UA72540C2 - Spiro compounds as antagonists of neuropeptide y receptor activity - Google Patents

Abstract

Compounds of formula (I) wherein T, U, V and W represent independently nitrogen atom or optionally substituted methine group, where at least two of them represent the said methine group; represents methine or nitrogen; represents optionally substituted imino or oxygen atom; and the like. Compounds of the present invention exhibit NPY antagonistic activities and are useful as agents for the treatment of various diseases related to NPY. (I)

Description

This invention is applicable in medical fields. In more detail, the novel spirocompounds of this invention are useful as neuropeptide B receptor antagonists and agents for the treatment of various types of cardiovascular disorders, central nervous system disorders, metabolic disorders, and the like.

Neuropeptide M (hereinafter referred to as MRU), a peptide consisting of 36 amino acids, was first isolated from the brain of a pig Ta (Etoio et al. in 1982 (Maishge, 296: 659 (1982)). MRU is widely distributed in the central nervous system and the peripheral nervous system and plays various roles as one of the most abundant peptides in the nervous system. Namely, MRU acts in the central nervous system as an appetite stimulant and markedly promotes fat accumulation through the secretion of various hormones or the action of the nervous system. It is known that that long-term intracerebroventricular administration of MRU causes obesity and insulin resistance (insulin resistance), based on these actions (Ipiegpaiopa! Chotsgtpa! oi ObBrevu, moI. 19: 517 (1995);

Epaoshypoiodu, moI.133: 1753 (1993)). It is also known that MRU has a central effect on such conditions as depression, anxiety, schizophrenia, pain, dementia and the like (Ogyd5, mo!.52, 371 (1996)). In addition, on the periphery

MRU coexists with norepinephrine in the sympathetic ending and is involved in the tone of the sympathetic nervous system. It is known that peripheral introduction of MRU causes narrowing of blood vessels and enhances the action of other vasoconstrictor substances, such as norepinephrine (Vgyi5p OUocygpa! oi RIagtasiodu, moi. 95: 419 (1988)).

It is also reported that MRU can participate in the development of cardiac hypertrophy as a result of sympathetic stimulation (Rgoseedipd Myopa! Asadetis Zsiepse OBA, mo1I.97, 1595 (2000)).

On the other hand, it is reported that MRU is also involved in the secretory function of sex hormones and growth hormone, sexual behavior and reproductive function, gastrointestinal motor function, bronchoconstriction, inflammation and alcohol abuse (Gite Zsiepse, moiI.55, 551 (1994); Tpe doshigpa! oi APegdu apa Ittypoiodu, moi.101, 5345 (1998); Maishge, moi. 396, 366 (1998)).

MRU has a variety of pharmacological effects due to the binding of MRU to MRU receptors. Others are related

MRU peptides, including peptide U U and pancreatic polypeptide, also bind MRU-receptors. It is known that such pharmacological effects are mediated by the action of at least five subtypes of receptors with or without synergistic interactions (Tgepaz ip Meigozsiepse, mo!.20.294 (1997)).

M1: A central effect mediated by the U1-receptor of MRMU has been reported to include significant stimulation of appetite (Epdoshypoiodu, moI.137, 3177 (1996); EpadoshypoIodu, moI.141, 1011(2000))M. It is also reported that the MI-receptor is involved in perceived anxiety and pain (Maishge, moI.259, 528 (1993); Vgaip

Kezeagsi, mo!. 859, 361 (2000)). In addition, it is also reported that the pressor effects mediated by the strong vasoconstrictive effect of MRU on the periphery are mediated by M! (REV5 Geneg5, moi.362, 192(1995); Maishge

Measipe, vol. 4, 722 (1998)).

U2: It is known that the inhibitory effect on the release of various neurotransmitters in sympathetic nerve endings is mediated by the MRU U2-receptor (Vgiizp doigpa!oi Rpagtasoioudu, mo!.102, 41 (1991); Zuparze, mo/.2, 299 (1988)) . At the periphery of the MRU causes the narrowing of blood vessels or the vas deferens directly or through the regulation of the release of various neurotransmitters (Tpe doigpa! oi Rpagtasoiodo apa Ekhregitepia! Tpegareshisv, mo0I.261, 863 (1992); Vgyizp Washigpai! oi Rpagptasoiodo, moi!. 100, 190(1990)). In addition, the inhibition of lipolysis in adipose tissue is known (Epaosgipoiodu, moI.131, 1970 (1992)). Inhibition of ion secretion in the gastrointestinal tract is also reported (Vglizp Uoigpai oi Rpagtasoiodo, moi. 101, 247 (1990)).

On the other hand, inhibitory effects on central nervous system functions such as memory and anxiety have been reported (Vgaip Kezeagsi, moi!.503, 73 (1989); Reriidev, moi/.19, 359 (1998)).

Ultrasound: It is reported that MRU ultrasound receptors are located mainly in the brain stem and in the heart and are related to the regulation of blood pressure and heart rate (Te 9doshigpa! oi RpagtasoYodu apa Ekhregitepia! Tpegareshisv5, moI.258, 633 ( 1991); Reride, vol. 11, 545 (1990)). In addition, it is known that the UZ3 receptor is involved in the regulation of catecholamine secretion in the adrenal glands (Pe doipai oi RpappasoYodu apa Ekhregitepia! Tpegaretisiv, moI. 244, 468 (1988); Me Zsiepse, moi!. 50, RI 7 (1992)) .

U4: MRU UV receptor has a high affinity for pancreatic polypeptide. Similar pharmacological effects mediated by the U4 receptor are reported to include inhibition of pancreatic secretion and motility of the gastrointestinal tract (Savzygoepiegoiodu, mo!.85, 1411 (1983)). In addition, it is reported that MRU increases the secretion of the sex hormone in the central nervous system (Epaoshypo!odu,

MmOI. 140, 5171 (1999)).

U5: The effect mediated by the MRU U5-receptor includes the stimulation of feeding and fat accumulation (Mayige, mo!.3 82, 168 (1996); Ategisap doipai oi Rpusioidodu, moI.277, K1428 (1999)). It is reported that MRU

The U5-receptor also mediates some effects of SM5, such as seizure and epilepsy, or pain and morphine withdrawal symptoms (Maiiga! Measipe, mo!.3, 761 (1997); Rgoseedipd Asadetis Zsiepse OBA, moI.96, 13518 (1999); Tpe doshigpai! oi Rpaptasiodu apa Ekhregitepia! Tpegareshiisv5, myI.284, 633 (1998)). It is reported that on the periphery the U5-receptor is involved in diuresis and the hypoglycemic effect caused by MRU

RPaptasiodu, moi!. 120, 1335 (1998); Epaoshypoiodu, moI. 139, 3018 (1998)). It is also reported that MRU increases cardiac hypertrophy due to the predominance of the sympathetic component (Rhoseedipd Mayopa! Asadetis

Zsiepse OBA, moi.97, 1595(2000)).

The effects of MRU occur (are revealed) when binding MRU receptors in the central and peripheral nervous systems. Thus, the action of MRU can be prevented by blocking the binding of MRU-receptors.

Substances that antagonize the binding of MRP to MRU receptors may be useful for the prevention or treatment of various diseases associated with MRU, such as cardiovascular disorders (eg, hypertension, nephropathy, heart disease, vasospasm), central nervous system disorders ( e.g., bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal syndrome), metabolic disorders (e.g., obesity, diabetes, hormonal disorders), sexual and reproductive dysfunction, gastrointestinal motility disorders, respiratory diseases , inflammation or glaucoma, and the like (Tgepaz ip Rpagtasoiodisa! 5siepsev, 15: 153 (1994); And Te bsiepse, 55, 551 (1994), Ogodv, moI.52: 371 (1996); Tne uChoshigpai! oi APegdu apa Ittipoiodu , moi.101, 5345 (1998); Mashgtge, moi.396, 366 (1998); Tpe

Udoigpai oi Rpaitasoiodu apa Ehregitepia! TPegaretsshchisv, mo!. 284, 633 (1998); Tgepav ip Rpappasoiodisa! Yes,

20, 104 (1999); Rgoseedipd Myopa! Asadetis bsiepse OA, moi.97,1595 (2000)).

According to the research of the authors of this invention, it was recently discovered that some types of MRP receptor antagonists are useful for the prevention or treatment of hypercholesterolemia, hyperlipidemia, and arteriosclerosis (publication of international application UUO99/279651.

The purpose of this invention is to provide new drugs that demonstrate MRU-antagonistic activity.

The applicants of this invention discovered that the compounds of the general formula (1):

TY is further defined where Ar is aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl , lower alkoxy, halo(lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by the formula -O-Ag"; where A!? represents aryl or heteroaryl, which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino, di(lower)alkyl )amino, lower alkanoyl and aryl; n is 0 or 1;

O represents a simple bond or carbonyl;

T, Y), M and M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of a lower alkyl halogen, a hydroxyl, and a lower alkoxy group, and at least two of them (T, Sh, M / and M) represent the indicated methane group; X represents a methine group or nitrogen;

Y represents an imino group, which may be substituted by lower alkyl, or oxygen; exhibit MRU-antagonistic activity and are useful as therapeutic agents for the treatment of various diseases associated with

MRU, which constitutes this invention.

Compounds (I) of the present invention are useful as agents for the treatment of various diseases associated with MRU, for example, cardiovascular disorders (e.g., hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis), central nervous system disorders (e.g., bulemia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal syndrome), metabolic disorders (for example, obesity, diabetes, hormonal disorders, hypercholesterolemia, hyperlipidemia), sexual and reproductive dysfunction, gastrointestinal disorders, respiratory diseases, inflammation, glaucoma and the like.

More specifically, the compounds of general formula (I) are useful agents for the treatment of bulimia, obesity, diabetes and similar conditions.

This invention relates to compounds of the general formula (I), their salts or ethers, the method of their preparation and use.

In another variant, the present invention relates to an intermediate product of the compound of general formula (I). Specifically, it refers to the compound represented by the general formula (MI-1): soon y (lm) ! и : ж (c) where и, m, мим independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy and optionally protected hydroxyl, and at least , two of them (i, i, m and m) represent the indicated methine group.

Next, the meanings of the terms used in this description are defined and a more detailed description of this invention is presented.

The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The term "lower alkyl" refers to a linear or branched C1-C8 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

The term "halo(lower)alkyl" refers to the lower alkyl indicated above, substituted by 1, 2 or more than 2, preferably 1-3 halogen atoms indicated above, the same or different in arbitrary positions amenable to substitution, such as, fluoromethyl, difluoromethyl , trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, bromomethyl, iodomethyl and the like.

The term "hydroxy(lower)alkyl" refers to the above lower alkyl substituted 1, 2 or more by 2 hydroxy groups, preferably 1 or 2 in any positions amenable to substitution, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1 -methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl and the like.

The term "cyclo(lower)alkyl" refers to a C3-C6 cycloalkyl group, such as cyclopropyl,

cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "lower alkenyl" refers to a linear or branched Co-Cv alkenyl group such as vinyl, 1-propenyl, 2-propenyl isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1 -methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like.

The term "lower alkoxy" refers to a linear or branched C 1 -C 6 alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, and the like.

The term "halo(lower) alkoxy" refers to the lower alkoxy group indicated above, substituted 1, 2 or more by 2 halogen atoms from the above, preferably 1-3, the same or different in arbitrary positions amenable to substitution, for example, fluoromethoxy, difluoromethoxy , trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, brommethoxy, iodomethoxy and the like.

The term "lower alkylthio" refers to a linear or branched C1-C8 aalkylthio group, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, and the like.

The term "lower alkanoyl" refers to an alkanoyl group containing the above lower alkyl, i.e., a C0-C7 alkanoyl group, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

The term "lower alkoxycarbonyl" refers to an alkoxycarbonyl group containing the above lower alkoxy, i.e. a C2-C7 alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like.

The expression "lower alkylene, optionally substituted with an oxo group" refers to a linear or branched C2-C8 alkylene group which may be substituted at any of the positions amenable to substitution, 1,2 or more by 2, preferably 1 oxo group, such as ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-oxoethylene, 1-oxotrimethylene, 2-oxotrimethylene, 1-oxotetramethylene, 2-oxotetramethylene and the like.

The term "aryl" includes phenyl, naphthyl and the like.

The term "heteroaryl" refers to a 5- or b-membered monocyclic heteroaromatic group containing 1, 2 or more than 2, preferably 1-3 heteroatoms, the same or different, selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom; or a fused hydroaromatic group, wherein the above monocyclic heteroaromatic group is fused with the above aryl group or with an identical or different above monocyclic heteroaromatic group, such as pyrrolyl, furyl, thienyl imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl , pyridoyi3,2-b|pyridyl and the like.

The term "lower alkylamino" refers to an amino group monosubstituted with the above-mentioned lower alkyl, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, and the like.

The term "di(lower alkyl)amino" refers to an amino group disubstituted by the same or different lower alkyls as mentioned above, such as dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, diisopropylamino, and the like.

Salts of compounds of formula (I) refer to pharmaceutically acceptable conventional salts, for example, base-addition salts of a carboxyl group if the compound has a carboxyl group, or acid-addition salts of an amino group or a basic heterocyclic radical, if the compound has an amino group or a basic heterocyclic group, and similar

The above-mentioned base-additive salts include salts with alkali metals (for example, sodium, potassium); alkaline earth metals (for example, calcium, magnesium); ammonia or organic amines (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procat, M,M'-dibenzylethylenediamine) and the like.

The above acid additive salts include salts with inorganic acids (for example, hydrochloric, sulfuric, nitric, phosphoric, perchloric); organic acids (for example, maleic, fumaric, tartaric, citric, ascorbic, trifluoroacetic); sulfonic acids (for example, methanesulfonic, isothionic, benzenesulfonic, para-toluenesulfonic) and the like.

Esters of compounds of formula (I) are, for example, pharmaceutically acceptable conventional carboxyl esters, if the compound has a carboxyl group, for example, lower alkyl esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl), aralkyls (e.g., benzyl, phenethyl), lower alkenyls (e.g., allyl, 2-butenyl), lower alkoxy(lower)alkyls (e.g., methoxymethyl, 2 -methoxyethyl, 2-ethoxyethyl), lower alkanoyloxy (lower) alkyls (for example, acetoxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl), lower alkoxycarbonyl (lower) alkyls (for example, methoxycarbonylmethyl, isopropoxycarbonylmethyl), carboxy (lower) alkyls ( e.g., carboxymethyl), lower alkoxycarbonyloxy-(lower) alkyls (e.g., 1-("ethoxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl), carbamoyloxy (lower)- alkyls (e.g., carbamoyloxymethyl), phthalidyl, (5-substituted-2-oxo-1,3-dioxol-4-yl)umethyl (e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl )umethylom) and the like.

The term "therapeutic agent" refers to a medicinal product that is used for the treatment and/or prevention of various diseases.

For a more detailed disclosure of the above-mentioned compounds of the general formula (I) in preferred versions, the designations used in formula (1) are explained in more detail.

Ag is aryl or heteroaryl which may be substituted, wherein the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by the formula -O-Ag".

The term "aryl or heteroaryl which may be substituted, wherein the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by the formula -O-Ag?" refers to the above unsubstituted aryl or heteroaryl or the above aryl or heteroaryl having a substituent(s) at any position(s) subject to substitution. The above substituents may be the same or different, one, two or more than 2, preferably 1 or 2, selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower) )-alkyl, lower alkenyl, lower alkoxy, halo(lower) alkoxy, lower, alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group of the formula: -O-A1.

The halogen atom as the above-mentioned substituent preferably includes a fluorine atom, a chlorine atom, and the like.

Lower alkyl as the above substituent preferably includes methyl, ethyl, propyl, isopropyl and the like.

Halo(lower)alkyl as the above-mentioned substituent preferably includes difluoromethyl, trifluoromethyl and the like.

Hydroxy(lower)alkyl as the above-mentioned substituent preferably includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and the like.

Cyclo(lower)alkyl as the above substituent preferably includes cyclopropyl, cyclobutyl and the like.

Lower alkenyl as the above substituent preferably includes vinyl, 1-propenyl, 2-methyl-1-propenyl and the like.

Lower alkoxy as the above-mentioned substituent preferably includes a methoxy, ethoxy group and the like.

Halogen(lower) alkoxy as the above-mentioned substitute preferably includes fluoromethoxy-, difluoromethoxy-, trifluoromethoxy group and the like.

Lower alkylthio as the above-mentioned substituent preferably includes methylthio, ethylthio group and the like.

Lower alkanoyl as the above substituent preferably includes acetyl, propionyl and the like.

Lower alkoxycarbonyl as the above substituent preferably includes methoxycarbonyl, ethoxycarbonyl and the like.

Lower alkylene, optionally substituted with an oxo group, as the above substituent preferably includes 1-oxotetramethylene and the like.

In the group of formulas-OH-A!? as defined above, the substituent A!" refers to aryl or heteroaryl, which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower) alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkanoyl and aryl;)

O-represents a single bond or carbonyl.

The term "aryl or heteroaryl which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower) alkyl, lower alkylamino, di(lower alkyl)amino, lower alkanoyl and aryl" refers to the above unsubstituted aryl or heteroaryl or the above aryl or heteroaryl having substituent(s) at any position(s) amenable to substitution. The above substituents may be the same or different, one or at least 2, preferably 1 or 2, selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkyl , halo(lower) alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkanoyl and aryl.

The halogen atom as the above-mentioned substituent preferably includes a fluorine atom, a chlorine atom, and the like.

Lower alkyl as the above substituent preferably includes methyl, ethyl, propyl, isopropyl and the like.

Halo(lower)alkyl as the above-mentioned substituent preferably includes difluoromethyl, trifluoromethyl and the like.

Hydroxy(lower)alkyl as the above-mentioned substituent preferably includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and the like.

Lower alkoxy as the above-mentioned substituent preferably includes a methoxy, ethoxy group and the like.

Halogen(lower) alkoxy as the above-mentioned substitute preferably includes fluoromethoxy-, difluoromethoxy-, trifluoromethoxy group and the like.

Lower alkylamino as the above-mentioned substituent preferably includes methylamino, ethylamino group and the like.

Di(lower alkyl)amino as the above-mentioned substituent preferably includes a dimethylamino group, diethylamino group, and the like.

Lower alkanoyl as the above substituent preferably includes acetyl, propionyl and the like.

Aryl as the above substituent preferably includes phenyl and the like.

Deputy (deputies) Ag? preferably includes halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, halo(lower)alkyl, and the like.

Aryl in AI?7 preferably includes phenyl and the like, and heteroaryl includes imidazolyl, pyridyl, benzofuranyl, quinolyl and the like.

So, the group of formula-O-AI? includes, for example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-

dichlorphenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluoro-5-methylphenyl, /3-fluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-fluoromethoxyphenyl, Z -difluoromethoxyphenyl, 3-(2-hydroxyethyl)phenyl, 3-hydroxymethyl-phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl , 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidinyl, 5 -pyrimidinyl, 4-benzo(p|furanyl, 5-benzo|b|furanyl, 7-benzo(b|furanyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 8-quinolyl , benzoin, 2-pyridylcarbonyl and the like and preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3-difluoromethoxyphenyl, 3-(2 -hydroxyethyl)phenyl, 3-hyd roxiphenyl, 4-hydroxyphenyl, 1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo|p|furanyl, 2-quinolyl, 3-quinolyl, benzoyl, 2-pyridylcarbonyl and the like.

Deputy Ah! preferably includes halogen, lower alkyl, halo(lower)alkyl, lower alkenyl, lower alkanoyl, lower alkylene, optionally substituted with an oxo group, and a group of the formula: -O-Ag and the like.

Aril in Ag! preferably includes phenyl and the like, heteroaryl in Ag" includes pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,2,4 - triazinyl, benzoxazolyl, benzothiazolyl, quinolyl, pyridoyi3,2-b|Ipyridyl and the like.

