Vanilloid receptor subtype 1 (vr1) antagonists and application thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula

, where X1, X2, Y, R1a, R1b, R2a, R2b, A1, A2, A3 and A4 have the values specified in the description, which are vanilloid receptor subtype 1 (VR1) antagonists.

EFFECT: preparing a pharmaceutical composition on the basis of the compounds of formula 1 and developing methods of managing pain, neurotic pain, allodynia, inflammation or inflammatory disease associated pain, inflammatory hyperalgesia, bladder hyperactivity and urine incontinence.

22 cl, 21 ex

 

RELATED APPLICATIONS

This application sets the priority of the provisional application U.S. serial number 60/792699, filed on April 18, 2006

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to compounds spiroxamine formula (I)which are useful for treating disorders caused by or intensified by activity vanilloideae receptor subtype 1 (VR1). The present invention also includes pharmaceutical compositions containing the compounds of formula (I) and methods of treating some types of pain, overactive bladder and urinary incontinence using the aforementioned compounds and the above pharmaceutical compositions.

DESCRIPTION of the PRIOR art

Pain receptors (nociceptors) are the primary sensory (C and Aδ nerve fibres) ascending neurons, which are activated by a wide range of painful stimuli, including chemical, mechanical, thermal and proton (pH < 6) methods of influence. Lipophilic vanilloid, capsaicin activates primary sensory nerve fibres through specific capsaicinoid receptor on the surface of cells, cloned as VR1. Intradermal injection of capsaicin is characterized by the initial burning sensation or heat, followed by a long period of mo is olivine. Suggest that the analgesic component activation receptor VR1 is due to capsaicin-induced loss of sensitivity of primary sensory afferent endings. Thus, long-lasting analgesic effects of capsaicin led to the clinical application of analogues of capsaicin as a pain-relieving substances. In addition, capsazepine, antagonist capsaicinoid receptor may decrease caused by inflammation of hyperalgesia in experimental animals. The VR1 receptors localized on sensory afferent neurons that Innervate the bladder. Capsaicin or resiniferatoxin been shown to improve the symptoms of incontinence after insertion into the bladder.

Receptor VR1 was named "polymodal detector" painful stimulus, because it can be activated in several ways. The receptor channel activated by capsaicin and other vanilloids and, thus, is classified as a controlled ion channel ligands. Activation of the receptor VR1 by capsaicin may be blocked by a competitive antagonist of the receptor VR1, capsazepine. The channel can also be activated by protons. In slightly acidic conditions (pH 6-7) the affinity of capsaicin in respect of the receptor is increased, while at pH<6 is the direct activation of the channel. In addition, when the temperature of member the s reaches 43°C, the channel opens. Thus, the heat can directly open the channel in the absence of ligand. The analogue of capsaicin, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to the introduction of capsaicin, acid, or heat.

The channel is a non-conductor of cations. As extracellular sodium and calcium penetrate through the gap of the channel, leading to depolarization of the cell membrane. This depolarization increases neural excitability, leading to the emergence of bioelectric potential and the transmission of painful nerve impulses to the spinal cord. In addition, depolarization of the peripheral nerve endings can lead to the selection of peptides in inflammation, such as, but not limited to, substance P and CGRP, leading to increased peripheral tissue sensitivity.

Not so long ago, two groups of researchers reported that displayed "silent" mouse that lacks the receptor VR1. Electrophysiological study of sensory neurons (ganglion of the rear spine) in these animals showed a significant lack of response caused by painful stimuli, including capsaicin, heat and decrease in pH. These animals did not show any obvious signs of violation of conduct and did not differ in responses to acute the e pain heat or mechanical stimulation in relation to nematanthus mouse. VR1 (-/-) mice also exhibited decreased sensitivity to the nerve of nociception induced by mechanical or thermal injuries. However, VR1 silent mouse was found to be insensitive to pain effects of capsaicin, introduced intradermally, exposure to intense heat (50-55°C) and unsuccessful attempts to cause thermal hyperalgesia after intradermal injection of carrageenan.

Compounds of the present invention represent a new VR1 antagonists useful in the treatment of disorders caused by or exacerbated by activity vanilloideae receptor subtype 1 (VR1), such as pain, neuropathic pain, allodynia, pain associated with inflammation or inflammatory disease, inflammatory hyperalgesia, overactive bladder and urinary incontinence.

DETAILED description of the INVENTION

Definition of terms

As used in this description and the attached claims, the following terms have the following meanings:

The term "alkenyl", as used here, denotes a linear or branched hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Representative examples of alkenyl include, but are not ogran shall receive, ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-Heptene and 3-decenyl.

The term "alkyl", as used here, denotes a linear or branched hydrocarbon chain containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylbutyl, 3-etylhexyl, 3,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "quinil", as used here, denotes a linear or branched hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of quinil include, but are not limited to, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

The term "alkoxy", as used here, means an alkyl group, as defined here, is attached to the main molecular fragment through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentox, hexyloxy.

The term "aryl", as used here, means a phenyl group, a bicyclic Ari is or tricyclic aryl. Bicyclic and tricyclic aryl aryl represent a condensed hydrocarbon ring system containing no heteroatoms, where one or multiple condensed rings represent a phenyl group. Bicyclic aryl is a phenyl group condensed with a monocyclic cycloalkyl group, as defined here, monocyclic cycloalkenyl group, as defined here, or another phenyl group. Tricyclic aryl is a bicyclic aryl fused with a monocyclic cycloalkyl group, as defined here, monocyclic cycloalkenyl group, as defined here, or another phenyl group. Phenyl group, a bicyclic arily and tricyclic arily of the present invention attached to the primary slice through any substitutable atom in the phenyl group, bicyclic Allah and the tricyclic Allah respectively. Phenyl group, a bicyclic arily and tricyclic arily of the present invention can be unsubstituted or substituted. Representative examples of aryl include, but are not limited to, anthracene, fluorene, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, inden-1-yl, inden-4-yl, naphthyl, phenyl, 5,6,7,8-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl and tetrahydronaphthyl.

The term "shall cloaker" or "cycloalkane", as used here, means a monocyclic cycloalkyl or bicyclic cycloalkyl. Monocyclic cycloalkyl represents a saturated hydrocarbon ring system containing three to eight carbon atoms and not containing heteroatoms. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl represents a condensed ring system in which monocyclic cycloalkyl ring condensed with another monocyclic cycloalkyl group, as defined here. Monocyclic cycloalkyl and bicyclic cycloalkyl of the present invention can be unsubstituted or substituted and attached to the main fragment of the molecule through any capable of substitution of the carbon atom monocyclic cycloalkyl or bicyclic cycloalkyl respectively.

The term "cycloalkenyl" or "cycloalkyl", as used here, means a monocyclic cycloalkenyl or bicyclic cycloalkenyl. Monocyclic cycloalkenyl represents a non-aromatic, partially unsaturated hydrocarbon ring system containing 4, 5, 6, 7 or 8 carbon atoms and not containing heteroatoms. 4-Membered ring system contains one double bond, 5 - or 6-membered olavie systems contain one or two double bonds, and 7 - or 8-membered ring system containing one, two or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl is a condensed hydrocarbon ring system in which monocyclic cycloalkenyl ring condensed with a monocyclic cycloalkyl group, as defined here, or another monocyclic cycloalkenyl group, as defined here. Representative examples of bicyclic cycloalkenyl include, but are not limited to, azulene, 4,5,6,7-tetrahydro-3aH-inden, octahydronaphthalene and 1,6-dihydro-pentalene. Monocyclic cycloalkenyl and bicyclic cycloalkenyl according to the present invention can be unsubstituted or substituted and attached to the main fragment of the molecule through any capable of substitution of the carbon atom monocyclic cycloalkenyl and bicyclic cycloalkenyl, respectively.

The term "halo" or "halogen", as used here, means-Cl, -Br, -I or-F.

The term "halogenoalkane", as used here, refers to an alkoxy group, as defined here, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Representative examples of g is loganholme groups include, but not limited to, chloromethoxy, 2-floratone, triptoreline, 2-chloro-3-fermentelos, pentaverate.

The term "halogenated", as used here, refers to an alkyl group, as defined here, in which one, two, three, or four, five or six hydrogen atoms are replaced by halogen. Representative examples of halogenoalkane include, but are not limited to, chloromethyl, 2-foretel, trifluoromethyl, pentafluoroethyl and 2-chloro-3-terpencil.

The term "heterocycle" or "heterocyclic", as used here, refers to monocyclic the heterocycle or the bicyclic heterocycle. Monocyclic heterocycle is a non-aromatic saturated or partially unsaturated hydrocarbon ring system containing at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur. Monocyclic ring systems are illustrated by examples 4-membered ring containing three carbon atoms and one heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6-, 7 - or 8-membered ring containing one, two, three or four heteroatoms, where the heteroatoms independently selected from nitrogen, oxygen and sulfur, and the remaining atoms are carbon atoms. 5-Membered ring has 0 or 1 double bond. 6-Membered ring contains 0, 1 or 2 double bonds. 7 - or 8-clinochlore contains 0, 1, 2 or 3 double bonds. Monocyclic heterocycle according to the invention can be unsubstituted or substituted. Representative examples of unsubstituted or substituted monocyclic ring systems include, but are not limited to, azetidine, azepane, azepine, diazepine, DIOXOLANYL, dioxane, dithienyl, imidazolines, imidazolidinyl, isothiazolines, isothiazolinones, isoxazolyl, isoxazolidine, morpholine, oxadiazolyl, oxadiazolidine, oxazoline, 2-oxo-oxazolidin, oxazolidinyl, piperazinil, piperidinyl (piperidyl), pyranyl, pyrazolyl, pyrazolidine, pyrrolidyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyranyl, tetrahydrofuryl, thiadiazolyl, thiadiazolidine, thiazolyl, diazolidinyl, thiomorpholine, 1,1-dioxythiophene (sulfon thiomorpholine), tiopronin, 1,4-diazepan and tritional. The bicyclic heterocycle is a monocyclic heterocycle condensed with a phenyl group, a monocyclic cycloalkenyl group, as defined here, monocyclic cycloalkyl group, as defined here, or monocyclic heterocyclic group. Bicyclic heterocycles according to the invention can be unsubstituted or substituted. Representative examples of bicyclic heterocycles include, but are not limiting who are, benzodioxolyl, benzopyranyl, benzothiophene, 2,3-dihydroindole, indolizinyl, tetrahydroisoquinoline, tetrahydroquinoline, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-C]pyrrolyl and octahedral[3,4-C]pyrrolyl. Monocyclic and bicyclic heterocycles heterocycles of the present invention attached to the main fragment of the molecule through any capable of replacing a carbon atom or monocyclic nitrogen in the heterocycle or bicyclic heterocycles, respectively. The nitrogen heteroatom may be quaternions or may not be quaternions, and nitrogen atoms or sulfur can be oxidized or may not be oxidized. In addition, the nitrogen-containing heterocyclic rings may or may not be N-protected.

The term "heteroaryl", as used here, means a monocyclic heteroaryl or bicyclic heteroaryl. Monocyclic heteroaryl is an aromatic five - or six-membered ring, in which at least one atom selected from the group consisting of N, O and S and the remaining atoms are carbon atoms. Five-membered ring contains two double bonds, and six-membered ring containing three double bonds. Bicyclic heteroaryl represents a monocyclic heteroaryl, conden is new with a phenyl group, monocyclic cycloalkyl, as defined here, a monocyclic cycloalkenyl, as defined here, a monocyclic heterocycle, as defined here, or a monocyclic heteroaryl. Representative examples of monocyclic and bicyclic heteroaryl include, but are not limited to, benzothiazyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, 6,7-dihydro-1,3-benzothiazolyl, furanyl (furyl), imidazolyl, imidazo[1,2-a]pyridinyl, indazoles, indolyl, isoindolyl, isoxazolyl, ethenolysis, isothiazolin, naphthyridine, oxadiazole, oxazole, predominately, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, chinoline, thiazolyl, thienyl, triazolyl, thiadiazolyl, tetrazolyl, 1,2,3,4-tetrahydro-1,8-naphthiridine-2-yl and 5,6,7,8-tetrahydroquinolin-5-yl. Monocyclic and bicyclic heteroaryl of the present invention can be substituted or unsubstituted and they are connected to the main fragment of the molecule through any substitutable carbon atom or nitrogen in the monocyclic or bicyclic heteroaryl, respectively. In addition, the nitrogen heteroatom may be quaternions or may not be quaternions, nitrogen atoms or sulfur group can be oxidized or may not be oxidized. The nitrogen-containing ring may or may not be N-protected.

