Pyrazines applicable as delta-opioid receptor modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

 

CROSS-REFERENCE TO RELATED INVENTIONS

This application will require priority is claimed to provisional patent application U.S. No. 61/256392, filed October 30, 2009, the contents of which are fully incorporated herein by reference.

The SCOPE of the INVENTION

The present invention relates to the creation of new opioid receptor modulators of formula (I). The present invention also relates to methods of making such compounds, pharmaceutical compositions containing such compounds and to their use for the treatment of disorders modulated opioid receptors.

BACKGROUND of the INVENTION

The term "opiate" is used to refer to a pharmacologically active alkaloids derived from opium, such as morphine, codeine, and many semi-synthetic analogues of morphine. After separation of the peptide compounds with morphine like action was introduced the term "opioid" for the generalized notation of any drug with morphine like action. In the class of opioids include various peptides with morphine like action, such as endorphins, enkephalins and dynorphin. However, in some sources, the term "opiate" is used in a generic sense, and in such contexts, the term "opiate" and "drug" are used interchangeably. In addition, the term "opioid" also of note is intended to refer to antagonists of morphine-like drugs as well as for characterizing the receptors or binding sites that can interact with these agents.

Opioids are widely used as analgesics, but they can also have many other pharmacological actions. Morphine and related opioids have the most pronounced effect on the Central nervous and digestive system. Action spectrum is quite broad and includes analgesic effect, drowsiness, mood changes, depression of respiratory functions, dizziness, distraction, restlessness, skin itching, increased pressure in the biliary tract, inhibition of motility of the gastrointestinal tract, nausea, vomiting, and changes in the endocrine and autonomic nervous systems.

When administered to patients with pain morphine in therapeutic dosages, there is a decrease in the intensity of pain, reduction associated with pain, discomfort or complete disappearance of pain. In addition to alleviating a pathological condition in a number of patients also feels a sense of euphoria. However, with the introduction of morphine is recommended to achieve the analgesic effect of dosages for patients who are not suffering from pain, the effect is not always favorable, often marked nausea and even vomiting. It is also possible drowsiness, inability to concentrate, decreased mental alertness, apathy is, decreased physical activity, decreased visual acuity and lethargy.

With opioid receptors may contact two classes of opioid molecules: these opioid peptides (e.g., enkephalins, dynorphin and endorphins) and alkaloid opiates (e.g. morphine, Etorphine, diprenorphine and naloxone). After the first demonstration of the binding sites of opiates (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014) for the classification of multiple opioid receptors were used differences in pharmacological and physiological actions of peptide analogues of opioids and alkaloid opiates. Respectively, were described in three molecular and pharmacological against different types of opioid receptors: Delta, Kappa and mu. Moreover, in each type, it is also common to distinguish subtypes (Wollemann, M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature(1977) 267:495-499).

Opioid receptors these three types have a common functional mechanisms at the cellular level. For example, opioid receptors cause inhibition of adenylate cyclase and neurotransmitter secretion by activation of potassium channels and inhibition of Ca2+channels (Evans, C. J., In: Biological Basis of Substance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford University Press (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975) 72:3092-96). Although these options the regional mechanisms are the same, behavioral manifestations selective to the type of receptor preparations vary considerably (Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such differences may be partly associated with the anatomical localization of receptors of different types.

Receptor type Delta distributed in the Central nervous system of mammals is more discrete than the receptor type mu and Kappa, their high concentration in the amygdala body, striped body, black substance, the olfactory bulb, olfactory tubercle, hippocampal formation and cerebral cortex (Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). Notable is the complete absence of opioid receptors, including Delta-opioid receptors in the cerebellum of the rat.

There is a continuing need for the development of new modulators of the Delta-opioid receptor for use as analgesics. There is also a need to develop selective agonist Delta-opioid receptor for use as analgesics with reduced side effects. In addition, there is a need for antagonists of the Delta-opioid receptor for use as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, agents for the treatment of urological conditions and disorders of the reproductive system, drugs for Les the program alcohol and drug addiction, agents for treating gastritis and diarrhea, agents for the treatment of cardio-vascular system and agents for the treatment of respiratory diseases with reduced side effects.

There is a continuing need for the development of new modulators of opioid receptors for use as analgesics. There is also a need to develop agonists Delta - and mu-opioid receptor for use as analgesics with reduced side effects. There is also a need for the development of agonists of mu-opioid receptor for use as analgesics with reduced side effects in the treatment of pain, modulation of immune function, the treatment of gastro-esophageal reflux and cough. In addition, there is also a need for agonist Delta-opioid receptor for use as anesthetic agents, agents for the treatment of respiratory diseases, agents for treating cardiovascular system, agents for the treatment of urological disorders and agents for the treatment of neurological and psychiatric conditions. There is also a need to develop agonists double action for Delta - and mu-opioid receptors.

BRIEF description of the INVENTION

The present invention relates to a compound of formula I

g is e

R1selected from the group consisting of

i) phenyl, optionally having one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, chlorine, and fluorine;

ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4of alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; and

iii) pyrimidine-5-yl;

or R1does not necessarily represent methoxymethyl, when Y represents ethinyl;

Y represents ethinyl or communications;

R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, optionally substituted stands, with phenyl optionally has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

or R2represents phenyl, having one C1-4alkylcarboxylic or 1H-imidazol-1-ilen Deputy;

X represents O or CH2;

L is absent, and R3is a 4-aminocyclohexanol, or L represents a methylene, and R3selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-aminoeth-1-yl; and

p> iii) 1-aminocyclopent-1-yl;

or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil, optionally substituted 4-C1-4by alkyl;

as well as its enantiomers, diastereomers, solvate and a pharmaceutically acceptable salt.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of formula (I) or its pharmaceutically acceptable salt.

Also in the present invention the methods of obtaining pharmaceutical compositions, comprising mixing the compounds of formula (I) and a pharmaceutically acceptable carrier.

The present invention also relates to methods of treating or alleviating the symptoms of disorders modulated opioid receptors. In particular, the methods of the present invention is directed to the treatment or relief of symptoms of disorders modulated opioid receptors, including but not limited to, inflammatory pain, pain, mediated by the Central nervous system, pain, mediated peripheral system, visceral pain, pain associated with structural disorders, cancer pain, pain associated with soft tissue injury, pain associated with advanced disease, neuropathic pain and acute pain associated with acute injury is, acute pain associated with trauma, acute pain associated with surgery, chronic headaches, chronic pain with neuropathic conditions, chronic pain in post-stroke conditions and chronic pain in migraine.

The present invention also proposed methods for obtaining such compounds and pharmaceutical compositions and the pharmaceutical products manufactured on the basis of them.

For the purposes of the present document, the following terms have the following definitions:

"Ca-b"(whereaandbare integers) refers to a radical containing fromatobcarbon atoms, inclusive. For example, C1-3denotes a radical containing 1, 2 or 3 carbon atoms.

In relation to substituents, the term "independently" means that when the opportunity to enter more than one of such substituents introduced substituents may be the same or different. Thus, the specified number of carbon atoms (for example, C1-8) independently represents the number of carbon atoms in the alkyl or cycloalkyl fragment or the alkyl portion of a larger substituent in which name is the root of "alkyl".

Unless specifically provided otherwise, the term "alkyl" as used herein alone or as part of the name of the Deputy,refers to linear or branched carbon chain, containing from 1 to 8 carbon atoms, or any number of carbon atoms within the indicated range. Used in this application, the term "alkoxy" refers to the Deputy type-O-alkyl, where "alkyl" is used in the sense indicated above. Similarly, used in this application the terms "alkenyl" and "quinil" refers to linear or branched carbon chain containing from 2 to 8 carbon atoms or any number of carbon atoms within the indicated range, with Alchemilla chain contains at least one double bond in the chain, and Alchemilla chain contains at least one triple bond in the chain. Alkyl and CNS circuits may be substituted on the carbon atom. The substituents containing several alkyl groups, for example (C1-6alkyl)-2-amino-C1-6, alkyl group dialkylamino can be the same or different.

The term "halogen-substituted alkyl" refers to saturated the alkyl radical is branched or linear chain, obtained by abstraction of one hydrogen atom from the parent alkane molecules. Maternal alkyl chain contains from 1 to 8 carbon atoms, 1 or more hydrogen atoms are replaced by halogen atoms, up to and including replacement of all hydrogen atoms by halogen atoms. Preferred halogenated the data alkyl groups include cryptomelane alkali, deformalization alkali and perftoralkil, more preferred fluorinated alkali include trifluoromethyl and deformity. The term "halogen-substituted alkoxy" refers to a radical derived from a halogen-substituted alkyl radical by its accession to the oxygen atom, the oxygen atom has one free valence for attachment to the parent structure.

Used in this application, the term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon containing from 3 to 20 carbon atoms (preferably from 3 to 14 carbon atoms). Examples of such groups are, inter alia, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and substituted. The term "cycloalkyl also includes cycloalkyl ring condensed with a benzene ring (benzoannelirovannykh cycloalkyl) or 5 - or 6-membered heteroaromatic ring (containing one of the atoms O, S or N and optionally one nitrogen atom) with the formation of heteroatomcontaining of cycloalkyl.

The term "heterocyclyl" refers to a 5-10 membered non-aromatic monocyclic ring in which from 1 to 4 members represent nitrogen atoms, or 5-10-membered non-aromatic monocyclic ring in which none, one, and and two members are nitrogen atoms and up to two members represent the atoms of oxygen or sulfur, when this ring optionally contains from zero to two unsaturated bonds. The term "heterocyclyl" includes a heterocyclic ring condensed with a benzene ring (benzoannelirovannykh heterocyclyl), 5 - or 6-membered heteroaromatic ring (containing one of O, S or N and optionally one nitrogen atom), a 5-7 membered cycloalkyl or cycloalkenyl ring, 5-7-membered heterocyclyl ring, in a higher sense, except for the condensed ring or a condensed one carbon atom cycloalkyl, cycloalkenyl or heterocyclyl ring with the formation of sproramentu. For compounds that are the subject of the present invention, the ring carbon atoms that form heterocyclyl ring is fully saturated. Other compounds in accordance with the present invention may be partially saturated heterocyclyl ring. In addition, the term "heterocyclyl also includes heterocyclic ring with the bridge, forming a bicyclic ring. Preferred partially saturated heterocyclyl ring can have from one to two double bonds. Such compounds are not considered fully aromatic and are not included in the concept of heteroaromatic compounds. Examples heterocyclyl groups, in addition to proces is, include pyrrolyl (including 2H-pyrrole, 2-pyrrolyl or 3-pyrrolyl), pyrrolidinyl, 2-imidazolyl, imidazolidinyl, 2-pyrazoline, pyrazolidine, piperidine, morpholine, thiomorpholine and piperazinil.

Used in this application, the term "aryl" refers to an unsaturated aromatic monocyclic ring of 6 carbon atoms or unsaturated polycyclic aromatic ring of 10-14 carbon atoms. Examples of such aryl rings, inter alia, include phenyl, naphthalenyl and anthracene. Preferred aryl groups for the practical implementation of the present invention are phenyl and naphthalenyl.

Used in this application, the term "heteroaryl" refers to 5 - or 6-membered aromatic ring, such ring consists of carbon atoms and contains at least one heteroatom. Corresponding heteroatoms include nitrogen, oxygen or sulfur. In the case of 5-membered ring heteroaryl ring contains one nitrogen atom, oxygen or sulfur, and may also contain up to three additional nitrogen atoms. In the case of 6-membered rings specified heteroaryl ring may contain one to three nitrogen atoms. In the case where the specified 6-membered ring containing three nitrogen atom, two nitrogen atoms are adjacent positions. The term "heteros is aryl includes heteroaryl ring, condensed with benzene ring (benzoannelirovannykh heteroaryl), 5 - or 6-membered heteroaryl ring (containing one of O, S or N and optionally one nitrogen atom), a 5-7 membered cycloalkyl ring or a 5-7 membered heterocyclyl ring, in a higher sense, except for the condensed ring). Examples of heteroaryl groups are, inter alia, include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, condensed heteroaryl groups include indolyl, isoindolyl, benzofuran, benzothiazyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzisoxazole, benzothiadiazoles, benzotriazolyl, honokalani, chinoline, ethenolysis or hintline.

The term "arylalkyl" denotes an alkyl group, substituted aryl group (for example, benzyl, phenetyl). Similarly, used in this application, the term "Allakaket" denotes CNS group, substituted aryl group (e.g., benzyloxy).

Used in this application, the term "halogen" refers to fluorine, chlorine, bromine and iodine. Substituents, substituted by halogen several provisions are replaced in such a way as to obtain the result of a consistent connection.

The term "oxo" as used alone or in the name of the Deputy refers to the fragment O= associated with the carbon atom or sulfur. For example, phthalimide and saccharin are examples of compounds with oxo-substituents.

If the term "alkyl" or "aryl" or either of formed from these roots prefixes are in the name of a substituent (for example, arylalkyl, alkylamino), it is assumed that all of the limitations described above for the terms "alkyl" and "aryl" also apply to derived names. Specifies the number of carbon atoms (for example, C1-C6) applies independently to the number of carbon atoms in the alkyl portion or the alkyl portion of a larger substituent in which name the root of "alkyl" is used as prefix. For alkyl and CNS substituents specified number of carbon atoms includes all of the independent members of the above range separately, as well as any combination of ranges in the specified bounds. For example, C1-6alkyl includes individually methyl, ethyl, propyl, butyl, pentyl and hexyl, as well as their podnominatsii (for example, C1-2C1-3C1-4C1-5,C2-6C3-6C4-6C5-6C2-5and so on).

Used in this application, the term "patient" means an animal, preferably a mammal, is more preferably human, which is the object of treatment, observation or experiment.

