Novel piperidine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

 

The technical field to which the invention relates.

The present invention relates to new derivatives of piperidine.

The level of technology

It is known that in living organisms, such as organisms typical mammals, histamine, which is a physiologically active endogenous factor that functions as a neurotransmitter and has a broad spectrum of pharmacological activities (see, for example, Life Science, Vol.17, p.503 (1975)).

Immunohistochemical studies have shown that histamine-agonistic (producing) cell body exists in papillary anchor the nucleus in the posterior hypothalamic area, and that histamine nerve fibers are projected in an extremely wide area of the brain, causing a variety of pharmacological effects of histamine (for example, see Journal of Comparative Neurology, Vol.273, p.283). The presence of histamine-agonistic nerves in papillary anchor the nucleus of the posterior hypothalamic region suggests that histamine may play an important role in the control of physiological functions associated with the activity of the brain, especially the hypothalamus function (sleep, wakefulness rhythm, increcia, intake of food and fluids, sexual activity, and the like) (see, for example, Progress in Neurobiology, Vol.63, p.637 (2001)).

The presence of the projection in the region of the brain that is associated with the maintenance of the rhythm of wakefulness, n is the sample in the cerebral cortex, talks about role in the regulation of wakefulness or cycle "Wake-sleep". The presence of the projection in many peripheral structures such as the hippocampus and the amygdala complex, speaks about the role in the control of autonomic nerves, emotional state, the control motivated activities and learning/memory.

Histamine with the release of producing its cells interacts with the specific polymer, called receptors, on the surface of the cell membrane or inside the target cells, providing, thus, a pharmacological effect on the regulation of various body functions. Previously identified four types of histamine receptors. In particular, in various pharmacological and physiological studies have shown the presence of a histamine receptor, which is involved in the function of the Central and peripheral nervous systems (see, for example, Trends in Pharmacological Science, Vol.8, p.24 (1987)). Previously identified genes histamine H3 receptor of human and rat and proved their existence (see, for example, Molecular Pharmacology, Vol.55, 1101 (1999)).

Histamine H3 receptor is a presynaptic membrane of the Central or peripheral neurocytol and functions as autoreceptor (chemoreceptor), therefore, controls the release of histamine and other neurotransm is therow. In particular, it was reported that agonist histamine H3 receptor or its antagonist or inverse agonist regulates the release of histamine, norepinephrine, serotonin, acetylcholine or dopamine from the nerve endings. For example, the release of these neurotransmitters is inhibited agonist, such as (R)-(α)-methylhistamine, and promoterwise antagonist or inverse agonist, such as topermit (see, for example, Trends in Pharmacological Science, Vol.19, p.177 (1998)).

Known compounds having an antagonistic effect against histamine H3 receptor, is described, for example, in WO 2004/089373 and WO 2004/35556. In particular, the compounds described in WO 2004/089373 contain in the structure piperidino the core, but differ from the compounds according to the present invention the position of the nitrogen atom in the structure piperidino kernel.

Patent reference 1: WO 2004/089373.

Description of the invention

The aim of the present invention is the provision of new substances with antagonistic effect against histamine H3 receptor (effect of inhibiting the binding of histamine to the histamine H3 receptor) or inverse agonistic effect (the effect of inhibiting the homeostatic activity, which has a histamine H3 receptor), or the provision of new substances that act as antagonist or inverse AG is nista histamine H3 receptor in living organisms.

To achieve the above objective, the authors present invention provides the following compounds or their pharmaceutically acceptable salts.

(1) the compounds of formula (I) or their pharmaceutically acceptable salts:

[where R1represents an aryl group, optionally containing from 1 to 3 substituents selected from the group of substituents α; 5 - or 6-membered heteroaryl group, containing 1 to 3 heteroatoms selected by their groups containing nitrogen atom, sulfur atom and oxygen atom, and optionally containing from 1 to 3 substituents selected from the group of substituents α; heteroallyl group, optionally containing from 1 to 3 substituents selected from the group of substituents α; aracelio group, optionally containing from 1 to 3 substituents selected from the group of substituents α; or arylcarboxylic group, optionally containing from 1 to 3 substituents selected from the group of substituents α; where the heteroaryl group may form a condensed ring with a phenyl group or peredelnoj group;

R2represents an aryl group; a heteroaryl group containing from 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom; a cyano; a lower alkyl group; a lower alkoxygroup; or Hydra is xygraph; or

R1and R2taken together, may form a 5 - or 6-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom, where the aliphatic heterocyclic group may form a condensed ring with a phenyl group or peredelnoj group, aliphatic heterocyclic group may contain 1 or 2 identical or different substituent selected from the group of substituents β, phenyl group or Peregrina group may be condensed with an aliphatic heterocyclic group with the formation of a condensed ring which may contain 1 or 2 identical or different substituent selected from the group of substituents γ;

R3represents a

a) a group of the formula (II-1):

(where R4and R5may be the same or different, and each represents a lower alkyl group optionally substituted by a halogen atom, or cycloalkyl group, optionally substituted by halogen atom; or R4and R5taken together with the nitrogen atom, form a 5-8-membered monocyclic ring or 6 to 8-membered bicyclic ring, where the monocyclic ring may contain as a substituent a lower alkyl group, not battelino substituted by halogen atom, halogen atom or oxoprop; m1 is an integer from 2 to 4; the hydrogen atom in -(CH2)m1 may be substituted by a lower alkyl group containing 1-3 carbon atoms),

b) a group of the formula (II-2):

(where R6represents a lower alkyl group or cycloalkyl group; m2 is an integer from 0 to 4), or

(C) a group of the formula (II-3):

(where R7and R8may be the same or different, and each represents a lower alkyl group optionally substituted by a halogen atom, or cycloalkyl group, optionally substituted by halogen atom; or R7and R8taken together with the nitrogen atom, form a 5-8-membered monocyclic ring or 6 to 8-membered bicyclic ring, where the monocyclic ring may contain as a substituent a lower alkyl group optionally substituted by a halogen atom, a halogen atom or oxoprop; m3 is an integer from 0 to 4),

X1-X4all are carbon atoms or 1 or 2 of X1-X4represent nitrogen atoms, and the remainder are carbon atoms; and when X1-X4represent carbon atoms, each of X1-X4may be substituted by a lower alkyl group optionally substituted by a halo atom is s or lower alkoxygroup, cycloalkyl group optionally substituted by a halogen atom or a lower alkoxygroup, lower alkoxygroup, optionally substituted by a halogen atom or a lower alkoxygroup, cyano or a halogen atom].

The group of substituents α: a lower alkyl group, optionally substituted by halogen atom, lower alkoxygroup, optionally substituted by a halogen atom, and halogen atom.

The group of substituents β: a halogen atom; oxoprop; a lower alkyl group optionally substituted by a halogen atom or a lower alkoxygroup; lower alkoxygroup, optionally substituted by a halogen atom or a lower alkoxygroup; 5-6-membered nitrogen-containing aliphatic heterocycle, optionally substituted by oxopropoxy or a lower alkyl group, and optionally contains in the ring 1 or 2 double bonds; kalkilya group; heteroallyl group; lower alkylsulfonyl group; cycloalkylcarbonyl group; aryl group; and a heteroaryl group (kalkilya group, heteroallyl group, lower alkylsulfonyl group, cycloalkylcarbonyl group, aryl group and heteroaryl group which may be substituted lower alkyl group, optionally substituted lower alkoxygroup or a halogen atom, cycloalkyl group optionally substituted by the Oh lowest alkoxygroup or halogen atom, lowest alkoxygroup, optionally substituted by halogen atom (when the group contains two such low alkoxygroup, taken together, they may form a 5 or 6-membered ring), a halogen atom, cyano, hydroxy-group, alkylsulfonyl group, cycloalkylcarbonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanolamines, alkylamines or dialkylamines).

The group of substituents γ: a lower alkyl group, optionally substituted lower alkoxygroup or a halogen atom, a lower alkoxygroup, optionally substituted by a halogen atom, and halogen atom.

Compounds (1) or their salts, described above, act as an antagonist or inverse agonist histamine H3 receptor in living organisms. Accordingly, the invention provides an antagonist or inverse agonist of the histamine H3 receptor containing compound (1)described above, or their pharmaceutically acceptable salts.

Studies conducted previously showed that histamine H3 receptor has extremely high homeostatic activities (activities observed in the absence of endogenous agonistic factor (e.g., histamine)receptor-expressing cells/tissues or in the membrane fraction obtained from expre shirouma cells/tissues and even in living organisms (see, for example, Nature, Vol.408, p.860). It was reported that these homeostatic activity inhibited inverse agonist. For example, cooperated or ciproxifan inhibits homeostatic chemoreceptor activity of the histamine H3 receptor and promotes the release of neurotransmitters (e.g., histamine) from the nerve endings.

A study on rats showed that a high content of a selective inhibitor histaminase (histidinazalactivity) inhibits wakefulness in rats, therefore, histamine is involved in the regulation of motor activity. A study in cats showed that the introduction of cats (R)-(α)-methylhistamine, which is an agonist of the histamine H3 receptor, enhances their deep medlennovolnovoj sleep (see, for example, Brain Research, Vol.523, p.325 (1990)).

Conversely, typename, which is an antagonist or inverse agonist of the histamine H3 receptor, dependent on dose, increase wakefulness and weakens medlennovolnovoj and a quick NAP (see, for example, Life Science, Vol.48, p.2397 (1991)). Typename representing antagonist or inverse agonist of the histamine H3 receptor, or GT-2331, reduces emotional cataplexy and sleep narcoleptic dogs (see, for example, Brain Research, Vol.793, p.279 (1998)).

All these data suggest that H3 Retz who ptor may be involved in the control cycle of waking, sleep and disease, related sleep disorder, which, in turn, suggests the possibility of using selective agonist, antagonist or inverse agonist histamine H3 receptor for the treatment of sleep disorders or diseases associated with sleep disorder (e.g., idiopathic-hypersomnia, repeating hypersomnia, the true hypersomnia, narcolepsy, a disorder associated with periodic hypermodernity in sleep syndrome sleep apnea, disorders of circadian rhythm, chronic fatigue syndrome, disorders of REM sleep, senile insomnia and idiopathic insomnia, repetitive insomnia and true insomnia caused by failure to comply with the requirements of sanitary norms in sleep mode working at night, depression, anxiety, schizophrenia). Accordingly, it can be considered that the above-described compound (1) or their salts, acting as an antagonist or inverse agonist histamine H3 receptor, can be effective for prophylaxis and treatment of sleep disorders and various diseases associated with sleep disturbance.

In rats antagonist or inverse agonist of the histamine H3 receptor, typename or GT-2331, reduces the learning disorder (LD) and disorder attention deficit/hyperactivity disorder (ADHD) (see, for example, Life Science, Vol.69, p.469 (2001)). In addition, in rats agonist guy who terminologi H3 receptor, (R)-(α)-methylhistamine, reduces the results of recognition of the objects and trainability in the test of recognition of the objects and passive shutdown.

On the other hand, in the experience of scopolamine-induced amnesia of topermit representing antagonist or inverse agonist of the histamine H3 receptor, dependent on the dose reduces the amnesia caused by exposure to chemicals (see, e.g., Pharmacology, Biochemistry and Behavior, Vol.68, p.735 (2001)).

These data confirm the possibility of applying antagonist or inverse agonist histamine H3 receptor for the prevention or treatment of memory disorders/learning and various diseases accompanied this disorder (for example, Alzheimer's disease, Parkinson's disease, attention deficit disorder/hyperactivity disorder). Accordingly, it can be considered that the above-described compound (1) or their salts can be effective for prevention or treatment of this disorder, memory/learning, and various diseases accompanied this disorder.

Experiments on rats have shown that the introduction of histamine in the stomach of rats inhibits their feeding behavior, confirming thus that histamine may be involved in the regulation of eating behavior (see, for example, Journal of discrimination and Pharmacology, Vol.49, p.191 (1998)). Actually, typename is the clinical antagonist or inverse agonist of the histamine H3 receptor, dependent on the dose way inhibits feeding behavior and promotes intracerebral release of histamine (see, for example, Behavioral Brain Research, Vol.104, p.147 (1999)).

These data suggest that histamine H3 receptor may participate in the control of eating behavior, and the antagonist or inverse agonist of the histamine H3 receptor may be useful for prevention or treatment of diseases associated with metabolic disorders (metabolic syndrome), such as a disorder associated with food intake, obesity, diabetes, cachexia, hyperlipemia. Accordingly, it can be considered that the above-described compound (1) or their salts can also be effective for prevention or treatment of such diseases associated with metabolic disorders.

In rats agonist histamine H3 receptor (R)-(α)-methylhistamine, dependent on dose, reducing their basal diastolic pressure, and this effect counteracts typename, which is an antagonist or inverse agonist of the histamine H3 receptor (see, for example, European Journal of Pharmacology, Vol.234, p.129, (1993)).

These data suggest that histamine H3 receptor may participate in the regulation of blood pressure, heart pulse and cardiac pulse, additionally confirming that the antagonist or inverse agonist of the histamine H3 p is Ceptor may be useful for prevention or treatment of diseases of the cardiovascular system, such as hypertension, and various heart disorders. Accordingly, it can be considered that the above-described compound (1) or their salts can be also effective for the prevention or treatment of such diseases of the cardiovascular system.

In experiments on mice, it was shown that cooperated, which is an antagonist or inverse agonist of the histamine H3 receptor-dependent dose way inhibit spasm caused by electric shock, or epileptic seizures caused by pentylenetetrazole (PTZ) (see, for example, European Journal of Pharmacology, Vol.234, p.129 (1993) and Pharmacology, Biochemistry and Behavior, Vol.68, p.735 (2001)).

These data confirm that the antagonist or inverse agonist of the histamine H3 receptor may be useful for prevention or treatment of epilepsy or seizures of Central origin. Accordingly, it can be considered that the above-described compound (1) or their salts can be also effective for the prevention or treatment of epilepsy or seizures of Central origin.

Accordingly, the invention also provides a preventive or remedy for the prevention or treatment of diseases associated with metabolic disorders, diseases of the cardiovascular system or diseases of the nervous system, where the specified medication contains as the active ingredient described above is connected to the I (1) or their pharmaceutically acceptable salts.

The diseases associated with metabolic disorders, include at least one disease selected from obesity, diabetes, disorders of hormone secretion, hyperlipemia, gout, or fatty liver disease.

To diseases of the cardiovascular system is at least one disease selected from stenocardia, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy and electrolyte disorders.

To diseases of the nervous system is at least one disease selected from sleep disorders, diseases accompanied by sleep disorder, bulimia, emotional disorder, epilepsy, disorders of consciousness, dementia, attention deficit disorder/hyperactivity disorder, memory disorders, Alzheimer's disease, Parkinson's disease, disorders of cognitive abilities, disorders of motor function, paresthesias, dysosmia, immunity to morphine, drug addiction, alcoholism and tremor.

To diseases of the nervous system also includes at least one disease selected from the idiopathic hypersomnia, repeating hypersomnia, the true hypersomnia, narcolepsy, a disorder associated with periodic hypermodernity in sleep syndrome sleep apnea, Rastro the STV circadian rhythm, chronic fatigue syndrome, disorders of REM sleep, senile insomnia and idiopathic insomnia, repetitive insomnia and true insomnia caused by failure to comply with the requirements of sanitary norms sleep at night, depression, anxiety, schizophrenia.

The above-described compound (1) or their pharmaceutically acceptable salts can be used in combination with other jointly used drugs. Accordingly, the invention additionally provides a preventive or remedy of diseases associated with metabolic disorders, diseases of the cardiovascular system or diseases of the nervous system, where the specified product contains the above-described compound (1) or their pharmaceutically acceptable salts and jointly-used drug as the active ingredients. The jointly-used drug includes a drug for the treatment of diabetes, a drug for the treatment of hyperlipemia, drug treatment for hypertension or remedy from obesity. According to the invention can be applied to two or more of such jointly used medicines in the form of the combined drugs.

Preventive or the remedy is a great tool for the treatment of diseases, associated with metabolic disorders, which provides the present invention may contain the compounds of groups (i), (ii) and (iii):

(i) any of the above-described compound (1) or its pharmaceutically acceptable salt;

(ii) at least one compound selected from the following groups of compounds (a)-(g);

(a) antagonist or inverse agonist of the histamine H3 receptor, with the exception of the compounds listed in (i);

(b) biguanide;

(C) a PPAR agonist (receptor-activated proliferation peroxisome);

(d) insulin;

(e) somatostatin;

(f) an inhibitor of α-glucosidase;

(g) an activator of insulin secretion;

(iii) a pharmaceutically acceptable carrier.

The invention provides a compound which has the effect of inhibiting the binding of histamine histamine H3 receptor, or having the activity of inhibiting the homeostatic activity, which has the histamine H3 receptor, i.e. a compound capable to function effectively as an antagonist or inverse agonist histamine H3 receptor when introduced into a living organism.

The best way of carrying out the invention

First describes the terminology used in this description, and then described compounds according to the invention.

The term "aryl group" includes aryl group with a hydrocarbon ring, terzidou from 6 to 14 carbon atoms, for example, a phenyl group, naftalina group, biphenylene group, untilnow group and others

The term "lower alkyl group" means a linear or branched alkyl group containing from 1 to 6 carbon atoms, and includes, for example, methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isoamylene group, neopentylene group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropylene group, hexoloy group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyloxy group and others

The term "cycloalkyl group" means cycloalkyl group containing from 3 to 9 carbon atoms, and specifically includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, cycloserine group and others

Those who min "inferior alkoxygroup" means a hydroxy-group, in which a hydrogen atom is substituted by the above lower alkyl group, and concretely includes, for example, a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, sec-butoxypropyl, tert-butoxypropyl, pentyloxy, isopentylamine, hexyloxy, isohexadecane and other

The term "lower alkylsulfonyl group" means sulfonyloxy the group to which is attached the above-described alkyl group, and concretely includes, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, butylsulfonyl group and others

The term "cycloalkylcarbonyl group" means sulfonyloxy the group to which is attached the above cycloalkyl group, and concretely includes, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylcarbonyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclododecatriene group and others

The term "kalkilya group" means the above lower alkyl group, containing the above-described aryl group, and specifically includes, for example, benzyl group, 1-phenylethylene group, 2-phenylethylene group, 1-naphthylmethyl group, 2-naphthylmethyl the group and other

The term "heteroaryl group" means a 5-7 membered monocyclic ring containing 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, or a bicyclic ring formed monocyclic ring condensed with the benzene ring or pyridine ring, and specifically includes, for example, follow group, thienyl group, pyrrolidino group, imidazolidinyl group, triazolyl group, thiazolidine group, thiadiazolyl group, isothiazolinone group, oxazolidinyl group, isoxazolyl group, pyridyloxy group, pyrimidinyl group, pyridazinyl group, pyrazolidine group, personilnya group, pinolillo group, izohinolinove group, chinadaily group, chinaliaoning group, khinoksalinona group, indolinyl group, benzimidazolyl group, imidazopyridine group, benzofuranyl group, naphthyridinone group, 1,2-benzisoxazole group, benzoxazolyl group, benzothiazolyl group, oxazolopyridine group, peridocially group, isocyanatopropyl group, benzothiazoline group and others

The term "halogen atom" means, for example, fluorine atom, chlorine atom, bromine atom or iodine atom.

The following describes the meaning of the symbols used in the formula (I) of the present invention:

[where the symbols have the meanings as described above]

R1represents an aryl group, optionally containing from 1 to 3 substituents selected from the group of substituents α; 5 or 6-membered heteroaryl group, containing 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, and optionally containing from 1 to 3 substituents selected from the group of substituents α; heteroallyl group, optionally containing from 1 to 3 substituents selected from the group of substituents α; aracelio group, optionally containing from 1 to 3 substituents selected from the group of substituents α; or arylcarbamoyl group, optionally containing from 1 to 3 substituents selected from the group of substituents α; where the heteroaryl group may form a condensed ring with a phenyl group or peredelnoj group.

The term "aryl group"related to R1can take the values defined above for aryl groups, and includes phenyl group, biphenylene group, naftalina group and other, preferably the phenyl group.

When the group defined as "5 - or 6-membered heteroaryl group, containing 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, and optionally containing from 1 to 3 substituents selected from the group of the s substituents α", is in R1and contains 2 or 3 heteroatoms in the ring, the heteroatoms may be the same or different. The term "5 - or 6-membered heteroaryl group" specifically includes, for example, follow group, thienyl group, pyrrolidino group, imidazolidinyl group, triazolyl group, thiazolidine group, thiadiazolyl group, isothiazolinone group, oxazolidinyl group, isoxazolyl group, pyridyloxy group, pyrimidinyl group, pyridazinyl group, pyrazolidine group, personilnya group and other Heteroaryl group may form a condensed ring with a phenyl group or peredelnoj group.

The term "heteroaryl group, optionally forming a condensed ring with a phenyl group or peredelnoj group"specifically includes benzoxazolyl group, benzimidazolyl group, indolenine group and others

The term "kalkilya group"related to R1includes the values defined above for Uralkaliy group, in particular, for example, benzyl group, phenylethylene group and others

The term "arylcarbamoyl group"related to R1that means a carbonyl group to which is attached a certain above "aryl group", and specifically includes, for example, phenylcarbonylamino group and others

R1may contain 1 to 3 substituents, selected from the group of substituents α.

In the case when R1contains 2 or 3 substituent selected from the group of substituents α, they can be the same or different.

The term "lower alkyl group optionally substituted by a halogen atom", referring to the Deputy, takes the values defined above for "lower alkyl group", or the means defined above lower alkyl group substituted by 1-3 halogen atoms. In particular, it includes, for example, methyl group, ethyl group, through the group, isopropyl group, triptorelin group, deformational group, formeterol group and others

The term "lower alkoxygroup, optionally substituted by halogen atom", referring to the Deputy, includes the values defined above, "low alkoxygroup or means defined above the lower alkoxygroup, substituted by 1-3 identical or different halogen atoms. In particular, it includes, for example, a methoxy group, ethoxypropan, cryptometer and other

The term "halogen atom", referring to the Deputy, includes the meaning of the term "halogen atom"defined above, and includes, for example, fluorine atom, chlorine atom, the bromine atom.

The above definition of R1not necessarily containing from 1 to 3 substituents selected from the group of substituents α", concr the IDT includes, for example, phenyl group, 2-florfenicol group, 3-florfenicol group, 4-florfenicol group, 2-chloraniline group, 3-chloraniline group, 4-chloraniline group, 2,4-differenly group, 3,4-differenly group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-metoksifenilny group, 3-metoksifenilny group, 3-methoxy-2-pyridyloxy group, 3-fluoro-4-pyridyloxy group, 3-fluoro-2-pyridyloxy group, 4-fluoro-3-pyridyloxy group, 4-trifluoromethyl-3-pyridyloxy group, 4-methoxy-3-pyridyloxy group, 4-methyl-3-pyridyloxy group, 6-chloro-2-pyridyloxy group, 5-chloro-2-pyridyloxy group, 4-chloro-2-pyridyloxy group, 4-chloro-3-pyridyloxy group, 5-chloro-3-pyridyloxy group, 2-chloro-4-pyridyloxy group, 3-chloro-4-pyridyloxy group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, benzyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, phenylcarbonylamino group and others

R1preferably represents an aryl group, optionally containing from 1 to 3 substituents selected from the group of substituents α or a 5-or 6-membered heteroaryl group, containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and optionally containing from 1 to 3 substituents selected from the group of substituents α.

R2represents an aryl group; a heteroaryl group containing from 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom; a cyano; a lower alkyl group; a lower alkoxygroup; or hydroxy-group.

The term "aryl group"related to R2includes the values defined above for the term "aryl group", and preferably means a phenyl group.

The term "heteroaryl group containing from 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom"related to R2takes the meaning of the term "heteroaryl group containing from 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom", referring to the above-described R1and specifically includes, for example, follow group, thienyl group, pyrrolidino group, imidazolidinyl group, triazolyl group, thiazolidine group, thiadiazolyl group, isothiazolinone group, oxazolidinyl group, isoxazolyl group, pyridyloxy group, pyrimidinyl group, pyridazinyl group, pyrazolidine group, personilnya group and others

The terms "lower alkyl group" and "lower alkoxygroup"related to R2take the values described above.

R2predpochtitel is but represents an aryl group, heteroaryl group containing from 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom; a cyano; a lower alkyl group or a hydroxy-group and other

R1and R2taken together, may form a 5 - or 6-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom, where this aliphatic heterocyclic group may further form a condensed ring with a phenyl group or peredelnoj group and may contain 1 or 2 identical or different substituent selected from the substituents group β, and phenyl or Peregrina group which may be condensed with an aliphatic heterocyclic group with the formation of the condensed ring may contain 1 or 2 identical or different substituent selected from the group of substituents γ.

The term "5 - or 6-membered aliphatic heterocyclic group"belonging to groups that can form R1and R2taken together, means a 5 - or 6-membered aliphatic heterocyclic group in which 1 to 3 of its constituent atoms are heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom.

When 5 - yl) - Rev. 6-membered heterocyclic group contains in the ring 2 or 3 heteroatoms, they may be the same or different.

In the case when R1and R2taken together form a 5 - or 6-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, sulfur atom and oxygen atom, it may contain 1 or 2 identical or different substituent selected from the group of substituents β described above.

The term "lower alkyl group", referring to the Deputy, takes the values defined above for "lower alkyl group", and specifically includes, for example, methyl group, ethyl group, isopropyl group and others

The term "lower alkoxygroup", referring to the Deputy, takes the values defined above for the lower alkoxygroup, and includes, for example, a methoxy group, ethoxypropan, isopropylacetate and other

These lower alkyl group and lower alkoxygroup can be substituted by a halogen atom or a lower alkoxygroup.

The term "kalkilya group", referring to the Deputy, takes the values defined above for Uralkaliy group, and concretely includes, for example, benzyl group, phenylethylene group, etc.

The term "heteroallyl group", referring to the Deputy, means a lower alkyl group, which is attached with defined above heteroaryl g is the SCP, and specifically includes, for example, pyridylmethyl group and others

The term "lower alkylsulfonyl group", referring to the Deputy, takes the values defined above for the lower alkylsulfonyl group, and concretely includes, for example, methylsulfonyl group, ethylsulfonyl group, isopropylphenyl group and others

The term "cycloalkylcarbonyl group", referring to the Deputy, takes the values defined above for cycloalkylcarbonyl group, and concretely includes, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group and others

The term "aryl group", referring to the Deputy, takes the values defined above for the aryl group, and specifically includes, for example, phenyl group and others

The term "heteroaryl group", referring to the Deputy, takes the values defined above for a heteroaryl group, and concretely includes, for example, pyridyloxy group, pyrimidinyl group, thienyl group, thiazolino group and others

Kalkilya group, heteroallyl group, lower alkylsulfonyl group, cycloalkylcarbonyl group, aryl group and heteroaryl group mentioned as the substituent can be substituted by a lower alkyl group, cycloalkyl g is oppoi (lower alkyl group and cycloalkyl group may be substituted by lower alkoxygroup or halogen atom, and when the group contains two alkoxygroup, they may be taken together to form a 5 - or 6-membered ring), a halogen atom, cyano, hydroxy-group, alkylsulfonyl group, cycloalkylcarbonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanolamines, alkylamines, dialkylamines.

The term "5 - or 6-membered aliphatic heterocyclic group" includes a group of the following formula (III):

[where X5represents an oxygen atom or a single bond; X6represents a carbon atom or an oxygen atom; X7represents a carbon atom or a nitrogen atom; X8represents a carbon atom or a nitrogen atom; when X8represents a carbon atom, then the group may be condensed with a phenyl group or peredelnoj group with the formation of the condensed ring in place between the X8and the carbon atom adjacent to X8].

A group of the formula (III) specifically includes, for example, groups of the formula (III-1):

[where

R9represents a

1) a lower alkyl group optionally substituted by a halogen atom or a lower alkoxygroup,

2) aryl group,

3) Uralkaliy group,

4) Goethe is arylalkyl group,

5) heteroaryl group,

where aryl, kalkilya, heteroallyl and heteroaryl groups can be substituted by halogen atom, lower alkyl group, optionally substituted lower alkoxygroup or 1-3 halogen atoms, lower alkoxygroup, optionally substituted by 1-3 halogen atoms, cyano, hydroxy-group, alkylsulfonyl group, cycloalkylcarbonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanolamines, alkylamines or dialkylamines;

R10represents a lower alkyl group, optionally substituted by 1-3 halogen atoms, or lower alkylsulfonyl group;

X9-X12represent a carbon atom or a nitrogen atom where the carbon atom may be independently substituted lower alkyl group, optionally substituted by a halogen atom or a lower alkoxygroup, cycloalkyl group optionally substituted by a halogen atom or a lower alkoxygroup, or cyano or a halogen atom].

The term "kalkilya group"related to R9takes the values defined above for Uralkaliy group, and concretely includes, for example, benzyl group, phenylethylene group and others

The term "heteroallyl group"related to R9oz ACHAT lower alkyl group, is attached to defined above heteroaryl group, and concretely includes, for example, pyridylmethyl group and others

In the case when R9represents an aryl group, aracelio group or heteroallyl group, these groups may be substituted by halogen atom, lower alkyl group (the lower alkyl group may be substituted by 1-3 halogen atoms) or lower alkoxygroup (lower alkoxygroup may be substituted by 1-3 halogen atoms).

The term "halogen atom", referring to the Deputy, means the above-defined halogen atom and includes, for example, fluorine atom, chlorine atom and bromine atom.

The term "lower alkyl group", referring to the Deputy, means defined above lower alkyl group, and concretely includes, for example, methyl group, ethyl group, isopropyl group and others

The term "lower alkyl group, a substituted lower alkoxygroup", referring to the Deputy specifically includes, for example, methoxymethyl group, ethoxymethyl group, methoxyamino group and others

The term "lower alkyl group substituted by 1-3 halogen atoms", referring to the Deputy specifically includes, for example, triptorelin group, deformational group, triptorelin group and others

The term "lower alkoxygroup", therefore, the Xia to the Deputy, takes the values defined above for the lower alkoxygroup, and specifically includes, for example, a methoxy group, ethoxypropan, isopropylacetate and other

The term "lower alkoxygroup substituted by a halogen atom", referring to R10includes cryptometer, dipterocarp, formatexpr, 2-floridacheap, 2,2-dipterocarp, 2,2,2-triptracker, etc. the Term "lower alkylsulfonyl group" includes methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group and others

X9-X12represent a carbon atom or a nitrogen atom where the carbon atom may be independently substituted lower alkyl group, optionally substituted lower alkoxygroup or a halogen atom, a lower alkoxygroup, optionally substituted by halogen atom, or a cyano or a halogen atom.

The term "lower alkyl group", referring to the Deputy of the carbon atom in X9-X12takes the values defined above for the lower alkyl group, and concretely includes, for example, methyl group, ethyl group, isopropyl group, and other Lower alkyl group may be substituted by lower alkoxygroup or a halogen atom.

The term "lower alkyl group, a substituted lower alkoxygroup", referring to the Deputy, concr the IDT includes, for example, methoxymethyl group, ethoxymethyl group, methoxyamino group and others

The term "lower alkyl group substituted by a halogen atom", referring to the Deputy specifically includes, for example, formeterol group, deformational group, triptorelin group and others

As described above, formula (V):

in the formula (I), where R1and R2taken together form a 5 - or 6-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom (aliphatic heterocyclic group may contain 1 or 2 identical or different substituent selected from the group of substituents β described above), specifically includes the following connections:

3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(pyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(pyridin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(pyridin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(pyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-(4-forfinal)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-herperidin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-triptorelin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-forfinal)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-herperidin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

-(6-diformylpiridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(5-herperidin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-herperidin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(3-forfinal)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(4-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(3-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-methylpyridin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(4-trifloromethyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-methyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-(4-hydroxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-were)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-about the,

4-(3,4-differenl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2,4-differenl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethyl-3-methyl-2-oxo-1,2-dihydropyridines-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethyl-3-methoxy-2-oxo-1,2-dihydropyridines-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-herperidin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-(3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,

4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-benzyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-isopropylpyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-ethoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[4-(Cryptor)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-oxo-1-ACS is -4,9-diazaspiro[5,5]undecane-4-yl)benzonitrile,

4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[3-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2,2,2-trifluoromethyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclobutyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclopentyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclohexyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-ethoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-(2-oxo-1-oxa-3,8-diazaspiro[4,5]on the Caen-2-yl)nicotinamide,

3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he and others

A group of the formula (III), the type of condensed cyclic group that is formed together R1and R2obtaining a 5 - or 6-membered aliphatic heterocycle containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom, when condensed with the phenyl group or peredelnoj group (condensed cyclic group may contain 1 or 2 identical or different substituent selected from the substituents described above for the groups γ), specifically includes, for example, tetrahydrofuranyl group, oxazolidinyl group, morpholinyl group, 1,3-dihydro-4-isobenzofuranyl group, 1,3-dihydrofuro[3,4-c]pyridyloxy group, 5,7-dihydrofuro[3,4-b]pyridyloxy group, 2,3-dihydro-1H-indolering group, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridinyl group, 2,3-dihydro[2,3-b]pyridinyl group, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridinyl group and others

Aliphatic heterocyclic group may contain 1 or 2 substituent selected from the above group of substituents β.

The term "lower alkyl group", referring to the Deputy, takes the values defined above for "lower alkyl group" or "lower alkyl group", for esenkoy a halogen atom.

The term "5 - or 6-membered heteroaryl group, containing in the ring 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom", relating to the Deputy specifically includes, for example, follow group, thienyl group, pyrrolidino group, imidazolidinyl group, triazolyl group, thiazolidine group, thiadiazolyl group, isothiazolinone group, oxazolidinyl group, isoxazolyl group, pyridyloxy group, pyrimidinyl group, pyridazinyl group, pyrazolidine group, personilnya group and others

The term "lower alkyl group", referring to the Deputy, takes the values defined above for "lower alkyl group"substituted by 1-3 halogen atoms. In particular, it includes, for example, methyl group, ethyl group, isopropyl group, through the group, triptorelin group, deformational group, formeterol group and others

The term "lower alkylsulfonyl group", referring to the Deputy, takes the values defined above for "lower alkylsulfonyl group, and concretely includes, for example, methylsulfonyl group, ethylsulfonyl group, isopropylphenyl group, propylsulfonyl group and others

Condensed cyclic group, aliphatic heterocyclic group, condensed the Oh with a phenyl group or peredelnoj group, may contain 1 or 2 substituent selected from the above group of substituents γ.

The term "lower alkyl group", referring to the Deputy, takes the values defined above for "lower alkyl group"substituted by 1-3 halogen atoms. He specifically includes, for example, methyl group, ethyl group, isopropyl group, through the group, triptorelin group, deformational group, formeterol group and others

The term "lower alkoxygroup relating to deputies, takes the values defined above for the lower alkoxygroup, in which the hydrogen atoms is substituted by 1-3 identical or different halogen atoms. The term specifically includes, for example, a methoxy group, ethoxypropan, cryptometer and other

The term "halogen atom", referring to the Deputy, takes the values defined above for the halogen atom, and specifically includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom.

R3represents a

a) a group of the formula (II-1):

[where the characters take the values defined above],

b) a group of the formula (II-2):

[where the characters take the values defined above], or

c) a group of the formula (II-3):

[where the characters take values defined the above].

a) in the case when R3represents a group of formula (II-1),

m1 is an integer from 2 to 4, preferably 3 or 4, more preferably 3.

R4and R5may be the same or different, and each represents a lower alkyl group optionally substituted by a halogen atom, or cycloalkyl group, optionally substituted by halogen atom; or R4and R5taken together with the nitrogen atom, form a 5-8-membered monocyclic ring, or 6-8 membered bicyclic ring, and the monocyclic ring may contain as a substituent a lower alkyl group optionally substituted by a halogen atom, a halogen atom or oxoprop; m1 is an integer from 2 to 4; the hydrogen atom in -(CH2)m1 may be substituted by a lower alkyl group containing 1-3 carbon atoms.

The term "lower alkyl group"related to R4and R5can take the values defined above for the lower alkyl groups, including methyl group, ethyl group, through the group, isopropyl group, and other Lower alkyl groups may be the same or different.

The term "cycloalkyl group"related to R4and R5can take the values defined above for cycloalkyl groups, including cyclopropyl group, cyclobutyl group and the R.

Monocyclic ring formed by R4and R5taken together with the nitrogen atom, comprises pyrolidine ring, piperidine ring, homopiperazine ring, heptamethylnonane ring, pieperazinove ring, morpholine ring, homomorpholine ring.

Bicyclic ring formed by R4and R5taken together with the nitrogen atom, represents azabicyclic ring and nonaromatic ring containing as the sole heteroatom, which is included in the heterocycle, the nitrogen atom, which is adjacent atom with respect to R4and R5in the above formula (II-1). Bicyclic ring preferably contains from 6 to 10 atoms forming the ring, more preferably from 7 to 9 atoms forming the ring.

Bicyclic ring includes, for example, groups of the formula (VI):

The hydrogen atom in the group -(CH2)m1 in the above formula (II-1) may be substituted by a lower alkyl group containing from 1 to 3 carbon atoms. The lower alkyl group includes methyl group, ethyl group, n-sawn group, isopropyl group and others

In the case when R3represents a group of formula (II-1), m1 is preferably 3 or 4, and R4and R5taken together with the nitrogen atom, form a 5-8-membered monocyclic is some ring (monocyclic ring may contain as a substituent a lower alkyl group, optionally substituted by a halogen atom, or a halogen atom) or 6-10-membered bicyclic ring; more preferably, m1 is 3, and R4and R5taken together with the nitrogen atom, form a 5-8-membered monocyclic ring (monocyclic ring may contain as a substituent a lower alkyl group optionally substituted by a halogen atom, or a halogen atom) or 6-10-membered bicyclic ring.

b) In the case when R3represents a group of formula (II-2):

m2 is an integer from 0 to 4, preferably equal to 2 or 3;

R6represents a lower alkyl group or cycloalkyl group.

The term "lower alkyl group"related to R6takes the values defined above for the lower alkyl group, including, for example, methyl group, ethyl group, through the group, boutelou group, pentelow group and others

The term "cycloalkyl group"related to R6takes the values defined above for cycloalkyl group, including, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group and others

In the case when R3represents a group of formula (II-2), two different carbon atoms of the carbon atoms constituting R3can connect to each other through -(CH2 m11(where m11 is an integer from 1 to 3) with the formation of the bicyclic ring. Bicyclic ring includes, for example, groups of the formula (VII):

(C) In the case when R3represents a group of formula (II-3),

m3 is an integer from 0 to 4, but preferably is 2 or 3.

R7and R8may be the same or different, and each represents a lower alkyl group optionally substituted by a halogen atom, or cycloalkyl group, optionally substituted by halogen atom; or R7and R8taken together with the nitrogen atom, form a 5-8-membered monocyclic ring or 6 to 8-membered bicyclic ring, and the monocyclic ring may contain as a substituent a lower alkyl group optionally substituted by a halogen atom, a halogen atom or oxoprop.

Preferred examples and preferred examples of R7and R8identical to the preferred and more preferred examples R4and R5.

In the case when R3represents a group of formula (II-3), two different carbon atoms of the carbon atoms constituting R3(with the exception of carbon atoms in R7and R8), can be connected to each other through a single bond or a group -(CH2)m11- (where m11 is an integer from 1 d is 3) with the formation of the bicyclic ring. Bicyclic ring includes, for example, groups of the formula (VIII):

[where the characters take the values defined above].

In the case when R3is a bicyclic ring of formula (VIII), preferred examples of R7and R8can be identical to the preferred examples of R4and R5.