The terminology is "heteroatom", as used here, refers to atoms of nitrogen, oxygen and sulphur.

The term "hydroxyalkyl", as used here, means an alkyl group, as defined here, in which one or two hydrogen atoms substituted by-OH. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxybutyl and 2-ethyl-4-hydroxyethyl.

The term "oxo"as used here, means =O group.

Obtaining the compounds of the present invention

The compounds of this invention can be obtained by various synthesis methods. Representative methods are shown, but not limited to, schemes 1, 2 and 3.

Scheme 1

Urea of the formula (4), where X1, Y, Z, R1A, R1b, R2A, R2b, A1, A2, A3, A4such as defined by formula (I)can be obtained as shown in scheme 1. Amines of formula (1) can be transformed into compounds of the formula (2) reacts with disuccinimidylsulfite in a solvent such as, but not limited to, acetonitrile, dichloromethane or tetrahydrofuran, at a temperature from about room temperature to about 50°C, over a period of time from about 2 hours to about 48 hours.

Treatment of compounds of formula (2) amine and formula (3) in the presence of a base, such as, but not limited to, diisopropylethylamine or triethylamine, in a solvent such as, but not limited to, N,N-dimethylformamide, leads to ureas of formula (4). The reaction can be carried out when a temperature of from about room temperature to about 50°C., over a period of time from about 2 hours to about 24 hours.

Scheme 2

Amines of formula (8), where Y represents O, S or N(R7), and X1, R1A, R1b, R2A, R2b, R7, A1, A2, A3, A4such as defined by formula (I)can be obtained as shown in scheme 2.

The compounds of formula (5) after processing cyclic ketones of the formula (6) in the presence of a base such as, but not limited to, pyrrolidine, give ketones of the formula (7). The reaction is generally accelerated in a solvent such as, but not limited to, toluene, boiling under reflux.

Ketones of the formula (7) can be transformed into amines of formula (8) (a) when processing compounds of the formula (7) hydrochloride methoxylamine and a base, such as, but not limited to, pyridine or triethylamine; and (b) during processing of the product obtained at stage (a) regenerating agent.

Stage (a) is usually carried out in an alcohol solvent such as, but not limited to, methane is l, at a temperature of from about room temperature to about 50°C, over a period of time from about 1 hour to about 10 hours.

Examples of reducing agents used in stage (b)include, but are not limited to, hydrogen and 10% palladium on carbon in acidic conditions, hydrogen/Raney Nickel and socialwise hydride.

Scheme 3

Amines of formula (12), where X1, R1a, R1b, A1, A3, A4are as defined in formula (I), and R101is alkyl or (R1aR1b)q-REwhere RE, q, R1aand R1bare as defined in formula (I)can be obtained as shown in scheme 3.

Cyclic ketones of the formula (6) can be transformed into compounds of formula (9), if you handle them bromoxynil acid and diethylphosphate in the presence of a base such as, but not limited to, sodium hydride, in a solvent such as, but not limited to, 1,2-dimethoxyethan, approximately at room temperature.

The compounds of formula (9) after treatment phosphorus(III) oxychloride and resorcinol in the presence of zinc chloride to give the compounds of formula (10).

Alkylation of compounds of formula (10) can be achieved, for example, by treatment with alkylating agent of formula R101-X, in which X I is is a leaving group, such as, but not limited to, Cl, Br, I, triflate or methanesulfonate in the presence of a base such as, but not limited to, potassium carbonate or sodium hydride.

The compounds of formula (11) can be transformed into compounds of formula (12), using reaction conditions for the conversion of (7) in (8)as described in scheme 2.

It should be understood that the described scheme are only for illustrative purposes and that under normal experimental work, including appropriate sequence synthetic approaches, protection of any chemical functional group, which is incompatible with the reaction conditions, and the removal of such protective groups is included in the scope of the invention.

Compounds of the present invention

Compounds according to the invention can have the formula (I)as described herein. In more detail, the compounds of formula (I) may include, but are not limited to, compounds where Y is chosen from the group consisting of-S-, -S(O), -S(O)2, -O-, -N(R7)- or-C(R1aR1b)-, more preferably-O-. The invention includes compounds where Y is O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds, g the s Y represents O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is-C(R1aR1b)m-, m can be 1, 2, 3 or 4, and X2represents-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2represents -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents N; A2represents N; A3before the hat is CR 5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)p-G1-C(R1aR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents N; A2represents N; A3represents CR5; A4is with the battle of CR 6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p is 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents N; A3represents CR5; A4represents CR6X1is-C(R1AR1b)p-G1-C(R1AR1b)-; p is 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, m may be equal to the 1, 2, 3, or 4, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1predstavljaet a N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)p-G1-C(R1aR1b)-; and p can be 1 or 2. The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1aR1b)-; and p may be equal to 1 or 2, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents N; and A 4represents CR6X1is -(CR1AR1b)p-G1-C(R1aR1b)-, p can be 1 or 2, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. Available in the du, for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)p-G1-(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p is 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p is 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all nizes EBUSY compounds R 1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is - N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R6, RA, RB, RE, R7, Z, Rgand R hare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in formula from which retene in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in formula izaberete the Oia in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is - N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2depict is to place a N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention is those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A41is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1I have is -(CR 1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is - N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R4, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is predstavljaet a O, A1represents CR3; A2represents N; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R3, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1is an R 3; A2represents CR4; A3represents N; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents Oh, A1represents N; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R3, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents N; A2is Soboh the CR 4; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4depict is to place a CR 6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents N; A2represents CR4; A3represents CR5; and A4is Soboh the CR 6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents N; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1I have is -(CR 1aR1b)m-, m can be 1, 2, 3 or 4, and X2is-N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; the X 2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p can be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents N; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4, and X2is - N(H)C(O)N(H)-z Link the mi according to the invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in this invention are also those in which Y represents O,A 1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y is predstavljaet a O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1aR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is - N(H)C(O)N(H)-Z. Compounds according to the invention are also those in which Y represents O, A1represents CR3; A2is own the th CR 4; A3represents CR5; and A4represents N, X1is -(CR1aR1b)m-, m can be 1, 2, 3 or 4, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3is the th CR 5; and A4represents N, X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR 5; and A4represents N, X1is -(CR1AR1b)p-G1-C(R1AR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R5, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, and m can be 1, 2, 3 or 4. The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 1, and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X 1is -(CR1AR1b)m-, m is 1, X2is-N(H)C(O)N(H)-Z, and Z is a monocyclic or bicyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl; where each Z is independently unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, halogenoalkane, halogen, -NO2, -CN, -OH, alkoxy, halogenoalkane, -NH2, -N(H)(alkyl), -N(alkyl)2, -C(O)alkyl, -C(O)OH, -C(O)Valkila, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -S(alkyl), -S(O)alkyl, -S(O)2of alkyl, -S(O)2N(H)2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, REand -(CR1AR1b)q-RE. Preferably Z is a bicyclic ring, most preferably heteroaryl, most preferably by indazolinone. The compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 1, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R4, R5,R 6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 2, and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 2, X2is-N(H)C(O)N(H)-Z, and Z is a monocyclic or bicyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl; where each Z is independently unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, halogenoalkane, halogen, -NO2, -CN, -OH, alkoxy, halogenoalkane, -NH2, -N(H)(alkyl), -N(alkyl)2, -C(O)alkyl, -C(O)OH, -C(O)Valkila, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -S(alkyl), -S(O)alkyl, -S(O)2of alkyl, -S(O)2N(H)2, -S(O)2N(H)(alkyl), -S(O)2 N(alkyl)2, REand -(CR1AR1b)q-RE. Preferably Z is a bicyclic ring, most preferably heteroaryl, most preferably by indazolinone. The compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 2, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, R3, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The invention includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 3, and X2is-N(H)C(O)N(H)-Z. Compounds included in the present invention are those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR 5; and A4represents CR6X1is -(CR1AR1b)m-, m is 3, X2is-N(H)C(O)N(H)-Z, and Z is a monocyclic or bicyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl; where each Z is independently unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, halogenoalkane, halogen, -NO2, -CN, -OH, alkoxy, halogenoalkane, -NH2, -N(H)(alkyl), -N(alkyl)2, -C(O)alkyl, -C(O)OH, -C(O)Valkila, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -S(alkyl), -S(O)alkyl, -S(O)2of alkyl, -S(O)2N(H)2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, REand -(CR1AR1b)q-RE. Preferably Z is a bicyclic ring, most preferably heteroaryl, most preferably indazoles. The compounds according to the invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)m-, m is 3, and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R 2b, Rx, Ry, R3, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, and n can be 1, 2 or 3. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n is 2, G represents O; and X2is-N(H)C(O)N(H)-Z. the Present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n is 2, G is an N(Rx); Rxis hydrogen, alkyl, halogenation, Ry, -C(O)Valkila or-C(O)ORy; and X2is-N(H)C(O)N(H)-Z. Compounds included the tion in the present invention, are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)nG1-, n can be 1, 2 or 3; and X2is - (CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1aR1b)-; and p can be 1 or 2. The present invention also includes compounds where Y is O, A1represents CR3; A2represents CR4; A3represents N; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1aR1b)-; p may be equal to 1 or 2; and X2is-N(H)C(O)N(H)-Z. Joint is mi, included in the present invention are also those in which Y represents O, A1represents CR3; A2represents CR4; A3represents CR5; and A4represents CR6X1is -(CR1AR1b)p-G1-C(R1aR1b)-; p may be equal to 1 or 2; and X2is -(CRgRh)q-N(H)C(O)N(H)-Z. we mean that for all the following compounds R1a, R1b, R2a, R2b, Rx, Ry, G1, R3, R4, R5, R6, RA, RB, RE, R7, Z, Rgand Rhare as described in the claims in claim 1.

Compositions of the invention

The invention provides pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula (I) in combination with a pharmaceutically acceptable carrier. The compositions contain compounds according to the invention, included in the formulation, together with one or more non-toxic pharmaceutically acceptable carriers. You can make the formulation of pharmaceutical compositions for oral administration in solid or liquid form, for parenteral injection, or for rectal application.

The term "pharmaceutically acceptable carrier", as used here, means toxiciy inert solid, semi-solid or liquid filler, diluent, the material to be concluded in capsule or supporting the formulation of any type. Some examples of substances which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch or potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; coconut oil and wax for suppositories; oils such as peanut oil, cotton seeds, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as etiloleat and tillaart; agar; sautereau agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic; ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and the composition may be present coloring additives, antiadhesive, enrobing means, sweeteners, flavorant and flavoring agents, preservatives and antioxidants, according to the decision of the expert in the field of composition is possible formulations.

The pharmaceutical compositions of this invention can enter the human or other mammals orally, rectally, parenterally, intracisternally, intrawaginalno, intraperitoneally, locally (powders, ointments or drops), buccal or oral or nasal sprays. The term "parenteral"as used here, refers to modes of administration, including intravenous, intramuscular, intraperitoneal, epigastric, subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for their recovery by dissolving in sterile, suitable for injection, solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like, and suitable mixtures of them), vegetable oils (such as olive oil) and suitable for injectable organic esters such as ethyl oleate, or a suitable mixture of them. Suitable fluidity of the composition can be maintained, for example, by using a covering layer, such as lecithin, by the maintenance of the required particle size in the case of the var the sea and through the use of surface-active substances.

These compositions may also contain auxiliary agents such as preservatives, humectants, emulsifiers and dispersing agents. Prevention of the action of microorganisms provide various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. is Also desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged adsorption pharmaceutical forms intended for injection, can be done through the use of agents that slow down absorption such as aluminum monostearate and gelatin.