So, Ah! includes, for example, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,

3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl, 4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl, 3 -(2-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 4-(2-ethyl-4-pyridyl)phenyl, 4- (4-pyrimidinyl)-phenyl, 4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-pyrrolyl, i-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl, 1 -(3-fluorophenyl)-4-imidazolyl, 1-(4-fluorophenyl)-4-imidazolyl, 1-(2,3-difluorophenyl)-4-imidazolyl, 1-(2,4-difluorophenyl)-4-imidazolyl , 1-(3,5-difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-imidazolyl, 1-(2-cyanophenyl)-4-imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl . methylethyl)phenyl|)-4-imidazolyl, 1-(3-methoxyphenyl)-4-imidazolyl, 1-(2-difluoromethoxyphenyl)-4-imidazolyl, 1-(3- difluoromethoxyphenyl)4-imidazolyl, 1-(4- difluoromethoxyphenyl)-4-imidazolyl, 1-(2-pyridyl)-4-imidazolyl, 1-(4- benzo(b|furanyl)-4- imidazolyl, 1-(5-benzo(p|furanyl)-4-imidazolyl, 1-(7-benzo|(b|furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl, 1-( 3-quinolyl)-4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl, 1-(5-quinolyl)4-imidazolyl, 1-(6-quinolyl)-4-imidazolyl, 1-(8-quinolyl) )4-imidazolyl, 1-phenyl-Z-pyrazolyl, 5-phenyl-Z-pyrazolyl, 1-phenyl-4-pyrazolyl, 1-(2-fluorophenyl)-Z-pyrazolyl, 5-(2-fluorophenyl)-Z -pyrazolyl, 5-(3-fluorophenyl)-3-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-pyrazolyl, 5-(4-fluorophenyl)-3-pyrazolyl , 5-(2-chlorophenyl)-Z-pyrazolyl, 5-(3-chlorophenyl)-Z-pyrazolyl, 5-(4-chlorophenyl)-Z-pyrazolyl, 5-(2-difluoromethoxyphenyl)-3-pyrazolyl, 5 -(3-difluoromethoxyphenyl)-Z-pyrazolyl, 2-methyl-5-phenyl-Z-pyrazolyl, 5-(2-pyridyl)-Z-pyrazolyl, 5-(2-quinolyl)-3-pyrazolyl, 5-( 3-quinolyl)-3-pyrazolyl, 4-phenyl-2-thiazolyl, 5-phenyl-2-thiazolyl, 5-(3-chlorophenyl)-2-thiazolyl, 5-(4-chlorophenyl)-2-thiazolyl, 5 -(4-methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl, 2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl, 4-( 2-fluoromethox iphenyl)-2-oxazolyl, 4-(3-fluoromethoxyphenyl)-2-oxazolyl, 5-phenyl-Z-isoxazolyl, Z-phenyl-5-isoxazolyl, 3-(2-chlorophenyl)-5-isoxazolyl, 3-( C-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5-isoxazolyl, 3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-1, 2, C-triazol-4-yl, 5 -phenyl-1, 2, 4-thiadiazol-3-yl, 5-phenyl-1,3,4-thiadiazol-d-yl, 5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl , 5-(2-pyridyl)-1,3,4-thiadiazol-2-yl, 5-(2-ethyl-4-pyridyl)-1,3,4-thiadiazol-2-yl, 5-phenyl-2 -pyridyl, b-phenyl-3-pyridyl, 2-phenyl-4-pyridyl, 5-(2-pyridyl)-2-pyridyl, 5-benzoyl-2-pyridyl, 6b-benzoyl-3-pyridyl, 5-chloro -2-pyrazinyl, 5-(2-methyl-1-propenyl)-2-pyrazinyl, 5-acetyl-2-pyrazinyl, 5-propionyl-2-pyrazinyl, 5-phenyl-2-pyrazinyl, 5-(3- hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-(1,2,4-thiadiazol-5-yl-2-pyrazinyl, 5-(1,3,4-thiadiazole-2 -yl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl, 5-(3-pyridyl)-2-pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl, 5-(3-quinolyl) )-2-pyrazinyl, 5-benzoyl-2-pyrazinyl, 5-(2-pyridylcarbonyl)-2-pyrazines l, 5-acetyl-2-pyrimidinyl, 5-acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl, 5-phenyl-2-pyrimidinyl, b-phenyl-4-pyrimidinyl, 2-phenyl- 5-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pyrimidinyl, 5-(4-fluorophenyl)-2-pyrimidinyl, 5-(2-chlorophenyl)-2- pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl, 5-(4-chlorophenyl)-2-pyrimidinyl, 5-(2-methylphenyl)-2-pyrimidinyl, 5-(3-methylphenyl)-2-pyrimidinyl, 5-(2-fluoromethylphenyl)-2-pyrimidinyl, 5-(3-fluoromethylphenyl)-2-pyrimidinyl, 5-(2-trifluoromethylphenyl)-2-pyrimidinyl, 5-(3-trifluoromethylphenyl)-2-pyrimidinyl, 5- (4-trifluoromethylphenyl)-2-pyrimidinyl, 5-(2-hydroxymethylphenyl)-2-pyrimidinyl, 5-(3-hydroxymethylphenyl)-2-pyrimidinyl, 5-(2-hydroxyphenyl)-2-pyrimidinyl, 5-(3 -hydroxyphenyl)-2-pyrimidinyl, 5-(2-methoxyphenyl)-2-pyrimidinyl, 5-(3-methoxyphenyl)-2-pyrimidinyl, 5-(4-methoxyphenyl)-2-pyrimidinyl, 5-(2-fluoromethoxyphenyl) )-2-pyrimidinyl, 5-(3-fluoromethoxyphenyl)-2-pyrimidinyl, 5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl, 5-(3-fluoro-5-methoxyphenyl)-2-pyr imidinyl, 6-phenyl-2-pyridazinyl, 6b-phenyl-1,2,4-triazin-3-yl, 5-chloro-2-benzoxazolyl, 5-fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl, 2-methyl-5-benzothiazolyl 4-methoxy-2-benzothiazolyl, 3-quinolyl, b6-quinolyl, 7-methyl-2-quinolyl-2-methyl-b-quinolyl, b-chloro-2-quinoxalinyl, pyridoyi3,2 -b|Ipyridin-2-yl, 7-chloropyridoyi3,2-

B|-pyridin-2-yl, 7-methylpyridoi3,2-b|pyridin-2-yl, 7--trifluoromethyl-pyrido|3,2-b|pyridin-2-yl, 1-difluoromethoxypyridoi|3,2- b|Ipyridin-2-yl, 7-acetylpyridoi|3,2-b|Ipyridin-2-yl and the like; preferred 3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl, 4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl, 4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-pyrrolyl, 1-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl, 1-(3,5-difluorophenyl) -4-imidazolyl, 1-(3Z-chlorophenyl)-4-imidazolyl, 1-(3-cyanophenyl)4- imidazolyl, 1-3-(2-hydroxyethyl)phenyl|-4-imidazolyl, 1--"Z- difluoromethoxyphenyl)-4-imidazolyl, 1-(7-benzo(b|furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl, 1-(3-quinolyl)-4-imidazolyl, 1-phenyl -Z-pyrazolyl, 5-phenyl-Z-pyrazolyl, 1-phenyl-4-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-Z-pyrazolyl, /5-(4 - chlorophenyl)-Z-pyrazolyl, 5-(3-quinolyl)-Z-pyrazolyl, 5-phenyl-2-thiazolyl, Z-phenyl-5-isoxazolyl, 5-(2-methyl-1-propenyl)-2- pyrazinyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl, 5-benzoyl- 2-pyrazinyl, 5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pi rimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl, 5-(3-trifluoromethylphenyl)-2-pyrimidinyl, 5-chloro-2-benzoxazolyl, 4-methyl-2-benzothiazolyl, 7-methyl-2-quinolyl, 7-trifluoromethylpyridoyl3,2-b|pyridin-2-yl and the like;

especially preferably 1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl, 5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl, 5-phenyl-2-garimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pyrimidinyl, 7-trifluoromethylpyrido3,2-b|pyridin-2-yl and the like. n is equal to 0 or 1, 0 is preferred.

T, U, M, and M/ independently represent a nitrogen atom or methine, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, and lower alkoxy, and at least two of them (T, O, M and MU) represent the specified metin.

The expression "methine which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl and lower alkoxy" refers to unsubstituted methine or methine having a substituent which may be selected from the group consisting of halogen, lower alkyl, hydroxyl and lower alkoxy group.

The halogen atom as the above-mentioned substituent preferably includes a fluorine atom, a chlorine atom, and the like.

Lower alkyl as the above substituent preferably includes methyl, ethyl and the like.

Lower alkoxy as the above-mentioned substituent preferably includes a methoxy, ethoxy group and the like.

The above substituent preferably includes halogen and the like.

A preferred variant of T, Y, M and M/ includes, for example, T, M, M and MU, which independently represent a methine, not necessarily one having the above-mentioned substituent, preferably a halogen; or the variant when one of T. Sh, M and M/ is a nitrogen atom.

X represents methine or az ot.

U represents an imino group, which may be substituted by lower alkyl, or oxygen.

The term "imino group which may be substituted with lower alkyl" refers to an unsubstituted imino group or an imino group substituted with lower alkyl.

The above lower alkyl preferably includes methyl, ethyl and the like.

U is preferably an unsubstituted imino group or oxygen, especially oxygen.

More specifically, the group of formula (15): x. what is my color

АХ t СН хо includes groups of formulas (16): i

V, ek V i -oeroyatyu v

Ber dae ve N x snu m KU Z GU i, no, no uhmere me M stelu y o KZ z y , Ne y s u I re ev i -k tor ayu oso gr ky ZAA ev, in 2 i ; It is not s pu h vk and the like.

Preferred compounds of general formula (I) are, for example, compounds of general formula (I-a):

Ky zdiyam, sh S U NN) a ru zy ge de V! means a hydrogen atom or a halogen, Ag! has the meaning specified above; or compounds of the general formula (I-B): o, p; va de x sv zh ikh Khy jah and de Ag", T, U, M and M/ have the above values.

As for the compound represented by the general formula (1-a), for example, compounds in which the aryl group in Ag! is phenyl, or a heteroaryl group in Ag! is imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or pyridoyl3,2-b|pyridyl.

As for the compound represented by the general formula (I-b), preferred are, for example, compounds in which the aryl group in Ag is phenyl, or the heteroaryl group in Ag is pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2,4-thiadiazolyl, sridyl, pyrazinyl, pyrimidinyl or 1,2,4-triazolyl.

In addition, with regard to the compound represented by the general formula (I-b), for example, compounds in which T, U, M and UM represent a nitrogen atom are preferred, and more preferred, for example, are compounds in which M represents an atom nitrogen, and T, O and UM represent an unsubstituted methane group.

The compounds of this invention may include stereoisomers such as optical isomers, diastereoisomers and geometric isomers or tautomers depending on the variant of the substituents. The compounds of this invention include all stereoisomers, tautomers and mixtures thereof.

For example, compounds of the general formula (I-B) include stereoisomers, such as the trans-form of the compound of the general formula (I-15): n (in /

Zh M n i: tdg (j-1" y

And yes

Us

Ge) and the cis-form of the compound of the general formula (1-25): "NO

M on MO (1-25) uh "Go "Ж in) and the predominant trans-form.

The scope of this invention also includes polymorphs, hydrates and solvates of the compounds of this invention.

This invention includes prodrugs of the compounds of this invention. In general, such prodrugs are functional derivatives of the compounds of this invention, which are easily converted into the required compounds.

Thus, in the methods of treatment of this invention, the term "treatment" refers to the treatment of various conditions described with the use of a specific disclosed compound or a compound that is not specifically disclosed but is converted into the described compound immediately after administration to the patient. Conventional methods of selection and preparation of appropriate derivative prodrugs are described, for example, in the publication "Oezidp oi Rgoagidv" ey. N. Vypda, aha, Eibzemieg, 1985, which is incorporated herein in its entirety by reference. Metabolites of these compounds include active species produced when the compounds of this invention are introduced into biological environments.

Specific compounds represented by the general formula (I) are, for example:

M-(4-benzoylphenyl)-3-oxospiro(isoindoline-1,4"-piperidine|-1-carboxamide,

Z-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isoindoline-1,4"-piperidine|-1"-carboxamide,

M-(7-methyl-2-quinolyl)-Z-oxospiro(isoindoline-1,4"-piperidine|-1"-carboxamide,

M-(4-benzoylphenyl)-2-3-oxospiro(isoindoline-1,4"-piperidine|-1-carboxamide,

M-(4-benzoylphenyl)-3,4-dihydro-Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-(5-phenyl -2-pyrazinyl)spiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-M-(7-methyl-2-quinolyl)-3-oxospiro(isoquinoline-1(2H ),4-piperidine|-1-carboxamide,

M-(4-acetylphenyl)-3,4-dihydro-3Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-|1-( 2-quinolyl)-4-imidazolyl|spiro(isoquinoline-1(2H),4-pileridine|-1-carboxamide,

C3,4-dihydro-3-oxo-M-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro(isoquinoline-1(2H),4-piperidine-1'-carboxamide, 3 ,4-dihydro-M-(5-(2-methyl-1-propenyl)-2-pyrazinyl|-3-oxospiro(isoquinoline-1(2H),4"-piperidine|-1-carboxamide, 3,4- dihydro-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(isoquinoline-1(2H),4"-piperidine|-1-carboxamide,

M-(11-(7-beazo|p|furanyl)-4-imidazolyl|-3,4-dihydro-Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide,

M-11-(3-difluoromethoxyphenyl)-4-imidazolyl|-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine-1"-carboxamide, 3,4-dihydro-3-oxo -M-I4-(2-pyridylcarbonyl)phenylspiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide,

M-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide,

M-(11-(3-chlorophenyl)-4-imidazolyl|-3,4-dihydro-3-oxospiro(isoquinoline-1(2H), 4"-piperidine|-1-carboxamide, 3,4-dihydro-3 -oxo-M-(5-phenyl-2-thiazolyl)spiro(isoquinoline-1(2H),4"-piperidine|-1"-carboxamide, 3,4-dihydro-3-oxo-M-|5-( 2-pyridyl)-2-pyrazinyl|spiro(isoquinoline-1(2H), 4-piperidine|-1"-carboxamide, 3,4-dihydro-M-(4-methyl-2-benzothiazolyl)-Z-oxospiro( isoquinoline-1(2H),4-piperidine|-1-carboxamide,

M-(B5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide,

M-(4-benzoylphenyl)-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1"-carboxamide,

Z-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

M-(7-methyl-2-quinolyl)-Z-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

Z-oxo-M-(3-phenyl-5-isoxazolyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

3-oxo-M-(7-trifluoromethylpyridoy3,2-b|pyridin-2-yl)spiro(isobenzofuran-1(ZH),4-piperidine|-1"-carboxamide,

Z-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

3-oxo-M-(1-(3-quinolyl)-4-imidazolyl|spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

Z-oxo-M-(5-phenyl-Z-pyrazolyl)spiro(isobenzofuran-1(ZH),4"-piperidine|-1-carboxamide,

M-I(I5-(4-chlorophenyl)-Z-pyrazolyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

Z-oxo-M-(5-(3-quinolyl)-Z-pyrazolyl|spiro(isobenzofuran-1(Z3H),4-piperidine|-1-carboxamide,

M-I5-(3-fluorophenyl)-2-pyrimidinyl|-Z-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

3-oxo-M-(5-(3-trifluoromethylphenyl)-2-pyrimidinyl|spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

M-I5-(3-chlorophenyl)-2-pyrimidinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

M-(7-difluoromethoxypyrido3,2-b|pyridin-2-yl)-3-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

3-oxo-M-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

M-(1-I3-(2-hydroxyethyl)uphenyl|-4-imidazolyl)-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

M-I(4-(1-ethyl-2-imidazoliluphenyl|-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

M-(1-(3-Methoxyphenyl)-4-imidazolyl|-3-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, b-fluoro-3-oxo-M-(5-phenyl -2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, b-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH) ,4-piperidine|-1-carboxamide, 5-fluoro-3-oxo-M-(3-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 5-fluoro -3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1"-carboxamide,

M-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro|(1H-2-benzopyran-1,4"-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M- (5-phenyl-2-pyrazinyl)spiro(1H-2-benzopyran-1,4"-piperidine|-1-carboxamide,

M-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro|(1H-2-benzopyran-1,4"-piperidine|-1-carboxamide, trans-M-(4-benzoylphenyl )-3'-oxospiro|(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(5-phenyl-2-pyrazinyl)spiro|cyclohexane-1 ,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(1-phenyl-4-imidazolyl)spiroYcyclohexane-1,1 (3'H)-isobenzofuran|-4- carboxamide, trans-3'-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-M-(1-(3 ,5-difluorophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(5-phenyl-Z -pyrazolyl)spiroYcyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-M-(1-(2-fluorophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1 '(3'H)-isobenzofuran|-4-carboxamide, trans-M-(4-acetyl-3-trifluoromethylphenyl)-3'-oxospiro|cyclohexane-1,1'(3'H)-isobenzofuran|-4- carboxamide, trans-3'-oxo-M-(1-(3-quinolyl)-4-imidazolyl|spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans -M-(1-(3-cyanophenyl)-4-imidazolyl|-3'-oxostro|cyclohexane-1,1 (3'H)-isobenzofuran|-4-carboxamide, trans-Mm-(4-benzoylphenyl)- 3-oxospiro(4-azaisobenzofuran-1(ZN),1-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(4-azaisobenzofuran-1(ZN), 1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(4-azaiisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-3 -oxo-M-(5-phenyl-2-pyrimidinyl)spiro(4-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-Mm-(4-benzoylphenyl)-Z-oxospiro(5- azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-Mm-(4-benzoylphenyl)-3-oxospiro(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide,

M-I5-(4-hydroxyphenyl)-2-pyrazinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide,

M-I5-(3-hydroxyphenyl)-2-pyrazinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 4-fluoro-3-oxo-M-(5-phenyl- 2-pyrimidinyl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1-carboxamide, 7-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH), 4-piperidine|-1-carboxamide, b-ethyl-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, b-hydroxy- 3-oxo-M-(5-phenyl-2-trazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrimidinyl) spiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-M-(5-(3-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H ),1'-cyclohexane|-4-carboxamide, trans-M-(5-(2-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(3H),1'-cyclohexane|-4 - carboxamide, trans-3-oxo-M-(4-phenyl-2-oxazolyl)spiro(5-azaisobenzofuran-1(ZH),1'-cyclohexane|-4-carboxamide, trans-M-(5-(2 -methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M-(5-(3-methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(3H),1'-cyclohexane|-4"-carboxamide, trans-M-(5-( 3-trifluoromethoxyphenyl)-2-pyrimidinyl|-3-oxospiro(5-azaisobenzofuran-1(3H),1"-cyclohexane|- 4-carboxamide, trans-M-(5-(3-trifluoromethylphenyl)-2-pyrimidinyl| -3Z-oxospiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl|-3-oxospiro|5 -azaisobenzofuran-1(ZH),1-cyclohexane|- 4-carboxamide, trans-M-(5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl|-Z-oxospiro(5-azaisobenzofuran-1(ZH ),1-cyclohexane|-4-carboxamide, trans-Mm-I4-(3-fluoromethoxyphenyl)-2-oxazolyl|-3-oxospiro|5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide,

trans-M-(5-(3-hydroxymethylphenyl)-2-pyrimidinyl|-3-oxospiro(5-azaiisobeiofuran-1(Z3H),1-cyclohexane|-2-carboxamide, trans-M-(5-(3- hydroxyphenyl)-2-pyrimidinyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrimidinyl) spiro(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(5-(3-fluoromethylphenyl)-2-pyrimidinyl|-3-oxospiro|b-azaisobenzofuran-1(Z3H) ,1-cyclohexane|-2-carboxamide, trans-M-(5-(3-fluoromethoxyphenyl)-2-pyrimidinyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1"-cyclohexane|-2-carboxamide , trans-3-oxo-M-(6-phethyl-1,2,4-triazin-3-yl)spiro|b-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M -(5--2-difluoromethoxyphenyl)-3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide, trans-M-(5-(3-difluoromethoxyphenyl)- 3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(5-(3-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b -azaisobenzofuran-1(Z3H),1'-cyclohexane|-4"- carb oxamide, trans-M-(5-(4-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1'-cyclohexane|-4"-carboxamide, trans-Mm-(4 -benzoylphenyl)-Z-oxospiro/7-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(1-(3,5-difluorophenyl)-4-imidazolyl|-Z-oxospiro| 7-azaisobenzofuran-1(ZN),1-cyclohexane|-4"-carboxamide, trans-3-oxo-M-(2-phenyl-4-pyridyl)spiro/7-azaisobenzofuran-1(ZN),1-cyclohexane |-4-carboxamide, trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro/(7-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-3-oxo- M-(1-phenyl-Z-pyrrolyl)spiro|7-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M-(1-(4-fluorophenyl)-3Z-pyrazolyl|- 3-oxospiro(7-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4"-carboxamide, trans-3-oxo-M-(1-phenyl-3-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH ),1"-cyclohexane|-4-carboxamide, trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans -M-(1-(3-fluorophenyl)-4-pyrazolyl|-3-oxospiro(4-azaisobenzofuran-1(Z3H) . -M-(1-(4-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4"-carboxamide, trans-M-(1-(2 -fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1'-cyclohexane|-4"-carboxamide, trans-3-oxo-M-(5-phenyl-1,2, 4-thiadiazol-Z-yl)spiro|b-azaisobenzofuran-1(ZH),1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-3-isoxazolyl)spiro|b- azaisobenzofuran-1(ZN),1-cyclohexane|-4-carboxamide, trans-3-oxo-M-(6-phenyl-3-pyridyl)spiro|(b-azaisobenzofuran-1(ZN),1-cyclohexane|- 4-carboxamide, trans-3-oxo-M-(2-phenyl-3-thiazolyl)spiro|(b-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, or trans-3-oxo- M-(2-phenyl-1,2,3-triazol-4-yl)spiro(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide.