As described above, R3includes, for example,

2-dimethylaminoethyl group, 2-diethylaminoethyl group,

2-di-n-propylaminoethyl group,

2-diisopropylaminoethyl group,

3-dimethylaminopropyl group, 3-diethylaminopropyl group,

3-di-n-propylaminoethyl group,

3-diisopropylaminoethyl group,

4-dimethylaminomethylene group, 4-diethylaminomethyl group,

4-di-n-propylaminoethyl group,

4-diisopropylaminoethyl group,

2-(ethylmethylamino)ethyl group,

2-(ethylpropylamine)ethyl group,

2-(ethylisopropylamine)ethyl group,

2-(methylisobutylketone)ethyl group,

2-(ethyl-n-propylamino)ethyl group,

3-(ethylmethylamino)through the group,

3-(ethylpropylamine)through the group,

3-(ethylisopropylamine)through the group,

3-(methylisobutylketone)through the group,

2-(ethyl-n-propylamino)through the group,

4-(ethylmethylamino)boutelou group,

4-(ethylpropylamine)boutelou group,

4-(ethylisopropylamine)boutelou group,

2-(ethyl-n-propylamino)boutelou group,

2-dicyclopentadienyl group,

2-disclosurepanel group,

2-dicyclopentadienyl group,

2-dicyclohexylmethane group,

3-dicyclopentadienyl group,

3-dictionaryamitriptyline group,

3-dicyclopentadienyl group,

3-dicyclohexylphosphino group,

4-dicyclopentadienyl group,

4-dicyclopentadienyliron group,

4-dicyclopentadienyl group,

4-dicyclohexylphosphino group,

2-(cyclobutanecarbonyl)ethyl group,

2-(cyclobutylmethyl)ethyl group,

2-(cyclohexylmethyl)ethyl group,

3-(cyclobutanecarbonyl)through the group,

3-(cyclobutylmethyl)through the group,

3-(cyclohexyldimethylamine)through the group,

4-(cyclobutanecarbonyl)boutelou group,

4-(cyclobutylmethyl)boutelou group,

4-(cyclohexyldimethylamine)boutelou group,

2-(cyclopropylamino)ethyl group,

2-(cyclopropylamino)ethyl group,

2-(cyclopropyl-n-propylamino)ethyl group,

2-(cyclopropylamino)ethyl group,

2(cyclobutylamine)ethyl group,

2-(cyclobutylamine)ethyl group,

2-(cyclobutyl-n-propylamino)ethyl group,

2-(cyclobutanecarbonyl)ethyl group,

2-(cyclopentylmethyl)ethyl group,

2-(cyclopentylamine)ethyl group,

2-(cyclopentyl-n-propylamino)ethyl group,

2-(cyclopentylpropionyl)ethyl group,

2-(cyclohexylethylamine)ethyl group,

2-(cyclohexylamino)ethyl group,

2-(cyclohexyl-n-propylamino)ethyl group,

2-(cyclohexylethylamine)ethyl group,

3-(cyclopropylamino)through the group,

3-(cyclopropylamino)through the group,

3-(cyclopropyl-n-propylamino)through the group,

3-(cyclopropylamino)through the group,

3-(cyclobutylmethyl)through the group,

3-(cyclobutylamine)through the group,

3-(cyclobutyl-n-propylamino)through the group,

3-(cyclobutylamine)through the group,

3-(cyclopentylmethyl)through the group,

3-(cyclopentylamine)through the group,

3-(cyclopentyl-n-propylamino)through the group,

3-(cyclopentylpropionyl)through the group,

3-(cyclohexylethylamine)through the group,

3-(cyclohexylethylamine)through the group,

3-(cyclohexyl-n-propylamino)through the group,

3-(cyclohexylethylamine)prop the optimum group,

4-(cyclopropylamino)boutelou group,

4-(cyclopropylamino)boutelou group,

4-(cyclopropyl-n-propylamino)boutelou group,

4-(cyclopropylamino)boutelou group,

4-(cyclobutylmethyl)boutelou group,

4-(cyclobutylamine)boutelou group,

4-cyclobutyl-n-propylamino)boutelou group,

4-(cyclobutanecarbonyl)boutelou group,

4-(cyclopentylmethyl)boutelou group,

4-(cyclopentylamine)boutelou group,

4-(cyclopentyl-n-propylamino)boutelou group,

4-(cyclopentylpropionyl)boutelou group,

4-(cyclohexylethylamine)boutelou group,

4-(cyclohexylethylamine)boutelou group,

4-(cyclohexyl-n-propylamino)boutelou group,

4-(cyclohexylethylamine)boutelou group,

2-pyrrolidin-1-ratelow group,

2-piperidine-1-ratelow group,

2-homopiperazin-1-ratelow group,

2-heptamethylnonane-1-ratelow group,

2-morpholine-4-ratelow group,

2-homomorpholine-4-ratelow group,

3-pyrrolidin-1-ylpropyl group,

3-piperidine-1-ylpropyl group,

3-homopiperazin-1-ylpropyl group,

3-heptamethylnonane-1-ylpropyl group,

3-morpholine-4-ylpropyl group,

3-homomorpholine-4-ylpropyl group,

4-pyrrolidin-1-albuterol group,

4-piperidine-albuterol group,

4-homopyrimidine-1-albuterol group,

4-heptamethylnonane-1-albuterol group,

4-morpholine-4-albuterol group,

4-homomorpholine-4-albuterol group,

2-(5-azabicyclo[2.1.1]hexane-5-yl)ethyl group,

2-(6-azabicyclo[3.1.1]heptane-6-yl)ethyl group,

2-(7-azabicyclo[2.1.1]heptane-7-yl)ethyl group,

2-(8-azabicyclo[3.2.1]Octan-8-yl)ethyl group,

2-(9-azabicyclo[3.3.1]nonan-9-yl)ethyl group,

3-(5-azabicyclo[2.1.1]hexane-5-yl)through the group,

3-(6-azabicyclo[3.1.1]heptane-6-yl)through the group,

3-(7-azabicyclo[2.1.1]heptane-7-yl)through the group,

3-(8-azabicyclo[3.2.1]Octan-8-yl)through the group,

3-(9-azabicyclo[3.3.1]nonan-9-yl)through the group,

4-(5-azabicyclo[2.1.1]hexane-5-yl)boutelou group,

4-(6-azabicyclo[3.1.1]heptane-6-yl)boutelou group,

4-(7-azabicyclo[2.1.1]heptane-7-yl)boutelou group,

4-(8-azabicyclo[3.2.1]Octan-8-yl)boutelou group,

4-(9-azabicyclo[3.3.1]nonan-9-yl)boutelou group,

1-methylisatin-3-ilen group,

1-methylaziridine-2-ilen group, 1-utilisation-3-ilen group,

1-utilisation-2-ilen group,

1-isopropylpyridine-3-ilen group,

1-isopropylpyridine-2-ilen group,

1-cyclopropylamino-3-ilen group,

1-cyclobutylmethyl-2-ilen group,

1-cyclobutylmethyl-3-ilen group,

1-cyclobutylmethyl-2-ilen group,

1-qi is opentradetime-3-ilen group,

1-cyclopentylmethyl-2-ilen group,

1-cyclohexylpiperidine-3-ilen group,

1-cyclohexylpiperidine-2-ilen group,

1 methylpyrrolidine-3-ilen group,

1 methylpyrrolidine-2-ilen group,

1-ethylpyrrolidin-3-ilen group,

1-ethylpyrrolidin-2-ilen group,

1-isopropylpyrimidine-3-ilen group,

1-isopropylpyridine-2-ilen group,

1-cyclopropylboronic-3-ilen group,

1-cyclopropylboronic-2-ilen group,

1-cyclobutylmethyl-3-ilen group,

1-cyclobutylmethyl-2-ilen group,

1-cyclopentenopyridine-3-ilen group,

1-cyclopentenopyridine-2-ilen group,

1-cyclohexylpiperidine-3-ilen group,

1-cyclohexylpiperidine-2-ilen group,

1 methylpiperidin-4-ilen group,

1 methylpiperidin-3-ilen group,

1 methylpiperidin-2-ilen group,

1-ethylpiperidine-4-ilen group,

1-ethylpiperidine-3-ilen group,

1-ethylpiperidine-2-ilen group,

1-isopropylpiperazine-4-ilen group,

1-isopropylpiperazine-3-ilen group,

1-isopropylpiperazine-2-ilen group,

1-cyclopropylidene-4-ilen group,

1-cyclopropylidene-3-ilen group,

1-cyclopropylidene-2-ilen group,

1-cyclobutylmethyl-4-ilen group,

1-cyclobutylmethyl-3-ilen group,

1-cyclobutylmethyl-2-ilnu the group,

1-cyclopentenopyridine-4-ilen group,

1-cyclopentenopyridine-3-ilen group,

1-cyclopentenopyridine-2-ilen group,

1-cyclohexylpiperidine-4-ilen group,

1-cyclohexylpiperidine-3-ilen group,

1-cyclohexylpiperidine-2-ilen group,

3-dimethylaminonaphthalene group,

3-diethylaminocoumarin group,

3-diisopropylaminoethyl group,

3-dicyclopentadienyl group,

3-dicyclopentadienyliron group,

3-dicyclopentadienyl group,

3-dicyclohexylmethane group,

2-dimethylaminonaphthalene group,

2-diethylaminocoumarin group,

2-diisopropylaminoethyl group,

2-dicyclopentadienyl group,

2-dicyclopentadienyliron group,

2-dicyclopentadienyl group,

2-dicyclohexylphosphino group,

3-(cyclopropylamino)cyclobutyl group,

3-(cyclopropylamino)cyclobutyl group,

3-(cyclobutylmethyl)cyclobutyl group,

3-(cyclobutylamine)cyclobutyl group,

3-(cyclopentylmethyl)cyclobutyl group,

3-(cyclopentylamine)cyclobutyl group,

3-(cyclohexylethylamine)cyclobutyl group,

2-(cyclopropylamino)cyclobutyl group,

2-(cyclopropylamino)C is clobutinol group,

2-(cyclobutylmethyl)cyclobutyl group,

2-(cyclobutylamine)cyclobutyl group,

2-(cyclopentylmethyl)cyclobutyl group,

2-(cyclopentylamine)cyclobutyl group,

2-(cyclohexylethylamine)cyclobutyl group,

3-pyrrolidin-1-enciclopedico group,

2-pyrrolidin-1-enciclopedico group,

3-pyrrolidin-1-enciclopedico group,

2-pyrrolidin-1-enciclopedico group,

4-pyrrolidin-1-illlogical group,

3-pyrrolidin-1-illlogical group,

2-pyrrolidin-1-illlogical group,

3-piperidine-1-enciclopedico group,

2-piperidine-1-enciclopedico group,

3-piperidine-1-enciclopedico group,

2-piperidine-1-enciclopedico group,

4-piperidine-1-illlogical group,

3-piperidine-1-illlogical group,

2-piperidine-1-illlogical group,

3-homopiperazin-1-enciclopedico group,

2-homopiperazin-1-enciclopedico group,

3-homopiperazin-1-enciclopedico group,

2-homopiperazin-1-enciclopedico group,

4-homopiperazin-1-illlogical group,

3-homopiperazin-1-illlogical group,

2-homopiperazin-1-illlogical group,

3-heptamethylnonane-1-enciclopedico group,

2-heptamethylnonane-1-enciclopedico group,

p> 3-heptamethylnonane-1-enciclopedico group,

2-heptamethylnonane-1-enciclopedico group,

4-heptamethylnonane-1-illlogical group,

3-heptamethylnonane-1-illlogical group,

2-heptamethylnonane-1-illlogical group,

2-morpholine-4-enciclopedico group,

3-morpholine-4-enciclopedico group,

2-morpholine-4-enciclopedico group,

3-morpholine-4-enciclopedico group,

2-morpholine-4-illlogical group,

3-morpholine-4-illlogical group,

4-morpholine-4-illlogical group,

2-homomorpholine-4-enciclopedico group,

3-homomorpholine-4-enciclopedico group,

4-homomorpholine-4-enciclopedico group,

2-homomorpholine-4-enciclopedico group,

3-homomorpholine-4-enciclopedico group,

4-homomorpholine-4-enciclopedico group,

2-homomorpholine-4-illlogical group,

3-homomorpholine-4-illlogical group,

4-homomorpholine-4-illlogical group,

2-(5-azabicyclo[2.1.1]hexane-5-yl)cyclobutyl group,

2-(6-azabicyclo[3.1.1]heptane-6-yl)cyclobutyl group,

2-(7-azabicyclo[2.1.1]heptane-7-yl)cyclobutyl group,

2-(8-azabicyclo[3.2.1]Octan-8-yl)cyclobutyl group,

2-(9-azabicyclo[3.3.1]nonan-9-yl)cyclobutyl group,

3-(5-azabicyclo[2.1.1]hexane-5-yl)cyclobutyl group,

3-(6-what sabillo[3.1.1]heptane-6-yl)cyclobutyl group,

3-(7-azabicyclo[2.1.1]heptane-7-yl)cyclobutyl group,

3-(8-azabicyclo[3.2.1]Octan-8-yl)cyclobutyl group,

3-(9-azabicyclo[3.3.1]nonan-9-yl)cyclobutyl group,

2-(5-azabicyclo[2.1.1]hexane-5-yl)cyclopentyloxy group,

2-(6-azabicyclo[3.1.1]heptane-6-yl)cyclopentyloxy group,

2-(7-azabicyclo[2.1.1]heptane-7-yl)cyclopentyloxy group,

2-(8-azabicyclo[3.2.1]Octan-8-yl)cyclopentyloxy group,

2-(9-azabicyclo[3.3.1]nonan-9-yl)cyclopentyloxy group,

3-(5-azabicyclo[2.1.1]hexane-5-yl)cyclopentyloxy group,

3-(6-azabicyclo[3.1.1]heptane-6-yl)cyclopentyloxy group,

3-(7-azabicyclo[2.1.1]heptane-7-yl)cyclopentyloxy group,

3-(8-azabicyclo[3.2.1]Octan-8-yl)cyclopentyloxy group,

3-(9-azabicyclo[3.3.1]nonan-9-yl)cyclopentyloxy group,

2-(5-azabicyclo[2.1.1]hexane-5-yl)tsiklogeksilnogo group,

2-(6-azabicyclo[3.1.1]heptane-6-yl)tsiklogeksilnogo group,

2-(7-azabicyclo[2.1.1]heptane-7-yl)tsiklogeksilnogo group,

2-(8-azabicyclo[3.2.1]Octan-8-yl)tsiklogeksilnogo group,

2-(9-azabicyclo[3.3.1]nonan-9-yl)tsiklogeksilnogo group,

3-(5-azabicyclo[2.1.1]hexane-5-yl)tsiklogeksilnogo group,

3-(6-azabicyclo[3.1.1]heptane-6-yl)tsiklogeksilnogo group,

3-(7-azabicyclo[2.1.1]heptane-7-yl)tsiklogeksilnogo group,

3-(8-azabicyclo[3.2.1]Octan-8-yl)tsiklogeksilnogo group,

3-(9-azabicyclo[3.3.1]nonan-9-yl)tsiklogeksilnogo group,

3-(7-what sabillo[2.2.1]hept-7-yl)through the group,

3-(8-azabicyclo[3.2.1]Oct-8-yl)through the group,

3-(3,3-debtorprovidian-1-yl)through the group,

3-(3-foreperiod-1-yl)through the group,

3-[(3R)-3-ftorpirimidinu-1-yl]through the group,

3-(4,4-deformability-1-yl)through the group,

3-(4-foreperiod-1-yl)through the group,

3-(3,3-deformability-1-yl)through the group,

3-[(3R)-3-methylpiperidin-1-yl]through the group,

3-[(2R,5R)-2,5-dimethylpiperidin-1-yl]through the group,

3-[3-methylpyrrolidine-1-yl]through the group,

3-[(2S)-2-methylpyrrolidine-1-yl]through the group,

3-[(2R)-2-methylpyrrolidine-1-yl]through the group,

3-[(3S)-3-methylpiperidin-1-yl]through the group,

3-(azepin-1-yl)through the group,

3-[(2-oxopyrrolidin-1-yl)]through the group, and others Among them, preferred are 3-piperidine-1-improperly group, 1-cyclobutylmethyl-4-ilen group, 1-cyclopentenopyridine-4-ilen group, 3-[(3S)-3-methylpiperidin-1-yl]sawn group, 3-[(2R)-2-methylpyrrolidine-1-yl]sawn group, 3-[(2S)-2-methylpyrrolidine-1-yl]through group, 1-cyclopentenopyridine-4-ilen group, 3-(pyrrolidin-1-yl)sawn group, 3-(piperidine-1-yl)through group and others

X1-X4all are carbon atoms, or 1 or 2 of X1-X4represent nitrogen atoms, and the remainder are carbon atoms.

Preferably,one of X 1-X4represents a nitrogen atom and the remainder are carbon atoms.

Based on the above, the preferred and recommended options connection according to the invention are the following compounds:

1) the compounds of formula (I), where R1represents an aryl group, optionally containing from 1 to 3 substituents selected from the group of substituents α or a 5 - or 6-membered heteroaryl group containing 1-3 heteroatoms selected from the group comprising a nitrogen atom, sulfur atom and oxygen atom, and optionally containing from 1 to 3 substituents selected from the group of substituents α;

2) the compounds of formula (I), where R2represents an aryl group, heteroaryl group containing 1-3 heteroatoms selected from the group comprising a nitrogen atom, sulfur atom and oxygen atom, or a cyano, a lower alkyl group or a hydroxy-group;

3) the compounds of formula (I), where R1and R2taken together form a 5 - or 6-membered aliphatic heterocyclic group containing 1-3 heteroatoms selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom;

4) the compound described in claim 3, where the 5 - or 6-membered aliphatic heterocyclic group represents:

5) the compounds of formula (I), where R1and R 2taken together form a 5 - or 6-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from the group comprising a nitrogen atom, sulfur atom and oxygen atom, and aliphatic heterocyclic group optionally condensed with a phenyl group or peredelnoj group with the formation of the condensed ring (aliphatic heterocyclic group may contain 1 or 2 identical or different substituent selected from the group of substituents β, and condensed ring aliphatic heterocyclic group with the phenyl group or peredelnoj group may contain 1 or 2 identical or different substituent selected from the group of substituents γ);

6) the compound described in claim 5, where 5 - or 6-membered aliphatic heterocyclic group represents:

7) the compounds of formula (I), where R3represents a group of formula (II-1) and m1 = 3;

8) compounds of formula (I), where R3selected from the group comprising 3-piperidine-1-ylpropyl group, 1-cyclobutylmethyl-4-ilen group, 1-cyclopentenopyridine-4-ilen group, 3-[(3S)-3-methylpiperidin-1-yl]sawn group, 2-[(2R)-2-methylpyrrolidine-1-yl]sawn group, 3-[(2S)-2-methylpyrrolidine-1-yl]sawn group, 1-cyclopentenopyridine-4-ilen group, 3-(pyrrolidin-1-is)through the group, and 3-(piperidine-1-yl)through the group.

Specific examples of compounds according to the present invention are, for example, the following connections:

1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],

4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol,

3-phenyl-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one,

4-phenyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-((2S)-2-methylpyrrolidine-1-yl)propoxy)phenyl]-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-((3S)-3-methylpiperidin-1-yl)propoxy)phenyl]-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

triptorelin 4-(4-forfinal)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol,

triptorelin 1-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-3-reparacin-4-ol,

triptorelin 4-(4-methoxyphenyl)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol,

triptorelin 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],

triptorelin 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,

triptorelin 7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,

triptorelin 5-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,

triptorelin 7-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,

triptorelin 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1H-Spiro[furo[3,4-c]pyridine-3,4'-piperidine]-1-it,

triptorelin 1-(methylsulphonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],

triptorelin 1-(ethylsulfonyl)-7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],

triptorelin 1-(ethylsulfonyl)-5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],

triptorelin 4-tert-butoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,

triptorelin 1-(ethylsulfonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],

triptorelin 3,3-dimethyl-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],

triptorelin 3-methyl-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],

triptorelin 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3,4-dihydrospiro[chroman-2,4'-piperidine],

triptorelin phenyl{1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-yl}methanone,

triptorelin 4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-carbonitrile,

triptorelin 4-benzyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-carbonitrile,

triptorelin 4-m is Tyl-4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine,

triptorelin 4,4-diphenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine,

triptorelin 4-(3-methoxyphenyl)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol,

4-(4-forfinal)-9-[4-(3-[(3S)-3-methylpiperidin-1-yl]propoxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-herperidin-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(methoxyphenyl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-were)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-4-(2-methylpyridin-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3,4-differenl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2,4-differenl)-9-[4-{3-[(3S)-3-piperidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-phenyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-4-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[6-(deformedarse)pyridine-3-yl]-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]is ndacan-3-one,

4-(6-isopropoxypyridine-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-isopropoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-[4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-forfinal)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-methoxyphenyl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1,3-benzodioxol-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-4-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]p is epoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(3-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-methoxyphenyl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-herperidin-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(1,3-thiazol-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-(4-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-(pyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-(pyridin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-herperidin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-herperidin-4-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-[6-(deformity)pyridine-3-yl]-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(5-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(3-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(4-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(3-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-methoxypyridine-3-yl)-8-[4-(3-piperidine-1-ylpropionic)Fe is Il]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-methylpyridin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[4-(triptoreline)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethyl-5-methoxy-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-herperidin-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-(methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-[1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl]-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(3-pyrrolidin-1 ipropose)phenyl]-4-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-isopropoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-ethoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyrazine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-chlorophenyl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(trifluoromethyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]benzonitrile,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(matilal the Nile)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}Hairdryer is l)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyrazine-2-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-ethyl-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-ethoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(1-methyl-1H-pyrazole-4-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(1-methyl-1H-pyrazole-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-[8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl]nicotinamide,

8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(6-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-methoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(5-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}f the Nile)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(2-methoxypyridine-5-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-isopropoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[3-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-imidazo[1,2-a]pyridine-3-the-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-(9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-oxo-1-OK the-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(3-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-(9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,

4-(2-ethoxypyridine-5-yl)-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

p> 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-(9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutyl ridin-4-yl)oxy]pyridin-3-yl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methylpyridin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-(8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-pyridin-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-imidazo[1,2-a]pyridine-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-herperidin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-herperidin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-ethyl-8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-(8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(3-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isoprop piperidin-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-herperidin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2,2,2-triptorelin)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-ethoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-(8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(6-methoxyphenyl the n-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyrazine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

5-(8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,

8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(4-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(4-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-herperidin-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-6-methoxypyridine-2-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-methyl-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-isopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-isopropyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-ethylpropyl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclobutyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclobutyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclopentyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclohexyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-benzyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[,5]undecane-3-one,

4-benzyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-benzyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-herperidin-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-9-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-methyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

3-(4-hydroxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclopropylidene-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,]undecane-3-one,

4-cyclobutyl-9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-cyclobutyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

Preferred are the following compounds:

4-(6-methoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(6-methoxypyridine-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[,5]undecane-3-one,

4-cyclobutyl-9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-(9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-ethyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

3-ethyl-8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methylpyridin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

4-(3-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-ethoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(2-ethoxypyridine-5-is)-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyrazine-2-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

4-methyl-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one and

9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

More preferred are the following compounds:

4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

4-methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,

9-{6-[(1-cyclobutylmethyl-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,

5-[9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide and

8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it.

The method of obtaining compounds of formula (I)

The compounds of formula (I) according to the invention (in the description referred to as compound (I)can be obtained, for example, in accordance with the following method:

[Symbols used in formulas that take the values defined above]

(Stage 1)

This stage is a method of preparing compounds (I) according to the invention by the interaction of the compounds (1) and compounds (2) in the presence of a base with the use of the ligand and a palladium catalyst. The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Journal of Organic Chemistry, Vol.66, 2001, pp.2560-2565), the same method or by a combination of this method with the standard method.

The basis which should be used at this stage include, for example, tert-piperonyl sodium, cesium carbonate, etc.

The amount of base can usually be from 1 to 5 equivalents per 1 equivalent of the compound (1), preferably 1 to 2 equivalents.

The ligand to be used in this reaction includes, for example, 2-dicyclohexylphosphino, 2-dicyclohexylphosphino-2'-dimethylaminophenyl, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, etc. the Number of ligand can typically range from 0.01 to 0.1 equivalent per 1 equivalent of the compound (1), preferably from 0.02 to 0.1 equivalent.

Pd catalyst to be used in this reaction includes, for example, Pd(OAc)2Pd(PPh3)4Pd2(dba)3, PdCl2(dppf)2etc. the Amount of Pd catalyst can typically be from 0.01 to 0.1 equivalent per 1 equivalent of the compound (1), preferably from 0.01 to 0.05 equivalent.

The solvent to be used in this reaction may be any solvent that does not adversely vozdeystviyna the course of the reaction, and includes, for example, dioxane, N,N-dimethylformamide, toluene, etc. Among them, preferred are dioxane, N,N-dimethylformamide, etc.

The reaction temperature can usually be in the range from 0°C to 150°C, preferably in the range from 60 to 100°C.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 2 to 15 hours.

Thus obtained compound (1) according to the present invention can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, presidenial, chromatography and other

The compound (I-1) according to the invention can be obtained in accordance with the following method:

[In the formulas, X represents an atom of halogena, and other characters take the values defined above.]

(Stage 2)

This stage is a method of obtaining compound (4) by the interaction of the compounds (1) and compound (3) in the presence of a base with ligand and Pd catalyst.

The type and amount of base used at this stage, the type and quantity of the ligand and the type and number of Pd catalyst identical to that used in stage 1.

The solvent to be used in the data the th reaction, can be any solvent that does not adversely impact on the course of the reaction, and includes, for example, 1,4-dioxane, N,N-dimethylformamide, toluene, etc. Among them, preferred are 1,4-dioxane, N,N-dimethylformamide, etc.

The reaction temperature can usually be in the range from 0°C to 150°C, preferably from 60 to 100°C.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 2 to 15 hours.

Thus obtained compound (4) according to the present invention at the next stage can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, presidenial, chromatography, etc. or can be obtained without isolation and purification.

(Stage 3)

This stage is a method of obtaining the compound (I-1) according to the invention by the interaction of the compound (4)obtained in the above stage 2, and the compound (5).

The compound (5)which should be used at this stage include, for example, dimethylamine, diethylamine, Diisopropylamine, ethylmethylamine, pyrrolidine, piperidine, homopiperazine and other Solvent that should be used in this reaction may be any dissolve the ü, no adverse effects on the course of the reaction, and includes, for example, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, toluene, and mixtures thereof. Preferred among them are acetone, tetrahydrofuran, N,N-dimethylformamide. The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 40°to 80°C. the Duration of the reaction can typically be from 1 hour to 48 hours, preferably from 1 to 12 hours.

Thus obtained compound (I-1) according to the present invention can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, precipitation, chromatography, etc.

The compound (I-2) according to the invention can be obtained in accordance with the following method using the compound (15) as the starting material. Below first describes the method of obtaining the compounds (15) and then the method of obtaining the compound (I-2).

The method of obtaining the compound (15):

[In the formulas, Z represents a benzyl or methyl group or groups of the following formulas:

Acronym TMS means trimethylsilyloxy group, X52represents a halo atom is s, other characters take the values defined above.]

(Stage 4)

This stage is a method of producing compound (8) by the interaction of the compounds (6) and compound (7) in the presence of a base. The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Journal of Organic Chemistry, Vol.66, 2001, pp.2560-2565), the same method or by a combination of this method with the standard method.

The basis which should be used at this stage include, for example, tert-piperonyl sodium, cesium carbonate and other Number bases can usually be from 1 to 5 equivalents per 1 equivalent of the compound (1), preferably 1 to 2 equivalents.

In the compound (7) X52represents a halogen atom, and specifically includes, for example, bromine atom and iodine atom, etc.

Compound (7) include, for example, 4-benzyloxyphenol, 4-benzyloxybenzyl, 4-methoxyphenol, 4-methoxybenzoyl and other

The amount of compound (7) can typically range from 1 to 10 equivalents per 1 equivalent of compound (6), preferably from 1 to 3 equivalents.

In this reaction, it is necessary to use the catalyst and ligand. The catalyst preferably is a Pd catalyst, and specifically includes, for example, Pd(OAc)2Pd(PPh3)4Pd2dba) 3, PdCl2(dppf)2etc. the Amount of Pd catalyst can typically range from 0.001 to 1 equivalent per 1 equivalent of compound (6), preferably from 0.01 to 0.05 equivalents.

The ligand includes, for example, 2-dicyclohexylphosphino, 2-dicyclohexylphosphino-2'-dimethylaminophenyl, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and other

The number of ligand can typically be from 0.01 to 1.0 equivalent per 1 equivalent of compound (6), preferably from 0.02 to 0.1 equivalent.

In the General case, the solvent to be used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, dioxane, N,N-dimethylformamide, toluene, etc. Among them, preferred are dioxane, N,N-dimethylformamide and other reaction Temperature can usually be in the range from 0°C to 150°C, preferably from 60°C. to 100°C. the Duration of the reaction can typically be from 1 to 48 hours, preferably from 2 to 15 hours.

Thus obtained compound (8) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or b is C separation and purification.

(Stage 5)

This stage is a method of producing compound (9) by removing acetyl groups from the compound (8)obtained in the above stage 4.

The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Journal of Medical Chemistry, Vol.29, 1986, pp.369-375), in a similar manner or way, which is a combination of this method with the standard method.

When Z in the compound (8) is, for example, benzyl group, compound (8) may be subjected to contact with an aqueous solution of formic acid, aqueous solution of acetic acid or monohydrate p-toluensulfonate acid. Among them, preferred is an aqueous solution of formic acid. The amount of formic acid that should be used at this stage can typically range from 1 to 100 equivalents per 1 equivalent of compound (8), preferably from 10 to 50 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, water, methyl alcohol, ethyl alcohol, acetone, etc. Among them, the preferred solvent is water.

The reaction temperature is usually may keep from 0°C to 150°C, preferably from 50°C. to 100°C.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 5 to 15 hours.

When Z in the compound (8) is, for example, methyl group, the compound (8) can be subjected to interaction with concentrated hydrochloric acid, concentrated sulfuric acid, aqueous solution of formic acid or aqueous solution of acetic acid, etc. Among them, preferred is concentrated hydrochloric acid.

The quantity of concentrated hydrochloric acid, which should be used at this stage can typically range from 1 to 100 equivalents per 1 equivalent of compound (8), preferably from 10 to 50 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, water, methyl alcohol, ethyl alcohol, acetone, etc. Among them, the preferred solvent is water.

The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 25°C. to 50°C.

The duration of the reaction can typically be from 1 to 30 hours, preferably from 5 to 15 hours.

(Stage 6)

This stage of the submitted is a method of producing compound (9) by the interaction of 1-ethyl-1-methyl-4-oxopiperidine and connections (10). The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Organic Letters, Vol.1, 1999, pp.1261-1262; European Journal of Medicinal Chemistry, Vol.35, 2000, pp.839-851), in a similar manner or way, which is a combination of this method with the standard method.

The basis which should be used at this stage include, for example, potassium carbonate, sodium carbonate and other Number bases can usually be from 1 to 5 equivalents per 1 equivalent of compound (10), preferably 1 to 2 equivalents.

The compound (10)which should be used at this stage include, for example, 4-benzyloxyaniline, 4-methoxyaniline, hydrochloride 4-(3-piperidine-1-ylpropionic)aniline, 4-methylbenzenesulfonate 4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}aniline, 4-methylbenzenesulfonate 4-[(1-cyclobutylmethyl-4-yl)oxy]aniline, 4-[(1-isopropylpiperazine-4-yloxy]aniline, 6-[(1-cyclobutylmethyl-4-yl)oxy]piperidine-3-aniline, 6-[(1-isopropylpiperazine-4-yl)oxy]piperidine-3-aniline and other

The number of 1-ethyl-1-methyl-4-oxopiperidine can typically be from 1 to 10 equivalents per 1 equivalent of compound (10), preferably from 1 to 3 equivalents.

In General, the reaction solvent may be any solvent that does not adversely impact on the course of the Rea is tion. We recommend using as solvent a mixture of ethanol-water.

The reaction temperature can usually be in the range from 0°C to 150°C, preferably from 80°to 100°C.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 4 to 10 hours.

Thus obtained compound (9) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 7)

This stage is a method of obtaining compound (11) by the interaction of the compound (9)obtained in stage 5 or stage (6), and trimethylsilylacetamide (TMSCN) in the presence of a base. The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Synthetic Communications, Vol.24, 1994, pp.1483-1487), the same method or by a combination of this method with the standard method.

The base is used at this stage include, for example, triethylamine, N-ethyldiethanolamine and other Number bases can usually be from 0.1 to 1 equivalent per 1 equivalent of compound (9), preferably from 0.1 to 0.5 equivalents

The number of trimethylsilylacetamide which should be used at this stage can typically be from 1 to 10 equivalents per 1 equivalent of compound (9), preferably from 1 to 3 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, chloroform, methylene chloride, etc. Among them, preferred is chloroform.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 1 to 15 hours.

The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 0°C. to 25°C.

Thus obtained compound (11) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 8)

This stage is a method of obtaining compound (12) recovery ceanography in the compound (11)obtained in the above stage 7.

The reducing agent to be used in this reaction includes LiAlH4, Raney Ni, etc. the Number of reset is novices can typically be from 1 to 10 equivalents per 1 equivalent of compound (11), preferably from 1 to 2 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and others Among them, preferred is tetrahydrofuran. The duration of reaction typically can range from 30 minutes to 48 hours, preferably from 30 minutes to 2 hours. The reaction temperature may usually range from 0°C to 100°C, preferably from 0°C. to 25°C.

Thus obtained compound (12) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 9)

This stage is a method of obtaining compound (13) by removal of the TMS group (trimethylsilyloxy group) from compound 12 obtained in the above stage 8.

Removal of the TMS group can be carried out, for example, by treating compound (12) 6N. hydrochloric acid in a solvent such as methanol.

The number of 6N. hydrochloric acid, which you should use is on this stage, usually can be from 1 to 10 equivalents per 1 equivalent of compound (12), preferably from 2 to 6 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, methanol, ethanol, etc. Among them, preferred is methanol.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 1 to 2 hours.

The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 10°C to 30°C.

Thus obtained compound (13) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 10)

This stage is a method of obtaining compound (14) by the interaction of the compound (13)obtained in the above stage 9, and 2-chloroacetamide in the presence of a base. The interaction at this stage can be carried out according to the method described in the literature (see, for example, Journal of Medicinal Chemistry, Vol.26, 1983, pp.855-861), in a similar way or Combinat is she of this method with the standard method.

The basis which should be used at this stage include, for example, potassium carbonate, sodium carbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine and other Number bases can usually be from 1 to 10 equivalents per 1 equivalent of compound (13), preferably 2 to 3 equivalents.

Number 2-chloroacetanilide can typically be from 1 to 10 equivalents per 1 equivalent of compound (13), preferably 1 or 2 equivalent.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, ethyl acetate, acetonitrile, tetrahydrofuran, etc. Among them, preferred is a mixed solvent consisting of acetonitrile and water. The duration of reaction typically can range from 30 minutes to 10 hours, preferably from 30 minutes to 2 hours.

The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 0°C. to 25°C.

Thus obtained compound (14) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromium is ografia and others, or without isolation and purification.

(Stage 11)

This stage is a method of obtaining compound (15) by intramolecular cyclization of the compound (14) in the presence of a base. The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Jornal of Medicinal Chemistry, Vol.26, 1983, pp.855-861), in a similar way or by a combination of this method with the standard method.

The basis which should be used at this stage include, for example, tert-piperonyl potassium tert-pentoxide, sodium and other Number bases can usually be from 1 to 10 equivalents per 1 equivalent of compound (14), preferably from 1 to 3 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol, 2-methyl-2-butyl alcohol. Among them, preferred is a mixed solvent, which represents N,N-dimethylformamide and 2-methyl-2-butyl alcohol, and other Duration of reaction typically can range from 30 minutes to 15 hours, preferably from 30 minutes to 1 hour. The reaction temperature can usually be in the range from 0°C to 100°C, prefer the Ino from 0°C to 25°C.

Thus obtained compound (15) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

The method of obtaining the compound (I-2)

[In the formula Bn means benzyl group; X50and X51each means a halogen atom; and other symbols take the values defined above.]

(Stage 12)

This stage is a method of obtaining compound (16) by introduction of the BOC-group in aminogroup compound (15-1), where Z is a benzyl group.

The introduction of the BOC group can be carried out in accordance with the method described in the literature (see, for example, Protective Groups in Organic Synthesis, T.W. Green, 2ndEd., John Wiley&Sins, 1991), in a similar way or by a combination of this method with the standard method. In particular, for the introduction of the BOC group, for example, the compound (15-1) is subjected to interaction with the (Re)2Oh, usually in an amount of from 1 to 3 equivalents to 1 equivalent of the compound (15-1), in the presence of a base, such as triethylamine, usually in an amount of from 1 to 3 equivalents to 1 equivalent of the compound (15-1), in rest retele, such as chloroform, to obtain the compounds (16). Usually in the reaction system may be present from 0.1 to 1 equivalent of 4-dimethylaminopyridine.

Thus obtained compound (16) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 13)

This stage represents a method of obtaining a compound (17) by removing the benzyl group from compound (16)obtained in the above stage 12.

The removal of the benzyl group can be carried out in accordance with the method described in the above publication, Protective Group in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

The removal of the benzyl group can be carried out, for example, by treating compound (16) a catalytic amount of Pd-C in a solvent such as methanol, in an atmosphere of hydrogen.

Thus obtained compound (17) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration at igenom pressure, crystallization, extraction with solvent, presidenial, chromatography, etc. or without isolation and purification.

(Stage 14)

This stage is a method of obtaining compound (19) by the interaction of the compound (17)obtained in the above stage 13, and the compound (18) in the presence of a base.

The basis which should be used at this stage include, for example, potassium carbonate, cesium carbonate, sodium carbonate and other Number bases can usually be from 1 to 10 equivalents per 1 equivalent of compound (17), preferably 3 to 5 equivalents.

X50in the formula of the compound (18) represents a halogen atom, and specifically includes, for example, iodine atom, bromine atom and a chlorine atom.

The compound (18) specifically includes, for example, hydrochloride, 1-(3-chloropropyl)piperidine hydrobromide 1-(3-bromopropyl)piperidine, 1-(3-improper)piperidine, hydrochloride 1-(3-chlorpropyl)pyrrolidine, hydrobromide 1-(3-bromopropyl)pyrrolidine, 1-(3-improper)pyrrolidin, hydrobromide (S)-1-(3-bromopropyl)-3-methylpiperidine, hydrobromide (2S)-1-(3-bromopropyl)-2-methylpyrrolidine the hydrobromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine.

The solvent to be used in this reaction may be any solvent that does not adversely impact on the course of the reaction, for example, AC is the tone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, toluene, etc. Among them, preferred are acetone, tetrahydrofuran, N,N-dimethylformamide.

The reaction temperature can usually be in the range from 0°C to 150°C, preferably from 25°C. to 80°C. the Duration of the reaction can typically be from 1 to 48 hours, preferably from 5 to 15 hours.

Thus obtained compound (19) according to the invention can be isolated and purified in accordance with the known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

(Stage 15)

This stage is a method of obtaining compound (20) removing the BOC group from the compound (19)obtained in the above stage 14.

Removal of the BOC group can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

In particular, for example, compound (19)containing BOC-group, may be subject to interaction with acid, such as triperoxonane acid (which hereinafter in the description called "TFUK"). The number used TFUK usually is about can be from 1 to 10 equivalents per 1 equivalent of compound (19), preferably 2 to 3 equivalents. The solvent to be used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, chloroform, methylene chloride, ethyl acetate, acetonitrile, 1,4-dioxane, etc. Among them, preferred are chloroform and methylene chloride. The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 0°C. to 25°C. the Duration of the reaction can typically be from 10 minutes to 48 hours, preferably from 30 minutes to 2 hours.

Thus obtained compound (20) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

(Stage 16)

This stage is a method of obtaining the compound (I-2) according to the invention by the interaction of the compound (20)obtained in the above stage 15, and the connection (21). The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Journal of American Chemical Society, Vol.124, 2002, pp.7421-7428), in a similar manner or way, which is a combination of this method with the standard pic the BOM.

The compound (21), which should be used at this stage include, for example, Brabanthal, 2-bramptonbest, 3-bramptonbest, 4-bramptonbest, 2-bromopyridine, 3-bromopyridine, 4-bromopyridine and other Amounts of the compound (21)used at this stage can typically be from 1 to 10 equivalents per 1 equivalent of compound (20), preferably from 1 to 2 equivalents.

In the reaction system to make the reaction are copper iodide (I), potassium phosphate and N,N'-dimethylaminoethyl.

The amount of copper iodide (I), which should be used at this stage can typically be from 0.01 to 10 equivalents per 1 equivalent of compound (20), preferably from 0.5 to 1.0 equivalent.

The quantity of phosphate of potassium, which should be used at this stage can typically be from 1 to 10 equivalents per 1 equivalent of compound (20), preferably from 1 to 3 equivalents.

The amount of N,N'-dimethylaminoethanol which should be used at this stage can typically be from 0.01 to 10 equivalents per 1 equivalent of compound (20), preferably from 0.5 to 1.0 equivalent.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, toluene, 1,4-dioxane, tetrahydrofur is h, N,N-dimethylformamide, etc. Among them, preferred are 1,4-dioxane, N,N-dimethylformamide. The reaction temperature can usually be in the range from 0°C to 150°C, preferably from 80°to 120°C. the Duration of the reaction can typically be from 1 to 48 hours, preferably from 5 to 15 hours.

Thus obtained compound (I-2) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compound (I-2) according to the invention can also be obtained, for example, in accordance with the following method.

[The symbols in the formulas take the values defined above.]

(Stage 17)

This stage is a method of obtaining compound (22) by the interaction of the compound (15) with compound (21). The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Journal of America Chemical Society, Vol.124, 2002, pp.7421-7428), in a similar manner or way, which is a combination of this method with the standard method.

The compound (21)used at this stage include, for example, Brabanthal, 2-bramptonbest, 3-bramptonbest, 4-bramp orbinson, 2-bromopyridine, 3-bromopyridine, 4-bromopyridine and other

For the implementation of the reaction system is added copper iodide (I), potassium phosphate and N,N'-dimethylaminoethyl.

The amount of copper iodide (I), potassium phosphate and N,N'-dimethylaminoethanol used at this stage, is identical to the number of specified reagents used in stage 16, and a solvent, duration of reaction and the reaction temperature is identical to the solvent, time and temperature specified above for stage 8.

Thus obtained compound (22) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 18)

This stage represents a method of obtaining a compound (23) by removing the protective group of the hydroxy-group of the compound (22)obtained in stage 17, as described above.

The interaction at this stage can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

When the protective group guide is actigraphy represents a benzyl group, 1 equivalent of the compound (22) may be subjected to processing of 0.1 to 1 equivalent, preferably 0.1 to 0.5 equivalent of 10% Pd-C in an atmosphere of hydrogen in methanol, tetrahydrofuran, ethyl acetate or their mixtures with obtaining, thus, compound (23). In the case where the protective group of the hydroxy-group is a methyl group, the compound (22) can be processed by tribromide usually boron in an amount of from 1 to 4 equivalents per 1 equivalent of compound (22), preferably 2-4 equivalents, in a solvent such as chloroform, methylene chloride, obtaining, thus, compound (23).

Thus obtained compound (23) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 19)

This stage is a method of obtaining the compound (I-2) according to the invention by the interaction of the compound (23)obtained in the above stage 18, with the compound (18) in the presence of a base. The interaction at this stage can be carried out similar to the interaction described above stage 14 from the point of view of the type and quantity of compounds (18), the reaction solvent, the reaction temperature and duration of reaction with the difference that instead of the compound (17) is used as a compound (23).

Thus obtained compound (I-2) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

The compound (I-3) according to the invention can be obtained in accordance with the following method:

[In the formulas, n is an integer from 0 to 4; and other symbols take the values defined above.]

(Stage 20)

This stage is a method of obtaining compound (25) by the interaction of the compound (23) with compound (24). The interaction at this stage is a reaction Mitsunobu, and the reaction Mitsunobu can be carried out in the presence of phosphine compounds and azo compounds in accordance with the method described in the literature (see, for example, Mitsunobu, O., “The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products”, Synthesis, Vol.1, 1981, pp.1-28), in a similar manner or way, which is a combination of this method with the standard method.

The amount of compound (24)used at this stage is generally the composition is better from 0.5 to 10 equivalents per 1 equivalent of compound (23), preferably from 1 to 3 equivalents.

Phosphine compound, which should be used at this stage include triphenylphosphine, triethylphosphine and other

The amount of the phosphine compound that should be used at this stage can usually be from 0.5 to 10 equivalents per 1 equivalent of compound (23), preferably from 1 to 3 equivalents.

Uzasadnienie which should be used at this stage include diethylazodicarboxylate, diisopropylsalicylic etc. the Number of compounds that should be used at this stage can usually be from 0.5 to 10 equivalents per 1 equivalent of compound (23), preferably from 1 to 3 equivalents.

The duration of the reaction can typically be from 1 to 48 hours, preferably from 4 to 12 hours. The reaction temperature can usually be in the range from room temperature to the boiling point of the solvent, preferably from 15°C to 30°C.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, tetrahydrofuran, toluene, etc.

Thus obtained compound (25) can be used at the next stage, after isolation and purification by known method ejecta and cleaning, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 21)

This stage is a method of obtaining compound (26) by removing the BOC group from the compound (25).

The interaction at this stage can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

For example, the compound (25) was processed 1-10 equivalents of TFWC on 1 equivalent of the compound (25), preferably 2-4 equivalents in the reaction solvent, such as methylene chloride, methanol and others, to obtain the compound (26).

Thus obtained compound (26) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 22)

This stage is a method of obtaining the compound (I-3) according to the invention by the interaction of the compound (26) with compound (27).

Simocatta at this stage is the so-called reductive amination. The amount of compound (27), which should be used at this stage can typically be from 1 to 10 equivalents per 1 equivalent of compound (26), preferably from 2 to 4 equivalents.

Compound (27) includes cyclobutanone, Cyclopentanone and other

The reducing agent to be used at this stage include ORGANOMETALLIC reagent, such as borohydride sodium, cyanoborohydride sodium, triacetoxyborohydride sodium, etc. the Amount of reducing agent can typically be from 1 to 5 equivalents per 1 equivalent of compound (26), preferably from 1 to 3 equivalents. In the reaction system may be a catalytic amount ZnCl2.

The reaction typically can be performed in an inert solvent. The inert solvent is preferably a methanol, ethanol, benzene, toluene, xylene, methylene chloride, chloroform, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and mixtures thereof.

The reaction temperature can usually be in the range from room temperature to the boiling point of the reaction solvent, preferably in the range from 20°C to 100°C. the Duration of the reaction can typically range from 30 minutes to 7 days, preferably from 3 hours to 2 days.

Thus obtained compound (I-3) according to the invention can be isolated and cleaned what about the known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compound (I-4) and (I-5) according to the invention can be obtained, for example, in accordance with the following method.

[The symbols in the formulas take the values defined above.]

(Stage 23)

This stage is a method of obtaining compound (28) by the interaction of the compound (13) with triphosgene. The interaction at this stage can be carried out in accordance with the method described in the literature (see, for example, Synthetic Communications, Vol.24, 1994, pp.1483-1487), in a similar manner or way, which is a combination of this method with the standard method.

The number of triphosgene which should be used at this stage can typically be from 1 to 10 equivalents per 1 equivalent of compound (13), preferably from 1 to 2 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, an inert solvent, such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride, tetrahydrofuran, diethyl ether, toluene, etc. or mixtures thereof. With the a single preferred are chloroform, methylene chloride, 1,2-dichloroethane.

The reaction temperature can usually be in the range from -40°C to 100°C, preferably from 10°C to 30°C. the Duration of the reaction can typically be from 1 to 48 hours, preferably from 1 to 15 hours.

Thus obtained compound (28) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

When Z in the compound (13) represents a group of the following formula:

the reaction leads to the production of the compound (I-4), and then the compound obtained may be subjected to interaction at the stage 26 with obtaining the compound (I-5).

In the case when Z is a benzyl group or a methyl group, the compound (I-4) can be obtained in accordance with the methods presented on stage stage 24 and 25.

(Stage 24)

This stage is a method of obtaining compound (29) by removing the protective group of the hydroxy-group in the compound (28)obtained in the above stage 23.

The interaction at this stage can be carried out in accordance with the method, opican the m in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

The removal of the protective group, this stage can be carried out in accordance with the method described above in stage 18, the same method or way, which is a combination of this method with the standard method.

Thus obtained compound (29) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 25)

This stage is a method of obtaining the compound (I-4) according to the invention by the interaction of the compound (29)obtained in the above stage 24, and the connection (18).

The interaction at this stage can be carried out according to the method described above stage 19, the same method or way, which is a combination of this method with the standard method, but with the difference that instead of the compound (23) is used as a compound (29). Thus obtained compound (I-4) can be used in the next stage after separation and purification by a known method : the population and cleaning, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 26)

This stage is a method of obtaining the compound (I-5) according to the invention by the interaction of the compound (I-4)obtained in the above stage 25, and the connection (21).

The interaction at this stage can be carried out in accordance with the method described above stage 17, in a similar manner or way, which is a combination of this method with the standard method, but with the difference that the compound (I-4) is used instead of the compound (15).

Thus obtained compound (I-5) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compound (I-5) according to the invention can also be obtained, for example, in accordance with the following method:

[Symbols used in formulas that take the values defined above.]

(Stage 27)

This stage is a method of obtaining compound (30) by the interaction of the compounds (28-1), i.e. the unity (28), obtained above in stage 23 where Z represents methyl, with a compound (21).

The interaction at this stage can be carried out in accordance with the method described above stage 17, in a similar manner or way, which is a combination of this method with the standard method, but with the difference that instead of the compound (15) is used as a compound (28-1).

Thus obtained compound (30) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 28)

This stage represents a method of obtaining a compound (31) by removing the protective group of the hydroxy-group of the compound (30)obtained in the above stage 27.

The interaction at this stage can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

The removal of the protective group, this stage can be carried out in accordance with the method described above stage 18, the same way is there any way combination of this method with the standard method.

Thus obtained compound (31) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 29)

This stage is a method of obtaining the compound (I-5) according to the invention by the interaction of the compounds (31)obtained in the above stage 28, with the compound (18).

The interaction at this stage can be carried out in accordance with the method described above stage 19, the same method or way, which is a combination of this method with the standard method, but with the difference that instead of the compound (23) is used as a compound (31). Thus obtained compound (I-5) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compound (I-6) according to the invention can be obtained, for example, in accordance with the following method:

[In the formula, R is 0 or 1; R91represents a lower alkyl group; X52represents a bromine atom or an iodine atom; and other symbols take the values defined above.]

(Stage 30)

This stage is a method of obtaining compound (34) by the interaction of the compound (32) (33) in the presence of a base.

The compound (33), used at this stage include, for example, methyliodide, ethylbromide and other

The amount of compound (33) can typically range from 1 to 10 equivalents per 1 equivalent of compound (32), preferably from 1 to 2 equivalents.

The basis which should be used at this stage include, for example, sodium hydride, lithium hydride, tert-piperonyl potassium and other Number bases can usually be from 1 to 10 equivalents per 1 equivalent of compound (32), preferably from 1 to 2 equivalents.

In General, the solvent used in this reaction may be any solvent that does not adversely impact on the course of the reaction, and includes, for example, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, etc. Among them, preferred is N,N-dimethylformamide.

The reaction temperature can usually be in the range from 0°C to 100°C, preferably from 10°C to 30°C. Continue inost reaction typically can be from 1 to 48 hours, preferably from 5 to 15 hours.

Thus obtained compound (34) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 31)

This stage is a method of obtaining compound (35) by removing the protective group of the hydroxy-group of the compound (34)obtained in the above stage 30.

The interaction at this stage can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method.