In some cases, for the implementation of the prolonged action of the medicinal product it is often desirable to slow the absorption of drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor water-solubility. The rate of absorption of the medicinal product may depend on its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, parenteral input medicines may be administered by dissolution or suspension of the drug in oil creditfederal.

Suspensions, in addition to the active compounds, may contain suspendresume agents, for example ethoxylated isostearyl alcohols, polyoxyethylenated and esters of sorbitol, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar, tragakant and mixtures thereof.

On request and for more effective distribution, the compounds according to the invention can be fed into the system slow release or targeted delivery, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through inhibiting bacteria filter or by introducing a sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environments, intended for injection, immediately prior to use.

Intended for injection forms of prolonged action can be made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug/polymer and the nature of each individual polymer used, it is possible to control the rate of release of the drug. Examples of other biodegradable polymers include poly(ortep the market) and poly(anhydrides). Intended for injection forms of prolonged action is also obtained by the introduction of the drug in liposomes or microemulsions that are compatible with body tissues.

Formulations intended for injection, can be sterilized, for example, by filtration through inhibiting bacteria filter or by introducing a sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environments, intended for injection, immediately prior to use.

Preparations intended for injection such as a sterile aqueous or oily suspension for injection, you can make the recipe according to the method known in this field, using suitable dispersing or wetting agents and suspendresume agents. A sterile preparation for injection may also be a sterile injectable solution, suspension for injection or emulsion for injection in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among suitable delivery vehicles or solvents that can be used are water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment of the commonly used sterile non-volatile oil. For this purpose you can use any mild non-volatile oils, including synthetic mono - or diglycerides. In addition, for the manufacture of tools for injection use fatty acids such as oleic acid.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, one or more compounds according to the invention are mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum Arabic; c) humectants such as glycerol; d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain silicates and sodium carbonate; e) retarding solution, such as paraffin; (f) adsorption accelerators, such as Quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, steer the calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also contain tabularasa agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using lactose or milk sugar, as well as glycols of high molecular mass.

Solid dosage forms as tablets, pills, capsules, pills and granules can be produced with coatings or shells, such as intersolubility coatings and other coatings well known in the preparation of pharmaceutical formulations. They may not necessarily contain cloud emulsions and can also be a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a slow way. Examples of materials used for slow release of the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal use are preferably suppositories which can be manufactured by mixing the compounds of this invention with suitable not cause irritation carriers such as cocoa butter, polyethylene glycol or the RSC for suppositories, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vagina, and secrete active connection.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, oil seeds, cotton, peanut, corn, butter, sprouted seeds, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids, sorbitol and their mixtures

Besides inert diluents, the oral compositions can also include ancillary tools, such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavorant additives and flavorings.

Dosage forms for local or percutaneous application of compounds of this invention include mA and, pastes, creams, lotions, gels, powders, solutions, sprays, means for inhalation or bandages. The desired compound according to the invention is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, which may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also considered as included in the scope of this invention. Ointments, pastes, creams and gels may contain, in addition to the active compounds according to the invention, animal and vegetable fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones substances, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to the compounds according to the invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorocarbons.

Compounds according to the invention can also be applied in the form of liposomes. As is well known in this field, liposomes is usually derived from phospholipids or other lipid substances. Liposomes typically form a mono - or multilamellar hydrated liquid crystals that are dispersed in the aquatic environment. You can use either toxiciy physiologically acceptable and metabolisable lipid, capable of forming liposomes. These compositions in the form of liposomes can contain, in addition to the compounds according to the invention, stabilizers, preservatives, etc. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithins), used separately or together.

Methods to form liposomes are known in this field. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.

Dosage forms for topical use the compounds of this invention include powders, sprays, ointments and drugs used for inhalation. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, powders and solutions are also considered as included in the scope of this invention. Aqueous liquid compositions according to the invention are also applicable in practice.

The term "pharmaceutically acceptable salt" refers to those salts which are, within the current medical judgment, suitable for use in contact with the tissues of humans and lower animals without causing excessive toxicity, irritation, allergic response and the like, in accordance with an acceptable ratio of benefit/risk. Pharmaceutically reception is going salts are well known in this field. Salt can be obtained in situ during the final isolation and purification of the compounds according to the invention or separately by the reaction of functional groups in free base with a suitable organic acid. Representative examples of acid additive salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic (isetionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluensulfonate, undecanoate.

Also, the basic nitrogen-containing groups can be quaternionic such agents as lower alkylhalogenide, such as methyl-, ethyl-, propyl - and butylchloride, bromides and iodides; diallylsulfide, such as dimethyl-, diethyl-, dibutil and dimycolate; long chain halides such as decyl-, lauryl-, myristyl and stearylamine, bromides and iodides; arylalkylamines, such as benzyl and phenetermine and others. You get a water or oil soluble or dispersible in water or in oil prod the points.

Examples of acids that can be used for the formation of pharmaceutically acceptable acid additive salts include such inorganic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

ó additive salts can be obtained in situ during the final isolation and purification of compounds of this invention by the reaction of the fragment containing carboxylic acid with a suitable base such as the hydroxide, carbonate or bicarbonate pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salt-based cations of alkali metals or alkaline earth metals such as lithium salts, sodium, potassium, calcium, magnesium and aluminum, and the like, and non-toxic cations of Quaternary ammonium and amines cations, including ammonium, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines suitable for education ó additive salts include Ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

The term "pharmaceutically acceptable prodrug" or "prodrug", as used here, refers to those prodrugs of the compounds according to the invention, which under the current medical opinion is suitable for use in contact with the tissues of humans and lower animals without causing excessive toxicity, irritation, allergic response and the like, in accordance with an acceptable ratio of benefit/risk, and effective for their purpose. Prodrugs according to the invention in vivo can be easily turned into a source compound of formula (I), for example, by hydrolysis in blood. A detailed discussion is presented in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

The invention considers pharmaceutically active compounds either chemically synthesized or formed by biotransformation in vivo to compounds of formula (I).

Methods of the invention

The compounds and compositions according to the invention is useful for improving or preventing violations are involved in activation of the receptor VR1, such as, but not limited to, pain, inflammatory thermal hyperalgesia, overactive bladder and urinary incontinence, as described by Nolano, M. et al., Pain. Vol. 81. pages 135-145, (1999); Caterina, M.J. and Julius, D., Annu. Rev. Neurosci. Vol. 24. pages 487-517 (201); Caterina, MJ. et al., Science Vol. 288 pages 306-313 (2000); Caterina, MJ. et al., Nature Vol. 389 pages 816-824 (1997); Fowler, C. Urology Vol. 55 pages 60-64 (2000); and Davis, J. et al., Nature Vol. 405 pages 183-187.

The present invention also provides pharmaceutical compositions which contain compounds of the present invention. The pharmaceutical compositions contain compounds of the present invention that can be included in the formulation, together with one or more nontoxic pharmaceutically acceptable carriers or diluents.

Examples

The following examples are intended to illustrate and not to limit the scope of the invention as defined in the attached claims.

Example 1

1-(1H-indazol-4-yl)-3-(Spiro[chroman-2,1'-cyclohexane]-4-yl)urea

Example 1A

Spiro[chroman-2,1'-cyclohexane]-4-one

A mixture of 2'-hydroxyacetophenone (Aldrich, CAS# 118-93-4, of 2.72 g, 20 mmol), cyclohexanone (2.7 ml) and 26.1 mmol) and pyrrolidine (of 1.66 ml, to 19.9 mmol) was stirred in 6 ml of toluene at room temperature for 1 h and boiling under reflux (with nozzle Dean-stark) for 4 hours After cooling to room temperature the mixture was diluted with ether (30 ml), successively washed with 2N HCl (10 ml), 2N NaOH (10 ml) and H2O (10 ml), dried over Na2SO4and filtered. Evaporation of volatiles under vacuum gave the crude named reception is e connection which was used without further purification.

Example 1B

Spiro[chroman-2,1'-cyclohexane]-4-amine

To a solution of the product from example 1A (3,022 g 13,99 mmol) in methanol (50 ml) were added hydrochloride methoxylamine (1,17 g, 14.0 mmol) and pyridine (5.7 ml, 70.5 mmol). The mixture was stirred over night at room temperature and then evaporated under vacuum. The residue was distributed between ethyl acetate and H2O and then the organic layer was dried over Na2SO4, filtered and evaporated under vacuum. Thus obtained residue was dissolved in methanol (50 ml) and was first made (from a cylinder) over 10% Pd on carbon in the presence of 4 drops of conc. HCl overnight at room temperature. After this time the catalyst was filtered through celite and the filtrate evaporated under vacuum. The residue was transferred into ether (50 ml) and was extracted with 1N HCl (3×20 ml). These acid extracts then zaslujivali to pH 10 2N NaOH and was extracted with ethyl acetate (3×20 ml). The organic extracts were dried over Na2SO4, filtered and evaporated under vacuum, getting named the title compound in the form of a yellow oil, 880 mg (29%).1H NMR (300 MHz, DMSO-d6) δ h/million 7,52 (m, 1H), 7,06 (m, 1H), PC 6.82 (TD, J=7,4, 1.3 Hz; 1H), 6,69 (DD; J=8,1, 1.3 Hz; 1H), 3,83 (DD; J=11,1, 6,3 Hz; 1H), 2,08 (DD; J=13,5, 6,3 Hz; 1H), 1,90 (m, 1H), 1,74 (m, 2H), 1,31-of 1.57 (m, 8H); MS (ESI+)m/z218 (M+H).

Example C

methyl-4-(3-Spiro[chroman-2,1'-cyclohexane]-4-yureina)-1H-indazol-1-carboxylate

The product of example 1B (880 mg, 4,06 mmol) was mixed with the product of example 1H (1,34 g, 4.04 mmol) and diisopropylethylamine (1.1 ml, 6,33 mmol) in 20 ml of N,N-dimethylformamide at room temperature for 2 hours after this time, N,N-dimethylformamide was removed under vacuum and the residue was dissolved in H2O. Forming thus the precipitate was separated by filtration and dried in the air, getting named the title compound in the form of a solid yellow-brown color, which was used without further purification.

Example 1D

1-(1H-indazol-4-yl)-3-(Spiro[chroman-2,1'-cyclohexane]-4-yl)urea

The product of example 1C (4,06 mmol) suspended in methanol (20 ml) and was treated with 5N methanolic solution of NaOH (3.3 ml, 16.5 mmol). The mixture was stirred at room temperature for 45 min, then poured in H2O (100 ml). The resulting precipitate was collected by filtration and dried in the air, getting named the title compound in the form of solids not quite white, 794 mg (43%).1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush., 1H), 8,67 (s, 1H), of 8.06 (s, 1H), 7,69 (d, J=7.5 Hz, 1H), 7,31 (d, J=7.8 Hz, 1H), 7.23 percent (J=7.8 Hz, 1H), 7,16 (m, 1H), was 7.08 (d, J=8.5 Hz, 1H), 6.90 to (dt; J=a 7.5, 1.0 Hz; 1H), 6,80 (DD; J=7,9, 1.0 Hz; 1H), 6,72 (d, J=8,1 Hz, 1H), to 4.98 (m, 1H), 2,24 (m, 1H), 1,33-to 1.82 (m, 11N). MS (ESI+)m/z 377 (M+H).

Example 1E

4-nitro-1H-indazol

2-Methyl-3-nitroaniline (20 g) in acetic acid (~200 ml) was treated with NaNO2(20 g) in water (50 ml) at 4°C with mechanical stirring). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure. The residue was treated with water (700 ml) and the mixture was filtered. The solid was dried at 45°C in a vacuum oven overnight to obtain specified in the connection header.1H NMR (DMSO-d6) δ 8,56 (s, 1H), 8,2-with 8.05 (DD, 2H), and 7.6 (t, 1H).