Among these compounds, the preferred ones are, for example,

Z-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide,

3-oxo-M-(7-trifluoromethylpyridoy3,2-b|pyridin-2-yl)spiro(isobenzofuran-1(ZH),4-piperidine|-1"-carboxamide,

M-I5-(3-fluorophenyl)-2-pyrimidinyl|-Z-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, trans-3'-oxo-p-(5-phenyl-2 -pyrimidinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-p-|1-(33-quinolyl)-4-imidazolyl|spiro(cyclohexane- 1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(4-azaisobenzofuran-1(ZH),1'-cyclohexane| -4-carboxamide, trans-M-(5-(3-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M- (5-(2-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M-(1-(3,5-difluorophenyl )-4-imidazolyl|-Z-oxospiro|7-azaisobenzofuran-1(ZH),1-cyclohexane|-4"-carboxamide, trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro(4 -azaisobenzofuran-1(ZN),1-cyclohexane|-4-carboxamide, trans-3-oxo-M-(1-phenyl-3-pyrazolyl)spiro(b-azaisobenzofuran-1(ZN),1'-cyclohexane| -4-carboxamide or trans-3-oxo-M-(2-phenyl-1,2,3-triazol-4-yl)spiro(b-azaisobenzofuran-1(Z3H), 1'-cyclohexane|-4-carboxamide.

Next, the method of obtaining the compounds of this invention is illustrated.

The compounds of the present invention (I) can be synthesized, for example, using the preparation methods or the methods shown in the examples, but it is understood that these options do not limit the method of preparation of the compounds (I) of the present invention.

Method of obtaining 1

Compounds of the general formula (II): (c) dbon-Я p

Where is Ag? is aryl or heteroaryl, which may be substituted, wherein the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkyl, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl,

a group represented by the formula -Or-Ag" and an optionally protected lower alkylene, optionally substituted by an oxo group, a hydroxy(lower) alkyl or a carboxyl group;

Adi?" represents aryl or heteroaryl, which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, di(lower alkyl)amino, lower alkanoyl, aryl and optionally protected hydro, xy(lower)alkyl, hydroxyl or lower alkylamino;

Az represents phenyl, which may be substituted by a halogen or a nitro group;

C represents a single bond or an optionally protected carbonyl; undergo interaction with a compound of the general formula (IP):

I

SS shchi (snu o dep,y, m, m, mu and Zh have the same values as indicated above; obtaining compounds of the general formula (IM-1):

N ruta

M sa (1u-1)

Ov m (snoud So deAge, m., Her, M, M, m and M have the same meanings as indicated above; with optional further removal of the protective group and obtaining a compound of the general formula (1-1):

Yes and yes

And in the book of

Hu ionuh to de Ag, n, T, U, M, M/ and M have the same values as indicated above.

This method of preparation refers to the method of preparation of the compound of the general formula (I), where X means a nitrogen atom, that is, the compound of the general formula (1-1).

If the reagent has an amino group, hydroxyl, carboxyl, oxo group, carbonyl or a similar group that does not participate in the interaction, then the reaction can be carried out after protecting the amino group, hydroxyl, carboxyl, oxo group, carbonyl or similar group with an amino-protecting, hydroxy-protecting, carboxy-protecting, oxo -or carbonyl protecting group with subsequent removal of the protection and completion of the reaction. "Amino protecting group" includes aralkyl (eg, benzyl, para-methoxybenzyl, 3,4-dimethoxybenzyl, ortho-nitrobenzyl, para-nitrobenzyl, benzhydryl, trityl); lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, pivaloyl); benzoyl; arylalkanoyl (eg, phenylacetyl, phenoxyacetyl); lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, tert-butoxycarbonyl); aralkyloxycarbonyl (eg, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl, phenethyloxycarbonyl); lower alkylsilyl (eg, trimethylsilyl, tert-butyldimethylsilyl) and the like, especially acetyl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl and the like. "Hydroxy protecting group" includes lower alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl); lower alkylsilyl (eg, trimethylsilyl, tert-butyldimethylsilyl); lower alkoxymethyl (eg, methoxymethyl, 2-methoxyethoxymethyl); tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl (eg, benzyl, para-methoxybenzyl, 2,3-dimethoxybenzyl, ortho-nitrobenzyl, para-nitrobenzyl, trityl); acyl (eg, formyl, acetyl) and the like, especially methyl, methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl and the like. "Carboxy-protecting group" includes lower alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl); lower haloalkyl (eg, 2,2,2-trichloroethyl); lower alkenyl (eg, 2-propenyl); aralkyl (eg, benzyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl, trityl) and the like, especially methyl, ethyl, tert-butyl, 2-propenyl, benzyl, para-methoxybenzyl, benzhydryl and the like. "Oxo- and carbonyl protecting groups" include oacetal or ketal (eg, ethylene ketal, trimethylene ketal, dimethyl ketal) and the like.

The interaction between the compound of the general formula (II) and the compound of the general formula (II) is usually carried out using an amount from an equivalent to a molar excess, preferably from an equivalent to 1.5 mol of the compound (II) per Tmol of the compound (II).

Usually, the interaction is carried out in an inert solvent and as an inert solvent preferably, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, their mixture and the like are used.

The above reaction can be carried out in the presence of a base, including organic bases (eg, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganic bases (eg,

sodium hydroxide, potassium hydroxide) and the like.

The amount of the base used usually ranges from an equivalent to a molar excess, preferably 1-5 mol of the base per Imol of the compound of the general formula (I).

The reaction temperature is usually from -30 to 200 °C, preferably from 20 to 10070.

The reaction time usually ranges from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

At the end of the reaction, the crude product of the compound of the general formula (IM-1) can be obtained by conventional processing. The compound of the general formula (TU-1) obtained in this way is purified by the usual method or is not purified, if a further optional combination of reactions is required to remove the amino-, hydroxy-, carboxy-, oxo-, oxo-, and carbonyl-protecting groups to obtain the compound of the general formula (1-1 ).

Removal of protective groups depending on the type of protective groups indicated above, the stability of the required compound (1-1), etc. can be carried out, for example, by the method described in the literature (|Rgoiesiime Sgotsirve ip Ogdapis bupipevib5, T.MU.geep, Shdopp UMieu 8 5Bop5 (1981)|) or by a similar method, for example, by silvolysis using an acid or a base, namely, for example, from O0.0imole to a large excess of an acid, preferably trifluoroacetic, formic, hydrochloric or similar acid, or from an equivalent to a large excess of a base, preferably potassium hydroxide, calcium hydroxide or the like; chemical reduction using a complex metal hydride or similar; or by catalytic reduction using a catalyst: palladium on carbon, Raney nickel or the like.

Method of obtaining 2

Compound of the general formula (M):

Ape-MN" (M) where Ag'? has the same meaning as above; subjected to interaction with the production of a carboxylic acid of the general formula (MI): on a y (M) x A

Bason o dep,y, y, m, m and Y have the same meanings as indicated above; or its reactive derivative, obtaining a compound of the general formula (IM-2): o M. dr»

K ) (17-) and (sn), Co deAgR, p, Y, M, M, M and M have the same values as indicated above; with optional subsequent removal of the protective group and obtaining a compound of the general formula (1-2):

And a-2) the one where АГ, п, Т, У, М, М/ and М have the same values as specified above.

This production method refers to the method of production of the compound of the general formula (I), where X means methine, that is, the compound of the general formula (1-2).

The reaction between a compound of general formula (M) and a carboxylic acid of general formula (MI) is usually carried out using from 0.5 mol to a molar excess, preferably from 1 mol to 1.5 mol of carboxylic acid (MI) per Tmol of compound (M).

The reaction is usually carried out in an inert solvent, and preferred examples of inert solvents include methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine, a mixture thereof, and the like.

The above interaction is preferably carried out in the presence of condensing agents, for example, M,M'-dicyclohexylcarbodiimide, M,M'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride , benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinephosphonium hexafluorophosphate, bromo-tris-(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, or the like.

It is usually used from mol to molar excess, preferably from Tmol to 1.5 mol of the indicated condensing agent per Tmol of the compound (MI).

The reaction temperature is usually from -50 to 100"C, preferably from -20 to 5070.

The reaction time usually ranges from 30 minutes to 7 days, preferably from 1 to 24 hours.

The compound of the formula (I--) is also obtained by reacting the compound of the general formula (M) with a reactive derivative of a carboxylic acid (MI) instead of a carboxylic acid (MI).

Reactive carboxylic acid derivatives of the general formula (MI) include acid halides, mixed acid halides, activated esters, activated amides, and the like.

Carboxylic acid halides of the general formula (MI) can be obtained in a conventional way by reacting a carboxylic acid of the general formula (MI) with a halogenating agent. The halogenating agent includes thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene, and the like.

Mixed carboxylic acid halides of the general formula (MI) can be obtained in a conventional way by reacting a carboxylic acid of the general formula (MI) with an alkyl chlorocarbonate (for example, ethyl chlorocarbonate); aliphatic carboxylic acid chloride (for example, pivaloyl chloride) and the like.

Activated carboxylic acid esters of the general formula (MI) can be obtained in a conventional way by reacting a carboxylic acid of the general formula (MI) with an M-hydroxy compound (for example, M-hydroxysuccinimide, M-hydroxyphthalimide, 1-hydroxybenzotriazole); a phenolic compound (for example, 4-nitrophenol, 2,4-dinitrophenyl, 2,4,5-trichlorophenol, pentachlorophenol) or similar in the presence of a condensing agent (for example, M,M'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)- 3- ethyl carbodiimide).

Activated amides of a carboxylic acid of the general formula (MI) can be obtained in a conventional manner by reacting a carboxylic acid of the general formula (MI), for example, with 1,1'-carbonyldiimidazole, 1,1'-carbonylbis(2-methylimidazole) or the like.

The interaction between a compound of the general formula (M) and a reactive carboxylic acid derivative of the general formula (MI) is usually carried out using from 0.5 mol to a molar excess, preferably from mol to 1.5 mol of a reactive carboxylic acid derivative (MI) per Tmol of the compound (M ),

The reaction is usually carried out in an inert solvent, and preferred examples of inert solvents include methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine, a mixture thereof, and the like.

This interaction takes place in the absence of bases, but it is preferable to carry out the interaction in the presence of bases, which contributes to the calm course of the reaction.

The above bases include organic bases (for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganic bases (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate) and the like.

It is preferable to use from one mole to a molar excess of the above-mentioned base per Tmol of the compound of the general formula (M). If the indicated base is a liquid, then it can also be used as a solvent.

The reaction temperature is usually from -50 to 100"C, preferably from -20 to 5070.

The reaction time usually ranges from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

The compound of the general formula (I-2) can be obtained by conventional processing of the reaction mixture at the end of the reaction after deprotection, if the product has a protecting group, or by conventional processing directly of the mixture, if the protecting group is absent.

Removal of protective groups, further processing and the like can be carried out by the method described above in preparation method 1.

Compounds of general formula (1-1) or (I--) can be easily isolated and purified by conventional separation methods, for example, solvent extraction, recrystallization, column chromatography, thin layer chromatography and/or the like.

These compounds can be converted into pharmaceutically acceptable salts or esters by conventional methods, on the other hand, conversion of salts or esters into free compounds can be carried out by conventional methods.

Compounds of the general formula (I), (1), (M) or (MI) are commercially available or are obtained by methods described in the literature (Charapeze Raiepi Opehatipea Rybiisayop Me94/263737-A, US Patent Me 3301857, 9. Oha.

Speth, 40:1427 (1975).

International Patent Application M/095/28389 or others), or similar methods, or the methods presented below or in the examples, not necessarily in combination.

Method of obtaining A.

Ag. MN, (U) about "AK i 1

Ge) kgo-YI

MA-Ah? (p)

H where I means halogen; Ag'R and A? have the same values as above.

This method relates to the method of obtaining the compound of the general formula (I). According to this method, the compound (it) is obtained by reacting a compound of the general formula (M) with a compound of the general formula I.

The interaction between the compound of the general formula (M) and the compound | usually carried out using from

0.5 mol to a molar excess, preferably from the equivalent to 1.5 mol of compound 1 per 1 mol of compound (M).

The interaction is usually carried out in an inert solvent, and preferred examples of inert solvents include methylene chloride, chloroform, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide, a mixture thereof, and the like.

It is preferable to conduct interaction in the presence of bases. Said bases include organic bases (for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganic bases (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate) and the like.

It is preferable to use from an equivalent to a molar excess of the indicated base per Tmol of the compound (M). If the specified base is a liquid, then it can also be used as a solvent.

The reaction temperature is usually from -78 to 100"C, preferably from -20 to 5070.

The reaction time usually ranges from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

Compounds of the formula | are commercially available or their. obtained in the usual way, by the methods described in the examples, or similar, not necessarily in combination.

The method of obtaining V o i a . Dr. "I don't" for me (dn

BA -- 5 5 o'clock p.m

There is chsosi 5 th pyknization -ya ' - -- "7 F and nenyh as the basis of 9 de

IS

" n / М V, t renoaling.

And (m) where P' represents an amino protecting group; B'E represents hydrogen, a nitro group, lower alkyl or lower alkoxy; И, и, М, m Ии м have the same values as given above.

This method refers to the method of obtaining compounds of the general formula (PI-1). Compound (PI-1) is prepared by the following process, wherein a compound of general formula 2 is subjected to condensation with dehydrogenation with a compound of general formula 3 to give a compound of general formula 4, which is reacted with a compound of general formula in the presence of a base to give a compound of general formula 6, and then compound 6 is cyclized by an intramolecular Heck reaction, obtaining a compound of the general formula 1, and then compound I is subject to reduction, optionally with subsequent removal of the amino protecting group P.

The amino-protecting group P' includes the amino-protecting groups described earlier in production method 1.

The step of obtaining compound 4 by condensation with dehydrogenation of compound 2 with compound C is usually carried out in an inert solvent, for example, benzene, toluene or the like.

The preferred reaction temperature is from room temperature to the boiling point of the solvent used, and the reaction time is preferably from 30 minutes to 24 hours.

The step of obtaining compound 6 from compound 4 is usually carried out in an inert solvent (for example, benzene, toluene, methylene chloride, chloroform, acetonitrile, dnmethylformamide) in the presence of a base (for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine).

The reaction temperature is preferably from 0°C to the boiling point of the solvent used, and the reaction time is preferably from 30 minutes to 24 hours.

At the stage of obtaining compound 7 from compound 6, the so-called Heck reaction, well known in the field of organic chemistry, can be used.

This stage is usually carried out in an inert solvent (for example, benzene, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, M-methylpyrrolidone) in the presence of a palladium catalyst (for example, palladium acetate, palladium chloride), a phosphine ligand (for example, triphenylphosphine, tri-2-furylphosphine ), bases (for example, potassium carbonate, triethylamine) and optionally additives (for example, tetraethylammonium chloride).

The preferred reaction temperature is from room temperature to the boiling temperature of the solvent used in the reaction, and the reaction time is preferably from 30 minutes to 24 hours.

As a method of reduction at the stage of obtaining compound (1-1) from compound 7, for example, catalytic reduction is preferred.

Catalytic reduction is usually carried out in an inert solvent (for example, methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, acetic acid) in the presence of a catalyst, such as palladium on coal, at a hydrogen pressure of 1 to 50 atmospheres.

The preferred reaction temperature is from room temperature to the boiling temperature of the solvent used in the reaction, and the reaction time is preferably from 30 minutes to 24 hours.

At the end of the reaction, if the reaction product has a protecting group, the compound (PI1--) can be obtained by removing the protecting group.

The removal of the protective group can be carried out by the method described above in preparation method 1.

This stage can be carried out by removing the protecting group of compound 7 followed by reduction of the resulting compound.

Compounds of the general formula 2, C or 5 are commercially available or can be obtained by a conventional method, the methods presented in the examples, or the like, optionally in combination.

SON of KozhakiH i

Angry! | e i zh che that o yav y Se i "he o i z Vnt sr

ЗК о укуля те Як

E Ar hechstochikhnyh I ate

The Lord has a fault and a fault! Ohm

N um gu o; - Uk o a her and o yalkishnyh obu, 7 more kit oukozivyh and "v

K: khi t y nuli KI / etc. in tu o o

C (mM) where / represents hydrogen or halogen;

RI represents phenyl; "U represents oxygen or an imino group substituted with lower alkyl or aryl;

Y, m, m and m/ have the same values as above.

This production method refers to the method of production of the compound of the general formula (MT-1). The compound represented by the general formula (M-1) is a new compound not disclosed in the literature. This compound can be obtained using this preparation method, namely, the compound of the general formula 8 is subjected to lithiation, interaction with the compound 9 and lactonization with an acid followed by deketalation to obtain the compound of the general formula 10; and 1) a methylene group is introduced into compound 10, followed by hydroboration to give a compound of general formula 11, and this compound is subjected to oxidation, or 2) compound 10 is reduced to give a compound of general formula 12, into which a leaving group is introduced, and then subjected to cyanation , obtaining a compound of the general formula III, with subsequent hydrolysis of compound 13 by the cyano group.

Lithination in the step of obtaining compound 10 from compound 8 is usually carried out by allowing an organolithium reagent (e.g., n-butyllithium, lithium 2,2,6,6-tetramethylpiperidide) to react with compound 8 in an inert solvent (e.g., tetrahydrofuran, diethyl ether).

The reaction temperature is usually from -120 to 0"C, preferably from -100 to -50"C, and the reaction time is preferably from 1 to 4 hours.

The interaction between the obtained lithium compound and the ketone of general formula 9 is usually carried out in an inert solvent (for example, tetrahydrofuran, diethyl ether).

The reaction temperature is preferably from -10°C to room temperature, and the reaction time is preferably from 10 minutes to 2 hours.

The resulting compound can be subjected to lactonization by acid treatment (for example, hydrochloric acid, sulfuric acid).

The reaction temperature is preferably from 0°C to the boiling point of the solvent used, and the reaction time is preferably from 30 minutes to 8 hours.

Compound 10 can be prepared by subjecting the resulting lactone-type compound to deketalization in a conventional manner.

The reaction temperature is preferably from 50°C to the boiling point of the solvent used, and the reaction time is preferably from 1 to 24 hours.

At the stage of obtaining compound 11 from compound 10, a method used to convert an oxo group into a hydroxymethyl group, which is well known in the field of organic chemistry, can be used, and this step is usually carried out by reacting compound 10, for example, with methylenetriphenylphosphorane, introducing a methylene group, followed by hydroboration in an inert solvent (for example, benzene, toluene, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, dimethylformamide).

At both stages of introduction of the methylene group and hydroboration, the reaction temperature is preferably from 0°C to the boiling point of the solvent used, and the reaction time is preferably from 30 minutes to 8 hours.

In the step of obtaining compound (MI-1) from compound 11, a method used to oxidize a hydroxymethyl group to a carboxyl group, which is well known in the field of organic chemistry, can be used, and this step is usually carried out using an oxidizing agent such as sodium periodate, and a catalytic amount of ruthenium chloride in an inert solvent (for example, benzene, toluene, methylene chloride, chloroform, acetonitrile, dimethylformamide).

The reaction temperature is preferably from 0°C to the boiling point of the solvent used, and the reaction time is preferably from 30 minutes to 8 hours.

In the step of obtaining compound 12 from compound 10, a method used to reduce an oxo group to a hydroxyl group, which is well known in the field of organic chemistry, can be used, and this step is usually carried out using a reducing agent (eg, sodium borohydride, lithium borohydride) in an inert solvent (for example, water, methanol, ethanol, tetrahydrofuran or their mixtures).

The reaction temperature is preferably from -20 to 50"C, and the reaction time is preferably from 10 minutes to 4 hours.

At the stage of obtaining compound 13 from compound 12, the method used to convert a hydroxy group into a cyano group, which is well known in the field of organic chemistry, can be used, and this stage is usually carried out when compound 12 reacts, for example, Kk! methanesulfonyl chloride, para-toluenesulfonyl chloride or the like with the conversion of the hydroxy group into a leaving group in the presence of a base (for example, triethylamine, pyridine) followed by the interaction of the resulting compound with cyanide (for example, sodium cyanide, potassium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide).

This stage of conversion of a hydroxy group into a leaving group is usually carried out in an inert solvent (for example, methylene chloride, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide).

The reaction temperature is preferably from -207C to room temperature, and the reaction time is preferably from 10 minutes to 8 hours.

The stage of interaction with cyanide is usually carried out in an inert solvent (for example, tetrahydrofuran, dioxane, dimethylformamide, M-methylpyrrolidone, dimethylsulfoxide). The reaction temperature is preferably from 50 to 120°C, and the reaction time is preferably from 2 to 24 hours.