Thus obtained compound (35) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 32)

This stage is a method of obtaining the compound (I-6) according to the invention by the interaction of the compound (35), the floor is built above the stage 31, with compound (18).

The interaction at this stage can be carried out in accordance with the method described above stage 19, the same method or way, which is a combination of this method with the standard method, but with the difference that instead of the compound (23) use of the compound (35).

Thus obtained compound (I-6) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compound (I-7) according to the invention can be obtained, for example, in accordance with the following method.

[The symbols in the formulas take the values defined above.]

(Stage 33)

This stage is a method of obtaining compound (36) the interaction of the compound (35)obtained in the above stage 31, with compound (24). The interaction at this stage can be carried out in accordance with the method described above the stage 20, the same method or way, which is a combination of this method with the standard method. Thus obtained compound (36) can be used at the next stage, after isolation and purification known for the m method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 34)

This stage is a method of obtaining compound (37) removing the BOC group from the compound (36)obtained in the above stage 33. This interaction can be carried out in accordance with the method described in the above publication, Protective Groups in Organic Synthesis, in a similar manner or way, which is a combination of this method with the standard method. More precisely, the interaction may be carried out in accordance with the method described above the stage 21, in a similar manner or way, which is a combination of this method with the standard method.

Thus obtained compound (37) can be used at the next stage, after isolation and purification by known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography, etc. or without isolation and purification.

(Stage 35)

This stage is a method of obtaining the compound (I-7) according to the invention by the interaction of the compound (37), obtained what about the above stage 34, with the connection (27).

The interaction at this stage is the so-called reaction of reductive amination.

Compound (27), which should be used at this stage, may be used in quantities of 1 to 10 equivalents per equivalent of compound (37), preferably from 2 to 4 equivalents.

Compound (27) includes cyclobutanone, Cyclopentanone and other

The reducing agent to be used at this stage include ORGANOMETALLIC reagent, such as borohydride sodium, cyanoborohydride sodium, triacetoxyborohydride sodium, etc. the Amount of reducing agent can typically be from 1 to 5 equivalents per 1 equivalent of compound (37), preferably from 1 to 3 equivalents.

In the reaction system may be a catalytic amount ZnCl2.

The interaction can usually be carried out in an inert solvent. The inert solvent is preferably a methanol, ethanol, benzene, toluene, xylene, methylene chloride, chloroform, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and mixed solvents thereof.

The reaction temperature can usually be in the range from 0°C to the boiling point of the reaction solvent, preferably in the range from 20°C to 100°C. the duration of the PE the options usually can range from 30 minutes to 7 days, preferably from 5 hours to 2 days.

Thus obtained compound (I-7) can be isolated and purified by a known method of isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, presidenial, chromatography and other

The compounds of formula (I), i.e. compounds (I-1), compound (I-2), compound (I-3), compound (I-4), compound (I-5), compound (I-6) and compound (I-7) according to the invention, obtained according to the above-described methods, can be easily isolated and purified by a standard method of isolation and purification. The method includes, for example, solvent extraction, recrystallization, re-precipitation, column chromatography, preparative thin-layer chromatography.

These compounds can be converted in the usual way in pharmaceutically acceptable salts or esters; and Vice versa, such salts or esters can be converted into the corresponding free compound in the usual way.

New derivatives of piperidine according to the present invention can exist in the form of pharmaceutically acceptable salts, and these salts can be obtained in the usual way using the compounds of formula (I). Acid additive salts include, for example, hydrogenogenic (for example, guide chloride, hydrohloride, hydrobromide, hydroiodide), inorganic salts (e.g., nitrates, perchlorates, sulfates, phosphates, carbonates), lower alkyl sulphonates (for example, methanesulfonate, triftoratsetata, econsultancy), arylsulfonate (for example, bansilalpet, p-toluensulfonate), organic acid salts (for example, fumarate, succinate, citrates, tartratami, oxalates, maleate), salt, amino acids (e.g. glutamate, aspartate).

Basically additive salts include, for example, alkali metal salts (e.g. sodium salt, potassium salt), salts of alkaline earth metals (e.g. calcium salt, magnesium salt), ammonium salt and an additive salts with organic bases (for example, guanidine, triethylamine, dicyclohexylamine). In addition, the compounds according to the invention can exist in any of hydrated or solvated form of the free compounds or salts.

The compounds of formula (I) and their pharmaceutically acceptable salts can be administered orally or parenterally.

The clinical application of the compounds according to the present invention for various drugs can be added various pharmaceutically acceptable additives, as appropriate to the intended route of administration. Various additives which are usually used in obtaining formats whitesky compositions and which can be used according to the present invention, include, for example, gelatin, lactose, white sugar, titanium oxide, starch, crystalline cellulose, hypromellose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, metasilicates magnesium, anhydrous calcium phosphate, citric acid, trinatriytsitrat, hydroxypropylcellulose, sorbitol, complex arbitarily a fatty acid ester, Polysorbate, sucrose complex fatty acid ester, polyoxyethylene, utverjdenie castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, guar gum, propylene glycol, polyalkyleneglycol, cyclodextrin, hydroxypropylcellulose and other

The mixture of compounds according to the invention and the above additives may be used in the form of solid preparations (e.g. tablets, capsules, granules, powders, suppositories) or liquid preparations (e.g., syrups, elixirs, injectables). Such preparations can be obtained by a standard method known in the field of pharmaceutical compositions. Liquid preparations may be presented in such form that they are dissolved or suspendible in water or any other suitable medium before use. Specifically, preparations for injection can dissolve or suspenderbelt the Xia, if necessary, in physiological saline or glucose solution, which can be added to the buffer and preservative. The preparations may contain the compound according to the invention in quantities of 1.0 to 100% (mass.), preferably from 1.0 to 60% (mass.) drug.

The composition according to the invention can be prepared in the form of the drug, for example, in accordance with the following examples of the preparation of drugs.

Example 1 drug

10 parts of the compound of example 1, described below, 15 parts of heavy magnesium oxide and 75 parts of lactose uniformly mixed to obtain a powdery or granular product with a particle size of at most 350 μm. The drug encapsulation with getting capsules.

Example product 2

45 parts of the compound of example 1, described below, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water are mixed until a homogeneous mixture, then grind, granularit and dried, then sieved through a sieve with obtaining a granulated product with a particle diameter in the range from 1410 to 144 μm.

The example of the drug 3

The granulated product receive in accordance with the method of example obtaining the drug 2. 96 parts of granulated drug is mixed with 3 parts is tarata calcium and molded by compression molding into tablets with a diameter of 10 mm

Example 4 drug

90 parts of a granular preparation obtained according to the method of example obtaining product 2, is mixed with 10 parts of crystalline cellulose and 3 parts of calcium stearate and molded by compression molding into tablets with a diameter of 8 mm. Tablet cover mixed suspension syrupy gelatin and precipitated calcium carbonate to obtain tablets coated with sugar.

These preparations may contain other therapeutically effective drug, as described below.

Compounds according to the present invention for use can be combined with another drug effective for the treatment (prophylaxis or therapy of metabolic disorders or disorders associated with food intake. Some of the ingredients that are combined, can be entered at different times or simultaneously in a single preparation or in the form of individual drugs. Link aggregation according to the invention with another drug effective for the treatment of metabolic disorders or disorders associated with eating, consists mainly of a combination of connection with any and every drug effective for the treatment of metabolic disorders or disorders associated with food intake.

Connection is according to the invention can also be combined with any other medicinal product (hereinafter defined as "jointly used drugs"), effective against hypertension, hypertension associated with obesity, disorders associated with hypertension, cardiomegaly, left ventricle hypertrophy, metabolic disorders, obesity, disorders associated with obesity. When combined with the connection according to the present invention such jointly used drugs can be administered simultaneously or at different times, or consistently properly for the prevention or treatment of the above disorders. When the connection according to the present invention is used simultaneously with one or more commonly used drugs, it can be in pharmaceutical compositions for administration in a single dose. However, when such combined therapy a composition comprising a compound according to the invention, and together used the drug can be administered to the patient simultaneously, separately or sequentially. Composition and jointly applied drug may be packaged separately. They can be entered at different times.

Dose jointly used drugs may depend on its clinical use and may appropriately be determined depending on the subject, which it is introduced, method of introduction, diseases and the x combinations. The form of jointly used drugs for injection is not specifically defined, and it can be combined with a compound according to the present invention in the introduction. The route of administration includes, for example, the following methods: (1) the compound according to the invention combined with the simultaneously introduced drug to produce a single product for a single injection; (2) the compounds according to the present invention and together entered the drug is prepared separately in two different products, and these drugs are administered simultaneously by the same method of administration; (3) the compound according to the invention and together entered the drug is made in two different products that are introduced at different times in the same method of administration; (4) the compound according to the invention and together entered the drug is made in two different drug that can be injected simultaneously by different routes of administration; (5) the compound according to the invention and together entered the drug is made separately in two different drug that can be injected to the patient at different times by different routes of administration (for example, the connection according to the invention and together entered the drug is injected in sequence or in reverse order). The ratio in the mixture with the unity of the invention and together entered the medicinal product may be determined appropriately depending on the subject, you enter the vehicle, the route of administration and the condition being treated.

Jointly entered medicines that can be used according to the invention include medicines for diabetes, therapeutic drugs from hyperlipemia, therapeutic drugs from hypertension and drugs against obesity. Two or more of these drugs may be combined in any desired ratio.

Therapeutic drugs for diabetes include, for example, the following medications:

1) agonists of PPAR γ (receptor-activated proliferation peroxisome), such as glitazone (for example, ciglitazone, darglitazone, englitazone, isopetasin, MCC-555, troglitazone, rosiglitazone, troglitazone, BRL49653, CLX-0921, 5-BTZD), GW-0207, LG-100641, LY-300512;

2) biguanides such as Metformin, buformin, phenformin;

3) inhibitors of protein-tyrosinosis;

4) sulfonylureas such as acetohexamide, chloropropamide, diabinese, glibenclamide, glipizide, gliburid, glimepiride, gliclazide, ClientID, glikvidon, glycolipid, trashed, tolbutamide;

5) meglitinide, such as Repaglinide, nateglinide;

6) inhibitors of α-glycosidically, such as acarbose, adipsin, camiglibose, emiglitate, miglitol, voglibose, promicin-Q, substation, CKD-711, MDL-25,673, MDL-73,945, MOR14;

7) inhibitors of α-amylase, such as tendamistat, trestain, A;

8) activators of insulin secretion, such as linogliride, A-4166;

9) inhibitors of fatty acid oxidation, such as clamoxyl, etomoxir;

10) A2 antagonists, such as midaglizole, icapital, deriglidole, idazoxan, Aaronson, flyproxy;

11) insulin or imitators of insulin, such as biota, LP-100, Novorapid, insulin-detemir, insulin-lispro, insulin glargine, insulin zinc, Lys-Pro insulin, GLP-1 (73-7), GLP1 (7-36)-NH2;

12) non-preparations of thiazolidinediones such as JT-501, farglitazar;

13) dual agonists, PPAR α/γ, such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, SB219994;

14) other activators of insulin;

15) VPAC2 agonists of the receptor.

Therapeutic drugs for the treatment of hyperlipemia include, for example, the following medications:

1) the promoters of absorption of bile acids, such as herstellen, colesevelam, colestipol, stitched extradisciplinary-derivatives, Colestid®, LoCholest®, Questran®;

2) inhibitors of HMG-CoA reductase inhibitor such as atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, mevastatin, rosuvastatin, simvastatin, ZD-4522;

3) inhibitors HMB-CoA synthase;

4) inhibitors of cholesterol absorption, such as complex Cytology ester, β-sitosterol, storyglossia, ezetimib;

5) inhibitors of ACAT (acyl-COA-cholesterol is reallcasper), such as avasimibe, eflucimibe, KY-505, SMP-709;

6) SERT inhibitors, such as JTT705, torcetrapib, CP532632, BAY-63-2149, SC 591, SC 795;

7) inhibitors stvalentines;

8) antioxidants, such as probucol;

9) PPARα agonists such as clofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, gemfibrozil, GW-7647, BM-170744, LY-518674, derivatives fibrillae acid (such as Atromid®, Lopid®and Tricor®);

10) FXR antagonists of the receptor, such as GW-4064, SR 103912;

11) LXR antagonists of the receptor, such as GW3965, T9013137, XTCO-179628;

12) inhibitors of the synthesis of lipoproteins, such as Niacin;

13) the system inhibitors of the renin-angiotensin;

14) partial agonists of PPARδ;

15) inhibitors of resorption of bile acids, such as BARA1453, SC435, PHA384640, S-435, AZD7706;

16) PPARδ agonists such as GW501516, GW590735;

17) inhibitors of the synthesis of triglycerides;

18) inhibitors MTTR (microsome transport triglycerides)such as implitapide, LAB687, CP346086;

19) modifying factors transcription;

20) inhibitors scaleability;

21) receptor inducers of LDL (low density lipoprotein);

22) inhibitors of agglutination of platelets;

23) inhibitors of 5-LO (5-lipoxygenase)/FLAP (5-lipoxidase-activated protein);

24) agonists Niacin receptor.

Therapeutic drugs for the treatment of hypertension include, for example, the following medicinal medium spans the VA:

1) thiazide diuretics, such as chlorthalidone, chlorthiazide, dichlorphenamide, hydrocortisol, indapamide, and hydrochlorothiazide; loop diuretics, such as bumetanide, ethacrynic acid, placeme, tolazamide; sodium diuretics, such as amiloride, triamteren; dieterici - antagonists aldosterone, such as spironolactone, Abilene;

2) blockers β-adrenaline, such as acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, timolol;

3) calcium channel blockers such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, zineldin, clevidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lumisden, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipin, manidipine, pranidipine, verapamil;

4) inhibitors angiotensin-konvertiruyuschih enzyme, such as benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, losinopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, perindopril, quinapril, spirapril, temocapril, trandolapril, zofenopril;

5) inhibitors of neutral endopeptidase, such as omapatrilat, tubs shall atril, ecadotril, fasidotril, sampatrilat, AVE7688, ER4030;

6) endothelin antagonists such as tezosentan, A, YM62899;

7) vasodilators such as hydralazine, clonidine, methoxide, nicotinebuy alcohol;

8) antagonists, angiotensin-II receptor, such as candesartan, eprosartan, irbesartan, losartan, pratosartan, tasosartan, telmisartan, valsartan, EXP-AT 3,137, FI6828K, RNH6270;

9) blockers α/β of adrenaline, such as nipradilol, arotinolol, amosulalol;

10) α1 blockers such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP164, XEN010;

11) α2 agonists, such as lofexidine, tiamenidine, moxonidine, rilmenidine, guanabenz;

12) inhibitors of aldosterone.

Drugs against obesity include, for example, the following medications:

1) inhibitors vectors NT (serotonin), such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, imipramine;

2) inhibitors vector NE (norepinephrine), such as GW320659, desipramin, talsupram, nomifensine;

3) antagonists/inverse agonists, CB-1 (cannabinoid-1 receptor), such as rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY-65-2520 (Bayer), SLV-319 (Sorbei), and compounds described in U.S. patent No. 5532237, U.S. patent No. 4973587, U.S. patent No. 5013837, U.S. patent No. 5081122, U.S. patent No. 5112820, U.S. patent No. 5292736, U.S. patent No. 562491, U.S. patent No. 6028084, WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 01/96330, WO 98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 02/076949, WO 01/64632, WO 01/64633, WO 01/64634, WO 03/006007, WO 03/007887 and EP-658546;

4) antagonists Perina, such as compounds described in WO 01/87355, WO 02/08250;

5) antagonists/inverse agonists of the histamine (H3) such as typename, 3-(1H-imidazol-4-yl)propyl-N-(pentenyl)carbonate, closedprofit, jodieproffit, impressive, GT2395, A331440, compounds described in International application WO 02/15905, O-[3-(1H-imidazol-4-yl)propanolamine, piperazine-containing antagonists of the H3-receptor (Lazewska, D. et al., Pharmazie, 56: 927-32 (2001)), derivatives of benzophenone (Sasse, A. Et al., Arch. Pharm. (Weinheim) 334: 45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000)), derivatives of proxiphen (Sasse, A. et al., J. Med. Chem., 43: 3335-43 (2000));

6) antagonists sit-1R (receptor 1 melamine-concentrating hormone), such as T-226296 (Takeda), SNP-7941 (Synaptic), other compound described in WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027 and JP-A-2001-226269;

7) agonists/antagonists of the sit-2R (receptor 2 melamine-concentrating hormone);

8) NPY1 antagonists (neuropeptide YY1), such as BIBP3226, J-115814, BIBO3304, LY-357897, CP-671906, GI-264879, and other compounds described in U.S. patent No. 6,001,836, WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173 and WO 01/89528;

9) antagonists NPY5 (neuropeptide YY5), such as 152804, GW-569180A, GW-59488A, GW-587081X, GW-548118X, FR235,208, FR226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, JCF-104, and H409/22 and other compounds described in U.S. patent No. 6140354, U.S. patent No. 6191160, U.S. patent No. 6258837, U.S. patent No. 6313298, U.S. patent No. 6337332, U.S. patent No. 6329395, U.S. patent No. 340683, U.S. patent No. 6326375, U.S. patent No. 6329395, U.S. patent No. 6337332, U.S. patent No. 6335345, EP-01010691, EP-01044970, WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 1/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592 WO 02/48152, WO 02/49648, WO 02/094789, and the compounds described in the publication of Norman et al., J. Med. Chem., 43:4288-4312 (2000);

10) reptile, such as recombinant reptin person (PEG-OB, Hoffman La Roche), recombinant nationality (Amgen);

11) derivative of retina, such as compounds described in U.S. patent No. 5552524, U.S. patent No. 5552523, U.S. patent No. 5552522, U.S. patent No. 5521283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, 96/23518, WO 96/23519 and WO 96/23520;

12) opioid antagonists such as narmeen (Revex®), 3-methoxylation, naloxone, naltrexone, compounds described in WO 00/21509;

13) antagonists Apraksina, such as SB-334867A and other compounds described in WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838 and WO 03/023561;

14) BRS3 agonist (barbesino receptor subtype-3);

15) agonists, CCK-A (cholecystokinin (A), such as AR-R15849, GI-181771, JMV-180, A-71378, A-71623, SR-I other compounds, described in U.S. patent No. 5739106;

16) CNTF (ciliary neurotrophic factors)such as GI-181771 (Glaxo-Smith Kline), SR146131 (Sanofi Synthelabo), Buchbinder, PD170,292, PS 149164 (Pfizer);

17) CNTF derivatives, such as axokine (Regeneron) and other compounds described in WO 94/09134, WO 98/22128, WO 99/43813;

18) agonists GHS (receptor secretion of growth hormone, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, L-163,255, and compounds described in U.S. patent No. 6358951, applications for U.S. patent No. 2002/049196, 2002/022637, WO 01/56592, WO 02/32888;

19) agonists 5HT2c (serotonin receptor 2c), such as BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, YM348 and other compounds described in U.S. patent No. 3914250, WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456 and WO 02/40457;

20) Mc3r agonist (malacorhynchos 3 receptor);

21) Mc4r agonists (malacorhynchos 4 receptor), such as CHIR86036 (Chiron), ME-10142, ME-10145 (Melacure), and other compounds described in WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 01/70708, WO 01/70337, WO 01/91752, WO 02/059095, WO 02/059107, WO 02/059108, WO 02/059117, WO 02/12166, WO 02/11715, WO 02/12178, WO 02/15909, WO 02/068387, WO 02/068388, WO 02/067869, WO 03/007949 and WO 03/009847;

22) inhibitors of reuptake of monoamines, such as sibutramine (By®/Reductil®) and its salts and other derivatives described in U.S. patent No. 4746680, U.S. patent No. 4806570, U.S. patent No. 5436272, application for U.S. patent No. 2002/0006964, WO 01/27068 and WO 01/62341;

23) inhibitors of reuptake of serotonin, such as dexfenfluramin, fluoxetine and other soy is inane, described in U.S. patent No. 6365633, WO 01/27060 and WO 01/162341;

24) agonists GLP1 (glucagon-like peptide-1);

25) topiramate (Topimax®);

26) Phytopharm connection 57 (for example, CP644,673);

27) inhibitors of ACC2 (acetyl-CoA carboxylase-2);

28) agonists A (adrenaline receptor 3), such as AD9677/TAK677 (Dai-Nippon Pharmaceutical/Takeda Chemical), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, W427353, trekkin, Zeneca D7114, SR59119A, and other compounds described in U.S. patent No. 5705515, U.S. patent No. 5451677, WO 01/74782 and WO 02/32897;

29) DGAT1 inhibitors (diacylglycerides-1);

30) DGAT2 inhibitors (diacylglycerides-2),

31) inhibitors of FAS (fatty acid synthetase), such as cerulenin, C75;

32) inhibitors PDE (phosphodiesterase), such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast;

33) agonists thyroid hormone β, such as KB-2611 (KaroBio BMS) and other compounds described in WO 02/15845 and JP-A-2000-256190;

34) activators UCP (uncoupling protein)-1, 2 or 3, such as Vitanova acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid and other compounds described in WO 99/00123;

35) allextract, such as oleoresin (described in the publication del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001)),

36) glucocorticoid antagonists;

37) inhibitors of 11-β HSD1 (11-β-hydraxis is heroindependent-1), such as BVT3498, BVT2733 and other compounds described in WO 01/90091, WO 01/90090, WO 01/90092;

38) inhibitors of SCD1 (stearoyl-CoA desaturase-1);

39) inhibitors of DP-IV (dipeptidylpeptidase-IV), such as isoleucine-thiazolidin, Valine-pyrrolidide, NVP-DPP728, AF237, P93/01, TSL225, TMC-2A/2B/2C, FE999011, P9310/K364, VIP0177, SDZ274-444 and other compounds described in WO 03/004498, WO 03/004496, EP1258476, WO 02/083128, WO 02/062764, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO 03/000180 and WO 03/000181;

40) lipase inhibitors, such as tetrahydrolipstatin (Orlistat/Xenical®), Triton WR1339, RHC80267, lipstatin, tea saponin, diethylaminopropyl, FL-386, WAY-121898, Bay-N-3176, Wallaceton, Esterhazy, belachan a, electon B, RHC80267, and other compounds described in International application WO 01/77094, U.S. patent No. 4598089, U.S. patent No. 4452813, U.S. patent No. 5512565, U.S. patent No. 5391571, U.S. patent No. 5602151, U.S. patent No. 4405644, U.S. patent No. 4189438 and U.S. patent No. 4242453;

41) inhibitors vectors fatty acids;

42) inhibitors vector in primary forms;

43) inhibitors vectors glucose;

44) inhibitors vectors phosphate;

45) agonists melanocortin, such as Melanotan II and other compounds described in WO 99/64002 and WO 00/746799;

46) antagonists at the melanin-concentrating hormone;

47) antagonists Galanina;

48) CCK agonists;

49) hormones release of corticotropin;

50) agonists PDE3 (phosphodiesterase 3B).

Compounds according to the invention can in order to be combined with one or more of the above jointly used drugs. The combination of the compounds according to the invention with one or more commonly used drugs from the group comprising drugs from diabetes and medicines from hyperlipemia, may be useful for prevention or treatment of metabolic disorders. In particular, the combination of compounds according to the present invention with a medicinal remedy for hypertension and drug against obesity, along with drug diabetes or drug from hyperlipemia can be used for prevention or treatment of metabolic disorders, due to their synergistic effect.

When the compounds according to the present invention used in clinical practice, the dose and frequency of injection may depend on gender, age, weight and condition of the patient, and the type and purpose of the treatment of the patient. When administered orally to an adult patient, the dose can usually be from 0.01 to 100 mg/kg/day, preferably from 0.03 to 1 kg/kg/day, and it can be injected once or a few times in small doses, repeated after a certain period of time. Usually therapists, veterinarians and clinicians can easily determine the effective dose required for slowing, inhibiting, or stopping disease development.

<> EXAMPLES

Hereinafter the invention is described more specifically with reference to examples and reference examples, which, however, are not intended to limit the scope of the present invention.

For thin-layer chromatography of the compounds in the examples used Silicagel plate 60F245 (Merck); for visualization used a UV detector. For column chromatography with silicagel filler used a column filled with silica gel (FLASH+™ cartridge KP-Sil FLASH 12+M, FLASH25+M or FLASH40+M (Biotage Japan)). For HPLC with reversed phase used column YMC-Comb Prep ProC18 (YMC). For mass spectrometry used QuattroII (Micromass) method ionization elektrorazpredelenie (ESI).

In NMR spectrometry of dimethyl sulfoxide was used as internal standard for measurement in a solution of deuterated dimethyl sulfoxide. The sample was analyzed with a spectrometer Gemini-200 (200 MHz; Varian), Gemini-300 (300 MHz; Varian), Mercury 400 (400 MHz; Varian) or Inova 400 (400 MHz; Varian) to determine the value of δ in ppm

In LC-MS for determination of retention time and molecular weight in the examples (2-4)-(2-27) was used column Wakopak Comb ODS fast (diameter: 2.0 mm × 30 mm). Conditions: liquid A - 0.1% TFWC/water, liquid B - 0.1% TFWC/acetonitrile. A/B: from 95/5 to 40/60, elution for 6 minutes with a linear concentration gradient. The flow rate 0.8 ml/min

Abbre is iatory, used in the following examples, have the following meanings:

i-Bu: isobutylene group

n-Bu: n-bucilina group

t-Bu: tert-bucilina group

Me: methyl group

Et: ethyl group

Ph: phenyl group

i-Pr: isopropyl group

n-Pr: n-sawn group

CDCl3: deuterated chloroform

CD3OD: deuterated methanol

DMSO-d6: deuterated dimethyl sulfoxide

Abbreviations used in the description of the spectrum of nuclear magnetic resonance, have the following meanings:

s: singlet;

d: doublet

DD: double doublet

t: triplet

m: multiplet

ush.: extended

square: Quartet

J: constant interaction

Hz: Hertz

Example 1:

Obtain 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]

A mixture of 3H-Spiro[2-benzofuran-1,4'-piperidine] (131 mg, 0,695 mmol), 1-[3-(4-iodinase)propyl]piperidine (200 mg, of 0.58 mmol)obtained in reference example (2), tert-butoxide sodium (78 mg, 0,812 mmol), Pd2(dba)3(5 mg, 0,0058 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7 mg, 0,0116 mmol) in 1,4-dioxane is stirred overnight in a nitrogen atmosphere at 60°C. the Reaction solution is filtered with suction through celite, diluted with ethyl acetate, washed successively with water, saturated salt solution and the organic layer with the shat over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified preparative thin-layer chromatography (eluate: chloroform/methanol=10/1), getting mentioned in the title compound as a colorless solid matter (of 60.5 mg, 26%).

1H-NMR (400 MHZ, CDCl3) δ: 1,43 (2H, USS), 1.56 to to 1.61 (4H, m)to 1.87 (2H, d, J=12.0 Hz), 1,92 of 1.99 (2H, m), 2,08-of 2.16 (2H, m), 2,39-2,48 (6H, m), 3,10 (2H, t, J=12,4 Hz), 3,43 (2H, d, J=11.2 Hz), of 3.96 (2H, t, J=6.4 Hz), 5,09 (2H, s), 6,83 (2H, d, J=8,8 Hz), of 6.96 (2H, d, J=8,8 Hz), 7,13-to 7.15 (1H, m), 7,21-7,28 (3H, m).

Example 1-1:

Getting 4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol

Specified in the title compound obtained as a colorless solid substance in accordance with the method of example 1 or in a similar way, but using 4-phenylpiperidine-4-ol instead of 3H-Spiro[2-benzofuran-1,4'-piperidine].

1H-NMR (400 MHZ, CDCl3) δ: 1,43 (2H, USS), 1.56 to to 1.61 (4H, m)to 1.87 (2H, d, J=13,2 Hz), 1,91-of 1.97 (2H, m), 2.26 and-2,48 (8H, m), 3,14 (2H, t, J=12,4 Hz), 3,40 (2H, d, J=13,2 Hz), of 3.95 (2H, t, J=6 Hz), 6,83 (2H, d, J=8,8 Hz), to 6.95 (2H,, d, J=8,8 Hz), 7,26 (1H, t, J=8.0 Hz), was 7.36 (2H, t, J=8.0 Hz), 7,53 (2H, DD, J=3,6, 2.0 Hz).

Example 1-2:

Obtaining 3-phenyl-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a colorless solid substance in accordance with the method of example 1 or in a similar way, but using 3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he instead of 3-Spiro[2-benzofuran-1,4'-piperidine].

1H-NMR (400 MHZ, CD3OD) δ: 1,49-is 1.51 (2H, m), 1,61-to 1.67 (4H, m), 1,89-of 2.15 (6H, m), 2,52 at 2.59 (6H, m), 3.15 and 3.21-in (2H, m), 3,24-3,26 (2H, m), 3,32-3,98 (4H, m), 6,83 (2H, d, J=9,2 Hz), 6,98 (2H, d, J=9,2 Hz), 7,13 (1H, t, J=7,2 Hz), was 7.36 (2H, t, J=7,6 Hz), EUR 7.57 (2H, d, J=8,8 Hz).

Example 2:

Obtain 1'-[4-(3-piperidine-1-ylpropionic)phenyl-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

A mixture of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one (164 mg, 0.81 mmol), 1-(3-chloropropoxy)-4-yogashala (200 mg, 0,674 mmol)obtained in reference example (1), tert-butoxide sodium (91 mg, 0,943 mmol), Pd2(dba)3(3 mg, 0,00337 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (8 mg, 0,0134 mmol) in 1,4-dioxane is stirred for 2.5 hours in a nitrogen atmosphere at 60°C. After cooling, the reaction solution is filtered with suction through celite, diluted with chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the resulting residue is suspended in diethyl ether and then filtered off with suction, receiving chloroform in the form of a yellow solid substance (90 mg, 36%).

The obtained chloroform (80 mg) is mixed with piperidine (1 ml) and stirred at 100°C for 6 hours. After cooling, the reaction solution was concentrated and the resulting residue is dissolved in chloroform, then washed successively with water and saturated R is the target salt and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water, liquid B: 0.1% TFWC/acetonitrile, A/B=90/10 to 50/50, elution within 8 minutes with a linear concentration gradient, flow rate 40 ml/min), the fraction containing the target product, collecting, receiving specified in the title compound in the form of a solid pale yellow substance (to 34.5 mg, 38%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (2H, USS), 1,58-to 1.63 (4H, m)and 1.83 (2H, d, J=13,6 Hz), 1,94 is 2.01 (2H, m), 2,34 is 2.51 (8H, m), 3,23 (2H, t, J=12,4 Hz), 3,52 (2H, d, J=12.0 Hz), 3,98 (2H, t, J=6.8 Hz), 6,86 (2H, d, J=8,8 Hz), 6,97 (2H,, d, J=8,8 Hz), the 7.43 (1H, d, J=7,2 Hz), 7,535 (1H, t, J=7.2 Hz), to 7.68 (1H, t, J=7.2 Hz), of 7.90 (1H, d, J=7,2 Hz).

Example 2-1:

Getting 4-phenyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 2, or a similar method, but using 4-phenyl-4,9-diazaspiro[5,5]undecane-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

1H-NMR (400 MHz, CDCl3) δ: 1,78-2,03 (8H, m), and 2.14 (2H, d, J=13,2 Hz)to 2.54 (4H, USS), 2,61-to 2.65 (2H, m), is 3.08 (2H, TD, J=11,6, 2.4 Hz), with 3.27 (2H, dt, J=9,3, 2.7 Hz), 3,48 (1H, dt, J=17,2, 7,2 Hz), to 3.64 (2H, s), 3,98 (2H, t, J=6.0 Hz), of 4.35 (2H, s), 6,83 (2H, d, J=8,8 Hz)6,91 (2H, d, J=8,8 Hz), 7,25-7,31 (3H, m), 7,39-the 7.43 (2H, m).

Example 2-2:

9-[4-(3-((2S)-2-methylpyrrolidine-1-yl)propoxy)phenyl]-4-Hairdryer is l-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 2, or a similar method, but using as the starting material 4-phenyl-4,9-diazaspiro[5,5]undecane-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one, hydrobromide (2S)-2-methylpyrrolidine obtained in accordance with methods described in the literature (Journal of Organic Chemistry, J.O.C., 1989, Vol.54, p.209), and D-prolinol instead of piperidine.

1H-NMR (400 MHz, CDCl3) δ: 1,12 (3H, USS), 1,46 is 2.00 (9H, m), 2,12 to 2.35 (4H, m), 2,98-3,11 (3H, m), 3.25 to be 3.29 (3H, m)to 3.64 (2H, s), 3.96 points-to 4.01 (2H, m), 4,36 (2H, s), at 6.84 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,27-7,31 (3H, m), 7,41-44 (2H, m).

Example 2-3:

9-[4-(3-((3S)-3-methylpiperidin-1-yl)propoxy)phenyl]-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 2, or a similar method, but using as the starting material 4-phenyl-4,9-diazaspiro[5,5]undecane-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one, (3S)-3-methylpiperidin-(2S)-hydroxy(phenyl)acetate obtained in accordance with the method described in the literature (Journal of Organic Chemistry, J.O.C., 1987, Vol.52, p.5467), and 3-methylpiperidin instead of piperidine.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.8 Hz), 1,61-2,03 (11H, m), 1,98 is 2.01 (2H, m), and 2.14 (2H, d, J=13,2 Hz)to 2.55 (2H, USS), of 2.92 (2H, USS), 3.04 from-3,11 (2H, m), 3,24-3,30 (2H, m), 3,64 (2, C)of 3.97 (2H, t, J=6.3 Hz), 4,36 (2H, s), for 6.81-6,85 (2H, m), 6,91-to 6.95 (2H, m), 7,26-7,31 (3H, m).

Example 2-4:

Getting trifenatate 4-(4-forfinal)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-(4-forfinal)piperidine-4-ol instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,16 min;

m/z: 413,3 [M+H]+.

Example 2-5:

Getting trifenatate 1-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-3-reparacin-4-ol

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-pyridin-3-reparacin-4-ol instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: up to 1.98 min;

m/z: 396,3 [M+H]+.

Example 2-6:

Getting trifenatate 4-(4-methoxyphenyl)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-(4-methoxyphenyl)piperidine-4-ol instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: is 3.08 min;

m/z: 425,3 [M+H]+.

Example 2-7:

aluchemie of triptoreline 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 5-fluoro-3H-Spiro[2-benzofuran-1,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,71 min;

m/z: 425,3 [M+H]+.

Example 2-8:

Getting trifenatate 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 5-fluoro-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,42 min;

m/z: RUR 439,3 [M+H]+.

Example 2-9:

Getting trifenatate 7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 7-fluoro-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,32 min;

m/z: RUR 439,3 [M+H]+.

Example 2-10:

Getting trifenatate 5-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperid is h]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 5-methoxy-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: to 3.58 min;

m/z: 451,3 [M+H]+.

Example 2-11:

Getting trifenatate 6-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 6-methoxy-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,56 min;

m/z: 451,3 [M+H]+.

Example 2-12:

Getting trifenatate 7-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 7-methoxy-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,60 min;

m/z: 451,3 [M+H]+.

Example 2-13:

Getting trifenatate 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1H-Spiro[furo[3,4-c]feast the Dean-3,4'-piperidine]-1-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 1H-Spiro[furo[3,4-c]pyridine-3,4'-piperidine]-1-he instead 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,11 min;

m/z: 422,3 [M+H]+.

Example 2-14:

Getting trifenatate 1-(methylsulphonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 1-(methylsulphonyl)-1,2-dihydrospiro[indole-3,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,76 min;

m/z: 484,3 [M+H]+.

Example 2-15:

Getting trifenatate 1-(ethylsulfonyl)-7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 1-(ethylsulfonyl)-7-fluoro-1,2-dihydrospiro[indole-3,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,98 min;

m/z: 516,3 [[M+H]+.

Example 2-16:

Getting trifenatate 1-(ethylsulfonyl)-5-ftor'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 1-(ethylsulfonyl)-5-fluoro-1,2-dihydrospiro[indole-3,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 4,17 min;

m/z: 516,3 [M+H]+.

Example 2-17:

Getting trifenatate 4-tert-butoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-tert-butoxy-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 4,39 min;

m/z: 493,4 [M+H]+.

Example 2-18:

Getting trifenatate 1-(ethylsulfonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 1-(ethylsulfonyl)-1,2-dihydrospiro[indole-3,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 4,06 min;

m/z: 498,3 [M+H]+.

Example 2-19:

Getting trifenatate 3,3-dimethyl-1'-[4-(3-Pieper is DIN-1 ipropose)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 3,3-dimethyl-3H-Spiro[2-benzofuran-1,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 4,00 min;

m/z: 435,4 [M+H]+.

Example 2-20:

Getting trifenatate 3-methyl-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 3-methyl-3H-Spiro[2-benzofuran-1,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: of 3.78 min;

m/z: 421,4 [M+H]+.

Example 2-21:

Getting trifenatate 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3,4-dihydrospiro[chroman-2,4'-piperidine]

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 3,4-dihydrospiro[chroman-2,4'-piperidine] instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,93 min;

m/z: 421,4 [M+H]+.

Example 2-22:

Getting trifenatate phenyl{1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-yl}methanone

Specified in sagola the COC connection receive in the form of a solid pale yellow substance in accordance with the method of example 2, or equivalent means, but using phenyl(piperidine-4-yl)methanon instead 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,29 min;

m/z: 407,3 [M+H]+.

Example 2-23:

Getting trifenatate 4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-carbonitrile

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-phenylpiperidine-4-carbonitrile instead 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,82 min;

m/z: 404,4 [M+H]+.

Example 2-24:

Getting trifenatate 4-benzyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-carbonitrile

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-benzylpiperidine-4-carbonitrile instead 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: of 3.78 min;

m/z: 418,4 [M+H]+.

Example 2-25:

Getting trifenatate 4-methyl-4-phenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-methyl-4-phenylpiperidine instead 3H-Spiro[2-benzofuran-1,4'-piperid is h]-3-one.

Retention time: 3,56 min;

m/z: 393,4 [M+H]+.

Example 2-26:

Getting trifenatate 4,4-diphenyl-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4,4-diphenylpiperazine instead 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 4,28 min;

m/z: 455,4 [M+H]+.

Example 2-27:

Getting trifenatate 4-(3-methoxyphenyl)-1-[4-(3-piperidine-1-ylpropionic)phenyl]piperidine-4-ol

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 2, or a similar method, but using 4-(3-methoxyphenyl)piperidine-4-ol instead of 3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one.

Retention time: 3,03 min;

m/z: 425,4 [M+H]+.

Example 3:

Getting 4-(4-forfinal)-9-[4-(3-[(3S)-3-methylpiperidin-1-yl]propoxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)1-oxa-4,9-diazaspiro[5,5]undecane-3-one (100 mg, 0.25 mmol)obtained in reference example 12-1, 1-bromo-4-fervently (52 mg, 0.25 mmol), potassium phosphate (110 mg, 0.50 mmol), copper iodide (23 mg, 0.125 mmol), N,N'-dimethylaminoethanol (22 mg, 0.25 mmol) in 1,4-dioxane is stirred over night in Germany is ichno a sealed tube at 110°C. The reaction solution was diluted with ethyl acetate, washed successively with water, saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water; liquid B: 0.1% TFWC/acetonitrile; A/B=90/10 to 50/50; elution with a linear concentration gradient over 8 min; flow rate 40 ml/min), collecting the fraction containing the target product. Then the solvent is evaporated under reduced pressure and the resulting residue is neutralized by adding 2n. an aqueous solution of sodium hydroxide. The mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution and dried over sodium sulfate. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as brown solid substance (83,7 mg, 68%).

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,53-1,72 (6H, m), 1,82-1,90 (3H, m), 1.93 and is 2.00 (2H, m), 2,13 (2H, d, J=12.9 Hz), 2,46-of 2.50 (2H, m), 2,83-2,90 (2H, m), of 3.07 (2H, t, J=10,6 Hz), with 3.27 (2H, d, J=12,5 Hz), 3,60 (2H, C)of 3.96 (2H, t, J=6.3 Hz), 4,35 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,92 (2H, d, J=9.0 Hz), 7,11 (2H, t, J=8.6 Hz), 7,26-7,28 (2H, m).

Example 3-1:

Getting 4-(6-herperidin-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as the solid pale yellow substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6,7 Hz), 1,61-of 1.73 (6H, m), 1,82-1,89 (3H, m)of 1.97 (2H, USS), 2,11-of 2.16 (2H, m), 2,52 (2H, s), 2,90 (2H, OSS), was 3.05 (2H, t, J=10,6 Hz), with 3.27 (2H, d, J=12.1 Hz), to 3.64 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,36 (2H, s), PC 6.82 (2H, d, J=9.0 Hz), 6,91 (2H, d, J=9.0 Hz), of 6.99 (1H, DD, J=8,6, 3.1 Hz), 7,80-a 7.85 (1H, m), 8,17 (1H, s).

Example 3-2:

Getting 4-(methoxyphenyl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 1-bromo-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,53-1,72 (10H, m), 1,82 is 2.00 (5H, m), 2,13 (2H, d, J=13.3 Hz), 2,48 (2H, t, J=7.0 Hz), 2,90-2,82 (2H, m), of 3.07 (2H, t, J=10.4 Hz), 3,26 (2H, d, J=12.1 Hz)and 3.59 (2H, s), 3,81 (3H, (C), of 3.96 (2H, t, J=6.5 Hz), 4,34 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,91-to 6.95 (4H, m), 7,20 (2H, d, J=9.0 Hz).

Example 3-3:

Getting 4-(4-were-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid blignault substances in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 1-bromo-4-methylbenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (4H, d, J=6.8 Hz), 1,53-1,72 (10H, m), 1,82-1,90 (3H, m), 1.93 and is 2.00 (2H, m), 2,13 (2H, d, J=12.9 Hz), a 2.36 (3H, s), 2,48 (2H, t, J=7.4 Hz), of 2.86 (2H, t, J=12,7 Hz), of 3.07 (2H, t, J=10,6 Hz), 3,26 (2H,, d, J=12.1 Hz), 3,61 (2H, s), of 3.96 (2H, t, J=6.5 Hz), 4,35 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,93 (2H, d, J=9.0 Hz), 7,17 (2H, d, J=8,2 Hz), 7.23 percent (2H, d, J=8,2 Hz).

Example 3-4:

Getting 4-(6-methoxypyridine-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1,54-1,72 (6H, m), 1,83-1,90 (3H, m), 1.93 and is 2.00 (2H, m), 2,13 (2H, d, J=12.9 Hz), 2.49 USD (2H, t, J=7.4 Hz), 2,83-only 2.91 (2H, m), of 3.07 (2H, t, J=10,6 Hz), with 3.27 (2H, d, J=12,5 Hz), 3,60 (2H, s), 3,94-3,98 (5H, m), 4,36 (2H, s), 6,78-6,85 (3H, m), 6,93 (2H, d, J=9.0 Hz), 7,55 (1H, DD, J=9,0, 2.7 Hz), 8,10 (1H, d, J=2.3 Hz).

Example 3-5:

9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-4-(2-methylpyridin-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header is the connection receive in the form of a solid pale yellow substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-2-methylpyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1.56 to at 1.73 (6H, m), 1,83 is 2.00 (5H, m), and 2.14 (2H, d, J=13.3 Hz), 2.49 USD (2H, t, J=7.2 Hz), to 2.57 (3H, s), 2,84-2,90 (2H, m), of 3.07 (2H, t, J=10.4 Hz), 3,26-3,29 (2H, m)to 3.64 (2H, s), of 3.96 (2H, t, J=6.5 Hz), 4,37 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,93 (2H, d, J=9.0 Hz), 7,22 (1H, d, J=8,2 Hz), 7,58 (1H, DD, J=8,2, 2.3 Hz), 8,46 (1H, d, J=2.7 Hz).

Example 3-6:

Getting 4-(3,4-differenl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 4-bromo-1,2-differenza instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1,54-of 1.73 (6H, m), 1,82-1,89 (3H, m), 1.93 and is 2.00 (2H, m), 2,11 (2H, d, J=12.1 Hz), 2.49 USD (2H, t, J=8,2 Hz), 2,87 (2H, t, J=13.5 Hz), 3,06 (2H, t, J=10,6 Hz), with 3.27 (2H, d, J=12,5 Hz), of 3.60 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,35 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,92 (2H, d, J=9.4 Hz), 7,05 (1H, d, J=9.0 Hz), 7,17-7,24 (2H, m).

Example 3-7:

Getting 4-(2,4-differenl)-9-(4-{3-[(3S)-3-piperidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header of the compounds is their gain in the form of a solid pale yellow substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 1-bromo-2,4-differenza instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1,54-of 1.73 (6H, m), 1,84 is 2.00 (5H, m), of 2.15 (2H, d, J=13.3 Hz), 2.49 USD (2H, t, J=7.4 Hz), 2,84-only 2.91 (2H, m), is 3.08 (2H, t, J=10.4 Hz), 3,26 (2H, d, J=12.1 Hz), of 3.56 (2H, s), of 3.96 (2H,, t, J=6.5 Hz), 4,37 (2H, s), at 6.84 (2H, d, J=9.0 Hz), 6,94 (4H, square, J=6.3 Hz), 7,26 (1H, s).

Example 3-8:

Getting 4-phenyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and bramasol instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: USD 1.43 (2H, m), 1.56 to to 1.60 (4H, m), 1,84 of 1.99 (4H, m), 2,13 (2H, d, J=13,2 Hz), 2.40 a-2,48 (6H, m), 3,05-3,10 (2H, m), 3,26 (2H, d, 3=a 12.4 Hz), to 3.64 (2H, s), of 3.96 (2H, t, J=6.4 Hz), 4,36 (2H, s), at 6.84 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,28-7,31 (3H, m), 7,41 was 7.45 (2H, m).