Alternatively, the 4-necked, 5-liter round bottom flask with the insulating cover is provided with a mechanical stirrer and a thermocouple was downloaded nitroaniline (100 g, 1.0 equiv.) and acetic acid (2000 ml). The solution was cooled to 14°C. Quickly in one step was added cooled to about 1°C (bath with ice) solution of sodium nitrite (100 g, 2.2 equiv.) in water (250 ml). The internal temperature rose from 14°C to 27.6°C for 5 min, remaining at this temperature for 5 min, before gradually be lowered to 15°C. the Mixture was stirred for 24 h, then concentrated under vacuum to a volume of approximately 500 ml Residue resuspendable in water (1800 ml) at ambient temperature for 21 hours. Solid orange color was filtered, washed in the Oh (3×250 ml) and dried in a vacuum oven at 70°C to obtain 97,0 g named in the title compound in the form of a solid bright orange color.

Example 1F

methyl-4-nitro-1H-indazol-1-carboxylate

NaH (0.3 g, 12.5 mmol) in N,N-dimethylformamide (5 ml) was treated with the product of example 1E (1,33 g, 10 mmol) at 0°C. the Reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was treated with methylchloroform (0.9 ml) and stirred at room temperature for 3 hours. The mixture was treated with water and filtered to obtain named the title compound as a solid substance.1H NMR (300 MHz, DMSO-d6) δ 4,19 (s, 3H), 7,9 (t, 1H), scored 8.38 (d, 1H), to 8.62 (d, 1H), cent to 8.85 (s, 1 H).

Alternatively, in a 3-necked 2-liter flask in shelter heat insulating casing, equipped with a mechanical stirrer, thermocouple and a funnel to add, downloaded for 95.2 g of the product from example 1E and N,N-dimethylformamide (650 ml). The dark solution was cooled to 10°C and through the funnel was added 1,8-diazabicyclo[5.4.0]undec-7-ene (96,0 g, 1.1 equiv.) so that the internal temperature did not exceed 15°C. After cooling the mixture to 10°C through a funnel was added methylchloroform (108,5 g, 2.0 equiv.) so that the internal temperature did not exceed 25°C. After 1 hour stirring at 10°C was added aqueous 10% solution vukislova potassium phosphate (500 ml) and the mixture was stirred for 15 hours. The resulting solid brown was filtered and the reaction vessel was washed water 0% solution vukislova potassium phosphate (2×150 ml). Wash solutions were added to the solid matter on the filter. The resulting solid is washed with aqueous 10% solution vukislova potassium phosphate (2×200 ml), water (2×200 ml) and dried in a vacuum oven at 70°C, receiving 122,2 g solids dark brown color. Solid resuspendable in isopropylacetate (2000 ml) for 2 hours. The solid was filtered off, washed with fresh isopropylacetate (2×250 ml) and dried in a vacuum oven at 70°C, receiving 110,2 g named in the title compound in the form of a solid light brown color.

Example 1G

methyl-4-amino-1H-indazol-1-carboxylate

The product of example 1F (1.66 g, 7.5 mmol) and 10% Pd/C were combined in ethanol (20 ml) and placed in an atmosphere of hydrogen. The reaction mixture was heated at 80°C for 20 minutes, allowed to cool to room temperature and filtered through celite. The filtrate is evaporated to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ 6,1 (s, 2H), 6,41 (DD, 1H), 7,21 (m, 2H), 8,42 (s, 1H).

Alternatively, the reaction vessel was loaded the product of example 1F, methanol (2000 ml) and 5% Pd/C (10.6 g). Above mixture was created pressure H2(40 psi) and stirred on a shaker at ambient temperature. The reaction was completed in 1.5 hours. The mixture was filtered to obtain the product in methanol. The reaction is ionic mixture was added conc. 37% HCl (100 ml). A solution of the product was concentrated to obtain a solid light brown color. Solid resuspendable in isopropyl alcohol (200 ml) for 15 minutes. The solid was filtered and washed with fresh isopropyl alcohol (3×50 ml) and dried in a vacuum oven, receiving of 94.9 g of methyl ester hydrochloride 4-aminodiol-1-carboxylic acid in the form of a solid light brown color.

Example 1H

Methyl ester of 4-(2,5-dioxo-pyrrolidin-1-yl-oxycarbonyl)-indazol-1-carboxylic acid

The product of example 1G (1.9 g, 10 mmol) and disuccinimidyl (2.8 g, 11 mmol) was stirred in acetonitrile (100 ml) for 48 hours in nitrogen atmosphere. A solid substance was separated by filtration, washed with acetonitrile (10 ml) and dried in a vacuum oven at ambient temperature, getting named the title compound (2,56 g, 77%) as a solid substance not quite white.

Example 2

1-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 2A

7 perspire[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 4'-fluoro-2'-hydroxyacetophenone (Aldrich, CAS# 1481-27-2).1H NMR (300 MHz, DMSO-d6) δ h/million for 7.78 (DD; J=8,5, 6,8 Hz; 1H), to 6.88(m, 2H), 2,78 (s, 2H), of 1.88 (m, 2H), 1,44-to 1.63 (m, 6H), of 1.24 to 1.37 (m, 2H). MS (DCI+)m/z235 (M+H), 252 (M+NH4).

Example 2B

7 perspire[chroman-2,1'-cyclohexane]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A example 2A.1H NMR (300 MHz, DMSO-d6) δ h/million EUR 7.57 (m, 1H), of 6.52 (m, 2H), 3,82 (m, 1H), 2,11 (m, 1H), 1,92 (m, 1H), 1,38-of 1.73 (m, 10H). MS (DCI+) 236 (M+H).

Example 2C

methyl-4-(3-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 2B. The crude compound was then used without further purification.

Example 2D

1-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 2C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,00 (s, 1H), 8,68 (s, 1H), of 8.06 (s, 1H), to 7.67 (d, J=7,4 Hz, 1H), 7,35 (m, 1H), 7,22 (t, J=8.0 Hz, 1H), was 7.08 (d, J=8,3 Hz, 1H), 6.75 in (m, 2H), only 6.64 (DD; J=10,3, 2,7 Hz; 1H), 4,96 (m, 1H), 2,25 (DD; J=13,5, 6,5 Hz; 1H), 1,33-to 1.79 (m, 11H). MS (ESI+)m/z395 (M+H), 417 (M+Na).

Example 3

1-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea

Example 3A

7 perspire[chroman-2,1'-CYCLOBUTANE]-4-one

Named in the title soedineniya, using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 4'-fluoro-2'-hydroxyacetophenone (Aldrich, CAS# 1481-27-2) and substituting cyclohexanone for cyclobutanone.1H NMR (300 MHz, DMSO-d6) δ h/million 7,80 (DD; J=8,6, and 6.6 Hz, 1H), 6,93 (m, 2H), 2,98 (s, 2H), 2,07-of 2.28 (m, 4H), 1,73 is 1.86 (m, 2H); MS (DCI+)m/z207 (M+H), 224 (M+NH4).

Example 3B

7 perspire[chroman-2,1'-CYCLOBUTANE]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A in example 3A.1H NMR (300 MHz, DMSO-d6) δ h/million 7,52 (m, 1H), 6,67 (m, 1H), of 6.52 (DD; J=a 9.5, 2.7 Hz; 1H), 3,80 (DD; J=10,9, 5.8 Hz; 1H, in), 2.25 (m, 2H), 2,09 (m, 4H), 1,57-1,71 (m, 2H). MS (DCI+)m/z208 (M+H), 225 (M+NH4).

Example 3C

methyl-4-(3-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B in example 3B. The crude compound was then used without further purification.

Example 3D

1-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 3C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush., 1H), 8,71 (s, 1H), 8,07 (s, 1H), 7,68 (d, J=7,4 Hz, 1H), 7,25 (m, 2H), to 7.09 (d, J=8,2 Hz, 1H), 6,78 (m, 2H), 6,67 (DD; J=10,5, 2,7 Hz; 1H), 4,94 (m, 1H), 2,41 DD; J=13,4, and 5.5 Hz, 1H), of 2.21 (m, 3H), 1.70 to of 1.97 (m, 4H). MS (ESI+)m/z367 (M+H).

Example 4

1-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea

A solution of the compound from example 3D (483 mg, 1,32 mmol) in N,N-dimethylformamide (5 ml) was treated with 60% NaH (65 mg, and 1.63 mmol) and the mixture was stirred at room temperature for 45 minutes Then add dimethylsulfate (0,14 ml, 1.48 mmol) and the reaction was left to mix for 1 hour. Concentration in vacuo followed by chromatography on silica gel (98:2 CH2Cl2-methanol eluent) gave named in the title compound in the form of solids not quite white, 121 mg (24%).1H NMR (300 MHz, DMSO-d6) δ h/million to € 8.74 (s, 1H), 8,03 (s, 1H), 7,72 (d, J=7,1 Hz, 1H), 7,29 (m, 2H), 7,16 (d, J=8.5 Hz, 1H), 6,77 (m, 2H), 6,66 (DD; J=10.5V, and 7.8 Hz, 1H), equal to 4.97 (m, 1H), 4,01 (s, 3H), 2.40 a (m, 1H), 2,12-of 2.30 (m, 4H), 1,65 of 1.99 (m, 3H). MS (ESI+)m/z381 (M+H).

Example 5

1-(6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 5A

6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 4',5'-dimethyl-2'-hydroxyacetophenone (Acros, CAS# 36436-65-4).1H NMR (300 MHz, DMSO-d6) δ 7,44 (s, 1H), 6,84 (s, 1H), 2,68 (s, 2H), of 2.23 (s, 3H), of 2.16 (s, 3H), 1,80-to 1.87 (m, 2H), 1,42-of 1.62 (m, 10H). MS (DCI+)m/z245 (M+H), 262 (M+NHsub> 4).

Example 5B

6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A in example 5A.1H NMR (300 MHz, DMSO-d6) δ h/million of 7.23 (s, 1H), of 6.49 (s, 1H), 3,78 (m, 1H), 2,02 (m, 2H), 1,59-of 1.73 (m, 2H), 1,24-of 1.53 (m, 8H). MS (DCI+)m/z246 (M+H).

Example 5C

methyl-4-(3-(6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 5B example 1B. The crude compound was then used without further purification.

Example 5D

1-(6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 5C example 1C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush, 1H), 8,65 (s, 1H), of 8.06 (s, 1H), 7,69 (d, J=7.5 Hz, 1H), 7,22 (t, J=8.0 Hz, 1H), 7,06 (m, 2H), 6,66 (d, J=8,1 Hz, 1H), is 6.61 (s, 1H), is 4.93 (m, 1H), 2,21 (DD; J=13,9, 6,1 Hz; 1H), 2,14 (, 3H), 2,12 (s, 3H), of 1.62-1.77 in (m, 4H), 1,44-to 1.61 (m, 7H). MS (ESI+)m/z405 (M+H).

Example 6

1-(6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 6A

6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in the example 1A, substituting 3,5-dichloro-2-hydroxyacetophenone (Lancaster, CAS# 3321-92-4) 2'-hydroxyacetophenone.1H NMR (300 MHz, DMSO-d6) δ h/million a 7.92 (d, J=2.4 Hz, 1H), 7.62mm (d, J=2.4 Hz, 1H), 2,87 (s, 2H), 1.91 a (m, 2H), 1,47 by 1.68 (m, 8H). MS (DCI+)m/z284 (M+H).

Example 6B

6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-amine

A mixture of the compound from example 6A (1,001 g, 3,51 mmol), hydrochloride of methoxylamine (293 mg, 3,51 mmol) and pyridine (1.4 ml, 17.3 mmol) in methanol (25 ml) was stirred overnight at room temperature. After this time the solvent is evaporated under vacuum, and the residue was dissolved in ether and washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated under vacuum, and the residue was further dried azeotrope (CH3CN). A solution of the residue in tetrahydrofuran (4 ml) was cooled to 0° and then slowly treated with 1M BH3-tetrahydrofuran (5 ml, 5 mmol). At the end of the addition the reaction was heated under reflux for 2.5 hours the Mixture was cooled to room temperature and carefully treated H2O (3 ml) and 20% aqueous KOH (3 ml), and then boiled under reflux for 1 h the Mixture was cooled and was extracted with ethyl acetate. The organic extracts were washed 1N Hcl. The aqueous layer was zaslujivali 2M NaOH followed by extraction with ethyl acetate, getting called in the header joint is in the form of a yellow oil, 64 mg (6%).1Η NMR (300 MHz, DMSO-d6) δ h/million of 7.55 (DD; J=14,9, 2,7 Hz; 1H), was 7.36 (m, 1H), 3,82 (m, 1H), 2,11 (m, 2H), 1,20-to 1.82 (m, 10H). MS (DCI+)m/z286 (M+H).