Used in this application, the term "therapeutically effective amount" means such amount of active compound or pharmaceutical agent that causes or biologically significant medical response system tissue, animal or human body, expected by the researcher, veterinarian, medical doctor or other Clinician, which includes alleviation of the symptoms of the disease or pathological state, whose treatment.

Used in this application, the term "drug" refers to any product, which consists of these components in the specified amounts, as well as any products that can be obtained, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

Used in this application, the term "acyl" refers to alkylcarboxylic deputies.

Within this document, first indicate the end part of the described side chain, and then transfer a functional group in the direction of the point of connection of the Deputy. For example, the Deputy of the "phenyl(C1-6)alkylaminocarbonyl(C1-6)alkyl" refers to a group of the following formula:

If not specified, it is assumed that the definition is of any substituent or variable at a given position in a molecule does not depend on the corresponding definitions in other parts of the molecule. It is assumed that substituents and substitution procedure, compounds of formula (I) can be selected by the person skilled in the art to provide chemically stable compounds that can be easily synthesized by known in this field techniques, as well as by the method described in this document.

For the purposes of the present invention, the term "modulating opioid receptor" is used to denote the state-dependent modulation of opioid receptor, including, without limitation, mediating opioid receptor.

DETAILED description of the INVENTION

Embodiments of the present invention include compounds of formula (I)

where

a) R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy, fluorine, chlorine and cyano; and

iii) pyrimidine-5-yl;

or R1does not necessarily represent methoxymethyl, when Y represents ethinyl;

b) R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and

iii) pyrimidine-5-yl;

c) R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, with optional ar is n Deputy, selected from the group comprising methoxy, and cyano; and

iii) pyrimidine-5-yl;

d) Y is a bond;

e) R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, optionally substituted stands, with phenyl optionally has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;

f) R2represents phenyl, optionally having one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;

g) R2represents phenyl, optionally having one Deputy selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

h) X represents O;

i) L is a methylene, and R3selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-aminoeth-1-yl; and

iii) 1-aminocyclopent-1-yl;

or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;

as well as any combination of variants of the above embodiments (a)-(i) provided that it is assumed that the combination of which must be combined in various embodiments of the same substituent, should be excluded; and enantiomers, diastereomers, solvate and a pharmaceutically acceptable salt.

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy, fluorine, chlorine and cyano; and

iii) pyrimidine-5-yl;

or R1does not necessarily represent methoxymethyl, when Y represents ethinyl;

Y represents a bond or ethinyl;

R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, optionally substituted stands, with phenyl optionally has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, is aftermatket, triptoreline and hydroxy;

or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;

X represents O or CH2;

L is absent, and R3is a 4-aminocyclohexanol, or L represents a methylene and R3selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-aminoeth-1-yl; and

iii) 1-aminocyclopent-1-yl;

or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;

as well as their enantiomers, diastereomers, solvate and a pharmaceutically acceptable salt.

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and

iii) pyrimidine-5-yl;

Y represents a bond;

R2represents phenyl, optionally having one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;

X pre is is O;

L represents a methylene and R3selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-aminoeth-1-yl; and

iii) 1-aminocyclopent-1-yl;

or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;

as well as their enantiomers, diastereomers, solvate and a pharmaceutically acceptable salt.

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group consisting of

i) phenyl;

ii) pyridinyl, optional with one Deputy, selected from the group comprising methoxy, and cyano; and

iii) pyrimidine-5-yl;

Y represents a bond;

R2represents phenyl, optionally having one Deputy selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;

X represents O;

L represents a methylene and R3selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-aminoeth-1-yl; and

iii) 1-aminocyclopent-1-yl;

or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;

as well as their enantiomers, diastereomers, solvate and a pharmaceutically acceptable salt.

Additional variant of implementation of the present invention includes compounds of formula (I)

selected from the group consisting of:

compounds in which R1represents a 6-methoxypyridine-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyridin-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyridin-3-yl, Y is ethinyl, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1is methoxymethyl, Y represents ethinyl, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X is O, L PR is dstanley a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-ethylphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents benzo[1,3]dioxol-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 3-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 2-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

connections, R 1represents pyrimidine-5-yl, Y is a bond, R2is a 3-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 2-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 3-methylcarbamoylmethyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents a 4-(1H-imidazol-1-yl)phenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 3-hydroxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyridin-3-yl, Y is a bond, R2pre is is a 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-cyanophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminoeth-1-yl; (1S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminoeth-1-yl; (1S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3presented yet a 1-aminocyclopent-1-yl;

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminocyclopent-1-yl;

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 3-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 2-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1is a-cyano-3-yl, Y represents a bond, R2is a 4-cyanomethylene, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents a 6-methylpyridin-3-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-deformational, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X is O, and R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazine-1-yl;

compounds in which R1represents pyridin-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X is O, and R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazine-1-yl;

compounds in which R1represents pyrimidine-5-yl, Y is the second link, R2is benzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents a 2,3-dihydrobenzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X is O, L is absent, and R3represents TRANS-4-aminocyclohexanol;

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X is O, L is absent, and R3represents CIS-4-aminocyclohexane;

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-trifloromethyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-ethylphenyl, X represents O, L represents soboyejo, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 3-hydroxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is benzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents indol-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 2-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 3-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)

and farmatsevticheskii salt.

For medical purposes salts of compounds of formula (I) are non-toxic "pharmaceutically acceptable salts". However, to obtain the compounds of formula (I) or their pharmaceutically acceptable salts can be used, and other salts. The objectives of the present invention pharmaceutically acceptable salts of compounds of formula (I) include salts of joining acids, for example, can be obtained by mixing a solution of one of the compounds that are the subject of the present invention, with a solution of a pharmaceutically acceptable acid, for example hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

In addition, when the compounds of formula (I) are acid fragment, the appropriate pharmaceutically acceptable salts may include alkali metal salts, for example sodium or potassium salts, alkaline earth metal, e.g. calcium or magnesium salts, and also salts with appropriate organic ligands, e.g. Quaternary ammonium salts. Thus, typical examples of pharmaceutically acceptable salts include salts include acetates, bansilalpet, benzoate, bicarbonates, bisulfate, bitarts is you, borates, bromides, calcium edetate, camsylate, carbonates, chlorides, clavulanate, citrates, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodides, isothionate, lactates, lactobionate, laurate, malate, maleate, mandelate, mesylates, methylbromide, methylnitrate, methylsulfate, Makati, napsylate, nitrates, N-methylglucamine ammonium salt, oleates, pamoate (embonate), palmitate, Pantothenate, phosphates/diphosphate, polygalacturonate, salicylates, stearates, sulfates, subacetate, succinate, tannate, tartratami, teoclate, tozilaty, triethiodide and valerate.

Typical examples of acids and bases that can be used to obtain pharmaceutically acceptable salts, include the following: acids, including acetic acid, 2,2-dichloracetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzosulfimide acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic, (+)-(1S)-camphor-10-acid, capric acid, Caproic acid, Caprylic acid, cinnamic acid, citric acid, reklamowy acid, dodecylthio acid, ethane-1,2-disulfo is islote, econsultation, 2-hydroxyethanesulfonic, formic acid, fumaric acid, galactarate acid, entityname acid, glucoheptonate acid, D-gluconic acid, D-glucoronosyl acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-almond acid, methanesulfonate, naphthalene-2-acid, naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, Orotava acid, oxalic acid, palmitic acid, pambou acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, ticinobuy acid, p-toluensulfonate and undecylenoyl acid;

and bases, including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, Ethylenediamine, N-methylglucamine, geranamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydro is led, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds of formula (I). Typically, these prodrugs are functional derivatives of the compounds that are the subject of the present invention, whichin vivoturn into the desired connection. Thus, in embodiments implementing the present invention related to methods of treatment, the term "introduction" covers the treatment of various diseases mentioned in the description of the compounds that are the subject of the present invention or compounds, not specified in the present description, but converted into the specified connectionin vivoafter its introduction to the patient. Conventional procedures for the selection and preparation of appropriate derivatives proletarienne forms are described, for example, in Design of Prodrugs, Ed. H. Bundgaard, Elsevier, 1985.

If the connection in accordance with the variants of implementation of the present invention have at least one chiral center, they may accordingly exist in the form of enantiomers. In those cases where the compounds possess two or more chiral centers, they may additionally exist in the form of diastereoisomers. You must understand that all such isomers and mixtures thereof are the scope of the present invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and as such they fall under the scope of the present invention. In addition, some of the compounds may form a solvate with water (hydrates) or common organic solvents, such solvate also fall within the scope of the present invention. Specialists in this field understand that used in this application, the term "connection" is deemed to include solvated compounds of formula I.

In those cases, when the processes of producing compounds in accordance with the variants of implementation of the present invention lead to the formation of a mixture of stereoisomers, these isomers can be isolated using standard methods such as preparative chromatography. The compound can be obtained in the form of racemates, or individual enantiomers may be obtained in the enantiospecific synthesis or by separation. The connection can, for example, be separated into its constituent enantiomers by using standard methods, such as the formation of diastereomeric couples through the formation of salts with optically active acids, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-VIN is acamana acid, followed by fractional crystallization and recovery of the free base. Compounds can also be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral partner. In another embodiment, the present invention such compounds can be separated using chiral columns for HPLC.

One way of implementing the present invention relates to compositions containing (+)-enantiomer of compounds of formula (I), with the specified composition essentially contains (-)-isomer of the compounds. In this context, the phrase "not substantially contain" means the content of (-)-isomer and less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1%, calculated as follows:

Another variant of implementation of the present invention is a composition containing (-)-enantiomer of compounds of formula (I), with the specified composition essentially contains (+)-isomer of the compounds. In this context, the phrase "not substantially contain" means the content of (+)-isomer and less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and the school more preferably less than 1%, calculated as follows.

.

During the process of producing compounds in accordance with the variants of implementation of the present invention may be necessary to protect sensitive or reactive groups on any of the examined molecules. For these purposes, can use standard protective group, for example, described in the publications byProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Presc, 1973; and T. W. Greene &P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Introduced protective groups can be subsequently removed at any convenient stage with the use of well-known specialists of ways.

Although forming the subject of the present invention compounds (including pharmaceutically acceptable salts and pharmaceutically acceptable solvate) can be administered to the patient separately, as a rule, they will be introduced in the form of a mixture with a pharmaceutically acceptable carrier, auxiliary substance or diluent selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, specific embodiments of the present invention relate to pharmaceutical compositions containing the compounds of formula (I) and one or more pharmaceutically acceptable carriers, excipients or rabbanites the th.

As an example, in the pharmaceutical and veterinary compositions in accordance with the variants of implementation of the present invention the compounds of formula (I) may be present in the form of a mixture with any (and) the corresponding (s), binder (s) substance (s), lubricant (s) substance (s), suspenders (s) substance (s) that cover (s) substance (s) and/or solubilizers (s) substance (s).

Tablets or capsules with compositions can be administered in one or two or more at one time, depending on the situation. These compounds can also be used in the form of compositions with delayed release.

In another embodiment of the present invention the compounds of formula (I) can be used in inhalations (intratracheal or intranasal) or in the form of suppositories or pessaries, and can also be applied topically in the form of lotions, solutions, creams, ointments or powders. For example, the described compounds can be introduced into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. You can also enter in a concentration of from 1 to 10 wt%. in the composition of ointments, having as a basis a white wax or white soft paraffin and also contains the necessary stabilizers and preservatives. An alternative method of transdermal injection is the use of layers of who I am.

For some applications, preferably oral administration of the compositions in the form of tablets containing such excipients as starch or lactose, or in capsules or pills, in pure form or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.

Composition (as well as connections separately) you can also enter parenterally by injection, for example, by vnutrikavernozno, intravenous, intramuscular, subcutaneous, intradermal or spinal injection. In this case, the composition will contain the corresponding carrier or diluent.

The best form of compositions for parenteral injection is sterile aqueous solution, which may also include other components, for example enough salts or monosaccharides to obtain isotonic blood diluent.

For transbukkalno or sublingual route of administration of the composition can enter the patient in the form of tablets or lozenges made by standard methods.

As an additional example, the pharmaceutical and veterinary compositions containing as an active ingredient one or more compounds of the formula (I) can be obtained by mixing the compound Il is compounds with a pharmaceutical carrier in accordance with standard pharmaceutical techniques. The media can have different shapes depending on the intended route of administration (e.g. oral, parenteral, and so on). Thus, for liquid oral dosage forms such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring, preservatives, stabilizers, dyes and so on; for solid oral dosage forms such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulomatous agents, lubricants, binders, additives to improve raspadaemosti tablets etc., Solid oral dosage forms can also be coated from substances such as sugar, or may be enteric-coated shell to change the principal place of absorption and dissolution of drugs. For parenteral administration the carrier, as a rule, consists of sterile water, at the same time to improve the solubility or conservation can be added to other ingredients. Injection input suspensions or solutions can also be manufactured using water media with appropriate additives.

A therapeutically effective amount of compounds of formula (I) or enclosing the pharmaceutical composition is a range of dozer the wok from about 0.1 to about 3000 mg, more specifically from about 1 to about 1000 mg, more specifically from about 10 to about 500 mg of the active component at the frequency of the reception from approximately 1 to 4 times per day for an average (70 kg) person, although the person skilled in the art will understand that a therapeutically effective amount of compounds that are the subject of the present invention will vary depending on the treatment of any condition is performed.

For oral administration the pharmaceutical composition is preferably used in the form of tablets containing 0,01, 10,0, 50,0, 100, 150, 200, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient receiving treatment.

The compounds of formula (I) can mainly be administered in a single daily dose or the total daily dosage may be administered multiple doses twice, thrice or four times a day. Moreover, the compounds of formula (I) can be administered with the help of local use of appropriate intranasal vehicles, or via transdermal skin patches well known to specialists in this field.

