-(2-methyl-(1,3|dioxolan-2-yl)- ethyl|-isoindole-1,3-dione (4.3 g) as a pale brown oil, KG0.68 (hexane/ethyl acetate, 5/1).

To a solution of 2-|1-benzyl-2-(2-methyl-(1,3|dioxolan-2-yl)-ethyl|-isoindole-1,3-dione (4.3 g, 13 mmol) in methanol ( 14 ml) add 9895 hydrazine monohydrate (14 ml, 260 mmol). The mixture is refluxed for 7 h. After cooling the reaction mixture, a 5 M KOH solution (20 ml) is added to the CT. The aqueous layer is extracted three times with dichloromethane (50 ml ). The combined organic layers are washed with saturated brine and dried over Mag50Ox4. After evaporation of the solvent under reduced pressure, 1-benzyl-2-(2-methyl-|(1,3|dioxolan-2-yl)u-ethylamine (2) is obtained .2 g, 7795) in the form of a yellow oil, which is further used without purification. IR-MS pt/2: 222 |Ma1|", retention time 2.27 min (conditions B).

To a solution of cyclopropanecarboxaldehyde (84 mg, 1.2 mmol) in dichloroethane (2 ml) with stirring is added Mdzo»x (1 g), then a solution of 1-benzyl-2-(2-methyl-(1,3|dioxolane-2) -yl)-ethylamine (221 mg, 1.0 mmol) in

SNesi" (1 ml). The resulting solution is heated under reflux until the amine is completely consumed (3-4 h), then cooled to room temperature and transferred through a cannula into a solution of dry p-T5oOnH (380 mg, 2.0 mmol) in toluene (3 ml). The resulting mixture is heated at 707C for 4 hours. After cooling, a saturated aqueous solution of Mansoz (15 ml) was added to the CT and the mixture was extracted with ethyl acetate (20 ml). The combined extracts were dried over Mag25O4 and evaporated under reduced pressure to give 7-benzyl-9-cyclopropyl-1,4-dioxa-8-azaspiro(4.5|decane (112 mg) as a brown oil, which was further used without purification. IER-MS t/2: 27411 |М-А1Т7", retention time 2.65 min (conditions B).

A mixture of 7-benzyl-9-cyclopropyl-1,4-dioxa-8-azaspiro(4.5|decane (100 mg, 0.37 mmol) and BOC anhydride (1 g, 4.6 mmol) is stirred at 70"C for 9 h and cooled to room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over Ma 5 O, filtered and concentrated under reduced pressure. 7-Benzyl-9-cyclopropyl-1,4-dioxa-8-azaspiro(4.5|decane -8-carboxylic acid tert-butyl ether is obtained in the form of a brown oil, which is further used without purification. IR-MS t/27: 374.02 |M.--11", retention time 5.02 min (conditions B).

A mixture of 7-benzyl-9-cyclopropyl-1,4-dioxa-8-azaspiro|(4.5|decane-8-carboxylic acid tert-butyl ether (0.25 mmol, 95.1 mg) and p-toluenesulfonic acid monohydrate ( 0.25 ml, 43 mg) in acetone (9 ml) is stirred at 50"С for 14 h and then a saturated aqueous solution of MnSOO is added. The mixture is extracted with ethyl acetate and the organic layer is dried over Mag5O»4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixture) to obtain 2-ethyl-6-(hydroxyphenylmethyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ether (36 mg, 43905 ). KG. 0.68 (hexane/ethyl acetate, 5/1). 38). Synthesis of isopropyl ether 4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|- 2,6-diethylpiperidine-1-carboxylic acid

Another | - MN. and h I

AH se TIYUIRI,, MaVN, n 1095 ROS (wet. 5095

Sho M F - 65656 « 64-NYA IUH ----- « «5 5 5 «5 5 5 52 5 5 5 5 5 5 5 5 « 5 I zho ppiitToTltTtTTnTTlyTtnininiiny M

A. -n meon EN A. o o ne M ko o

With Zh

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ER sh ne Ve ru in: -V St EE so M -- Ve al Me: M iRt;viM She h. v y -- -yaft --n t - -- - - - t - -6--Ж--- ' - - -»5- dit wa Man, dmF ba no oo o

A mixture of 2,6-diethyl-4-oxopiperidine-1-carboxylic acid isopropyl ether (41.5 mmol, 10 g), benzylamine (62.3 mmol, 6.8 mL) and titanium isopropoxide (50 mmol, 15 mL) in 100 ml of methanol is stirred at room temperature for 17 hours. Mavna (62.3 mmol, 2.35 g) was added portionwise to the mixture at 0"C and stirred for 3.5 h. The reaction was stopped by adding water and the mixture was stirred at room temperature for 1.5 h. The suspension was filtered and washed with ethyl acetate . The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and isopropyl ether of 4-benzylamino-2,6-diethylpiperidine-1-carboxylic acid is obtained (8.94 g , 6595)