Example 6C

methyl-4-(3-(6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 6B. The crude compound was then used without further purification.

Example 6D

1-(6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C example 6C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,00 (ush, 1H), 8,83 (s, 1H), 8,10 (s, 1H), to 7.64 (d, J=7.7 Hz, 1H), 7,47 (d, J=2.5 Hz, 1H), 7,29 (m, 1H), 7.23 percent (t, J=8.0 Hz, 1H), to 7.09 (d, J=8,3 Hz, 1H), make 6.90 (d, J=4.3 Hz, 1H), of 5.05 (m, 1H), of 2.23 (DD; J=13,4, and 6.6 Hz, 1H), 1,74-of 1.85 (m, 4H), 1,43-of 1.66 (m, 7H). MS (ESI+)m/z445 (M+H).

Example 7

1-(6-chlorpro[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 7A

6 harsper[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 5'-chloro-2'-hydroxyacetophenone (Aldrich, CAS# 1450-74-4).1H NMR (300 MHz, DMSO-d6) δ h/million of 7.64 (d, J=2.7 Hz, 1H), 7,60 (DD; J=8,6, and 2.7 Hz, 1H), to 7.09 (d, J=9,2 Hz, 1H), 2,80 (s, 2H), 1,85 (who, 2H), 1,45-to 1.60 (m, 8H). MS (DCI+)m/z251 (M+H), 268 (M+NH4).

Example 7B

6 harsper[chroman-2,1'-cyclohexane]-4-amine

Named in the title compound was obtained using the procedure described in example 6B, substituting example 6A example 7A.1H NMR (300 MHz, DMSO-d6) δ h/million 7,58 (d, J=2.7 Hz, 1H), was 7.08 (DD; J=8,8, 2,7 Hz; 1H), of 6.71 (d, J=8,8 Hz, 1H), 3,81 (m, 1H), 2,05-2,11 (m, 1H), 1,15-of 1.74 (m, 11H). MS (DCI+)m/z252 (M+H).

Example 7C

methyl-4-(3-(6-chlorpro[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B in example 7B. The crude compound was then used without further purification.

Example 7D

1-(6-chlorpro[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C example 7C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,02 (ush, 1IH), 8,79 (s, 1H), 8,10 (s, 1H), to 7.67 (d, J=7,4 Hz, 1H), 7,28 (m, 1H), 7.18 in-of 7.23 (m, 2H), to 7.09 (d, J=8.5 Hz, 1H), 6,82-to 6.88 (m, 2H), free 5.01 (m, 1H), and 2.26 (m, 1H), 1,72 (m, 4H), 1,35-1,76 (m, 7H). MS (ESI+)m/z411 (M+H).

Example 8

1-(7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea

Example 8A

4'-tert-butyl-2'-hydroxyacetophenone

A mixture of 3-tert-butylphenol (4.8 g, 32 mmol) and acetate of soda is I (6.5 g) was boiled under reflux in acetic anhydride (27 ml) for 3 hours After cooling to room temperature the mixture was poured into water and was extracted with ether. The ethereal extracts are then thoroughly mixed with solid K2CO3throughout the night. Filtration, followed by drying over Na2SO4and evaporation in vacuum led to the corresponding crude acetate in the form of oil pale yellow color, which was used directly without further purification.

To this crude acetate (5,96 g, was 31.0 mmol) was added AlCl3(7,16 g of 53.7 mmol) and the mixture was heated with mechanical stirring at 120°C for 2.5 h, the Reaction mixture was then cooled to room temperature and carefully poured the H2O and 6N HCl. Extraction with ether followed by chromatography on silica gel (95:5 hexane-ethyl acetate to 9:1 hexane-ethyl acetate gradient as eluent)gave named the title compound as a thick oil yellow, 2,165 g (36%).1H NMR (300 MHz, DMSO-d6) δ h/million 12,01 (ush, 1H), 7,81 (d, J=8.5 Hz, 1H), 7,01 (DD, J=8,5, 2.0 Hz, 1H), 6,91 (d, J=2.0 Hz, 1H), 2,61 (s, 2H), 1.27mm (s, 9H). MS (ESI)m/z193 (M+H).

Example 8B

7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone on the compound from example 8A and cyclohexanone to CYCLOBUTANE.1H NMR (300 MHz, DMSO-d6) δ h/m is n of 7.64 (d, J=8,4 Hz, 1H), 7,11 (DD; J=8,5) and 1.7 Hz, 1H), 6,99 (d, J=1.7 Hz, 1H), 2,92 (s, 2H), 2,08-of 2.26 (m, 4H), to 1.76 (m, 2H), 1.27mm (s, 9H). MS (DCI+)m/z245 (M+H), 262 (M+NH4).

Example 8C

7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A example 8B.1H NMR (300 MHz, DMSO-d6) δ h/million 7,41 (d, J=8.5 Hz, 1H), 7,03 (DD; J=8,1, 2,1 Hz; 1H), PC 6.82 (d, J=2.0 Hz, 1H), 4,51 (m, 1H), 1,99-of 2.21 (m, 3H), 1,65 is 1.91 (m, 5H), 1,24 (s, 9H). MS (DCI+)m/z246 (M+H).

Example 8D

methyl-4-(3-(7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 8C. The crude compound was then used without further purification.

Example 8E

1-(7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 8D.1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush, 1H), 8,66 (s, 1H), with 8.05 (s, 1H), 7,69 (d, J=7,1 Hz, 1H), 7,20 (m, 2H), was 7.08 (d, J=8.5 Hz, 1H), of 6.96 (DD; J=7,7, 1,8 Hz; 1H), 6,78 (d, J=2.0 Hz, 1H), 6,74 (d, J=7.8 Hz, 1H), 4,94 (m, 1H), 2,14-to 2.41 (m, 3H), 1.75 is of 1.99 (m, 5H), 1,24 (s, 9H). MS (ESI+)m/z405 (M+H), 427 (M+Na).

Example 9

1-(6,8-dipersio[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 9A

6,8-dipersio[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 3.5-debtor-2-hydroxyacetophenone (Apollo, CAS# 140675-42-9).1H NMR (300 MHz, DMSO-d6) δ h/million of 7.65-7,72 (m, 1H), 7.23 percent-7,31 (m, 1H), 7,14-7,19 (m, 1H), 2,88 (s, 2H), 1,89 (m, 2H), 1,46-of 1.62 (m, 8H). MS (DCI+)m/z253 (M+H).

Example 9B

6,8-dipersio[chroman-2,1'-cyclohexane]-4-amine

Named in the title compound was obtained using the procedure described in example 6B, substituting example 6A example 9A.1H NMR (300 MHz, DMSO-d6) δ h/million 7,20-7,25 (m, 1H), 7,01-was 7.08 (m, 1H), 3,79-of 3.85 (m, 1H), 2,11 (m, 1H), 1,33-of 1.73 (m, 11H). MS (DCI+)m/z254 (M+H), 271 (M+NH4).

Example 9C

methyl-4-(3-(6,8-dipersio[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 9B. The crude compound was then used without further purification.

Example 9D

1-(6,8-dipersio[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C example 9C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,00 (ush, 1H), 8,76 (s, 1H), 8,08 (s, 1H), to 7.64 (s, 1H), 7,16-7,25 (m, 2H), 7.09 in d, J=8,3 Hz, 1H), 6,97 (m, 1H), 6,83 (d, J=8,3 Hz, 1H), free 5.01 (m, 1H), to 2.29 (m, 1H), 1,66-to 1.82 (m, 5H), 1,44-to 1.63 (m, 6H). MS (ESI+)m/z413 (M+H), 435 (M+Na).

Example 10

1-(6-toxisperma[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 10A

6 toxisperma[chroman-2,1'-cyclohexane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 5'-ethoxy-2'-hydroxyacetophenone (Aldrich, CAS# 56414-14-3).1H NMR (300 MHz, DMSO-d6) δ h/million 7,13-to 7.18 (m, 2H), 6,95 (d, J=8,4 Hz, 1H), 3,99 (kV, J=7,1 Hz, 2H), 2,73 (s, 2H), 1,74 is 1.86 (m, 2H), 1,39-of 1.66 (m, 8H), of 1.30 (t, J=7,1 Hz, 3H). MS (DCI+)m/z261 (M+H), 278 (M+NH4).

Example 10B

6 toxisperma[chroman-2,1'-cyclohexane]-4-amine

The mixture of example 10A (1,182 g, 4,55 mmol), hydrochloride of methoxylamine (380 mg, 4,55 mmol) and pyridine (1.8 ml, of 22.3 mmol) in methanol (15 ml) was stirred overnight at room temperature. After this time the solvent is evaporated in vacuo, then the residue was dissolved in ether and washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo, and the residue was further dried azeotrope (CH3CN). A solution of the residue (942 mg, 3,26 mmol) in tetrahydrofuran (10 ml) was slowly treated with 1M LiAlH4in tetrahydrofuran (5 ml, 5 mmol). At the end of the addition the reaction was subjected to boiling the reflux for 2.5 hours The mixture was cooled to room temperature and carefully poured water, and then filtered. The filter cake was washed with ethyl acetate and the combined filtrates evaporated in vacuum, obtaining the oil is Golden in color. This oil is moved in ether and was extracted with 1N HCl, then the acidic extracts zaslujivali 2N NaOH and was extracted with ethyl acetate. Drying of the organic extracts (Na2SO4), filtration followed by evaporation in vacuum gave named in the title compound in the form of oil, gold color, 320 mg (38%).1H NMR (300 MHz, DMSO-d6) δ h/million 7,10 (d, J=2.7 Hz, 1H), 6,58 of 6.66 (m, 2H), 3,93 (kV, J=7,1 Hz, 2H), 3,78 (m, 1H), 2,04 (m, 1H), 1,36-to 1.77 (m, 11H), of 1.17 (t, J=7.0 Hz, 3H). MS (DCI+)m/z262 (M+H).

Example 10C

methyl-4-(3-(6-toxisperma[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 10B. The crude compound was then used without further purification.

Example 10D

1-(6-toxisperma[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 10C.1H NMR (300 MHz, DMSO-d6) δ h/million 12,99 (ush, 1H), 8,72 (s, 1H), 8,08 (d, J=1.0 Hz, 1H), 7,68 (DD; J=7,8, 1.5 Hz; 1H), 7,21 (m, 2H), was 7.08 (d, J=8,1 Hz, 1H), 6,84 (who, 1H), 6,76 (m, 2H), 4,94 (m, 1H), 3,92 (kV, J=7,1 Hz, 2H), 2,23 (m, 1H), 1,71 (m, 4H), 1,42-to 1.59 (m, 7H), of 1.26 (t, J=7,1 Hz, 3H). MS (ESI+) 421 (M+H).

Example 11

1-(1H-indazol-4-yl)-3-(6-methylspiro[chroman-2,1'-cyclopentane]-4-yl)urea

Example 11A

6 methylspiro[chroman-2,1'-cyclopentane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 2'-hydroxy-5'-methylacetophenone (Aldrich, CAS# 1450-72-2) and cyclohexanone in Cyclopentanone.1H NMR (300 MHz, DMSO-d6) δ h/million 7,51 (m, 1H), 7,35 (m, 1H), 6.87 in (d, J=8.5 Hz, 1H), 2,85 (s, 2H), and 2.26 (s, 3H), 1,89-of 1.95 (m, 2H), 1,59-to 1.79 (m, 6H). MS (DCI+)m/z217 (M+H), 234 (M+NH4).

Example 11B

6 methylspiro[chroman-2,1'-cyclopentane]-4-amine

Named in the title compound was obtained using the procedure described in example 10B, substituting example 10A for example 11A.1H NMR (300 MHz, DMSO-d6) δ h/million at 6.84 (m, 2H), 6,54 (m, 1H), 3,78 (m, 1H, in), 2.25 (m, 1H), 2,17 (s, 3H), 1,43 is 1.86 (m, 9H). MS (DCI+)m/z218 (M+H).