The specialist in this area it is also clear that a therapeutically effective dose of the active compounds of the formula (I) or containing pharmaceutical HDMI the Nations will vary depending on the desired effect. Therefore, the optimal prescribed dose can be easily defined and vary depending on exactly which connection to use, method of administration, strength of the drug and the severity of the pathological condition. In addition, factors associated with individual treatment of the patient, such as age, weight, diet, time of administration, should also be taken into account when adjusting the dose to achieve the desired therapeutic level. So the above dosages are exemplary of some average case. Of course, in some cases, require the use of higher or lower range of doses, and such cases are included in the scope of the present invention.

The compounds of formula (I) can be entered for the patient in the form of any of the above compositions and any of the above-described mode of taking or using any generally accepted in the field of compositions and modes of reception in all cases, when the needy in this patient required the introduction of the compounds of formula (I).

Examples of pain, falling within the scope of the present invention, inter alia, include inflammatory pain, pain, mediated by the Central nervous system, pain, mediated peripheral system, visceral pain, pain caused by structural the disorders or injuries of the soft tissues, pain associated with advanced disease, neuropathic pain and acute pain such as pain associated with acute lesions, trauma or surgery and chronic pain, such as chronic headaches and chronic pain, called neuropathic conditions, post-stroke conditions, cancer and migraine.

The compounds forming the subject of the present invention can also be used as immunosuppressants, antiinflammatory agents, agents for the treatment and prevention of neurological and psychiatric conditions such as depression and Parkinson's disease, agents for the treatment of urological conditions and disorders of the reproductive system, such as urinary incontinence and premature ejaculation, drugs for the treatment of alcohol and drug abuse, agents for treating gastritis and diarrhea, agents for the treatment of cardio-vascular system and cardiotoxin agents and agents for the treatment of respiratory diseases.

The compounds forming the subject of the present invention, applicable in the treatment of pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, headache, toothache, burn, sunburn, snake bite (in particular the bite of a poisonous snake, spider bite, insect sting, neurogenic bladder p is Siri, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulite, causalgia, neuritis of the sciatic nerve, neuralgia in the temporomandibular joint, peripheral neuritis, polyneuritis, stump pain, phantom pain, post-operative intestinal obstruction, cholecystitis, pain after mastectomy, neuropathic pain in the mouth syndrome Charcot, reflex sympathetic dystrophy, Guillain-Barre syndrome, paresteticheskih meralgia syndrome burning sensation in the mouth, cluster headache, bilateral peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, optic neuritis, postpuberty neuritis, migrating neuritis, segmental neuritis, neuritis Gombo, neurons, cervico-brachial neuralgia, cranial neuralgia, geniculate neuralgia site, neuralgia glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, neuralgia in the mammary glands, neuralgia Morton syndrome nourishing nerve, occipital neuralgia, erythromelalgia, neuralgia of Cloudera, sphenopalatine neuralgia site, supraorbital neuralgia nerve, neuralgia medieva nerve, inflammatory diseases Kish is nick, irritable bowel syndrome, sinus headache, tensiona headache, cramping, childbirth, menstrual pain, and cancer.

In respect of the application of these compounds in treating diseases and pathological conditions, similar to the above, a therapeutically effective dosage can be determined by experts in the field through the use of standard models for animals. A therapeutically effective dosage of the compounds of formula (I) when used in such treatment is in the range from about 0.001 to about 300 mg/kg/day. More specifically, the specified range is from approximately 0.5 to approximately 5.0 mg/kg of body weight per day, more particularly from about 1.0 to about 3.0 mg/kg of body weight per day. Connections can be assigned to reception mode from 1 to 4 times a day.

GENERAL METHODS of SYNTHESIS

Typical examples of the compounds of the present invention can be synthesized in accordance with the General synthesis methods described below and shown in the following schemes and examples. As the diagrams illustrate, the present invention should not be interpreted as limited by the chemical reactions and conditions described in the diagrams. Various substances are listed on the schemes used in Arah, are commercially available or can be obtained by methods well known to specialists in this field. The fragments correspond to the description given in this document.

In the present description, in particular in the schemes and the examples, the following abbreviations are used:

AcClacetylchloride
AcOHglacial acetic acid
aq.water
Bn or Bzlbenzil
conc.concentrated
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DCMdichloromethane
DMFN,N-dimethylformamide
DMSOthe sulfoxide
dppf1,1'-bis(diphenylphosphino)ferrocene
ERIEelectrospray ionization
EtOActhe ethyl acetate
EtOHethanol
hhour (s)
HATUO-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyleneglutaric
HPLChigh performance liquid chromatography
Memethyl
MeOHmethanol
MHzMHz
minminutes
GHSDliquid chromatography medium pressure
MSmass spectrometry
NMRnuclear magnetic resonance
n/anot investigated
Phphenyl
Pd/Cpalladium on activated carbon
Ph3Ptriphenylphosphine
PP polyphosphoric acid
rtroom temperature
TBDMStert-butyldimethylsilyl
TEA/Et3Nthe triethylamine
TFAtriperoxonane acid
THFtetrahydrofuran
TLCthin-layer chromatography
TMStetramethylsilane was or trimethylsilyl.

In the diagram A shows the formation of compounds of formula I-A in which X is O, Y is a bond, L is a methylene, and R3is pyrrolidin-2-yl.

Connection A1 is available for sale or can be obtained by known methods described in the scientific literature. The amino group of compound A1 can be alkylated by reductive amination using an aldehyde of the formula A2, where P is a standard protective group for the amino group in the presence of a source of the hydride ion with the formation of the compounds of formula A3. The group R1connection is by means of formula (I) can be entered catalyzed by palladium reaction cross-combinations using the appropriately substituted boronic acid or a complex ester (A4) in the presence of an appropriate base, such as potassium carbonate. These reactions may be carried out in the presence or in the absence of additional ligands for palladium, which, if used, can include one or more of the following compounds include triphenylphosphine, tri-o-tolylphosphino, three(tert-butyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, bis[2-(diphenylphosphino)phenyl]ether, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, hexaflurophosphate 1-butyl-3-methylimidazole, etc. Possible solvents include ethanol, THF, DMF, toluene, DME, dioxane and benzene. The compounds of formula A5 can be bromirovanii in the presence of an appropriate brainwashes agent such as NBS, obtaining the compounds of formula A6. Reaction with an appropriately substituted alcohol of formula A7, optionally in the presence of a base, allows to obtain a compound of formula A8. Removing the protective group from the amino group (P) using well-known specialists of ways gives compound of formula (I).

In scheme B presents an alternative method of preparing compounds of formula I-A in which X is O, Y is a bond, L is a methylene, and R3is pyrrolidin-2-yl.

Connection A1 is available for sale or can be obtained by known methods described in the scientific literature. Connection Voget to be introduced into reaction with a compound of formula A7, not necessarily in the presence of a base, to obtain the compounds of formula B2. Reductive amination of the compounds of formula A2 in the presence of a source of the hydride ion, such as triacetoxyborohydride sodium, allows to obtain a compound of formula B3. The compound of formula B3 can be introduced into the reaction cross-combination with boric acid or ester of formula A4, as described for scheme A, to obtain the compounds of formula B4. Removing the protective group from the amino group of compounds of formula B4 gives compound of formula (I).

In the diagram C shows the method of obtaining compounds of formula I-C in which X represents O; Y represents a bond, and R3together with L and the nitrogen atom is attached to L, combined with education piperazinilnom rings.

The connection C1 is available for sale or can be obtained by known methods described in the scientific literature. Connection C1 can be introduced in the reaction of aromatic nucleophilic substitution with a compound of formula A7, optionally in the presence of a base, to obtain the compounds of formula C2. By heating the compounds of formula C2 with an amine of the formula C3 can be obtained compound of formula C4. The compound of formula C4 can also be obtained by treating compound of formula C2 with the amine of the formula C3 in the presence of a palladium catalyst and a suitable the x ligands. Aromatic bromination using brainwashes agent such as NBS, allows to obtain the compound of formula C5. Bromide of the formula C5 can be introduced into the reaction catalyzed by palladium cross-combination, as described in this application, to obtain the compounds of formula C6. Removing the protective group from the amino group gives compound of formula I-C.

In scheme D describes the method for obtaining compounds of formula I-D in which X represents CH2, Y is a bond, L is a methylene, and R3is pyrrolidin-2-yl.

Compound B1 can be alkylated using the appropriately substituted R2-methylaniline formula D1 in an aprotic solvent, such as THF, in the presence of zinc chloride and a palladium catalyst to obtain the compounds of formula D2. Reductive alkylation of compounds of formula A2 allows to obtain a compound of formula D3. R1can be entered using catalyzed by palladium reaction cross-combination with the compound of the formula A4, as described in this application, to obtain the compounds of formula D4. Removing the protective group from the amino group gives compound of formula I-D.

In scheme E describes the method for obtaining compounds of formula I-E in which X represents O, Y represent the possessing ethinyl, L represents a methylene, and R3is pyrrolidin-2-yl.

The compound of formula B3 can be introduced into the reaction cross-combination with a commercially available R1-replaced by acinom formula E1 in the presence of a palladium catalyst and copper iodide, and organic bases such as TEA, obtaining the compounds of formula E2. Standard removing the protective group from the amino group allows to obtain the compound of formula (I)-E.

In scheme F presents a method of obtaining compounds of formula I-F in which X represents O; Y represents ethinyl, L represents CH2and R3is pyrrolidin-2-yl.

The compound of formula B3 can be introduced into the reaction cross-combination with TMS protected by Alcina formula F1 in the presence of a palladium catalyst and copper iodide, and organic bases such as TEA, obtaining the compounds of formula F2. Removal of the TMS group with a source of fluoride ion, such as TBAF, allows to obtain a compound of the formula F3. The compound of formula F3 can be introduced into the reaction cross-combination with R1the bromide or iodide in the presence of a palladium catalyst and copper iodide, and organic bases such as TEA, obtaining the compounds of formula F4. Standard removal of the protective group with whom aminogruppy allows to obtain the compound of formula (I)-E.

In scheme G describes the method for obtaining compounds of formula I-G in which X is O, Y is a bond, L is absent, and R3is a 4-aminocyclohexanol.

The compound of the formula C2 can be treated with an amine of the formula G1, where P represents a protective group for the amino group, to obtain the intermediate product G2. Subsequent aromatic bromination using brainwashes agent such as NBS, allows to obtain the compound of formula G3. Bromide of the formula G3 can be introduced into the reaction catalyzed by palladium cross-combination, as described in this application, to obtain the compounds of formula G4. Standard removing the protective group from the amino group (P) allows to obtain the compound of formula I-G in accordance with the present invention.

In scheme H describes the method for obtaining compounds of formula I-H in which X is O, Y is a bond, L is a methylene, and R3is a 1-aminoeth-1-yl or 1-aminocyclopent-1-yl.

RHrepresents methyl or pyrocondensation cyclopentyl

The compound of formula B2 can be introduced into a condensation reaction with an aldehyde of the formula H1 in the presence of a source of the hydride ion, where RHrepresents meth is l or pyrocondensation cyclopentyl, obtaining an intermediate product H2. The aldehydes of the formula H1 commercially available or can be obtained by recovering the corresponding carboxylic acids. Bromide of the formula H2 may be introduced into the reaction catalyzed by palladium cross-combination, as described in this application, with boric acid or ester of formula A4, obtaining the compounds of formula H3. Standard removing the protective group from the amino group (P) allows to obtain the compound of formula I-H in accordance with the present invention.

Scheme I describes the method for obtaining compounds of formula (I)-I, in which X represents CH2Y represents ethinyl, L represents a methylene, and R3is pyrrolidin-2-yl.

The compound of formula D3 can be introduced into the reaction cross-combination with a commercially available R1-replaced by acinom formula E1 in the presence of a palladium catalyst and copper iodide, and organic bases such as TEA, obtaining the compounds of formula I1. Standard removing the protective group from the amino group allows to obtain the compound of formula (I)-I.

Specific examples of

All reagents were purchased from commercially available sources. The spectra of nuclear magnetic resonance (NMR) hydrogen atoms have been removed in the indicated solvent using tet is Americana (TMS) as internal standard spectrometer Bruker Avance or Varian (300 or 400 MHz). The obtained values are given in ppm in the low side of the field from the signal TMS. Mass spectra (MS) were obtained on a spectrometer Micromass Platform LC or Agilent 1100 LCMS in ERIEm/z(M+H+) using electrospray ionization. Accelerated microwave heating reaction was performed using a CEM microwave devices Discover or Biotage, if not stated otherwise, the reaction mixture was placed in a hermetically closed vessel. Stereoisomeric compounds can be characterized as racemic mixtures or as individual diastereomers and enantiomers using x-ray crystallography and other well-known specialists of ways. Unless otherwise noted, all used in the following examples, the materials were obtained from standard commercial suppliers of reagents or were synthesized by standard methods known to experts in the field of chemical synthesis. Unless otherwise specified, the substituents, which vary between examples were hydrogen atoms.

Example 1

A. 5-Bromo-3-(4-methoxyphenoxy)-pyrazin-2-ylamine (1b). To a suspension of NaH (60% in mineral oil) (0,264 g, 6.6 mmol) in DMF (13 ml) was dropwise added a solution of 4-methoxyphenol (0,63 g, 5.08 mmol) in DMF (2 ml). The resulting mixture was stirred at room temperature for 30 minutes in the atmosphere arg is on. Then the reaction mixture was added a solution of 3,5-dibromopyridin-2-ylamine (compound 1a, 1,285 g, 5.08 mmol) in DMF (5 ml) and passed the resulting mixture at a temperature of 70°C for 1 hour. The mixture was cooled to room temperature, then repaid with ice water and stirred for 10 minutes. The obtained solid substance was collected by filtration and was given a dark brown precipitate. The obtained residue was dissolved in EtOAc, then recrystallize from a mixture of Et2O-hexane and got the connection 1b (0,784 g, yield 52%) as a solid orange color.1H NMR (400 MHz, CDCl3): δ 7,76 (s, 1H), 7,07-7,16 (m, 2H), 6.89 in-6,98 (m, 2H), 4,94 (ush. S., 2H), of 3.84 (s, 3H).