Example 3-9:

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-4-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-is propoxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12 and 4-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: 1,43-to 1.45 (2H, m), 1.56 to to 1.61 (4H, m), 1,82-1,90 (2H, m), 1.91 a-to 1.98 (2H, m), 2,11 (2H, d, J=12,4 Hz), 2,39 (4H, USS), 2,44-2,48 (2H, m), 3,06 (2H, TD, J=11,6, 2.0 Hz), or 3.28 (2H, dt, J=12,4, 4.0 Hz), 3,68 (2H, ), of 3.96 (2H, t, J=6.4 Hz), 4,37 (2H, s), at 6.84 (2H, d, J=8.0 Hz), 6,92 (2H, d, J=8.0 Hz), 7,39-7,41 (2H, m), 8,62-8,64 (2H, m).

Example 3-10:

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 2-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, DMSO-d6) δ: 1,44 (2H, USS), 1,58-to 1.61 (4H, m), 1.85 to to 1.98 (4H, m)2,07 (2H, d, J=13,6 Hz)to 2.41 (4H, USS), 2,48 (2H, t, J=7,6 Hz), 3.04 from-3,11 (2H, m), 3.25 to or 3.28 (2H, m), of 3.96 (2H, t, J=6,4 Hz)to 4.01 (2H, s), 4,37 (2H, C)6,83 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,11-7,14 (1H, m), 7,70-7,74 (1H, m), of 8.09 (1H, d, J=8,4 Hz), 8,42-8,43 (1H, m).

Example 3-11:

Getting 4-[6-(deformedarse)pyridine-3-yl]-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-METI is piperidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-1, and 5-bromo-2-(deformedarse)pyridine obtained in reference example 16, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.8 Hz), 1,57-1,72 (6H, m), 1,83-1,90 (3H, m), 1,95-2,00 (2H, m), 2,13 (2H, d, J=a 12.7 Hz), 2,46-of 2.50 (2H, m), 2,83-2,90 (2H, m), of 3.07 (2H, TD, J=11,2, 2.4 Hz), or 3.28 (2H, dt, J=12,2, a 3.9 Hz), 3,63 (2H, s), of 3.96 (2H, t, J=6.6 Hz), 4,37 (2H, s), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,9 Hz), of 6.96 (1H, d, J=8,8 Hz), 7,44 (1H, t, J=73,2 Hz), 7,74 (1H, DD, J=8,8, 2,9 Hz), 8,17 (1H, d, J=2,4 Hz).

Example 3-12:

Getting 4-(6-isopropoxypyridine-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-2-isopropoxypyridine obtained in reference example 17, instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), of 1.34 (6H, d, J=6.3 Hz), 1,57-of 1.73 (6H, m), 1,82-1,90 (3H, m), 1,95 of 1.99 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2,48 (2H, USS,), 2,87 (2H, USS), of 3.07 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=12,7, 4,4 Hz), of 3.60 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,35 (2H, s), 5,24-5,31 (1H, m), 6,72 (1H, d, J=8,8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), 7,51 (1H, DD, J=8,8, 2.4 Hz), 8,07 (1H, d, J=2,9 Hz).

Example 3-13:

Getting 4-(6-isopropoxypyridine-3-yl)-9-[4-(3-piperidin is-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound as yellow solid substances receive in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 5-bromo-2-isopropoxypyridine obtained in reference example 17, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.34 (6H, d, J=6.3 Hz), the 1.44 (2H, USS), 1,58-to 1.61 (4H, m), 1,83-1,90 (2H, m), 1,92 of 1.99 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2,39-2,49 (6H, m), of 3.07 (2H, TD, J=11,6, 2.4 Hz), with 3.27 (2H, dt, J=12,2, and 3.7 Hz), 3,60 (2H, s), of 3.96 (2H, t, J=6.6 Hz), 4,35 (2H, s), 5,24-5,31 (1H, m), 6,72 (1H, d, J=8,8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,4 Hz), 7,51 (1H, DD, J=8,8, 2,9 Hz), of 8.06 (1H, d, J=2,4 Hz).

Example 3-14:

Getting 4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 5-bromo-2-(deformedarse)pyridine obtained in reference example 16, instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: 1,44 (2H, s), 1.56 to of 1.62 (4H, m), 1,83-1,90 (2H, m), 1,92 of 1.99 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2.40 a-2,48 (6H, m), of 3.07 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, 3,9 Hz), 3,63 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,37 (2H, s), at 6.84 (2H,dt, J=9,3, 3,4 Hz)6,91 (2H, dt, J=9,3, 3,4 Hz), of 6.96 (1H, d, J=8,8 Hz), 7,44 (1H, t, J=73,7 Hz), 7,74 (1H, DD, J=8,5, 2.7 Hz), 8,17 (1H, d, J=2.0 Hz).

Example 3-15:

Getting 4-(2-methoxypyridine-5-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, s), 1.56 to of 1.62 (4H, m), 1,83-1,90 (2H, m), 1,92 of 1.99 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2.40 a-2,48 (6H, m), of 3.07 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, 3,9 Hz), 3,63 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,37 (2H, s), at 6.84 (2H, dt, J=9,3, 3,4 Hz)6,91 (2H, dt, J=9,3, 3,4 Hz), of 6.96 (1H, d, J=8,8 Hz), 7,44 (1H, t, J=73,7 Hz), 7,74 (1H, DD, J=8,5, 2.7 Hz), 8,17 (1H, d, J=2.0 Hz).

Example 3-16:

Getting 4-(2-methoxypyridine-5-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CCl 3) δ: 0,86 (3H, d, J=6.3 Hz), 1,55-1,72 (6H, m), 1,84 is 1.91 (3H, m), 1,94 is 2.00 (2H, m), and 2.14 (2H, d, J=13,2 Hz), 2,46-of 2.50 (2H, USM), 2,83-2,89 (2H, USM), 3,06 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, a 3.9 Hz), 3,63 (2H, s), of 3.96 (2H, t, J=6.6 Hz), a 4.03 (3H, s), 4,37 (2H, s), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), 8,53 (2H, s).

Example 3-17:

Getting 4-(6-methoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2 and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,79-1,90 (6H, m), 1,97-2,04 (2H, m), 2,13 (2H, d, J=a 12.7 Hz), of 2.56 (4H, s)of 2.64 (2H, t, J=7,3 Hz), of 3.07 (2H, TD, J=11,7, 2.3 Hz), with 3.27 (2H, dt, J=12,7, 3,9 Hz), of 3.60 (2H, s), of 3.94 (3H, s), 3,98 (2H, t, J=6.6 Hz), 4,35 (2H, s), 6,79 (1H, d, J=8,8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), 7,54 (1H, DD, J=8,8, 2.4 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-18:

Getting 4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a colorless oily substance according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]at the decane-3-one, obtained in reference example 12-3, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.47 (1H, m), 1,58 is 2.01 (7H, m), 2,09 of-2.32 (5H, m), 2,94-a 3.01 (1H, m), 3,03-3,10 (2H, m), 3,16-is 3.21 (1H, m), 3,24-3,29 (2H, m), of 3.60 (2H, s), of 3.94 (3H, s), 3.95 to 4,01 (2H, m), of 4.35 (2H, s), 6,79 (1H, d, J=8,8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,54 (1H, DD, J=8,8, 2.4 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-19:

Getting 4-(6-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]-undecane-3-one

Specified in the title compound obtained as a brown viscous substance in accordance with the method of example 3 or in a similar way, using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), of 1.42 (1H, USS), 1,61-2,01 (7H, m), 2,08-2,31 (5H, m), 2,94-a 3.01 (1H, m), of 3.07 (2H, TD, J=11,2, 2,9 Hz), 3.15 and 3.21-in (1H, m), with 3.27 (2H, dt, J=11,7, 3,9 Hz), of 3.60 (2H, s), of 3.94 (3H, s), 3,95-4,01 (2H, m), 4,35 (2H, s), 6,79 (1H, d, J=8,8 Hz), 6,85 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), 7,55 (1H, DD, J=8,8, 2,9 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-20:

Getting 4-(4-forfinal)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the methods of the IR of example 3 or equivalent means, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 1-bromo-4-torbenson.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=6.3 Hz), 1,39 of 1.46 (1H, m), 1,58 is 2.01 (7H, m), 2,07-of 2.21 (4H, m), 2,24 of-2.32 (1H, m), 2,93-a 3.01 (1H, m), 3.04 from-3,10 (2H, m), 3,15-3,20 (1H, m), 3.25 to be 3.29 (2H, m), of 3.60 (2H, s), 3.95 to 4,01 (2H, m), 4,35 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,08-7,14 (2H, m), 7,25-7,29 (2H, m).

Example 3-21:

Getting 4-(4-methoxyphenyl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a buttery pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 1-bromo-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=6.3 Hz), 1,37 of 1.46 (1H, m), 1,57-2,01 (7H, m), 2,07-of 2.21 (4H, m), 2,25 of-2.32 (1H, m), 2.93 which is 3.00 (1H, m), 3.04 from-3,11 (2H, m), 3,15-3,20 (1H, m), 3,24-3,29 (2H, m)and 3.59 (2H, s), 3,81 (3H, s), 3,95-4,01 (2H, m), 4,34 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,92-to 6.95 (4H, m), 7,20 (2H, d, J=8,8 Hz).

Example 3-22:

Getting 4-(1,3-benzodioxol-5-yl)-9-(4-{3-[2R]-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid in accordance with the methodology primer or equivalent means, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 5-bromo-1,3-benzodioxol instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=5,9 Hz), 1,39 of 1.46 (1H, m), 1.56 to a 2.00 (7H, m), 2,07-2,31 (5H, m), 2.93 which is 3.00 (1H, m), 3,03-3,10 (2H, m), 3,15-3,20 (1H, m), 3,24 of 3.28 (2H, m), of 3.57 (2H, s), 3,94-4,01 (2H, m)to 4.33 (2H, s), of 5.99 (2H, s)of 6.71 (1H, DD, J=8,3, 2.4 Hz), 6,78 (1H, d, J=2.0 Hz), 6,82-6,86 (3H, m), 6,93 (2H, d, J=9,3 Hz).

Example 3-23:

Getting 4-(2-methoxypyridine-4-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 4-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,51-1,72 (6H, m), 1,80-of 1.88 (3H, m), 1,92 of 1.99 (2H, m), is 2.09 (2H, d, J=13,2 Hz), the 2.46 (2H, t, J=7,6 Hz), 2,81-is 2.88 (2H, m), 3,05 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=11,2, 3,9 Hz), to 3.64 (2H, s), 3,94-3,97 (5H, m), 4,35 (2H, s), of 6.75 (1H, d, J=1.5 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,4 Hz),? 7.04 baby mortality (1H, DD, J=2.0 a, 5,9 Hz), 8,16 (1H, d, J=5,9 Hz).

Example 3-24:

Getting 4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Pointed to by the e in the title compound obtained as yellow solid substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-1-methylpyridin-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.85 (3H, t, J=6.6 Hz), 1,51-1,71 (6H, m), 1,81-of 1.88 (3H, m), 1,92 of 1.99 (2H, m), is 2.09 (2H, d, J=13,2 Hz), 2,47 (2H, t, J=7,6 Hz), 2,81-2,89 (2H, m), 3,05 (2H, TD, J=11,7, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,4 Hz), 3,52 (2H, s), 3,55 (3H, s), of 3.96 (2H, t, J=6.6 Hz), 4,32 (2H, s), 6,62 (1H, d, J=9.8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,4 Hz), 7,25-7,28 (1H, m), 7,39 (1H, d, J=2,9 Hz).

Example 3-25:

Getting 4-(2-methoxypyridine-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a viscous brown substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12 and 4-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,43 (2H, s), 1.56 to to 1.61 (4H, m), 1,81-of 1.88 (2H, m), 1,92 of 1.99 (2H, m), is 2.09 (2H, d, J=a 12.7 Hz), 2,39-2,48 (6H, m), 3,05 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,9 Hz)to 3.64 (2H, s), 3.95 to 3,97 (5H, m), 4,35 (2H, s), of 6.75 (1H, d, J=2.0 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,4 Hz),? 7.04 baby mortality (1H, DD, J=5,4, 2.0 Hz), 8,16 (1H, d, J=5,9 Hz).

Example 3-26:

Getting 4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 5-bromo-1-methylpyridin-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, s), 1,57-to 1.63 (4H, m), 1,81-of 1.88 (2H, m), 1.93 and of 1.99 (2H, m), is 2.09 (2H, d, J=13,2 Hz), 2.40 a-2,49 (6H, m), 3,05 (2H, TD, J=11,7, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,4 Hz), 3,52 (2H, s), 3,55 (3H, s), of 3.96 (2H, t, J=6.6 Hz), 4,32 (2H, s), 6,62 (1H, d, J=9.8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz)6,91 (2H, dt, J=9,3, 3,4 Hz), 7,25-7,28 (1H, m), 7,39 (1H, d, J=2,9 Hz).

Example 3-27:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.47 (1H, m), 1,57-2,01 (7H, m), 2.05 is-of 2.21 (4H, m), 2,25-2,31 (1H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,11 (2H, m), 3,15-3,20 (1H, m), 3.25 to 3,30 (2H, m), 3.95 to 4,01 (4H, m), 4,37 (2H, C)at 6.84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,13 (1H, DDD, J=7,3, a 4.9, 1.0 Hz), 7,73 (1H, DDD, J=8,8, to 6.8, 1.5 Hz), of 8.09 (1H, d, J=8,3 Hz), 8,43 (1H, DQC, J=4,9, 1.0 Hz).

Example 3-28:

Getting 4-(5-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-5-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=5,9 Hz), of 1.37 to 1.47 (1H, m), 1,64-to 1.82 (2H, m), 1.85 to a 2.01 (5H, m), 2.05 is-a 2.12 (3H, m), 2,14-2,22 (1H, m), 2.26 and is 2.33 (4H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,10 (2H, m), 3,15-3,20 (1H, m), 3,24-3,29 (2H, m), 3.95 to 4,01 (4H, m), 4,35 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 7,54 (1H, DD, J=9,0, 2.2 Hz), to 7.93 (1H, d, J=8,8 Hz), 8,24 (1H, s).

Example 3-29:

Getting 4-(4-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-4-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), of 1.37 to 1.47 (1H, m), 1,57-of 1.81 (2H, m), 1,84 is 2.01 (5H, m), 2,04-2,12 (3H, m), 2,15-2,22 (1H, m), 2,25 of-2.32 (1H, m), 2,39 (3H, s), 2,94-a 3.01 (1H, m), 3,4-3,10 (2H, m), 3,15-3,20 (1H, m), 3,24-3,29 (2H, m), 3.95 to 4,01 (4H, m), 4,36 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), of 6.96 (1H, d, J=4.4 Hz), 7,87 (1H, s), of 8.28 (1H, d, J=4,9 Hz).

Example 3-30:

Getting 4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.47 (1H, m), 1,57-of 1.81 (2H, m), 1,88 is 2.01 (5H, m), 2,08-2,22 (4H, m), 2,24 of-2.32 (4H, m), 2,94-a 3.01 (1H, m), 3,06-of 3.12 (2H, m), 3,16-is 3.21 (1H, m), 3.25 to and 3.31 (2H, m), 3,34-3,47 (1H, USS), 3,94-4,10 (3H, m), 4,36 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,21 (1H, DD, J=7,6, 4.6 Hz), to 7.61 (1H, DD, J=7,3, 1.5 Hz), scored 8.38 (1H, DD, J=4,6, 1.2 Hz).

Example 3-31:

Getting 4-(5-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-5-methoxypyridine instead Brom-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.48 (1H, m), 1.56 to is 1.81 (2H, m), 1.85 to a 2.01 (5H, m), 2.06 to of 2.23 (4H, m), 2,27 is 2.33 (1H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,11 (2H, m), 3,16-is 3.21 (1H, m), 3,24-3,29 (2H, m), a 3.87 (3H, C)3,93 (2H, s), 3.95 to 4,01 (2H, m), 4,35 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,27 (1H, DD, J=8,5, and 3.7 Hz), 7,92 (1H, d, J=9.3 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-32:

Getting 4-(6-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-6-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.47 (1H, m), 1,58 and 1.80 (5H, m), 1.85 to 2.00 in (5H, m), 2.05 is-2,22 (4H, m), 2,25 is 2.33 (1H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,11 (2H, m), 3,16-is 3.21 (1H, m), 3,24-3,30 (2H, m)to 3.89 (3H, s), 3.95 to 4,01 (4H, m), 4,35 (2H, s), to 6.57 (1H, DD, J=7,8, 1.0 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,60-to 7.68 (2H, m).

Example 3-33:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(3-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]ProPak and}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 3-bromothiophene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=6.3 Hz), 1,42-1,49 (1H, m), 1,59-2,02 (7H, m), 2,08 was 2.25 (4H, m), 2,31-of 2.38 (1H, m), 2,96-is 3.08 (3H, m), 3,18-3,30 (3H, m)to 3.67 (2H, s), 3.95 to 4,01 (2H, m), 4,34 (2H, s), at 6.84 (2H, d, J=and 9.3 Hz), 6,93 (2H, d, J=8,8 Hz), 7,31-7,33 (3H, m).

Example 3-34:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromothiophene instead of 1-bromo-4-fervently.

1H-NMR (400 MHZ, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), of 1.40 to 1.48 (1H, m), 1,57-of 1.81 (2H, m), 1.85 to 2,02 (5H, m), 2,09-of 2.24 (4H, m), and 2.27 to 2.35 (1H, m), 2.95 and-is 3.08 (3H, m), 3,17-up 3.22 (1H, m), 3,26-and 3.31 (2H, m), 3,74 (2H, s), 3.95 to 4,01 (2H, m), and 4.40 (2H, s), to 6.67 (1H, DD, J=3,9, 1.5 Hz), 6,85 (2H, d, J=9.3 Hz), 6,91-6,94 (3H, m), 7,01 (1H, DD, J=5,9, 1.5 Hz).

Example 3-35:

Getting 4-(4-methoxyphenyl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5|undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, sex is obtained in reference example 12-2, and 1-bromo-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,82-1,89 (6H, m), 2,02-of 2.15 (4H, m), 2,66-to 2.74 (6H, m), of 3.07 (2H, TD, J=11,7, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,9 Hz)and 3.59 (2H, s), 3,81 (3H, s)to 3.99 (2H, t, J=6.3 Hz), 4,34 (2H, s), 6,83 (2H, dt, J=9,3, 3,4 Hz), 6,91-of 6.96 (4H, m), 7,20 (2H, dt, J=9,3, 3,4 Hz).

Example 3-36:

Getting 4-(6-herperidin-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound in the form of hard yellow substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2 and 5-bromo-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,84 is 1.91 (6H, m), 2.05 is-of 2.15 (4H, m), 2,69 is 2.75 (6H, m), of 3.07 (2H, TD, J=11,7, 2.4 Hz), 3,29 (2H, dt, J=12,2, 3,9 Hz), the 3.65 (2H, s)to 3.99 (2H, t, J=6.3 Hz), 4,37 (2H, s), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), 7,00 (1H, DD, J=8,8, 3,4 Hz), 7,81-7,86 (1H, m), 8,18-8,19 (1H, m).

Example 3-37:

Getting 4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2 and 5-bromo-2-(debtor is ethoxy)pyridine, obtained in reference example 16, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,77-of 1.81 (4H, m), 1,83-1,90 (2H, m), 1,95-2,02 (2H, m), 2,13 (2H, d, J=a 12.7 Hz), of 2.51-of 2.54 (4H, m), 2,61 (2H, t, J=7,6 Hz), 3,06 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,7, 2,9 Hz), 3,63 (2H, s), 3,98 (2H, t, J=6.6 Hz), 4,37 (2H, s), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz), of 6.96 (1H, d, J=8,8 Hz), 7,44 (1H, t, J=72,7 Hz), 7,74 (1H, DD, J=8,8, 2.4 Hz), 8,16 (1H, d, J=2,4 Hz).

Example 3-38:

Getting 5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinanilide

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), of 1.41 to 1.47 (1H, m), 1,58-to 1.79 (2H, m), 1,84 is 2.01 (5H, m), 2,11 is 2.33 (5H, m), 2.95 and-to 3.09 (3H, m), 3,16-up 3.22 (1H, m), 3.27 to of 3.32 (2H, m), 3,71 (2H, s), 3,94-4,01 (2H, m), and 4.40 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=8,8 Hz), 8,10 (1H, DD, J=2,2, 1,1 Hz), 8,76 (1H, d, J=1.5 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-39:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(1,3-thiazol-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 3 or anal is the same way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-1,3-thiazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.14 in (3H, d, J=6.3 Hz), 1,43-of 1.52 (1H, m), 1,59-2,09 (9H, m), 2,14-of 2.30 (2H, m), 2,34 is 2.46 (1H, m), 2,98-to 3.09 (3H, m), 3,22-of 3.31 (3H, m), 3,94-was 4.02 (2H, m)to 4.16 (2H, s), to 4.46 (2H, s), at 6.84 (2H, d, J=and 9.3 Hz), 6,93 (2H, d, J=9.3 Hz), was 7.08 (1H, d, J=3,4 Hz), 7,53 (1H, d, J=3,4 Hz).

Example 3-40:

Obtaining 3-(4-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-4-torbenson.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,58-to 1.59 (4H, m), 1,94-of 2.05 (4H, m), of 2.15 (2H, d, J=13,6 Hz), 2.40 a (4H, USS), 2,47 (2H, t, J=7.2 Hz), 3,24-of 3.27 (4H, m), of 3.78 (2H, s), of 3.97 (2H, t, J=16.4 Hz), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), was 7.08 (2H, t, J=8.0 Hz), 7,52 (2H, DD, J=9,2, 4,8 Hz).

Example 3-41:

Getting 8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-(pyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-di is suspiro[4,5]decane-2-it, obtained in reference example 15 and 2-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,43-to 1.45 (2H, m), 1.56 to to 1.60 (4H, m), 1.93 and e 2.06 (4H, m), 2,13-2,17 (2H, m), 2,39 (4H, USS), the 2.46 (2H, t, J=7,6 Hz), 3,22-3,26 (4H, m), of 3.95 (2H, t, J=6.0 Hz), Android 4.04 (2H, s), PC 6.82 (2H, d, J=8,8 Hz)6,91 (2H, d, J=8,8 Hz), 7,01? 7.04 baby mortality (1H, m), to 7.67-7,72 (1H, m), 8,23 (1H, d, J=8,4 Hz), 8,29-8,31 (1H, m).

Example 3-42:

Getting 8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-(pyridin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 4-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45 of 1.46 (2H, m), 1,57-to 1.63 (4H, m), 1,94-of 2.08 (4H, m)of 2.16 (2H, DD, J=2,3, or 12.8 Hz), 2.40 a (4H, USS), a 2.45-2.49 USD (2H, m), 3,24 of 3.28 (4H, m), with 3.79 (2H, s), of 3.96 (2H, t, J=6.4 Hz), at 6.84 (2H, d, J=9,2 Hz), 6,92 (2H, d, J=9,2 Hz), 7,49 (2H, d, J=6.0 Hz), 8,54 (2H, d, J=6.0 Hz).

Example 3-43:

Obtaining 3-(6-herperidin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and Brom-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,58-to 1.63 (4H, m), 1,94-of 2.08 (4H, m)of 2.16 (2H, d, J=12,8 Hz)to 2.41 (4H, USS), 2,46-of 2.50 (2H, m), 3,21-of 3.31 (4H, m), 3,81 (2H, s), of 3.97 (2H, t, J=6.4 Hz), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), of 6.99 (1H, DD, J=3.2, and an 8.8 Hz), 8,09-8,10 (1H, m), 8,39-8,44 (1H, m).

Example 3-44:

Getting 8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 5-bromo-2-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,57-of 1.62 (4H, m), 1.93 and-of 2.09 (4H, m), 2,17 (2H, d, J=13,2 Hz), 2.40 a (4H, USS), a 2.45-2.49 USD (2H, m), 3,21-of 3.32 (4H, m), a 3.87 (2H, s), of 3.97 (2H, t, J=6.4 Hz), 6,85 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,71 (1H, d, J=8,8 Hz), to 8.45 (1H, DD, J=8,8, 2,8 Hz), 8,67 (1H, d, J=2,4 Hz).

Example 3-45:

Obtaining 3-(2-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-2-torbenson instead of 1-bromo-4-f is orbasala.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,57-to 1.63 (4H, m), 1,95 e 2.06 (4H, m), 2,20 (2H, d, J=13,2 Hz)to 2.41 (4H, USS), 2,48 (2H, t, J=7.2 Hz), 3,24-of 3.27 (4H, m), 3,82 (2H, s), of 3.96 (2H, t, J=6.4 Hz), 6,76 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,12-7,26 (2H, m), 7,56 (1H, TD, J=7,8, and 1.6 Hz).

Example 3-46:

Obtaining 3-(2-herperidin-4-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15 and 2-fluoro-4-yodellin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,59-to 1.61 (4H, m), 1,95-of 2.08 (4H, m), of 2.15 (2H, d, J=12,8 Hz)to 2.41 (4H, USS), 2,48 (2H, t, J=7.2 Hz), 3,21 of 3.28 (4H, m), with 3.79 (2H, s), of 3.97 (2H, t, J=6.0 Hz), 6,85 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), to 7.15 (1H, d, J=1.6 Hz), 7,42 (1H, DD, J=6,0, 2.0 Hz), 8,16 (1H, d, J=6.0 Hz).

Example 3-47:

Obtain 3-[6-(deformity)pyridine-3-yl]-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 5-bromo-2-(deformity)pyridine instead of 1-bromo-4-fluoro what insole.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,56-of 1.62 (4H, m), 1,97-of 2.09 (4H, m), 2,17 (2H, d, J=14,0 Hz), 2.40 a (4H, USS), a 2.45-2.49 USD (2H, t, J=7.2 Hz), 3,21-of 3.32 (4H, m), 3,86 (2H, s), of 3.97 (2H, t, J=6.4 Hz), only 6.64 (1H, t, J=55,2 Hz), 6,85 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), to 7.67 (1H, d, J=8,8 Hz), at 8.36 (1H, DD, J=8,4, 2.4 Hz), 8,64-8,65 (1H, m).

Example 3-48:

Obtain 3-(5-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15 and 2-bromo-5-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,56-of 1.62 (4H, m), 1,92-2,07 (4H, m), 2,13-of 2.16 (2H, m), 2.40 a (4H, USS), 3,23-3,26 (4H, m), of 3.96 (2H, t, J=6.4 Hz), was 4.02 (2H, s), at 6.84 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,44-7,49 (1H, m), 8,16 (1H, d, J=2,8 Hz), of 8.27 (1H, DD, H=a 9.2, 4.0 Hz).

Example 3-49:

Obtaining 3-(6-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15 and 2-bromo-6-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,58-of 1.62 (4H, m), 1,95-2,07 (4H, m), and 2.14 (2H, d, J=13,2 Hz), 2,42 (4H, USS), 3,23-of 3.25 (4H, m), of 3.97 (2H, t, J=6,4 Hz)to 4.01 (2H, s), of 6.65 (1H, DD, H=8.0 a, 2,8 Hz), at 6.84 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,81 (1H, Quint., J=8.0 Hz), to 8.12 (1H, DD, H=a 8.4, 2.0 Hz).

Example 3-50:

Obtaining 3-(3-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-3-torbenson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45 (2H, USS), 1,60-of 1.62 (4H, m), 1,96 e 2.06 (4H, m), and 2.14 (2H, d, J=13,2 Hz), 2,43 (4H, USS), 2,49-of 2.50 (2H, m), 3,24-3,26 (4H, m), of 3.78 (2H, s), of 3.97 (2H, t, J=6.4 Hz), 6,83-6,86 (3H, m), 6,93 (2H, d, J=9,2 Hz), 7,25 (1H, d, J=8,4 Hz), 7,30 and 7.36 (1H, m), 7,45 (1H, dt, H=11,2, 2,4 Hz).

Example 3-51:

Obtaining 3-(4-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400MHz, CDCl3) δ: 1,47 (2H, USS), of 1.65 (4H, USS), 1,97-2,04 (4H, m), of 2.15 (2H, d, J=12,8 Hz), 2,47-of 2.58 (6H, m), 3.25 to 3.27 to (4H, m), of 3.77 (2H, s), 3,81 (3H, s), of 3.97 (2H, t, J=6.0 Hz), at 6.84 (2H, d, J=8,8 Hz), 6,91-6,94 (4H, m), was 7.45 (2H, d, H=9,2 Hz).

Example 3-52:

Obtaining 3-(3-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-3-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48 (2H, USS), of 1.66 (4H, USS), 1,98-of 2.05 (4H, m), and 2.14 (2H, d, J=13,2 Hz), 2,50-to 2.57 (6H, m), 3.25 to 3.27 to (4H, m), of 3.78 (2H, s), 3,83 (3H, s), of 3.97 (2H, t, J=6.4 Hz), 6,70 (2H, DD, J=7,6, 2.0 Hz), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz),? 7.04 baby mortality (1H, DD, H=7,6, 2,4 Hz) 7,26-7,30 (2H, m).

Example 3-53:

Obtaining 3-(6-methoxypyridine-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,57-to 1.61 (4H, m), 195-2,06 (4H, m)of 2.16 (2H, d, J=13,2 Hz), 2,42 (4H, USS), 2,48 (2H, t, J=7,6 Hz), 3,24 of 3.28 (4H, m), of 3.77 (2H, s), 3,93 (3H, s), of 3.97 (2H, t, J=6.4 Hz), 6,78 (2H, d, J=8,8 Hz), at 6.84 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), of 8.06 (1H, d, H=2,8 Hz), 8,11 (1H, DD, J=8,8, 2,8 Hz).

Example 3-54:

Obtaining 3-(6-methylpyridin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 5-bromo-2-methylpyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,58-to 1.61 (4H, m), 1,95-of 2.08 (4H, m)of 2.16 (2H, d, J=12,8 Hz)to 2.41 (4H, USS), 2,46-of 2.50 (2H, m), of 2.54 (3H, s), 3,24-3,29 (4H, m), 3,81 (2H, s), of 3.97 (2H, t, J=6.4 Hz), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9,2 Hz), 7,18 (1H, d, J=8,8 Hz), 8,14 (1H, DD, H=a 8.8 and 2.8 Hz), to 8.41 (1H, d, J=2,8 Hz).

Example 3-55:

Obtaining 3-(2-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-2-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45 (2H, the .c), of 1.63 (4H, USS), 1,99-2,04 (4H, m), of 2.21 (2H, d, J=13,2 Hz), 2,45-2,52 (6H, m), 3,24-of 3.27 (4H, m), of 3.73 (2H, s), a 3.87 (3H, s), of 3.97 (2H, t, J=6.4 Hz), at 6.84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 6,95-6,99 (2H, m), 7,29 (1H, TD, J=8,2, 1,6 Hz), 7,37 (1H, DD, J=8.0 a, 1,6 Hz).

Example 3-56:

Getting 8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[4-(triptoreline)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 1-bromo-4-(triptoreline)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,59-of 1.62 (4H, m), 1.93 and e 2.06 (4H, m), of 2.15 (2H, d, J=13,2 Hz)to 2.41 (4H, USS), 3,24-3,26 (4H, m), 3,80 (2H, s), of 3.97 (2H, t, J=6.0 Hz), 6,85 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7.24 to (2H, d, J=8,4 Hz), to 7.59 (2H, d, J=8,4 Hz).

Example 3-57:

Getting 4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-1-ethylpyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (00 MHz, CDCl3) δ: of 0.85 (3H, t, J=6.6 Hz), to 1.38 (3H, t, J=7,3 Hz), 1,51 is 1.75 (6H, m), 1,80-1,90 (3H, m), 1.91 a-2,02 (2H, m), 2,10 (2H, d, J=13,2 Hz), 2,48 (2H, t, J=7,6 Hz), 2,80-only 2.91 (2H, USM), 3,06 (2H, TD, J=11,7, 2,4 Hz)that is 3.27 (2H, dt, J=12,2, 3,9 Hz), 3,52 (2H, s), 3,93-was 4.02 (4H, m), 4,32 (2H, s), 6,60 (1H, d, J=9.8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,25 (1H, DD, J=9,8, 2,9 Hz), 7,38 (1H, d, J=2,9 Hz).

358 for example:

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.85 (3H, t, J=6.3 Hz), 1,53-1,72 (6H, m), 1,79 is 2.01 (5H, m), 2,08 (2H, d, J=13,2 Hz), 2,48 (2H, t, J=7,6 Hz), 2,84-is 2.88 (2H, USM), is 3.08 (2H, TD, J=11,2, 2,9 Hz), with 3.27 (2H, dt, J=12,7, 3,4 Hz), 3,94-3,98 (4H, m)to 4.41 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), scored 8.38 (2H, s), at 9.53 (1H, d, J=1.0 Hz).

Example 3-59:

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained is in reference example 12-1, and 2-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,48 is 1.75 (6H, m), 1,78-2,13 (7H, m), 2,48 (2H, USS), of 2.86 (2H, USS), is 3.08 (2H, TD, J=11,7, 2.4 Hz), with 3.27 (2H, dt, J=12,7, 4,4 Hz), of 3.96 (2H, t, J=6.3 Hz), to 4.01 (2H, s), 4,37 (2H, s), 6,83 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,13 (1H, DD, J=7,3, a 4.9 Hz), 7,72 (1H, TD, J=8,3, 2.0 Hz), of 8.09 (1H, d, J=8,3 Hz), 8,43 (1H, DD, J=4,9, 1.5 Hz).

Example 3-60:

Getting 4-(3-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 2-bromo-3-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.8 Hz), 1,49 to 1.76 (6H, m), 1,79-2,03 (5H, m), 2,17 (2H, d, J=13,7 Hz), 2,48 (2H, t, J=7,3 Hz), 2,79-to 2.94 (2H, m)to 3.09 (2H, TD, J=11,2, 2,9 Hz), 3,26 (2H, dt, J=12,2, 3,9 Hz), 3,66 (2H, USS), 3,88 (3H, s), of 3.96 (2H, t, J=6.3 Hz), 4,36 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7.24 to 7,34 (4H, m)to 8.12 (1H, DD, J=4,4, 2.0 Hz).

Example 3-61:

Getting 4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or as the illogical way but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-1-ethyl-3-methylpyridin-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6,8 Hz)to 1.37 (3H, t, J=7,3 Hz), 1,48 is 1.75 (6H, m), 1,79-1,90 (3H, m), 1,92-2,02 (2H, m), 2,10 (2H, d, J=12,7 Hz)of 2.16 (3H, s), 2,48 (2H, USS), 2,78-to 2.94 (2H, USM), 3,06 (2H, TD, J=11,7, 2,4 Hz), or 3.28 (2H, dt, J=12,2, 3,9 Hz), 3,52 (2H, s), 3.95 to 4,01 (4H, m), 4,32 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,11-7,14 (1H, m), 7.23 percent (1H, d, J=2,9 Hz).

Example 3-62:

Getting 4-(1-ethyl-5-methoxy-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-1-ethyl-3-methoxypyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), of 1.37 (3H, t, J=7,3 Hz), 1,50 to 1.76 (6H, m), 1,79-2,05 (5H, m), 2,11 (2H, d, J=13,2 Hz), 2.49 USD (2H, USS), 2,87 (2H, USS), 3,06 (2H, TD, J=11,2, 2.4 Hz), 3,29 (2H, d, J=and 12.2 Hz), of 3.54 (2H,, (C)a 3.83 (3H, s), 4,06-3,93 (4H, m), 4,32 (2H, s), of 6.52 (1H, d, J=2.4 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,97-6,89 (3H, m).

Example 3-63:

Getting 4-(5-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diaza the pyro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 2-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,48 to 1.76 (5H, m), 1,78-2,02 (6H, m)2,07 (2H, d, J=13,2 Hz), 2,47 (2H, t, J=7,3 Hz), 2,79 of 2.92 (2H, m), of 3.07 (2H, TD, J=11,2, 2.0 Hz), 3,26 (2H, dt, J=12,7, 4,4 Hz), a 3.87 (3H, s), 3,93 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,35 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,29-of 7.25 (1H, m), 7,92 (1H, d, J=8,8 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-64:

Getting 4-(5-herperidin-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 2-bromo-5-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,49 is 1.75 (6H, m), 1,79 is 2.01 (5H, m)to 2.06 (2H, d, J=13,7 Hz), 2,48 (2H, t, J=7,6 Hz), 2,79-of 2.93 (2H, USM), of 3.07 (2H, TD, J=11,2, 2,9 Hz), with 3.27 (2H, dt, J=12,7, 3,9 Hz), 3,93-3,99 (4H, m)4,36 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,42-7,49 (1H, m), 8,11 (1H, DD, J=9,0, 4,1 Hz), compared to 8.26 (1H, d, J=3,4 Hz).

Note the p 3-65:

Getting 5-[9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]nicotinanilide

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: from 0.88 (3H, t, J=8.5 Hz), 1,48 to 1.76 (6H, m), 1,78-2,02 (5H, m), and 2.14 (2H, d, J=13,2 Hz), 2,48 (2H, t, J=7,6 Hz), 2,80 of 2.92 (2H, m), 3,06 (2H, TD, J=11,7, 2.3 Hz), 3,30 (2H, d, J=and 12.2 Hz), 3,71 (2H, s), 3.96 points (2H, t, J=6.3 Hz), and 4.40 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,10 (1H, t, J=2.2 Hz), 8,76 (1H, d, J=2.0 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-66:

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 0.85 (3H, t, J=6.8 Hz), 1,49 is 1.75 (6H, m), 1,79 is 2.01 (5H, m)2,07 (2H, d, J=13,2 Hz), 2,47 (2H, t, J=7,6 Hz), of 2.86 (2H, t, J=13,4 Hz), of 3.07 (2H, TD, J=11,2, 2,9 Hz), 3,26 (H, dt, J=12,7, 3,4 Hz), a 3.87 (3H, s), 3,93 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,35 (2H, s), 6,83 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,29-of 7.25 (1H, m), 7,92 (1H, d, J=9.3 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-67:

Getting 4-[1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl]-1-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-1, and 5-bromo-1-(deformity)pyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,50-1,75 (6H, m), 1,79 is 1.91 (3H, m), 1,92-2,03 (2H, m), 2,10 (2H, d, J=and 12.2 Hz), 2,48 (2H, t, J=6.8 Hz), 2.77-to 2,95 (2H, USM), was 3.05 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, 3,4 Hz), 3,55 (2H, s), of 3.96 (2H, t, J=6.6 Hz), to 4.33 (2H, s), 6,60 (1H, d, J=9.3 Hz), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,40 (1H, DD, J=10,2, 2,9 Hz), was 7.45 (1H, d, J=2,9 Hz), 7,66 (1H,t, J=60,0 Hz).

Example 3-68:

Getting 4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]at the decane-3-one, obtained in reference example 12-1, and 5-bromo-1-isopropylpyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), of 1.37 (6H, d, J=6.8 Hz), 1,49 is 1.75 (6H, m), 1,80 is 1.91 (3H, m), 1,92-2,03 (2H, m), 2,10 (2H, d, J=a 12.7 Hz), 2.49 USD (2H, t, J=6.3 Hz), 2,79-2,95 (2H, USM), 3,06 (2H, TD, J=11,2, 2,4 Hz), or 3.28 (2H, dt, J=12,2, 3,4 Hz), 3,53 (2H, s), of 3.96 (2H, t, J=6.3 Hz), 4,32 (2H, s), to 5.21 is 5.28 (1H, m), 6,60 (1H, d, J=9.8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,22 (1H, DD, J=9,8, 2,9 Hz), 7,40 (1H, d, J=2,4 Hz).

Example 3-69:

9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow oily substance according to the method of example 3 or in a similar way, but using 9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,39 is 1.48 (2H, USM), 1,54 was 1.69 (4H, m), 1,84 is 2.01 (4H, m), 2,08 (2H, d, J=13,2 Hz), 2,35 is 2.51 (6H, m), is 3.08 (2H, TD, J=11,2, 2.0 Hz), with 3.27 (2H, dt, J=12,2, 4,4 Hz), 3,93-3,99 (4H, m)to 4.41 (2H, s), at 6.84 (2H, d, J=9,3 Hz), 6,93 (2H, d, J=8,8 Hz), scored 8.38 (2H, s), at 9.53 (1H, d, J=1.0 Hz).

Example 3-70:

Getting 4-(3,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but use the Zuya 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-2 and 4-bromo-1,2-differenza instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,79 of 1.99 (6H, m), 2,03-2,17 (4H, m), 2,59-of 2.86 (6H, USM), 3,06 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, 3,9 Hz), of 3.60 (2H, s), of 4.00 (2H, t, J=6,1 Hz), 4,34 (2H, s), 6,83 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,01-was 7.08 (1H, m), 7,25-7,16 (2H, m).

Example 3-71:

Getting 4-(2,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2, and 1-bromo-2,4-differenza instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,81-2,03 (6H, m), and 2.14 (4H, d, J=a 12.7 Hz), 2,64 are 2.98 (6H, m), is 3.08 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,9 Hz), of 3.56 (2H, s), of 4.00 (2H, t, J=5,9 Hz), 4,37 (2H, s), 6,83 (2H, d, J=9.3 Hz), 6.90 to-6,98 (4H, m), 7,30-7,21 (1H, m).

Example 3-72:

9-[4-(3-pyrrolidin-1 ipropose)phenyl]-4-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2 and 5-bromo-2-(t is iformity)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,82-to 1.98 (6H, m), and 2.14 (4H, d, J=a 12.7 Hz), of 2.81 (6H, s), of 3.07 (2H, t, J=10.5 Hz), 3,29 (2H, d, J=and 12.2 Hz), and 3.72 (2H, s), of 4.00 (2H, t, J=6,1 Hz), and 4.40 (2H, s), 6,83 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,74 (1H, d, J=8,8 Hz), of 7.96 (1H, DD, J=8,3, 2.4 Hz), the rate of 8.75 (1H, d, J=2,4 Hz).

Example 3-73:

Getting 4-(6-isopropoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-2 and 5-bromo-2-isopropoxypyridine obtained in reference example 17, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.34 (6H, d, J=6.3 Hz), 1,76-of 1.92 (6H, m), 1,97-2,04 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2.57 m (4H, OSS), to 2.65 (2H, t, J=7,3 Hz), of 3.07 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,9 Hz), of 3.60 (2H, s), 3,99 (2H, t, J=6.3 Hz), 4,35 (2H, s), 5,24-5,31 (1H, m), 6,72 (1H, d, J=8,8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,51 (1H, DD, J=8,8, 2,9 Hz), of 8.06 (1H, d, J=2.0 Hz).

Example 3-74:

Getting 4-(2-ethoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 5-bromo-2-ethoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5.4 Hz), the 1.44 (3H, t, J=7,1 Hz), 1,53-of 2.05 (8H, m), 2.05 is is 2.55 (5H, m), 2,90-of 3.12 (3H, m), 3,19 (1H, USS), or 3.28 (2H, dt, J=12,2, 3,9 Hz), 3,62 (2H, s), 3,93-Android 4.04 (2H, m), 4,37 (2H, s), of 4.44 (2H, q, J=7.2 Hz), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,51 (2H, s).

Example 3-75:

Getting 4-(5-methoxypyrazine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=4.9 Hz), 1,34-2,53 (13H, m), 2,92-3,13 (3H, m), 3,14-of 3.31 (3H, m), 3,88 (2H, s), 3,92-Android 4.04 (5H, m), to 4.38 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,03 (1H, d, J=1.5 Hz), 8,84 (1H, d, J=1.5 Hz).

Example 3-76:

Getting 4-(4-chlorophenyl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diesase what about the[5,5]undecane-3-one, obtained in reference example 12-4, and 1-bromo-4-chlorobenzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.47 (1H, m), 1.56 to 2,01 (7H, m), 2,08-of 2.23 (4H, m), 2,25 is 2.33 (1H, m), 2,94-a 3.01 (1H, m), 3,03-3,10 (2H, m), 3.15 and 3.21-in (1H, m), 3,24-3,29 (2H, m), 3,61 (2H, s), 3.95 to 4,01 (2H, m), 4,34 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,25 (2H, d, J=8,8 Hz), 7,39 (2H, d, J=8,8 Hz).

Example 3-77:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(trifluoromethyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 1-bromo-4-(trifluoromethyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.47 (1H, m), 1,58 is 2.00 (7H, m), 2,08-of 2.23 (4H, m), 2,27 of-2.32 (1H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,10 (2H, m), 3.15 and 3.21-in (1H, m), 3,26-3,30 (2H, m)to 3.67 (2H, s), 3,94-to 4.01 (2H, m)4,37 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 7,47 (2H, d, J=8,3 Hz), to 7.68 (2H, d, J=8,8 Hz).

Example 3-78:

Getting 4-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]benzonitrile

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-who ethylpyrrolidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 4-bromobenzonitrile instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.47 (1H, m), 1,58 is 2.01 (7H, m), 2,08 of-2.32 (5H, m), 2,94-a 3.01 (1H, m), 3,03-3,10 (2H, m), 3.15 and 3.21-in (1H, m), 3.25 to and 3.31 (2H, m)to 3.67 (2H, s), 3.96 points-to 4.01 (2H, m), 4,37 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9,3 Hz)to 7.50 (2H, d, J=8,8 Hz), 7,71 (2H, d, J=8,3 Hz).

Example 3-79:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.14 in (3H, d, J=6.3 Hz), 1,43-2,05 (7H, m), 2,11-to 2.40 (5H, m), 2,99-3,10 (3H, m), 3,06 (3H, s), 3,23-of 3.31 (3H, m), of 3.69 (2H, s), 3,94-a 4.03 (2H, m), to 4.38 (2H, s), at 6.84 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=9,3 Hz), 7,58 (2H, d, J=8,8 Hz), 8,00 (2H, d, J=8,8 Hz).