Example 11C

methyl-4-(3-(6-methylspiro[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 11B. The crude compound was then used without further purification.

Example 11D

1-(1H-indazol-4-yl)-3-(6-methylspiro[chroman-2,1'-cyclopentane]-4-and the)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 11C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,00 (ush, 1H), to 8.70 (s, 1H), 8,07 (s, 1H), of 7.70 (d, J=7,1 Hz, 1H), 7,22 (m, 2H), 7,11 (m, 1H), of 6.96 (m, 1H), 6.75 in (d, J=6,8 Hz, 1H), only 6.64 (d, J=7.9 Hz, 1H), equal to 4.97 (m, 1H), of 2.21 (s, 3H), 2,18 (m, 1H), 1,39 of-1.83 (m, 9H). MS (ESI+) 377 (M+H), 399 (M+Na).

Example 12

1-(7-toxisperma[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 12A

7 toxisperma[chroman-2,1'-cyclopentane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 4'-ethoxy-2'-hydroxyacetophenone (Aldrich, CAS# 37470-42-1) and cyclohexanone in Cyclopentanone.1H NMR (300 MHz, DMSO-d6) δ h/million of 7.65 (d, J=8.6 Hz, 1H), to 6.57 (DD; J=8,4, 2,3 Hz; 1H), 6,45 (d, J=2.4 Hz, 1H), 4,08 (kV, J=7,1 Hz, 2H), and 2.79 (s, 2H), was 1.94 (m, 2H), 1,60-1,80 (m, 6H), 1,32 (t, J=7.0 Hz, 3H). MS (DCI+)m/z247 (M+H), 264 (M+NH4).

Example 12B

7 toxisperma[chroman-2,1'-cyclopentane]-4-amine

Named in the title compound was obtained using the procedure described in example 10, substituting example 10A example 12A was used without further purification.

Example 12C

methyl-4-(3-(7-toxisperma[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the methodology described in note the PE 1C, substituting example 1B example 12B. The crude compound was then used without further purification.

Example 12D

1-(7-toxisperma[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C example 12C.1H NMR (300 MHz, DMSO-d6) δ h/million 12,99 (ush, 1H), 8,67 (s, 1H), of 8.06 (s, 1H), 7,68 (d, J=7,0 Hz, 1H), 7,19 (m, 2H), 7,07 (d, J=8,3 Hz, 1H), 6,66 (d, J=6.3 Hz, 1H), 6,50 (DD; J=8,5, 2,5 Hz; 1H), 6,28 (d, J=2.5 Hz, 1H), 4.92 in (m, 1H), of 3.97 (q, J=7,0 Hz, 2H), 2,18 (m, 1H), was 1.94 (m, 1H), 1,61-of 1.84 (m, 8H), of 1.29 (t, J=7,1 Hz, 3H). MS (ESI+)m/z407 (M+H), 429 (M+Na).

Example 13

1-(6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea

Example 13A

6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting 2'-hydroxyacetophenone 4',5'-dimethyl-2'-hydroxyacetophenone (Acros, CAS# 36436-65-4) and cyclohexanone in Cyclopentanone.1H NMR (300 MHz, DMSO-d6) δ h/million 7,46 (s, 1H), 6,79 (s, 1H), 2,80 (s, 2H), 2,22 (s, 3H), 2,17 (s, 3H), 1,90 (m, 2H), of 1.66 (m, 6H). MS (DCI+)m/z231 (M+H), 248 (M+NH4).

Example 13B

6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-amine

Named in the title compound was obtained using the procedure described in example 10B, substituting example 10A for example 13A.1H NMR (300 MHz, DMSO-d/i> 6) δ h/million 6,69 (m, 1H), 6,45 (m, 1H, in), 3.75 (m, 1H), 2,24 (m, 1H), 2,11 (s, 3H), 2,07 (s, 3H), 1.41 to to 1.86 (m, 9H).

Example 13C

Methyl-4-(3-(6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 13B. The crude compound was then used without further purification.

Example 13D

1-(6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 13C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush, 1H), 8,67 (s, 1H), of 8.06 (s, 1H), of 7.70 (d, J=7,1 Hz, 1H), 7,22 (m, 1H), 7,07 (d, J=8,2 Hz, 1H), 7,05 (s, 1H), of 6.68 (d, J=7.8 Hz, 1H), 6,56 (s, 1H), 4.92 in (m, 1H), 2,19 (m, 1H), 2,14 (, 3H), 2,12 (s, 3H), 1.93 and (m, 1H), 1,55-of 1.84 (m, 8H). MS (ESI+) 391 (M+H), 413 (M+Na).

Example 14

1-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea

Named in the title compound was obtained using the procedure described in example 4, substituting example 3D example 2D.1H NMR (300 MHz, DMSO-d6) δ 8,71 (s, 1H), 8,03 (d, J=1.1 Hz, 1H), of 7.70 (DD; J=7,9, 1,1 Hz; 1H), 7,25-7,35 (m, 2H), 7,17 (d, J=8.5 Hz, 1H), 6,62-of 6.78 (m, 3H), 4,94 (m, 1H), 4.00 points (s, 3H), of 2.23 (m, 1H), 1,51 is 1.75 (m, 11H). MS (ESI+)m/z409 (M+H), 431 (M+Na).

Example 15

1-(1-methyl-1H-indazol-4-yl)-3-(Spiro[chroman-2,1'-cyclohexane]-4-yl)mochaui is and

Named in the title compound was obtained using the procedure described in example 4, substituting example 3D example 1D.1Η NMR (300 MHz, DMSO-d6) δ to 8.70 (s, 1H), 8,03 (d, J=1.1 Hz, 1H), 7,72 (d, J=7.5 Hz, 1H), 7,25-to 7.32 (m, 2H), 7,16 (m, 2H), 6.90 to (m, 1H), 6,80 (d, J=8,1 Hz, 1H), of 6.71 (d, J=8,8 Hz, 1H), 4,99 (m, 1H), 4.00 points (s, 3H), and 2.26 (m, 1H), of 1.42-1.77 in (m, 11H). MS (ESI+)m/z391 (M+H).

Example 16

1-(1H-indazol-4-yl)-3-(7-methoxamine[chroman-2,1'-cyclohexane]-4-yl)urea

Example 16A

7 hidroxizina[chroman-2,1'-cyclohexane]-4-one

To a solution of diethylphosphate (4 ml) was 31.0 mmol) in 1,2-dimethoxyethane (100 ml) was added 60% NaH (3,72 g, 93 mmol). When the gas is practically ceased (10 min), was slowly added to the solution bromoxynil acid (4.3 g, of 30.9 mmol) in 1,2-dimethoxyethane (30 ml). When he again stopped the evolution of gas was added dropwise cyclohexanone (3.2 ml, of 30.9 mmol). The reaction mixture was stirred at room temperature for 1 h, then poured ethanol (5 ml) and poured into ice-cold water. The aqueous layer was washed with ether, acidified to pH 4 conc. HCl and then was extracted with ether. The extracts were dried over Na2SO4, filtered and evaporated in vacuum. Has been named the title compound in the form of butter yellow-orange color that was mixed with POCl3(25 ml, 268,2 mmol), resorcinol (3,39 g, 30,8 mmol) and ZnCl2(5.9 g, a 43.3 mmol). The mixture was stirred p. and room temperature for 5.5 h and then poured into ice. Extraction with ethyl acetate followed by drying over Na2SO4, filtration and evaporation under vacuum gave the crude product as a dark orange oil. Chromatography on silica gel (7:3 hexane-ethyl acetate eluent) gave named in the title compound in the form of solids not quite white, 3,14 g (44%).1H NMR (300 MHz, DMSO-d6) δ 10,47 (ush, 1H), 7,56 (d, J=8.5 Hz, 1H), gold 6.43 (m, 1H), 6,28 (d, J=2.4 Hz, 1H), 2.63 in (s, 2H), 1,44-to 1.87 (m, 10H). MS (DSI+)m/z233 (M+H).

Example 16B

7 hidroxizina[chroman-2,1'-cyclohexane]-4-one O-methyloxime

The product of example 16A (479 mg, of 2.06 mmol), hydrochloride of methoxylamine (275 mg, 3,29 mmol) and pyridine (0,36 ml of 4.45 mmol) was stirred in methanol (5 ml) at room temperature over night. After this time the solvent is evaporated in vacuo, and the residue was transferred into ethyl acetate and washed with 1N HCl and brine. The organic solution was dried over Na2SO4and evaporated in vacuum. Chromatography on silica gel (4:1 hexane-ethyl acetate eluent) gave named the title compound as a colourless oil, 524 mg (97%).1H NMR (300 MHz, DMSO-d6) δ 9,79 (ush, 1H), 7,54 (d, J=8,8 Hz, 1H), 6.35mm (m, 1H), from 6.22 (m, 1H), 3,84 (s, 3H), 2,68 (s, 2H), 1,25-to 1.79 (m, 10H). MS (DCI+)m/z262 (M+H).

Example 16C

7 methoxamine[chroman-2,1'-cyclohexane]-4-amine

The product of example 16B (0,169 g, 0,647 mmol) of p is remedial with MeI (0,080 ml, 1.3 mmol) and K2CO3(0,267 g of 1.93 mmol) in acetone (2 ml) at 65°C over night. The solvent is evaporated and the residue was dissolved in ethyl acetate, washed with water, then brine, and then dried (Na2SO4), and concentrated. The crude substance was dissolved in methanol (5 ml) and mixed on a rocking chair with Raney Nickel (300 mg) under H2(60 psi) overnight. The mixture was filtered and evaporated, receiving of € 0.195 g of the crude amine in the form of a filmy white solid, which was used without further purification.

Example 16D

1-(1H-indazol-4-yl)-3-(7-methoxamine[chroman-2,1'-cyclohexane]-4-yl)urea

The product of example 16C (of € 0.195 g) was mixed with the product of example 1H (0,215 g, 0,647 mmol) and diisopropylethylamine (0.15 ml, 0.86 mmol) in 2 ml of N,N-dimethylformamide at room temperature for 1 h, after this time the mixture was diluted with H2O. Formed in this way, the precipitate was collected by filtration, dissolved in methanol (2 ml) and tetrahydrofuran (0.5 ml) and was treated with 1N water. NaOH (0.75 ml, 0.75 mmol). The mixture was stirred at room temperature for 3 h and was besieged by H2O. the Precipitate was dissolved in ethyl acetate and washed with water and brine, dried (Na2SO4) and evaporated to obtain the product as a solid yellow-brown (0,219 is, 0,540 mmol, 83%).1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush s, 1H), 8,65 (s, 1H), 8,06 (ush s, 1H), 7,68 (d, 1H), 7,21 (m, 2H), 7,07 (d, 1H), only 6.64 (d, 1H), 6,51 (DD, 1H), 6.35mm (d, 1H), 4.92 in (m, 1H), 3,71 (s, 3H), 2,22 (DD, 1H), 1,25-of 1.80 (m, 12H); MS (ESI+)m/z407,2 (M+H).

Example 17

1-(1H-indazol-4-yl)-3-(1'-methylspiro[chroman-2,4'-piperidine]-4-yl)urea

Example 17A

1'-methylspiro[chroman-2,4'-piperidine]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting cyclohexanone 1-methyl-4-piperidone.1NMR (300 MHz, DMSO-d6) δ 7,72 (DD; J=7,9) and 1.7 Hz, 1H), 7,56 (m, 1H), 7,00-7,05 (m, 2H), and 2.79 (s, 2H), 2,45 (m, 1H), 2,23-is 2.37 (m, 3H), of 2.18 (s, 3H), 1,83-of 1.93 (m, 2H), 1,65-to 1.77 (m, 2H). MS (DCI+)m/z232 (M+H).