B. Tert-butyl ester 2-(S)-{[5-bromo-3-(4-methoxyphenoxy)-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (1d). To a solution of compound 1b (0,487 g of 1.64 mmol) in 1,2-dichloroethane (7 ml) at room temperature was added Boc-L-prolinal (compound 1c) (0,557 g, 2.8 mmol) and glacial acetic acid (0.35 ml), after which the resulting solution was stirred for 2 hours in nitrogen atmosphere. Then the mixture was treated with NaBH(OAc)3(0,765 g, 3.61 mmol) and continuously stirred at room temperature for 20 hours. In the reaction mixture was added compound 1c (0,186 g of 0.93 mmol) and was stirred for additional 2 hours. Then the mixture was treated with NaBH(OAc)3(0,255 g, 1.20 mmol) and continuously lane is massively at room temperature for 20 hours. The resulting mixture was diluted with CH2Cl2, washed saturated aqueous NaHCO3and H2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.After that, the mixture was filtered, the filtrate was evaporated under reduced pressure and the obtained source material. The initial material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of EtOAc-hexane, and received a compound 1d (0,562 g, yield 72%).1H NMR (400 MHz, CDCl3): δ 7,72 (ush. S., 1H), 7,12 (ush. S., 2H), 6,92 (ush. S., 2H), 4,20-4,51 (m, 1H), 3,83 (ush. C., 3H), 3,40 of 3.56 (m, 4H), 1,76 with 2.14 (m, 4H), 1,45 (ush. C., 9H).

C. Tert-butyl ester 2-(S)-{[3-(4-methoxyphenoxy)-5-pyridin-3-Alperin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (1f). In a closed septum with Teflon flask Slanka put a mixture of compound 1d (160 mg, 0,334 mmol), pyridine-3-elborno acid (compound 1e) (61,5 mg, 0,501 mmol), Na2CO3/H2O (70,8 mg, 0,668 mmol in 0.5 ml of H2O) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (27.3 mg, 0,0334 mmol) in dioxane (2 ml) and kept at a temperature of 85°C for 3 hours. The resulting mixture was diluted with EtOAc and washed with saturated aqueous solution of NH4Cl and H2O. the Organic layer was washed H2O, and then dried over Na2SO4.The mixture was filtered, f is ltrate was evaporated under reduced pressure and the obtained source material. The initial material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of EtOAc-hexane, and received a compound 1f (80 mg, yield 50%).1H NMR (400 MHz, CDCl3): δ of 8.95 (s, 1H), 8,46 (d, 1H), 8,16 (s, 1H), to 7.93 (d, 1H), 7,09-7,26 (m, 4H), 6,94 (d, 2H), 4,19 was 4.42 (m, 1H), 3,86 (s, 3H), 3,37 at 3.69 (m, 4H), 1.77 in-of 2.16 (m, 4H), of 1.47 (s, 9H), MS: m/z 478,2 (M + H)+.

D. [3-(4-Methoxyphenoxy)-5-pyridin-3-yl-pyrazin-2-yl]-pyrrolidin-2-(S-ylmethylamino (compound 2). To a solution of compound 1f (80 mg, of) 0.157 mmol) in CH2Cl2(1 ml) at room temperature was added triperoxonane acid (0.7 ml). The reaction mixture was stirred 3 hours at room temperature. Then the pH of the medium was brought to pH~12, using 1N aqueous solution of NaOH. The resulting mixture was divided between CH2Cl2and H2O. the Organic layer was washed H2O and dried over Na2SO4. After that, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in CH2Cl2(1 ml) and treated with 1.0 M HCl in Et2O (0.16 ml, 0.16 mmol) at room temperature. The reaction mixture was stirred 3 hours at room temperature. After the reaction mixture was concentrated under reduced pressure, and rubbed the residue with Et2O. the Solid was collected by vacuum filtration and dried, obtaining compound 2 (61 mg, output is 94%) as hydrochloride. The HCl salt:1H NMR (400 MHz, DMSO-d6): δ 9,45 (ush. S., 1H), 8,97 (s, 1H), 8,97 (ush. S., 1H), 8,58 (d, 1H), 8,48 (s, 1H), 8,31 (d, 1H), to 7.77 (t, 1H), 7,65 (DD, 1H), 7,26-7,33 (m, 2H), 7,01-7,07 (m, 2H), 3,82-to 3.89 (m, 1H), 3,80 (s, 3H), 3.72 points-of 3.78 (m, 2H), 3,12-3,29 (m, 2H), 2,03 and 2.13 (m, 1H), 1,82-2,02 (m, 2H), 1,69-of 1.81 (m, 1H); MS: m/z 378,2 (M + H)+.

Following the procedure described above for example 1, but using the appropriate reagents, the starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M+H)+
1408,2
19377,2
20353,2
21417,2
22393,2

Example 2

A. Tert-butyl ester 2-(S)-{[3-(4-methoxyphenoxy)-5-pyridin-3-Latinamerican-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (2a). In a dry flask Slanka put a mixture of compound 1d (100 mg, 0.21 mmol), 3-ethynylpyridine (54 mg, 0.52 mmol), copper iodide (I) (4 mg, 0.02 mmol), dichloride bis(triphenylphosphine)palladium (II) (15 mg, 0.02 mmol) and Et3N (0.25 ml). Number is s closed septum with Teflon coating, pumped out and filled with argon. Then use the syringe to the mixture was added THF (1 ml). The resulting mixture is passed at a temperature of 70°C for 3 hours. The resulting mixture was diluted with EtOAc and washed with saturated aqueous solution of NH4Cl and H2O. the Organic layer was washed H2O, and then dried over Na2SO4.The mixture was filtered, the filtrate was evaporated under reduced pressure and the obtained source material. The initial material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of EtOAc-hexane, and received the compound 2a (57 mg, yield 54%).1H NMR (400 MHz, CDCl3): δ 8,72 (s, 1H), and 8.50 (d, 1H), 7,94 (s, 1H), to 7.77 (dt, 1H), 7,24 (DD, 1H), 7,07-7,20 (m, 2H), 6,92 (d, 2H), 4,18-4,39 (m, 1H), 3,83 (s, 3H), 3,35-to 3.67 (m, 4H), 1,75-of 2.15 (m, 4H), 1,45 (s, 9H).

B. [3-(4-Methoxyphenoxy)-5-pyridin-3-ylethynyl-pyrazin-2-yl]-pyrrolidin-2-(S-ylmethylamino (compound 3). To a solution of compound 2a (50 mg, 0.10 mmol) in CH2Cl2(1 ml) was added TFA (0.7 ml) at room temperature. The reaction mixture was stirred 3 hours at room temperature. Then the pH of the medium was brought to pH~12, using 1N aqueous solution of NaOH. The resulting mixture was divided between CH2Cl2and H2O. the Organic layer was washed H2O and dried over Na2SO4. After that, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2/sub> Cl2(1 ml) and treated with 1.0 M HCl in Et2O (0.2 ml, 0.2 mmol) at room temperature. The reaction mixture was stirred 3 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure, and rubbed the residue with Et2O. the Solid was collected by vacuum filtration and dried, obtaining the compound 3 (40 mg, yield 84%) as hydrochloride. The HCl salt:1H NMR (400 MHz, DMSO-d6): δ 9,39 (ush. S., 1H), 8,87 (ush. S., 1H), 8,78 (s, 1H), to 8.62 (d, 1H), 8,07 (d, 1H), 8,03 (s, 1H), 7,92 (t, 1H), 7,53-7,58 (m, 1H), 7,17-7,22 (m, 2H), 6,99-7,05 (m, 2H), 3,80-of 3.85 (m, 1H), of 3.78 (s, 3H), 3,71 is 3.76 (m, 2H), 3,11 of 3.28 (m, 2H), 2,02-2,12 (m, 1H), 1,83 is 2.01 (m, 2H), 1,67-to 1.79 (m, 1H); MS: m/z 402,2 (M+H)+.

Following the procedure described above for example 2, but using the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M + H)+
4369,2

Example 3

A. Tert-butyl ester 2-(S)-[(5-bromopyrazine-2-ylamino)-methyl]-pyrrolidin-1-carboxylic acid (3b). To a solution of compound 3a (5.75 g, 33,05 mmol) in 1,2-dichloroethane (60 ml) at room temperature was added Boc-L-prolinal (with the Association 1c) (which 9.22 g, for 46.3 mmol) and glacial acetic acid (3 ml) and the resulting solution was stirred for 2 hours in nitrogen atmosphere. Then the mixture was treated with NaBH(OAc)3(12,6 g, 59.5 mmol) and continuously stirred at room temperature for 4 hours. The resulting mixture was diluted with CH2Cl2and washed saturated aqueous NaHCO3and H2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of EtOAc-hexane, and received the compound 3b (8,97 g, yield 76%).1H NMR (400 MHz, CDCl3): δ 8,03 (s, 1H), 7,68 (s, 1H), 6,68 (ush. S., 1H), 4,15-to 4.28 (m, 1H), 3,23-of 3.60 (m, 4H), 1,69-2,12 (m, 4H), 1,45-1,55 (m, 9H).

B. Tert-butyl ester 2-(S)-[(5-pyrimidine-5-Alperin-2-ylamino)-methyl]-pyrrolidin-1-carboxylic acid (3d). In a closed septum with Teflon flask Slanka put a mixture of compound 3b (1,742 g, 4,88 mmol), pyrimidine-5-boronic acid (compound 3c) (0,725 g of 5.85 mmol), 1.5 M aqueous solution of Na2CO3(6.5 ml, 9,76 mmol) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (0.32 g, 0,392 mmol) in dioxane (26 ml) and kept at a temperature of 85°C for 5 hours. Receiving the ing the mixture was diluted with EtOAc and washed with saturated aqueous solution of NH 4Cl and H2O. the Organic layer was washed H2O, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and got the 3d connection (0.8 g, yield 46%).1H NMR (400 MHz, CDCl3): δ 9,20 (s, 2H), 9,17 (s, 1H), 8,43 (s, 1H), 8,02 (d, 1H), 6,99 (ush. S., 1H), 4,21-or 4.31 (m, 1H), 3.33 and-3,55 (m, 4H), 2,03-of 2.16 (m, 1H), 1,86-2,02 (m, 2H), 1,74-of 1.85 (m, 1H), 1,50 (s, 9H); MS: m/z 357,2 (M + H)+.

C. Tert-butyl ester 2-(S)-[(3-bromo-5-pyrimidine-5-Alperin-2-ylamino)-methyl]-pyrrolidin-1-carboxylic acid (3e). To a cooled to 0°C solution of compound 3d (0,255 g, 0,715 mmol) in DMF (2 ml) under nitrogen atmosphere dropwise added a solution of N-bromosuccinimide (140 mg, 0.786 mmol) in DMF (1 ml). The reaction mixture was stirred at 0°C for 2 hours, and then continuously stirred at room temperature for 3 hours. The resulting mixture was extinguished with water and was extracted with Et2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO21H NMR (400 MHz, CDCl3): δ 9,18 (s, 2H), 9,18 (s, 1H), 8,40 (s, 1H), 7,54 (ush. S., 1H), 4,30-4,39 (m, 1H), 3,34-of 3.60 (m, 4H), 2,04-of 2.16 (m, 1H), 1,88-2,02 (m, 2H), 1,72-of 1.84 (m, 1H) and 1.51 (s, 9H); MS: m/z 435,0 (M + H)+, 437,0 (M+3)+.

D. Tert-butyl ester 2-(S)-{[3-(2-chlorophenoxy)-5-pyrimidine-5-Alperin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (3f). To a suspension of NaH (60% in mineral oil) (9.5 mg, 0.24 mmol) in DMF (1 ml) in an argon atmosphere dropwise added 2-chlorophenol (of 0.03 ml, 0.26 mmol). The mixture was stirred for 30 minutes at room temperature. Then the reaction mixture was added a solution of compound 3e (80 mg, 0,184 mmol) in DMF (2 ml) and kept it at a temperature of 90°C for 6 hours. The mixture was cooled to room temperature, then repaid with ice water and was extracted with EtOAc. The organic layer was washed H2O, and then dried over Na2SO4. Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 3f (39 mg, yield 44%). MS: m/z 483,2 (M + H)+.

E. [3-(2-Chlorophenoxy)-5-pyrimidine-5-Alperin-2-yl]-pyrrolidin-2-(S-ylmethylamino (compound 12). To a solution of compound 3f (39 mg, 0.08 mmol) in CH 2Cl2(1 ml) at room temperature was added triperoxonane acid (0.7 ml). The reaction mixture was stirred 3 hours at room temperature. Then the pH of the medium was brought to pH~12, using 1N aqueous solution of NaOH. The resulting mixture was divided between CH2Cl2and H2O. the Organic layer was washed H2O and dried over Na2SO4. After that, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in CH2Cl2(1 ml) and treated with 1.0 M HCl in Et2O (0.16 ml, 0.16 mmol) at room temperature. The reaction mixture was stirred 3 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure, and rubbed the residue with Et2O. the Solid was collected by vacuum filtration and dried, obtaining the connection 12 (32 mg, yield 87%) as hydrochloride. Free base:1H NMR (400 MHz, CDCl3): δ 9,06 (s, 1H), 8,95 (s, 2H), 8,21 (s, 1H), of 7.48-rate of 7.54 (m, 1H), 7,32-7,38 (m, 2H), 7.23 percent-7,29 (m, 1H), 6,09 (t, 1H), 3.72 points-is 3.82 (m, 1H), to 3.58-to 3.67 (m, 1H), 3.43 points-of 3.54 (m, 1H), 2,98-3,13 (m, 2H), 1,98-of 2.09 (m, 1H), 1,75-of 1.97 (m, 2H), 1,54-to 1.67 (m, 1H); MS: m/z of 383.0 (M+H)+.