At the stage of obtaining the compound (MI-1), hydrolysis of the cyano group can be carried out, which is well known in the field of organic chemistry, namely the hydrolysis of the cyano group of compound B, and this stage is usually carried out using an acid (for example, hydrochloric acid, sulfuric acid) or; a base (for example, sodium hydroxide, potassium hydroxide, calcium hydroxide) in a solvent (for example, methanol, ethanol, tetrahydrofuran, dioxane, water or a mixture thereof).

The reaction temperature is preferably from 50°C to the boiling point of the solvent used, and the reaction time is preferably from 1 to 48 hours.

Compounds of the general formula (MI-1) have two types of stereoisomers, represented by the general formulas (MI-1-a) and (MI-1-5):

DREAM "MN

In the 2nd; : i ; :

Mk tu o d) (Mi-a) (Un-v) dei, i, m im have the same meanings as indicated above.

These stereoisomers can be isolated from the mixture by a well-known method, such as chromatography, fractional recrystallization, and the like.

Compounds of the general formula (MI-1-a) or (MI-1-5) can be obtained using an intermediate product obtained by separating the stereoisomers of a compound of the general formula 11, 12 or 13.

Compounds of the general formula 8 or 9 are commercially available or are obtained using a conventional method, the methods described in the examples or similar methods, optionally in combination.

The applicability of the compounds of this invention as medicinal products is ensured by the description of MRU-antagonistic activity, for example, in the following pharmacological tests.

Pharmacological test 1 (study of MRU binding inhibition)

The cDNA sequence encoding the human MRU U5 receptor (publication of the international patent M/096/165421, cloned in the expression vectors rsOMAZ, rs/kZM (obtained by Bimigodep Ips.) and rsi-peo (obtained by Rgoteda

Ips.). The resulting expression vectors are transfected into host cells СО5-7, CHO and CM(IR-) (Ategisap Toure

Siyige SoiPesiyop) method using cationic lipids (developed in Maiyop! Asadetu oi 5siepsev5 oi

Ophthalmology and Ategis, 84: 7413 (1987)), receiving cells expressing MRU U5-repep Tor.

Membrane samples obtained from cells that express MRU U5-receptors are incubated together with the compound under investigation and GzCpeptide UM (MEM) (20000 beats/min.) in a buffer solution (25 mM Tris-buffer, pH 7.4, containing 10 mM magnesium chloride, 1M phenylmethylsulfonyl fluoride, 0.190 bacitracin and 3.595 bovine serum albumin (35A)) at 25"C for 2 hours, then filtered through a glass OR/C filter and washed with 5mM Tris buffer (pH 7.4) containing 0.395 B5BA The radioactivity of the precipitate is measured on a glass filter. The non-specific binding is measured in the presence of 1 mM of the UM peptide and the concentration of the test compound that causes 5095 inhibition (IC30) of the specific binding of the peptide is determined

MU (Epdoshypoiodu, 131: 2090 (1992)). The results are summarized in table 1. (table 11 Inhibitory activity of MRU-receptor binding

As shown above, the compounds of this invention effectively inhibit the binding of the UMH peptide (MRU homologue) with

MRU by U5 receptors.

Pharmacological test 2 (Antagonistic effect on BRR-induced feeding behavior)

A guide cannula (outer diameter 0.8mm, inner diameter 0.5mm, length 10mm) is stereotaxically inserted into the right lateral ventricle of the brain of male 5O rats (age 7-8 weeks, 200-300g) under pentobarbital anesthesia (one intraperitoneal injection of 5Omg/ kg) and fixed with dental resin. The upper end of the cannula is placed 0.9 mm above bregma, 1.2 mm to the right of the midline and 1.5 mm deep from the surface of the brain, so that when the injection needle is inserted into the guide cannula, it protrudes 2 mm above the upper edge guide cannula and reached the lateral ventricle of the brain. After approximately 1 week of the recovery period, bovine pancreatic polypeptide (PP, 5μg/1Ωcl/head, 0.01M, pH 7.4 phosphate buffered saline containing 0.0595 bovine serum albumin) is injected into the lateral ventricle of the brain. The test compound, suspended in aqueous 0.595 methylcellulose, is administered orally 2 hours before administration of pPPR and food intake is determined 2 hours after administration of ORP.

The compounds of this invention significantly inhibit the increase in food intake caused by BRR (homolog of MRU) injected into the lateral ventricle of the brain.

The compounds of general formula (I) may be administered orally or parenterally and may be formulated into a suitable dosage form to provide an agent for the treatment of various diseases associated with

MRUs, which include, for example, cardiovascular disorders (eg, hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis), central nervous system disorders (eg, bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, syndrome drug withdrawal), metabolic disorders (for example, obesity, diabetes, hormonal disorders, hypercholesterolemia, hyperlipidemia), sexual and reproductive dysfunction, gastrointestinal motility disorders, respiratory diseases, inflammation or glaucoma and the like, mainly bulemia, obesity, diabetes and the like . In clinical use, the compounds of this invention can be administered after the preparation of the corresponding drug together with pharmaceutically acceptable additives in accordance with the method of administration. As the specified additives, you can use additives that are usually used in the preparation of pharmaceutical preparations, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, petroleum jelly, magnesium aluminate metasilicate, anhydrous calcium phosphate , citric acid, sodium citrate, hydroxypropyl cellulose, sorbitol, ester of sorbitol and fatty acid, polysorbate, ester of sucrose and fatty acid, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light silicon anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin.

The mixture with the specified additives can be prepared in the form of solid preparations (for example, tablets, capsules, granules, powders, suppositories) or liquid preparations (for example, syrups, elixirs, preparations for injections). Such preparations can be prepared according to methods well known in the field of obtaining pharmaceutical preparations. Liquid preparations may be in the form of preparations which, when administered, are dissolved or suspended in water or other suitable media, and mainly injectable preparations may be dissolved or suspended in physiological saline or, if necessary, in glucose, optionally together with buffer and preservative.

Such preparations may contain from 0.1 to 10% by weight, preferably from 1.0 to 9% by weight, of the compounds of this invention, and may also contain other therapeutically effective compounds.

The compounds of this invention can be used in combination with other agents useful in the treatment of metabolic and/or nutritional disorders. The individual components of such combinations can be taken separately at different times during the course of therapy or together as separate or single combined forms. Thus, it should be understood that the present invention includes all such regimens of simultaneous or alternate treatment and the term "administration" should be interpreted accordingly. It should also be understood that the scope of combinations of the compounds of this invention with other agents useful for the treatment of metabolic and/or nutritional disorders includes, in principle, any combination with any pharmaceutical composition useful for the treatment of metabolic and/or nutritional disorders.

If the compounds of this invention are used clinically, the dose and frequency of administration may be varied depending on gender, age, body weight, degree of symptoms, and the type and range of therapeutic effects required. The daily dose for an adult is 0.01-100mg/kg, preferably 0.03-Zmg/kg orally, or 0.001-10mg/kg, preferably 0.001-0.1mg/kg parenterally, preferably in a single dose or divided into several doses.

A general practitioner, veterinarian, or clinician can easily determine and prescribe the effective amount of medication needed to prevent, counteract, or suppress the development of a disease state.

The best method of carrying out the invention

The following examples are provided to more specifically illustrate the present invention, but are in no way intended to limit it.

Unless otherwise noted, melting points are determined using Modei's MR-53! (production

Mmapaditoio 5eizakizpo) and disclosed in this description without corrections.

Example 1

Preparation of M-(4-benzoylphenyl)-3-oxospiro(isoindoline-1,4"-piperidine|-1-carboxamide (1) Preparation of M-benzyl-M-(1-tert-butoxycarbonyl-1,2,3,6 -tetrahydropyridin-4-yl)-2-iodobenzamide.

A mixture of M-tert-butoxycarbonyl-4-piperidone (1.11 g) and benzylamine (597 mg) dissolved in toluene (20 ml) is stirred at 1007C for 3 hours and then concentrated. Toluene (30 ml), ortho-iodobenzoyl chloride (1.13 g) and triethylamine (0.70 g) were added to the residue, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous MagnO and concentrate. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2), obtaining the specified compound (2.44 g). (2) Preparation of 2-benzyl-1'-tert-butoxycarbonyl-1", b'-dihydrospiro(1H-insol-1,4'(5'H)-pyridine|-3(2H)-one.

Palladium acetate (830 mg), tryphen l of phosphine (187 mg), anhydrous K»CO3 (987 mg) and tetraethylammonium chloride (591 mg) and stirred at 8°C for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Mag25O: and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) to give the indicated compound (1.64g).(3) Preparation of 2-benzyl-1'-tert-butoxycarbonylspiro|1H-isoindole-1,4 "-piperidine|-3(2H)-one.

To a solution of /2-benzyl-1-tert-butoxycarbonyl-1",b'-dipdrosp1rro(1H-zoindole-1,4(5'H)-pyridin|-3(2H)-one (1.0 g) in trifluoroacetic acid (20ml) is added to chloroform (200ml) and the mixture is stirred for 1 hour. The reaction mixture is concentrated. The residue is dissolved in methanol and hydrogenated with a mixture of 4M hydrogen chloride/ethyl acetate in the presence of 2095 palladium on carbon at a hydrogen pressure of 7atm for 14 hours. The catalyst is removed by filtration and The filtrate is concentrated.Aqueous sodium hydroxide (5 ml), di-tert-butyl dicarbonate (655 mg) and dioxane (1 ml) are added to the residue, and the mixture is stirred at room temperature for 4 hours.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous

Mag25O4 and concentrate. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2), obtaining the specified compound (200mg). (4) Preparation of spiro|1H-isoindole-1,4"-piperidini|-3(2H)-one hydrochloride. 2-Benzyl-1"-tert-butoxycarbonylspiro|1H-isoindole-1,4"-piperidiniI- 3(2H)-one (200mg) was added to sodium metal (235mg) in liquid ammonia (10ml) and the mixture was stirred for 30 minutes.Methanol neutralized with saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate.

The organic layer is dried over anhydrous Mag5Ox and concentrated. The residue is dissolved in methanol and mixed with a mixture of 4M hydrogen chloride/ethyl acetate at 507C for 1 hour. The reaction solution is concentrated to obtain the indicated compound (591 mgHg). 1H YAMRE (z00mhz, DMSO-adv, om.d.): 1.70-1.90 (2H, m), 2.00-2.20 (2H, m), 3.00-3.20 (2H , m), 4.20-4.40 (2H, m), 7.40 (1H, d, 9-7.5Hz), 7.51 (1H, t, U9-7.5Hz), 7.59 (1H, t, 9-7.5Hz), 7.84 (1H, d, 9-7.5Hz). (5) Preparation of phenyl M-(4-benzoylphenyl)carbamate.

Phenylchlorocarbonate (1.38g) was added to 4-aminobenzophenone (1.97g) dissolved in pyridine (50ml) at 02C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous Ma»5O» and evaporated. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2), obtaining the specified compound (3.1 g). (6) Preparation of M-(4-benzoylphenyl)-3-oxospiro|isoindoline-1,4"-piperidine|-1-carboxamide.

A mixture of spiro|1H-isoindole-1,4"-piperidin|-3(2H)-one hydrochloride (48mg), triethylamine (0.14ml) and phenyl M-(4-benzoylphenyl)carbamate (5d8mg) is stirred in chloroform at 80"C for 2 hours. The reaction mixture is poured into water and extracted with chloroform. The organic layer is dried over anhydrous Ma250Ox and concentrated.

The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) and crystallized from a mixture of ethyl ether-hexane, obtaining the specified compound (49 mg) in the form of colorless crystals (melting point 253"7С).

The compounds of examples 2 and 3 are obtained similarly to the method of example 1-(6), replacing the phenyl M-(4-benzoylphenyl)carbamate used in example 1-(6) with the corresponding substances.

Example 2

Z-oxo-M-(5-phenyl-2-pyrazinyl)stro(isoindoline-1,4"-piperidine|-1-carboxamide

Melting point 286-287"

Example C

M-(7-methyl-2-quinolyl)-3-oxospiro|(isoindoline-1,4"-piperidine|-1-carboxamide

Melting point 194-19670

Example 4

Preparation of M-(4-benzoylphenyl)-3-oxospiro|isoindoline-1,4"-piperidine|-1-carboxamide.

The indicated compound is obtained similarly to the method of example 1-(6), replacing spiro(1H-isoindole-1,4-piperidin(|-3(2H)-one hydrochloride with //2-methylespiro(1H-isoindole-1,4" -piperidine|-3(2H)-one hydrochloride.

Melting point 154-15670

Example 5

Preparation of M-(4-benzoylphenyl)-3,4-dihydro-3Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Spiro(isoquinoline-1(2H),4"-piperidine|-3(4H)-one hydrochloride (30mg) and phenyl M-(4-benzoylphenyl)carbamate (37mg) are dissolved in dimethylsulfoxide (2ml) and mixed together with aqueous 10n with sodium hydroxide (12 µL) at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), then dried over anhydrous Mag5O4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/equalacetate from 4/1 to 1/2) and recrystallized from a mixture of chloroform-acetone (1:3), obtaining the specified compound (81 mg) in the form of colorless crystals (melting point 241-243").

The compounds of examples 6-21 are obtained similarly to the method of example 1-(6) or example 5, using spiro(isoquinolin-1(2H),4"-piperidinyl-3(4H)-one hydrochloride and phenyl carbamate derivatives corresponding to the required compounds.

Example 6 3,4-Dihydro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Melting point 237-23970

Example 7

3,4-Dihydro-M-(7-methyl-2-quinolyl)-3-oxospiro|isoquinoline-1(2H),4"-piperidine|-1--carboxamide

Melting point 216-21870

Example 8

M-(4-acetylphenyl)-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Melting point x2300"7C

Example 9 3,4-Dihydro-3-oxo-M-|1-(2-quinolyl)-4-imidazolyl|spiro(isoquinoline-1(2H)4"-piperidine-1-carboxamide

Melting point 264-266"

Example 10

3,4-Dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro(isoquinoline-1(2H),4-piperidine-1"-carboxamide

Melting point 220.5-222.276

Example 11 3,4-Dihydro-M-|5-(2-methyl-1-propenyl)-2-pyrazinyl|-Z-oxospiro(isoquinoline-1(2H,4"-piperidine|-1-carboxamide

Melting point 232.9-236.570

Example 12 3,4-Dihydro-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(isoquinoline-1(2H),4-piperidine|-1--carboxamide

Melting point 239-241"70

Example 13

M-(1-(7-benzo(B|furanyl)-4-imidazolyl|-3,4-dihydro-Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Melting point 192-19470

Example 14

M-11-(3-difluoromethoxyphenyl)-4-imidazolyl|-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine-1"-carboxamide

The melting point is 161-1637C

Example 15 3,4-Dihydro-3-oxo-M-(4-(2-pyridylcarbonyl)phenyl|spiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Melting point 162-164"

Example 16

M-3,4-dichlorophenyl)-3,4-dihydro-3Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

Melting point x2300"7C

Example 17

M-(11-(3-Chlorophenyl)-4-imidazolyl|-3,4-dihydro-3-oxostro(isoquinoline-1(2H,4-piperidine-1-carboxamide

Melting point 255-25870

Example 18 3,4-Dihydro-3-oxo-M-(5-phenyl-2-thiazolyl)spiro(isoquinoline-1(2H),4-piperidine|-1--carboxamide

Melting point x2300"7C

Example 19 3,4-Dihydro-3-oxo-M-|5-(2-pyridyl)-2-pyrazinyl|spiro(isoquinoline-1(2H),4-piperidine-1"-carboxamide

Melting point 223-22570

Example 20 3,4-Dihydro-M-(4-methyl-2-benzothiazolyl)-3Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide

The melting point is 144-1467C

Example 21

M-(B5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro(isoquinoline-1(2H,4-piperidine|-1-carboxamide

Melting point 256-25870

Example 22

Preparation of M-(4-benzoylphenyl)-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1--carboxamide

A mixture of spiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride (48 mg), fedyl M-(4-benzoylphenyl)carbamate (58 mg) and triethylamine (0.14 ml) in chloroform (ml) is stirred at 80 "C for 2 hours. The reaction mixture is poured into water and extracted with chloroform (20 ml). The organic layer is washed with saturated saline solution (20 ml), then dried over anhydrous Mag25O4 and concentrated. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4 /1 to 1/2) and recrystallized from a mixture of ethyl ether-hexane, obtaining the indicated compound (81 mg) in the form of colorless crystals (melting point 161-163).

Example 23

Preparation of 3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(ZH 4 -piperidine (|-1-carboxamide) (1) Preparation of phenyl-M-(5-phenyl-2-pyrazinyl)ucarbamate

Phenylchlorocarbonate (15.05ml) is added at 0"C to a solution of 2-amino-5-phenylpyrazine (17.12g) in pyridine (200ml). The mixture is stirred at room temperature for 2 hours. Water (200ml) and ethyl ether are added to the reaction mixture. (200 ml).Everything is mixed, obtaining a suspension containing the specified compound in the form of crystals.

The crystals are collected by filtration and washed with ethyl ether (50 ml), then dried under reduced pressure, obtaining the specified compound (24.57 g) in the form of colorless crystals (melting point 192-1987C, decomposes). (2) Preparation of /3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzo-furan-1(3H),4-piperidine|-1-carboxamide (crystalline form A)

A mixture of spiro(isobenzofuran-1(,H),4"-piperidini|-3-one hydrochloride (6.24g, 26.6mmol), phenyl.M-(5-phenyl-2-pyrazinyl)carbamate (7.59g, 26.0mmol) and triethylamine (13ml, 1380mmol) in chloroform (200ml) are stirred at 80°C for 3 hours. The reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate

(100ml). Then the organic layer is washed with 1095 aqueous solution of citric acid (100 ml), then with aqueous sodium hydroxide (100 ml) and then with saturated saline solution (100 ml), the organic layer is dried over anhydrous Mag5O4 and concentrated. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate-1/2), obtaining the specified compound as a colorless solid. This solid was washed with diethyl ether (30 mL) to give the indicated compound (8.23 g) as crude crystals. The crystals are dissolved in hot ethyl acetate (300 ml). After removal of approximately 100 ml of ethyl acetate, a white suspension begins to form by distillation. At this point, the distillation is stopped, the mixture is cooled and stored at room temperature for 14 hours. The colorless prisms formed are collected by filtration and washed with heptane (20 ml). The obtained crystals are dried at 50"C in a vacuum for 6 hours, obtaining the specified compound (crystalline form A) (5.17g) in the form of colorless prisms (melting point 210-2117C). X-ray powder diffraction

The above X-ray powder diffraction data were measured on a KIMT1100 (production

Kidaki Ipiegpaiopai! Sogrogayop), the analysis conditions are as follows:

X-ray source: Si, tube voltage: 4kV, tube current: ZOMA, monochromator: automatic monochromator, mono-receiver slit: Both, goniometer: wide-angle goniometer, scan step: O.02 deg., scan speed: 2.00 deg/min., deflecting slit (05): 1 deg., scattering slit: 1 deg., receiving slit (KB): 0 15MM, temperature measurement temperature: ambient (3) Preparation of /3-oxo-M-(5-phenyl-2-pyrazinyl)spiro (isobenzo-furan-1(3H),4-piperidine|-1-carboxamide (crystalline form A)-alternative method-preparation

Crude crystals (2g), obtained by the method (2) described above, are dissolved under heating in tetrahydrofuran (20ml). After making sure of complete dissolution, cool the mixture to room temperature, leaving it to stand at room temperature. Heptane (27 ml) was added dropwise to the tetrahydrofuran solution with further stirring at room temperature for 15 hours. The obtained colorless crystals were collected by filtration, washed with heptane (5 ml) and dried in a vacuum at 30°C for 15 hours, obtaining the above compound in crystalline form A (1.82 g). (4) Preparation of /3-oxo-M-(5 -phenyl-2-pyrazinyl)spiro(isobenzo-furan-1(3H),4-piperidine|-1-carboxamide (crystalline form B)

Crude crystals (2g), obtained by the method described above (2), are dissolved by heating in dimethylformamide (bml). After making sure of complete dissolution, water (1 ml) is added drop by drop at 80"C and the resulting mixture is cooled to room temperature, followed by stirring for 15 hours.

The resulting colorless crystals were collected by filtration at room temperature, washed with heptane (5 ml) and dried under vacuum for 15 hours at room temperature, obtaining 1.78 g of the above compound in crystalline form B in the form of colorless prisms (melting point 208°C, measured without correction when using Meiipd Royipi 8-545 distributed by Sotrap Island).X-ray powder diffraction

The above X-ray powder diffraction data were measured under the same conditions as in Example 23(2). (5) Preparation of /3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzo-furan-1(3H),4-piperidine|-1-carboxamide (crystalline form C)

Crude crystals (2g), obtained by the method (2) described above, are dissolved under heating in tetrahydrofuran (20ml). After making sure of complete dissolution, the solution is cooled to -30"C. Heptane (30 ml) is added dropwise to the tetrahydrofuran solution with further stirring at -30"C for one hour.