Example 17B

1'-methylspiro[chroman-2,4'-piperidine]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A example 17A.1Η NMR (300 MHz, DMSO-d6) δ 7,52 (d, J=7.5 Hz, 1H), 7,06 (m, 1H), 6,84 (dt; J=7,5, 1,1 Hz; 1H), 6,70 (DD; J=8,2, 1.0 Hz; 1H), 3,85 (m, 1H), 2,35 is 2.55 (m, 2H), 2,18 (s, 3H), of 2.16 (m, 1H), 1,99-2,05 (m, 2H), 1,47-1,72 (m, 5H). MS (DCI+)m/z233 (M+H).

Example 17C

methyl-4-(3-(1'-methylspiro[chroman-2,4'-piperidine]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 17B. The crude compound was then used without further the preliminary cleanup.

Example 17D

1-(1H-indazol-4-yl)-3-(1'-methylspiro[chroman-2,4'-piperidine]-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 17C.1H NMR (300 MHz, DMSO-d6) δ 13,02 (ush, 1H), 8,73 (s, 1H), 8,07 (s, 1H), 7,68 (d, J=7.5 Hz, 1H), 7,14-7,33 (m, 3H), was 7.08 (d, J=8,1 Hz, 1H), 6,91 (t, J=7.5 Hz, 1H), 6,77-PC 6.82 (m, 2H), free 5.01 (m, 1H), has 2.56 (m, 2H), of 2.38 (m, 2H), 2,22 (m, 1H), measuring 2.20 (s, 3H), 1,63-of 1.81 (m, 5H). MS (ESI+)m/z392 (M+H), 414 (M+Na).

Example 18

1-(1H-indazol-4-yl)-3-(2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)urea

Example 18A

2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting cyclohexanone for tetrahydro-4H-Piran-4-one.1H NMR (300 MHz, DMSO-d6) δ 7,71 (DD; J=7,8) and 1.7 Hz, 1H), 7,58 (m, 1H), 7,02-7,10 (m, 2H), 3,63-to 3.73 (m, 4H), 2,85 (s, 2H), 1.70 to to 1.87 (m, 4H). MS (DCI+)m/z219 (M+H), 236 (M+NH4).

Example 18B

2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-amine

Named in the title compound was obtained using the procedure described in example 1B, substituting example 1A example 18A.1Η NMR (300 MHz, DMSO-d6) δ 7,53 (d, J=7.5 Hz, 1H), was 7.08 (m, 1H), 6,85 (dt; J=7,5, and 1.4 Hz, 1H), 6.75 in (DD; J=8,1, 1.0 Hz; 1H), a 3.87 (m, 1H), 3,56-3,82 (m, 4H), 2,10 (m, 1H), 1,76 (m, 1H), 1,50 was 1.69 (m, 4H). MS (DCI+)m/z220 (M+H).

Example 18C

methyl-4-(3-(2',3',5',6'-tetrahydrofuro[the novel-2,4'-Piran's]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, substituting example 1B example 18B. The crude compound was then used without further purification.

Example 18D

1-(1H-indazol-4-yl)-3-(2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, substituting example 1C in example 18C.1H NMR (300 MHz, DMSO-d6) δ 13,01 (ush, 1H), 8,73 (s, 1H), 8,08 (d, J=0.7 Hz, 1H), 7,68 (d, J=7,1 Hz, 1H), 7,32 (d, J=7,4 Hz, 1H), 7,16-7,25 (m, 2H), was 7.08 (d, J=8,4 Hz, 1H), 6,84-to 6.95 (m, 2H), 6,79 (d, J=8,1 Hz, 1H), to 5.03 (m, 1H), 3,61-3,82 (m, 4H), 2,28 (m, 2H), 1.70 to to 1.83 (m, 4H). MS (ESI+)m/z379 (M+H), 401 (M+Na).

Example 19

1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(1H-indazol-4-yl)urea

Example 19A

7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-one

Named in the title compound was obtained using the procedure described in example 1A, substituting cyclohexanone for tetrahydro-4H-Piran-4-one and 2'-hydroxyacetophenone 4'-fluoro-2'-hydroxyacetophenone.1H NMR (300 MHz, DMSO-d6) δ h/million 7,80 (DD, J=8,81, is 6.78 Hz, 1H), 6.87 in-7,01 (m, 2H), 3,62-3,74 (m, 4H), of 2.86 (s, 2H), 1,73 is 1.86 (m, 4H). MS (DCI+)m/z237 (M+H), 254 (M+NH4).

Example 19B

7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-amine

Named in the title compound was obtained using the methodology described is annoy in example 1B, substituting example 1A in example 19A.1H NMR (300 MHz, DMSO-d6) δ h/million 7,56 (t, J=7,80 Hz, 1H), 6,69 (TD, J=8,65, a 2.71 Hz, 1H), return of 6.58 (DD, J=10,85, a 2.71 Hz, 1H), 3,80-a 3.87 (m, 1H), 3,64-of 3.78 (m, 2H), 3,55-3,63 (m, 2H), 2,04 with 2.14 (m, 1H), up to 1.98 (m, 1H), 1,67-to 1.77 (m, 2H), 1,60-1,65 (m, 2H). MS (DCI+)m/z238 (M+H), 255 (M+NH4).

Example 19C

methyl-4-(3-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)ureido)-1H-indazol-1-carboxylate

Named in the title compound was obtained using the procedure described in example 1C, using the example 19B instead of example 1B. The crude compound was then used without further purification.

Example 19D

1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(1H-indazol-4-yl)urea

Named in the title compound was obtained using the method described in example 1D, using the example 19C instead of example 1C.1H NMR (300 MHz, DMSO-d6) δ h/million 13,01 (ush, 1H), total of 8.74 (s, 1H), 8,08 (s, 1H), 7,65-of 7.70 (m, 1H), 7,31-7,37 (m, 1H), 7,17-7,26 (m, 1H), was 7.08 (d, J=8,14 Hz, 1H), 6,69-for 6.81 (m, 3H), free 5.01 (s, 1H), 3,69-3,82 (m, 2H), 3,61-3,66 (m, 2H), 2.23 to-2,31 (m, 2H), 1,69-of 1.84 (m, 4H). MS (ESI+)m/z397 (M+H), 419 (M+Na).

Example 20

1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea

Named in the title compound was obtained using the procedure described in example 4, using the example 19D instead of example 3D.1H NMR (300 MHz, DMSO-d6) δ h/million 8,76 (s, 1H), 8,04 (s, 1H), 768-7,72 (m, 1H), 7,28-7,37 (m, 2H), 7,15-7,19 (m, 1H), 6,72-for 6.81 (m, 3H), free 5.01 (s, 1H), 4.00 points (s, 3H), 3,71-with 3.79 (m, 2H), 3,61 at 3.69 (m, 2H), 2.23 to-2,31 (m, 1H), 1.69-of 1.84 (m, 5H).

Example 21

1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(2-methyl-2H-indazol-4-yl)urea

Named the title compound is obtained as a by-product upon receipt of the example 20.1H NMR (300 MHz, DMSO-d6) δ h/million 8,55-8,59 (m, 1H), 8,21 (s, 1H), 7,45-7,49 (m, 1H), 7.29 trend was 7.36 (m, 1H), 7,08-to 7.18 (m, 2H), 6,64-for 6.81 (m, 3H), free 5.01 (s, 1H), 4.16 the (s, 3H), 3,69-with 3.79 (m, 2H), 3,61-to 3.67 (m, 2H), and 2.26 (m, 1H), 1,69-1,84 (m, 5H). MS (ESI+)m/z411 (M+H), 433 (M+Na).

Biological activity

Data of in vitro Determination of inhibitory abilities

Modified by way of Dulbecco Wednesday Needle (D-MEM) (with 4.5 mg/ml glucose) and fetal calf serum were obtained from the company Hyclone Laboratories, Inc. (Logan, Utah). Phosphate buffer solution, Dulbecco (D-PBS) (1 mg/ml glucose and 3.6 mg/l Na pyruvate) (with phenol red), L-glutamine, hygromycin B and Iipofectamine™ were obtained from the company Life Technologies (Grand Island, NY). G418 sulfate was obtained from the company Calbiochem-Novabiochem Corp. (San Diego, CA). Capsaicin (8-methyl-N-vanillyl-6-nonenamide) was obtained from the company Sigma-Aldrich, Co. (St. Louis, MO). Fluo-4 AM (N-[4-[6-[(atomic charges)methoxy]-2,7-debtor-3-oxo-3H-xanthene-9-yl]-2-[2-[2-[bis[2-[(atomic charges)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(atomic charges)methoxy]-2-oxyethyl]-glycine (atomic charges)methyl ester) was purchased on the company Molecular Probes (Eugene, OR). kankala receptor VR1 man was identified by polymerase chain reaction with reverse transcription (RT-PCR) of poly A+RNA of the small intestine of man, supplied by Clontech (Palo Alto, CA), using primers designed to capture the originating and terminating codons, identical to the published sequences (Hayes et al. Pain 88: 205-215, 2000). The resulting cDNA as PCR products were subcloned into the expressing vector mammals pCIneo (Promega) and sequenced using stop-reagent-based fluorescent dye (Prism, Perkin-Elmer Applied Biosystems Division) and DNA-sequencing machine Perkin-Elmer Applied Biosystems model 373 or genetic analyzer model 310. Expressing plasmids encoding hVR1 cDNA was transfusional individually in cells 1321N1 astrocytoma person using Lipofectamine™. Forty-eight hours after transfection resistant to neomycin cells selectively in the environment for growth, containing 800 μg/ml Geneticin (Gibco BRL). Separate the surviving colonies were isolated and skanirovali in relation to the activity of the receptor VR1. Cell expressed recombinante governe VR1 receptors kept at 37°C in D-MEM containing 4 mm L-glutamine, 300 μg/ml G418 (Cal-biochem) and 10% fetal calf serum in a humid atmosphere with 5% CO2.

The functional activity of compounds against receptor VR1 was determined by analysis of Ca2+inflow and measurement of the levels of intracellular Ca2+([Ca2+]i). All compounds were tested in 11 points in prologa epicheskom range of concentrations. Solutions of compounds were prepared in D-PBS (4-fold final concentration) and were serially diluted in 96-well culture tablets with v-bottom, using automatic robotic workstation Biomek 2000 (Beckman-Coulter, Inc., Fullerton, CA). 0.2 μm solution of the VR1 antagonist, capsaicin, also prepared in D-PBS. Fluorescent Ca2+chelating dye fluo-4 was used as an indicator of the relative levels of [Ca2+]iin 96-well format using fluorescent spot reader (FLIPR) (Molecular Devices, Sunnyvale, CA). Cells were grown to confluence in 96-well culture tablets black. Then, before analysis, the cells were added at 100 µl per well of fluo-4 AM (2 μm in D-PBS) for 1-2 hours at 23°C. was Performed by washing the cells to remove extracellular fluo-4 AM (2×1 ml D-PBS per well) and then the cells were placed in a cell reading device FLIPR. 50 μl of solutions of compounds were added to cells at 10-th second timestamp from the beginning of the experiment. Then, after a 3-minute delay at the 190-th second was added 50 μl of a solution of capsaicin (0.05 μm final concentration) (final volume = 200 μl) in order to cause the response of the receptor VR1. The duration of the experimental cycle was 240 seconds. Read fluorescence during the experimental cycle was performed at intervals of 1-5 seconds. The increase of the maximum in the relative Fluor is santich units (minus baseline) counted from 190-second timestamp to the end of the experimental cycle and were expressed as percentage of the response of 0.05 μm capsaicin (control). Curves constructed according to the data were processed using the four-parameter logarithmic equation of hill software package GraphPad Prism® (GraphPad Software, Inc., San Diego, CA), and was calculated values IC50.

Compounds of the present invention, as has been discovered, are antagonists vanilloideae receptor subtype 1 (VR1) with values IC50less than 1 μm, preferably smaller than 0.5 μm, more preferably less than 0.1 μm and most preferably less than 0.1 microns.