Following the procedure described above for example 3, but using the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M+H)+ConnectionMS (M+H)+
5to 379.26377,2
7393,09397,2
10383,111of 383.0
13406,214415,2
18374,232391,2

Compound 8. The desired compound was obtained by following the procedure described above for example 3, substituting in the procedure D, 2-chlorophenol 3-fluoro-4-methoxyphenol1. Free base:1H NMR (400 MHz, CDCl3): δ remaining 9.08 (s, 1H), 9,00 (s, 2H), to 8.20 (s, 1H), 6,98-7,06 (m, 3H), 5,97 (ush. S., 1H), 3,95 (s, 3H), 3,70 (DDD, 1H), 3.46 in-3,55 (m, 1H), 3,32 is 3.40 (m, 1H), 2,96-to 3.02 (m, 2H), 1,94-2,04 (m, 1H), 1.70 to of 1.92 (m, 2H), 1,47 is 1.58 (m, 1H); MS:m/z397,2 (M+H)+.

13-Fluoro-4-methoxyphenol received as follows:

A. 3-Fluoro-4-methoxyphenol. A mixture of 3-fluoro-4-methoxyacetophenone (5,16 g, 30,8 mmol) and mCPBA (8.65 g, 38,61 mmol) in CH2Cl2boiled under reflux for 48 hours. Then the reaction mixture was cooled to room temperature, diluted CH2Cl2, washed with 5% aqueous solution of K2CO3, dried over Na2SO4and concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), and then slowly treated with a solution of NaOH (5.2 g) in H2O (6 ml). The resulting mixture was stirred at room temperature for 3 hours. The mixture is then concentrated and the residue is divided between water and Et2O. the Mixture was acidified with diluted aqueous HCl solution and was extracted with Et2O. the Organic layers were combined, washed with saturated saline, dried over Na2SO4and concentrated under reduced pressure, obtaining the source material. The source material was stirred in hexano and the solid precipitate was collected by vacuum filtration, obtaining the desired connection.1H NMR (400 MHz, CDCl3) δ: 6,85 (t, 1H), 6,66 (DD, 1H), 6,54 (DDD, 1H), 4,59 (ush. S., 1H), 3,85 (s, 3H).

The connection 33. The desired compound was obtained by following the procedure described above for example 3, substituting in the procedure D, 2-chlorophenol 2,3-dihydrobenzofuran-5-ol2. Free base:1H NMR (400 MHz, CDCl3): δ 9,07 (s, 1H), 9,00 (s, 2H), 8,17 (s, 1H), 7,05 (d, 1H), 6,94 (DD, 1H), for 6.81 (d, 1H), 6,00 (t, 1H), 4,66 (t, 2H), of 3.73 (DDD, 1H), 3,53-3,63 (m, 1H), 3,41 (DDD, 1H), 3.27 to (t, 2H), 2,95-to 3.09 (m, 2H), 1,96-2,05 (m, 1H), 1,74-of 1.94 (m, 2H), 1,50-to 1.61 (m, 1H) MS:m/z391,2 (M + H)+.

22,3-Dihydrobenzofuran-5-ol obtained in the following way, as shown in the diagram:

A. Benzofuran-5-ol. To a solution of BBr3-SMe2(of 9.45 g, 30,22 mmol) in dichloroethane (50 ml) was added 5-methoxybenzophenone (1.28 g, 8,64 mmol) and the resulting mixture was boiled under reflux in nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was carefully added water and stirred for 20 minutes. The resulting mixture was diluted with CH2Cl2, washed with saturated saline, dried over Na2SO4and concentrated under reduced pressure, obtaining the source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and got the desired connection.1H NMR (400 MHz, CDCl3) δ: 7,60 (d, J=2.3 Hz, 1H), 7,37 (d, 1H), 7,02 (d, 1H), PC 6.82 (DD, 1H), of 6.68 (DD, 1H), 4,59 (s, 1H).

B. 2,3-Dihydrobenzofuran-5-ol. To a solution of benzofuran-5-ol (300 mg, 2,24 mmol) in ethanol (10 ml) was added 10% Pd-C (20 mg) and the resulting mixture was shaken in a hydrogen atmosphere at a pressure of 0.34 MPa (50 psi) in a hydrogenating apparatus Parr for 19 hours. Then the reaction mixture was filtered and concentrated by getting the source material. The original m is a material predetermined recrystallize twice from toluene. The solid precipitate was collected by vacuum filtration and dried, obtaining the desired compound (155 mg, 51% yield).1H NMR (400 MHz, CDCl3): δ of 6.71-6.75 in (m, 1H), 6,62 of 6.66 (m, 1H), 6,55-6,60 (m, 1H), 4,54 (t, 2H), 4,35 (s, 1H), 3,18 (t, 2H).

Example 4

A. Tert-butyl ester 2-(S)-{[3-(3-acetoxyphenyl)-5-pyrimidine-5-yl-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (4a). To a suspension of NaH (60% in mineral oil) (18 mg, 0.45 mmol) in DMF (1 ml) in an argon atmosphere dropwise added 3-hydroxyphenylethyl ether acetic acid (0.06 ml, 0,488 mmol). The mixture was stirred for 30 minutes at room temperature. Then the reaction mixture was added a solution of compound 3e (163 mg, the 0.375 mmol) in DMF (2 ml) and passed her at a temperature of 80°C for 6 hours. The mixture was cooled to room temperature, then repaid with ice water and was extracted with EtOAc. The organic layer was washed H2O, and then dried over Na2SO4.After that, the mixture was filtered, the filtrate was evaporated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and received the compound 4a (69 mg, yield 36%). MS: m/z 507,2 (M+H)+.

B. Tert-butyl ester 2-(S)-{[3-(3-hydroxyphenoxy)-5-pyrimidine-5-yl-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (4b) To a solution of compound 4a (20 mg) in EtOH/ H 2O (2/2 ml) was added 1N aqueous NaOH (2 ml) and the resulting mixture is passed at a temperature of 80°C for 2 hours. The reaction mixture is allowed to cool to room temperature, and then drove an organic solvent. the pH of the aqueous residue was brought to pH~6 with 2N aqueous HCl, then was extracted with him EtOAc and dried over Na2SO4. The resulting mixture was concentrated and purified using preparative TLC, after receiving the connection 4b.1H NMR (400 MHz, CDCl3): δ 9,19 (s, 1H), 9,06 (s, 2H), 8,13 (s, 1H), 7,22 (m, 1H), 6,69-to 6.80 (m, 3H), 4,21-4,34 (m, 1H), 3,32 at 3.69 (m, 4H), 1,87-2,11 (m, 3H), 1,68-to 1.77 (m, 1H), 1,43-1,49 (m, 9H); MS: m/z 465,2 (M+H)+.

C. 3-{6-Pyrimidine-5-yl-3-[(pyrrolidin-2-(S-ylmethyl)-amino]-pyrazin-2-yloxy}-phenol (compound 15). To a solution of compound 4b in CH2Cl2(1 ml) at room temperature was added triperoxonane acid (0.7 ml). The reaction mixture was stirred 3 hours at room temperature. Then the pH of the medium was brought to pH~12, using 1N aqueous solution of NaOH. The resulting mixture was divided between CH2Cl2and H2O. the Organic layer was washed H2O and dried over Na2SO4. After that, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2(1 ml) and treated with 1.0 M HCl in Et2O at room temperature. The reaction mixture was stirred 3 hours pikantnoi temperature. Then the reaction mixture was concentrated under reduced pressure, and rubbed the residue with Et2O. the Solid was collected by vacuum filtration and dried, obtaining the connection 15 in the form of hydrochloride. Free base:1H NMR (400 MHz, CDCl3): δ of 9.02 (s, 1H), to 8.94 (s, 2H), 8,04 (s, 1H), 7,11-7,19 (m, 1H), 6,66-6,76 (m, 3H), 6,21 (t, 1H), 3.95 to a 4.03 (m, 1H), 3,64 of 3.75 (m, 2H), 3,26-to 3.36 (m, 2H), 1,95-of 2.27 (m, 3H), 1,76-1,89 (m, 1H); MS: m/z 365,3 (M + H)+.

Example 5

A. Tert-butyl ester 2-(S)-{[5-(5-cyano-3-yl)-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (5b). In a closed septum with Teflon flask Slanka put a mixture of compound 3b (2.0 g, the ceiling of 5.60 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinanilide (compound 5a) (1.55 g, 6,72 mmol), K2CO3(1,547 g, and 11.2 mmol) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (274 mg, 0,336 mmol) in a mixture of CH3CN (8 ml) and H2O (2 ml) and irradiated it in a microwave reactor at a temperature of 140°C for 20 minutes. The resulting mixture was diluted with EtOAc and then washed with a saturated aqueous solution of NH4Cl and H2O. the Organic layer was washed H2O, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2),using as eluent a gradient mixture of heptane-EtOAc, and received the compound 5b (1.56 g, yield 73%) as a powder reddish color.1H NMR (400 MHz, CDCl3): δ 9,27 (d, 1H), 8,79 (s, 1H), 8,42-charged 8.52 (m, 2H), 8,00 (d, 1H), 7,09 (ush. S., 1H), 4,05-4,34 (m, 1H), 3,30-3,59 (m, 4H), 2,03-2,17 (m, 1H), 1,86 is 2.01 (m, 2H), 1,73-of 1.84 (m, 1H), 1,50 (s, 9H); MS: m/z 381,2 (M + H)+.

B. Tert-butyl ester 2-(S)-{[3-bromo-5-(5-cyano-3-yl)-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (5c). To a cooled to 0°C solution of compound 5b (1,53 g, 4.02 mmol) in DMF (8 ml) under nitrogen atmosphere dropwise added a solution of N-bromosuccinimide (800 mg, of 4.49 mmol) in DMF (6 ml). The reaction mixture was stirred at 0°C for 2 hours, and then continuously stirred at room temperature for 3 hours. The resulting mixture was extinguished with water and was extracted with Et2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 5c (1.22 g, yield 66%).1H NMR (400 MHz, CDCl3): δ9,24 (d, 1H), 8,80 (d, 1H), 8,46 (t, 1H), 8,43 (s, 1H), 7,63 (ush. S., 1H), 4,10-to 4.41 (m, 1H), 3,32-3,62 (m, 4H), 2,04-of 2.20 (m, 1H), 1.85 to 2,03 (m, 2H), 1,71-of 1.85 (m, 1H), 1,44-and 1.54 (m, 9H); MS: m/z 459,0 (M + H)+, 461,0 (M + 3)+.

C. the pet-butyl ester 2-( S)-{[5-(5-cyano-3-yl)-3-(3-hydroxyphenoxy)-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (5d). In a closed septum with Teflon flask Slanka put a mixture of compound 5c (100 mg, 0,218 mmol), benzene-1,3-diol (150 mg, 1,362 mmol) and K2CO3(60 mg, 0,434 mmol) in DMF (1 ml) and irradiated it in a microwave reactor at a temperature of 160°C for 15 minutes. The resulting mixture was divided between Et2O and H2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 5d (86,2 mg, yield 81%).1H NMR (400 MHz, CDCl3): δ 9,12 (d, 1H), to 8.70 (s, 1H), 8,12 compared to 8.26 (m, 2H), 7,42 (ush. S., 1H), 7.23 percent-7,29 (m, 1H), 6,67-6,86 (m, 3H), 5,85-6,10 (m, 1H), 4,19-4,39 (m, 1H), 3,36-3,68 (m, 4H), 1,71-2,17 (m, 4H), of 1.47 (s, 9H); MS: m/z 489,2 (M + H)+.

D. 5-{6-(3-Hydroxyphenoxy)-5-[(pyrrolidin-2-(S-ylmethyl)-amino]-pyrazin-2-yl}-nicotinamide (compound 38). To a solution of compound 5d (86,2 mg, 0,176 mmol) in CH2Cl2(3 ml) at room temperature was added triperoxonane acid (0.4 ml). The reaction mixture was stirred 3 hours at room temperature. After distillation dissolve the El and purification of the residue using reversed-phase HPLC, using as eluent a gradient mixture of CH3CN-H2O received connection 38 in the form of triptoreline (61,5 mg, yield 57%).1H NMR (400 MHz, DMSO-d6): δ 9,79 (s, 1H), 9,14 (d, 1H), 9,03 (ush. S., 1H), 8,90 (d, 1H), 8,54 (t, 1H), 8,51 (s, 1H), of 8.47 (ush. S., 1H), of 7.75 (t, 1H), 7.24 to 7,32 (m, 1H), 6,68-6,79 (m, 3H), of 3.77-to 3.89 (m, 1H), 3,68-of 3.77 (m, 2H), 3,12-of 3.32 (m, 2H), 2,04-of 2.16 (m, 1H), 1,83-2,03 (m, 2H), 1,68-of 1.81 (m, 1H); MS: m/z 389,3 (M + H)+.