The obtained colorless crystals were collected by filtration, washed with heptane (5 ml) and dried in vacuum at room temperature for 15 hours, obtaining 1.90 g of the above products (monotetrahydrofuran solvate, crystalline form C) in the form of colorless small granules. X-ray diffraction of nisin pi powder

The above X-ray powder diffraction data were measured under the same conditions as in Example 23(2). (6) Preparation of 3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzo-furan-1(ZH),4-piperidine|-1'-carboxamide (crystalline form 0)

Spiro(isobenzofuran-1(ZN),4-piperidine|-3-one hydrochloride (515 mg) and phenyl M-(5-phenyl-2-pyrazinyl)carbamate (583 mg) are dissolved in dimethyl sulfoxide (2.bml), and then added dimethylbenzylamine (0.33 ml) drop by drop.

The temperature of the resulting mixture is raised to 50"C and the mixture is stirred for one hour. The reaction mixture is cooled to room temperature and a mixed solution of acetonitrile/water (1:2) (7.ml) is added dropwise. When 0.2ml of the mixed solution is added, add seed crystal. The resulting mixture was stirred at room temperature for 2 hours. The resulting colorless crystals were collected by filtration, washed with acetonitrile/water (1:1) and dried in vacuo at room temperature for 15 hours to give the above compound (79 mg) as crude colorless crystals. Crude crystals (26 g), obtained by repeating the above-described method, are suspended in a mixture of water and saturated isopropyl acetate (14 ml). The seed crystal is added to the mixture and stirred at room temperature for 18 hours. The resulting crystals are collected by filtration, washed with isopropyl acetate (20 ml) and dried in a vacuum at 30"C for 15 hours, obtaining the above-mentioned compound in the crystalline form of OO (25.2 g) in of colorless crystals (melting point 206"С, measured without correction when using Meiipd Roipi B-545, distributed by Sotrap Island). X-ray powder diffraction

The above X-ray powder diffraction data were measured under the same conditions as in Example 23(2). (7) Preparation of /3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzo-furan-1(3H),4-piperidine|-1-carboxamide (crystalline form B) - an alternative method of preparation.

Crude crystals (26 g), obtained by the method described above (6), are suspended in acetonitrile (260 ml). The seed crystal obtained by the method described above (4) is added to the mixture and stirred at room temperature for 24 hours. The obtained crystals are collected by filtration, washed with acetonitrile (5 Oml) and dried in a vacuum at 30"C for 15 hours, obtaining the above product in crystalline form

In (25.5 Gh).

The compounds of examples 24-39 are obtained similarly to the method of example 22, replacing the phenyl M-(4-benzoylphenyl)carbamate used in example 22 with the corresponding substance.

Example 24

M-(7-methyl-2-quinolyl)-Z-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide

Melting point 178-180"

Example 25

Z-oxo-M-(4-phenyl-5-isoxazolyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide

Melting point 239-242"70

Example 26

3-oxo-M-(7-trifluoromethylpyrido3,2-b|pyridin-2-yl)spiro(isobenzofuran-1(ZH,4-piperidine|-1-carboxamide

The melting point is 246-248"7C

Example 27 3-Oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide

Melting point 211-214"70

Example 28

Z-oxo-M-|1-(3-quinolyl)-4-imidazolylspiro(isobenzofuran-1(ZN,4-piperidine|-1-carboxamide

Melting point 251-254"7C

Example 29

Z-oxo-M-(5-phenyl-Z-pyrazolyl)spiro(isobenzofuran-1 (ZN.4-piperidine|-1-carboxamide

Melting point 160-165"

Example 30

M-I5-(4-chlorophenyl)-3Z-pyrazolyl-3-oxospiro(isobenzofuran-1 (ZN.4"-piperidine|-1-carboxamide

Melting point 255-25870

Example 31

Z-oxo-M-(5-(3-quinolyl)-Z-pyrazolyl|spiro(isobenzofuran-1(ZN,4-piperidine|-1-carboxamide

Melting point 253-257"

Example 32

M-I5-(3-Fluorophenyl)-2-pyrimidinyl|-Z-oxospiro(isobenzofuran-1(ZN,4-piperidine-1--carboxamide

Melting point 122-12570

X-ray powder diffraction

The above X-ray powder diffraction data were measured on a KIMT2100

ShKitanzuziet (2KM) (manufactured by Ridaka Ipiegpayop! Sogrogayop), the analysis conditions are as follows: X-ray source: Si, tube voltage: 4kV, tube current: ZOMA, and automatic monochromator: monochromator, monoreceiving slit: 0.15mm, goniometer: horizontal goniometer I , scanning step: 0.02 degrees, scanning speed: 2.00 degrees/min, deflecting slit (05): 1 degree, diffusing slit: 1 degree, receiving slit (K5): 0.15mm, temperature measurement temperature: ambient environment

Example 33 3-Oxo-M-(5-(3-trifluoromethylphenyl)-2-pyrimidinyl|spiro(isobenzofuran-1(ZH),4-piperidine|-1 carboxamide

Melting point 190-19270

Example 34

M-I5-(3-chlorophenyl)-2-pyrimidinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide

The melting point is 126-128"7C

Example 35

M-(7-difluoromethoxytridoi3,2-B|pyridin-2-yl)-3-oxospiro(isobenzofuran-1(3H),4-piperidine|-1'-carboxamide

Melting point 19370

Example 36 3-Oxo-M-(5-phenyl-1,2,4-thiadiazol-Z-yl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1-carboxamide

Melting point 239-241"70

Example 37

MH-(1-I3-(2-hydroxyethyl)phenyl|-4-imidazolyl)y-3-oxospiro(isobenzofuran-1 (ZH),4-piperidine|-1-carboxamide

Melting point 99-1007C

Example 38

M-(4-(1-ethyl-2-imidazoliluphenyl|-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide

The melting point is 221-223"7C

Example 39

M-(1-(3-Methoxyphenyl)-4-imidazolyl|-3-oxospiro(isobenzofuran-1(3H),4-piperidine|-1--carboxamide

Melting point 208-210"

Example 40

Preparation of 6b-fluoro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiroisobenzofuran-1(ZH),4-piperidine-1"-carboxamide

A mixture of 6b-fluorospiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride (b4 mg), phenyl M-(5-phenyl-2-pyrazinyl)carbamate (7 mg) and triethylamine (174 μl) in chloroform (Hml ) are stirred at 80"C for 2 hours. The reaction mixture is poured into water and extracted with chloroform (20ml). The organic layer is washed with saturated saline solution (20ml), then dried over anhydrous Ma»25O4 and concentrated. The residue is purified by column chromatography on silica gel ( hexane/ethyl acetate from 4/1 to 1/2) and recrystallized from a mixture of ethyl ether-hexane, obtaining the indicated compound (101 mg) in the form of colorless crystals (melting point 222-22475).

Example 41

Preparation of b-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1'-carboxamide

The specified compound is prepared similarly to the method of example 40, replacing phenyl M-(5-phenyl-2-pyrazinylcarbamate) used in example 40 with phenyl M-(5-phenyl-2-pyrimidinyl)carbamate.

Melting point 176-178"

Example 42

Preparation of 5-fluoro-3-oxo-M-I5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide

A mixture of 5-fluorospiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride (b4mg), phenyl M-(5-phenyl-2-

pyrazinyl)ucarbamate (7mg) and triethylamine (174µl) in chloroform (5Xml) were stirred at 80°C for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20ml). The organic layer was washed with saturated saline (20ml), then dried over anhydrous Mag25O4 and concentrate. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) and recrystallized from a mixture of ethyl ether-hexane, obtaining the indicated compound (100 mg) in the form of colorless crystals (melting point 236-23 8"C).

Example 43

Preparation of 5-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1"-carboxamide

The specified compound is obtained similarly to the method of example 42, replacing phenyl M-(5-phenyl-2-pyrazinylcarbamate) used in example 42 with phenyl M-(5-phenyl-2-pyrimidinyl)carbamate.

Melting point 255-257"

Example 44

Preparation of M-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro(1H-2-benzopyran-1,4"-piperidine|-1-carboxamide

Spiro(1H-2-benzopyran-1,4"-piperidinyl-3(4H)-one hydrochloride (50.6mg) and phenyl.M-(4-benzoylphenyl)carbamate (63.4mg) are suspended in dimethylsulfoxide (1, 0ml) and the suspension is intensively stirred with 10M aqueous sodium hydroxide (30ml) for 5 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated saline, then dried over anhydrous

Mag25O»4 and concentrate. The residue is crystallized from a mixture of methanol-isopropyl ether, obtaining the specified compound (68.Omg) in the form of colorless crystals (melting point 138-146").

The compounds of examples 45 and 46 are obtained similarly to the method of example 44, replacing the phenyl M-(4-benzoyl)carbamate used in example 44 with the corresponding substances.

Example 45 3,4-Dihydro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(1H-2-benzopyran-1,4"-piperidine|-1-carboxamide

Melting point 22170

Example 46

M-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro|1 H-2-benzopyran-1,4-piperidine(|-1-carboxamide

Melting point 128-13170

Example 47

Preparation of trans-M-(4-benzoylphenyl)-3'-oxospiro|cyclohexane-1,1(3'H)-isobenzofuran|-4-carboxamide (1) Preparation of stro|cyclohexane-1,1'(3'H) -isobenzofuran-34-dione

A solution of 2-bromobenzoic acid (4.77g) in anhydrous tetrahydrofuran (100ml) is cooled to -787C in a nitrogen atmosphere, and n-butyllithium (1.53M solution in hexane, Ziml) is added dropwise, maintaining the internal temperature below -55 "C. After stirring for 1 hour, a solution of monoethylene ketal 1,4-cyclohexanedione (5.18 g) in anhydrous tetrahydrofuran (10 ml) is added dropwise to the mixture, maintaining the internal temperature below -67"C. After raising the temperature to room temperature, the reaction solution is distributed between water (150 ml) and hexane (100 ml). The aqueous layer is acidified with concentrated hydrochloric acid and refluxed for 2 hours with acetone (1 Oml). After cooling, the mixture thus obtained is neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer is washed with saturated saline, then dried over anhydrous Mag5O4 and evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give the indicated compound (2.42 g). (2) Preparation of 4-methylenespiro|cyclohexane-1,1'(3'H)-isobenzofuran|-Z-one

A suspension of methyltriphenylphosphonium bromide (715mg) in anhydrous tetrahydrofuran (7.0ml) is cooled to 0"C in a nitrogen atmosphere, n-butyllithium (1.53M solution in hexane, 1.3ml) is added to it, stirred at this temperature for 20 minutes and then cooled to -78"C. A solution of spiroIcyclohexane-1,1(3'H)-isobenzofuran|-3',4-dione (216 mg) in anhydrous tetrahydrofuran (3ml) is added to the reaction mixture and the temperature is raised to 0"C. After stirring for 20 minutes, the resulting mixture aqueous ammonium chloride is added and the resulting crude product is extracted with ethyl acetate. The organic layer is washed with saturated saline, then dried over anhydrous Ma»5O4 and concentrated. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate-4/1), obtaining the specified compound (196 mg (3) Preparation of 4-hydroxymethylstro|cyclohexane-1,1'(3'H)-isobenzofuran|-3'-one

A solution of 4-methylenespiroIcyclohexane-1,1'(3'H)-isobenzofuran|-3-one (196 mg) in anhydrous tetrahydrofuran (5 Oml) is cooled to 0"C, a borane-dimethylsulfoxide complex (2M solution in tetrahydrofuran, 690μl) and the mixture is stirred at this temperature for 1.5 hours, then for another 20 minutes together with 2M aqueous sodium hydroxide (5.00ml) and 30906 aqueous hydrogen peroxide (5.0ml). The reaction mixture is diluted with water, extracted with ethyl acetate, washed with saturated saline solution, then dried over anhydrous

Mag25O4 and evaporate. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate/1), obtaining the specified compound (19mg) in the form of diastereoisomers. (4) Preparation of trans-3'-oxostro|cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxylic acid

A mixture of 4-hydroxymethylstro|cyclohexane-1,1'(3'H)-isobenzofuran|-3'-one (190mg), chloroform (2.0ml), acetonitrile (2.0)ml and sodium phosphate buffer (pH 6.5 , 2.00 ml) is cooled to 0"C, sodium periodate (612 mg) and ruthenium (II) chloride n-hydrate (1 Omg) are added to it, and the mixture is stirred for 30 minutes. This reaction mixture is stirred together with hydrochloric acid (2.0 ml ) for 30 minutes and partitioned between water (5O0ml) and ethyl acetate (50O0ml). The organic layer was washed with saturated saline solution, dried over anhydrous

Mag25O4 and concentrate. The residue is purified by column chromatography on silica gel (chloroform/methanol--100/1), obtaining the indicated compound (98.6 mgHg). (5) Preparation of trans-M-(4-benzothylphenyl)-3'-oxospiro-(cyclohexane-1,1'(3Z'H)-isobenzofuran|-4-carboxamide

4-aminobenzophenone (19.8 mg) and 1-( (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (57.5 mg) and the mixture is stirred at 50"C for 2 hours. This reaction mixture is partitioned between water and ethyl acetate. The organic layer is washed with aqueous potassium hydrogen sulfate, aqueous sodium hydrogen carbonate, and saturated saline. and then dried over anhydrous Mag25O4 and evaporated. The residue was recrystallized from a mixture of ethyl acetate-hexane, obtaining the specified compound (31.2 mg) in the form of colorless crystals (melting point 1947C). The compounds of examples 48-56 are obtained similarly to the method of example 47-(5), replacing the 4-aminobenzophenone used in example 47-(5) with the corresponding substances.

Example 48

Trans-3'-oxo-M-(5-phenyl-2-pyrazinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

The melting point is 223"7C

Example 49 Trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro-cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

The melting point is 2647C

Example 50

Trans-3'-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran-4-carboxamide

Melting point 1847C

Example 51

M-(1-(3,5-difluorophenyl)-4-imidazolyl-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran-4-carboxamide

Melting point 29470

Example 52

Trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro-cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

Melting point 2387

Example 53

Trans-M-(1-(2-fluorophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran-4-carboxamide

Melting point 25870

Example 54

Trans-M-(4-acetyl-3-trifluoromethylphenyl)-3'-oxospiroI(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

Melting point 274-27570

Example 55

Trans-3'-oxo-p-|1-(3-quinolyl)-4-imidazolyl|spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

Melting point x2300"7C

Example 56

Trans-M-|1-(3Z-cyanophenyl)-4-imidazolyl|-3'-oxospiro|cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide

Melting point 268-270"

Example 57

Preparation of trans-M-(4-benzoylphenyl)-3Z-oxospiro(4-azaisobenzofuran-1(3'H),1"-cyclohexane|-2-carboxamide (1) Preparation of dispiro(4-azaisobenzofuran-1(ZH), 1'-cyclohexane-4",2"-1",3"-dioxolane(|-Z-one

A solution of M-methyl-2-pyridinecarboxamide (9.53g) in anhydrous tetrahydrofuran (400ml) is cooled to -78°C in a nitrogen atmosphere, n-butyllithium (1.54M solution in hexane, 1000ml) is added dropwise to it. After stirring. a solution of monoethylene ketal 1,4-cyclohexanedione (10.93 g) in anhydrous tetrahydrofuran (100 ml) was added dropwise to the mixture for 1.5 hours at the same temperature. After raising the temperature to room temperature, the reaction mixture was partitioned between water (300 ml) and ethyl ether ( 100 ml).

The aqueous layer is acidified with 2N hydrochloric acid, stirred for 30 minutes, neutralized with potassium carbonate and left overnight. The resulting precipitate was collected by filtration and dried to give the indicated compound (6.84 g). (2) Preparation of spiro|(4-azaisobenzofuran-1(ZH),1'-cyclohexane|-3,4-dione

A mixture of dispiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane-4"2"-1,3"-dioxolan|-Z-one (6.8g), 2N hydrochloric acid (20ml) and acetone (5ml ) is heated at reflux for 13 hours. After cooling, the mixture is neutralized with potassium carbonate and stirred with isopropyl ether (5 mL) for

From hours The resulting precipitate was collected by filtration and dried to give the indicated compound (3.39 g). (3) Preparation of cis-4"-hydroxyspiro(4-azaisobenzofuran-1(Z3H),1'-cyclohexane|-3-one

Spiro(4-azaisobenzofuran-1(Z3H),1'-cyclohexane|-3,4-dione (5,7) is dissolved in tetrahydrofuran (50ml) and water (10ml) and cooled to 0"C. The solution is stirred together with borohydride of sodium (993 mg) for 20 minutes, acidify with 1095 sulfuric acid, bring the pH to 7.4 with a saturated aqueous solution of sodium bicarbonate and extract with a mixture of chloroform-ethanol and a mixture of chloroform-tetrahydrofuran. The organic layer is dried over anhydrous Ma»5O4 and concentrated. The residue is crystallized from mixture of ethyl acetate-isopropyl ether, obtaining the indicated compound (2.02 g).

To a solution of cis-4-hydroxystro(4-azaisobenzofuran-1(ZH),1'-cyclohexane|-Z-one (2.02g) in anhydrous tetrahydrofuran (bOml) add triethylamine (3.0v8ml) and cool to 0"С . Methanesulfonyl chloride (1.3 ml) is added dropwise to the mixture and stirred at this temperature for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The organic layer is dried over anhydrous Mag5O"x and evaporated. The residue is recrystallized from a mixture of ethyl acetate-isopropyl ether, obtaining the mesylate (2.47g). The mesylate thus obtained is dissolved in dimethylformamide (25ml) and stirred together with tetramethylammonium cyanide (3.25g) at 100"C for 3 hours. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried over anhydrous

Mag25O4 and then concentrate. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate-2/3), obtaining the specified compound (1.0 g). (5) Preparation of trans-3-oxospiro(4-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxylic acid

A solution of trans-3-oxospiro(-azaisobenzofuran-1(ZH),1"-cyclohexane|--carbonitrile (1.0 g) in 3095 sulfuric acid is heated at reflux for 11 hours. After cooling, the reaction mixture is diluted with water and adjusted the pH to 6 with potassium carbonate. The resulting precipitate was collected by filtration, washed with water, and air-dried to give the indicated compound (974 mgH). (6) Preparation of trans-M-(4-benzoylphenyl)-3-oxospiro|(4-azaisobenzofuran- 1(ZH),1'-cyclohexane|-2-carboxamide

4-aminobenzophenone (52.6 mg) and 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (153 mg) and the mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous MagnO and then concentrated. The residue was crystallized from mixture of ethyl acetate-hexane, obtaining the specified compound (94 4mg) in the form of colorless crystals (melting point 237"С).

The compounds of examples 58-60 are obtained similarly to the method of example 57-(6), replacing the 4-aminobenzophenone used in example 57-(6) with the corresponding substances.