Data in vivo determination of the analgesic effect

The experiments were conducted on 400 adult males 129J mice (Jackson Laboratories, Bar Harbor, ME) weighing 20-25, Mice were kept in a vivarium at 22°C with 12-hour cycle lighting day/night, with food and water available without restrictions. All experiments were performed during the daily cycle. Animals were randomly divided into groups of 10 mice each. Each animal was used only for a single experiment and were killed immediately after the end of the experiment. All operations on the treatment of animals and experimental procedures were approved by the Committee on bioethics. Analysis of thermal hyperalgesia induced complete Freud's adjuvant (CFA) described in Pircio et al. Eur J Pharmacol. Vol. 31 (2) pages 207-215 (1975). One group of rats induced chronic inflammatory hyperalgesia, followed by injection the Oia complete Freud's adjuvant (CFA, 50%, 150 μl) into the surface of the sole of the right hind legs 48 hours before the study. End pain thresholds were determined at three different groups of rats. The magnitude of the ED50was determined on the basis of oral administration. The connection is studied in relation to in vivo activity, had ED50less than 500 nmol/kg

In vitro and in vivo data demonstrate that the compounds of the present invention are antagonists of the receptor VR1 and suitable for treatment of pain, overactive bladder and urinary incontinence.

1. The compound of formula (I) or its pharmaceutically acceptable salt, where

X1is -(CRlaR1b)m-, -(CRlaRlb)nG1- or -(CRlaRlb)p-G1-(RlaRlb)-;
m is 1, 2 or 3;
n is 1, 2 or 3;
p is 1;
G1represents O or N(Rx);
Rlaand Rlbin each case represent independently hydrogen;
R2aand R2bin each case represent independently hydrogen;
Rxrepresents hydrogen or alkyl;
And1is CR3;
And2is CR4;
And3is CR5;
And4is CR6;
R3, R4, R5and R6each independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, Galaga is the alkyl, halogen, -CN, -NO2HE, alkoxy, halogenoalkane, -ORE, -O-(CRlaRlb)q-RE, -N(RA)(RB), -C(O)RB, -C(O)N(RA)(RB), -C(O)ORB, -S(RB), -S(O)RB, -S(O)2RB, -S(O)2N(RA)(RB), REand -(CRlaRlb)q-RE;
q is 1, 2, 3, 4, 5 or 6;
RAin each case represents independently hydrogen, alkyl or halogenated;
RBin each case represents independently hydrogen, alkyl, alkenyl, halogenated, REor -(CRlaRlb)q-RE,
REin each case represents independently monocyclic or bicyclic ring independently selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl; where each REis independently unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, halogenoalkane, halogen, oxo, -CN, -NO2HE, alkoxy, halogenoalkane, -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(O)alkyl, -N(alkyl)C(O)alkyl, -N(H)C(O)Valkila, -N(alkyl)C(O)Valkila, -C(O)H, -C(O)alkyl, -C(O)HE, -C(O)Valkila, -C(O)NH2-C(O)N(H)(alkyl), -C(O)N(alkyl)2, -S(alkyl), -S(O)alkyl, -S(O)2of alkyl, -S(O)2N(H)2, -S(O)2N(H)(alkyl) and-S(O)2N(alkyl)2,
Y represents-O-;
X2the two who is-N(H)C(O)N(H)-Z; and
Z is indazolinone; where each Z is independently unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -C(O)and(O)of Valkila; where the monocyclic heterocycle is a non-aromatic saturated or partially unsaturated hydrocarbon ring system containing at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur;
the bicyclic heterocycle is a monocyclic heterocycle condensed with a phenyl group, a monocyclic cycloalkenyl group, monocyclic cycloalkyl group
or monocyclic heterocyclic group;
monocyclic heteroaryl is an aromatic five - or six-membered ring, in which at least one atom selected from the group consisting of N, O and S and the remaining atoms are carbon atoms;
bicyclic heteroaryl represents a monocyclic heteroaryl condensed with a phenyl group, a monocyclic cycloalkyl, monocyclic cycloalkenyl, a monocyclic heterocycle or a monocyclic heteroaryl;
monocyclic aryl is a phenyl group; and
bicyclic aryl is a phenyl group condensed with a monocyclic cycloalkyl group, monocyclic the coy cycloalkenyl group or another phenyl group.

2. The compound according to claim 1, where
X1is -(CRlaR2b)m-;
m is 1, 2 or 3; and
Rlaand Rlbare as defined in claim 1.

3. The compound according to claim 2, where m is equal to 1.

4. The compound according to claim 3, selected from the group consisting of:
methyl-4-(3-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea;
1-(7-perspire[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea and
1-(7-tert-Butylimino[chroman-2,1'-CYCLOBUTANE]-4-yl)-3-(1H-indazol-4-yl)urea.

5. The compound according to claim 1, where
X1represents -(CRlaRlb)nG1-;
n is 1, 2 or 3;
Rlaand Rlbare as defined in claim 1; and
G1represents O, and N(Rx).

6. The compound according to claim 5, where
G1represents O.

7. The compound according to claim 1, where the compound is chosen from the group consisting of:
1-(1H-indazol-4-yl)-3-(2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)urea;
methyl-4-(3-(2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(1H-indazol-4-yl) urea;
methyl-4-(3-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(7-fluoro-2',3',5',6'-tetrahydrofuro[HRO is an-2,4'-Piran's]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea and
1-(7-fluoro-2',3',5',6'-tetrahydrofuro[chroman-2,4'-Piran's]-4-yl)-3-(2-methyl-2H-indazol-4-yl)urea.

8. The compound according to claim 5, where
G1represents N(Rx).

9. The compound according to claim 1, where the compound is chosen from the group consisting of:
1-(1H-indazol-4-yl)-3-(1'-methylspiro[chroman-2,4'-piperidine]-4-yl)urea and
methyl-4-(3-(1'-methylspiro[chroman-2,4'-piperidine]-4-yl)ureido)-1H-indazol-1-carboxylate.

10. The compound according to claim 1, where
X1is -(CRlaRlb)p-Gl-C(RlaRlb)-;
Rlaand Rlbare as defined in claim 1; and
p is 1.

11. The compound according to claim 2, where m is equal to 2.

12. Connection claim 11, selected from the group consisting of:
methyl-4-(3-(6-methylspiro[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(1H-indazol-4-yl)-3-(6-methylspiro[chroman-2,1'-cyclopentane]-4-yl)urea;
methyl-4-(3-(7-toxisperma[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(7-toxisperma[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl-4-(3-(6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-yl)ureido)-1H-indazol-1-carboxylate and
1-(6,7-dimethylimino[chroman-2,1'-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea.

13. The compound according to claim 2, where
m is equal to 3.

14. The connection 13, selected from the group consisting of:
methyl-4-(3-Spiro[chroman-2,1'-cyclohexane]-4-yureina)-1H-indazol-1-ka is barcelata;
1-(1H-indazol-4-yl)-3-(Spiro[chroman-2,1'-cyclohexane]-4-yl)urea;
methyl-4-(3-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl-4-(3-(6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(6,7-dimethylimino[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl-4-(3-(6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(6,8-dichlorprop[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl-4-(3-(6,8-dipersio[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(6,8-dipersio[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl-4-(3-(6-toxisperma[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate;
1-(6-toxisperma[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
1-(7-perspire[chroman-2,1'-cyclohexane]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea;
1-(1-methyl-1H-indazol-4-yl)-3-(Spiro[chroman-2,1'-cyclohexane]-4-yl)urea;
1-(1H-indazol-4-yl)-3-(7-methoxamine[chroman-2,1'-cyclohexane]-4-yl)urea;
1-(6-chlorpro[chroman-2,1'-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea and
methyl-4-(3-(6-chlorpro[chroman-2,1'-cyclohexane]-4-yl)ureido)-1H-indazol-1-carboxylate.

15. Pharmaceutical composition having activity related and receptor VR1, containing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt, and a non-toxic pharmaceutically acceptable carrier or diluent.

16. A method of treating disorders caused by or exacerbated by activity vanilloideae receptor, comprising introducing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.

17. The method according to clause 16, where the violation improve by inhibiting the activity vanilloideae receptor subtype 1 (VR1) with the introduction of therapeutically effective amounts of compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.

18. The method according to 17, in which the violation is chosen from the group consisting of pain, neuropathic pain, allodynia, pain associated with inflammation, inflammatory hyperalgesia, overactive bladder and urinary incontinence.

19. A method of treating overactive bladder in a mammal in need of such treatment, comprising introducing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.

20. A method of treating urinary incontinence in a mammal in need of such treatment, comprising introducing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or pharmaceutical is Ki acceptable salt.

21. A method of treating pain in a mammal in need of such treatment, comprising introducing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.

22. A method of treating inflammatory hyperalgesia in a mammal in need of such treatment, comprising introducing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): or to their pharmaceutically acceptable derivatives selected from a group consisting of pharmaceutically acceptable salts and esters; in which: R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c and R8d are such as presented in the patent claim 1. The invention also refers to compounds of formula (I), to a compounds selected from a group, to a pharmaceutical composition, to methods of treating, to a method of decreasing the plasma cholesterol level in a patient, to a method of modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, to a method of modulating farnesoid X receptor activity, to a compound representing 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b]indole-5-isopropylcarboxamide, to a composition, to a method of reducing the risk of an onset or a recurrence, to a method of modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal, and also to a method of modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal.

EFFECT: preparation of the new biologically active compounds showing possessing nuclear receptor activity.

73 cl, 76 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: chemistry.

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

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

11 cl, 8 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

The invention relates to compounds of formula (I)

where NRR1attached a 5 - or 6-position of the ring properidine; R is hydrogen, C1-C4-alkyl, or COR2; R1represents (CH2)nAr, CH2CH=CHAr, or CH2With?CAr; n is 0-3; a is N or NO; Ar represents a 5 - or 6-membered aromatic or heteroaromatic ring which contains 0 to 4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom; or an 8-, 9 - or 10-membered condensed aromatic or heteroaromatic cyclic system containing 0-4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom, any of which may be optionally substituted by 1-2 substituents independently selected from halogen, trifloromethyl or1-C4-alkyl; R2represents hydrogen; C1-C4-alkyl; C1-C4-alkoxy or phenyl ring, optionally substituted by 1-3 of the following substituents: halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, CO2R5, -CN, -NO2, -NR3R4or-CF3; R3, R4and R5can be hydrogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, -CN, -NO2or-CF3; to their enantiomers and pharmaceutically acceptable salts

The invention relates to new biologically active compounds, namely spiroheterocyclic heterocyclic compounds of the formula I

< / BR>
where n is 0 or 1;

m is 0 or 1;

p is 0;

X represents oxygen or sulfur;

Y represents CH, N or NO;

W represents oxygen or H2;

And represents N or C(R2);

G represents N or C(R3);

D represents N or C(R4)

provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;

R1represents hydrogen or C1-C4-alkyl;

R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D southwest a hydrogen, WITH1-C4-alkyl, C(O)R7C(O)OTHER8WITH(O)OR9, SO2R10, -NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond; j is 2 and k is 0 to 2;

R7, R8, R9, R10and R11are independently C1-C4-alkyl, NH2, aryl or its enantiomer,

and their pharmaceutically acceptable salts, and methods for their preparation, intermediate compounds and pharmaceutical compositions, which has an activating effect against nicotine7-acetylcholine receptors and can be used for the treatment and prevention of psychotic disorders and disorders of the type of lower intellectual

The invention relates to a method for producing derivatives 4A,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, in the case neobmennoe alkyl group; at least one lower, if necessary, the branched alkinoos group; at least one lower, if necessary branched alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, the nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, halides

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

Gsk-3 inhibitors // 2449998

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula , wherein RB is specified in: while R3, R4, R'2, R'3, R'4, R'5, and R'6 represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered a combination for preventing or treating a proliferative disease, containing a microtubular active agent epothilone B and a pharmaceutically active agent, 1H-pyrazolo[3,4-d]pyrimidine-4-amine 3-(4-chloriophenyl)-1-(1,1-dimethylethyl)-(9CI); the related pharmaceutical composition containing said combination, methods of preventing and treating (versions), a commercial packing including said combination (versions). Particularly, the proliferative disease can represent ovarian cancer, carcinoma of lung and melanoma.

EFFECT: what is shown is synergism of the combination in growth inhibition of non-small cell carcinoma of lung in relation to independent action of its ingredients.

17 cl, 3 dwg, 1 tbl

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