Example 3-80:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-the KSA-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), of 1.39 to 1.48 (1H, m), 1,58-2,02 (7H, m), 2.05 is-of 2.34 (5H, m), 2.95 and-to 3.02 (1H, m), 3,05-3,11 (2H, m), 3,17-up 3.22 (1H, m), 3.25 to 3,30 (2H, m), 3.95 to 4.00 points (4H, m)to 4.41 (2H, s), at 6.84 (2H, d, J=9,3 Hz), 6,93 (2H, d, J=9.3 Hz), scored 8.38 (2H, s), at 9.53 (1H, s).

Example 3-81:

Getting 4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.48 (1H, m), 1,57-2,01 (7H, m), 2,09-of 2.23 (4H, m), 2,27 is 2.33 (1H, m), 2,94-a 3.01 (1H, m), 3,03-to 3.09 (2H, m), 3,16-is 3.21 (1H, m), 3,26-and 3.31 (2H, m), 3,63 (2H, s), 3,94-to 4.01 (2H, m), a 4.03 (3H, s), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,53 (2H, s).

Example 3-82:

Getting 4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5|undecane-3-one

Specified in the title compound obtained as an oily pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,64 (3H, d, J=6.3 Hz), 2,01-2,54 (7H, m), 2,83-of 3.06 (4H, m), 3,20-3,30 (2H, m), 3,42 (3H, s), 3,49-and 3.72 (6H, m), 3,93-3,98 (2H, m), 4,13-4,18 (2H, m), and 4.40 (2H, s), 7,02 (2H, d, J=8,8 Hz), 7,27-7,31 (1H, m), of 7.70 (1H, d, J=7.8 Hz), 7,81 (2H, d, J=8,8 Hz), 8,39 (1H, d, J=6.0 Hz).

Example 3-83:

Getting 4-(3-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 2-bromo-3-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.16 (3H, d, J=5,9 Hz), 1,46 e 2.06 (8H, m), 2,14-2,31 (4H, m), 2,39 at 2.45 (1H, m), 2,99-of 3.12 (3H, m), 3,23 of 3.28 (3H, m), 3,66 (2H, USS), 3,88 (3H, s), 3,94-a 4.03 (2H, m), 4,36 (2H, s), at 6.84 (2H, d, J=9,3 Hz), 6,93 (2H, d, J=8,8 Hz), 7,26-7,33 (2H, m)to 8.12 (1H, DD, J=4,4, 2.0 Hz).

Example 3-84:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}Hairdryer is l)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 12-4, and 3-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.48 (1H, m), 1,53-2,01 (7H, m), 2,08-of 2.24 (4H, m), 2,27-of 2.34 (1H, m), 2,94-a 3.01 (1H, m), 3.04 from-3,10 (2H, m), 3,15-up 3.22 (1H, m), 3.25 to of 3.32 (2H, m), 3,68 (2H, s), 3,94-to 4.01 (2H, m)to 4.38 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 7,37 (1H, DD, J=8,3, a 4.9 Hz), 7,73 (1H, DQC, J=8,3, 1.3 Hz), 8,53 (1H, DD, J=4,9, 1.5 Hz), 8,61 (1H, d, J=2,4 Hz).

Example 3-85:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 3-bromo-5-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), of 1.39 to 1.48 (1H, m), 1,57-to 1.82 (2H, m), 1.85 to a 2.01 (5H, m), 2,10-of 2.24 (4H, m), 2,27-of 2.34 (1H, m), 2,94-a 3.01 (1H, m), 3,03-3,10 (2H, m), 3.15 and 3.21-in (1H, m), 3.27 to of 3.32 (2H, m), 3,71 (2H, C)3,94-a 4.03 (2H, m), and 4.40 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 8,00 (1H, s), 8,78 (1H, s), 8,84 (1H, d, J=2,4 Hz).

Example 3-86:

Getting 4-(1-methyl-1H-pyrazole-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid in accordance with what logikoi example 3 or equivalent means, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), to 1.38 to 1.47 (1H, m), 1,57-2,01 (7H, m), 2,04-of 2.23 (4H, m), 2.26 and of-2.32 (1H, m), 2.93 which is 3.00 (1H, m), 3,02-to 3.09 (2H, m), 3,15-3,20 (1H, m), 3,24-3,29 (2H, m), of 3.84 (3H, s), a 3.87 (2H, s), 3,93-4,01 (2H, m)to 4.33 (2H, s), 6,83-6,85 (3H, m), 6,92 (2H, d, J=8,8 Hz), 7,29 (1H, d, J=2.0 Hz).

Example 3-87:

Getting 4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), of 1.40 to 1.48 (1H, m), 1,57-2,01 (7H, m), 2.06 to of 2.23 (5H, m), 2.26 and is 2.33 (1H, m), 2,94-2,99 (1H, m), 3,01-is 3.08 (2H, m), 3,16-is 3.21 (1H, m), 3,24-3,30 (2H, m)and 3.59 (2H, s), 3,90 (3H, s), 3,95-4,01 (2H, m), 4,32 (2H, s), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,47 (1H, s), 8,03 (1H, s).

Example 3-88:

Getting 4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with methodical the example 3 or equivalent means, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), of 1.40 to 1.48 (1H, m), 1,53-2,01 (7H, m), 2,08 of-2.32 (5H, m), 2,94-2,99 (1H, m), 3.04 from-3,10 (2H, m), 3,15-up 3.22 (1H, m), 3.25 to and 3.31 (2H, m)to 3.67 (2H, s), 3,88 (3H, s), 3.95 to 4,01 (2H, m), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,28 (1H, t, J=2.4 Hz), to 8.20 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=2,4 Hz).

Example 3-89:

Getting 5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinanilide

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-4, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), of 1.41 to 1.47 (1H, m), 1,58-to 1.79 (2H, m), 1,84 is 2.01 (5H, m), 2,11 is 2.33 (5H, m), 2.95 and-to 3.09 (3H, m), 3,16-up 3.22 (1H, m), 3.27 to of 3.32 (2H, m), 3,71 (2H, s), 3,94-4,01 (2H, m), and 4.40 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=8,8 Hz), 8,10 (1H, DD, J=2,2, 1,1 Hz), 8,76 (1H, d, J=1.5 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-90:

9-(4-{3-[(2S)-2-methylpyrrolidine-1 yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as TV is Gogo pale brown substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 3-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), 1,40-1,49 (1H, m), 1,58-2,02 (7H, m), 2,11-of 2.24 (4H, m), 2,28-of 2.36 (1H, m), 2.95 and-3,10 (3H, m), 3,17-up 3.22 (1H, m), 3.25 to and 3.31 (2H, m), 3,68 (2H, s), 3.95 to as 4.02 (2H, m), to 4.38 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 7,37 (1H, DD, J=8,3, a 4.9 Hz), 7,73 (1H, DQC, J=8,3, 1.5 Hz), 8,53 (1H, DD, J=4,9, 1.5 Hz), 8,61 (1H, d, J=2,4 Hz).

Example 3-91:

Getting 4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=5,9 Hz), to 1.38 to 1.47 (1H, m), 1,57-to 1.79 (2H, m), 1,83 is 2.01 (5H, m), 2,07-2,22 (4H, m), 2,25-2,31 (1H, m), 2.93 which is 3.00 (1H, m), 3,03-3,10 (2H, m), 3,15-3,20 (1H, m), 3,26-and 3.31 (2H, m), 3,63 (2H, s), 3.95 to 4,01 (2H, m), a 4.03 (3H, s), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,53 (2H, s).

Example 3-92:

Getting 5-[9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinanilide

Specified in the header connection poluchaut the form of a solid pale brown substance in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.14 in (3H, d, J=6.3 Hz), 1,46 e 2.06 (8H, m), 2,11-of 2.36 (5H, m), 2,98-3,10 (3H, m), 3,20-of 3.32 (3H, m), 3,71 (2H, s), 3.95 to as 4.02 (2H, m), and 4.40 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,10 (1H, s), 8,76 (1H, d, J=1.5 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-93:

Getting 4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=6.3 Hz), 1.41 to a 1.50 (1H, m), 1,59-2,03 (7H, m), 2,12-of 2.26 (4H, m), 2,32-is 2.37 (1H, m), 2,96-3,10 (3H, m), 3,18-of 3.31 (3H, m), 3,66 (2H, s), 3,88 (3H, s), 3,94-a 4.03 (2H, m), 4,37 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), 7,28 (1H, t, J=2.4 Hz), to 8.20 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=2,4 Hz).

Example 3-94:

Getting 4-(5-methoxypyrazine-2-yl)-9-(4-{3-(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale brown substances is in accordance with the method of example 3 or equivalent means, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=6.3 Hz), 1.41 to a 1.50 (1H, m), 1,63-2,03 (7H, m), 2.06 to to 2.25 (4H, m), 2,30-is 2.37 (1H, m), 2,96-3,11 (3H, m), 3,18 to be 3.29 (3H, m), 3,88 (2H, s), 3,94-was 4.02 (2H, m)to 3.99 (3H, s), to 4.38 (2H, s), 6,84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=9.3 Hz), of 8.04 (1H, d, J=1.5 Hz), 8,84 (1H, d, J=1.5 Hz).

Example 3-95:

Getting 4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 12-3, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.13 (3H, d, J=5,9 Hz), 1,43 of 1.50 (1H, m), 1,64-2,03 (7H, m), 2,07-of 2.26 (4H, m), 2,32-of 2.38 (1H, m), 2,96-of 3.07 (3H, m), 3,19-of 3.31 (3H, m)and 3.59 (2H, s), 3,90 (3H, s), 3,94-a 4.03 (2H, m), 4,32 (2H, s), 6,84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,47 (1H, s), of 8.04 (1H, s).

Example 3-96:

Obtain 3-ethyl-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he (100 mg, 0,268 mmol)obtained in Ref is cnom example 13-5, dissolved in N,N-dimethylformamide, to the solution was cooled to 0°C. add sodium hydride (16 mg, 0,402 mmol) and bromate (32 mg, 0,295 mmol) and the mixture is stirred over night at room temperature. Add water to the mixture, the solvent is evaporated under reduced pressure, then the residue is dissolved in ethyl acetate and washed successively with water and saturated salt solution. The organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure and the residue purified by thin-layer chromatography (eluate: chloroform/methanol=9/1), getting mentioned in the title compound (17 mg, 16%) as a yellow solid substance.

1H-NMR (400 MHz, CDCl3) δ: 1,08-1,22 (6H, m), 1,38-2,59 (13H, m), 2,99 (1H, USS), 3,16-up 3.22 (5H, m), 3,31-3,37 (4H, m), 3,93-a 4.03 (2H, m), 6,83 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 Hz).

Example 3-97:

Getting 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,13 (3H, s), 1,38-to 2.57 (13H, m), 2.95 and-,09 (4H, m), 3,18-to 3.34 (5H, m), 3,85 (2H, s), 3,94-of 4.05 (2H, m), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,78 (2H, d, J=9.3 Hz), of 7.96 (2H, d, J=9,3 Hz).

Example 3-98:

Obtaining 3-(2-ethoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 5-bromo-2-ethoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,12 (3H,s)of 1.43 (3H, t, J=7,1 Hz)and 1.51-2,56 (13H, m)of 3.00 (1H, USS), 3,14-to 3.35 (5H, m), of 3.77 (2H, s), 3.95 to as 4.02 (2H, m), 4,42 (2H, q, J=7.0 Hz), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), a total of 8.74 (2H, s).

Example 3-99:

Obtaining 3-(1-methyl-1H-pyrazole-4-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, DD, J=13,7, 6.3 Hz), 1,35-2,52 (13H, m), 3,13-of 3.31 (1H, m), 3,17-3,26 (5H, m), 3,66 (2H, s), 3,90 (3H, s), 3.9 to Android 4.04 (2H, m), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), was 7.36 (1H, s), to 7.77 (1H, s).

Example 3-100:

Obtaining 3-(1-methyl-1H-pyrazole-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=6.3 Hz), USD 1.43 (1H, USS), and 1.56 is 2.51 (12H, m), 2,92 totaling 3.04 (1H, m), 3,13-3,32 (5H, m), 3,82 (3H, s), a 3.87 (2H, s), 3,93-Android 4.04 (2H, m), only 6.64 (1H, d, J=2.4 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,28 (1H, d, J=2.0 Hz).

Example 3-101:

Getting 5-[8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl]nicotinanilide

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), 1,37-1,49 (1H, USM), 1,50 is 2.51 (12H, m), 2,93-3,03 (1H, m), 3,15-to 3.35 (5H, m), 3,85 (2H, s), 3,94-Android 4.04 (2H, m)6,86 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz),8,55 are 8.53 (1H, m)8,64 (1H, d, J=1.5 Hz), 8,82 (1H, d, J=2,9 Hz).

Example 3-102:

Getting 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=5,9 Hz), 1,36-2,55 (13H, m), 2,94-of 3.06 (1H, USM), 3,13-to 3.35 (5H, m), 3,94-of 4.05 (4H, m), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), compared to 8.26-8.30 to (1H, m), with 8.33 (1H, d, J=2.4 Hz), 9,60 (1H, d, J=1.5 Hz).

Example 3-103:

Obtaining 3-(6-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), 1,36-2,52 (13H, m), 2,93-3,03 (1H, m), 3,15-3,32 (5H, m), of 3.77 (2H, s), 3,93 (3H, s), 3,94-Android 4.04 (2H, m), 6,79 (1H, d, J=8,3 Hz), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9,3 Hz), of 8.06 (1H, d, J=2.4 Hz), 8,11 (1H, DD, J=9,3, 2,9 Hz).

When the EP 3-104:

Obtaining 3-(2-methoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=4.9 Hz), 1,33-2,46 (13H, m), 2.93 which was 3.05 (1H, USM), 3,14-3,33 (5H, m), of 3.78 (2H, s), 3,97-was 4.02 (5H, m), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 8,76 (2H, s)

Example 3-105:

Obtain 3-(5-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-5, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), 1,35-2,58 (13H, m), 2,93-3,03 (1H, USM), 3,15-3,33 (5H, m), 3,82 (2H, s)to 3.89 (3H, s), 3,94-Android 4.04 (2H, m), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), of 7.96 (1H, t, J=2,4 Hz), 8,08 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=2,4 Hz).

Example 3-106:

Obtaining 3-(2-methoxypyridine the-5-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 15, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45 (2H, OSS), to 1.60 (4H, USS), 1,93 is 2.10 (4H, m), 2,17 (2H, d, J=13,2 Hz), 2,31 is 2.55 (6H, m), 3,21-3,30 (4H, m), of 3.77 (2H, s), of 3.97 (2H, t, J=6.3 Hz), was 4.02 (3H, s), 6,85 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9,3 Hz), 8,76 (2H, s).

Example 3-107:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily white matter in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 1-iodine-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,58-2,14 (16H, m), 2,55-2,87 (3H, m), 3,03-3,13 (2H, m), 3,23-of 3.32 (2H, m)and 3.59 (2H, s), 3,81 (3H, s), 4,24 (1H, USS), 4,34 (2H, s), at 6.84 (2H, d, J=8,8 Hz)6,91 (2H, d, J=8,8 Hz)6,94 (2H, d, J=9,1 Hz), 7,20 (2H, d, J=9.1 Hz).

Example 3-108:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid which CSOs yellow substances in accordance with the method of example 3 or equivalent means, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-2-methylpyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.41 to 2.26 and (16H, m), 2,52-and 2.79 (3H, m), 3.00 and is 3.15 (2H, m), 3,21-3,37 (2H, m)to 3.64 (2H, s), 4,22 (1H, USS), 4,36 (2H, s), at 6.84 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 7,21 (1H, d, J=8,3 Hz), 7,58 (1H, DD, J=8,3, 2.4 Hz), 8,46 (1H, d, J=2,4 Hz).

Example 3-109:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-2-(deformedarse)pyridine obtained in reference example 16, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,27 (16H, m), 2,52-2,87 (3H, m), 3.00 and is 3.15 (2H, m), 3,24-to 3.34 (2H, m), 3,63 (2H, s), 4,22 (1H, USS), 4,36 (2H, s), 6,85 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), of 6.96 (1H, d, J=8,8 Hz), the 7.43 (1H, t, J=72,7 Hz), 7,74 (1H, DD, J=8,8, 2.7 Hz), 8,16 (1H, d, J=2.7 Hz).

Example 3-110:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the tvii to the method of example 3-96 or equivalent means, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 2-bromopropane instead of brometane.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (6H, d, J=6.8 Hz), 1,55-2,30 (16H, m), 2.57 m-2,84 (3H, m), 2,98-of 3.07 (2H, m), 3,10 (2H, s), 3,19 of 3.28 (2H, m), 4,17 (2H, s), 4,22 (1H, USS), is 4.93 (1H, septet, J=6.8 Hz), at 6.84 (2H, d, J=9.1 Hz), make 6.90 (2H, d, J=9.1 Hz).

Example 3-111:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-isopropoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-2-isopropoxypyridine obtained in reference example 17, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.34 (6H, d, J=6.3 Hz), 1,50-2,30 (16H, m), 2,55-to 2.85 (3H, m), 3,03-of 3.12 (2H, m), 3,22-of 3.32 (2H, m)and 3.59 (2H, s)to 4.23 (1H, USS), 4,35 (2H, s), 5,27 (1H, septet, J=6.3 Hz), 6,72 (1H, d, J=8,8 Hz), 6,85 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 7,51 (1H, DD, J=8,8, 2.7 Hz), of 8.06 (1H, d, J=2.7 Hz).

Example 3-112:

9-{4-[(1-celebutopia-4-yl)oxy]phenyl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the tvii to the method of example 3 or equivalent means, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-2-isopropoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.40 (6H, d, J=6.3 Hz), 1,46-2,28 (16H, m), 2,54-to 2.85 (3H, m), 2,99-3,14 (2H, m), 3,21-to 3.35 (2H, m), 3,62 (2H, s), 4,24 (1H, USS), 4,37 (2H, s), of 5.26 (1H, septet, J=6.3 Hz), 6,85 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 8,49 (2H, s).

Example 3-113:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,40-2,36 (16H, m), 2,50-2,87 (3H, m), 2,98-3,14 (2H, m), 3,20-3,37 (2H, m), 3,83 (3H, s), a 3.87 (2H, s), 4,22 (1H, OSS), to 4.33 (2H, s), 6,83 (1H, d, J=2.4 Hz), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=8,8 Hz), 7,29 (1H, d, J=2,4 Hz).

Example 3-114:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cycle is butylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 9-2, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,50-2,29 (16H, m), 2,54-of 2.86 (3H, m), 3.00 and is 3.15 (2H, m), 3,21-to 3.36 (2H, m), 3,66 (2H, s), 3,88 (3H, s)to 4.23 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,28 (1H, DD, J=2,9, 2.0 Hz), 8,19 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=2,9 Hz).

Example 3 through 115:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 3-bromo-5-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,24 (16H, m), 2,56-2,84 (3H, m), 3,01-3,14 (2H, m), 3,26-to 3.36 (2H, m), 3,71 (2H, s), 4,22 (1H, USS), and 4.40 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,00 (1H, DD, J=2.0 a, 1.0 Hz), 8,78 (1H, d, J=1.0 Hz), 8,84 (1H, d, J=2.0 Hz).

Example 3-116:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[3-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as colorless oily substance according to the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-di is suspiro[5,5]undecane-3-one, obtained in reference example 9-2, and 2-bromo-3-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,43-2,38 (16H, m), 2,55-to 2.94 (3H, m), 3,01-3,17 (2H, m), 3,21-to 3.36 (2H, m), of 3.46 (1H, d, J=11.7 Hz), 3,88 (1H, d, J=11.7 Hz), 4,15-to 4.46 (1H, m), 4,32 (1H, d, J=17,8 Hz), and 4.40 (1H, d, J=17,8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), of 7.48 (1H, DD, J=7,7, 5.0 Hz), 8,11 (1H, d, J=7,7 Hz), 8,77 (1H, d, J=5.0 Hz).

Example 3-117:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 2-bromo-6-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,49-2,23 (16H, m), 2,55-2,84 (3H, m), 3,03-3,14 (2H, m), 3,23-to 3.33 (2H, m)to 3.89 (3H, s), of 4.00 (2H, s)to 4.23 (1H, USS), 4,35 (2H, s), to 6.58 (1H, DD, J=7,8, 1.0 Hz), 6,85 (2H, d, J=9.1 Hz), 6,92 (2H, d, J=9.1 Hz), a 7.62 (1H, t, J=7.8 Hz), to 7.67 (1H, DD, J=7,8, 1.0 Hz).

Example 3-118:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-imidazo[1,2-a]pyridine-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl--yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 9-2, and 3 itemids[1,2-a]pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45-2,29 (16H, m), 2,53-to 2.85 (3H, m), 3,02-3,17 (2H, m), 3,24-to 3.38 (2H, m), 3,70 (2H, s)to 4.23 (1H, OSS), to 4.46 (2H, s), 6,82-of 6.96 (2H, m)6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,56 (1H, s), a 7.62 to 7.67 (1H, m), 7,71-7,76 (1H, m).

Example 3-119:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,35 (16H, m), 2,55-to 2.85 (3H, m), 3,03-of 3.12 (5H, m), is 3.08 (3H, s), 3,26-to 3.34 (2H, m), of 3.69 (2H, s), 4,22 (1H, OSS), to 4.38 (2H, s), 6,85 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 7,58 (2H, d, J=8,6 Hz), 8,00 (2H, d, J=8.6 Hz).

Example 3-120:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in the MTEF the adjustment example 9-2, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,46-of 2.26 (16H, m), 2,54-2,87 (3H, m), 3,02-3,14 (2H, m), 3,22-to 3.34 (2H, m), 3,98 (2H, s)to 4.23 (1H, OSS), to 4.41 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), scored 8.38 (2H, s), at 9.53 (1H, s).

Example 3-121:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,21 (16H, m), of 2.28 (3H, s), 2,54-to 2.85 (3H, m), 3.04 from-and 3.16 (2H, m), 3,22-to 3.36 (2H, m), a 3.87-4,18 (2H, USM), 4,22 (1H, USS), 4,36 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,21 (1H, DD, J=7,0, 4,8 Hz), a 7.62 (1H, d, J=7,0 Hz), of 8.37 (1H, d, J=4,8 Hz).

Example 3-122:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 2-bromo-5-methoxypyridine instead of 1-bromo-4-torbenson is.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,24 (16H, m), of 2.51-to 2.85 (3H, m), 3,02-and 3.16 (2H, m), 3,22-to 3.34 (2H, m), a 3.87 (3H, s), of 3.94 (2H, s), is 4.21 (1H, USS), 4,35 (2H, s), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,27 (1H, DD, J=8,8, 2,9 Hz), 7,92 (1H, d, J=8,8 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 3-123:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 1-bromo-4-torbenson.

1H-NMR (400 MHz, CDCl3) δ: 1,46-2,24 (16H, m), 2,58-2,90 (3H, m), 3,03-3,13 (2H, m), 3,24-of 3.32 (2H, m), of 3.60 (2H, s), 4.26 deaths (1H, USS), 4,34 (2H, s), at 6.84 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 7,10 for 7.12 (2H, m), 7,26-7,28 (2H, m,).

Example 3-124:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,27 (16H, m), 2,52-only 2.91 (3H, m), 2,94-of 3.12 (2H, m), 318-3,36 (2H, m)and 3.59 (2H, s), 3,90 (3H, s), 4,24 (1H, USS), 4,32 (2H, s), at 6.84 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz), 7,46 (1H, s), of 8.04 (1H, s).

Example 3-125:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,46-2,38 (16H, m), 2,50-2,87 (3H, m), 3.00 and-of 3.12 (2H, m), of 3.25 to 3.35 (2H, m), 3,63 (2H, s), a 4.03 (3H, s)to 4.23 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=8,8 Hz)6,91 (2H, d, J=9.3 Hz), 8,53 (2H, s).

Example 3-126:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-1-methylpyridin-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,46-of 2.26 (16H, m), 2,53-to 2.85 (3H, m), 3.00 and-3,11 (2H, m), 3,23-to 3.33 (2H, m), 3,51 (2H, s), of 3.54 (3H, s)to 4.23 (1H, USS), or 4.31 (2H, s), is 6.61 (1H, is, J=9.6 Hz), at 6.84 (2H, d, J=8,9 Hz)6,91 (2H, d, J=8,9 Hz), 7,26 (1H, DD, J=9,6, 2,9 Hz), 7,39 (1H, d, J=2,9 Hz).

Example 3-127:

9-(4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl)-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 4-iodine-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,50-of 2.26 (16H, m), 2,50-2,87 (3H, m), 2,97-of 3.12 (2H, m), 3,21-3,37 (2H, m), 3,68 (2H, s)to 4.23 (1H, OSS), to 4.38 (2H, s), 6,85 (2H, d, J=8,8 Hz)6,91 (2H, d, J=8,8 Hz), 7,11 (1H, d, J=2.5 Hz), 7,34 (1H, DD, J=5,6, 2,5 Hz), 8,23 (1H, d, J=5.6 Hz).

Example 3-128:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-1-ethylpyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: to 1.38 (3H, t, J=7.2 Hz), 1,45-2,30 (16H, m), of 2.51-is 2.88 (3H, m), 2,98-3,14 (2H, m), 3,20-3,37 (2H, m), 3,53 (2H, s), 3,8 (2H, kV, J=7,2 Hz), 4,23 (1H, USS), 4,32 (2H, s), 6,60 (1H, d, J=9.8 Hz), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,25 (1H, DD, J=9,8, 2.4 Hz), 7,38 (1H, d, J=2,4 Hz).

Example 3-129:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromo-1-isopropylpyridine-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.37 (6H, d, J=6.8 Hz), 1,44 e 2.06 (16H, m), of 2.51-to 2.85 (3H, m), 2,99-of 3.12 (2H, m), 3,22-to 3.35 (2H, m), 3,53 (2H, s)to 4.23 (1H, USS), 4,32 (2H, in), 5.25 (1H, septet, J=6.8 Hz), 6,60 (1H, d, J=9.8 Hz), 6,85 (2H, d, J=9.0 Hz), 6,91 (2H, d, J=9.0 Hz), 7,22 (1H, DD, J=9,8, 2.7 Hz), 7,40 (1H, d, J=2.7 Hz).

Example 3-130:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 3-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,28-2,28 (16H, m, 2,45-to 2.85 (3H, m), 2,99-3,10 (2H, m), 3,21-and 3.31 (2H, m)to 3.64 (2H, s), 4,19 (1H, USS), 4,34 (2H, s), for 6.81 (2H, d, J=9.1 Hz), to 6.88 (2H, d, J=9.1 Hz), 7.29 trend and 7.36 (1H, m), 7,65-7,72 (1H, m), 8,46-charged 8.52 (1H, m), 8,56-8,59 (1H, m).

Example 3-131:

Getting 5-(9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinanilide

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.41 to 2,25 (16H, m), 2,45-2,87 (3H, m), 2,98-to 3.09 (2H, m), 3,22-of 3.32 (2H, m)to 3.67 (2H, s), 4,19 (1H, USS), 4,36 (2H, s), for 6.81 (2H, d, J=9.1 Hz), to 6.88 (2H, d, J=9.1 Hz), 8,03-8,08 (1H, m), 8,70-a total of 8.74 (1H, m,), 8,80-8,83 (1H, m).

Example 3-132:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-2, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,59-2,09 (16H, m), 2,63-to 2.74 (3H, m), is 3.08 (2H, TD, J=11,2, 2,9 the TS) of 3.28 (2H, dt, J=12,7, 3,4 Hz), 3,88 (2H, s)to 3.99 (3H, s), is 4.21 (1H, USS), 4,37 (2H, s), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 8,03 (1H, d, J=1.5 Hz), 8,84 (1H, d, J=1.5 Hz).

Example 3-133:

Getting 4-ethyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3-96 or a similar method, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and bromatan.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz)and 1.15 (3H, t, J=7,3 Hz), 1,72-of 1.85 (4H, m), from 2.00 (4H, d, J=13,2 Hz), is 2.37 (2H, USS), 2,80 (3H, OSS), to 3.02 (2H, TD, J=11,7, 2,8 Hz), 3,20 of 3.28 (4H, m), of 3.46 (2H, q, J=7,3 Hz), 4,13-4,23 (3H, m), at 6.84 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 Hz).

Example 3-134:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3-96 or a similar method, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 2,2,2-triftoratsetilatsetonom instead of brometane.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=5.4 Hz), 1,76 is 1.86 (4H, m), 2,02 (4H, d, J=13,2 Hz), 2,39 (2H, USS), of 2.81 (3H, OSS), to 3.02 (2H, TD, J=11,7, 2,8 Hz)at 3.25 (2H, dt, J=12,2, 3,9 G is), of 3.42 (2H, s)4,06 (2H, q, J=8,9 Hz), 4,20 (1H, USS), 4,27 (2H, s), 6,85 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 Hz).

Example 3-135:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (6H, s), 1,73-of 1.93 (4H, m), 1,94-of 2.20 (4H, m), 2.40 a (2H, USS), 2,82 (3H, USS), 3,03-of 3.12 (5H, m), 3,30 (2H, d, J=a 12.7 Hz), of 3.69 (2H, s), is 4.21 (1H, OSS), to 4.38 (2H, s), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,58 (2H, d, J=8,8 Hz), 8,00 (2H, d, J=8,8 Hz).

Example 3-136:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 3-bromo-5-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=5.4 Hz), 1,72-of 2.08 (6H, m), of 2.15 (2H, d, J=a 12.7 Hz), of 2.38 (2H, the .c), 2,80 (3H, USS), is 3.08 (2H, TD, J=11,2, 2,4 Hz)and 3.31 (2H, dt, J=12,7, 3,9 Hz), 3,71 (2H, s), 4,20 (1H, USS), and 4.40 (2H, s)6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,00 (1H, t, J=2.0 Hz), 8,78 (s,1H), 8,84 (1H, d, J=2,4 Hz).

Example 3-137:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, USS), 1,73-of 2.09 (6H, m), 2,13 (2H, d, J=13,2 Hz), 2,39 (2H, USS), 2,80 (3H, USS), is 3.08 (2H, TD, J=11,2, 2.0 Hz), 3,29 (2H, dt, J=12,7, 3,4 Hz), 3,66 (2H, s), 3,88 (3H, s), 4,20 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,28 (1H, t, J=2.2 Hz), to 8.20 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=2,4 Hz).

Example 3-138:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 2-idperson instead of 1-bromo-4-fervently.

1 H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz), 1,73-of 1.94 (4H, m), 1,95 and 2.13 (4H, m), of 2.38 (2H, USS), 2,70-of 2.86 (3H, OSS), to 3.09 (2H, TD, J=11,2, 2,9 Hz), 3,29 (2H, dt, J=12,2, 4,4 Hz), 3,98 (2H, s), 4,19 (1H, OSS), to 4.41 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), scored 8.38 (2H, s), at 9.53 (1H, s).

Example 3-139:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(3-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow oily substance according to the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 2-bromo-3-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=5,9 Hz), 1,73-of 2.09 (6H, m), 2,17 (2H, d, J=13,7 Hz), 2,39 (2H, USS), 2,70-of 2.86 (3H, USM), 3,10 (2H, TD, J=11,2, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 3,9 Hz), 3,70 (2H, USS), 3,88 (3H, s), 4,19 (1H, USS), 4,36 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,34-7,27 (2H, m)to 8.12 (1H, DD, J=4,4, 2.0 Hz).

Example 3-140:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example the e 9-3, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 HZ), 1,75-of 1.92 (4H, m), a 2.01 (2H, USS), and 2.14 (2H, d, J=13,2 Hz), 2.40 a (2H, USS), 2,72-2,89 (3H, USM), of 3.07 (2H, TD, J=11,7, 2.4 Hz), 3,30 (2H, dt, J=12,7, 3,4 Hz), 3,63 (2H, s), a 4.03 (3H, s), 4,20 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,53 (2H, s).

Example 3-141:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.3 Hz), 1,73-of 1.93 (4H, m), 1,95-2,11 (4H, m), 2,32-to 2.42 (2H, m), 2,69-2,84 (3H, m), 3,06 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,2, 3,9 Hz), 3,83 (3H, s), a 3.87 (2H, s), 4,18 (1H, USS), to 4.33 (2H, s), 6.87 in-PC 6.82 (3H, m)6,91 (2H, d, J=9.3 Hz), 7,29 (1H, d, J=2,4 Hz).

Example 3-142:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]is ndacan-3-one, obtained in reference example 9-3, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.3 Hz), 1,73 is 1.91 (4H, m), 1.93 and with 2.14 (4H, m), of 2.38 (2H, USS), 2,69-to 2.85 (3H, USM), was 3.05 (2H, TD, J=11,7, 2.4 Hz), or 3.28 (2H, dt, J=12,7, 3,9 Hz)and 3.59 (2H, s), 3,90 (3H, s), 4,19 (1H, USS), 4,32 (2H, s), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,46 (1H, s), 8,03 (1H, s).

Example 3-143:

Getting 5-(9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinanilide

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz), 1,73-of 1.93 (4H, m), 1,99 (2H, USS), and 2.14 (2H, d, J=a 12.7 Hz), of 2.38 (2H, USS), 2,71-2,84 (3H, USM), of 3.07 (2H, TD, J=11,7, 2,4 Hz)and 3.31 (2H, dt, J=12,7, 3,9 Hz), 3,71 (2H, s), 4,19 (1H, USS), 4,39 (2H, s)6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,10 (1H, t, J=2.2 Hz), 8,76 (1H, d, J=2.0 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-144:

Getting 4-(2-ethoxypyridine-5-yl)-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 9-3, and 5-bromo-2-ethoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, USS), the 1.44 (3H, t, J=7,1 Hz), 1,74-2,19 (8H, m), 2.40 a (2H, USS), 2,71-2,90 (3H, USM), of 3.07 (2H, TD, J=11,7, 2.4 Hz), 3,30 (2H, dt, J=12,2, 3,9 Hz), 3,62 (2H, s), is 4.21 (1H, s), 4,37 (2H, s), of 4.44 (2H, kV, J=7,2 Hz), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,51 (2H, s).

Example 3-145:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 3 or in a similar way, but using 9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-3, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz), 1,72-of 1.95 (4H, m), 1,95 and 2.13 (4H, m), 2,39 (2H, USS), 2,70-of 2.86 (3H, USM), is 3.08 (2H, TD, J=11,2, 2.0 Hz), or 3.28 (2H, dt, J=12,2, 4,4 Hz), 3,88 (2H, s)to 3.99 (3H, s), 4,19 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,03 (1H, d, J=1.5 Hz), 8,84 (1H, d, J=1.5 Hz).

Example 3-146:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in reference example 9-3, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.18 to about 1.35 (6H, m), 1.70 to 2,47 (8H, m), was 2.76-3,36 (9H, m), of 3.60 (2H, s), of 3.94 (3H, s), 4,36 (2H, s), 4,36-4,47 (1H, m), 6,79 (1H, d, J=8,8 Hz), at 6.84 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9.3 Hz), 7,54 (1H, DD, J=8,8, 2.2 Hz), 8,10 (1H, d, J=2.2 Hz).

Example 3-147:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44-2,30 (16H, m), 2.57 m) of 2.92 (3H, m), 2,99-3,13 (2H, m), 3,20-and 3.31 (2H, m), of 3.84 (3H, s), 3,88 (2H, s)to 4.33 (2H, s), 4,99 (1H, USS), of 6.65 (1H, d, J=8,8 Hz), at 6.84 (1H, d, J=2.0 Hz), 7,29 (1H, d, J=2,0 Hz), 7,31 (1H, DD, J=8,8, 2.7 Hz), 7,80 (1H, d, J=2.7 Hz).

Example 3-148:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazep the ro[5,5]undecane-3-one, obtained in reference example 9-4, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (CDCl3) δ: 1,49-of 2.26 (16H, m), 2,58-to 2.85 (3H, m), 2,99-3,11 (2H, m), 3,20-3,30 (2H, m), of 3.60 (2H, s), 3,90 (3H, s), 4,32 (2H, s), equal to 4.97 (1H, USS), of 6.66 (1H, d, J=8,9 Hz), 7,30 (1H, DD, J=8,9 and 3.1 Hz), 7,46 (1H, d, J=1.0 Hz), 7,80 (1H, d, J=3.1 Hz), of 8.04 (1H, d, J=1.0 Hz).

Example 3-149:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily orange substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 5-bromo-2-isopropoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: of 1.40 (6H, d, J=6.3 Hz), 1,47-2,27 (16H, m), 2,56-to 2.85 (3H, m), 2,99-3,14 (2H, m), 3,21-of 3.32 (2H, m), 3,62 (2H, s), 4,37 (2H, s), equal to 4.97 (1H, USS), 5,27 (1H, septet, J=6.3 Hz), of 6.66 (1H, d, J=9,2 Hz), 7,30 (1H, DD, J=9,2, 3.1 Hz), 7,81 (1H, d, J=3.1 Hz), 8,49 (2H, s).

Example 3-150:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, according to the scientists in reference example 9-4, and 3-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,29 (16H, m), 2.57 m-2,86 (3H, m), 3.00 and is 3.15 (2H, m), 3,20-to 3.33 (2H, m), 3,68 (2H, s), to 4.38 (2H, s), to 4.98 (1H, USS), of 6.66 (1H, d, J=8,8 Hz), 7,31 (1H, DD, J=8,8, 2,9 Hz), 7,35-7,40 (1H, m), 7,69-7,76 (1H, m), 7,81 (1H, d, J=2,9 Hz), 8,50-8,56 (1H, m), 8,59-8,64 (1H, m).

Example 3-151:

Getting 5-(9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinanilide

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,24 (16H, m), 2.57 m-2,82 (3H, m), 3.00 and is 3.15 (2H, m), 3,21-to 3.35 (2H, m), 3,71 (2H, s), and 4.40 (2H, s), equal to 4.97 (1H, USS), of 6.66 (1H, d, J=8,9 Hz), 7,30 (1H, DD, J=8,9 and 3.1 Hz), 7,81 (1H, d, J=3.1 Hz), 8,09 (1H, DD, J=2,4, 2.0 Hz), 8,76 (1H, d, J=2.0 Hz), cent to 8.85 (1H, d, J=2,4 Hz).

Example 3-152:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained the first in reference example 9-4, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44-2,24 (16H, m), 2,49-2,87 (3H, m), 2,97-3,10 (2H, m), 3,03 (3H, s), 3,17-3,29 (2H, m), 3,66 (2H, s), 4,35 (2H, s), of 4.95 (1H, USS), 6,62 (1H, d, J=9,2 Hz), 7,27 (1H, DD, J=9,2, 2.7 Hz), 7,54 (2H, d, J=8,7 Hz), to 7.77 (1H, d, J=2.7 Hz), of 7.96 (2H, d, J=8.7 Hz).

Example 3-153:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 1-iodine-4-methoxybenzoyl instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,44-2,32 (16H, m), 2.57 m-2,86 (3H, m), 3,02-3,14 (2H, m), 3,18-3,30 (2H, m)and 3.59 (2H, s), 3,82 (3H, s), 4,34 (2H, s), 4,99 (1H, USS), of 6.66 (1H, d, J=8,9 Hz)6,94 (2H, d, J=9.3 Hz), 7,20 (2H, d, J=9,3 Hz), 7,30 (1H, DD, J=8,9 and 3.1 Hz), 7,81 (1H, d, J=3.1 Hz).

Example 3-154:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in rabochem example 9-4, and 5-bromo-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,30 (16H, m), 2,58-is 2.88 (3H, m), 3,01-3,13 (2H, m), 3,22-of 3.32 (2H, m), of 3.69 (2H, s), 4,39 (2H, s), 4,99 (1H, OSS), to 6.67 (1H, d, J=8,8 Hz), 7,09-7,13 (1H, m), 7,31 (1H, DD, J=8,8, 2,9 Hz), 7,31-7,37 (1H, m), 7,81 (1H, d, J=2,9 Hz), 8,21 compared to 8.26 (1H, m).

Example 3-155:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 4-iodine-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,42-2,35 (16H, m), 2,60-2,87 (3H, m), 3,02-3,14 (2H, m), 3,22-of 3.32 (2H, m), 3,66 (2H, s), 4,37 (2H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=8,8 Hz), 6,97? 7.04 baby mortality (1H, m), 7,31 (1H, DD, J=8,8, 2,9 Hz), 7,81 (1H, d, J=2,9 Hz), 7,82-7,88 (1H, m), 8.17 and is 8.22 (1H, m).

Example 3-156:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, obtained in the MTEF the adjustment example 9-4, and 5-bromo-2-(deformedarse)pyridine obtained in reference example 16, instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,40-2,30 (16H, m), 2.57 m-of 2.93 (3H, m), 3,02-3,13 (2H, m), 3,20-and 3.31 (2H, m), 3,63 (2H, s), 4,36 (2H, s)5,00 (1H, USS), of 6.66 (1H, d, J=9.1 Hz), of 6.96 (1H, d, J=9.1 Hz), 7,30 (1H, DD, J=9,1, 2,9 Hz), 7,43 (1H, t, J=72,7 Hz), 7,74 (1H, DD, J=9,1, 2,5 Hz), 7,81 (1H, d, J=2,9 Hz), 8,16 (1H, d, J=2.5 Hz).

Example 3-157:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 1-bromo-4-torbenson.

1H-NMR (400 MHz, CDCl3) δ: 1.41 to 2,40 (16H, m), 2.57 m-2,90 (3H, m), 3,01 is 3.15 (2H, m), 3,19-and 3.31 (2H, m), 3,61 (2H, s), 4,34 (2H, s), 4,99 (1H, USS), of 6.66 (1H, d, J=9,2 Hz), 7,10 (2H, d, J=8,8 Hz), 7,12 (2H, d, J=8,8 Hz), 7,30 (1H, DD, J=9,2, 3,3 Hz), 7,81 (1H, d, J=3.3 Hz).

Example 3-158:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4-diazaspiro[5,5]undecane-3-one, obtained in reference example 9-4, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,30 (16H, m), 2,58-of 2.86 (3H, m), 3,01-3,13 (2H, m), 3,19-and 3.31 (2H, m), of 3.60 (2H, s), of 3.94 (3H, s), 4,35 (2H, s), to 4.98 (1H, USS), of 6.66 (1H, d, J=8,9 Hz), 6,79 (1H, d, J=8,8 Hz), 7,30 (1H, DD, J=8,9 and 3.1 Hz), 7,54 (1H, DD, J=8,8, 2.7 Hz), 7,81 (1H, d, J=3.1 Hz), 8,10 (1H, d, J=2.7 Hz).

Example 3-159:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3-96 or a similar method, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and bromatan.

1H-NMR (400 MHz, CDCl3) δ: of 1.16 (3H, t, J=7,3 Hz), 1,43-2,35 (16H, m), 2,54-2,90 (3H, m), 2,96-to 3.09 (2H, m), 3,14 is 3.23 (2H, m), 3,23 (2H, s), of 3.46 (2H, q, J=7,3 Hz)to 4.16 (2H, s), to 4.98 (1H, USS), of 6.65 (1H, d, J=9,2 Hz), 7,29 (1H, DD, J=9,2, 3.1 Hz), 7,79 (1H, d, J=3.1 Hz).

Example 3-160:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one, sex is obtained in reference example 9-4, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,24 (16H, m), 2,56-is 2.88 (3H, m), 2,99 is 3.15 (2H, m), 3,20-to 3.34 (2H, m), 3,63 (2H, s), a 4.03 (3H, s), 4,37 (2H, s), equal to 4.97 (1H, USS), of 6.66 (1H, d, J=8,9 Hz), 7,30 (1H, DD, J=8,9 and 3.1 Hz), 7,81 (1H, d, J=3.1 Hz), 8,53 (2H, s).

Example 3-161:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9-4, and 5-bromo-2-methylpyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,28 (16H, m), to 2.57 (3H, s), 2,60-2,87 (3H, m), 3.00 and-3,14 (2H, m), 3,19-of 3.32 (2H, m)to 3.64 (2H, s), 4,36 (2H, s), to 4.98 (1H, USS), of 6.66 (1H, d, J=8,8 Hz), 7,21 (1H, d, J=8,3 Hz), 7,30 (1H, DD, J=8,8, 2,9 Hz), 7,58 (1H, DD, J=8,3, 2.7 Hz), 7,81 (1H, d, J=2,9 Hz), to 8.45 (1H, d, J=2.7 Hz).

Example 3-162:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained is in reference example 9-4, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,54-2,25 (16H, m), 2,60-2,82 (3H, USM), is 3.08 (2H, TD, J=11,2, 2,9 Hz)at 3.25 (2H, dt, J=12,7, 4,4 Hz)to 3.89 (2H, s)to 3.99 (3H, s), 4,37 (2H, s), equal to 4.97 (1H, USS), of 6.66 (1H, d, J=9.3 Hz), 7,30 (1H, DD, J=9,0, 3,2 Hz), 7,81 (1H, d, J=2,9 Hz), 8,03 (1H, d, J=1.5 Hz), 8,84 (1H, d, J=1.5 Hz).

Example 3-163:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methylpyridin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 5-bromo-2-methylpyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,25 (16H, m)to 2.54 (3H, s), 2.57 m-and 2.83 (3H, m), 3,18-to 3.36 (4H, m), 3,81 (2H, s), 4,22 (1H, USS), 6,85 (2H, d, J=9.1 Hz), 6,92 (2H, d, J=9.1 Hz), 7,18 (1H, d, J=8,8 Hz), 8,14 (1H, DD, J=8,8, 2,9 Hz), to 8.41 (1H, d, J=2,9 Hz).

Example 3-164:

Getting 5-(8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinanilide

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 5-br is nicotinamide instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,49-2,27 (16H, m), 2,52-of 2.86 (3H, m), 3,18-3,39 (4H, m), 3,85 (2H, s), 4,22 (1H, USS), 6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,54 (1H, DD, J=2,6, 1.9 Hz), 8,64 (1H, d, J=1.9 Hz), 8,81 (1H, d, J=2,6 Hz).