Following the procedure described above for example 5, but using the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M + H)+ConnectionMS (M + H)+
24403,226UAH 421,2
27412,228388,2
29439,036457,0
37401,239413,0
40 412,241407,0
42407,0

The connection 25. The desired compound was obtained by following the procedure described above for example 5, substituting in the procedure C benzene-1,3-diol 3-fluoro-4-methoxyphenol1. The HCl salt:1H NMR (400 MHz, DMSO-d6): δ was 9.33 (ush. S., 1H), 9,12 (ush. S., 1H), 8,91 (ush. S., 1H), 8,82 (ush. S., 1H), 8,56 (t, 1H), charged 8.52 (s, 1H), 7,81 (t, 1H), 7,39 (DD, 1H), 7.24 to 7,31 (m, 1H), 7,15-7,21 (m, 1H), 3,88 (s, 3H), 3,79-3,86 (m, 1H), 3,71-of 3.78 (m, 2H), 3,11-3,30 (m, 2H), 2,02 with 2.14 (m, 1H), 1,82 is 2.01 (m, 2H), 1,68-of 1.81 (m, 1H); MS:m/z421,0 (M + H)+.

Example 6

A. 5-Bromo-3-(4-methoxybenzyl)-pyrazin-2-ylamine (6a). A solution of zinc chloride (0.5 M solution in THF) (26,3 ml, 13,23 mmol) was added to a solution of chloride of 4-methoxybenzylamine (0.25 M solution in THF) (50 ml, 12.5 mmol) at room temperature under nitrogen atmosphere. The obtained turbid mixture was stirred at room temperature for 15 minutes. To the resulting mixture at room temperature sequentially added dichloride bis(triphenylphosphine)palladium (II) (0,185 g to 0.263 mmol) and a solution of 2-amino-3,5-dibromopyrazine (compound 1a) (1,33 g of 5.26 mmol) in THF (4 ml). The mixture of orange color was stirred at room temperature for 54 hours, and then extinguished with water (10 ml) at 0°C. P is obtained mixture was diluted with ethyl acetate (200 ml) and water (60 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified column flash chromatography (SiO2, 30% ethyl acetate in hexano) and received a compound 6a (1,36 g, yield 88%).1H NMR (400 MHz, CDCl3): δ of 8.04 (s, 1H), 7,11-to 7.18 (m, 2H), at 6.84-6.89 in (m, 2H), 4,37 (ush. S., 2H), a 4.03 (s, 2H), 3,80 (s, 3H).

B. Tert-butyl ester 2-(S)-{[5-bromo-3-(4-methoxybenzyl)-pyrazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (6b). To a solution of compound 6a (1,37 g of 4.66 mmol) in 1,2-dichloroethane (30 ml) at room temperature was added Boc-L-prolinal (compound 1c) (1,114 g, 5,59 mmol) and glacial acetic acid (1.5 ml) and the resulting solution was stirred for 2 hours in nitrogen atmosphere. Then the mixture was treated with NaBH(OAc)3(1,38 g 6,524 mmol) and continuously stirred at room temperature for 20 hours. In the reaction mixture was added compound 1c (0.56 g, 2.8 mmol) and stirred for 2 hours. Then the mixture was treated with NaBH(OAc)3(0,69 g, 3,26 mmol) and continuously stirred at room temperature for 20 hours. The resulting mixture was diluted with CH2Cl2, washed saturated aqueous NaHCO3and H2O. the Organic layer was successively washed H2O and saturated saline solution, and C is the dried over Na 2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of EtOAc-hexane, and received a compound 6b (1.56 g, yield 70%). MS: m/z 477,1 (M + H)+, 479,1 (M + 3)+.

C. Tert-butyl ester 2-(S)-{[3-(4-methoxybenzyl)-5-pyrimidine-5-Alperin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid (6c). In a closed septum with Teflon flask Slanka put a mixture of compound 6c (200 mg, 0.42 mmol), pyrimidine-5-boronic acid (compound 3c) (78 mg, 0,63 mmol), Na2CO3/H2O (89 mg, 0.84 mmol in 0.5 ml of H2O) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (34,3 mg 0,042 mmol) in dioxane (2 ml) and kept at a temperature of 100°C for 4 hours. The resulting mixture was diluted with EtOAc, sequentially washed with a saturated aqueous solution of NH4Cl and H2O, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 6c (88 mg, yield 44%).1H NMR (400 MHz, CDCl3): δ of 9.21 (s, 2H), 9,14 (s, 1H), at 8.36 (s, 1H), was 7.36 (d, 2H), 7,19-7,24 (m, 1H), 6,86 (d, 2H),4,19-4,31 (m, 1H), 4,06 (s, 2H), 3,80 (s, 3H), 3,32-3,55 (m, 4H), 2.00 in and 2.14 (m, 1H), 1,81 is 2.00 (m, 2H), 1,66 and 1.80 (m, 1H), 1,53 (s, 9H); MS: m/z 477,3 (M + H)+.

D. [3-(4-Methoxybenzyl)-5-pyrimidine-5-yl-pyrazin-2-yl]-pyrrolidin-2-(S-ylmethylamino (compound 17). To a solution of compound 6c (88 mg, 0.185 mmol) in CH2Cl2(1 ml) at room temperature was added triperoxonane acid (0.7 ml). The reaction mixture was stirred 3 hours at room temperature. Then the pH of the medium was brought to pH~12, using 1N aqueous solution of NaOH. The resulting mixture was divided between CH2Cl2and H2O. the Organic layer was washed H2O and dried over Na2SO4. After that, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2(1 ml) and treated with 1.0 M HCl in Et2O (0,39 ml to 0.39 mmol) at room temperature. The reaction mixture was stirred 3 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure, and rubbed the residue with Et2O. the Solid was collected by vacuum filtration and dried, obtaining the connection 17 (71 mg, yield 86%) as hydrochloride. Free base:1H NMR (400 MHz, CDCl3): δ of 9.21-a 9.25 (m, 2H), 9,17-9,20 (m, 1H), 8,35 (s, 1H), 7,21-7,26 (m, 2H), for 6.81-6,86 (m, 2H), 5,97-6,14 (m, 1H), 4.16 the (s, 2H), 3,90-4,01 (m, 1H), 3,68-3,81 (m, H), of 3.78 (s, 3H), 3,23-to 3.33 (m, 1H), 2,99-to 3.09 (m, 1H), 2.06 to of 2.16 (m, 1H), 1,85 of 1.99 (m, 2H), 1,60 by 1.68 (m, 2H) MS: m/z 377,3 (M + H)+.

Following the procedure described above for example 6, but using the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M + H)+ConnectionMS (M + H)+
16376,223401,2

Example 7

A. 2-Chloro-3-(4-methoxyphenoxy)-pyrazin (7b). A mixture of 2,3-dichloropyrazine (compound 7a) (0.88 g, 5,91 mmol), 4-methoxyphenol (0,81 g, 6.5 mmol) and potassium carbonate (1.63 g, 11,82 mmol) in ethanol (20 ml) was stirred at room temperature for 20 hours. The resulting mixture was concentrated under reduced pressure and the residue was separated between EtOAc and water. The organic layer was successively washed with diluted aqueous solution of HCl and H2O, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOc, and received compound 7b (0,755 g, yield 54%).1H NMR (400 MHz, CDCl3): δ of 8.04 (d, 1H), to 7.99 (d, 1H), 7,07-to 7.15 (m, 2H), 6,93-7,00 (m, 2H), of 3.84 (s, 3H).

B. Tert-butyl ether 3'-(4-methoxyphenoxy)-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-carboxylic acid (7c). In a closed septum with Teflon flask Slanka put a mixture of compound 7b (243 mg, of 1.03 mmol) and tert-butyl methyl ether piperazine-1-carboxylic acid (478 mg, 2.57 mmol) in a mixture of i-D/dioxane (4/0,5 ml) and passed her at a temperature of 98°C for 48 hours. The resulting mixture was diluted with EtOAc, sequentially washed H2O and saturated saline and dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 7c (290 mg, yield 73%).1H NMR (400 MHz, CDCl3): δ of 7.82 (d, 1H), 7,54 (d, 1H), 7,05-to 7.09 (m, 2H), 6,93-6,98 (m, 2H), 3,83 (s, 3H), 3,60 (s, 8H), of 1.50 (s, 9H).

C. Tert-butyl ester 5'-bromo-3'-(4-methoxyphenoxy)-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-carboxylic acid (7d). To a cooled to 0°C solution of compound 7c (196 mg, 0.51 mmol) in DMF (2 ml) under nitrogen atmosphere dropwise added a solution of N-bromosuccinimide (110 mg, 0.61 mmol) in DMF (1 ml). The reaction mixture was stirred at 0°C for 2 hours, and then ararauna was stirred at room temperature for 3 hours. The resulting mixture was extinguished with water and was extracted with Et2O. the Organic layer was successively washed H2O and saturated saline, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column flash chromatography (SiO2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 7d (166 mg, yield 70%).1H NMR (400 MHz, CDCl3): δ of 7.90 (s, 1H), 7.03 is-7,10 (m, 2H), 6.90 to-6,97 (m, 2H), of 3.84 (s, 3H), 3,52-3,61 (m, 8H), for 1.49 (s, 9H).

D. Tert-butyl ester 5'-(5-cyano-3-yl)-3'-(4-methoxyphenoxy)-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-carboxylic acid (7e). In a closed septum with Teflon flask Slanka put a mixture of compound 7d (120 mg, 0.26 mmol), compound 5a (89 mg, 0,387 mmol), Na2CO3/H2O (55 mg, 0.52 mmol) in 0.4 ml of H2O) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (21 mg, was 0.026 mmol) in dioxane (2 ml) and kept at a temperature of 90°C for 1 hour. The resulting mixture was diluted with EtOAc and washed with saturated aqueous solution of NH4Cl and H2O. the Organic layer was washed H2O, and then dried over Na2SO4.Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the obtained source material. The source material was purified column F. the ash-chromatography (SiO 2), using as eluent a gradient mixture of heptane-EtOAc, and the obtained compound 7e (100 mg, yield 79%). MS: m/z 489,2 (M + H)+.

E. 5-[3'-(4-Methoxyphenoxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-nicotinamide (compound 30). Using an adaptation of the method described in procedure D of example 1, and replacing compound 1f in connection 7e, received the connection 30 in the form of hydrochloride. Free base:1H NMR (400 MHz, CDCl3): δ 9,12 (d, 1H), total of 8.74 (d, 1H), 8,32 (s, 1H), 8,16 (t, 1H), 7,08-7,13 (m, 2H), 6,95-7,00 (m, 2H), a 3.87 (s, 3H), 3,76-3,82 (m, 4H), 3.04 from-of 3.12 (m, 4H); MS: m/z 389,0 (M + H)+.

Following the procedure described above for example 7, but using the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M + H)+ConnectionMS (M + H)+
31364,234417,2
35417,2

Using the procedure described above, were synthesized in the table below soybeans is inane 1-42 formula (I).

Table 1
ConnectionR1YR2XLR3Stereochemistry
16-methoxypyridine-3-yllink4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
2pyridine-3-yllink4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
3pyridine-3-ylethinyl4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
methoxymethylethinyl4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
5pyrimidine-5-yllink4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
6pyrimidine-5-yllink4-ethyl
phenyl
Omethylenepyrrolidin-2-yl(2S)
7pyrimidine-5-yllinkbenzo
[1,3]deok-Sol-5-yl
Omethylenepyrrolidin-2-yl(2S)
8pyrimidine-5-yllink3-fluoro-4-methoxy-phenyl Omethylenepyrrolidin-2-yl(2S)
9pyrimidine-5-yllink2-fluoro-4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
10pyrimidine-5-yllink4-chloro
phenyl
Omethylenepyrrolidin-2-yl(2S)
11pyrimidine-5-yllink3-chloro
phenyl
Omethylenepyrrolidin-2-yl(2S)
12pyrimidine-5-yllink2-chloro
phenyl
Omethylenepyrrolidin-2-yl(2S)
pyrimidine-5-yllink3-methyl
carbonyl-amino-phenyl
Omethylenepyrrolidin-2-yl(2S)
14pyrimidine-5-yllink4-(1H-imidazol-1-yl)
phenyl
Omethylenepyrrolidin-2-yl(2S)
15pyrimidine-5-yllink3-hydroxy
phenyl
Omethylenepyrrolidin-2-yl(2S)
16pyridine-3-yllink4-methoxy-phenylCH2methylenepyrrolidin-2-yl(2S)
17pyrimidine-5-yllink 4-methoxy-phenylCH2methylenepyrrolidin-2-yl(2S)
18pyrimidine-5-yllink4-cyano
phenyl
Omethylenepyrrolidin-2-yl(2S)
195-cyano-pyridin-3-yllink4-methoxy-phenylOmethylene1-aminoeth-1-yl(1S)
20pyrimidine-5-yllink4-methoxyphenylOmethylene1-aminoeth-1-yl(1S)
215-cyano-pyridin-3-yllink4-methoxy-phenylOmethylene1-aminocyclopent-1-yl
22pyrimidine-5-yllink4-methoxyphenylOmethylene1-aminocyclopent-1-yl
235-cyano-pyridin-3-yllink4-methoxy-phenylCH2methylenepyrrolidin-2-yl(2S)
245-cyano-pyridin-3-yllink4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
255-cyano-pyridin-3-yllink3-fluoro-4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
265-cyano-pyridin-3-ylcommunication/td> 2-fluoro-4-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
275-cyano-3-yllink4-cyano
methyl-phenyl
Omethylenepyrrolidin-2-yl(2S)
285-cyano-3-yllink6-methyl-pyridin-3-ylOmethylenepyrrolidin-2-yl(2S)
295-cyano-3-yllink4-debtor-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
305-cyano-3-yllink4-methoxy-phenylO R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil
31pyridine-3-yllink4-methoxy-phenylOR3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil
32pyrimidine-5-yllinkbenzo
furan-5-yl
Omethylenepyrrolidin-2-yl(2S)
33pyrimidine-5-yllink2,3-dihydro-benzofur-ran-5-ylOmethylenepyrrolidin-2-yl(2S)
345-cyano-3-yllink4-methoxy-phenylOno4-amino-cyclohexylt is ANS
355-cyano-3-yllink4-methoxy-phenylOno4-amino-cyclohexylCIS
365-cyano-3-yllink4 trifter-methoxy-phenylOmethylenepyrrolidin-2-yl(2S)
375-cyano-3-yllink4-ethyl
phenyl
Omethylenepyrrolidin-2-yl(2S)
385-cyano-3-yllink3-hydroxy
phenyl
Omethylenepyrrolidin-2-yl(2S)
395-cyano-3-yllink benzo
furan-5-yl
Omethylenepyrrolidin-2-yl(2S)
405-cyano-3-yllinkindol-5-ylOmethylenepyrrolidin-2-yl(2S)
415-cyano-3-yllink2-chloro
phenyl
Omethylenepyrrolidin-2-yl(2S)
425-cyano-3-yllink3-chloro
phenyl
Omethylenepyrrolidin-2-yl(2S)

Biological studies

In vitro studies

Example 1

24-hole analysis of the binding of Delta-opioid receptors on the cell line NG108-15

Methods: the membrane of the cell line NG108-15 were purchased from the company Applied Cell Sciences, Of Rockville, Maryland, USA). Membrane protein was suspended at a concentration of 5 mg/ml in 10 mm buffer solution TRIS-HCl at a pH of 7.2 with the addition of 2 mm EDTA, 10% sucrose. The contents of each vial homogenized in 5 ml of 50 mm Tris buffer solution at pH of 7.4 using multiple short pulses on the homogenizer transmitter station. The obtained homogenate was diluted in 50 mm Tris buffer solution containing 5 mm MgCl2to the concentration of 330 mg/ml working solution to obtain a final protein concentration of 133 μg/well. The resulting preparation was used to conduct 24-hole analysis of binding to Delta opioid receptors.