Example 58

Trans-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(4-azaisobenzofuran-1(3H),1-cyclohexane-4-carboxamide

The melting point is 203"7C

Example 59

Trans-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(4-azaiobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

Melting point 21770

Example 60

Trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(4-azaisobenzofuran-1(ZH),1-cyclohexane-4-carboxamide

Melting point 2377

Example 61

Preparation of trans-M-(4-benzoylphenyl)-3Z-oxospiro(5-azaisobenzofuran-1(ZH)-1'-cyclohexane|-24-carboxamide (1) Preparation of dispiro|(5-azaisobenzofuran-1(ZH)),1 -Cyclohexane-/,2"-1,3"-dioxolane|-Z-one 2,.2,6,6-Tetramethylpiperidine (41.1 ml) is dissolved in anhydrous tetrahydrofuran (400 ml), cooled to -507C, to it sequentially add n-butyllithium (1.50 M solution in hexane, 217 ml) and nicotinic acid (10.0 g). After stirring for 1 hour at -50"C, add a solution of 1,4-cyclohexanedione monoethylene ketal (13.9 g) in anhydrous tetrahydrofuran (25ml) and the mixture is stirred at -507C for 1 hour. After the temperature rises to room temperature, the reaction mixture is poured into water (800ml) and extracted with a mixture of hexane-ether (111, 500ml). The pH of the aqueous layer is adjusted to 3 with the help of bn hydrochloric acid and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with water. The solid thus obtained was dissolved in chloroform (300 ml), washed with with an aqueous solution of sodium bicarbonate (150 ml), dried and then concentrated. The residue was recrystallized from a mixture of ethyl acetate-hexane, obtaining the indicated compound (4.29 g). (2) Preparation of spiro|5-azaisobenzofuran-1(ZH),1'-cyclohexane|-3,4"-dione

Dispiro(5-azaisobenzofuran(ZH),1'-cyclohexan-4",2"-1",3"-dioxylan|-Z-one (4.29g) and para-toluenesulfonic acid monohydrate (3.74g) are dissolved in acetone (80ml) and water (3ml) and the solution is heated at reflux for 3 hours. After cooling, the acetone is evaporated and chloroform (100ml) is added to the residue. The mixture is washed with a saturated aqueous solution of sodium bicarbonate (50ml/h), dried over anhydrous Mag50O54 and evaporate. The obtained crystals are recrystallized from a mixture of ethyl acetate-hexane, obtaining the specified compound (2.68 g). (3) Preparation of cis-4"-hydroxyspiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-Z-one

A suspension of spiro(5-azaiisobenzofuran-1(Z3H),1'-cyclohexane|-3,4-dione (167 mg) in a tetrahydrofuran-water mixture (10:1, 4 ml) is cooled to 0"C and mixed with sodium borohydride ( 32mg) at 0"C for 30 minutes. The reaction mixture was poured into water (5ml), stirred for 30 minutes at room temperature and then extracted with chloroform (20mlx3). The extract was dried over anhydrous Mag25O:4 and concentrated. The residue was recrystallized from a mixture of ethyl acetate-hexane , obtaining the indicated compound (77.7 mg). (4) Preparation of trans-3-oxospiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|/-carbonitrile

A solution of cis-4-hydroxyspiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-Z-one) (1.31g) in anhydrous tetrahydrofuran (20ml) is cooled to 0"C and mixed with methanesulfonyl chloride (0.555ml) at

OS within 1 hour. The reaction mixture was poured into water (50ml), extracted with ethyl acetate (100ml/h), dried over anhydrous Mag5Ox and concentrated to give crude mesylate (1.87g). This mesylate is dissolved in anhydrous dimethylformamide (30ml) and stirred together with triethylammonium cyanide (2.98g) at 100" for 5 hours. The reaction mixture is poured into water (100ml) and extracted with ether (150mlx3) and an ether-ethyl acetate mixture (2:11 , 200 ml). The combined extracts are dried over anhydrous Ma25O4 and concentrated. The resulting oily residue is purified by column chromatography on silica gel (hexane/ethyl acetate/methanol from 2/1/0 to 1/1/0 and further 30/30/1) and the resulting solid was recrystallized from ethyl acetate-hexane to give the indicated compound (631 mg). (5) Preparation of trans-3-oxospiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxylic acid

A mixture of trans-3-oxospiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|--carbonitrile (100 mg), water (0.7 ml) and concentrated sulfuric acid (0.3 ml) is refluxed for 11 hours The reaction mixture is cooled to room temperature and the pH is adjusted to 4 with 4N sodium hydroxide.

The resulting precipitate was collected by filtration, washed successively with water, ethanol and diisopropyl ether and then dried to give the indicated compound (78mgHg).

IN YAME (200mhz, DMSO-dv bm.d.): 1.63-1.87 (2Н, m), 1.88-2.20 (6Н, m), 2.70 (1Н, m), 7 .76 (1H, dd, uU-5.2, 1.1Gu), 8.86 (1H, d, U-5.2Hz), 9.06 (1H, d, 9-11), (6) Obtaining trans-M-(4-benzoylphenyl)-3Z-oxospiro(5-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide

A solution of trans-3-oxospiro(5-azaisobenzefuran-1(ZH),1'-cyclohexane|-4-carboxylic acid (20 mg) and 4-

of aminobenzophenone (1 mg) in anhydrous pyridine (0.5 ml) is mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg) at 60"C for 2 hours. The reaction mixture is poured into water (10 ml) and extracted with ethyl acetate ( The combined organic layers were dried over anhydrous Ma250O5 and concentrated.

The obtained oily residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 1/1 to 1/2) and the solid obtained is recrystallized from a mixture of ethyl acetate and hexane, obtaining the specified compound (10 mg) in the form of colorless crystals (melting point 256-25775 ).

Example 62

Preparation of trans-M-(4-benzoylphenyl)-3-oxospiro(b-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide (1) Preparation of dispiro(b-azaisobenzofuran-1(ZH),1- Cyclohexane-4",27-1",3"-dioxolane|-Z3-one 2,2,6,6-Tetramethylpiperidine (50 ml) is dissolved in anhydrous tetrahydrofuran (500 ml) and this solution is cooled to -507"С , n-butyllithium (1.50 M solution in hexane, 270.7 ml) and isonicotinic acid (12.5 g) are sequentially added to it. The reaction mixture is stirred for 10 minutes at -507C and the temperature is raised to 25"C in 30 minutes. The reaction mixture stir for another 10 minutes at 25"7C and cool to -657"C. Add monoethylene ketal 1,4-cyclohexanedione (19g) and stir the reaction mixture at -657"C for 10 minutes.

The temperature of the reaction mixture is raised to -157C in 1 hour, then to 0C in 30 minutes. Then this mixture is poured into water (300 ml) and the aqueous layer is separated. The organic layer is extracted with 2N aqueous sodium hydroxide. The pH of the combined aqueous layers is adjusted to With the help of concentrated hydrochloric acid and extracted with ethyl acetate (500 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (200 ml), saturated saline solution, dried over anhydrous Md5O: and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate from 1 /0 to 4/1 and further .372) and recrystallized from a mixture of ethyl acetate-hexane, obtaining the indicated compound (7.20 g). (2) Preparation of spiro|b-azaisobenzofuran-1 (ZH), 1-cyclohexane|-3, 4-dione

Dispiro|b-azaisobenzofuran-1(ZH),1'"cyclohexane-4",2"-1",3"-dioxolan|-Z-one (7.20g) and para-toluenesulfonic acid monohydrate (5.80g) dissolved in acetone (150ml) and water (15ml) and the solution was heated at reflux for 5.5 hours. After cooling, the acetone was evaporated and the residue was extracted with ethyl acetate (100mlx3). The combined organic layers were washed with saturated saline (50ml ), dried over anhydrous Md5O4 and evaporated. The obtained crystals were recrystallized from a mixture of ethyl acetate and isopropyl ether, obtaining the indicated compound (1.96 g). (3) Preparation of cis-4"-hydroxyspiro|b-azaisobenzofuran-1(Z3H),1' -cyclohexane|-3-one

A solution of spiro|b-azaiisobenzofuran-1(Z3H),1'-cyclohexane|-3,4"-dione (1.0 g) in ethanol (100 ml) is cooled to 0"C and stirred together with sodium borohydride (174 mg) at 0 "C for 1 hour. The pH of the reaction mixture is brought to 4 with the help of 1095 sulfuric acid, then with the help of a saturated aqueous solution of sodium bicarbonate it is made basic and further extracted with chloroform (200 mlx2). The extract is dried over anhydrous

M9zo»h and concentrate. The residue was recrystallized from a mixture of ethyl acetate-hexane, obtaining the specified compound (954.5 mg). (4) Preparation of trans-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carbonitrile

A solution of /cis-4-hydroxyspiro|(b-azaisobenzofuran-1(Z3H),1-cyclohexane|-Z-one (954 mg) and triethylamine (0.9 ml) in dimethylformamide (10 ml) is cooled to 0"C and mixed together with methanesulfonyl chloride (0.4 Oml) at 0"C for 1 hour. The reaction mixture is diluted with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium bicarbonate (50 ml) and a saturated saline solution (50 ml), dried over anhydrous Md5Ox and concentrated. The residue is recrystallized from the mixture ethyl acetate-isopropyl ether, obtaining mesylate (995 mg). This mesylate is dissolved in anhydrous dimethylformamide (30 ml) and stirred together with triethylammonium cyanide (1.57 g) at 100"C for 1.5 hours. The reaction mixture is diluted with ethyl acetate (200 ml) and successively washed with water (200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and saturated saline solution (100 ml). The organic layer was dried over anhydrous

MBO" and concentrate. The residue was recrystallized from a mixture of ethyl acetate and isopropyl ether to give the indicated compound (447 mg). (5) Preparation of trans-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxylic acid

A mixture of trans-3-oxospiro(b-azaisobenzofuran-1(ZH),1"-cyclohexane|--carbonitrile (445 mg), water |3.5 ml) and concentrated sulfuric acid (1.5 ml) is refluxed for 6 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 8 with 5N sodium hydroxide, then to pH with concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water and dried to give the indicated compound (416bmg) as colorless crystals (temperature melting point 222-22375).

IN NMR (Zbomgc, DMSO-av, bm.d.): 1.7-2.2 (BN, m), 2.65-2.75 (1Н, m), 7.83 (1Н, dd, 9 -1.2, 4.9Hz), 8.86 (1H, d, y-4.9Hz), 9.05 (1H, d, 9U-1.2Hz), 12.3 (1H, sh.s) . (6) Preparation of trans-M-(4-benzoylphenyl)-3-oxospiro(b-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide

A solution of trans-3-oxospiro|b-azaisobenzofuran-1(ZH),1'-cyclohexane|-4-carboxylic acid (50 mg) and 4-aminobenzophenone (51.6 mg) in anhydrous pyridine (Iml) is mixed together with 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.7 mg) at 60"C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and successively washed with water (20 ml), 1095 aqueous solution of citric acid (20 ml xX 2 ), saturated aqueous sodium bicarbonate solution and saturated saline. The organic layer is dried over anhydrous M95O4 and concentrated. The resulting oily residue is purified by column chromatography on silica gel (hexane/ethyl acetate from 3/2 to 1/4) and the resulting solid is recrystallized from a mixture of ethyl acetate and hexane , obtaining the indicated compound (62.7 mg) in the form of colorless crystals (melting point 147-149).

Example 63

Preparation of M-I5-(4-hydroxyphenyl)-2-pyrazinyl|-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine-1'-carboxamide (1) Preparation of 2-amino-5-(4-hydroxyphenyl) pyrazine

To a solution of 2-amino-5-bromopyrazine (36 mg) in dimethoxyethane (20 ml) add 4-hydroxyphenylboronic acid (320 ml), 1.5 N aqueous sodium carbonate solution (2.5 ml) and tetrakis(triphetylphosphine)palladium(0) (54 mg ).

The mixture is stirred at 80"C for 3 hours. Water (20 ml) is added to the reaction mixture and everything is extracted with ethyl acetate (50 mlx3). The extract is washed with saturated saline, then dried over anhydrous

Mag25O4. Removal of the solvent gave a crystalline residue, which was washed with diethyl ether (10 mL) to give the title compound (305 mg). (2) Preparation of phenyl M-|5-(4-hydroxyphenyl)-2-pyrazinyl|-carbamate

To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine (20 ml), phenyl chloroformate (199 μl) was added while cooling with ice, and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The organic layer is washed with saturated saline solution and dried over anhydrous Mag25O4. Concentration of the solution gave a crystalline residue, which was washed with diethyl ether (10 mL) to give the title compound (314 mg). (3) Preparation of /- M-(5-(4-hydroxyphenyl)-2-pyrazinyl|-Z-oxospiro-(isobenzofuran-1(ZH),4-piperidinyl|-1'-carboxamide

A mixture of spiro(isobenzofuran-1(ZN),4-piperidin|-3-one hydrochloride (9 mg), phenyl M-(4-hydroxyphenyl)-2-pyrazinyl carbamate (128 mg) and triethylamine (279 μl) in chloroform (5 ml) is stirred at 80"C for 2 hours.

The reaction mixture was poured into water and extracted with chloroform (20 ml). The organic layer is washed with saturated saline solution (20 ml) and dried over anhydrous Mag50O»x.

Concentration of the solution provides a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) followed by recrystallization from a mixture of ethyl ether-hexane, obtaining the indicated compound (114 mg) in the form of colorless crystals (melting point 263- 26570).

Example 64

Preparation of M-I5-(3-hydroxyphenyl)-2-pyrazinyl|-Z-okeospiro(isobenzofuran-1(Z3H),4-piperidine-1"-carboxamide. (1) Preparation of 2-amino-5-(Z-methoxyphenyl)pyrazine

To a solution of 2-amino-5-bromopyrazine (642mg) in dimethoxyethane (40ml) add 3-methoxyphenylboronic acid (560mg), 1.5N aqueous sodium carbonate solution (4ml) and tetrakis(triphenylphosphine)palladium(0) (86bmgH).

The mixture is stirred at 80"C for 6 hours. Water (20ml) is added to the reaction mixture and everything is extracted with ethyl acetate (50mlx3). The extract is washed with saturated saline and then dried over anhydrous

Mag25O4. Concentration of the solution gave a crystalline residue, which was washed with ethyl ether (10 ml) to give the indicated compound (7600 mg). (2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine 2-Amino-5-(3-methoxyphenyl)pyrazine (56 mg) was dissolved in methylene chloride (1 mL). Boron tribromide (53 Ωcl) is added to the mixture while cooling with ice, and everything is stirred at room temperature for 14 hours. Aqueous sodium hydroxide is added to the reaction mixture. All are extracted with ethyl acetate (ZbOmlhg).

The organic layer is washed with saturated saline and dried over anhydrous Mag250. Concentration of the solution gave the indicated compound (94 mg) as a yellow solid. (3) Preparation of phenyl M-(3-hydroxyphenyl)-2-pyrazinyl|-carbamate

To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine (10 mL), phenyl chloroformate (b3 mL) was added while cooling with ice. The mixture is stirred for 1 hour and poured into water (30ml), extracted with ethyl acetate (20mlx3). The extract is washed with saturated saline and then dried over anhydrous

Mag25O4. Concentration of the solution gave a crystalline residue, which was washed with ethyl ether (10 mL) to give the title compound (51 mg). (4) Preparation of M-I5-(3-hydroxyphenyl)-2-pyrazinyl|-3-oxospiro-(isobenzofuran-1(ZH),4-piperidine|-1'-carboxamide

A mixture of spiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride (40 mg), phenyl.M-(5-(3-hydroxyphenyl)-2-pyrazinylcarbamate (51 mg) and triethylamine (119 μl) in chloroform ( 5ml) is stirred at 80"C for 2 hours. The reaction mixture is poured into water and extracted with chloroform (20ml). The organic layer is washed with saturated saline solution (20ml) and dried over anhydrous Mag5O4. Concentration of the solution gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) followed by recrystallization from an ethyl ether-hexane mixture to give the indicated compound (24 mg) as colorless crystals (m.p. 257-259").

Example 65

Preparation of 4-fluoro-3-oxo-M-(5-phenyl-2-trimidinyl)spiro(isobenzofuran-1(ZH), 4-piperidine|-1"-carboxamide

A mixture of 4-fluorospiro(isobenzofuran-1(ZN), 2-piperidin|-3-one hydrochloride (150mg), phenyl M-(5-phenyl-2-pyrimidinylcarbamate (17mg) and triethylamine (0.24ml) in chloroform (2ml) ) are stirred at 60"C for 3 hours. Concentration of the reaction mixture gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate/methanol--1/1/0-8/8/1-6/6/1) with further recrystallization from a mixture of ethyl acetate-hexane, obtaining the indicated compound (190 mg) in the form of colorless crystals (melting point 247-24975).

Example 66

Preparation of 7-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH),4-piperidine-1'-carboxamide

A mixture of 7-fluorospiro(isobenzofuran-1(ZN), 2-piperidin|-3-one hydrochloride (150mg), phenyl M-(5-phenyl-2-pyrimidinylcarbamate (17mg) and triethylamine (0.24ml) in chloroform (2ml) ) is stirred at 60"C for 2 hours. The reaction mixture is diluted with ethyl acetate. The entire mixture is washed with 1095 aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated saline solution and then dried over anhydrous Mag250O54. Concentration of the reaction mixture gives a residue, which is recrystallized from ethyl acetate , obtaining the indicated compound (202 mg) in the form of colorless crystals (melting point 244-2467C).

Example 67

Preparation of 6b-ethyl-3-oxo-N-(5-phenyl-2-pyraylinyl)spiro(isobenzofuran-1(ZH),4"-piperidine|-1-carboxamide (1) Preparation of 2-(4-ethylphenyl)- 4,4-dimethyl-2-oxazoline

Triphenylphosphine (20g), 2-amino-2-methyl-1-propanol (2.74ml) and triethylamine (28.2ml) are added to a solution of 4-ethylbenzoic acid (3.80g) in anhydrous acetonitrile (10O0ml) under a nitrogen atmosphere. . The mixture is cooled in an ice bath and then tetrachloromethane (5.3 bml) is added. The reaction mixture is left at room temperature and stirred for 18 hours. Ethyl acetate and hexane were added to the reaction mixture, and the precipitate was removed by filtration. Concentration of the filtrate gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 9/1 to 6/1) to give the indicated compound (1.15 g). (2) Preparation of 1-benzyl-b-ethylspiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride

In a nitrogen atmosphere, a solution of /2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline (1,15) in anhydrous tetrahydrofuran (100 ml) is cooled to -78°C. To this solution, a 1.5M solution of butyllithium in hexanes (4.53ml). After stirring for 1 hour, 1-benzyl-4-piperidone (1.05ml) was added dropwise. Then the temperature of the reaction mixture was allowed to rise to room temperature and 2N hydrochloric acid was added to the reaction mixture, making the mixture acidic. The whole the mixture was refluxed for 2 hours. After cooling, aqueous sodium hydroxide solution was added, making the reaction mixture basic. This mixture was extracted with ethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous Ma»5O4. Concentration of the organic solution gave a residue which is purified by column chromatography on silica gel (hexane/ethyl acetate-3/2), obtaining the indicated compound (409 mgHg). (3) Preparation of 6-ethylspiro(isobenzofuran-1(ZH),4-piperidin|-3-one hydrochloride 1-Benzyl-b-ethylspiro (isobenzofur an-1(ZN),4-piperidin|-3-one hydrochloride (400 mg) is dissolved in methanol (10 ml) and 1095 palladium on charcoal is added. The mixture is stirred in a hydrogen atmosphere for 1.5 hours. After removal of palladium-charcoal by filtration, the filtrate is concentrated to obtain a residue, which is subjected to crystallization from a mixture of methanol-ethyl ether, obtaining the specified compound (222mMg). (4) Preparation of b-ethyl-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1 (ZH), 4-piperidine|-1'-carboxamide

To a suspension of b-ethylpyro(isobenzofuran-1 (ZH),42-piperidin|-3-one hydrochloride (5mg) and phenyl M-(5-phenyl-2-pyrazinyl)ucarbamate (58mg) in dimethylsulfoxide (tml) and add 10M of aqueous sodium hydroxide solution (0.02 mL).The mixture was stirred vigorously for 5 minutes and then partitioned between water and ethyl acetate.

The organic layer is separated and washed with saturated saline, and then dried over anhydrous

Mag25O4. Concentration of the organic solution gave a residue, which was crystallized from ethyl acetate to give the indicated compound (4 mg) as crystals (m.p. 1176-1785).

Example 68

Preparation of b-hydroxy-3-oxo-M-(5-phenyl-2-pyrazinyl)sylro(isobenzofuran-1 (ZH),4-piperidine|-1'-carboxamide (1) Preparation of 2-(4-methoxyphenyl)- 4,4-dimethyl-2-oxazoline

To a solution of 2-amino-2-methyl-1-propanol (14.4 g) and triethylamine (23 ml) in dry THF (200 ml), a solution of 4-methoxybenzoyl chloride (25 g) in dry THF (20 ml) is added dropwise while cooling with ice. The mixture is stirred at room temperature for 1 hour and water (200 ml) is added. The reaction mixture was extracted twice with ethyl acetate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Concentration of the organic solution gave the compound (29.5 g) as a white solid. To the above white solid was added thionyl chloride (25ml) and the reaction was carried out at room temperature for one hour. The reaction mixture is basified by adding 5N aqueous sodium hydroxide solution and extracted twice with ethyl acetate (100 ml). The combined organic layer is washed with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. The solvent was evaporated to give the above compound (22g) as a colorless oil. (2) Preparation of 1'-benzyl-b-methoxyspiro(isobenzofuran-1(ZH), 4-piperidin|-3-one

In a nitrogen atmosphere, a 1.5 M solution of butyllithium in hexane (28 ml) is added dropwise under ice cooling to a solution of 2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in anhydrous toluene (100 ml) . After stirring for 3 hours at the same temperature, 1-benzyl-4-piperidone (8g) in anhydrous toluene (20ml) was added dropwise. After stirring the reaction mixture at room temperature for 14 hours, a saturated aqueous solution of ammonium chloride (5 Oml) was added. The mixture was extracted twice with ethyl acetate (100 ml). The organic layer is washed with a saturated saline solution and dried over anhydrous Mag250O.