To a solution of isopropyl ether of 4-benzylamino-2,6-diethylpiperidine-1-carboxylic acid (27 mmol, 8.94 g) in ethanol (90 ml) add 1095 Ra/C (humidity 5095). The mixture is stirred in a hydrogen atmosphere at 40"C for 5 hours. The suspension is filtered and the filtrate is concentrated under reduced pressure to obtain isopropyl ether of 4-amino-2,6-diethylpiperidine-1-carboxylic acid (6.34 g, 9795)

A solution of 4-amino-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (26.2 mmol, 6.34 g), 5-bromo-2-chloropyrimidine (31.4 mmol, 6.1 g) and M. M-diisopropylethylamine (31.4 mmol, 5.5 ml) in DMF (80 ml) is heated to 120°C and stirred for 3.5 h. The mixture is cooled to room temperature, then water is added. The mixture is extracted with EtOAc. The combined organic layer is dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc)) and isopropyl ether 4-(5-bromopyrimidine-2- ylamino)-2,6-diethylpiperidine-1-carboxylic acid (6.2 g, 5995); IER-MS t/g2: 399 (Ma, retention time 2.79 min (conditions A).

Sodium hydride is added to a solution of 4-(5-bromopyrimidine-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ether (14.85 mmol, 5.93 g) in DMF (75 ml) at 0"C (6095 suspension in oil, 30 mmol, 1.2 g) and stirred at room temperature for 30 min. 1-bromomethyl-3-chloro-5-trifluoromethylbenzene (22.3 mmol, 3.6 ml) and stirred at room temperature for three hours. Water is added to the mixture and extracted with EUAbs. The combined organic layer is dried over Na»5O», filtered and concentrated under reduced pressure. The obtained residue is purified by chromatography on a column with silica gel (eluent: a mixture of hexane/E(OAc) and 4-(5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2 isopropyl ether is obtained ,6-diethylpiperidine-1-carboxylic acid (7.2 g, 8295); IR-MS t/l:: 591 (MaА1Г", retention time 5.93 min (conditions B).

The following compounds are obtained according to the method described above.

E and I E o

Isopropyl ether and Ebe (28,48,65)-4-((3,5-bis- M Vg M trifluoromethylbengu A zyl)-h(5- M 624,626 | 2.59 A /y bromopyrimidine-2- il)-" "59 (conditions l) ryamino|-2,6-1-Bromomethyl-3,5-bis-diethylpiperidine-1-M trifluoromethylbenzene carboxylic acid oo instead of 1-bromomethyl-

A. 3-chloro-5-trifluoromethylbenzene neti -1 min.

Oh)

Isopropyl ether o (28,48,65)-4-((5-M Ve bromopyrimidin-2-yl)-AZH (3-chloro-5-MOM trifluoromethylbenzyl-553 2,10 (conditions A) Xyl)-amino |-2,6-oto dimethylpiperidin-1-MA carboxylic acid A va v.

Oh)

Isopropyl ether o (28,6H8)-4-((5-M Ve bromopyrimidin-2-yl)-AZH (Z-chloro-5-M 5bA 2,11 (conditions A) x trifluoromethylbenzyl)-amino| -2,6-oso dimethylpiperidin-1- TM A of carboxylic acid A

J

39). Synthesis of isopropyl ether (25,4H8,68)-4-(3Z-chloro-5-trifluoromethylbenzyl)-I(5-(1-trityl-1H-imidazol-4-yl)-pyrimidin-2-yl|-amino )-2,6-diethylpiperidine-1-carboxylic acid

And it

E and te - and bor sh vi Ki I si o,

Or Vg sha Y ee E | i I i x o AIMZ pe Shin

She Ra RA, mm | and Talupl

And Sho is Shchi

And Oecho r

A mixture of isopropyl ether (25,48,6H8)-4-((5-bromopyrimidin-2-yl)-(3-chloro-5-trifluoromethylbenzyl)-amino|-2,6-diethylpiperidine-1-carboxylic acid (118 mg , 0.20 mmol), 1-trityl-4-tributylstannyl-1H-imidazole (144 mg, 0.24 mmol) and RD(RRPz)" (23 mg, 0.02 mmol) in toluene (3 ml) under nitrogen at 1307 for 4.5 h. The mixture was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Mag5O4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on a column with silica gel (hexane-ethyl acetate) and isopropyl ether (25,4K,6K)-4-((3-chloro-5-trifluoromethylbenzyl)-|5-(1-trityl-1H-imidazol-4-yl) is obtained )-pyrimidin-2-yl|-amino)-2,6-diethylpiperidine-1-carboxylic acid (170 mg); IR-MS t/g: 821 (Ma1|", retention time 5.02 min (conditions B) .