After incubation with the Delta-selective ligand, ~0.2 nm [3H]naltrindole, at 25°C for 2.5 hours on a 24-hole tablet with a total volume of 1 ml of the contents of the tablet was filtered through a filter UniFilter24, GF/B. This tablet is pre-soaked in 0.3% PEI and was filtered through a 24-hole system for collecting cells. The specified filter UniFilter24 washed three times with 2 ml of 10 mm HEPES buffer solution (pH of 7.4) and dried in an oven at a temperature of 37°C for 1.5 hours. To each well was added 150 μl Scint0 (PerkinElmer, catalog No. 6013611). Then the tablets were analyzed on the scanner TopCount.

Analysis: data from the scintillation counter was used to calculate the percentage degree of ingibirovany is compared to control binding (when determined the effect only for a single concentration of test compound) or values of K i(when tested concentration range). As a negative control was used nonspecific binding (N. C. - 1 mm naloxone), as a positive control was used, the total binding (C. C. only the membrane and the ligand). In the analysis of a single concentration of interest, the degree of inhibition was calculated as (number of counts per minute for the total binding minus the number of counts per min for the tested compound) divided by (number of counts per minute for the total binding minus the number of counts per min for nonspecific binding). Each following interest degree of inhibition was obtained by averaging the results of three measurements. When working with multiple concentrations obtained values were analyzed using nonlinear regression to link one site from the software package Prism to obtain values of Ki. The maximum and minimum values are used as global. Each is given a value of Kiwas obtained by averaging the results of three measurements.

The data obtained are shown in table 2 below.

Example 2

Analysis of binding to Delta opioid receptors in rat brain

Procedure: male Wistar rats (150-250 g, VAF, the company Charles River, Kingston, new York) was slaughtered CO2 the brain was removed and immediately placed in ice-cold buffer solution Tris HCl (50 mm, pH 7,4). The front divisions were separated from the rest of the brain using coronal sections, starting from the top of the mounds and through the incision down through the mid-brain connection to the bridge. After opening the front brain is homogenized in a Tris buffer solution in the Teflon®-glass homogenizer. The obtained homogenate was diluted to a concentration of 1 g tissue forebrain 80 ml of buffer solution and centrifuged at a speed 39000×g for 10 minutes. The precipitate resuspendable in the same volume of Tris buffer solution with addition of 5 mm MgCl2using several small pulses at the homogenizer transmitter station. The resulting preparation was used for analysis of binding to Delta opioid receptors. After incubation with the Delta-selective peptide ligand, ~4 nm [3H]DPDPE or 0.25 nm [3H]naltrindole, at 25°C for 2.5 hours in 96-well-plate with a total volume of 1 ml of the contents of the tablet was filtered through filters Wallac filtermat B sheet on 96-well collection system cells Tomtec. These filters are washed three times with 2 ml of 10 mm HEPES buffer solution (pH of 7.4) and twice were dried in a microwave oven with a capacity of 650 watts for 1.75 minutes. For each zone with the sample was placed 2×50 μl of scintillation liquid is barb Betaplate Scint (LKB) and quantitatively determined the radioactivity using a liquid scintillation counter company LKB (Wallac) 1205 BetaPlate.

Analysis: data from the scintillation counter was used to calculate the percentage degree of inhibition compared to control binding (when determined the effect only for a single concentration of test compound) or values of Ki(when tested concentration range). The percentage degree of inhibition was calculated as [(number of decays per minute for the total binding is the number of disintegrations per minute per connection)/(number of decays per minute for the total binding is the number of disintegrations per minute for nonspecific binding)]*100. Values of Kdand Kiwas calculated using the program for data analysis GraphPad PRISM. The data obtained are shown in table 2 below.

Example 3

Analysis of binding to mu-opioid receptors in rat brain

Procedure: male Wistar rats (150-250 g, VAF, the company Charles River, Kingston, new York) was slaughtered CO2the brain was removed and immediately placed in ice-cold buffer solution Tris HCl (50 mm, pH 7,4). The front divisions were separated from the rest of the brain using coronal sections, starting from the top of the mounds and through the incision down through the mid-brain connection to the bridge. After conducting cross section of the obtained front parts of the brain homogenized in a Tris buffer solution in a Teflon®-glass homogenisator the E. The obtained homogenate was diluted to a concentration of 1 g tissue forebrain 80 ml of buffer solution and centrifuged at a speed 39000×g for 10 minutes. The precipitate resuspendable in the same volume of Tris buffer solution with addition of 5 mm MgCl2using several small pulses at the homogenizer transmitter station. The resulting preparation was used for analysis of binding to mu-opioid receptors. After incubation with mu-selective peptide ligand, ~0.8 nm [3H]DAMGO, at 25°C for 2.5 hours in 96-well-plate with a total volume of 1 ml of the contents of the tablet was filtered through filters Wallac filtermat B sheet on 96-well collection system cells Tomtec. These filters are washed three times with 2 ml of 10 mm HEPES buffer solution (pH of 7.4) and twice were dried in a microwave oven with a capacity of 650 watts for 1.75 minutes. For each zone with the sample was placed 2×40 μl of scintillation fluid Betaplate Scint (LKB) and quantitatively determined the radioactivity using a liquid scintillation counter company LKB (Wallac) 1205 BetaPlate.

Analysis: data from the scintillation counter was used to calculate the percentage degree of inhibition compared to control binding (when determined the effect only for a single concentration of test compound) or values of Ki(when the TEC is Aravali range of concentrations). The percentage degree of inhibition was calculated as [(number of decays per minute for the total binding is the number of disintegrations per minute per connection)/(number of decays per minute for the total binding is the number of disintegrations per minute for nonspecific binding)]*100. Values of Kdand Kiwas calculated using the program for data analysis GraphPad PRISM. The data obtained are shown in table 2 below.

Table 2
Data binding to Delta - and mu-opioid receptors
Connection # δ-binding on the cell membrane NG108
Ki(µmol)
δ-binding
(ligand DPDPE)
Ki(µmol)
δ-binding
(ligand naltrindole)
Ki(µmol)
δ-binding
Ki(µmol)
10,00062,3950
20,00210,8162
3 0,00153,2441
40,00194,9808
50,0027
60,0323
70,4910
80,00080,2018
90,0012
100,0011
110,0018
12 0,0007
130,0040
140,4114
150,0004
160,0150
170,0199
180,0764
190,0003
200,0006
21/td> 0,0006
220,0029
230,0024
24is 0.0002
25is 0.0002
26is 0.0002
270,0064
280,0132
290,0003
300,0001
310,0003
320,0013
330,0043
340,0007
350,0004
360,0014
370,0005
380,000086
39is 0.0002

Example 4

[35S]GTPγS the analysis of binding to the membranes of the cell line NG108-15 (functional test for Delta-opioid receptors) - screened at a concentration of 200 nm

Method: the cell membrane NG108-15 acquired the company Applied Cell Sciences, Rockville, Maryland). 5 mg/ml of membrane proteins suspended in 10 mm buffer solution TRIS-HCl c pH to 7.2, 2 mm EDTA, 10% sucrose. The membrane was kept at a temperature of 4-8°C. 1 ml of the preparation of the membranes was added in 10 ml of cold buffer solution for the test. Buffer solution for the test contained 50 mm Tris buffer solution with a pH of 7.6, 5 mm MgCl2, 100 mm NaCl, 1 mm DTT and 1 mm EGTA. Suspension of membranes twice homogenized in the homogenizer transmitter station and centrifuged at a speed of 3 000 rpm for 10 minutes. Then, the collected supernatant was centrifuged at a speed of 18 000 rpm for 20 minutes. In the tube containing the precipitate was added to 10 ml of buffer solution for the test. The precipitate and the buffer was stirred using a homogenizer transmitter station.

The incubation procedure: besieged membrane (75 µg/ml) pre-incubated with particles for scintillation analysis approach (particle SPA) (10 mg/ml) at 25°C in techenie minutes in a buffer solution for the test. Then contacting membranes (37,5 mg/ml) particles SPA (5 mg/ml) were incubated with 0.1 nm [35S] GTPγS in the same Tris buffer solution containing 100 μm GDP, in a total volume of 200 μl. To stimulate the binding of [35S]-GTPγS was added 200 nm agonists of the receptor. The core level binding was tested in the absence of agonist, and the level of nonspecific binding was tested in the presence of 10 μm unlabeled GTPγS. Data were analyzed on the counter Packard Top Count, the results are shown in table 3 below.

DATA

% of base=(stimulated-nonspecific)*100/(base-nonspecific).

The relative efficacy of compounds at a concentration of 200 nm=(% from baseline for the test compound at 200 nm)/(maximum occupancy-curve effect dose for SNC80; the curve in the package prism).

Example 5

[35S]GTPγS the analysis of binding to the membranes of the cell line CHO-hMOR (functional test of mu-opioid receptors)

Methods: the membrane of the cell line CHO-hMOR were purchased from companies Receptor Biology, Inc. in Baltimore, Maryland, USA). Membrane protein was suspended in a concentration of approximately 10 mg/ml in 10 mm buffer solution TRIS-HCl at a pH of 7.2 with the addition of 2 mm EDTA, 10% sucrose, the suspension was kept on ice. 1 ml of the preparation of the membranes was added to 15 ml of cold buffer solution for the test, which the soda is shaking 50 mm HEPES buffer solution, pH of 7.6, 5 mm MgCl2, 100 mm NaCl, 1 mm DTT and 1 mm EDTA. Suspension of membranes homogenized in the homogenizer transmitter station and centrifuged at a speed of 3 000 rpm for 10 minutes. Then, the collected supernatant was centrifuged at a speed of 18 000 rpm for 20 minutes. The precipitate resuspendable in 10 ml of buffer solution for the test in the homogenizer transmitter station. Membranes pre-incubated with covered agglutinins from wheat germ particles SPA (Amersham) at a temperature of 25°C for 45 minutes in a buffer solution for the test. Then contacting membranes particles SPA (5 mg/ml) were incubated with 0.5 nm [35S]GTPγS in the buffer solution for the test. Basic binding, which was carried out in the absence of added test compound was taken as 100%, while agonist-stimulated binding was reached levels far exceeding this value. To stimulate the binding of [35S]GTPγS used a range of concentrations of the agonists of the receptor. Both basic and non-specific binding was tested in the absence of agonist, to determine the level of nonspecific binding used 10 μm unlabeled GTPγS.

Compounds were tested for activity as an antagonist by assessing their potential inhibition of agonist-stimulated binding GTPγ. Radioactivity was quantitatively determined on the counter Packard TopCount. Expected the following options:

The values of EC50calculated in the program GraphPad Prism and are shown in table 3 below.

Table 3
Functional characteristics of Delta - and mu-opioid receptors
Connection # GTPγS
δ is the relative efficiency at 200 nm
GTPγS
δ-opioid receptor, EC50(µm)
GTPγS
δ-opioid receptor, Rel.
efficiency
GTPγS
δ-opioid receptor, % inhib. when
10 µm
GTPγS
δ-opioid receptor, EC50(µm)
GTPγS
δ-opioid receptor
% inhib.
at 10 µm
10,05850,86966,5738
20,02971,04301,0000the
30,04621,07971,0000
40,08250,94771,0000
50,34861,0984
60,45971,1553
80,14781,0302
90,28111,1022
100,2150
110,2102
120,2356
130,0800
167,31980,3985
170,1065
180,1065
200,68900,05051,0287
210,2481
220,2384
230,1174
240,1669
250,91300,03131,0387
26 1,01800,02711,0534
270,91790,03421,0035
280,1492
290,0000
300,59990,11111,1345
310,75790,00811,0012
320,55020,0793at 1,047
350,41570,09521,2053
360,55980,02970,9719
370,3353
380,64720,06661,1104
391,07650,00461,0736
400,66060,03931,1190
410,30490,29811,2922
420,71110,08441,1894

In vivo

Example 6

Model of inflammatory pain based on hypersensitivity to radiated heat in rats caused by the introduction of the CFA

Introduction complete adjuvant's adjuvant (CFA) into the sole of the foot causes the rodent strong and long-lasting inflammatory reaction, which is characterized by chronic pronounced hyperalgesia as to thermal and mechanical stress. These effects reach a maximum intensity in the period from 24 to 72 hours after injection and can last from several days to several weeks. To assess the ability of compounds to conversion of thermal hyperalgesia in the bottom of the left hind legs of the male rats Sprague-Dawley (200-350 g) may be introduced by injection of CFA (1:1 CFA:saline, 100 μl). After 24-hour incubation period was determined delay response to sluchayem heat stimulator feet (RH), which is against the Vali with the background delay before the introduction of the CFA. The stimulator automatically recorded the lifting of the foot from the surface of the glass. The analysis was continued only for rats that had at least 25% reduction in latent period of reaction (that is, had the place hyperalgesia). After determining the delay after injection of CFA rats orally was administered (2.5 ml/kg) test compound or inert media (hypromellose, HPMC). For each animal was calculated interest degree for the treatment of hyperalgesia as (reaction after administration of test compound - reaction after injection of CFA)/(reaction to the introduction of the CFA reaction after injection of CFA)×100. Thus, the return to the normal threshold of sensitivity to the introduction of the CFA was defined as 100% efficiency, whereas no differences from the sensitivity threshold after CFA injection was evaluated as 0% efficiency. Then for each group was calculated the average interest degree for the treatment of hyperalgesia (n=6-8 rats/group).