Concentration of the organic solution gave the compound (8.3 g) as a white solid. This compound is dissolved in methanol (50 ml) and concentrated sulfuric acid (4 ml) is added. The mixture is stirred for 1 hour at room temperature. An aqueous solution of sodium hydroxide is added to the reaction mixture, making the mixture basic. This mixture was extracted twice with ethyl acetate (100 ml). The organic layer is washed with saturated saline and dried over anhydrous Ma»5O»x. Concentration of the organic solution gives the specified compound (b, bg) as a yellow solid. (3) Preparation of b6-hydroxyspiro(isobenzofuran-1(Z3H),4-piperidin|-3-one hydrochloride 1-Benzyl-b-methoxyspiro(isobenzofuran-1(ZH),4-piperidin|-3-one) (1, 8g) is dissolved in methylene chloride (20ml). Boron tribromide (1.3ml) is added to this solution while cooling with ice. After stirring the reaction mixture at room temperature for 14 hours, an aqueous solution of sodium hydroxide is added. The mixture is extracted twice with ethyl acetate (ZbOml). Organic the layer is washed with a saturated saline solution, and then dried over anhydrous Ma»b5Ox. Concentration of the organic solution gives the compound (1.2 g) as a yellow solid, which is dissolved in methanol (30 mL). To this solution, a mixture is added

4N hydrogen chloride-ethyl acetate (5 ml), 2095 palladium hydroxide on charcoal (330O0mg). The mixture is stirred in a hydrogen atmosphere for 14 hours. After removing the catalyst by filtration, the filtrate was concentrated to give the indicated compound (891 mg) as a white solid. (4) Preparation of b-hydroxy-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro-(isobenzofuran-1(Z3H),4-piperidine|-1'-carboxamide

A mixture of b-hydroxyspiro(isobenzofuran-1(ZN),2-piperidin|-3-one hydrochloride (51 mg), phenyl M-(5-benyl-2-trazinyl)/ucarbamate (5 mg) and triethylamine (119 μl) in chloroform ( Khml) is stirred at 80"C for 2 hours. The reaction mixture is poured into water and then extracted with chloroform (20ml). The organic layer is washed with saturated saline solution (20ml) and dried over anhydrous Mag25O". Concentration of the organic solution gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 1/2) followed by recrystallization from a mixture of ethyl ether-hexane, obtaining the specified compound (29 mg) in the form of colorless crystals (melting point 206-2087С).

The compounds of examples 69-79 are obtained by a method similar to that described in example 61, using the corresponding starting substances instead of 4-aminobenzophenone used in example 61.

Example 69

Trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(5-azaisobeneofuran-1 (ZH),1-cyclohexane|-4-carboxamide

Melting point 215-217"

Example 70

Trans-M-|5-(3-Fluorophenyl)-2-pyrimidinyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

Melting point 205-2077C

Example 71

Trans-M-|5-(2-fluorophenyl)-2-pyrimidinide|-3-oxospiro(5-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide

Melting point 226-2287C

X-ray powder diffraction 7.2822. | ..ЮюЮюЮЙЙ'Й' 690 p

The X-ray powder diffraction data given above were measured under the same conditions as in example 32.

Example 72

Trans-3-oxo-M-(4-phenyl-2-oxazolyl)spiro|5-azaisobenzofuran-1(ZH)1'-cyclohexane|-4-carboxamide

Melting point 273-27570

Example 73

Trans-M-|5-(2-methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide

Melting point 213-21570

Example 74

Trans-M-|5-(3-methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide

The melting point is 145-1477C

Example 75

Trans-M-|5-(3-trifluoromethoxyphenyl)-2-pyrimidinyl|-3-oxospiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|- 4-carboxamide

Melting point 157-15970

Example 76

Trans-M-I|5-(3-Fluoromethylphenyl)-2-pyrimidyl|-3-oxospiro(5-azaisobenzofuran-1(ZH),1"-Cyclohexane|-2-carboxamide

Melting point 153-15570

Example 77

Trans-M-|5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl|-Z-oxospiro|5-azaisobenzofuran-1 (ZH),1"-cyclohexane|- 4-carboxamide

Melting point 218-22070

Example 78

Trans-M-|5-(2-fluoro-5-methylphenyl)-2-trimidinyl|-3-oxospiro|5-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide

Melting point 151-15370

Example 79

Trans-M-I4-(3-fluoromethoxyphenyl)-2--oxazolyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1'-cyclohexane|-24-carboxamide

Melting point 214-21770

Example 80

Preparation of trans-M-(5-(3-hydroxymethylphenyl)-2-pyrimidinyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1-cyclohexane-4"-carboxamide

To a solution of 2-chloro-1,3-dimethylimidazolium chloride (61 mg) in chloroform (100 ml) add pyridine (0.489 ml), trans-3-oxospiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxylic acid (300 mg) and 2-amino-5-bromopyrimidine (211 mg). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate.

The entire reaction mixture was washed with 1095% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, saturated saline solution, and then dried over anhydrous Mag5O4. Concentration of the organic solution gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 1/1 to 1/3, then 1/4, and then 1/5) followed by recrystallization from ethyl acetate, obtaining the required amide (210 mg) . This amide is suspended in ethylene glycol dimethyl ether (3.5 ml) and water (0.5 ml), 3-hydroxymethylphenylboronic acid (95 mg), 2M aqueous sodium carbonate solution (0.31 ml) and tetrakistriphenylphosphine palladium (30 mg) are added there.

The mixture is refluxed for 2 hours and then diluted with water. The entire mixture was extracted with ethyl acetate and then dried over anhydrous Mag5O4. Concentration of the organic solution gives a residue, which is purified by column chromatography on silica gel (ethyl acetate/methanol from 1/0 to 30/1, then 20/1, and then 15/11), obtaining the indicated compound (151 mg) in the form of light yellow crystals (melting point 207-20975).

Example 81

Preparation of trans-M-(5-(3-hydroxyphenyl)-2-pyrimidinyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

To a solution of 2-chloro-1,3-dimethylimidazolium chloride (622 mg) in chloroform (ml) add pyridine (0.50 ml), trans-3-oxospiro(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carbon acid (303 mg) and 2-amino-5-(3-benzyloxyphenyl)-pyrimidine (340 mg).The mixture was stirred at room temperature overnight.

Dilute the reaction mixture with ethyl acetate. The entire mixture is washed with 1095 aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, saturated saline solution and then dried over anhydrous

Mag25O4. Concentration of the organic solution gives a residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 1/1 to 1/2, then 1/4, 1/5 and then 1/6) followed by recrystallization from ethyl acetate, obtaining the required amide ( 210 mg). This amide is dissolved in methanol (ml) and tetrahydrofuran (5 ml) and 1095 palladium on charcoal (120 mg) are added. The mixture is stirred at room temperature under a hydrogen atmosphere overnight. The catalyst is removed by filtration. The filtrate is concentrated to give a residue which is purified by column chromatography on silica gel (chloroform/methanol from 50/1 to 30/1) to give a solid compound. This solid compound was recrystallized from ethyl acetate, obtaining the specified compound (95 mg) in the form of light yellow crystals (melting point 260-26275).

The compounds of examples 82-89 are obtained by a method similar to that described in example 62, using the appropriate starting substances instead of 4-aminobenzophenone used in example 62.

Example 82

Trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

Melting point 189-19170

Example 83

Trans-M-|5-(Z-fluoromethylphenyl)-2-pyrimidinyl|-Z-oxospiro(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4"-carboxamide

Melting point 199-200"

Example 84

Trans-M-|5-(3-Fluoromethoxyphenyl)-2-pyrimidinyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide

Melting point 198-200"

Example 85

Trans-3-oxo-M-(6-Phenyl-1,2,4-triazin-3-yl)spiro|b-azaisobenzofuran-1(ZN),1-cyclohexane-4"-carboxamide

Melting point 272-27570

Example 86

Trans-M-|5-(2-difluoromethoxyphenyl)-3-pyrazolyl|-Z-oxospiro|b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide

The melting point is 239-240"7C

Example 87

Trans-M-I|5-(Z-difluoromethoxyphenyl)-3-pyrazolyl|-Z-oxospiro|b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboceamide

Melting point 183-185"

Example 88

Trans-M-|5-(3-Fluorophenyl)-3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4"-carboxamide

Melting point 182-184"

Example 89

Trans-M-|5-(4-fluorophenyl)-3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(3H),1'-cyclohexane|-4"-carboxamide

Melting point 228-22970

Example 90

Preparation of trans-M-(4-benzoylphenyl)-3-oxospiro|7-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide (1) Preparation of 3-cyano-2-hydroxypyridine

0.5 N hydrochloric acid (40 ml) is added to bisdimethyl acetal of malonaldehyde (16.4 g). The mixture is stirred for 20 minutes at 507C and then cooled to room temperature. Triethylamine (1 mL) was added to the reaction mixture, followed by 2-cyanoacetamide (9 g). All are stirred at room temperature for 30 minutes and heated at 60"C for 90 minutes and at 100"C for 2 hours. After cooling, the reaction mixture is concentrated, obtaining a residue, which is recrystallized from a mixture of ethanol-ethyl ether, obtaining the specified compound (7.49 g). (2) Preparation of 2-bromo-3-cyanopyridine

Tetrabutylammonium bromide (35.4 g) and diphosphorpentoxide (15.58 g) are suspended in toluene (100 ml). After stirring at 70°C for 30 minutes, 3-cyano-2-hydroxypyridine (6.59g) was added. The mixture was refluxed for 4 hours. The reaction mixture was poured into ice water (200g) and extracted with ethyl acetate (200mlx2). The organic layer is dried over anhydrous Ma»25O4. Concentration of the solution gives an oily residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 4/1 to 3/1), obtaining a solid compound. This solid compound is recrystallized from a mixture of ethyl acetate-hexane, obtaining the specified compound (5.16 g). (3) Preparation of spiro|7-azaisobenzofuran-1(ZH),1-cyclohexane|-3,4-dione 2-Bromo-3-cyanopyridine (2.96 g) and 1.4 -cyclohexanedione monoethylene ketal (3.47g) is dissolved in anhydrous tetrahydrofuran (Zdml). After cooling to -78"C, n-butyllithium (1.5M solution in hexane, 12.64ml) is added and the mixture is stirred at -78"C for 30 minutes Allow the reaction temperature to rise to room temperature.

The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer is dried over anhydrous Md5O»x. Concentration of the solution gives a residue, which is recrystallized from a mixture of ethyl ether and hexane, obtaining an iminoether compound (2.93 g). This compound is dissolved in acetone (5ml) and 2N hydrochloric acid (30ml). The solution is boiled for 2 hours under reflux. After cooling, a 2N aqueous solution of sodium hydroxide was added to the reaction mixture, bringing the pH to 4. The entire mixture was extracted with ethyl acetate (100 mLx3). The organic layer is dried over anhydrous M95O4. Concentration of the solution gave a residue, which was recrystallized from an ether-hexane mixture to give the indicated compound (1.07 g). (4) Preparation of cis-4"-hydroxyspiro|(7-azaiisobenzofuran-1(Z3H),1'-cyclohexane|-3-one

Spiro|7-azaisobenzofuran-1(Z3H),1'-cyclohexane|-3,4-dione (1.6 g) is suspended in tetrahydrofuran (37 ml).

After cooling to 0"C, lithium tert-butoxyaluminum hydride (1.0M solution in tetrahydrofuran, 9.58ml) is added dropwise to the mixture. After stirring the mixture at 0"C for 90 minutes, 1N hydrochloric acid is added, bringing the pH to 2. This mixture extracted with ethyl acetate (100mlx4). The organic layer is dried over anhydrous Md5O. Concentration of the solution gives the indicated compound (1.58 g). (5) Preparation of trans-3-oxospiro-7-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carbonitrile

Cis-4-hydroxyspiro|7-azaisobenzofuran-1(Z3H),1-cyclohexane|-Z-one (1.58g) and triethylamine (1.81ml) were dissolved in chloroform (28ml). After cooling the solution to 0"C, methanesulfonyl chloride (0.67ml) is added to it. The mixture is stirred at room temperature for 2 hours and then poured into a saturated aqueous solution of sodium bicarbonate (500ml). The entire mixture is extracted with chloroform (100mlx3). The organic layer is dried over anhydrous Md5O". Concentration gives an oily residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 2/1 to 1/2), obtaining a solid compound. This solid compound is recrystallized from a mixture of ethyl acetate-hexane, obtaining the required mesylate (2, 03g). This compound is dissolved in anhydrous dimethylformamide (30ml) and triethylammonium cyanide (3.2g) is added. The mixture is stirred at 1007C for 3 hours. After cooling, the reaction mixture is poured into water (100ml). The whole mixture is extracted with ethyl acetate (100mx3). Organic layer is dried over anhydrous Md5Ox4. Concentration of the solution gives an oily residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 3/1 to 2/1), obtaining a solid compound. This solid compound was recrystallized from an ethyl ether-hexane mixture to give the indicated compound (515 mgH). (6) Preparation of trans-3-oxospiro-7-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxylic acid

Water (6.bml) and concentrated sulfuric acid (2.2ml) are added to trans-3-oxospiro/7-azaisobenzofuran-

1(ZH),1'-cyclohexane|-4-carbonitrile (515 mg). The mixture is refluxed for 13 hours.

After cooling the reaction mixture to 0"C, a 4N aqueous solution of sodium hydroxide is added, bringing the pH to 4. The precipitated crystals are collected by filtration, washed with water, ethanol, and isopropyl ether and dried. The indicated compound (500 mgH) is obtained.

IN YAME (Z00mgz, DMSO-av, bm.d.): 1.73-1.80 (2Н, m), 1.81-1.94 (2Н, m), 1.99-2.08 (2Н , m), 2.14-2.22 (2H, m), 2.64-2.68 (1H, m), 7.63 (1H, dd, 9U-7.8, 4.68Hz), 8 .28 (1H, dd, 97.8, 1.5Hz), 8.89 (1H, dd, 9-48, 1.5Hz). (7) Preparation of trans-M-(4-benzoylphenyl)-3-oxospiro|7-azaisobenzofuran-1(ZH),1'-cyclohexane|-2-carboxamide

Trans-3-oxospiro|7-azaisobenzofuran-1(3H),1'-cyclohexane|--carboxylic acid (26mg) and 4-aminobenzophenone (20mg) were dissolved in anhydrous pyridine (Iml). Add 1-(33-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg). The mixture is stirred at room temperature for 18 hours.

The reaction mixture is poured into water (100 ml). The entire mixture was extracted with ethyl acetate (30 mL). The combined organic layer is dried over anhydrous M95O.4. Concentration of the solution gives an oily residue, which is purified by column chromatography on silica gel (hexane/ethyl acetate from 3/1 to 2/1) to give a solid compound. Then this solid compound is recrystallized from a mixture of ethyl acetate-hexane, obtaining the specified compound (30 mg) in the form of colorless crystals (melting point 214-216").

The compounds of examples 91-95 are prepared using a technique essentially similar to that described in example 90-(7), replacing the 4-aminobenzophenone used in example 90-(7) with the corresponding amines.

Example 91

Trans-M-|1-(3,5-difluorophenyl)-4-imidazolyl|-3Z-oxospiro/7-azaiisobenzofuran-1(ZH),1-cyclohexane-4"-carboxamide

Melting point 269-27170

X-ray powder diffraction 1990 | ..YuyuYuYuyvyu ssgs2shu

The X-ray powder diffraction data given above were measured under the same conditions as in example 32.

Example 92

Trans-3-oxo-M-(2-phenyl-4-pyridyl)spiro/7-azaisobenzofuran-1(ZN),1"-cyclohexane|-4-carboxamide

The melting point is 221-223"7C

Example 93

Trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro(7-azaisobenzofuran-1(ZH),1"-cyclohexane|--carboxamide

Melting point 240-242"

Example 94

Trans-3-oxo-M-(1-phenyl-3-pyrrolyl)spiro|7-azaisobenzofuran-1(ZH),1'-cyclohexane-1-4-carboxamide

Melting point 214-217"

Example 95

Trans-M-|1-(4-Fluorophenyl)-3-trazolyl|-3-oxosteric|7-azaisobenzofuran-1(ZN),1-cyclohexane|-4-carboxamide

Melting point 210-21270

The compounds of examples 96-98 are obtained using a technique essentially similar to that described in example 57-(b), replacing the 4-aminobenzophenone used in example 57-(b) with the corresponding amines.

Example 96

Trans-3-oxo-M-(1-phenyl-3-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane|--carboxamide

The melting point is 200-202"7C

Example 97

Trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane|--carboxamide

Melting point 223-22570

X-ray powder diffraction

The X-ray powder diffraction data given above were measured under the same conditions as in example 32.

Example 98

Trans-M-|1-(3-fluorophenyl)-4-pyrazolyl|-3-oxospiro|(4-azaisobenzofuran-1(ZH),1-cyclohexane(c-4"-carboxamide

Melting point 176-178"

The compounds of examples 99-106 are prepared using a technique essentially similar to that described in example 62-(6), replacing the 4-aminobenzophenone used in example 62-(6) with the corresponding amines.

Example 99

Trans-3-oxo-M-(1-phenyl-3-pyrazolyl)spiro(b-azaisobenzofuran-1(ZH),1"-cyclohexane!-4"-carboxamide

Melting point 249-25070

Example 100

Trans-M-|1-(4-fluorophenyl)-3-pyrazolyl|-3-oxostro|b-azaisobenzofuran-1 (ZH),1-cyclohexane|-4-carboxamide

Melting point 254-257"

Example 101

Trans-M-|1-(2-fluorophenyl)-3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(3H),1'-cyclohexane|-4"-carboxamide

Melting point 239-241"70

Example 102

Trans-3-oxo-M-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

The melting point is 221-223"7C

Example 103

Trans-3-oxo-M-(5-phenyl-3-isoxazolyl)spiro|(b-azazirbenzofuran-1 (ZH),1-cyclohexane|-4-carboxamide

Melting point 259-26170

Example 104

Trans-3-oxo-M-(6-phenyl-3-pyridyl)stro|(b-azaisobenzofuran-1(ZH),1"-piclohexane|-4-carboxamide

Melting point 249-25170

Example 105

Trans-3-oxo-M-(2-phenyl-3-thiazolyl)spiro|(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide

Melting point 278-280"

Example 106

Trans-3-oxo-M-(2-phenyl-1,2,3-triazol-4-yl)spiro(b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide

Melting point 232-233"7C

Preparation example 1 20.0 g of the compound of example 1, 417 g of lactose, 80 g of crystalline cellulose, 80 g of incomplete α-starch are mixed using an M-conical mixer. 3.0 g of magnesium stearate is added to the mixture and everything is mixed. 3000 tablets are pressed from the mixed powder in the usual way, so that each tablet has a mass of 150 mg and a diameter of 7.00 mm.

Composition of one tablet weighing 150 mg: compound of example 1 5.0 mg lactose 104.25 mg crystalline cellulose 20.0 mg incomplete o-starch 20.0 mg magnesium stearate 0.75 mg

Example of preparation 2 10.8 g of hydroxypropyl cellulose 2910 and 2.1 g of polyethylene glycol 6000 are dissolved in 172.5 g of purified water. In this solution, 2.1 g of titanium oxide is dispersed, obtaining a coating liquid. 2,500 tablets obtained in preparation example 71 are coated by spraying the coating liquid using

NISOATEV-MIMI and receiving coated tablets weighing 155 mg.

The composition of one tablet (155 mg): the tablet obtained in the example of the preparation 1 150 mg hydroxypropyl cellulose 2910 Z,bmg polyethylene glycol 6000 0.7 mg titanium dioxide 0.7 mg

Industrial applicability

The compounds of the present invention exhibit MRU-antagonistic activity and are useful as agents for the treatment of various diseases associated with MRU, for example, cardiovascular disorders such as hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis and the like, central nervous system disorders, such as bulemia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal syndrome and the like, metabolic disorders such as obesity, diabetes, hormonal disorders, hypercholesterolemia, hyperlipidemia and the like, sexual and reproductive dysfunction, gastrointestinal intestinal disorders, respiratory disorders, inflammation or glaucoma and the like.