Example 3-165:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-pyridin-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 3-bromopyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,40-2,31 (16H, m), 2,50 of 2.92 (3H, m), 3,17-to 3.38 (4H, m), a-3.84 (2H, s), 4,24 (1H, USS), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,33 (1H, DD, J=8,4, 4,4 Hz), 8,24 (1H, DDD, J=8,4, 2,4, 1.5 Hz), to 8.41 (1H, DD, J=4,4, 1.5 Hz), 8,59 (1H, d, J=2,4 Hz).

Example 3-166:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5] decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,46-2,25 (16H, m), 2,53-2,8 (3H, m), 3,17-of 3.32 (4H, m), 3,66 (2H, s)to 3.89 (3H, s), 4,22 (1H, USS), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,35 (1H, s), to 7.77 (1H, s).

Example 3-167:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,43-2,30 (16H, m), 2,53-only 2.91 (3H, m), 3,16-to 3.33 (4H, m), 3,82 (3H, s), a 3.87 (2H, s), 4,24 (1H, ass), only 6.64 (1H, d, J=2.2 Hz), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,28 (1H, d, J=2.2 Hz).

Example 3-168:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,42-2,27 (16H, m), of 2.51-to 2.85 (3H, m), 3,17-to 3.35 (4H, m), 3,76 (2H, s)to 3.92 (3H, s), 4,22 (1H, USS), 6,79 (1H, d, J=9.4 Hz), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), with 8.05 (1H, d, J=2.4 Hz), 8,11 (1H, DD, J=9,4, 2,4 Hz).

Example 3-169:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-imidazo[1,2-a]pyridine-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the header connection receive in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 3 itemids[1,2-a]pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,42-2,37 (16H, m), 2,53-2,89 (3H, m), 3,21-to 3.38 (4H, m), 3,81 (2H, s), 4,24 (1H, USS), 6,86 (2H, d, J=9.1 Hz), 6,89-of 6.96 (1H, m), 6,93 (2H, d, J=9.1 Hz), 7,21-to 7.32 (1H, m), EUR 7.57-of 7.70 (2H, m), 7,88-of 7.97 (1H, m).

Example 3-170:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the header connection receive in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,48-2,30 (16H, m), is 2.37 (3H, s), 2,52-of 2.86 (3H, m), 3,19-to 3.35 (4H, m)4,00 (2H, s), 4,22 (1H, USS), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,16 (1H, DD, J=7,4, 4.6 Hz), to 7.61 (1H, d, J=7,4 Hz), of 8.28 (1H, d, J=4,6 Hz).

Example 3-171:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-herperidin-3-yl)-1-oxa-8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 5-bromo-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45-2,29 (16H, m), of 2.51-and 2.83 (3H, m), 3,17-to 3.36 (4H, m), 3,81 (2H, s), is 4.21 (1H, USS), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), of 6.96-7,01 (1H, m), 8.07-a to 8.12 (1H, m), of 8.37-to 8.45 (1H, m).

Example 3-172:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,47-2,28 (16H, m), 2,54-2,82 (3H, m), 3,05 (3H, s), 3,18-3,37 (4H, m), 3,85 (2H, s), 4,22 (1H, USS), 6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), to 7.77 (2H, d, J=8,8 Hz), of 7.96 (2H, d, J=8,8 Hz).

Example 3-173:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-herperidin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale-orange substances is in accordance with the method of example 3 or equivalent means, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 4-iodine-2-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,43-2,23 (16H, m), 2,56-only 2.91 (3H, m), 3,17-to 3.36 (4H, m), with 3.79 (2H, s), 4,20 is 4.36 (1H, m), 6,85 (2H, d, J=9.1 Hz), 6,92 (2H, d, J=9.1 Hz), 7,14 (1H, d, J=2.0 Hz), 7,41 (1H, DD, J=6,1, 2.0 Hz), 8,16 (1H, d, J=6,1 Hz).

Example 3-174:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale green substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-1, and 5-bromo-1-methylpyridin-2(1H)-he instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,45-2,29 (16H, m), 2,52-2,90 (2H, m), 3,16-to 3.34 (4H, m), of 3.57 (3H, s), 3,68 (2H, s), 4,25 (1H, USS), 6,62 (1H, d, J=9.8 Hz), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,47 (1H, DD, J=9,8, 2,9 Hz), of 7.70 (1H, d, J=2,9 Hz).

Example 3-175:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-cycle is butylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it, obtained in reference example 13-1, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,51-2,45 (16H, m), 2,53-to 2.94 (3H, m), 3,12-3,39 (4H, m), of 3.78 (2H, s), was 4.02 (3H, s), 4,27 (1H, USS), 6,85 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), the rate of 8.75 (2H, s).

Example 3-176:

Obtain 3-ethyl-8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3-96 or a similar method, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and bromatan.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=5,9 Hz), of 1.17 (3H, t, J=7,3 Hz), 1,73-of 2.09 (8H, m), of 2.38 (2H, USS), 2,70-of 2.86 (3H, USM), and 3.16-3.24 in (4H, m), 3,31-3,37 (4H, m), 4,19 (1H, s), at 6.84 (2H, d, J=9.3 Hz), 6.89 in (2H, d, J=9,3 Hz).

Example 3-177:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz), 1,73-to 1.87 (2H, the mkm), 1,94 e 2.06 (5H, m), 2,13 (2H, d, J=13,2 Hz), of 2.38 (2H, USS), 2,70-to 2.85 (3H, USM), 3,21-3,29 (4H, m), 3,66 (2H, s)to 3.89 (3H, s), 4,20 (1H, USS), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,35 (1H, d, J=1,0 Hz), to 7.77 (1H, s).

Example 3-178:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy}phenyl-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.8 Hz), 1,74 is 1.86 (2H, USM), 1,95-of 2.08 (5H, m), and 2.14 (2H, d, J=13,2 Hz), 2,39 (2H, USS), 2,70-of 2.86 (3H, USM), 3,20 of 3.28 (4H, m), 3,82 (3H, s), a 3.87 (2H, s), 4,20 (1H, ass), only 6.64 (1H, d, J=2,4 Hz), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9.3 Hz), 7,28 (1H, d, J=2,4 Hz).

Example 3-179:

Getting 5-(8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinanilide

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, who, J=6.3 Hz), 1,74 is 1.86 (2H, USM), 1,93-2,12 (4H, m), 2,17 (2H, d, J=13,2 Hz), of 2.38 (2H, USS), 2,69-of 2.86 (3H, USM), 3,21-to 3.33 (4H, m), 3,85 (2H, s), 4,20 (1H, USS), 6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,56 are 8.53 (1H, m)8,64 (1H, d, J=2.0 Hz), 8,81 (1H, d, J=2,4 Hz).

Example 3-180:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=5,9 Hz)and 1.83 (2H, USS), 1,97 is 2.10 (4H, m), 2,17 (2H, d, J=13,2 Hz), 2,42 (2H, USS), 2,82 (3H, USS), 3,26-of 3.27 (4H, m)4,00 (2H, s), 4,22 (1H, s)6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=and 9.3 Hz), of 8.27 (1H, DD, J=2.7, and 1.7 Hz), with 8.33 (1H, d, J=2.4 Hz), 9,60 (1H, d, J=1.5 Hz).

Example 3-181:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 2-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl 3) δ with 1.07 (6H, d, J=5,9 Hz), equal to 1.82 (2H, USS), 1,97-to 2.06 (4H, m), 2,10-2,19 (2H,m), 2,39 (2H, USS), 2,70-to 2.85 (3H, USM), 3,22 of 3.28 (4H, m), 3,85 (3H, s)to 4.01 (2H, s), 4,20 (1H, USS), 6,85 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), 7,30 (1H, DD, J=9,3, 2,9 Hz), to 7.99 (1H, d, J=3,4 Hz), 8,17 (1H, d, J=9.8 Hz).

Example 3-182:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 5-iodine-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=6.3 Hz), equal to 1.82 (2H, USS), 1,97 is 2.10 (4H, m), 2,17 (2H, d, J=13,2 Hz)to 2.41 (2H, USS), 2,73-is 2.88 (3H, USM), 3,19-to 3.35 (4H, m), of 3.78 (2H, s), was 4.02 (3H, s), is 4.21 (1H, USS), 6,86 (2H, d, J=9,3 Hz), 6,92 (2H, d, J=9.3 Hz), 8,76 (2H, s).

Example 3-183:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(3-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as yellow oily substance according to the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 2-bromo-3-methoxypyridine instead of 1-bromo-4-fervently.

1H is the Mr (400 MHz, CDCl3) δ: 1,09 (6H, d, J=6.3 Hz), of 1.84 (2H, USS), 2,03 (4H, d, J=28,3 Hz), 2,24 (2H, d, J=a 12.7 Hz), a 2.45 (2H, USS), and 2.83 (3H, USS), 3,19-of 3.32 (4H, m), 3,90 (2H, s), 3,91 (3H, s), 4,22 (1H, USS), 6,85 (2H, d, J=9,3 Hz), 6,91 (2H, d, J=9.3 Hz), 7.23 percent (1H, DD, J=8,3, a 4.9 Hz), 7,31 (1H, DD, J=8,3, 1.5 Hz), of 8.06 (1H, DD, J=4,4, 1.5 Hz).

Example 3-184:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-2, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (6H, d, J=6.3 Hz), equal to 1.82 (2H, USS), 1,99 e 2.06 (4H, m), of 2.15 (2H, d, J=a 12.7 Hz), 2.40 a (2H, USS), 2,73-to 2.85 (3H, USM), 3,20-to 3.34 (4H, m), of 3.77 (2H, s)to 3.92 (3H, s), is 4.21 (1H, USS), is 6.78 (1H, d, J=9,3 Hz), 6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9.3 Hz), of 8.06 (1H, d, J=2.4 Hz), 8,11 (1H, DD, J=8,8, 2,9 Hz).

Example 3-185:

Getting 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 3 or in a similar way, but using 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in the reference note is re 13-2, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (6H, s)of 1.84 (2H, USS), 2,00-2,07 (4H, m)of 2.16 (2H, d, J=13,7 Hz), 2,42 (2H, USS), 2,82 (3H, USS), 3,21-to 3.34 (4H, m), 3,82 (2H, s)to 3.89 (3H, s), 4,22 (1H, USS), 6,86 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9,3 Hz), of 7.96 (1H, t, J=2.4 Hz), 8,08 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=2,4 Hz).

Example 3-186:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 2-bromo-3-methylpyridin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,58-2,25 (16H, m), is 2.37 (3H, s), 2,59-2,82 (3H, USM), 3,22-3,29 (4H, m)to 4.01 (2H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=8,8 Hz), 7,16 (1H, DD, J=7,8, and 4.9 Hz), 7,31 (1H, DD, J=8,8, 2,9 Hz), to 7.61 (1H, d, J=6,3 Hz), 7,81 (1H, d, J=2,9 Hz), of 8.28 (1H, DD, J=4,9, 1.5 Hz).

Example 3-187:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,Decan-2-it, obtained in reference example 13-3, and 2-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,23 (16H, m), 2,60-of 2.81 (3H, USM), 3,21 of 3.28 (4H, m), 3,85 (3H, s), was 4.02 (2H, s), to 4.98 (1H, USS), of 6.66 (1H, d, J=8,8 Hz), 7,34-7,28 (2H, m), 7,81 (1H, d, J=2,9 Hz), to 7.99 (1H, d, J=2.4 Hz), 8,17 (1H, d, J=9,3 Hz).

Example 3-188:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-herperidin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 2-bromo-5-herperidin instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,49-2,28 (16H, m), 2,58-of 2.86 (3H, USM), 3,21-of 3.27 (4H, m), was 4.02 (2H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=9.3 Hz), 7,30 (1H, DD, J=8,8, 2,9 Hz), 7,50-the 7.43 (1H, m), 7,81 (1H, d, J=2,9 Hz), 8,16 (1H, d, J=2,9 Hz), of 8.27 (1H, DD, J=9,3, 3,9 Hz).

Example 3-189:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3-96 or a similar method, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, bromatan.

1H-NMR (400 MHz, CDCl3) δ: 1,17 (3H, t, J=7,3 Hz), 1,54-2,24 (16H, m), 2,59 is 2.80 (3H, USM), 3,20 (4H, DD, J=8.0 a, and 3.7 Hz), 3,29-to 3.38 (4H, m), equal to 4.97 (1H, USS), of 6.65 (1H, d, J=8,8 Hz), 7,28 (4H, DD, J=8,8, 2,9 Hz), 7,79 (1H, d, J=2.4 Hz).

Example 3-190:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2,2,2-triptorelin)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3-96 or a similar method, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 2,2,2-triftoratsetilatsetonom instead of brometane.

1H-NMR (400 MHz, CDCl3) δ: 1,49-of 2.26 (16H, m), 2.57 m-2,86 (3H, USM), 3,14-of 3.27 (4H, m), 3,47 (2H, s)to 3.89 (2H, square, J=8,8 Hz), to 4.98 (1H, USS), of 6.66 (1H, d, J=8,8 Hz), 7,30-of 7.25 (4H, m), 7,79 (1H, d, J=2,9 Hz).

Example 3-191:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 1-bromo-4-(methylsulphonyl)benzene instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,56-of 2.26 (6H, m), 2,61-and 2.83 (3H, USM), was 3.05 (3H, s), 3,22-3,30 (4H, m), 3,86 (2H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=8,8 Hz), 7,31 (1H, DD, J=8,8, 2,9 Hz), to 7.77 (2H, d, J=8,8 Hz), 7,82 (1H, d, J=2,9 Hz), of 7.96 (2H, d, J=8,8 Hz).

Example 3-192:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-ethoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 5-bromo-2-ethoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: the 1.44 (3H, t, J=7,1 Hz), 1,65-2,19 (16H, m), 2,60-2,82 (3H, USM), 3,19-3,32 (5H, m), of 3.78 (2H, s), 4,42 (2H, q, J=7.2 Hz), equal to 4.97 (1H, OSS), to 6.67 (1H, d, J=8,8 Hz), 7,30 (1H, DD, J=9,0, 3.2 Hz), 7,81 (1H, d, J=2,9 Hz), a total of 8.74 (2H, s).

Example 3-193:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,66-2,16 (16H, m), 2,61-and 2.83 (3H, the mkm), 3,21 of 3.28 (4H, m)to 3.67 (2H, s)to 3.89 (3H, s), to 4.98 (1H, USS), of 6.66 (1H, d, J=9.3 Hz), 7,30 (1H, DD, J=8,8, 2,9 Hz), 7,35 (1H, s), to 7.77 (1H, s), 7,81 (1H, d, J=2,9 Hz).

Example 3-194:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 3-iodine-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.56 to 2,25 (16H, m), 2,60-and 2.83 (3H, USM), 3,17-of 3.31 (4H, m), 3,82 (3H, s), a 3.87 (2H, s), to 4.98 (1H, USS), 6,68-6,63 (2H, m), 7,29 (2H, DD, J=a 9.5, 2.7 Hz), 7,80 (1H, d, J=2,4 Hz).

Example 3-195:

Getting 5-(8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinanilide

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,54-2,23 (16H, m), 2,61-of 2.81 (3H, USM), 3,20-to 3.33 (4H, m), 3,86 (2H, s), to 4.98 (1H, USS), of 6.68 (1H, d, J=9.3 Hz), 7,31 (1H, DD, J=9,0 3,2 Hz), of 7.82 (1H, d, J=2,9 Hz), 8,55 are 8.53 (1H, m), 8,65 (1H, d, J=2.0 Hz), 8,81 (1H, d, J=2,4 Hz).

Example 3-196:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,61-2,19 (16H, m), 2,60 is 2.80 (3H, USM), 3,21-3,29 (4H, m)4,00 (2H, s), equal to 4.97 (1H, OSS), to 6.67 (1H, d, J=9.0 Hz), 7,31 (1H, DD, J=9,0, 3.2 Hz), 7,82 (1H, d, J=2.2 Hz), of 8.27 (1H, s), a 8.34 (1H, d, J=2.5 Hz), a 9.60 (1H, s).

Example 3-197:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,52-2,21 (16H, m), 2,61-of 2.81 (3H, USM), 3,22-3,30 (4H, m), of 3.77 (2H, s), 3,93 (3H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=9.0 Hz), 6,79 (1H, d, J=9,2 Hz), 7,30 (1H, DD, J=9,1, 2,8 Hz), 7,81 (1H, d, J=3.1 Hz), ,06 (1H, d, J=2.7 Hz), 8,11 (1H, DD, J=9,0, 2,9 Hz).

Example 3-198:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1.60-to 2,19 (16H, m), 2,62 is 2.80 (3H, USM), 3,21-3,30 (4H, m), of 3.78 (2H, s), was 4.02 (3H, s), to 4.98 (1H, OSS), to 6.67 (1H, d, J=9.0 Hz), 7,31 (1H, DD, J=9,2, 2.7 Hz), 7,81 (1H, d, J=2.7 Hz), the rate of 8.75 (2H, s).

Example 3-199:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 3-bromo-5-(trifluoromethyl)pyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,59-of 2.20 (16H, m), 2,61-and 2.83 (3H, USM), 3,19-to 3.35 (4H, m), 3,88 (2H, s), 4,99 (1H, USS), of 6.68 (1H, d, J=8,8 Hz), 7,31 (1H, DD, J=9,0, 3.2 Hz), 7,82 (1H, d, J=2,9 Hz), 8,43 (1H, s), 8,67 (1H, s), cent to 8.85 (1H, is).

Example 3-200:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 3-bromo-5-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,61-2,18 (16H, m), 2,60-2,84 (3H, USM), 3,18-to 3.33 (4H, m), 3,83 (2H, s)to 3.89 (3H, s), 4,99 (1H, OSS), to 6.67 (1H, d, J=9.3 Hz), 7,31 (1H, DD, J=9,3, 2,9 Hz), 7,82 (1H, d, J=2,9 Hz), of 7.96 (1H, t, J=2.2 Hz), 8,08 (1H, d, J=2.4 Hz), 8,13 (1H, d, J=2,4 Hz).

Example 3-201:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyrazine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-3, and 2-bromo-5-methoxypyrazine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,59-2,18 (16H, m), 2,58-2,82 (3H, USM), 3,18-3,30 (4H, m), 3,97 (5H, s), equal to 4.97 (1H, OSS), to 6.67 (1H, d, J=9.0 Hz), 7,30 (1H, DD, J=9,0, 3.2 Hz), 7,81 (1H, d, J=2,9 Hz), to 7.93 (1H, d, J=1.5 Hz), 9,03 (1H, d, J=1.5 Hz).

Example 3-202:

Getting 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 3 or in a similar way, but using 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-4, and 5-bromo-2-methoxypyridine instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=6.3 Hz), 1,72-1,89 (2H, m), 1,97-of 2.23 (6H, m), 2,35-of 2.54 (2H, m), 2,69-2,90 (3H, m), 3,18-to 3.33 (4H, m), of 3.78 (2H, s), was 4.02 (3H, s), 4.92 in-5,04 (1H, m), of 6.68 (1H, d, J=8,9 Hz), 7,31 (1H, DD, J=8,9 and 3.1 Hz), 7,82 (1H, d, J=3.1 Hz), the rate of 8.75 (2H, s).

Example 3-203:

Getting 5-(8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinanilide

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-4, and 5-bromonicotinate instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (6H, d, J=6.3 Hz), 1,76-1,90 (2H, m), 2,01-of 2.24 (6H, m), 2.40 a at 2.59 (2H, m), a 2.75-2.91 in (3H, m), 3,19-to 3.35 (4H, m), 3,86 (2H, s), 4.92 in-5,04 (1H, m), of 6.68 (1H, d, J=9,2 Hz), 7,31 (1H, DD, J=9,2, 2.7 GHz), of 7.82 (1H, d, J=2.7 Hz), 8,54 (1H, DD, J=28, 1,6 Hz), 8,65 (1H, d, J=1.6 Hz), 8,82 (1H, d, J=2,8 Hz).

Example 3-204:

Getting 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-4, and 2-idperson instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (6H, d, J=6.3 Hz), 1,72-of 1.92 (2H, m), 1,98 was 2.25 (6H, m), 2,33-to 2.57 (2H, m), 2,68-to 2.94 (3H, m), 3,19-of 3.31 (4H, m)4,00 (2H, s), 4,89-5,02 (1H, m), of 6.68 (1H, d, J=9,2 Hz), 7,31 (1H, DD, J=9,2, 2,9 Hz), of 7.82 (1H, d, J=2,9 Hz), of 8.27 (1H, DD, J=2,6, and 1.6 Hz), a 8.34 (1H, d, J=2.6 Hz), 9,60 (1H, d, J=1.6 Hz).

Example 3-205:

Getting 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid according to the method of example 3 or in a similar way, but using 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-he obtained in reference example 13-4, and 4-bromo-1-methyl-1H-pyrazole instead of 1-bromo-4-fervently.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (6H, d, J=6.3 Hz), 1,72 is 1.91 (2H, m), 1,94-of 2.23 (6H, m), 2,34-2,61 (2H, m), 2,69-2,95 (3H, m), 3,16-of 3.32 (4H, m)to 3.67 (2H, s), 3,90 (3H, s), 4,91-5,02 (1H, m), to 6.67 (1H, d, J=8,9 is C), 7,30 (1H, DD, J=8,9 and 3.1 Hz), was 7.36 (1H, s), to 7.77 (1H, s), 7,81 (1H, d, J=3.1 Hz).

Example 4:

Getting 4-(4-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a)9-[4-(Benzyloxy)phenyl]-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one (500 mg, of 1.42 mmol)obtained in reference example 9, 1-iodine-4-methoxybenzene (400 mg, 1.70 mmol), potassium phosphate (603 mg, 2,84 mmol), copper iodide (30 mg, 0,142 mmol) and N,N'-dimethylaminoethanol (26 mg, 0,284 mmol) in 1,4-dioxane is stirred overnight in a sealed tube at 110°C. the Reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated and the residue purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=60/40 to 75/25)to give specified in the title compound (530 mg, 81%) as a white solid.

(b) 9-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Benzyloxy-compound (529 mg, 1.15 mmol)obtained in stage (a), is dissolved in a mixed solvent (methanol/tetrahydrofuran 1/1), then to the mixture is added 10% palladium on carbon (110 mg, 0,103 mmol) and the resulting mixture is stirred overnight in an atmosphere of water the ode. The reaction solution is filtered through celite, the celite is washed with a mixture of chloroform/methanol and uterine fluid concentrate, getting mentioned in the title compound (350 mg, 82%) as a solid purple substance.

(c) 4-(4-Methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of phenol derivative (288 mg, 0,781 mmol)obtained in stage (b), hydrobromide 1-(3-bromopropyl)piperidine (450 mg, 1.56 mmol)obtained in accordance with methods described in U.S. patent No. 4751302, and cesium carbonate (1,02 g of 3.12 mmol) in N,N-dimethylformamide is stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated aqueous salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water, liquid B: 0.1% TFWC/acetonitrile, A/B=90/10 to 50/50, elution with a linear concentration gradient over 8 min, flow rate 40 ml/min) and the fraction containing the target product, collecting, receiving the product in the form of a solid pale yellow substance (285 mg, 74%). The solid product is recrystallized in a mixture of ethanol/water (2/1), getting mentioned in the title compound in the form of a solid pale-rozovo the substance (184 mg, 48%).

1H-NMR (400 MHz, CDCl3) δ: 1,43 (2H, s), 1,54-to 1.63 (4H, m), 1,82-1,90 (2H, m), 1,92 of 1.99 (2H, m), 2,13 (2H, d, J=a 12.7 Hz), 2,39-2,48 (6H, m), 3.04 from-3,10 (2H, m), 3,24-3,29 (2H, m)and 3.59 (2H, s), 3,81 (3H, s), of 3.96 (2H, t, J=6,6 Hz), 4,34 (2H, s), 6,82-6,86 (2H, m), 6,91-of 6.96 (2H, m), 7.18 in-7,22 (2H, m), 7,26 (2H, s).

Example 4-1:

Getting 4-(3-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(3-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(a) or a similar method, but using 1-bromo-3-methoxybenzoyl instead of 1-iodine-4-methoxybenzene.

(b) 9-(4-Hydroxyphenyl)-4-(3-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pink substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(3-Methoxyphenyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,58 is 1.60 (4H, m), 1,82-1,90 (2H, m), 1.93 and with 2.14 (2H, m), 2,13 (2H, the, J=12,4 Hz), 2.40 a (4H, USS), 2,47 (2H, t, J=11,6 Hz), of 3.07 (2H, t, J=6.8 Hz), 3,26 (2H, d, J=12,4 Hz), 3,62 (2H, s), 3,82 (3H, s), of 3.96 (2H, t, J=6.4 Hz), 4,35 (2H, s), 6,82-6,93 (7H, m), 7,32 (2H, t, J=9,2 Hz).

Example 4-2:

Getting 4-(4-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(a) or a similar method, but using 1-bromo-4-torbenson instead of 1-iodine-4-methoxybenzoyl.

(b) 4-(4-Forfinal)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pink substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(4-Forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,53 (2H, s), 1,76-1,89 (6H, m), 2.13 and (4H, d, J=a 12.7 Hz), of 2.51-and 2.83 (6H, USM), of 3.07 (2H, TD, J=11,6, and 2.6 Hz), or 3.28 (2H, d, J=a 12.7 Hz), of 3.60 (2H, s), 3,98 (2H, t, J=6,1 Hz), 4,35 (2H, s), 6,80-6,85 (2H, m), 6,90-to 6.95 (2H, m), 7,08-7,14 (2H, m), 7,247,30 (2H, m).

Example 4-3:

Getting 4-(6-herperidin-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(a) or a similar method, but using 5-bromo-2-herperidin instead of 1-iodine-4-methoxybenzoyl.

(b) 4-(6-Herperidin-3-yl)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid purple substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(6-Herperidin-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, USS), 1,57-to 1.61 (4H, m), 1,83 is 1.91 (2H, m), 1.93 and is 2.00 (2H, m), 2,13 (2H, d, J=12,4 Hz), 2,42 (4H, USS), 2,49 (2H, t, J=7.2 Hz), 3,03-to 3.09 (2H, m), 3.27 to 3.30 is (2H, m), of 3.95 (2H, s), of 3.96 (2H, t, J=6,4 Hz), 4,37 (2H, s), at 6.84 (2H, d, J=9,2 Hz), 6,92 (2H, d, J=9,2 Hz), 7,00 (1H, DD, J=8,8, 3.2 Hz), 7,81-7,86 (1H, m), 8,19 (1H, d, J=1.6 Hz).

Example 4-4:

Paul is an increase of 4-(6-methoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(a) or a similar method, but using 5-bromo-2-methoxypyridine instead of 1-iodine-4-methoxybenzene.

(b) 9-(4-Hydroxyphenyl)-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid purple substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(6-Methoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, d, J=4.9 Hz), 1.56 to to 1.61 (4H, m), 1,83-1,90 (2H, m), 1,92 of 1.99 (2H, m), 2,13 (2H, d, J=13,2 Hz), 2,39-2,48 (6H, m), of 3.07 (2H, TD, J=11,6, 2.4 Hz), with 3.27 (2H, dt, J=12,2, 4,4 Hz), of 3.60 (2H, s), 3,94-3,98 (5H, m), 4,35 (2H, s), 6,79 (1H, d, J=8,8 Hz), at 6.84 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=8,8, 3,4 Hz), 7,55 (1H, DD, J=8,8, 2,9 Hz), 8,10 (1H, d, J=3,4 Hz).

Example 4-5:

Getting 4-(6-methoxypyridine-2-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

a) 9-[4-(Benzyloxy)phenyl]-4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(a) or a similar method, but using 6-bromo-2-methoxypyridine instead of 1-iodine-4-methoxybenzene.

(b) 9-(4-Hydroxyphenyl)-4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid purple substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(6-Methoxypyridine-2-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,47 (2H, USS), of 1.65 (4H, USS), 1.85 to 1.91 a (2H, m), 1,92-of 2.08 (4H, m), 2,45 is 2.55 (6H, m), 3,05-3,10 (2H, m), 3.25 to or 3.28 (2H, m)to 3.89 (2H, s), of 3.97 (2H, t, J=6.0 Hz), of 4.00 (2H, s), 4,35 (2H, s), to 6.57 (1H, DD, J=8,0, 1.2 Hz), 6,83 (2H, d, J=9,2 Hz), 6,93 (2H, d, J=9,2 Hz), 7,52-to 7.68 (2H, m).

Example 4-6:

4-Methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-methyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 and the and in a similar way, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9, and jodean.

(b) 9-(4-Hydroxyphenyl)-4-methyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-Methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=5,9 Hz), of 1.39 to 1.48 (1H, m), 1,58-to 1.82 (4H, m), 1,88-2,04 (5H, m), 2,10-of 2.24 (2H, m), and 2.27 to 2.35 (1H, m), 2,94 totaling 3.04 (3H, m)of 3.00 (3H, s), 3,16-of 3.27 (3H, m), 3,24 (2H, s), 3,93-was 4.02 (2H, m), to 4.17 (2H, s), at 6.84 (2H, d, J=93 Hz), 6,91 (2H, d, J=93 Hz).

Example 4-7:

Getting 4-methyl-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in example 4-6-(b), and hydrogen bromide (2S)-1-3-bromopropyl)-2-methylpyrrolidine, obtained in reference example 4-1.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=6.3 Hz), 1,39-1,49 (1H, m), 1.60-to to 1.83 (4H, m), 1,88-2,04 (5H, m), 2,09-of 2.24 (2H, m), 2,28-of 2.34 (1H, m), 2.95 and totaling 3.04 (3H, m)of 3.00 (3H, s), 3,17-3,26 (3H, m), 3,24 (2H, s), 3,93-a 4.03 (2H, m), to 4.17 (2H, s), at 6.84 (2H, d, J=93 Hz), 6,92 (2H, q, j 9.3 Hz).

Example 4-8:

Getting 4-ethyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9, and bromatan.

(b) 4-ethyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-ethyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2.

1H-NMR (400 MHz, CDCl3) δ: of 1.16 (3H, t, J=7,3 Hz)to 1.22 (3H, d, J=63 Hz), 1,53-of 1.62 (1H, m), 1,74-to 1.82 (3H, m), 1.85 to of 1.93 (1H, m), 1,98-2,12 (5H, m), 2,29 is 2.43 (2H, m), 2,49-of 2.58 (1H, m), 2,98-of 3.12 (3H, m), 3,20-of 3.27 (2H, m), 3,23 (2H, s), 3,29-to 3.36 (1H, m), of 3.46 (2H, q, J=7.2 Hz), 3.95 to Android 4.04 (2H, m)to 4.16 (2H, s), 6,83 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=9,3 Hz).

Example 4-9:

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9 and 1-bromopropane.

(b) 9-(4-Hydroxyphenyl)-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: 0,81-of 0.90 (1H, m)0,86 (3H, d, J=6.3 Hz), of 0.93 (3H, t, J=7,3 Hz), 54-1,89 (10H, m), 1,94-2,02 (4H, m), 2.49 USD (2H, t, J=7,3 Hz), and 2.83-2.91 in (2H, m), to 3.02 (2H, TD, J=11,7, 2.4 Hz), 3,20-of 3.25 (2H, m), up 3.22 (2H, s), 3,37 (2H, t, J=7,6 Hz), of 3.96 (2H, t, J=6.3 Hz), 4,17 (2H, s), 6,83 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-10:

Getting 4-isopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9 and 2-bromopropane.

(b) 9-(4-Hydroxyphenyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-Isopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), of 1.12 (6H, d, J=6.8 Hz), 1,54-to 1.79 (8H, m), 1,82-1,89 (1H, m), 1.9 to a 2.00 (4H, m), 2.49 USD (2H, t, J=7,6 Hz), 2,84-only 2.91 (2H, m), 2,99 was 3.05 (2H, m), 3,10 (2H, s), 3,20-of 3.25 (2H, m), of 3.96 (2H, t, J=6.3 Hz), 4,17 (2H, s), 4,88-to 4.98 (1H, m), 6,83 (2H, d, J=8,8 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-11:

Getting 4-isopropyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 4-(c) or a similar method, but using 9-(4-hydroxyphenyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-10(b) -, hydrobromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2.

1H-NMR (400 MHz, CDCl3) δ: 1,10-of 1.13 (9H, m), to 1.38 to 1.48 (1H, m), 1,58-to 1.79 (4H, m), 1,88 of 1.99 (5H, m), 2,09-of 2.23 (2H, m), 2,27-of 2.34 (1H, m), 2,94 was 3.05 (3H, m), 3,10 (2H, s), 3,17-of 3.25 (3H, m), 3.95 to 4,01 (2H, m), 4,18 (2H, s), 4,90-equal to 4.97 (1H, m), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-12:

Getting 4-(1-ethylpropyl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9, and 3-bromopentane.

(b) 4-(1-ethylpropyl)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

MC is connected to the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (a).

(c) 4-(1-Ethylpropyl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: 0,83-0,91 (10H, m), 1,36-1,88 (12H, m), 1.93 and-2,05 (4H, m), 2,48 (2H, t, J=7,6 Hz), and 2.83-2.91 in (2H, m), 3.00 and-a 3.06 (2H, m), 3,01 (2H, s), 3,21-3,26 (2H, m), of 3.96 (2H, t, J=6.3 Hz), to 4.23 (2H, s), 4,45-to 4.52 (1H, m), 6,83 (2H, d, J=8,8 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-13:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-[4-(Benzyloxy)phenyl]-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9, and 2,2,2-triftoratsetilatsetonom.

(b) 9-(4-Hydroxyphenyl)-4-(2,2,2,-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or Ana is ulichnym way but using benzyloxy-compound obtained in stage (a).

(c) 9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (b), and hydrogen bromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=5,9 Hz), 1.41 to a 1.50 (1H, m), 1.60-to of 1.84 (4H, m), 1,89-2,05 (5H, m), 2,13-of 2.27 (2H, m), 2,33-of 2.38 (1H, m), 2,96 was 3.05 (3H, m), 3,19-3,26 (3H, m)to 3.41 (2H, s), 3,93-4,01 (2H, m)4,06 (2H, q, J=8,9 Hz), 4,27 (2H, s), at 6.84 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-14:

Getting 4-cyclopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 1-[4-(Benzyloxy)phenyl]-4-[(cyclopropylamino)methyl]piperidine-4-ol

A mixture of 6-[4-(benzyloxy)phenyl]-1-oxa-6-azaspiro[2,5]octane (500 mg, was 1.69 mmol) and cyclopropylamine (195 mg, to 3.38 mmol) in methanol is refluxed over night. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the crude product.

The obtained residue pre the excitation crude product, purified column chromatography (silica gel, elution gradient: methanol/chloroform=1/99 to 6/94), getting mentioned in the title compound (511 mg, 85%) as yellow solid substance.

(b) N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloro-N-cyclopropylacetic

To a mixture of pyridine (460 mg, 5,78 mmol) and a solution of N-cyclopropylamino compound (511 mg, 1,45 mmol)obtained in stage (a), N,N-dimethylformamide (5 ml) with stirring under ice cooling are added dropwise chlorocatechol (230 mg, 2.02 mmol) and the resulting mixture is stirred over night at room temperature. To the reaction solution was added methanol, dilute the mixture with ethyl acetate, washed successively with water and saturated salt solution. The organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure, obtaining the crude product. The crude product was then purified column chromatography (silica gel, elution gradient: ethyl acetate/chloroform=1/99 to 6/94), getting mentioned in the title compound (422 mg, 68%) as a white solid.

(c) 9-[4-(benzyloxy)phenyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

The solution chloroceryle derived (422 mg, 0,983 mmol)obtained in stage (b), in N,N-dimethylformamide (3 ml) at room temperature add the keys to a solution of tert-butoxide potassium (280 mg, the 2.46 mmol) in 2-methylbutane-2-OLE (12 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated and the residue is dissolved in ethyl acetate and washed with water and saturated salt solution. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure, obtaining mentioned in the title compound in the form of the crude product (372 mg, 96%).

(d) 4-Cyclopropyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily pale brown substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (c).

(e) 4-Cyclopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (d), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: of 0.64 to 0.68 (2H, m), 0,81-of 0.91 (6H, m), 1,53-1,78 (7H, m), 1,82-of 1.88 (1H, m), 1.93 and is 2.00 (4H, m), 2,48 (2H, t, J=7,6 Hz), 2,73-and 2.79 (1H, m), 2,83-2,90 (2H, m), 2,97-3,03 (2H, m), 3,18-3,24 (2H, m), 3,19 (2H, C)of 3.96 (2H, t, J=6.3 Hz), is 4.15 (2H, s), 6,83 (2H, d, J=9,3 Hz)6,91 (2H, the, J=8,8 Hz).

Example 4-15:

Getting 4-cyclobutyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 1-[4-(Benzyloxy)phenyl]-4-[(cyclobutylamine)methyl]piperidine-4-ol

To a mixture of 4-(aminomethyl)-1-[4-(benzyloxy)phenyl]piperidine-4-ol (5 g, 16.0 mmol)obtained in reference example 7, and chloride of zinc (654 mg, 4.8 mmol) in methanol add cyclobutanone (1.2 ml, 16.0 mmol) and centripetality sodium (2,01 g of 32.0 mmol) and the resulting mixture is stirred over night at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with chloroform, the organic layer washed successively with water and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the crude product was then purified column chromatography (silica gel, elution gradient: methanol/chloroform=2/98 to 10/90)to give specified in the header connection (3,59 g, 61%) as a solid orange substance.

(b) N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloro-N-cyclobutylamine

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 4-14-(b) or a similar method, but using N-cyclopropyl raspertova derivative, obtained in stage (a).

(c) 9-[4-(Benzyloxy)phenyl]-4-cyclobutyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 4-14-(c) or a similar method, but using chloracetamide the compound obtained in stage (b).

(d) 4-Cyclobutyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pink substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (c).

(e) 4-Cyclobutyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in stage (d), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.8 Hz), 1,50-1,91 (11H, m), 1.93 and is 2.00 (4H, m), 2,03-of 2.16 (4H, m), 2.49 USD (2H, t, J=7,6 Hz), 2,81-2,95 (2H, USM), to 3.02 (2H, TD, J=11,7, 2.4 Hz), 3,21-3,26 (4H, m), of 3.96 (2H, t, J=6.3 Hz), 4,16 (2H, s), of 5.05-5,13 (1H, m), 6,83 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9,3 Hz).

Example 4-16:

Getting 4-cyclobutyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-about the sa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid milky white substance in accordance with the method of example 4-(c) or a similar method, but using the phenol compound obtained in example 4-15(d), and hydrogen bromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2.

1H-NMR (400 MHz, CDCl3) δ: 1,10 (3H, d, J=6.3 Hz), to 1.38 to 1.48 (1H, m), 1,59-of 1.81 (6H, m), 1,88 is 2.00 (5H, m), 2,03-of 2.23 (6H, m), 2,28-of 2.34 (1H, m), 2,94-of 3.06 (3H, m), 3,17-3,26 (3H, m), 3,24 (2H, s), 3,94-4,01 (2H, m)to 4.16 (2H, s), of 5.05-5,14 (1H, m), at 6.84 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9,3 Hz).

Example 4-17:

Getting 4-cyclopentyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 1-[4-(Benzyloxy)phenyl]-4-[(cyclopentylamine)methyl]piperidine-4-ol

Specified in the header connection receive in accordance with the method of example 4-15(a) or a similar method, but using 4-(aminomethyl)-1-[4-(benzyloxy)phenyl]piperidine-4-yl, obtained in reference example 7, and Cyclopentanone instead of cyclobutanone.

(b) N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloro-N-cyclopentylacetic

Specified in the title compound obtained as an oily brown substance in accordance with the method of example 4-14-(b) or a similar method, but using N-cyclopropylamino the compound obtained in stage (a).

(c) 9-[4-(Benzyloxy)phenyl-4-cyclopentyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 4-14-(c) or a similar method, but using chloracetamide derivative obtained in stage (b).

(d) 4-Cyclopentyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pink substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-derivative obtained in stage (c).

(e) 4-Cyclopentyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as colorless oily substance according to the method of example 4-(c) or a similar method, but using the phenol derivative obtained in stage (d), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: 0,81-of 0.91 (1H, m)0,86 (3H, d, J=6.3 Hz), to 1.38 to 1.47 (2H, m), 1,53-1,79 (11H, m), 1,82-of 1.88 (3H, m), 1,94 of 1.99 (4H, m), 2,48 (2H, t, J=7,6 Hz), 2,82-2,90 (2H, m), to 3.02 (2H, TD, J=11,7, and 2.6 Hz), of 3.12 (2H, ), up 3.22 (2H, TD, J=8,2, 4,1 Hz), of 3.96 (2H, t, J=6.3 Hz), 4,18 (2H, s), 4,99 is 5.07 (1H, m), 6,83 (2H, d, J=8,8 Hz)6,91 (2H, d, J=8,8 Hz).

Example 4-18:

Getting 4-cyclohexyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 1-[4-(Benzyloxy)phenyl]-4-[(C is chlorexidine)methyl]piperidine-4-ol

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-15(a) or a similar method, but using 4-(aminomethyl)-1-[4-(benzyloxy)phenyl]piperidine-4-ol obtained in reference example 7, and cyclohexanone instead of cyclobutanone.

(b) N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloro-N-cyclohexylacetate

Specified in the title compound obtained as an oily pale yellow substance in accordance with the method of example 4-14-(b) or a similar method, but using N-cyclopropylamino the compound obtained in stage (a).

(c) 9-[4-(Benzyloxy)phenyl]-4-cyclohexyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-14-(c) or a similar method, but using chloracetamide the compound obtained in stage (b).

(d) 4-Cyclohexyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pink substance in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-compound obtained in stage (c).

(e) 4-Cyclohexyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as colorless oily substance according to the method of example 4-(c) or a similar method, but using the phenol derivative obtained in stage (d), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (CDCl3) δ: 0,80-0,90 (1H, m)0,86 (3H, d, J=6.3 Hz), 1,03 is 1.13 (1H, m), of 1.25 to 1.47 (5H, m), 1,52 is 1.86 (12H, m), 1,92 of 1.99 (4H, m), 2,47 (2H, t, J=7,6 Hz), 2,82-2,89 (2H, m), 3.00 and-a 3.06 (2H, m), 3,13 (2H, s), 3,19-3,23 (2H, m), of 3.96 (2H, t, J=6.3 Hz), 4,18 (2H, s), 4,46-to 4.52 (1H, m), 6,83 (2H, d, J=9,3 Hz)6,91 (2H, d, J=9,3 Hz).

Example 4-19:

Getting 4-benzyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-Benzyl-9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 3-96 or a similar method, but using 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in reference example 9, and (methyl bromide)benzene.

(b)4-Benzyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the header connection receive in accordance with the method of example 4-(b) or a similar method, but using benzyloxy-derivative obtained in stage (a).

(c) 4-Benzyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

The decree is Noah in the title compound obtained as yellow solid substance in accordance with the method of example 4-(c) or in a similar way, but using the phenol compound obtained in stage (b), and hydrogen bromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz), 1,50 to 1.76 (8H, m), 1,80 for 2.01 (5H, m), 2,43 of $ 2.53 (2H, m), 2,80-to 3.02 (4H, m), 3,06-3,11 (2H, m), 3,12 (2H, s), of 3.94 (2H, t, J=6.6 Hz), 4.26 deaths (2H, s), to 4.62 (2H, s), to 6.80 (2H, d, J=9,3 Hz), 6,85 (2H, d, J=9.3 Hz), 7,25-7,38 (5H, m).

Example 4-20:

Getting 4-benzyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as yellow solid substance in accordance with the method of example 4-(c) or a similar method, but using 4-benzyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-19-(b), and the hydrobromide of 1-(3-bromopropyl)pyrrolidine obtained in accordance with methods described in U.S. patent No. 4751302.

1H-NMR (400 MHz, CDCl3) δ: 1,57 was 1.69 (4H, m), is 1.81 (4H, USS), 1,89-2,04 (4H, m), 2,52-2,69 (4H, m), 2,92-a 3.01 (2H, m), 3,06-and 3.16 (4H, m), of 3.97 (2H, t, J=6.3 Hz), 4.26 deaths (2H, s), to 4.62 (2H, s), for 6.81 (2H, d, J=9,3 Hz)6,86 (2H, d, J=9,3 Hz), 7,38-7,27 (8H, m).

Example 4-21:

Getting 4-benzyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 4-(c) or a similar method, but using 4-benzyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]is ndacan-3-one, obtained in example 4-19-(b), and the hydrobromide of 1-(3-bromopropyl)pyrrolidine obtained in accordance with methods described in U.S. patent No. 4751302.

1H-NMR (400 MHz, CDCl3) δ: 1,39 is 1.48 (2H, USM), 1,56 by 1.68 (6H, m), 1,89 is 2.00 (4H, m), 2,35-2,52 (6H, m), of 2.97 (2H, TD, J=11,2, 2,9 Hz), 3,06-3,14 (4H, m), of 3.94 (2H, t, J=6.3 Hz), 4.26 deaths (2H, s), to 4.62 (2H, s), for 6.81 (2H, d, J=9.3 Hz), 6,85 (2H, d, J=9.3 Hz), 7,38-7,27 (5H, m).

Example 5:

Getting 4-(3-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-(3-Forfinal)-9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of 9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one (200 mg, 0,723 mmol)obtained in reference example 9-1, 1-bromo-3-fervently (152 mg, 0,868 mmol), potassium phosphate (307 mg, 1,45 mmol), copper iodide (14 mg, 0,0723 mmol) and N,N'-dimethylaminoethanol (13 mg, 0,145 mmol) in 1,4-dioxane is stirred overnight at 110°C in a tightly a sealed tube. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated and the residue purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=20/80 to 70/30), getting mentioned in the title compound (205 mg, 76%) as a white solid.