1. The compound of formula 1

where
R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and
iii) pyrimidine-5-yl;
or R1does not necessarily represent methoxymethyl, when Y represents ethinyl;
Y represents ethinyl or SV is z;
R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, substituted by the stands, while the phenyl has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;
or R2represents phenyl, having one C1-4alkylcarboxylic or 1H-imidazol-1-ilen Deputy;
X represents O or CH2;
L is absent, a R3is a 4-aminocyclohexanol, or L represents a methylene, and R3selected from the group consisting of
i) pyrrolidin-2-yl;
ii) 1-aminoeth-1-yl; and
iii) 1-aminocyclopent-1-yl;
or R3United in one cycle with L the nitrogen atom is attached to L, with the formation of piperazinil;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and
iii) pyrimidine-5-yl;
or R1does not necessarily represent methoxymethyl, when Y represents ethinyl.

3. Connection on p. 2, in which R1selected from the group consisting of
ii) pyridinyl, it is certainly having one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and
iii) pyrimidine-5-Il.

4. Connection on p. 3 in which R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group comprising methoxy, and cyano; and
iii) pyrimidine-5-Il.

5. Connection on p. 1, in which Y represents a bond.

6. Connection on p. 1, in which R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, substituted by stands, with phenyl optionally has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;
or R2represents phenyl, having one Deputy C1-4alkylcarboxylic.

7. Connection on p. 6, in which R2represents phenyl, having one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy; or R2represents phenyl, having one Deputy C1-4alkylcarboxylic.

8. Connection on p. 7, in which R2represents phenyl, having one Deputy selected from the group, ostoja from C 1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy.

9. Connection on p. 1, in which X represents O.

10. Connection on p. 1, in which L represents a methylene and R3selected from the group consisting of
i) pyrrolidin-2-yl;
ii) 1-aminoeth-1-yl; and
iii) 1-aminocyclopent-1-yl;
or R3United in one cycle with L the nitrogen atom is attached to L, with the formation of piperazinil.

11. The compound of formula (I)

where
R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and
iii) pyrimidine-5-yl;
or R1does not necessarily represent methoxymethyl, when Y represents ethinyl;
Y represents a bond or ethinyl;
R2represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl, substituted by the stands, while the phenyl has from one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;
or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;
X represents O or CH ;
L is absent, and R3is a 4-aminocyclohexanol, or L represents a methylene and R3selected from the group consisting of
i) pyrrolidin-2-yl;
ii) 1-aminoeth-1-yl; and
iii) 1-aminocyclopent-1-yl;
or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

12. The compound of formula (I)

where
R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group consisting of C1-4alkoxy and cyano; and
iii) pyrimidine-5-yl;
Y represents a bond;
R2represents phenyl, having one to two substituents independently selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;
or R2represents phenyl, having one Deputy C1-4alkylcarboxylic;
X represents O;
L represents a methylene and R3selected from the group consisting of
i) pyrrolidin-2-yl;
ii) 1-aminoeth-1-yl; and
iii) 1-aminocyclopent-1-yl;
or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;
and it enantiomer is s, diastereoisomers and pharmaceutically acceptable salts.

13. The compound of formula (I)

where
R1selected from the group consisting of
ii) pyridinyl, optional with one Deputy, selected from the group comprising methoxy, and cyano; and
iii) pyrimidine-5-yl;
Y represents a bond;
R2represents phenyl, having one Deputy selected from the group consisting of C1-4of alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, deformedarse, triptoreline and hydroxy;
X represents O;
L represents a methylene and R3selected from the group consisting of
i) pyrrolidin-2-yl;
ii) 1-aminoeth-1-yl; and
iii) 1-aminocyclopent-1-yl;
or R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazinil;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

14. The compound of formula (I)

selected from the group consisting of:
compounds in which R1represents a 6-methoxypyridine-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyridin-3-yl, Y is the IDE, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyridin-3-yl, Y is ethinyl, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1is methoxymethyl, Y represents ethinyl, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, a R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-ethylphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents benzo[1,3]dioxol-5-yl, X represents O, L represents a methylene, and R3p is ecstasy pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 3-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 2-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 3-chlorophenyl, X represents O, L represents a methylene, a R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 2-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2predstavljaet a 3-methylcarbamoylmethyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents a 4-(1H-imidazol-1-yl)phenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 3-hydroxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyridin-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-cyanophenyl, X represents O, L represents a methylene, and R3is the anon who lidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminoeth-1-yl; (1S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminoeth-1-yl; (1S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminocyclopent-1-yl;
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is a 1-aminocyclopent-1-yl;
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents CH2L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y, not only is em a relationship R2represents 4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 3-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, a R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 2-fluoro-4-methoxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-cyanomethylene, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents a 6-methylpyridin-3-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-deformational, X represents the FDS is th O L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O and R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazine-1-yl;
compounds in which R1represents pyridin-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O and R3United in one cycle with L and the nitrogen atom is attached to L, with the formation of piperazine-1-yl;
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is benzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2represents a 2,3-dihydrobenzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L is absent, and R3represents the t of a TRANS-4-aminocyclohexanol;
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 4-methoxyphenyl, X represents O, L is absent, and R3represents CIS-4-aminocyclohexane;
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-trifloromethyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 4-ethylphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 3-hydroxyphenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is benzofuran-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is Soboh the link, R2represents indol-5-yl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2represents 2-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
compounds in which R1represents 5-cyano-3-yl, Y is a bond, R2is a 3-chlorophenyl, X represents O, L represents a methylene, and R3is pyrrolidin-2-yl; (2S)
and its pharmaceutically acceptable salts.

15. Pharmaceutical composition having activity for modulating the activity of opioid receptors containing compound under item 1 and at least one of the substances pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent.

16. The pharmaceutical composition according to p. 15, in which the composition is a solid dosage form for oral administration.

17. The pharmaceutical composition according to p. 15, in which the composition is a syrup, elixir or suspension.

18. Way to treat pain ranging from moderate to strong from needing so is m the treatment of the patient, includes introduction to the patient a therapeutically effective amount of the compounds under item 1.

19. The method according to p. 18, in which the pain can range from moderate to strong caused by a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostate hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulite, causalgia, sciatic neuritis nerve, pain in the temporomandibular joint, peripheral neuritis, polyneuritis, cult of pain, phantom pain, post-operative intestinal obstruction, cholecystitis, pain after mastectomy, neuropathic pain in mouth syndrome Charcot, reflex sympathetic dystrophy, Guillain-Barre syndrome, paresteticheskih meralgia, syndrome of burning in the mouth, post herpetic neuralgia, trigeminal neuralgia, cluster headaches, headaches, migraines, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfiling neuritis, migrate the existing neuritis, segmental neuritis, neuritis Gombo, neurons, cervico-brachial neuralgia, cranial neuralgia, geniculate neuralgia site, neuralgia glossopharyngeal neuralgia, migraine, neuralgia, idiopathic neuralgia, intercostal neuralgia, pain in the breast, neuralgia Morton, syndrome nourishing nerve, occipital neuralgia, erythromelalgia, neuralgia of Cloudera, sphenopalatine neuralgia site, supraorbital neuralgia nerve, neuralgia medieva nerve, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tensional headache, labor, childbirth, menstrual pain and cancer.

20. The method according to p. 18, in which the pain is selected from the group consisting of inflammatory pain, centrally mediated pain, perifericheskie-mediated pain, visceral pain, pain associated with structural disorders, cancer pain, pain associated with soft tissue injury, pain associated with advanced disease, neuropathic pain, acute pain associated with acute injury, acute pain associated with trauma, acute pain associated with surgery, chronic headache, chronic pain associated with neuropathologies, chronic pain post-stroke period, and chronic pain from migraines.

21. The method of treatment and prevention of the disease or condition, selected from the group consisting of depression, Parkinson's disease, drug dependence, alcohol dependence, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases, and the method includes the step of introducing in need of such treatment to the mammal a therapeutically effective amount of a compound or salt according to p. 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 3-benzofuranylindol-2-one derivatives substituted in position 3 of formula wherein: R1 means a hydrogen atom; R2, R3, R4 equal or different, found in any accessible position of the phenyl ring, means independently a hydrogen atom or a halogen atom; R5 means (C1-6) alkyl group; n means 1; in the form of the base or acid-additive salt, as well as to a therapeutic agent and a pharmaceutical composition based on the above compounds possessing the ghrelin receptor antagonist activity, and to using this compounds for preparing the therapeutic agent for preventing or treating obesity, diabetes, appetite disorders and overweight.

EFFECT: preparing the therapeutic agent used for preventing or treating obesity, diabetes, appetite disorders and overweight.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 3-benzofuranyl-indol-2-one-3-acetamidopiperazine derivatives of formula

,

wherein: R1 means hydrogen atom; R2, R3, R4 are identical or different, found in any accessible position of phenyl nucleus; they independently mean hydrogen atom and halogen atom; R5 and R6 are identical or different, mean hydrogen atom, (C1-6) alkyl group; R7 means (C1-6) alkyl group; R8 and R9 found in any accessible position of piperazine nucleus, mean hydrogen atom, or (C1-6)alkyl group; at least one of R8 and R9 is differed from H; n means 1; which are present in the form of a base or an acid addition salt, as well as to methods for preparing these compounds, a therapeutic agent or a based pharmaceutical composition for treating obesity, diabetes, appetite disorder and overweight and to therapeutic use of these compounds.

EFFECT: preparing the compounds for treating obesity, diabetes, appetite disorder and overweight and to therapeutic use of these compounds.

10 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to pigment dispersion that can find application in electrophoretic displays. The dispersion contains α) a bis-(oxodihydroindolilene)benzodifuranone colouring agent of formula I wherein R1-R10 have values specified in cl.1, β) a special polymer dispersing agent containing modified poly(meth)acrylates, and γ) a solvent applicable for dispersions used in the electrophoretic displays. There are also described new colouring agents of bis-(oxodihydroindolilene)benzodifuranone compounds, dispersing agents and the electrophoretic display comprising these agents.

EFFECT: presented colouring agents have low conductivity and using them as black pigments in the electrophoretic displays enables reducing energy consumption as compared to using state-of-art carbon black.

11 cl, 1 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new macrocyclic compounds of formula

or their tautomer, pharmaceutically acceptable salt, solvate or ester, wherein: X represents O or NR; Y represents -O-(CH2)mCOOR or -O-(CH2)mCON(R)2, wherein groups related to a nitrogen atom, can be in a Z- or E-configuration; R1 and R2 independently represent hydrogen or halogen; R3, R4, R5, R6, R7, R8, R9 and R10 independently represent hydrogen, alkyl, OR, -O(CH2)mC(O)(CH2)pN(R)2, -O(CH2)mN(R)C(O)(CH2)pOR, -(CH2)mN3 or -O(CH2)mN3; and each R independently represents R11, hydrogen, alkyl, alkylamino, dialkylamino, alkoxycarbonyl, phenyl or a protective group; or two R on the same nitrogen are taken together with nitrogen for producing a 5-6-merous heterocyclic or heteroaryl ring; wherein the group contains more than one substitute R; wherein R is optionally substituted, and each R can be identical or different, and wherein the protective group is specified in ethoxymethyl, methoxymethyl, tert-butyldimethylsilyl (TBS), phenylmethylsilyl, trimethylsilyl (TMS), 2-trimethylsilyl ethoxymethyl (SEM), 2-trimethylsilylethyl, benzyl and substituted benzyl; R11 represents a group

,

wherein Z represents an inorganic or organic counter-ion specified in a halogen, -O-alkyl, toluene sulphonate, methylsulphonate, sulphonate, phosphate, formiate or carboxylate; n represents 0, 1 or 2; m and p independently represent 0, 1 or 2; and dashed lines mean either a single, or a double bond, wherein the necessary conditions of the valence are observed by additional hydrogen atoms; and wherein in formula I′, when n represents 1, and X represents O, and the double bond is present between the carbon atoms having R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 are other than hydrogen; and wherein in formula I′, when n represents 1, and X represents O, and the bond between the carbon atoms having R9 and R10, represents the single bond, then at least one of R5, R6, R7 or R8 is other than hydrogen. The invention also refers to pharmaceutical compositions containing these compounds, using them and methods of treating diseases mediated by kinases and a heat-shock protein 90 HSP90.

EFFECT: preparing the new macrocyclic compounds.

28 cl, 5 dwg, 3 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a preparation which inhibits microbial growth, which includes an arylamide compound as an active compound and kleptose or captisol.

EFFECT: methods of producing the preparation, use and method of treating microbial infections are disclosed.

21 cl, 5 dwg, 11 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

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