Claims (40)

1. The compound represented by the general formula (I) where Ag is aryl or heteroaryl, which may be substituted, and the substituent is selected from the group including halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted an oxo group, and a group represented by the formula -O-Agg; DI? - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino , di(lower alkyl)amino, lower alkanoyl and aryl; n is equal to 0 or 1; O - simple bond or carbonyl; T, U, M, and M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, and lower alkoxy, and at least two of the indicated T, y, M, and M/ represent the specified methine group; X is a methine group or nitrogen; U is an imino group that can be substituted by lower alkyl or oxygen; its salt or ester. 2. The compound according to item 1, where aryl in Ag" is phenyl. 3. The compound according to item 1, where heteroaryl in Ag means pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,2, 4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl or pyridoyi3,2-b|pyridyl. 4. The compound according to item 1, in which T, O, M, Its M/ independently is methine, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl and lower alkoxy. 5. The compound according to item 4, in which T, O, M and M/ are independently methine, which can be replaced by halogen. 6. The compound according to item 1, in which T, O, M and MU/ are nitrogen. 7. The compound according to item 1, in which U represents an unsubstituted imino group or oxygen. 8. The compound according to item 1, in which U is oxygen. 9. The compound according to point 1, which is represented by the general formula (I-a): N ох / ши M и Аг! o o (I-a), where Ag! - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halogen (lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by the formula -O-Agg; yes - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino , di(lower alkyl)amino, lower alkanoyl and aryl; O is a simple bond or carbonyl; IN! - hydrogen atom or halogen. 10, Compound according to item 9, where aryl in Ag! means phenyl. 11. The compound according to item 9, where heteroaryl in Ar' means imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or pyridoyl3,2-b|pyridyl. 12. The compound according to point 1, which is represented by the general formula (1-5): N F) / B M Ag! M at 7 p.m M. Uh o (1-5), where Ag! - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halogen (lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by the formula -O-Agg; yes - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino , di(lower alkyl)amino, lower alkanoyl and aryl; O - simple bond or carbonyl; T, U, M, and M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, and lower alkoxy, and at least two T, SHO), M, and M / represent the indicated methine group. 13. The compound of claim 12, wherein aryl in Ag is phenyl. 14. The compound according to item 12, where the heteroaryl in Ag! means pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1,2,4-triazinyl. 15. The compound according to item 12, in which one of T, O, M and MU is nitrogen. 16. The compound according to item 12, in which M is nitrogen, and each of T, 0 and M/ is a methine group. 17. The compound according to item 1, which is M-(4-benzoylphenyl)-3-oxospiro(isoindoline-1,4"-piperidine|-1-carboxamide, Z-oxo-M-(5-phenyl-2-pyrazinyl )spiro(isoindoline-1,4"-piperidine|-1"-carboxamide, M-(7-methyl-2-quinolyl)-Z-oxospiro(isoindoline-1,4"-piperidine|-1"-carboxamide, M -(4-benzoylphenyl)-2-methyl-3-oxospiro(isoindoline-1,4"-piperidine|-1"-carboxamide, M-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro(isoquinoline- 1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isoquinoline-1(2H),4-piperidine|-1 -carboxamide, 3,4-dihydro-M-(7-methyl-2-quinolyl)-3-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, M(4-acetylphenyl)-3, 4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-IM-|1-(2-quinolyl)-4-imidazolyl|spiro (isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro( isoquinoline-1(2H),4-piperidine|-1-carboxamide, 3,4-dihydro-M-(5-(2-methyl-1-propenyl)-2-pyrazinyl|-Z-oxospiro(isoquinoline-1( 2 H),4-piperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide , M-(11-(7-benzo(p|furanyl)-4-imidazolyl|-3,4-dihydro-Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, M-11 -(3-difluoromethoxyphenyl)-4-imidazolyl|-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine-1-carboxamide, 3,4-dihydro-3-oxo-M-( 4-(2-pyridylcarbonyl)phenyl|spiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, M-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro(isoquinoline-1 (2H),4-piperidine|-1"-carboxamide, M-(P1-(3-chlorophenyl)-4-imidazolyl|-3,4-dihydro-3-oxospiro(isoquinoline-1(2H),4-piperidine |-1"-carboxamide, 3,4-dihydro-3-oxo-M-(5-phenyl-2-thiazolyl)spiro(isoquinoline-1(2H),4"-piperidine|-1"-carboxamide, 3, 4-dihydro-3-oxo-M-|5-(2-pyridyl)-2-pyrazinyl|spiro(isoquinoline-1(2H),4"-piperidine|-1"-carboxamide, 3,4-dihydro-M -(4-methyl-2-benzothiazolyl)-Z-oxospiro(isoquinoline-1(2H),4-piperidine|-1-carboxamide, M-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3 -oxospiro(isoquinoline-1(2 H),4-piperidine|-1"-carboxamide, M-(4-benzoylphenyl)-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, Z-oxo-M-(5- phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, M-(7-methyl-2-quinolyl)-Z-oxospiro(isobenzofuran-1(3H),4-piperidine |-1-carboxamide, 3-oxo-M-(4-phenyl-5-isoxazolyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 3-oxo-M-(7-trifluoromethylpyridoi3, 2-b|pyridin-2-yl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH ),4-piperidine|-1-carboxamide, Z-oxo-M-(1-(3-quinolyl)-4-imidazolyl|spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, Z- oxo-M-(5-phenyl-Z-pyrazolyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, M-I5-(4-chlorophenyl)-Z-pyrazolyl|-3-oxospiro( isobenzofuran-1 (ZH),42-piperidine|-1-carboxamide, 3-oxo-M-(5-(3-quinolyl)-3-pyrazolyl|spiro(isobenzofuran-1(3H),4-piperidine|-1 -carboxamide, M-I5-(3-fluorophenyl)-2-pyrimidinyl|-Z-oxospiro(isobenzofuran-1(3H),4-piperidine|-1-carbo xamide, 3-oxo-M-(5-(3-trifluoromethylphenyl)-2-pyrimidinyl|spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, М-I5-(3-chlorophenyl)-2 -pyrimidinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, M-(7-fluoromethoxypyridoi3,2-b|pyridin-2-yl)-3-oxospiro(isobenzofuran-1( ZH),4-piperidine|-1"-carboxamide, Z-oxo-M-(5-phenyl-1,2,4-thiadiazol-Z-yl)spiro(isobenzofuran-1(ZH),4-piperidine|- 1-carboxamide, M-(1-I3-(2-hydroxyethylphenyl|-4-imidazolyl)-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, M-(4-(1- ethyl-2-imidazoliluphenyl|-Z-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, M-(11-(Z-methoxyphenyl)-4-imidazolyl|-Z-oxospiro(isobenzofuran-1 (3H),4-piperidine|-1-carboxamide, b-fluoro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, b-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 5-fluoro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 5-fluoro-3-oxo-M-(5- phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1"-carboxamide, M-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro|(1H-2-benzopyran -1,4"-tperidine|-1-carboxamide, 3,4-dihydro-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro| 1H-2-benzopyran-1,4"-piperidine| -1-carboxamide, M-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro|(1H-2-benzopyran-1,4"-piperidine|-1"-carboxamide, trans- M-(4-benzoylphenyl)-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(5-phenyl-2-pyrazinyl) spiro|cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(1-phenyl-4-imidazolyl)spiro(cyclohexane-1,1'(3' N)-isobenzofuran|-4-carboxamide, trans-3'-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans -M-(1-(3,5-difluorophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-3'-oxo- M-(5-phenyl-3-pyrazolyl)c pyroIcyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-M-(1-(2-fluorophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1'(3 'H)-isobenzofuran|-4-carboxamide, trans-M-(4-acetyl-3-trifluoromethylphenyl)-3'-oxospiro|cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans -3'-oxo-M-(1-(3-quinolyl)-4-imidazolyl|spiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-M-(1-( 3-cyanophenyl)-4-imidazolyl|-3'-oxospiro(cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide, trans-Mm-(4-benzoylphenyl)-3-oxospiro|(4 -azaisobenzofuran-1(ZN),1"-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(4-azaisobenzofuran-1(ZN),1"-cyclohexane |-4-carboxamide, trans-3-oxo-M-(3-phenyl-5-isoxazolyl)spiro(4-azaiisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-3-oxo- M-(5-phenyl-2-pyrimidinyl)spiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-Mm-(4-benzoylphenyl)-3-oxospiro|5-azaiisobenzofuran- 1(ZH),1"-cyclohexane|-4-carboxamide, trans-Mm-(4-benzoylphenyl)-Z-oxospiro| b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, M-I5-(4-hydroxyphenyl)-2-pyrazinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|- 1-carboxamide, M-I5-(3-hydroxyphenyl)-2-pyrazinyl|-3-oxospiro(isobenzofuran-1(ZH),4-piperidine|-1-carboxamide, 4-fluoro-3-oxo-M-( 5-phenyl-2-pyrimidinyl)spiro(isobenzofuran-1(Z3H),4-piperidine|-1"-carboxamide, 7-fluoro-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(isobenzofuran- 1(ZH),4-piperidine|-1-carboxamide, b-ethyl-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide , b-hydroxy-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide, trans-3-oxo-M-(5-phenyl -2-trimidinyl)spiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-Mm-(5-(3-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5- azaisobenzofuran-1(Z3H),1-cyclohexane|-4-carboxamide, trans-Mm-(5-(2-fluorophenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1-cyclohexane |-4-carboxamide, trans-3-oxo-M-(4-phenyl-2-oxazolyl)spiro(5-azaisobenzofur an-1(ZH),1"-cyclohexane|-4-carboxamide, trans-M-(5-(2-methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1' -cyclohexane|-4-carboxamide, trans-M-(5-(3-methylphenyl)-2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(3H),1'-cyclohexane|-4-carboxamide, trans -Mm-(5-(3-fluoromethoxyphenyl)-2-pyrimidinyl|-Z-oxospiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide, trans-Mm-(5-(3 -fluoromethylphenyl)-2-pyrimidinyl|-3-oxospiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide, trans-Mm-(5-(3-fluoro-5-methoxyphenyl)- 2-pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(Z3H),1-cyclohexane|-2-carboxamide, trans-M-(5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl|-Z -oxospiro(5-azaisobenzofuran-1(ZN),1-cyclohexane|-4"-carboxamide, trans-Mm-I4-(3-fluoromethoxyphenyl)-2-oxazolyl|-3-oxospiro|5-azaisobenzofuran-1(ZN ),1"-cyclohexane|-2-carboxamide, trans-M-(5-(3-hydroxymethylphenyl)-2-pyrimidinyl|-3-oxospiro(5-azaisobenzofuran-1(ZH),1"-cyclohexane|-4 "- carboxamide, trans-M-(5-(3-hydroxyphenyl)-2-pyr midinyl|-3-oxospiro(5-azaisobenzofuran-1(Z3H),1-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(b-azaisobenzofuran-1( ЗН),1"-cyclohexane|-4-carboxamide, trans-Mm-(5-(3-fluoromethylphenyl)-2-pyrimidinyl|-3-oxospiro|b-azaisobenzofuran-1(ЗН),1"-cyclohexane|- 4"-carboxamide, trans-Mm-(5-(3-fluoromethoxyphenyl)-2-pyrimidinyl|-Z-oxospiro|b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"- carboxamide, trans-3 -oxo-M-(6-phenyl-1,2,4-triazin-3-yl)spiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(5-- 2-difluoromethoxyphenyl)-3-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide, trans-Mm-(5-(3-difluoromethoxyphenyl)-3-pyrazolyl|- 3-oxospiro|b-azaisobenzofuran-1(ZH),1-cyclohexane|-2-carboxamide, trans-M-(5-(3-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1( 3H),1'-cyclohexane|-4-carboxamide, trans-M-(5-(4-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b-azaisobenzofuran-1(3H),1'-cyclohexane|- 4-carboxamide, trans-Nm-(4-benzoylphenyl)-33-oxospi ro/7-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-M-(1-(3,5-difluorophenyl)-4-imidazolyl|-Z-oxospiro/7-azaisobenzofuran-1 (ZH),1"-cyclohexane|-4-carboxamide, trans-3-oxo-M-(2-phenyl-4-pyridyl)spiro/7-azaisobenzofuran-1(ZH),1"-cyclohexane|-4- carboxamide, trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro/(7-azaisobenzofuran-1(ZH),1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-( 1-phenyl-Z-pyrrolyl)spiro|7-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(1-(4-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro( 7-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-(1-phenyl-3-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1-cyclohexane |-4-carboxamide, trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(1- (3-fluorophenyl)-4-pyrazolyl|-3-oxospiro(4-azaisobenzofuran-1(3H),1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-(1-phenyl-3-pyrazolyl )spiro(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide, trans-M-(1-(4-fluorophenyl)-3Z-pyrazo lyl|-3-oxospiro|b-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-M-(1-(2-fluorophenyl)-3Z-pyrazolyl|-3-oxospiro|b- azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro|b-azaisobenzofuran-1( ЗН),1-cyclohexane|-4-carboxamide, trans-3-oxo-M-(5-phenyl-3-isoxazolyl)spiro(b-azaisobenzofuran-1(ЗН),1"-cyclohexane|-4-carboxamide, trans-3-oxo-M-(6-phenyl-3-pyridyl)spiro(b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4-carboxamide, trans-3-oxo-M-(2-phenyl-3-thiazolyl)spiro|(b-azaisobenzofuran-1(Z3H),1'-cyclohexane|-4-carboxamide, or trans-3-oxo-M-(2 -phenyl-1,2,3-triazol-4-yl)spiro(b-azaisobenzofuran-1(ZH),1"-cyclohexane|-2"-carboxamide. 18. The compound according to item 1, which is 3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(ZH),4-piperidine-1-carboxamide. 19. The compound according to item 1, which is //3-oxo-M-(7-trifluoromethylpyridoyl3,2-b|pyridin-2-yl)spiro(isobenzofuran-1(3H),4-piperidine|-1-carboxamide . 20. The compound according to item 1, which is M-I5-(Z-fluorophenyl)-2-pyrimidinyl|-Z-oxospiro(isobenzofuran-1(Z3H),4-piperidine-1-carboxamide. 21. The compound according to item 1, which is trans-3'-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(cyclohexane-1,1'(3'H)-isobenzofuran-4-carboxamide. 22. The compound according to item 1, which is trans-3'-oxo-M-|1-(3-quinolyl)-4-imidazolyl|spiro-cyclohexane-1,1'(3'H)-isobenzofuran|-4-carboxamide . 23. The compound according to item 1, which is trans-3-oxo-M-(5-phenyl-2-pyrazinyl)spiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide. 24. The compound according to item 1, which is trans-M-(5-(3-fluorophenyl)-2pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 25. The compound according to item 1, which is trans-M-(5-(2-fluorophenyl)-2pyrimidinyl|-3-oxospiro|5-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 26. The compound according to item 1, which is trans-M-(P1-(3,5-difluorophenyl)-4-imidazolyl|-3-oxospiro7-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 27. The compound according to item 1, which is trans-3-oxo-M-(1-phenyl-4pyrazolyl)spiro(4-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide. 28. The compound according to item 1, which is trans-3-oxo-M-(1-phenyl-Zpyrazolyl)spiro|b-azaisobenzofuran-1(ZH),1"-cyclohexane|-4"-carboxamide. 29. The compound according to item 1, which is trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro(b-azaiisobenzofuran-1(ZH),1-cyclohexane| -4-carboxamide. 30. The method of obtaining a compound of the general formula (I-1): y o M y ZAG M AT o U mu s o de Ag - aryl or heteroaryl, which can be substituted, and the substituent is selected from the group including halogen, nitro group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkyl, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted an oxo group, and a group represented by the formula -O-Ag; DI? - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino , di(lower alkyl)amino, lower alkanoyl and aryl; O - simple bond or carbonyl; T, Y, M, and M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, and lower alkoxy, and at least two of them represent the specified methine group; n and Z have the meanings described below; of its salt or complex ester, which includes the interaction of a compound of the general formula (1): P AgO p M--Age H (1), where Ag is aryl or heteroaryl, which can be substituted, and the substituent is selected from the group including halogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halogeno)alkoxy, lower alkylthio), lower alkanoyl, lower alkoxycarbonyl, a group represented by the formula -Or-Al7? and optionally protected lower alkylene, optionally substituted with oxo, hydroxy(lower)alkyl or carboxyl; Ag" is aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkyloxy, di(lower alkyl)amino, lower alkanoyl, aryl and optionally protected hydroxy(lower)alkyl, hydroxyl or lower alkylamino; Az - phenyl, which can be replaced by a halogen or a nitro group; Or is a simple bond or an optionally protected carbonyl; with a compound of the general formula (IP): N. M. Ik M. (1, where n is 0 or 1; and, m, m, and m independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and neoob necessarily substituted hydroxyl, and at least two of them (Yi, y, m and m) represent the specified methine group; MU is an imino group that can be substituted by a lower alkyl or an oxygen atom; with the preparation of a compound of the general formula (IM-1) : N om M ! SHCHI g M. zu sno (IM-1), where Ag'R, p, Her, M, mm, m and M have the same meanings as indicated above; with optional subsequent removal of the protecting group. 31. The method of obtaining a compound of the general formula (I-2): N o M - Ag Te u Di M u snu mi (sn Zo (I-2), where Ag is aryl or heteroaryl, which can be substituted, and the substituent is selected from groups including halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group represented by the formula -O-Ag; diaryl or heteroaryl which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halogen (lower )alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halogen(lower) alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkanoyl and aryl; O is a simple bond or carbonyl; T, 3, M M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydro xyl and a lower alkoxy group, and at least two of them (T, U, M and MU) represent the specified methine group; n and M have the same values as defined below; its salt or ester, which includes the interaction of the compound (M): Agv-MH" (M), where Ag is aryl or heteroaryl, which can be substituted, and the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halogen (lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkyl, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, a group of the formula -Or-Al7e? and optionally protected lower alkylene, optionally substituted with oxo, hydroxy(lower)alkyl or carboxyl; Ag" is aryl or heteroaryl, which may be substituted, wherein the substituent is selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, di(lower alkyl)amino, lower alkanoyl, aryl and optionally protected hydroxy(lower) alkyl, hydroxyl or lower alkylamino group; Or - a simple bond or optionally protected carbonyl; with a carboxylic acid of the general formula (MI): and and | In n (MI), where n is equal to 0 or 1; and, m, m, and m independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, lower alkoxy, and optionally protected hydroxyl, with at least two of them ( Her, ts, m and mu) represent the indicated methine group; U is an imino group that can be substituted by lower alkyl or an oxygen atom; or its reactive derivative, to obtain a compound of the general formula (IM-2): ом сх, дув и и. | in Usuu sn i g/l OO (IM-g), where Ag, p, Y, M, M, M and M have the same values as described above; with optional subsequent removal of the protecting group. 32. Antagonist of the receptor of neuropeptide B, which contains as an active ingredient a compound of the general formula (1): And | And where is Ah! - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halogen (lower) alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an sxo group, and a group represented by the formula -O-Agg; DI? - aryl or heteroaryl, which may be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxyl, lower alkoxy, halo(lower)alkyl, lower alkylamino , di(lower alkyl)amino, lower alkanoyl and aryl; n is equal to 0 or 1; O - simple bond or carbonyl; T, Y, M, and M/ independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl, and lower alkoxy, and at least two of them (T, Y, M and MU) represent the indicated methine group; X - methine or nitrogen; U is an imino group that can be substituted by lower alkyl or oxygen; its salt or ester. 33. An agent for the treatment of bulemia, obesity or diabetes, which contains as an active ingredient a compound of the general formula (1): y o M y ZA h AH Y re M u sn "mi (sn zo o de Ag! - aryl or heteroaryl, which can be substituted, and the substituent is selected from the group including halogen, nitro group, lower alkyl, halogen (lower) alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene, optionally substituted with an oxo group, and a group represented by with the formula -O-Agg; di? - aryl or heteroaryl, which can be substituted, and the substituent is selected from the group consisting of halogen, cyano group, lower alkyl, halo(lower) alkyl, hydroxy(lower) alkyl, hydroxyl, lower alkoxy, halo(lower) alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkanoyl and aryl; n is 0 or 1; O is a single bond or carbonyl; T, 3, M and M/ independently represent a nitrogen atom or methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, hydroxyl and lower alkoxy group, pr why at least two of them (T, U, M and MU) represent the specified methine group; X - methine or nitrogen; U is an imino group that can be substituted by lower alkyl or oxygen; its salt or ester. 34. Compounds of the general formula (MI-1): СоооНн ! ТЯ o) M i, (MI-1), where i, i, m and m independently represent a nitrogen atom or a methine group, which may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy and neobo necessarily protected hydroxyl, and at least two of them (Her, i, m and m) represent the specified methine group. 35. The compound according to claim 1, which is trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(4-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 36. The compound according to claim 1, which is trans-M-|5-(2-methylphenyl)-2-pyrimidinyl|-3-oxospiro|(5-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide . 37. The compound according to claim 1, which is trans-3-oxo-M-(5-phenyl-2-pyrimidinyl)spiro(b-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 38. The compound according to claim 17, which is trans-3-oxo-M-(1-phenyl-4-pyrazolyl)spiro/7-azaisobenzofuran-1(3H),1-cyclohexane|-4-carboxamide. 39. The compound according to item 1-7, which is trans-M-|1-(3-fluorophenyl)-4-pyrazolyl|-Z-oxospiro(4-azaiisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide . 40. The compound according to item 1-7, which is trans-M-P1-(2-fluorophenyl)-Z-pyrazolyl|-3Z-oxospiro|(b-azaisobenzofuran-1(ZH),1-cyclohexane|-4-carboxamide .