(b) 4-(3-Forfinal)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Met the XI-derived (205 mg, 0,553 mmol)obtained in stage (a), dissolved in chloroform, the resulting solution at 0°C is added dropwise 1.0m solution tribromide boron in dichloromethane (2.2 ml, 2.2 mmol) and the resulting mixture is stirred over night at room temperature. The reaction solution was cooled to 0°C, neutralized by addition of aqueous 2n. the sodium hydroxide solution, extracted with chloroform and the organic layer was washed with a saturated solution of salt. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure, obtaining the phenol derivative in the form of the crude product (165 mg, 84%).

(c) 4-(3-Forfinal-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of phenol derivative (100 mg, 0.28 mmol)obtained in stage (b), hydrobromide 1-(3-bromopropyl)piperidine (161 mg, 0,56 mmol), obtained in accordance with methods described in U.S. patent No. 4751302, and potassium carbonate (155 mg, 1.12 mmol) in N,N-dimethylformamide is stirred overnight at 60°C. the Reaction solution was diluted with chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water, liquid B: 0.1% TFWC/acetonic is l, A/B=90/10 to 50/50, elution with a linear concentration gradient over 8 min, flow rate 40 ml/min) and the fraction containing the target product, collecting, receiving specified in the header connection (34,6 mg, 32%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, OSS), to 1.59 (4H, t, J=6.0 Hz), 1,82 of 1.99 (4H, m), 2,12 (2H, d, J=12,8 Hz), 2,41-2,49 (6H, m), 3,01-to 3.09 (2H, m), 3.25 to be 3.29 (2H, m), 3,62 (2H, s), of 3.96 (2H, t, J=6.4 Hz), 4,35 (2H, s), 6,83-6,85 (2H, m), 6,91-6,94 (2H, m), 6,98-7,02 (1H, m), 7,07 for 7.12 (2H, m), 7,35-7,41 (2H, m).

Example 5-1:

Getting 4-(2-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-(2-Forfinal)-9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 5-(a) or a similar method, but using 1-bromo-2-torbenson instead of 1-iodine-4-methoxybenzene.

(b) 4-(2-Forfinal)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(b) or a similar method, but using methoxy-compound obtained in stage (a).

(c) 4-(2-Forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow washes the VA in accordance with the method of example 5-(c) or in a similar way, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,44 (2H, OSS), to 1.59 (4H, t, J=6.0 Hz), 1,85 of 1.99 (4H, m), of 2.15 (2H, d, J=13,6 Hz), 2.40 a-2,49 (6H, m), is 3.08 (2H, t, J=11.2 Hz), 3,24 of 3.28 (2H, m)and 3.59 (2H, s), of 3.96 (2H, t, J=6.4 Hz), to 4.38 (2H, s), 6,84 (2H, d, J=8,8 Hz), 6,93 (2H, d, J=8,8 Hz), 7,15-7,22 (2H, m), 7,27-to 7.35 (2H, m).

Example 5-2:

Getting 4-(2-herperidin-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-(2-Herperidin-4-yl)-9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5']undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 5-(a) or a similar method, but using 2-fluoro-4-yodellin instead of 1-iodine-4-methoxybenzene.

(b) 4-(2-Herperidin-4-yl)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(b) or a similar method, but using methoxy-compound obtained in stage (a).

(c)4-(2-Herperidin-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(c) or a similar method, but using the phenol derivative obtained in stage (b).

1H-NMR 400 MHz, CDCl3) δ: 1,44-to 1.45 (2H, m), 1.56 to to 1.59 (4H, m), 1,82-1,89 (2H, m), 1,92 of 1.99 (2H, m), 2,10 (2H, d, J=12,8 Hz), 2.40 a (4H, m), 2,47 (2H, t, J=7.2 Hz), 3,05 (2H, TD, J=2,8, and 11.8 Hz), 3.27 to 3.30 is (2H, m), 3,68 (2H, s), of 3.96 (2H, t, J=6.4 Hz), to 4.38 (2H, s), at 6.84 (2H, d, J=9,2 Hz), 6.87 in (2H, d, J=9,2 Hz), 7,11 (1H, d, J=1.6 Hz), 7,34 (1H, dt, J=5,6, 1.2 Hz), by 8.22 (1H, d, J=5.6 Hz).

Example 5-3:

Getting 4-ethyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-Ethyl-9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

To a solution of 9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one (800 mg, 2.89 mmol)obtained in reference example 9-1, N,N-dimethylformamide, cooled to 0°C. add sodium hydride (140 mg, 3,47 mmol) and Iodate (542 mg, 3,47 mmol) and the resulting mixture is stirred over night at room temperature. Add water to the mixture, the solvent is evaporated under reduced pressure, the residue is dissolved in ethyl acetate and washed successively with water and saturated salt solution. The organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure and the residue purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=40/60 to 100/0), getting mentioned in the title compound (682 mg, 77%) as a yellow solid substance.

(b) 4-Ethyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid which CSOs brown substance in accordance with the method of example 5-(b) or a similar method, but using methoxy-compound obtained in stage (a).

(c) 4-Ethyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 5-(c) or a similar method, but using the phenol compound obtained in stage (b), and the hydrobromide of 1-(3-bromopropyl)piperidine obtained in accordance with methods described in U.S. patent No. 4751302.

1H-NMR (400 MHz, CDCl3) δ: 1,15 (3H, t, J=7.2 Hz), 1,44-to 1.45 (2H, m), 1.56 to of 1.62 (4H, m), of 1.78 (2H, TD, J=and 11.2, 3.6 Hz), 1,92-2,02 (4H, m), 2.40 a (4H, USS), 2,47 (2H, t, J=7,6 Hz), to 3.02 (2H, TD, J=11.8 in, 2,8 Hz), 3,20-of 3.25 (4H, m), 3.46 in (2H, Quint, J=7.2 Hz), of 3.96 (2H, t, J=6.4 Hz), 4,16 (2H, s), 6,83 (2H, d, J=9,2 Hz), 6,91 (2H, d, J=9,2 Hz).

Example 5-4:

Getting 4-ethyl-9-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(c) or a similar method, but using 4-ethyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 5-3(b) -, hydrobromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4 instead of the hydrobromide of 1-(3-bromopropyl)piperidine.

1H-NMR (400 MHz, CDCl3) δ: 0,86 (3H, d, J=6.3 Hz)and 1.15 (3H, t, J=7.2 Hz), 1,57 is 1.86 (9H, m), 1,95 for 2.01 (4H, m), 2.49 USD (2H, USS), of 2.86 (2H, OSS), to 3.02 (2H, t, J10,4 Hz), 3,21-3,26 (4H, m), of 3.46 (2H, q, J=7,3 Hz), of 3.96 (2H, t, J=6.5 Hz), 4,16 (2H, s), 6,83 (2H, d, J=9.4 Hz), 6,91 (2H, d, J=9.0 Hz).

Example 5-5:

Getting 4-methyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-Methyl-9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-3(a) or a similar method, but using itmean instead of iodata.

(b) 4-Methyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(b) or a similar method, but using methoxy-compound obtained in stage (a).

(c) 4-Methyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 5-(c) or a similar method, but using the phenol compound obtained in stage (b).

1H-NMR (400 MHz, CDCl3) δ: 1,44-to 1.45 (2H, m), 1.56 to of 1.62 (4H, m)to 1.79 (2H, TD, J=11,4, 4,4 Hz), 1.93 and-2,03 (4H, m), 2.40 a (4H, USS), 2,47 (2H, t, J=7.2 Hz), 2,97 totaling 3.04 (5H, m), 3,22-3,26 (4H, m), of 3.95 (2H, t, J=6.8 Hz), 4,17 (2H, s), 6,83 (2H, d, J=9,2 Hz), 6,91 (2H, d, J=9,2 Hz).

Example 6:

Getting 8-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-3-phenyl-1-oxa-3,8-d is azaspiro[4,5]decane-2-it

(a) 8-(4-Methoxyphenyl)-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he

A mixture of 8-(4-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (935 mg, of 3.56 mmol)obtained in reference example 13, yogashala (872 mg, 4,28 mmol), potassium phosphate (1.51 g, 7,12 mmol), copper iodide (68 mg, 0,356 mmol) and N,N'-dimethylaminoethanol (62 mg, 0,712 mmol) in 1,4-dioxane is stirred overnight at 110°C in a sealed tube. The reaction solution was diluted with chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound, the crude product (1,15 g, 95%) as a white solid.

(b) 8-(4-Hydroxyphenyl)-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he

Methoxy-derivative (1,15 g, 3,39 mmol)obtained in stage (a), dissolved in chloroform and treated with 1.0m solution tribromide boron in dichloromethane (11 ml, 11 mmol) at 0°C in accordance with the method of example 5-(b) or a similar way, getting mentioned in the title compound in the form of the crude product (308 mg, 28%).

(c) 8-[4-(3-chloropropoxy)phenyl]-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he

A mixture of phenol derivative (150 mg, 0,462 mmol)obtained in stage (b), 1-bromo-3-chloropropane (145 mg, 0,924 mmol) and potassium carbonate (255 mg, of 1.85 mmol) in N,N-dimethyl ramide stirred over night at 60°C. The reaction solution was diluted with chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water, liquid B: 0.1% TFWC/acetonitrile, A/B=90/10 to 50/50, elution with a linear concentration gradient over 8 min, flow rate 40 ml/min) and the fraction containing the target product, collecting, receiving specified in the title compound (61 mg, 32%).

(d) 8-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he

A mixture of chlorine-derivative (61 mg, 0,152 mmol)obtained in stage (c), mandelate (3S)-3-methylpiperidine-(R) (80 mg, 0,304 mmol), obtained from the original 3-methylpiperidine in accordance with the methods described in the literature (Journal of Organic Chemistry (J.O.C), 1987, Vol.52, p.5467), and potassium carbonate (85 mg, 0,608 mmol) in N,N-dimethylformamide is stirred overnight at 60°C. the Reaction solution was diluted with ethyl acetate, washed sequentially water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water; liquid B: 0.1% TFWC/acetonitrile; A/B=90/10 to 50/50; elwira is the W for 8 minutes with a linear concentration gradient; flow rate: 40 ml/min) and the fractions containing the desired product are pooled, and thus specified in the title compound (30 mg, 43%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1,58-of 1.73 (6H, m), 1,86 e 2.06 (5H, m), of 2.15 (2H, d, J=12,5 Hz), 2,50 (2H, USS), 2,85 of 2.92 (2H, m), 3.25 to or 3.28 (4H, m), 3,81 (2H, s), of 3.97 (2H, t, J=6.5 Hz), at 6.84 (2H, d, J=9.0 Hz), 6,93 (2H, d, J=9.0 Hz), to 7.15 (1H, t, J=7.4 Hz), 7,39 (2H, t, J=8.0 Hz), 7,56 (2H, d, J=7,8 Hz).

Example 7:

Obtaining 3-(4-hydroxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

A mixture of 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-she (110 mg, 0,295 mmol)obtained in reference example 15, 4-(benzyloxy)-1-yogashala (110 mg, 0,353 mmol), potassium phosphate (125 mg, 0.59 mmol), copper iodide (6 mg, 0,029 mmol) and N,N'-dimethylaminoethanol (6 mg, 0,058 mmol) in 1,4-dioxane is stirred overnight at 110°C in a sealed tube. The reaction solution was diluted with chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water; liquid B: 0.1% TFWC/acetonitrile; A/B=90/10 to 50/50; elution with a linear concentration gradient over 8 min; flow rate: 40 ml/min and fractions, sod is readie target product, unite, thus obtaining benzyloxy-derived (130 mg, 79%). Received benzyloxy-derived (130 mg, 0.23 mmol) is dissolved in methanol, then add 10% palladium on carbon (30 mg, 0,028 mmol) and the resulting mixture is stirred overnight under nitrogen atmosphere. The reaction solution is filtered through celite, the celite was washed with chloroform and uterine fluid concentrate, getting mentioned in the title compound (47 g, 43%) as a solid gray matter.

1H-NMR (400 MHz, CDCl3) δ: 1,88-of 1.92 (4H, m), 2,18-of 2.24 (4H, m), of 2.38 (2H, USS), 2,71-2,78 (4H, m), 3,18-3,19 (2H, m), 3,39-to 3.41 (4H, m), 3,61 (2H, d, J=10.0 Hz), 3,81 (2H, s)4,08 (2H, s), 6,84-7,05 (4H, m), 7,31-EUR 7.57 (4H,m).

Example 8:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 9-(4-Methoxyphenyl)-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(a) or a similar method, but using bramasol instead of 1-bromo-3-fervently.

(b) 9-(4-Hydroxyphenyl)-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of example 5-(b) or a similar method, but using methoxy-compound obtained in stage (a).

(c) Tert-butyl 4-[4-(3-OK, what about the-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-9-yl)phenoxy]piperidine-1-carboxylate

To a mixture of phenol derivative (100 mg, 0,295 mmol)obtained in stage (b), tert-butyl-4-hydroxypiperidine-1-carboxylate (120 mg, 0,591 mmol) and triphenylphosphine (155 mg, 0,591 mmol) in tetrahydrofuran at 0°C is added dropwise diisopropylethylamine (120 mg, 0,591 mmol) and the resulting mixture is stirred over night at room temperature. The solvent is evaporated and the residue purified by thin-layer chromatography (eluate: ethyl acetate/hexane=2/1)to give specified in the header connection (92,3 mg, 60%) as a solid pale yellow substance.

(d) 9-{4-[(1-Cyclobutylmethyl-4-yl)oxy]phenyl}-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

To the compound (92,3 mg, 0.18 mmol)obtained in (c), add triperoxonane acid (0.5 ml) at 0°C and the resulting mixture is stirred for 1 hour at room temperature. The solvent is evaporated, the residue is dissolved in ethyl acetate, neutralized by addition of aqueous 2n. the sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and the solvent is evaporated under reduced pressure, thus obtaining piperidine derived in the form of a crude product. Received piperidine derived (and 88.5 mg, 0.21 mmol) is dissolved in methanol, to the mixture add cyclobutanone (30 mg, 0.42 mmol) and 0.5m dissolve the mixture centripetality sodium/zinc chloride (1/1) in methanol (2.5 ml, of 1.26 mmol) and the resulting mixture is stirred over night at room temperature. The solvent is evaporated, to the residue add water 2H. the sodium hydroxide solution and ethyl acetate, then dropped to precipitate a white solid removed by filtration through celite, the filtrate diluted with ethyl acetate and washed with a saturated solution of salt. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified preparative HPLC with reversed-phase (liquid A: 0.1% TFWC/water, liquid B: 0.1% TFWC/acetonitrile, A/B=90/10 to 50/50, elution with a linear concentration gradient over 8 min, flow rate 40 ml/min), collecting fractions containing the target product. The fractions containing the desired product, purified by thin-layer chromatography (eluate: chloroform/methanol=9/1)to give specified in the header connection (to 31.2 mg, 31%) as a viscous pale yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 1,64-2,18 (17H, m), 2,67-2,77 (2H, m)to 3.09 (2H, t, J=10,8 Hz), 3,29 (2H, t, J=12.0 Hz), to 3.64 (2H, s), 4,25 (1H, USS), 4,36 (2H, s), 6,85 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,28-to 7.32 (3H, m), 7,41 was 7.45 (2H, m).

Example 8-1:

9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) Tert-butyl 4-[4-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-9-yl)phenoxy]piperidine-1-carboxylate

The decree is Noah in the title compound obtained as a solid pale yellow substance in accordance with the method of example 8(c) or in a similar way, but using 4-ethyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 5-3-(b), instead of 9-(4-methoxyphenyl)-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

(b)9-[4-(1-Cyclobutylmethyl-4-yloxy)phenyl]-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as white solid according to the method of example 8(d) or a similar method, but using N-Boc-compound obtained in stage (a).

1H-NMR (400 MHz, CDCl3) δ: 1,15 (3H, t, J=7.2 Hz), 1,62-2,12 (15H, m), 2,62-of 2.72 (4H, m), to 3.02 (2H, t, J=10.4 Hz), 3,24 (4H, d, J=12.9 Hz), of 3.46 (2H, q, J=7.2 Hz), 4,16 (2H, s), 4,20 (1H, s), at 6.84 (2H, d, J=9.0 Hz), make 6.90 (2H, d, J=9,0 Hz).

Example 8-2:

9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) Tert-butyl 4-{4-[4-(6-herperidin-3-yl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-9-yl]phenoxy}piperidine-1-carboxylate

Specified in the title compound obtained as crude product in accordance with the method of example 8(c) or a similar method, but using 4-(6-herperidin-3-yl)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-3-(b), instead of 9-(4-hydroxyphenyl)-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

(b) 9-[4-(1-Cyclobutylmethyl-4-yloxy)phenyl]-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

The decree of the TES in the title compound obtained as yellow solid substance in accordance with the method of example 8(d) or a similar method, but using the crude product obtained in (a).

1H-NMR (400 MHz, CDCl3) δ: 1,64-2,18 (16H, m), 2,64-2,77 (3H, m), 3.04 from-3,11 (2H, m), 3,30 (2H, d, J=12,5 Hz), the 3.65 (2H, s), 4,22 (1H, USS), 4,37 (2H, s), 6,85 (2H, d, J=9.0 Hz), 6,92 (2H, d, J=9.0 Hz), 7,00 (1H, DD, J=8,8, 3,3 Hz), 7,81-7,86 (1H, m), 8,19 (1H, USS).

Example 8-3:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) Tert-butyl 4-{4-[4-(6-methoxypyridine-3-yl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-9-yl]phenoxy}piperidine-1-carboxylate

Specified in the title compound obtained as crude product in accordance with the method of example 8(c) or a similar method, but using 4-(6-methoxypyridine-3-yl)-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-4-(b), instead of 9-(4-hydroxyphenyl)-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

(b) 9-[4-(1-Cyclobutylmethyl-4-yloxy)phenyl]-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of example 8(d) or a similar method, but using the crude product obtained in (a).

1H-NMR (400 MHz, CDCl3) δ: 1,50-2,40 (16H, m), 2,50-are 3.90 (3H, m), 2.95 and is 3.15 (2H, m), 3,15-to 3.35 (2H, m), of 3.60 (2H, s), of 3.94 (3H, s)to 4.23 (1H, USS), 4,35 (2H, s), 6,79 (1H, d, J=8.0 Hz), 6,85 (2H, d, J=12 Hz), 6,92 (1H, d, J=12 Hz), 7,55 (1H, DD, J=8,0, 4.0 Hz), 810 (1H, d, J=4.0 Hz).

Example 8-4:

9-{4-[(1-cyclopropylidene-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-(6-Methoxypyridine-3-yl)-9-[4-(piperidine-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

The crude product representing piperidine derivative containing N-BOC-protective group, 4-(6-methoxypyridine-3-yl)-9-[4-(piperidine-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one is obtained in accordance with the method of example 8(C)-or a similar method, but using 9-(4-hydroxyphenyl)-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-4-(b), and the resulting N-Boc-protected compound is treated in accordance with the method of example 8(d) or a similar method, thus obtaining piperidine derived in the form of a yellow oily substance.

(b) 9-{4-[(1-Cyclopropylidene-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of example 4-14-(a) or a similar method, but using piperidine derivative obtained in stage (a), and (1-amoxicilpin)(trimethyl)silane instead of cyclobutanone.

1H-NMR (400 MHz, CDCl3) δ: 0,34-0,54 (4H, m), 1,53-2,04 (7H, m), 2.06 to of 2.21 (2H, m), 2,37-of 2.56 (2H, m, 2,85-2,96 (2H, m), 3,02-3,13 (2H, m), 3,23-of 3.32 (2H, m), of 3.60 (2H, s), of 3.94 (3H, s), 4,16-4,27 (1H, m), 4,35 (2H, s), 6,79 (1H, d, J=8,8 Hz)6,86 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,54 (1H, DD, J=8,8, 2,9 Hz), 8,10 (1H, d, J=2,9 Hz).

Example 8-5:

Getting 4-cyclobutyl-9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

(a) 4-Cyclobutyl-9-[4-(piperidine-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

N-Boc-protected pyridine derivative, 4-cyclobutyl-9-[4-(piperidine-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one is obtained in accordance with the method of example 8(C)-or a similar method, but using 4-cyclobutyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 4-15(d), and N-Boc-protected compound was processed in accordance with the method of example 8(d) or a similar method, thus obtaining piperidine derived in the form of a white solid.

(b) 4-Cyclobutyl-9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily orange substance in accordance with the method of example 4-15-(a) or a similar method, but using piperidine derivative obtained in stage (a), and cyclobutanone.

1H-NMR (400 MHz, CDCl3) δ: 1,51-2,27 (22H, m), 2,56-2,84 (3H, m), 2,98-is 3.08 (2H, m), 3,19-3,29 (2H, m), 3,24 (2H, s), is 4.15 (2H, s), 4,22 (1H, USS), 5,01-5,17 (1H, m), at 6.84 (2H, d, J=9.1 Hz), make 6.90 (2H, d, J=9.1 Hz).

Example 8-6:

Getting 4-cyclobutyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as an oily orange substance in accordance with the method of example 4-15(a) or a similar method, but using 4-cyclobutyl-9-[4-(piperidine-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one obtained in example 8-5(a), and acetone.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=6.8 Hz), 1,61-1,90 (8H, m), 1,92-of 2.20 (6H, m), 2,32-2,49 (2H, m), 2,70-is 2.88 (3H, m), 2,96-3,10 (2H, m), 3,19-3,29 (2H, m), 3,24 (2H, s)to 4.16 (2H, s), 4,17-4,24 (1H, m), 5,09 (1H, septet, J=the 6.8 Hz), 6,85 (2H, d, J=9,3 Hz)6,91 (2H, d, J=8,8 Hz).

Obtaining the compounds used in the preparation of the compounds in the above examples, is described in reference examples

Reference example 1:

Obtaining 1-[(3-chloropropyl)oxy]-4-yogashala

A mixture of 4-itfinal (10 g, to 45.4 mmol), 1-bromo-3-chloropropane (7 g, 50.0 mmol) and potassium carbonate (rate of 7.54 g of 54.5 mmol) in DMF was stirred at room temperature for 15 hours. The liquid reaction mixture is diluted with diethyl ether, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified column chromatography (silica gel, elution: ethyl acetate/hexa is=5/95), getting listed in the title compound (11.1 g, 82.3 per cent) in the form of a solid pale yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 2,20-of 2.26 (2H, m), of 3.73 (2H, t, J=6.3 Hz), 4,08 (2H, t, J=5,9 Hz), 6,69 (2H, dt, J=8,8, 3,4 Hz), 7,53-EUR 7.57 (2H, m).

Reference example 2:

Obtaining 1-[3-(4-iodinase)propyl]piperidine

A mixture of 1-[(3-chloropropyl)oxy]-4-yogashala (10 g, or 33.7 mmol) and piperidine (2,87 g of 67.4 mmol) was stirred at 85°C for 4 hours. The mixture is cooled to room temperature, concentrated and the residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated and the residue purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=50/50 to chloroform/methanol=10/1)to give specified in the header connection (8,39 g, 72%) as a brown solid substance.

1H-NMR (400 MHz, CDCl3) δ: 1,42 of 1.46 (2H, m), 1.56 to of 1.62 (4H, m), 1,92 is 2.00 (2H, m), 2,39-2,47 (6H, m), of 3.96 (2H, t, J=6.3 Hz), to 6.67 (2H, TD, J=6,1, 3,4 Hz), 7,53 (2H, TD, J=6,1, 3,4 Hz).

Reference example 3:

Obtain 3-[(2S)-2-methylpyrrolidine-1-yl]propan-1-ol

The mixture hydrobromide (2S)-2-methylpyrrolidine (2.70 g, 16.3 mmol), obtained from D-prolinol in accordance with the methods described in the literature (Journal of Organic Chemistry (J. O. C.) 1989, Vol.54, p.209), 3-bromo-1-propanol (2,49 g of 17.9 mmol) is potassium carbonate (6.75 g, for 48.9 mmol) in tetrahydrofuran (20 ml) was stirred at 60°C for 18 hours. The precipitate is removed by filtration and the filtrate concentrated. The residue is distilled under reduced pressure, obtaining mentioned in the title compound (1.88 g, 80%) as a colourless oil.

1H-NMR (400 MHz,CDCl3)δ: 1.14 in (3H, d, J=5,9 Hz), 1,34 was 1.43 (1H, m), 1,50 is 1.58 (1H, m), 1,66-of 1.78 (2H, m), 1.85 to of 1.97 (2H, m), is 2.09 (1H, q, J=8,9 Hz), 2,25-of 2.34 (1H, m), 2,38 is 2.43 (1H, m), 2,99 (1H, TD, J=12,0, 3,4 Hz), 3,31-3,37 (1H, m), 3,79-a 3.83 (2H, m).

Reference example 3-1:

Obtain 3-[(2R)-2-methylpyrrolidine-1-yl]propan-1-ol

Specified in the title compound obtained as a colorless oil in accordance with the method of reference example 3 or in a similar way, but using the hydrobromide (2R)-2-methylpyrrolidine obtained from 1-prolinol in accordance with the method described in the literature (Journal of Organic Chemistry (J. O. C.) 1989, Vol.54, p.209).

1H-NMR (400 MHz, CDCl3) δ: 1.14 in (3H, d, J=5,9 Hz), 1,33 was 1.43 (1H, m), 1,50 is 1.58 (1H, m), of 1.66-1.77 in (2H, m), 1,86-of 1.97 (2H, m), is 2.09 (1H, q, J=8,9 Hz), 2,25-of 2.34 (1H, m), 2,38 is 2.43 (1H, m), 2,99 (1H, TD, J=12,0, 3,4 Hz), 3,31-3,37 (1H, m), 3,81 (2H, DD, J=7,8, 2,4 Hz).

Reference example 3-2:

Obtain 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol

Specified in the title compound obtained as a colorless oil in accordance with the method of reference example 3 or in a similar way, but using (R)-mandelate (3S)-3-methylpiperidine obtained from 3-methylpiperid is in accordance with the methodology described in the literature (Journal of Organic Chemistry (J. O. C.) 1987, Vol.52, p.5467), instead hydrobromide (2S)-2-methylpyrrolidine.

1H-NMR (400 MHz, CDCl3) δ: of 0.82 to 0.92 (4H, m), USD 1.43-1,74 (7H, m), 1,79-of 1.88 (1H, m), 2,55-of 2.58 (2H, m)to 2.94 (2H, OST, J=10,7 Hz), 3,80 (2H, t, J=5.4 Hz), of 5.84 (1H, USS).

Reference example 4:

Getting hydrobromide (3S)-1-(3-bromopropyl)-3-methylpiperidine

A mixture of 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol (10 g, of 63.6 mmol)obtained in reference example 3-2, and 25% solution of hydrogen bromide in acetic acid is stirred overnight at 100°C. the Mixture is allowed to cool, the solvent is evaporated, then the residue is added diethyl ether, the solid precipitate is removed by filtration and the obtained residue is dried overnight under reduced pressure at 50°C, obtaining the target compound (18 g, 94%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 0,98 (3H, d, J=6.3 Hz), 1,07-1,17 (1H, m), 1,88-to 1.98 (2H, m), 2,25-to 2.65 (6H, m), 3,11-3,17 (2H, m), 3,45-3,61 (4H, m).

Reference example 4-1:

Getting hydrobromide (2S)-1-(3-bromopropyl)-2-methylpyrrolidine

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 4 or in a similar way, but using 3-[(2S)-2-methylpyrrolidine-1-yl]propan-1-ol obtained in reference example 3.

1H-NMR (400 MHz, CDCl3) δ: 1,71 (3H, d, J=6.8 Hz), 2,01 is 2.44 (5H, m), 2,81-3,20 (3H, m), 3,30-3,75 (nm), 3.95 to Android 4.04 (1H, m).

Reference example 4-2:

Getting hydrobromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine

Specified in the title compound obtained as white solid in accordance with the method of reference example 4 or in a similar way, but using 3-[(2R)-2-methylpyrrolidine-1-yl]propan-1-ol obtained in reference example 3-1.

1H-NMR (400 MHz, CDCl3) δ: 1,71 (3H, d, J=6.8 Hz), 2,02 with 2.14 (2H, m), 2,24-of 2.36 (3H, m), 2,81 of 2.92 (2H, m), 2,98-is 3.08 (1H, m), 3,28-to 3.36 (1H, m), 3,41-of 3.53 (2H, m), 3,55-3,61 (1H, m), 3,93-4,00 (1H, m).

Reference example 5:

Getting 8-[4-(benzyloxy)phenyl]-1,4-dioxa-8 azaspiro[4,5]decane

A mixture of 1,4-dioxa-8 azaspiro[4,5]decane (653 g, 4,56 mol), 1-(benzyloxy)-4-yogashala (1 g, 3.8 mol), tert-butoxide sodium (511 g, 5,32 mol), Pd(OAc)2(17 g, 76 mmol) and biphenyl-2-yl(DICYCLOHEXYL)phosphine (54 g, 152 mmol) in 1,4-dioxane is stirred over night at 80°C in nitrogen atmosphere. The reaction solution is cooled in an ice bath, diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the residue is purified column chromatography (silica gel, elution: chloroform/ethyl acetate=10/1), the crude product is suspended in a mixture of chloroform/hexane and filtered off with suction, receiving specified in C is the cylinder connection (910 g 73%) as a brown solid substance.

1H-NMR (400 MHz, CDCl3) δ: to 1.86 (4H, t, J=6.0 Hz), 3,19 (4H, t, J=6.0 Hz), 3,99 (4H, s), free 5.01 (2H, s), 6,88-6,91 (4H, m), 7,31-the 7.43 (5H, m).

Reference example 5-1:

Getting 8-(4-methoxyphenyl)-1,4-dioxa-8 azaspiro[4,5]decane

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 5 or a similar method, but using 1-iodine-4-methoxybenzoyl instead of 1-(benzyloxy)-4-yogashala.

1H-NMR (400 MHz, CDCl3) δ: to 1.86 (4H, t, J=5,9 Hz), 3,19 (4H, t, J=5,9 Hz), of 3.77 (3H, s)to 3.99 (4H, s), 6,83 (2H, dt, J=9,3, 3,4 Hz), 6,93 (2H, dt, J=9,3, 3,4 Hz).

Reference example 6:

Obtaining 1-[4-(benzyloxy)phenyl]piperidine-4-it

A mixture of 8-[4-(benzyloxy)phenyl]-1,4-dioxa-8 azaspiro[4,5]decane (910 g, 2.8 mol)obtained in reference example 5, and aqueous 40% solution of formic acid (10 l) was stirred at 90°C for 14 hours. The obtained reaction solution was cooled to room temperature, added to a mixed solution of chloroform (7 l) in water (12 l)containing sodium bicarbonate (7,25 kg), and the resulting mixture is stirred for 4 hours. The reaction solution is extracted with chloroform, washed with saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the resulting residue is suspended in the art chloroform/hexane and filtered off with suction, getting listed in the title compound (671 g, 85%) as yellow solid substance.

1H-NMR (400 MHz, CDCl3) δ: 2.57 m (4H, t, J=6.0 Hz), 3,47 (4H, t, J=6.0 Hz), to 5.03 (2H, s), 6,92-6,97 (4H, m), 7,30-7,44 (5H, m).

Reference example 6-1:

Obtaining 1-(4-methoxyphenyl)piperidine-4-it

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 6 or in a similar way, but using 8-(4-methoxyphenyl)-1,4-dioxa-8 azaspiro[4,5]decane obtained in reference example 5-1, instead of 8-[4-(benzyloxy)phenyl]-1,4-dioxa-8 azaspiro[4,5]decane.

1H-NMR (400 MHz, CDCl3) δ: 2.57 m (4H, t, J=6,1 Hz), of 3.46 (4H, t, J=5,9 Hz), of 3.78 (3H, s), 6.87 in (2H, dt, J=8,8, 3,4 Hz), 6,97 (2H, dt, J=8,8, 3,4 Hz).

Reference example 7:

Getting 4-(aminomethyl)-1-[4-(benzyloxy)phenyl]piperidine-4-ol

To a solution of 1-[4-(benzyloxy)phenyl]piperidine-4-it (671 g of 2.38 mol), obtained in accordance with the method of reference example 6, in chloroform, cooled to 0°C, add triethylamine (24,1 g, 0.24 mol) and triethylsilane (260 g, 2,62 mol) and the resulting mixture is stirred for 20 minutes under ice cooling. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, stirred, the organic layer was washed with saturated salt solution and dried over sodium sulfate. The solvent is evaporated under reduced is the first pressure, receiving the crude product (1-[4-(benzyloxy)phenyl]-4-[(trimethylsilyl)oxy]piperidine-4-carbonitrile) (837,9 g, total yield 92%) as a brown solid substance. A solution of the crude product (837 g, 2.2 mol) in tetrahydrofuran under ice cooling are added dropwise to a solution of lithium aluminum hydride (108,5 g of 2.86 mol) in tetrahydrofuran and the resulting mixture is stirred for 1,2 hours under ice cooling. To the reaction solution add 10-hydrate of sodium sulfate (450 g), cooled to 0°C., and the mixture is stirred over night at room temperature. The mixture is filtered through celite with suction and the solvent is evaporated under reduced pressure, obtaining the crude product (1.07 kg). To a methanol solution of the crude product (1.07 kg) under cooling with ice add 6N. hydrochloric acid (2 l), the mixture allow to warm to room temperature, the mixture is then stirred for 1 hour. The mixture is neutralized by addition of an aqueous 5N sodium hydroxide solution under ice cooling, and the solvent is evaporated under reduced pressure. The residue is dissolved in chloroform, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, then the residue is suspended in a mixture of chloroform/hexane and the mixture is filtered with suction, getting listed in the title compound (562,7 g, 75,5%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1.50 in (2H, USS), 1,65 by 1.68 (4H, m)to 2.66 (2H, s), 3,03-3,10 (2H, m), 3.27 to 3.30 is (2H, m), free 5.01 (2H, s), 6.89 in-6,95 (4H, m), 7,31-7,44 (5H, m).

Reference example 7-1:

Getting 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol

Specified in the title compound obtained as white solid in accordance with the method of reference example 7 or a similar method, but using 1-(4-methoxyphenyl)piperidine-4-one obtained in reference example 6-1, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, CDCl3) δ: 1,66 was 1.69 (4H, m)to 2.66 (2H, s), 3,03-3,10 (2H, m), 3,31-of 3.25 (2H, m), of 3.77 (3H, s), 6,83 (2H, dt, J=8,8, 3,9 Hz), to 6.95 (2H, dt, J=8,8, 3,9 Hz).

Reference example 7-2:

Getting 4-(aminomethyl)-1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-ol

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 7 or a similar manner, but using as the starting material 1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-one obtained in reference example 21, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, CDCl3) δ: 1,33-of 2.26 (16H, m), 2,54-of 2.81 (3H, m)to 2.66 (2H, s), 3.00 and-3,13 (2H, m), 3,23-to 3.34 (2H, m), 4,20 (1H, USS), 6,83 (2H, d, J=9.1 Hz), 6,91 (2H, d, J=9.1 Hz).

Reference ol the measures 7-3:

Getting 4-(aminomethyl)-1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-ol

Specified in the title compound obtained as white solid in accordance with the method of reference example 7 or a similar manner, but using as the starting material 1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-one obtained in reference example 21-1, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, CD3OD) δ: of 1.13 (6H, d, J=4,8 Hz), 1,72-of 1.84 (6H, m), 1,98-of 2.08 (2H, m), 2,42-2,52 (2H, m), 2.63 in (2H, s), 2,74-2,82 (1H, m), 2,84-only 2.91 (2H, m), 3,02-to 3.09 (2H, m), 3,26 (2H, d, J=9.0 Hz), 4.26 deaths-4,34 (1H, m), 6.89 in (2H, d, J=6.6 Hz), 7,01 (2H, d, J=6,6 Hz).

Reference example 7-4:

Getting 4-(aminomethyl)-1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}piperidine-4-ol

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 7 or a similar manner, but using as the starting material 1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}piperidine-4-one obtained in reference example 21-2, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, CDCl3) δ: 1.18 to 2,31 (16H, m), 2,56-to 2.85 (3H, m), 2,65 (2H, s), 3.00 and is 3.15 (2H, m), 3,18-and 3.31 (2H, m), equal to 4.97 (1H, ass), only 6.64 (1H, d, J=8,8 Hz), 7,30 (1H, DD, J=8,8, 2,9 Hz), 7,81 (1H, d, J=2,9 Hz).

Reference example 7-5:

Getting 4-(aminomethyl)-1-{6-[(1-isopropylpiperazine-4-the l)oxy]pyridin-3-yl}piperidine-4-ol

Specified in the title compound obtained as white solid in accordance with the method of reference example 7 or a similar manner, but using as the starting material 1-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}piperidine-4-one obtained in reference example 21-3, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, DMSO-d6) δ: 0,95 (10H, d, J=5,9 Hz), 1,44-to 1.61 (6H, m), 1,86 is 1.96 (2H, m), 2.21 are of 2.30 (2H, m), 2,63-to 2.74 (5H, m), with 2.93 (2H, TD, J=10,7, 3,4 Hz), 3,19 (2H, dt, J=12,2, 3,9 Hz), 4,84-of 4.75 (1H, m), 6,62 (1H, d, J=8,8 Hz), 7,38 (1H, DD, J=9,0, 3.2 Hz), 7,74 (1H, d, J=2,9 Hz).

Reference example 7-6:

Getting 4-(aminomethyl)-1-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)piperidine-4-ol

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 7 or a similar manner, but using as the starting material 1-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)piperidine-4-one obtained in reference example 21-4, instead of 1-[4-(benzyloxy)phenyl]piperidine-4-it.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=3.0 Hz), of 1.35 to 2.35 (14H, m)to 2.66 (2H, s), 2,92-of 3.12 (3H, m), with 3.27 (2H, d, J=9.0 Hz), 3.95 to 3,98 (2H, m), 6,83 (2H, d, J=9.3 Hz), 6,93 (2H, d, J=9,3 Hz).

Reference example 8:

Obtain N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloracetamide

To a suspension of 4-(aminomethyl)-1-[4-(benzyloxy)phenylpiperidine-4-ol (250 g, 800 mmol)obtained in reference example 7, in acetonitrile (5 l) was added water (2.5 l) solution of potassium carbonate (221,2 g, 1.6 mol), to the mixture with stirring under ice cooling are added dropwise chlorocatechol (109,7 g, 971 mmol) and the mixture is stirred for 40 minutes. To the resulting mixture while cooling with ice, add methanol (2.5 l), then the mixture is diluted with chloroform, allow it to warm to room temperature and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure, obtaining the crude product. The crude product is suspended in a mixture of toluene/hexane and filtered off with suction, getting mentioned in the title compound (297 g, 95,5%) as a yellow solid substance.

1H-NMR (400 MHz, DMSO-d6) δ: 1.56 to to 1.60 (4H, m), 2.91 in-2,99 (2H, m), 3,16-is 3.21 (4H, m), is 4.15 (2H, s), of 5.03 (2H, s), 6.89 in (4H, s), 7,33 was 7.45 (5H, m), 8,19 (1H, USS).

Reference example 8-1:

Getting 2-chloro-N-{[4-hydroxy-1-(4-methoxyphenyl)piperidine-4-yl]methyl}ndimethylacetamide

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of reference example 8 or a similar method, but using 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol obtained in reference example 7-1, instead of 4-(aminomethyl)-1-[4-(benzyloxy)phenyl]piperidine-4-ol.

p> 1H-NMR (400 MHz, CDCl3) δ: 1,71-of 1.80 (4H, m), 3,01-a 3.01 (2H, m), 3,23-of 3.27 (2H, m)to 3.41 (2H, d, J=6.4 Hz), of 3.77 (3H, s), 4,11 (2H, s), 6,82-6,85 (2H, m), 6,92 (2H, DD, J=8,8 Hz).

Reference example 8-2:

Getting 2-chloro-N-[(1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-hydroxypiperidine-4-yl)methyl]ndimethylacetamide

4-(Aminomethyl)-1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-ol (5 g, a 13.9 mmol)obtained in reference example 7-2, suspended in dimethylformamide, cooled to 0°C, to a suspension successively added pyridine (4.5 ml, at 55.6 mmol) and chlorocatechol (1,4 ml of 18.1 mmol) and the resulting mixture is stirred for 2 hours. To complete the reaction, to the mixture, water is added and the pH of the system was adjusted to 9 by addition of an aqueous 4N solution of sodium hydroxide. The mixture is then extracted with a 10% solution of methanol/chloroform, washed with saturated salt solution and dried over sodium sulfate. The organic solvent is evaporated under reduced pressure, the resulting residue is crystallized from isopropyl ether/ethyl acetate, getting mentioned in the title compound as brown solid substance (2.55 g, 42%).

1H-NMR (400 MHz, CDCl3) δ: 1,46-2,24 (16H, m), 2,53-to 2.85 (3H, m), 2,99-3,11 (2H, m), 3,19-of 3.32 (2H, m)to 3.41 (2H, d, J=6.8 Hz), 4,11 (2H, s), 4,20 (1H, USS), 6,83 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9.3 Hz), of 6.99 (1H, d, J=6,8 Hz).

Reference example 8-3:

Getting 2-chloro-N-[(4-hydroxy-1-{4-[(1-isopropylpiperazine-4-yloxy]phenyl}piperidine-4-yl)methyl]ndimethylacetamide

Specified in the title compound obtained as an oily brown substance in accordance with the method of reference example 8-2 or a similar manner, but using as the starting material 4-(aminomethyl)-1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-ol obtained in reference example 7-3, instead of 4-(aminomethyl)-1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-ol.

1H-NMR (400 MHz, CD3OD) δ: 1,11 (6H, d, J=6.0 Hz), 1,71-1,90 (6H, m), is 2.05 (2H, USS), 2,48 (2H, USS), 2,89 (3H, USS), 3,02-is 3.08 (2H, m), 3,23-3,30 (2H, m)to 3.41 (2H, d, J=6.0 Hz), 4,11 (2H, s)to 4.23 (1H, OSS), at 6.84 (2H, d, J=6,6 Hz), 6,89 (2H, d, J=6.6 Hz), 7,00 (1H, USS).

Reference example 8-4:

Getting 2-chloro-N-[(1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-hydroxypiperidine-4-yl)methyl]ndimethylacetamide

Specified in the title compound obtained as an oily brown substance in accordance with the method of reference example 8-2 or a similar manner, but using as the starting material 4-(aminomethyl)-1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}piperidine-4-ol obtained in reference example 7-4, instead of 4-(aminomethyl)-1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-ol.

1H-NMR (400 MG, CDCl3) δ: 1,46-2,43 (16H, m), 2,58-of 2.86 (3H, m), 3.00 and-of 3.12 (2H, m), 3,16 to be 3.29 (2H, m)to 3.41 (2H, d, J=6.0 Hz), of 4.12 (2H, s), equal to 4.97 (1H, ass), only 6.64 (1H, d, J=8,8 Hz), 7,00 (1H, t, J=6.0 Hz), 7,29 (1H, DD, J=8,8, 2,9 Hz), 7,79 (1H, d, J=2,9 Hz).

Reference example 9:

9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A solution of N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloroacetamide (297 g, 766 mmol)obtained in reference example 8, N,N-dimethylformamide (1.5 l) at room temperature are added to a solution of tert-butoxide potassium (233 g of 2.08 mol) in 2-methylbutane-2-Ola (6 l) and the resulting mixture is stirred for 2.5 hours at room temperature. To the mixture of acetic acid (100 ml), then saturated sodium hydrogen carbonate solution and the resulting mixture is extracted with a mixture of chloroform/methanol. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure, obtaining the crude product. The crude product is suspended in a mixture of chloroform/hexane and filtered off with suction, getting mentioned in the title compound (229.6 g, 85,0%) as a brown solid substance.

1H-NMR (400 MHz, CDCl3) δ: 1,77-of 1.84 (2H, m), 2,04 (2H, d, J=12,8 Hz), 2,99 was 3.05 (2H, m), 3,24 of 3.28 (2H, m), 3,30 (2H, d, J=2.4 Hz), is 4.21 (2H, s), 5,02 (2H, s), of 6.02 (1H, USS), 6,89-6,94 (4H, m), 7,30-the 7.43 (5H, m).

Reference example 9-1:

9-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of reference example 9 or a similar method, but using 2-chloro-N-{[hydroxy-1-(4-methoxyphenyl)piperidine-4-yl]methyl}acetamide", she obtained in reference example 8-1, instead of N-({1-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-4-yl}methyl)-2-chloracetamide.

1H-NMR (400 MHz, CDCl3) δ: 1,80 of-1.83 (2H, m), is 2.05 (2H, d, J=13,2 Hz), 2,99-of 3.06 (2H, m)of 3.25 (2H, dt, J=12,7, 4,4 Hz), 3,30 (2H, d, J=2.4 Hz), of 3.78 (3H, s), 4,20 (2H, s), to 6.43 (1H, OSS), at 6.84 (2H, dt, J=9,3, 3,4 Hz)6,94 (2H, d, J=8,8 Hz).

Reference example 9-2:

9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

To a solution of tert-butoxide potassium (1.6 g, 14.6 mmol) in tert-butanol (50 ml) and dimethylformamide (6 ml) under stirring at room temperature for 15 minutes and added dropwise a solution of 2-chloro-N-[(1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-hydroxypiperidine-4-yl)methyl]ndimethylacetamide (2,54 g, 5.83 mmol)obtained in reference example 8-2. The mixture is stirred for 4 hours, then to complete the reaction, to the mixture add water. The mixture is extracted with ethyl acetate, washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the residue purified column chromatography (silica gel, elution gradient: methanol/chloroform=2/98 to 15/85), getting mentioned in the title compound in the form of a solid pale yellow substance (1.6 g, 69%).

1H-NMR (400 MHz, CDCl3) δ: 1,56-2,29 (16H, m), 2,53-2,82 (3H, m), 2.95 and-is 3.08 (2H, m), 3,19-3,29 (2H, m), 3,29 (1H, s), 3,30 (1H, s), to 4.17-4.26 deaths (1H, m), 4,20 (2H, s), of 6.31 (1H, OSS), at 6.84 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 the C).

Reference example 9-3:

9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method of reference example 9-2 or a similar manner, but using as the starting material 2-chloro-N-[(4-hydroxy-1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-yl)methyl]acetamide", she obtained in reference example 8-3, instead of 2-chloro-N-[(1-{4-[(1-cyclobutylmethyl-4-yl)hydroxy]phenyl}-4-hydroxypiperidine-4-ylmethyl]ndimethylacetamide.

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.3 Hz), 1,73 is 1.86 (4H, m), 1.93 and-of 2.09 (4H, m), 2,30 is 2.44 (2H, USM), 2,69-2,84 (3H, USM), to 3.02 (2H, TD, J=1,2, 2,9 Hz)at 3.25 (2H, dt, J=12,7, 3,9 Hz), 3,30 (2H, d, J=2.4 Hz), 4,14-of 4.25 (3H, m), the 6.06 (1H, USS), 6,85 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 Hz).

Reference example 9-4:

9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 9-2 or a similar manner, but using as the starting material 2-chloro-N-[(1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-hydroxypiperidine-4-yl)methyl]acetamide", she obtained in reference example 8-4, instead of 2-chloro-N-[(1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-hydroxypiperidine-4-yl)IU is Il]ndimethylacetamide.

1H-NMR (CDCl3) δ: 2,04-3,31 (23H, m), and 3.31 (2H, s), 4,20 (2H, s), 5,09 (1H, USS), of 6.02 (1H, USS), of 6.65 (1H, d, J=8,9 Hz), 7,30 (4H, DD, J=8,9, 2,8 Hz), 7,79 (1H, d, J=2,8 Hz).

Reference example 10:

Obtain tert-butyl-9-[4-(benzyloxy)phenyl]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate

A mixture solution of 9-[4-(benzyloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one (5 g, of 14.2 mmol)obtained in reference example 9, in chloroform, di-tert-BUTYLCARBAMATE (6.2 g, 28.4 mmol), triethylamine (1.45 g, of 14.2 mmol) and 4-dimethylaminopyridine (350 mg, 2,84 mmol) is stirred overnight at room temperature. The reaction solution was diluted with chloroform, then washed successively with water, saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography (silica gel, elution gradient: chloroform/ethyl acetate=95/5 to 88/12), the resulting product is suspended in diisopropyl ether and filtered off with suction, getting mentioned in the title compound (5.34 g, 83%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 1.55 (9H, s), 1,77-of 1.84 (2H, m)of 1.97 (2H, d, J=13,2 Hz), to 3.02 (2H, TD, J=11,2, 2,4 Hz)at 3.25 (2H, dt, J=12,7, 3,9 Hz)to 3.64 (2H, s), 4,22 (2H, s), 5,02 (2H, s)6,91 (4H, s), 7,30-7,44 (5H, m).

Reference example 11:

Obtain tert-butyl-9-[4-(hydroxyphenyl)]-3-oxo-1-oxa,9 diazaspiro[5,5]undecane-4-carboxylate

Tert-butyl-9-[4-(benzyloxy)phenyl]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (5.34 g, and 11.8 mmol)obtained in reference example 10, dissolved in a mixture of methanol/ethyl acetate to the mixture is added 10% palladium on carbon (1.1 g, of 1.03 mmol) and the resulting mixture is stirred overnight in a hydrogen atmosphere. The reaction solution is filtered through celite, the celite is washed with a mixture of chloroform/methanol and uterine fluid concentrate, getting mentioned in the title compound (4,54 g, 100%) as a solid purple substance.

1H-NMR (CDCl3) δ: 1.57 in (9H, s), 1,98-2,07 (4H, USM), 3,14-of 3.32 (4H, m), of 3.73 (2H, s)to 4.23 (2H, s), for 6.81 (2H, d, J=8,8 Hz), 7,05 (2H, USS).

Reference example 12:

9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

A mixture of tert-butyl 9-[4-(hydroxyphenyl)]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (2 g, 5,52 mmol)obtained in reference example 11, hydrobromide 1-(3-bromopropyl)piperidine (2.37 g, of 8.28 mmol), obtained in accordance with methods described in U.S. patent No. 4751302, and cesium carbonate (5.4 g, of 16.6 mmol) in N,N-dimethylformamide is stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer dried over sodium sulfate. The solvent is evaporated under reduced Yes the tion, receiving the crude product tert-butyl 3-oxo-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one) (2.64 g). To the crude product type triperoxonane acid while cooling the mixture with ice and the mixture was stirred at room temperature for 1 hour. The mixture is neutralized by adding aqueous 2n. solution of sodium hydroxide under ice cooling and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is suspended in hexane and the mixture is filtered with suction, getting mentioned in the title compound (1,58 g, 74%) as a solid pale yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 1,43-to 1.45 (2H, USM), 1,58 is 1.60 (4H, m), 1.77 in-of 1.84 (2H, m), 1.93 and of 1.99 (2H, m), 2,04 (2H, d, J=13,2 Hz), 2,42 (4H, USS), 2,48 (2H, t, J=7,6 Hz), 3,01 (2H, TD, J=11,7, 2,9 Hz), 3,24 (2H, dt, J=12,7, 4,4 Hz), 3,30 (2H, d, J=2,9 Hz), of 3.96 (2H, t, J=6.3 Hz), 4,20 (2H, s), 6,18 (1H, USS), 6,83 (2H, dt, J=9,3, 3,9 Hz), 6,92 (2H, dt, J=9,3, 3,9 Hz).

Reference example 12-1:

9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 12, the same method or by a combination of this method with the traditional method, but using t the et-butyl 9-[4-(hydroxyphenyl)]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate, obtained in reference example 11, and the hydrobromide (3S)-1-(3-bromopropyl)-3-methylpiperidine obtained in reference example 4 instead of the hydrochloride of 1-(3-bromopropyl)piperidine.

1H-NMR (400 MHz, CDCl3) δ: of 0.87 (3H, d, J=6.3 Hz), 1,57-1,72 (6H, m), 1.77 in-of 1.84 (3H, m), 1.93 and is 2.00 (2H, m), 2,04 (2H, d, J=a 12.7 Hz), 2,50 (2H, USS), 2,85 of 2.92 (2H, USM), a 3.01 (2H, TD, J=2,8, 11.7 Hz), 3,24 (2H, dt, J=3,4, and 12.2 Hz), 3,30 (2H, d, J=2,9 Hz), of 3.96 (2H, t, J=6.3 Hz), is 4.21 (2H, s), 6,03 (1H, s), 6,83 (2H, dt, J=9,3, 3,4 Hz)6,91 (2H, dt, J=9,3, 3,4 Hz).

Reference example 12-2:

9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 12, the same method or by a combination of this method with the traditional method, but using tert-butyl 9-[4-(hydroxyphenyl)]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate obtained in reference example 11, and the hydrobromide of 1-(3-bromopropyl)pyrrolidine obtained in accordance with methods described in U.S. patent No. 4751302, instead hydrobromide 1-(3-bromopropyl)piperidine.

1H-NMR (400 MHz, CDCl3) δ: 1,77-of 1.84 (6H, m), 2.00 in to 2.06 (4H, m), 2,62 (4H, USS), 2,70 (2H, t, J=7,3 Hz), 3,01 (2H, TD, J=11,7, 2,9 Hz), 3,24 (2H, dt, J=12,7, a 4.9 Hz), 3,30 (2H, d, J=2,9 Hz), 3,98 (2H, t, J=6.3 Hz), is 4.21 (2H, s), 6,05 (1H, USS), 6,83 (2H, dt, J=9,3, 3,4 Hz), 6,92 (2H, dt, J=9,3, 3,4 Hz).

Reference example 12-3:

9-(4-{3-[(2S)-2-methylp Raiden-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as a solid pale brown substance in accordance with the method of reference example 12, or a similar method, but using tert-butyl 9-[4-(hydroxyphenyl)]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate obtained in reference example 11, and the hydrobromide (2S)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-1, instead hydrobromide 1-(3-bromopropyl)piperidine.

Reference example 12-4:

9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 12, the same method or by a combination of this method with the traditional method, but using tert-butyl 9-[4-(hydroxyphenyl)]-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate obtained in reference example 11, and the hydrobromide (2R)-1-(3-bromopropyl)-2-methylpyrrolidine obtained in reference example 4-2, instead hydrobromide 1-(3-bromopropyl)piperidine.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (3H, d, J=6.3 Hz), 1,37 of 1.46 (1H, m), 1.56 to of 1.84 (4H, m), 1,87-2,21 (7H, m), 2,24 of-2.32 (1H, m), 2,93 totaling 3.04 (3H, m), 3,15-3,29 (5H, m), 3.95 to 4,01 (2H, m), 4,19 (2H, s), only 6.64 (1H, OSS), at 6.84 (2H, d, J=9,2 Hz), 6,91 (2H, d, J=9,2 Hz).

Reference example 13:

Getting 8-(4-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]Decan-it

A mixture of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol (1 g, to 4.23 mmol)obtained in reference example 7-1, and triphosgene (1.26 g, to 4.23 mmol) in chloroform is stirred overnight at room temperature. The reaction solution was diluted with chloroform, add saturated aqueous solution of sodium carbonate, extracted with chloroform and washed with a saturated solution of salt. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure, obtaining specified in the header connection (1,17 g, 100%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,97-of 2.15 (4H, m), 3,26 (4H, USS), of 3.46 (2H, s), of 3.78 (3H, s), 4,99 (1H, USS), 6,86-7,01 (4H,m).

Reference example 13-1:

Getting 8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid pale orange substance in accordance with the method of reference example 13 or a similar manner, but using as the starting material 4-(aminomethyl)-1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-ol obtained in reference example 7-2, instead of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol.

1H-NMR (400 MHz, CDCl3) δ: 1,59-2,17 (16H, m), 2,53-and 2.83 (3H, m), 3,14 of 3.28 (4H, m), 3,39 (2H, s), is 4.21 (1H, USS), of 4.95 (1H, USS,), at 6.84 (2H, d, J=9.3 Hz), 6.89 in (2H, d, J=9,3 Hz).

Reference example 13-2:

P is torching 8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid in accordance with the method of reference example 13 or a similar manner, but using as the starting material 4-(aminomethyl)-1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-ol obtained in reference example 7-3, instead of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol.

1H-NMR (400 MHz, CDCl3) δ: 1,37 (4H, OSS), to 1.67 (6H, s), 1.85 to 2,19 (7H, m), 2.95 and-of 3.31 (6H, m), 3,35-3,47 (3H, m), 6,83 (2H, d, J=9.3 Hz), 6,92 (2H, d, J=9,3 Hz).

Reference example 13-3:

Getting 8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as white solid in accordance with the method of reference example 13 or a similar manner, but using as the starting material 4-(aminomethyl)-1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}piperidine-4-ol obtained in reference example 7-4, instead of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol.

1H-NMR (400 MHz, CDCl3) δ: 1,27-2,13 (16H, m), 2,65-of 2.97 (3H, USM), 3,15-3,24 (4H, m), 3,40 (2H, s), of 5.03 (1H, USS), 5,19 (1H, USS), of 6.65 (1H, d, J=9.3 Hz), 7,29 (1H, DD, J=9,0, 3.2 Hz), 7,79 (1H, d, J=2,9 Hz).

Reference example 13-4:

Getting 8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as a solid is th white matter in accordance with the method of reference example 13 or equivalent means, but using as the starting material 4-(aminomethyl)-1-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}piperidine-4-ol obtained in reference example 7-5, instead of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol.

1H-NMR (400 MHz, CDCl3) δ: of 1.06 (6H, d, J=6.3 Hz), 1,72-of 1.84 (2H, m), 1,87 of 1.99 (2H, m), 2.00 in 2,17 (4H, m), 2,35-2,48 (2H, m), of 2,75 2,85 (2H, m)of 2.75 (1H, t, J=6.3 Hz), 3,14-3,26 (4H, m), 3,40 (2H, s), 4,93-4,94 (1H, m), 5,18 (1H, USS), of 6.66 (1H, d, J=9.3 Hz), 7,28 (3H, DD, J=9,3, 2,9 Hz), 7,80 (1H, d, J=2,9 Hz).

Reference example 13-5:

Getting 8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

Specified in the title compound obtained as brown solid substance in accordance with the method of reference example 13 or a similar manner, but using as the starting material 4-(aminomethyl)-1-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)piperidine-4-ol obtained in reference example 7-5, instead of 4-(aminomethyl)-1-(4-methoxyphenyl)piperidine-4-ol.

1H-NMR (400 MHz, CDCl3) δ: of 1.12 (3H, d, J=5,9 Hz), 1,44-2,48 (14H, m), 2,94-3,03 (1H, m), 3,16-3,24 (4H, m), 3,39 (2H, s), 3,94-4,01 (2H, m), and 5.30 (1H, USS), 6,83 (2H, d, J=9.3 Hz), make 6.90 (2H, d, J=9,3 Hz).

Reference example 14:

Getting 8-(4-hydroxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it

To a solution of 8-(4-methoxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (8,43 g, 32 mmol)obtained in reference example 13, in chloroform at 0°C dropwise add the 1.0m solution tribromide boron in dichloromethane (96 ml, 96,4 mmol) and the resulting mixture is stirred over night at room temperature. The solution is cooled to 0°C, neutralized by adding a saturated aqueous solution of carbonate and extracted with a mixture of chloroform/methanol (4/1). The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is suspended in a mixture of chloroform/methanol and filtered with suction, getting mentioned in the title compound (7,46 g, 93,4%) as a brown solid substance.

1H-NMR (400 MHz, CD3OD) δ: 2,35-of 2.38 (2H, m)to 3.34 (2H, s), 3,53 (2H, USS), 3,63-3,66 (2H, USM), 3,78-a 3.83 (2H, USM), 6,94 (2H, d, J=8,8 Hz), 7,54 (2H, d, J=8,8 Hz).

Reference example 15:

Getting 8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it

A mixture of 8-(4-hydroxyphenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (1,72 g, 6,92 mmol)obtained in reference example 14, the hydrochloride of 1-(3-chloropropyl)piperidine (1.51 g, 7.62 mmol), obtained in accordance with the method described in WO 03/101931, or equivalent means, and potassium carbonate (2,87 g, 20,76 mmol) in DMF is stirred overnight at 80°C. the Solvent is evaporated under reduced pressure, the residue is dissolved in chloroform and washed successively with water and saturated salt solution. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The remainder of WM is androuet in a mixture of ethyl acetate/diethyl ether (1/1) and filtered with suction, getting listed in the title compound (1.45 g, 56%) as a brown solid substance.

1H-NMR (400 MHz, CDCl3) δ: 1,47 (2H, s)of 1.66 (4H, s), 1,89 is 1.96 (2H, m), 1,99 e 2.06 (2H, m), 2,11 (2H, d, J=13,2 Hz), of 2.51-2.57 m (6H, m), 3,20 (4H, DD, J=9,0, and 3.7 Hz), 3,39 (2H, s), of 3.97 (2H, t, J=6,1 Hz), are 5.36 (1H, USS), PC 6.82 (2H, d, J=8,8 Hz), make 6.90 (2H, d, J=8,8 Hz).

Reference example 16:

Getting 5-bromo-2-(deformedarse)pyridine

A mixture of 5-bromopyridin-2(1H)-it is a (17.4 g, 100 mmol), sodium sulfate (1.42 g, 10 mmol) and 2-(persulfonic)DIPEROXY acid (11,4 ml, 100 mmol) in acetonitrile is stirred over night at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solvent is evaporated under reduced pressure. The residue is dissolved in diethyl ether, washed with saturated salt solution, the organic layer dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=20/80 to 50/50), receiving specified in the header connection (18.75 g, 84%) as an oily pale yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 6,83 (1H, d, J=9.3 Hz), 7,40 (1H, t, J=72,7 Hz), 7,82 (1H, DD, J=8,8, 2.4 Hz), of 8.25 (1H, d, J=2,4 Hz).

Reference example 17:

Getting 5-bromo-2-isopropoxypyridine

To a mixture of 5-bromopyridin-2(1H)-she (5 g, 28,7 IMO the ü) and potassium carbonate (to 9.93 g, 71,8 mmol) in dimethyl sulfoxide at room temperature, add 2-todesopfer (to 3.73 ml, of 37.3 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed successively with water and saturated salt solution. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified column chromatography (silica gel, elution gradient: ethyl acetate/hexane=20/80 to 50/50), getting mentioned in the title compound (4.72 in g, 76%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: of 1.33 (6H, d, J=6.3 Hz), 5,18 is 5.28 (1H, m), 6,59 (1H, d, J=8,8 Hz), to 7.61 (1H, DD, J=8,8, 2,9 Hz), 8,17 (1H, d, J=2.0 Hz).

Reference example 18:

Obtain tert-butyl 4-[(5-nitropyridine-2-yl)oxy]piperidine-1-carboxylate

Specified in the title compound obtained as a solid pale yellow substance in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using instead 4-fluoro-1-nitrobenzene as the starting material 2-chloro-5-nitropyridine.

1H-NMR (400 MHz, CDCl3) δ: to 1.48 (9H, s), 1,67 of-1.83 (2H, m), 1,94-2,07 (2H, m), 3,23-to 3.36 (2H, m), 3,70-3,86 (2H, m), from 5.29 of 5.39 (1H, m), to 6.80 (1H, d, J=9.6 Hz), 8,35 (1H, DD, J=a 9.6, 2.7 Hz), 9,05 (1H, d, J=2.7 Hz)

Reference example 19:

Obtain 1-isopropyl-4-(4-nitrophenoxy)PI is uridine

Specified in the title compound obtained as a solid orange substance in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 4-(4-nitrophenoxy)piperidine.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=6.3 Hz), 1,81-of 1.92 (2H, m), 2,01-2,12 (2H, m), 2.40 a is 2.51 (2H, m), 2,74-to 2.85 (3H, m), 4,40-4,48 (1H, m), to 6.95 (2H, d, J=9.3 Hz), 8,19 (2H, d, J=9,3 Hz).

Reference example 19-1:

Getting 2-[(1-cyclobutylmethyl-4-yl)oxy]-5-nitropyridine

Specified in the title compound obtained as a solid orange substance in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 5-nitro-2-(piperidine-4-yloxy)pyridine obtained by removal of the Boc-group from tert-butyl 4-[(5-nitropyridine-2-yl)oxy]piperidine-1-carboxylate obtained in reference example 18.

1H-NMR (400 MHz, CDCl3) δ: 1,58-2,27 (12H, m), 2,56-2,84 (3H, m), a total of 5.21 (1H, USS,), 6,79 (1H, d, J=9,2 Hz), a 8.34 (1H, DD, J=9,2, 2,8 Hz), 9,05 (1H, d, J=2,8 Hz).

Reference example 19-2:

Getting 2-[(1-isopropylpiperazine-4-yl)oxy]-5-nitropyridine-4-methylbenzenesulfonate

Specified in the title compound obtained as white solid, in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 5-neath the o-2-(piperidine-4-yloxy)pyridine, obtained by removing the Boc group from tert-butyl 4-[(5-nitropyridine-2-yl)oxy]piperidine-1-carboxylate obtained in reference example 18.

1H-NMR (400 MHz, DMSO-d6) δ: of 1.28 (6H, t, J=5,1 Hz), 1,82-to 1.87 (1H, m), 2,19-of 2.20 (2H, m), is 2.30 (3H, s), 2,35 (2H, d, J=9.3 Hz), 3,10-3,26 (2H, m), 3,47-to 3.58 (2H, m), 5,32-of 5.48 (1H, m), 7,06-to 7.09 (1H, m), 7,13 (2H, d, J=6.3 Hz), 7,49 (2H, d, J=6.3 Hz), 8,51-to 8.57 (1H, m), 9,16 (1H, USS), which is 9.09 (1H, DD, J=2,1, 7,2 Hz).

Reference example 20:

Getting 4-[(1-isopropylpiperazine-4-yl)oxy]aniline

Specified in the title compound obtained as a solid substance in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 1-isopropyl-4-(4-nitrophenoxy)piperidine obtained in reference example 19.

1H-NMR (400 MHz, CDCl3) δ: of 1.05 (6H, d, J=4,8 Hz), 1,73-of 1.81 (2H, m), 1,95-of 1.97 (2H, m), 2,32-of 2.38 (2H, m), 2.71 to of 2.81 (3H, m), 4,07-4,11 (1H, m), 6,59 (2H, d, J=6.6 Hz), 6,74 (2H, d, J=6,6 Hz).

Reference example 20-1:

Obtaining 5-amino-2-[(1-cyclobutylmethyl-4-yl)oxy]pyridine

Specified in the title compound obtained as a brown liquid in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 2-[(1-cyclobutylmethyl-4-yl)oxy]-5-nitropyridine obtained in reference example 19-1.

1H-NMR (400 MHz, CDCl3) δ: 1,52-of 2.25 (10H, m), 2,50-2,78 (3H, m), 3,15-3,51 (2H, m), 4,2-to 4.98 (1H, m)to 6.57 (1H, d, J=8.7 Hz), 7,01 (1H, DD, J=8,7, 2,8 Hz), 7,63 (1H, d, J=2,8 Hz).

Reference example 20-2:

Obtaining 5-amino-2-[(1-isopropylpiperazine-4-yl)oxy]pyridine

Specified in the title compound obtained as an oily substance in accordance with the method described in the patent (WO 2005/077905), or a similar method, but using as the starting material 2-[(1-isopropylpiperazine-4-yl)oxy]-5-nitropyridine-4-methylbenzenesulfonate obtained in reference example 19-2.

1H-NMR (400 MHz, CDCl3) δ: 1,08 (6H, d, J=4,8 Hz), 1,75 of-1.83 (2H, m), 2,04-of 2.08 (2H, m), 2,39 is 2.46 (2H, m), 2,73-2,84 (3H, m), 3,37 (2H, USS), 4,87-4,94 (1H, m), 6,60 (1H, d, J=6.3 Hz),? 7.04 baby mortality (2H, DD, J=2.1 a, and 6.6 Hz), 7,66 (1H, d, J=2,4 Hz).

Reference example 21:

Obtain 1-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}piperidine-4-it

4-[(1-Cyclobutylmethyl-4-yl)oxy]aniline (41 g, 170 mmol), obtained in accordance with methods described in the patent (WO 2005/077905), and potassium carbonate (33 g, 238 mmol) is suspended in a mixture of ethanol (1.35 l) and water (470 ml) and the resulting mixture is refluxed for one hour, adding dropwise an aqueous solution (about 200 ml) of 1-ethyl-1-methyl-4-oxopiperidine (64 g, 238 mmol)obtained from 1-methylpiperidin-4-in accordance with the methods described in the literature (Organic Letters, Vol.1, 1999, pp.1261-1262). The resulting mixture was stirred for additional 2 hours. The mixture is allowed to cool, ethanol is pariwat under reduced pressure and the residue extracted with water (700 ml) and chloroform (400 ml). The aqueous layer was extracted three times with chloroform (400 ml) and the organic layer is dried over magnesium sulfate. The solvent is evaporated, the residue is purified column chromatography (silica gel, elution gradient: methanol/chloroform=2/98 to 4/96) and crystallized from isopropyl ether/hexane=1/9, getting mentioned in the title compound in the form of a solid light-brown substance (28 g, 50%).

1H-NMR (400 MHz, CDCl3) δ: 1,58-2,50 (12H, m), of 2.56 (4H, t, J=6,1 Hz), 2,62-and 2.79 (2H, m), is 2.88 (1H, USS), 3,47 (4H, t, J=6,1 Hz), 4,30 (1H, USS), 6,86 (2H, d, J=8,8 Hz)6,94 (2H, d, J=8,8 Hz).

Reference example 21-1:

Obtain 1-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}piperidine-4-it

Specified in the title compound obtained as an oily brown substance in accordance with the method of reference example 21 or a similar manner, but using as the starting material 4-[(1-isopropylpiperazine-4-yl)oxy]aniline obtained in reference example 20 instead of 4-[(1-cyclobutylmethyl-4-yl)oxy]aniline.

1H-NMR (400 MHz, CD3OD) δ: to 0.92 (6H, d, J=4,8 Hz), 1,52-of 1.66 (6H, m), 1,76 is 1.86 (2H, m), of 2.44-2.50 (2H, m), 2.63 in (2H, s), 2,74-is 2.88 (3H, m), 2,82 are 2.98 (2H, m), a 4.03-of 4.12 (1H, m), 6.89 in (2H, d, J=6.0 Hz), 7,01 (2H, d, J=6.0 Hz).

Reference example 21-2:

Obtain 1-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}piperidine-4-it

Specified in the title compound obtained as a solid orange ve is esta in accordance with the method of reference example 21 or equivalent means, but as the initial substance using 5-amino-2-[(1-cyclobutylmethyl-4-yl)oxy]pyridine obtained in reference example 20-1, instead of 4-[(1-cyclobutylmethyl-4-yl)oxy]aniline.

1H-NMR (400 MHz, CDCl3) δ: 1,57-of 1.97 (6H, m), 1,98 was 2.25 (6H, m), 2,58 (4H, t, J=6,1 Hz), 2,60-of 2.81 (3H, m), 3,44 (4H, t, J=6,1 Hz), 4,89-5,04 (1H, m), 6,69 (1H, d, J=8,8 Hz), 7,33 (1H, DD, J=8,8, 2,9 Hz), to 7.84 (1H, d, J=2,9 Hz).

Reference example 21-3:

Obtain 1-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}piperidine-4-it

Specified in the title compound obtained as an oily brown substance in accordance with the method of reference example 21 or a similar manner, but using as the starting material 5-amino-2-[(1-isopropylpiperazine-4-yl)oxy]pyridine obtained in reference example 20-2, instead of 4-[(1-cyclobutylmethyl-4-yl)oxy]aniline.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (6H, d, J=5,1 Hz), 1,78-to 1.87 (2H, m), 2.06 to and 2.14 (2H, m), 2,42-2,52 (2H, m)2,60 (4H, t, J=4.5 Hz), was 2.76-is 2.88 (3H, m), of 3.46 (4H, t, J=4.5 Hz), 4,94-5,02 (1H, m), of 6.71 (1H, d, J=6.6 Hz), 7,35 (2H, DD, J=2.1 a, and 6.6 Hz), 7,87 (1H, d, J=2.1 Hz).

Reference example 21-4:

Obtaining 1-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)piperidine-4-it

Specified in the title compound obtained as an oily brown substance in accordance with the method of reference example 21 or a similar manner, but using as the starting material 4-methylbenzoic Thonet 4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}aniline, obtained in accordance with methods described in the patent (WO 2005/077905), instead of 4-[(1-cyclobutylmethyl-4-yl)oxy]aniline.

1H-NMR (400 MHz, CDCl3) δ: 1,11 (3H, d, J=5,9 Hz), 1,38-1,49 (1H, m), 1,67-to 1.82 (2H, m), 1,89-2,02 (3H, m), 2,09-of 2.26 (2H, m), 2,27-of 2.38 (1H, m), 2.57 m (4H, t, J=6,1 Hz), 2,93-3,03 (1H, m), 3,16 is 3.23 (1H, m), of 3.46 (4H, t, J=5,9 Hz), 3.95 to Android 4.04 (2H, m)6,86 (2H, d, J=8,8 Hz), to 6.95 (2H, d, J=8,8 Hz).

The following are examples of pharmacological testing of compounds according to the present invention.

Example pharmacological test 1: test for inhibition of binding of analogues of histamine

the cDNA sequence encoding the histamine H3 receptor (see WO 00/39164), clone with expression vectors pCR2.1, pEFlx (Invitrogen) and CI-neo (Promega). The resulting expression vector transferout in the host cells: HEK293 and CHO-K1 (Americal Type Culture Collection) in accordance with the cationic lipid method [see Preceedings of the National Axademy of Sciences of the United States of America, Vol., 84, p.7413 (1987)] to obtain cells of the expression of the histamine H3 receptor.

Sample membranes obtained from cells containing expressed histamine H3 receptor, incubated in sample buffer (50 mm Tris-buffer, pH 7,4) together with the test compound and 20,000 cpm of [3H] N-methylhistamine (NEN) at 25°C for 2 hours and then filtered through a glass filter GF/C. the Filter was washed with Tris-buffer (pH 7.4), and determine the radioactivity of the glass filter. Nesp nificence binding determined in the presence of 10 μm hyperemia (SIGAM) and calculate the concentration of the test compound, at which there is 50% inhibition (IC50) specific binding of N-alpha-methylhistamine [Molecular Pharmacology, Vol.55, p.1101 (1999)]. IC50the test compounds are presented in table 1.

Table 1
ExampleIC50(nm)ExampleIC50(nm)
2-63,003-960,41
3-84,203-1070,18
3-150,223-1381,08
3-420,943-1500,66
3-790,193-1680,09
3-951,204-171,20

From the above results show that the compounds according to the SNO present invention significantly inhibit the binding of N-alphamethylstyrene (similar to histamine) with histamine H3 receptor.

Example pharmacological test 2: test for antagonistic activity with respect to water consumption, caused by the selective agonist histamine H3 receptor R-α-methylhistamine.

Male SD rats (age 7-10 weeks, 300-300 g)under anesthesia (ketamine-xylazine, a single intraperitoneal injection, 74 and 11 mg/kg), in the third ventricle of the brain give stereotactic device for operations on the brain, is inserted into the permanent guide cannula (caliber 26, length 11 mm) and fixed with dental resin. The position of the pointed end of the guide cannula: 2.2 mm below bregma in the midline at a depth of 8 mm from the surface of the skull. After a rehabilitation period (about 1 week) in the third ventricle enter R-alpha methylhistamine (0,3 μg/1 μl/head, 30% in liquid propylene glycol). The test compound (the compound of example 3-8), suspended in aqueous 0.5% solution of methylcellulose, administered to rats orally 2 hours prior to the introduction of R-alpha-methylhistamine and determine the amount of water drunk by the rat for 1 hour. As a result of introduction of the test compounds at a dose of 30 mg/mg significantly slows down the increase in water consumption caused by the introduction of R-alpha-methylhistamine in the third ventricle of the rat brain.

Example pharmacological test 3: test transition Golo is Noah brain/spinal fluid

The test compound (the compound of example 3-8) orally or intravenously administered to male SD rats (age 7-10 weeks, 200-400 g) under anesthesia (ether) during a predefined period of time from the abdominal aorta selected whole blood using a syringe treated with heparin. Then remove the skin from the head and cervical spine to impose a 30 G dental needle to pass through the subarachnoid space. Through a tube, connected 30 G dental needle with a syringe of 1 ml is taken from 50 to 100 μl of cerebrospinal fluid and then remove the brain. A sample of whole blood centrifuged (4°C., 6000 g, 10 min) and the resulting plasma is stirred with ethanol (containing a substance used as an internal standard)is added in a quantity exceeding the quantity of plasma three times. Sample brain homogenized with 2 ml of water added to it; a sample of the mixture taken and mixed with ethanol (containing a substance used as an internal standard)is added in a quantity exceeding the sample three times. Cerebrospinal fluid is mixed with ethanol (containing a substance used as an internal standard)is added in a quantity exceeding the quantity of liquid three times. All samples incubated at -20°C for 20 minutes, then CE is trifoglio (4°C, 12000 g, 10 min) and the supernatant analyzed LC/MS/MS. The concentration of the compound in plasma, brain and cerebrospinal fluid is determined in accordance with the method of calibration curves. The results show that 3 hours after oral administration (10 mg/kg) concentration of the test compounds in the brain is 0.99 nmol/g in the cerebrospinal fluid of 0.74 μm, plasma - 0.6 microns.

Industrial applicability

The invention provides a remarkable compound that has an antagonistic action or reverse action of the agonist on the histamine H3 receptor, i.e. acts as an antagonist or inverse agonist against histamine H3-receptor in living organisms and, therefore, is useful as a preventive or therapeutic medicines for the treatment of diseases associated with metabolic disorders such as obesity, diabetes, disorders of hormone secretion, hyperlipemia, gout, or fatty liver disease, for the treatment of cardiovascular disorders such as stenocardia, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy and electrolytic disorders, for the treatment of sleep disorders and diseases accompanied by sleep disorder such as idiopathic the Russian-hypersomnia, repeating hypersomnia, the truth hypersomnia, narcolepsy, a disorder associated with periodic hypermodernity in sleep syndrome sleep apnea, disorders of circadian rhythm, chronic fatigue syndrome, disorders of REM sleep, senile insomnia and idiopathic insomnia, repetitive insomnia and true insomnia caused by failure to comply with the requirements of sanitary norms in sleep mode when working at night, diseases of the Central and peripheral nervous system such as bulimia, emotional disorder, depression, anxiety, delirium, dementia, schizophrenia, attention deficit disorder/hyperactivity disorder, memory disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, reduced cognitive ability, disturbance of motor function, paresthesias, dysosmia, epilepsy, immunity to morphine, drug addiction and alcoholism.

1. The compounds of formula (I) or their pharmaceutically acceptable salts

where R1and R2taken together, represent a group chosen from groups of formula (III-1):
and
where R9represents a
1) lower alkyl which the Rupp, optionally substituted by a halogen atom or a lower alkoxygroup,
2) aryl group,
3) Uralkaliy group,
4) heteroallyl group,
5) heteroaryl group, where the aryl, kalkilya, heteroallyl and heteroaryl groups can be substituted by halogen atom, lower alkyl group, optionally substituted lower alkoxygroup or 1-3 halogen atoms, lower alkoxygroup, optionally substituted by 1-3 halogen atoms, cyano, hydroxy-group, alkylsulfonyl group, cycloalkylcarbonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanolamines, alkylamines or dialkylamines;
R10represents a lower alkyl group, optionally substituted by 1-3 halogen atoms, or lower alkylsulfonyl group;
X9-X12represent a carbon atom or a nitrogen atom where the carbon atom may be independently substituted lower alkyl group, optionally substituted by a halogen atom or a lower alkoxygroup, lower alkoxygroup, optionally substituted by halogen atom, or a cyano or a halogen atom;
R3represents a
a) a group of the formula (II-1):

where R4and R5taken together with the nitrogen atom, form a 5 - and 6-membered monocyclic ring, where the monocyclic ring may contain as a substituent a lower alkyl group; m1 is an integer of 3; or
b) a group of the formula (II-2):

where R6represents a lower alkyl group or cycloalkyl group; m2 is an integer 1 or 2;
X1-X4all are carbon atoms, or 1 of X1-X4represents a nitrogen atom and the remainder are carbon atoms;
and where "heteroaryl" in each case refers to 5 - or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where the group formed together R1and R2represents a group of formula (III-2) or formula (III-3):

where R9takes the values defined in claim 1.

3. The compound or its pharmaceutically acceptable salt according to claim 1, where the group formed together R1and R2represents a group of formula (III-4), formula (III-5) or formula (III-6):

where R10X9, X10, X11and X12take the values defined in claim 1.

4. Connection is out or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where all X1-X4represent carbon atoms.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where one of X1-X4represents a nitrogen atom and the other represents carbon atoms.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where R3represents a group of formula (II-1).

7. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where R3represents a group of formula (II-2).

8. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound of formula (I) represents the following link:
1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],
3-phenyl-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-one,
4-phenyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(3-((2S)-2-methylpyrrolidine-1-yl)propoxy)phenyl]-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(3-((3S)-3-methylpiperidin-1-yl)propoxy)phenyl]-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
triptorelin 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],
triptorelin 5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 5-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 6-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 7-methoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1H-Spiro[furo[3,4-C]pyridine-3,4'-piperidine]-1-it,
triptorelin 1-(methylsulphonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],
triptorelin 1-(ethylsulfonyl)-7-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],
triptorelin 1-(ethylsulfonyl)-5-fluoro-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine],
triptorelin 4-tert-butoxy-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine]-3-it,
triptorelin 1-(ethylsulfonyl)-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-1,2-dihydrospiro [indole-3,4'-piperidine],
triptorelin 3,3-dimethyl-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],
triptorelin 3-methyl-1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3H-Spiro[2-benzofuran-1,4'-piperidine],
triptorelin 1'-[4-(3-piperidine-1-ylpropionic)phenyl]-3,4-dihydrospiro[chroman-2,4'-piperidine],
4-(4-forfinal)-9-[4-(3-[(3S)-3-methylpiperidin-1-yl]propoxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]round the EN-3-one,
4-(6-herperidin-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(methoxyphenyl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-were)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-3-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-4-(2-methylpyridin-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3,4-differenl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2,4-differenl)-9-[4-{3-[(3S)-3-piperidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-phenyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-4-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-[6-(deformedarse)pyridine-3-yl]-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-isopropoxypyridine-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-isopropoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-piperidine-1-improp the XI)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-5-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-5-yl)-9-[4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-5-yl)-9-[4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-forfinal)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-methoxyphenyl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1,3-benzodioxol-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-4-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro the[5,5]undecane-3-one,
4-(5-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-methylpyridin-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(3-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2-thienyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-methoxyphenyl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-herperidin-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-[6-(deformedarse)pyridine-3-yl]-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(1,3-thiazol-2-yl)-1-oxa-4,9-diazaspiro [5,5]undecane-3-one,
3-(4-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-[4-(3-piperidine-1-ylpropionic)phenyl]--(pyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-(pyridin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(6-herperidin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-herperidin-4-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-[6-(deformity)pyridine-3-yl]-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(5-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(6-herperidin-2-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(3-forfinal)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(4-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(3-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(6-methoxypyridine-3-yl)-8-[4-(3-piperidine-1-ylpropionic) phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(6-methylpyridin-3-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-methoxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-[4-(3-piperidine-1-ylpropionic)phenyl]-3-[4-(triptoreline)phenyl]-1-oxa-3,8-diaza the pyro[4,5]decane-2-it,
4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-pyridin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-ethyl-5-methoxy-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-methoxypyridine-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-herperidin-2-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-[9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy)phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,
9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-[1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl]-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]University is a perfect combination-3-one,
9-[4-(3-piperidine-1-ylpropionic)phenyl]-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2,4-differenl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(3-pyrrolidin-1 ipropose)phenyl]-4-[6-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-isopropoxypyridine-3-yl)-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-ethoxypyridine-5-yl)-9-[4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-methoxypyrazine-2-yl)-9-[4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro [5,5]undecane-3-one,
4-(4-chlorophenyl)-9-[4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(trifluoromethyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]benzonitrile,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-methylpyridin-2-is)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-methoxypyridine-2-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-methyl-1H-pyrazole-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,
9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-[9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]nicotinamide,
4-(5-methoxypyridine-3-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(5-methoxypyrazine-2-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-methyl-1H-pyrazole-4-yl)-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]p is epoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
3-ethyl-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-ethoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(1-methyl-1H-pyrazole-4-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(1-methyl-1H-pyrazole-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
5-[8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl]nicotinamide,
8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(6-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-methoxypyridine-5-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(5-methoxypyridine-3-yl)-8-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(2-methoxypyridine-5-yl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-CEC is butylpiperazine-4-yl)oxy]phenyl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-isopropoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[3-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-imidazo[1,2-a]pyridine-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-(9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-ethyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro [5,5]is ndacan-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-pyrazin-2-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(3-methoxypyridine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-(9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,
4-(2-ethoxypyridine-5-yl)-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]University is a perfect combination-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-isopropoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
5-(9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[4-(methylsulphonyl)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(4-methoxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-herperidin-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-[6-(deformedarse)pyridine-3-yl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(4-forfinal)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]-undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}--(6-methylpyridin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(5-methoxypyrazine-2-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methylpyridin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
5-(8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-pyridin-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-imidazo[1,2-a]pyridine-3-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(6-herperidin-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(2-herperidin-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-cycle is butylpiperazine-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-ethyl-8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
5-(8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl)-3-(3-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(3-methylpyridin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-herperidin-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]PI is one-3-yl}-3-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2,2,2-triptorelin)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[4-(methylsulphonyl)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-ethoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
5-(8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(6-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-[5-(trifluoromethyl)pyridin-3-yl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyridine-3-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(5-methoxypyrazine-2-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}3-(2-methoxypyridine-5-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
5-(8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-2-oxo-1-oxa-3,8-diazaspiro[4,5]Decan-3-yl)nicotinamide,
8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-pyrazin-2-yl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
8-{6-[(1-isopropylpiperazine-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
4-(4-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-methoxyphenyl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(4-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-herperidin-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-3-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(6-methoxypyridine-2-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-methyl-9-(4-{3-[(2S)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-ethyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4-propyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-isopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-isopropyl-9-(4-{3-[(R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(1-ethylpropyl)-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-4-(2,2,2-triptorelin)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclopropyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclobutyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclobutyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclopentyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclohexyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-benzyl-9-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-benzyl-9-[4-(3-pyrrolidin-1 ipropose)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-benzyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(3-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-forfinal)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-(2-herperidin-4-yl)-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-ethyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-ethyl-9-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-1-oxa,9 diazaspiro[5,5]undecane-3-one,
4-methyl-9-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
8-[4-(3-(3S)-methylpiperidin-1 ipropose)phenyl]-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
3-(4-hydroxyphenyl)-8-[4-(3-piperidine-1-ylpropionic)phenyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-phenyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-[4-(1-cyclobutylmethyl-4-yloxy)phenyl]-4-(6-herperidin-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
9-{4-[(1-cyclopropylidene-4-yl)oxy]phenyl}-4-(6-methoxypyridine-3-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclobutyl-9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one,
4-cyclobutyl-9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-1-oxa-4,9-diazaspiro[5,5]undecane-3-one.

9. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound of formula (I) represents the following link:
4-(2-methoxypyridine-5-yl)-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
4-methyl-9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
5-[9-(4-{3-[(2R)-2-methylpyrrolidine-1-yl]propoxy}phenyl)-3-oxo-1-oxa-4,9-diazaspiro[5,5]round the EN-4-yl]nicotinamide;
9-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-pyridin-3-yl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
8-{6-[(1-cyclobutylmethyl-4-yl)oxy]pyridin-3-yl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he;
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-ethyl-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
9-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-4-(1-methyl-1H-pyrazole-4-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
8-{4-[(1-cyclobutylmethyl-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-he;
9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-4-(2-methoxypyridine-5-yl)-1-oxa-4,9-diazaspiro[5,5]undecane-3-one;
5-[9-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-oxo-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl)nicotinamide; or
8-{4-[(1-isopropylpiperazine-4-yl)oxy]phenyl}-3-(1-methyl-1H-pyrazole-4-yl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it.

10. Antagonist or inverse agonist of the histamine H3 receptor, containing as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 9.

11. Preventive or drug containing as an active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 9, from metabolic diseases such as obesity, diabetes,impaired secretion of hormones the hyperlipemia, gout and fatty liver, cardiovascular system, for example, stenocardia, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy and electrolyte disorders, sleep disorders and diseases accompanied by sleep disorder such as idiopathic-hypersomnia, repeating hypersomnia, the true hypersomnia, narcolepsy, a disorder associated with periodic hypermodernity in sleep syndrome sleep apnea, disorders of circadian rhythm, chronic fatigue syndrome, disorders of REM sleep, senile insomnia and idiopathic insomnia, repetitive insomnia and true insomnia caused by failure to comply with the requirements sanitary norms sleep working at night, diseases of the Central and peripheral nervous system such as bulimia, emotional disorder, depression, anxiety, delirium, dementia, schizophrenia, attention deficit disorder/hyperactivity disorder, memory disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, reduced cognitive ability, disturbance of motor function, paresthesias, dysosmia, epilepsy, immunity to morphine, drug addiction and alcoholism.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

The invention relates to compounds of formula (I)

where NRR1attached a 5 - or 6-position of the ring properidine; R is hydrogen, C1-C4-alkyl, or COR2; R1represents (CH2)nAr, CH2CH=CHAr, or CH2With?CAr; n is 0-3; a is N or NO; Ar represents a 5 - or 6-membered aromatic or heteroaromatic ring which contains 0 to 4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom; or an 8-, 9 - or 10-membered condensed aromatic or heteroaromatic cyclic system containing 0-4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom, any of which may be optionally substituted by 1-2 substituents independently selected from halogen, trifloromethyl or1-C4-alkyl; R2represents hydrogen; C1-C4-alkyl; C1-C4-alkoxy or phenyl ring, optionally substituted by 1-3 of the following substituents: halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, CO2R5, -CN, -NO2, -NR3R4or-CF3; R3, R4and R5can be hydrogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, -CN, -NO2or-CF3; to their enantiomers and pharmaceutically acceptable salts

The invention relates to new biologically active compounds, namely spiroheterocyclic heterocyclic compounds of the formula I

< / BR>
where n is 0 or 1;

m is 0 or 1;

p is 0;

X represents oxygen or sulfur;

Y represents CH, N or NO;

W represents oxygen or H2;

And represents N or C(R2);

G represents N or C(R3);

D represents N or C(R4)

provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;

R1represents hydrogen or C1-C4-alkyl;

R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D southwest a hydrogen, WITH1-C4-alkyl, C(O)R7C(O)OTHER8WITH(O)OR9, SO2R10, -NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond; j is 2 and k is 0 to 2;

R7, R8, R9, R10and R11are independently C1-C4-alkyl, NH2, aryl or its enantiomer,

and their pharmaceutically acceptable salts, and methods for their preparation, intermediate compounds and pharmaceutical compositions, which has an activating effect against nicotine7-acetylcholine receptors and can be used for the treatment and prevention of psychotic disorders and disorders of the type of lower intellectual

The invention relates to a method for producing derivatives 4A,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, in the case neobmennoe alkyl group; at least one lower, if necessary, the branched alkinoos group; at least one lower, if necessary branched alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, the nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, halides

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

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